Lippincott textbook of neurology part 2

CHAPTER 65. INTERVERTEBRAL DISCS AND RADICULOPATHY MERRITT’S NEUROLOGY

CHAPTER 65. INTERVERTEBRAL DISCS AND RADICULOPATHY PAUL C. MCCORMICK Pathogenesis Incidence Lumbar Intervertebral Disc Rupture Thoracic Intervertebral Disc Rupture Cervical Disc Disease Other Diagnostic Features Treatment Suggested Readings

Rupture of an intervertebral disc into the body of a vertebra was first described by Schmorl in 1927. Earlier, in a 1909 text on neurologic surgery, Krause described operating on an iceman who had been diagnosed by Oppenheimer as suffering from a lesion localized to L-4. Krause found an extradural mass that was described pathologically as a chondroma; the operation apparently effected a cure. There were other reports of “chondromas” removed at explorations of the intervertebral area. It remained for Mixter and Barr in 1934 to point out that these lesions were actually fragments of intervertebral discs and that they were responsible for sciatica.

PATHOGENESIS Displaced disc material may create signs and symptoms by bulging or protruding beneath an attenuated annulus fibrosus, or the material may extrude through a tear in the annulus and project directly into the spinal canal. In either case, the encroaching disc material may irritate or compress nerve roots that are coursing to foramina of exit. In the cervical or thoracic regions, the problem is more complex neurologically because the spinal cord itself, as well as the adjacent nerve roots, may be involved. There, signs and symptoms are caused by either cord compression or a combination of cord and root compression. In the lumbar region, signs and symptoms relate to an individual root lesion (compressed laterally) or to compression of the cauda equina if the disc is large enough to crowd the entire spinal canal. In the cervical region, the levels most commonly affected are in the C-5 to C-7 segments ( Table 65.1). In the lumbar, area most disc protrusions occur at L4-5 and L5-S1. This pattern suggests that the dynamics of pathologic change are partly related to the trauma of motion and wear and tear. Thoracic disc protrusion, except at the lower thoracic levels, differs from cervical and lumbar disorders in genesis and histopathology. Motion plays no role there because the thoracic vertebrae are designed for stability rather than motion, and the heavy rib cage contributes to the rigidity of this structure. One must therefore look elsewhere for the cause of thoracic disc rupture. On gross and microscopic examination, the lesion is unique, markedly degenerated, and characterized by gritty calcified deposits; it almost never has the consistency of cervical and lumbar ruptured discs; thoracic disc protrusion is more granular and yellowish.

TABLE 65.1. COMMON ROOT SYNDROMES OF INTERVERTEBRAL DISC DISEASE

Although trauma has been accepted as the prime cause of disc herniation, it is not the only cause. There seems to be a genetic predisposition in many patients. Trauma may aggravate this propensity and ultimately cause rupture. In the most florid preordained syndrome, there may be multiple levels of severe disc degeneration throughout the spine with progressive clinical involvement in different areas. This syndrome may explain why fusion often fails to prevent recurrent symptoms. Spinal stenosis, which is an abnormally narrow spinal canal, is an example of an inherited anomaly, as are the spinal abnormalities of achondroplastic dwarfism. These abnormal spinal configurations, along with spondylosis, are major contributors to compression syndromes of the spinal cord and cauda equina. When disc protrusion occurs in a patient with spinal stenosis, it further compromises an already limited canal, as do changes caused by arthritic proliferation or ligamentous degeneration. The signs and symptoms of herniated discs relate not only to the size and strategic location of the disc fragments but also to the size and configuration of the canal. The anteroposterior and lateral dimensions of the canal, particularly the foramina, play a key role. Spinal stenosis and osteoarthritic changes may compress roots, even with small protrusions. In a canal of normal dimensions, the severity of compression depends more on the site of rupture and the volume of the extruded material. There may be single-root compression or cauda equina compression. A laterally placed lesion in the cervical region may involve a single root, but if it is large enough, it may compress the cord. This is also true in the thoracic region. Although single-root syndromes in the lumbar region are usual, truly ventral or large lesions can lead to less easily recognized clinical pictures. For instance, scoliosis may be the major feature, with severe back pain and muscle splinting but without signs of mechanical root compression in the straight leg-raising test.

INCIDENCE Rupture of an intervertebral disc is common, especially in the fourth to sixth decades of life. It is rare before age 25 years and uncommon after age 60. About 80% of patients are men. Many patients have a history of earlier trauma.

LUMBAR INTERVERTEBRAL DISC RUPTURE Root syndromes of intervertebral disc disease are often episodic, so that remissions are characteristic. Pain may be aggravated by Valsalva maneuvers (coughing, sneezing, or straining at defecation). The pain may be restricted to the back or follow a radicular distribution in one or both legs. Lumbar pain may increase after heavy lifting or twisting of the spine. No matter how severe the pain is when the patient is erect, characteristically it is promptly relieved when the patient lies down. Some patients, however, are more comfortable sitting, and some can find no comfortable position. Relief of pain on bedrest is useful in diagnosing disc disease from intraspinal tumor, in which pain is often not relieved or may be worsened. Examination reveals loss of lumbar lordosis or flattening of the lumbar spine, with splinting and asymmetric prominence of the long erector muscles. A list or tilt may be present, with one iliac crest elevated. This asymmetry is responsible for the commonly diagnosed “longer leg on one side” and the erroneous assignment of the back pain to asymmetry of leg length. (This asymmetry often causes a patient to raise the heel on the shoe of the “short” leg to level of the pelvis.) Range of motion of the lumbar spine is reduced by the protective splinting of paraspinal muscles, and attempted movement in some planes induces severe back pain. There may be tenderness of the adjacent vertebrae. When the patient is erect, one gluteal fold may hang down and show added skin creases because the gluteus is wasted, evidence of involvement of the S-1 root. Passive straight leg raising is reduced in range and increases back and leg pain. Muscle atrophy and weakness or sciatic tenderness and discomfort may occur on direct pressure at some point along the nerve from the sciatic notch to the calf. This is particularly true in older patients.

Paresthesia in the realm of the involved root is common; fasciculation is rare. The typical syndromes of root compression at lumbar levels are given in Table 65.2, although the signs may not be as distinct in actual practice as the table implies. More than 80% of syndromes affect L-5 or S-1 (Fig. 65.1 and Fig. 65.2). When the lesion affects L-4 or higher roots, straight leg raising does not stretch the roots above L-5. The affected roots may be tensed, however, by extension of the limb with the knee flexed when the patient is prone, thus reproducing the typical radicular spread of pain.

TABLE 65.2. SIGNS OF LUMBAR DISC HERNIATION IN 97 PATIENTS

FIG. 65.1. Lumbar disc herniation. A: Lateral film from a lumbar myelogram demonstrates a large ventral defect at L4-5. The L5-S1 level is unremarkable. B: Left posterior oblique projection demonstrates swelling and amputation of the left L-5 root and possible compression of the left S-1 root with subtle thinning of the contrast. C: Postmyelogram axial CT at the L4-5 level confirms a large herniated nucleus pulposus obliterating the neural foramina bilaterally with eccentric deformity of the sac on the left. D: At the L5-S1 level, CT is more sensitive than myelography in diagnosing lateral disc herniation into the left foramen. Compare its appearance with that of the preserved lucent fat in the right foramen. Minimal deformity of the sac ventrally accounts for the unimpressive myelogram at this level. (Courtesy of Dr. J.A. Bello, Dr. T.L. Chi, and Dr. S.K. Hilal.)

FIG. 65.2. Lumbosacral disc herniation. Sagittal proton-density (A) and axial T1-weighted (B) MRI demonstrate a large L5-S1 disc herniation on the left side. Clinically, this patient had an S-1 radiculopathy that did not respond to conservative therapy. Complete relief of symptoms followed lumbar discectomy.

About 10% of lumbar disc herniations occur lateral to the spinal canal and root sleeve. Myelography is unrevealing in these cases. These far lateral disc herniations compress the rostral lumbar nerve root at the affected level. A far lateral L3-4 lumbar disc herniation, for example, may compress the L-3 nerve root either within the foramen or more distally as the root passes over the disc space ( Fig. 65.3). These herniations often affect higher lumbar (e.g., L3-4) levels and are likely to cause objective neurologic deficit. A far lateral disc herniation should be suspected with acute onset of an isolated upper lumbar radiculopathy, one that affects L-2, L-3, or L-4. Diagnosis of far lateral lumbar disc herniation is made by computed tomography (CT) or magnetic resonance imaging (MRI).

FIG. 65.3. A: Two sites of possible upper nerve root compression from a far lateral disc herniation. Root compression may occur at the level of the disc space ( 1) or from a rostrally migrated fragment into the foramen of the upper nerve root ( 2). B: CT demonstrates a large far lateral disc herniation ( arrow).

THORACIC INTERVERTEBRAL DISC RUPTURE Because the thoracic spine is designed for rigidity rather than excursion, wear and tear from motion and stress cannot cause thoracic disc protrusion, and clinical disorders are rare. Thoracic disc disease may result from chronic vertebral changes incident to Scheuermann disease or juvenile osteochondritis with later trauma. The radiographic changes of Scheuermann disease, when seen with thoracic cord compression, should raise the possibility of disc protrusion ( Fig. 65.4). Calcific

changes in the intervertebral disc and the typical vertebral changes of that disease are diagnostic markers.

FIG. 65.4. A: Sagittal T1-weighted MRI demonstrates two large thoracic discs in a patient with a subacute myelopathy. B: Postmyelographic CT in the same patient demonstrates a large calcified thoracic disc at T-6 compressing the spinal cord.

The small capacity of the thoracic canal makes clinical syndromes of cord compression more critical than at other levels. By the same token, decompressive operations are more precarious and require meticulous care to avoid damaging the spinal cord. The lower thoracic levels, however, are more capacious, and although the conus medullaris or cauda equina may be damaged by disc protrusions, surgical approaches are less hazardous than at higher levels.

CERVICAL DISC DISEASE Cervical disc herniation may involve both the root and the spinal cord, depending on the volume of the canal and the size of the lesion. Cord compression is uncommon, except with spinal stenosis or massive rupture of a disc. The sites of the most frequent disc herniations are C5-6 ( Fig. 65.5) and C6-7; C4-5 and C7-T1 are less frequently affected, and other levels are rarely involved ( Table 65.3). Because movement of the cervical spine is normally incremental, any process contributing to focal stress at individual levels adds to local wear and tear and to progressive pathologic changes in the disc and in joint mechanics. Development of a new fulcrum of motion above a fusion or congenital block vertebrae increases susceptibility to these changes.

FIG. 65.5. A: Sagittal T2-weighted MRI shows C5-6 disc herniation. B: Axial MRI demonstrates foraminal disc herniation in a patient with radiculopathy.

TABLE 65.3. FREQUENCY OF COMPRESSION OF THE CERVICAL ROOTS BY RUPTURED INTERVERTEBRAL DISC

The signs and symptoms of cervical disc disease usually begin with stiff neck, reactive splinting of the erector capital muscles, and discomfort at the medial order of the scapula. Radicular paresthesia and pain supervene when the root is more severely compromised. These symptoms are worsened by movements of the head and neck and, often, by stretching of the dependent arm. For relief, the patient often adopts a position with the arm elevated and flexed behind the head, unlike the patient with shoulder disease who maintains the arm in a dependent position, avoiding elevation or abduction at the shoulder joint. As compression proceeds, discrete root syndromes appear (see Table 65.1 and Table 65.2). C-5 lesions cause pain in the shoulder and dermatomic sensory diminution with weakness and atrophy of the deltoid. C-6 lesions cause paresthesia of the thumb and depression of the biceps reflex with weakness and atrophy of that muscle. In C-7 lesions, paresthesia may involve the index and middle fingers, and even the thumb, with atrophy and weakness in the triceps muscles, wrist extensors, and pectoral muscles, as well as a parallel reflex depression. C-8 subserves important intrinsic muscle functions in the hand and sensation in the fourth and fifth fingers. Because these are important in discriminatory and fine finger maneuvers, C-8 damage can be disabling. Large disc protrusions, particularly with spinal stenosis, can cause clinical syndromes of cord compression. Lesions such as supraspinatus tendinitis, arthritic changes in the acromioclavicular joint, and rotator cuff tears may be difficult to differentiate from cervical root compression, especially because prolonged pain and lack of range of motion lead to atrophy and frozen shoulder in these syndromes. C-8 and T1 lesions commonly cause a partial Horner syndrome. A diagnostic workup for syndromes of these levels must include apical lordotic views of the chest, and special care must be taken to rule out sulcus neoplasms or abnormal cervical ribs.

OTHER DIAGNOSTIC FEATURES Because many disc syndromes are genetic, abnormal skeletal features throughout the spine should be sought on radiographs. These include spinal stenosis, spondylolisthesis, widespread disc disease, or Marfan syndrome. Acquired disorders, such as osteochondritis juvenilis, and metabolic states such as osteoporosis, may contribute to pathologic changes in the disc and adjacent joints, as do several forms of arthritis. MRI is the imaging procedure of choice for the evaluation of disc disorders. MRI identifies spinal cord or root compression and also shows the degree of degenerative change within the disc. It clearly delineates both intra- and extradural structure and is the ideal screening procedure for the differential diagnosis of structural

disorders affecting the spinal cord and nerve roots. Myelography has largely been replaced by MRI in the evaluation of disc disease. However, myelography does allow scrutiny of the entire spinal canal and can identify dynamic changes of spinal canal size that may occur with standing and flexion or extension of the spine. Postmyelography CT is useful as an adjunct to MRI if equivocal or multilevel disc disease is present; it is particularly useful in evaluating foraminal nerve root compression. Electromyography and evoked potentials studies can be helpful in localizing root involvement but are not essential. The cerebrospinal fluid protein level is only rarely higher than 100 mg/dL; higher values are more characteristic of tumors. Disc syndromes can be duplicated by tumors (primary or metastatic), infections (e.g., epidural abscess), and arachnoiditis. Epidural lipomatosis, a rare cause of low-back syndromes, is a complication of steroid therapy.

TREATMENT Conservative treatment should continue as long as the patient shows improvement. Most acute attacks subside spontaneously, with analgesics and bedrest for lumbar disc disorders and immobilization of the neck by a collar for cervical disc disorders. Surgery for a lumbar disc disorder is indicated when there is no improvement over a reasonable period of strict bedrest or when a severe neurologic disorder is found on examination. Discectomy of a herniated lumbar disc fragment almost always results in long-term satisfactory relief of symptoms. Lumbar fusion is rarely required for treatment of radiculopathy from a herniated lumbar disc. Excessively prolonged physiotherapy and bedrest may cause emotional exhaustion, muscle loss, or drug dependence. Use of chymopapain (Chymodiactin) or collagenase to digest the disc material is controversial. Cord compression requires consideration of decompressive measures as soon as it is recognized. Root syndromes of the cervical spine can be separated into those that require careful supervision and early operation and those that tolerate and may respond to conservative care. The muscles served by C-5 may rapidly atrophy, leaving abduction paresis, poor prognosis for restoration of function, and a painful frozen shoulder. C-8 is also vulnerable, and unrelieved compression may lead to irreversible atrophy with complex shoulder-arm-hand disorders that include circulatory and sweating abnormalities. C-6 and C-7 subserve large muscles and tolerate pressure more benignly, even for long periods, and with good functional return. Cervical root syndromes are less likely to recur than lumbar disorders, and conservative therapy is worthwhile within the outlines described. Removal of a cervical herniated disc may be performed through either a posterior laminotomy or an anterior approach. Excellent results may be anticipated in appropriately selected patients. Success in disc surgery also includes adequate evaluation of psychologic patterns and motivation. SUGGESTED READINGS Awwad EE, Martin DS, Smith KR Jr, Baker BK. Asymptomatic versus symptomatic herniated thoracic discs: frequency and characteristics as detected by computed tomography after myelography. Neurosurgery 1991;28:180–186. Borenstein D. Epidemiology, etiology, diagnostic evaluation, and treatment of low back pain. Curr Opin Rheumatol 1992;4:226–232. Cavanagh S, Stevens J, Johnson JR. High-resolution MRI in the investigation of recurrent pain after lumbar discectomy. J Bone Joint Surg Br 1993;75:524–528. Charlesworth CH, Savy LE, Stevens J, et al. MRI demonstration of arachnoiditis in cauda equina syndrome of ankylosing spondylitis. Neuroradiology 1996;65:462–465. Conforti R, Scuotto A, Muras I, et al. Herniated disk in adolescents. J Neuroradiol 1993;20:60–69. Deyo RA. Conservative therapy for low back pain: distinguishing useful from useless therapy. JAMA 1983;250:1057–1062. Deyo RA, Cherkin DC, Loeser JD, et al. Morbidity and mortality in association with operations on the lumbar spine. J Bone Joint Surg Am 1992;74:536–543. Esses SI, Morley TP. Spinal arachnoiditis. Can J Neurol Sci 1983;10:2–10. Fessler RG, Johnson DL, Brown FD, et al. Epidural lipomatosis in steroid-treated patients. Spine 1992;17:183–188. Fiirgaard B, Marsden FH. Spinal epidural lipomatosis: case report and review of the literature. Scand J Med Sci Sports 1997;7:354–357. Francavilla TL, Powers A, Dina T, Rizzoli HV. Case report: MR imaging of thoracic disk herniations. J Comput Assist Tomogr 1987;2:1062–1065. Hansen FR, Bendix T, Skov P, et al. Intensive, dynamic back muscle exercises, conventional physiotherapy, or placebo-control treatment of low back pain: a randomized, observer-blind trial. 1993;18:98–108.

Spine

Hardy RW Jr, ed. Lumbar disc disease. New York: Raven Press, 1982. Koenigsberg RA, Klahr J, Zito JL, et al. Magnetic resonance imaging of cauda equina syndrome in ankylosing spondylitis: a case report. J Neuroimaging 1995;5:46–48. Maroon JC, Kupitnik TA, Schulhuf LA. Diagnosis and microsurgical approach to far lateral disc herniations in the lumbar spine. J Neurosurg 1990;72:378–652. Martin DS, Awwad EE, Pittman T, et al. Current imaging concepts of thoracic intervertebral disks. Crit Rev Diagn Imaging 1992;33:109–181. Milamed DR, Warfield CA, Hedley-Whyte J, Mosteller F. Laminectomy and the treatment of lower back pain in Massachusetts. Int J Technol Assess Health Care 1993;9:426–439. Mixter WJ, Barr JS. Rupture of the intervertebral disc with involvement of the spinal canal. N Engl J Med 1934;211:210. Mohanty S, Sutter B, Mokry M, Ascher PW. Herniation of calcified cervical intervertebral disk in children. Surg Neurol 1992;65:407–410. Noel P, Pepersack T, Vanbinst A, Alle JL. Spinal epidural lipomatosis in Cushing's syndrome secondary to an adrenal tumor. Neurology 1992;42:1250–1251. Onel D, Sari H, Donmez C. Lumbar spinal stenosis: clinical/radiologic therapeutic evaluation in 145 patients: conservative treatment or surgical intervention? Spine 1993;18:291–298. Pyeritz RE, Sack GH Jr, Udvarhelyi GB. Thoracolumbosacral laminectomy in achondroplasia: long-term results in 22 patients. Am J Med Genet 1987;28:433–444. Robertson SC, Traynelis VC, Follett KA, et al. Idiopathic spinal epidural lipomatosis. Neurosurgery 1997;41:68–74. Ross JS, Ruggieri P, Tkach J, et al. Lumbar degenerative disk disease: prospective comparison of conventional T2-weighted spin-echo imaging and T2-weighted rapid acquisition relaxation-enhanced imaging. AJNR 1993;14:1215–1223. Shapiro S. Cauda equina syndrome secondary to lumbar disc herniation. Neurosurgery 1993;332:743–747. Shaw MDM, Russell JA, Grossart KW. Changing pattern of spinal arachnoiditis. J Neurol Neurosurg Psychiatry 1978;41:97–107. Thornbury JR, Fryback DG, Turski PA, et al. Disk-caused nerve compression in patients with acute low-back pain: diagnosis with MR, CT myelography, and plain CT. Radiology 1993;186:731–765. Turner JA, Ersek M, Hernon L, et al. Patient outcomes after lumbar spinal fusions. JAMA 1992;268:907–911. Yoss RE, Corbin KB, MacCarty CS, Love JG. Significance of symptoms and signs in localization of involved root in cervical disc protrusion. Neurology 1957;7:673–683.

CHAPTER 66. CERVICAL SPONDYLOTIC MYELOPATHY MERRITT’S NEUROLOGY

CHAPTER 66. CERVICAL SPONDYLOTIC MYELOPATHY LEWIS P. ROWLAND AND PAUL C. MCCORMICK Incidence Pathology Symptoms and Signs Laboratory Data Differential Diagnosis Treatment Suggested Readings

Cervical spondylosis is a condition in which progressive degeneration of the intervertebral discs leads to proliferative changes of surrounding structures, especially the bones, meninges, and supporting tissues of the spine. Damage to the spinal cord can be demonstrated at autopsy. The myelopathy is attributed to one or more of three possible mechanisms: (1) direct compression of the spinal cord by bony or fibrocalcific tissues, (2) ischemia caused by compromise of the vascular supply to the cord, and (3) repeated trauma in the course of normal flexion and extension of the neck. It is difficult, however, to be precise in identifying this type of myelopathy in living patients. The very concept may be one of the persistent myths of clinical neurology, and the situation begs for critical review.

INCIDENCE Radiographic evidence of cervical spondylosis increases with each decade of life. It is seen in 5% to 10% of people between 20 and 30 years of age and increases to more than 50% by 45 years and to more than 90% after age 60 years. Signs of cervical myelopathy of unknown cause appear in only a few patients. Victims of myelopathy do not usually have a history of repeated single-root syndromes; that is, radiculopathy caused by cervical disc herniation and myelopathy seem to be distinct syndromes affecting different populations.

PATHOLOGY The water content of the intervertebral disc and annulus fibrosus declines progressively with advancing age. Concomitantly, there are degenerative changes in the disc. The intervertebral space narrows and may be obliterated, and the annulus fibrosus protrudes into the spinal canal. Osteophytes form at the margins of the vertebral body, converge on the protruded annulus, and may convert it into a bony ridge or bar. The bar may extend laterally into the intervertebral foramen; there is also fibrosis of the dural sleeves of the nerve roots. All these changes narrow the canal, a process that may be aggravated by fibrosis and hypertrophy of the ligamenta flava. The likelihood of cord compression or vascular compromise increases in direct relation to the decrease in the original diameter of the spinal canal. Spondylotic bars may leave deep indentations (visible at autopsy) on the ventral surface of the spinal cord. At the level of the lesion (there may be several levels), there is degeneration of the gray matter, sometimes with necrosis and cavitation. Above the compression, there is degeneration of the posterior columns; below the compression corticospinal tracts are demyelinated. Dense ossification of the posterior longitudinal ligament is a variant of cervical spondylosis that may also cause progressive myelopathy. The condition may be focal or diffuse and seems to be most common in Asians. One theory of pathogenesis holds that the cord is damaged by tensile stresses transmitted from the dura via the dentate ligaments. The spondylotic bar increases dentate tension by displacing the cord dorsally while the ligaments are anchored.

SYMPTOMS AND SIGNS Neck pain may be prominent. Root pain is uncommon, but paresthesias may indicate the most affected root. The most common symptom is spastic gait disorder (Table 66.1). Weakness and wasting of the hands may be seen. Fasciculations may also be noted. Urinary sphincter symptoms occur in a minority of patients. Overt sensory loss is uncommon, but the diagnosis is facilitated if there is a sensory level or if there is sensory loss that occurs in the distribution of a cervical dermatome. The course of the disorder is slowly progressive, but the natural history is not well delineated. Study of patients who were not treated surgically indicates that the condition may become arrested or even improve spontaneously. In one report, 39 of 45 patients were unchanged or better without surgery many years after the original diagnosis.

TABLE 66.1. CLINICAL MANIFESTATIONS OF CERVICAL SPONDYLOTIC MYELOPATHY

LABORATORY DATA Formerly, the most important diagnostic tests were plain radiographs of the cervical spine and myelography. Plain radiographs show narrowing of the disc spaces and the presence of osteophytes, especially at C5-6 and C6-7. Posterior osteophytes tend to be smaller than anterior projections and may not be seen without tomography. The disc bodies may be normal or show sclerosis. Changes in the zygapophyseal joints account for the designation “osteoarthritis” and may encroach on the intervertebral foramen; the changes may cause subluxation of the articular surfaces or compression of vertebral arteries. Computed tomography (CT) has supplanted plain radiographic examination because it can show evidence of disc degeneration and protrusion of bars into the spinal canal. Combining CT with intrathecal injection of water-soluble contrast agents ( CT–iohexol myelography) shows where and how severely the spinal cord is compressed and distorted. Spinal cord “atrophy” has become a new diagnosis. Myelography in patients with spinal cord compression is associated with a slight risk that the existing myelopathy may worsen and become permanent. Magnetic resonance imaging (MRI) is therefore the procedure of choice; it is noninvasive and provides exquisite resolution of spinal cord structures ( Fig. 66.1 and Fig. 66.2). MRI allows evaluation of spondylosis and the alternative possibilities: Chiari malformation, arteriovenous malformation, extramedullary tumor, syringomyelia, or multiple sclerosis (MS). In time, the technical advances in MRI may make myelography obsolete.

FIG. 66.1. Sagittal proton-density MRI demonstrates extensive spinal cord compression caused by a combination of ventral bone spurs and preexisting (congenital) canal stenosis.

FIG. 66.2. A: Sagittal T1-weighted MRI shows focal spinal cord compression from a single osteophyte at the C3-4 level. This dense calcification is typical of segmental ossification of the posterior longitudinal ligament. B: Axial CT scan in same patient.

Somatosensory evoked responses have been used to aid in diagnosis but are not crucial. The cerebrospinal fluid (CSF) is usually normal or has a protein concentration of 50 to 100 mg/dL. Higher protein levels or CSF pleocytosis should raise the question of MS or tumor, including meningeal carcinomatosis. The role of transcranial magnetic stimulation in diagnosis remains to be ascertained.

DIFFERENTIAL DIAGNOSIS There are two types of problems in the differential diagnosis. In one group, there is compression of the cervical spinal cord, but not by spondylosis (or at least not by spondylosis alone). Cervical spinal tumors are the best example of this category of problem. Such lesions are revealed by MRI. In other compressive lesions, the primary bony changes are congenital (anomalies of the craniocervical junction) or acquired (rheumatoid arthritis or basilar impression) and may be further complicated by spondylosis. These disorders are recognized by CT or MRI. Arteriovenous malformations may also be found. Another group of myelopathies presents more of a diagnostic problem. Cervical spondylosis is so common in the general population that it may be present by chance and harmless in a person with another disease of the spinal cord. The ultimate test of the pathogenic significance of spondylosis would be complete relief of symptoms after decompressive surgery, but this is rarely seen. Among the other diseases that can cause clinical syndromes similar to those attributed to spondylosis are MS, amyotrophic lateral sclerosis (ALS), neurosyphilis, and possibly subacute combined system disease. In 12% of patients diagnosed with spondylotic myelopathy, some other diagnosis was ultimately made. MS is probably the most common cause of spastic paraplegia in middle life and is probably the actual cause of the disorder in some people who have had cervical laminectomies. Therefore, before laminectomy it is imperative to test for MS by use of visual, somatosensory, and brainstem evoked responses; CSF gamma globulin and oligoclonal bands; and MRI examination of the cerebral white matter, foramen magnum, brainstem, and cervical spinal cord. Proper use and interpretation of the test results often remove diagnostic uncertainty. ALS must be considered whenever wasting and fasciculations are seen in arm and hand muscles, and especially when there are fasciculations in the legs. The presence of overt fasciculation makes it unlikely that spondylotic myelopathy is the cause of symptoms; in such cases caution is warranted when laminectomy is being considered. There is no diagnostic test for ALS, however, and the distinction may be difficult. Rare causes of spastic paraplegia in middle life are tropical myelopathy caused by human T-cell lymphotropic virus type I and adult-onset adrenoleukodystrophy. The diagnosis of exclusion, when no other cause is identified, is primary lateral sclerosis, which is almost as common a diagnosis as MS. In northern England, a prospective survey of 585 patients with nontraumatic spastic paraparesis gave the following order of frequency of diagnosis: cervical spondylotic myelopathy, 24%; tumor, 16%; MS, 18%; diagnosis uncertain, 19%; and ALS, 4%. The absence of primary lateral sclerosis from this list suggests regional differences in making a diagnosis. Of course, the problem is ascertaining the diagnosis of spondylotic myelopathy. An old adage: Be wary of the diagnosis of cervical spondylotic myelopathy if there is no sensory loss.

TREATMENT The natural history of cervical spondylotic myelopathy varies greatly and is unpredictable in individual patients. Moreover, no controlled trials of surgical therapy have been undertaken, and several different operations have been advocated. Therefore, uniform recommendations for treatment have been difficult to establish. Decompressive operations include posterior laminectomy, anterior discectomy, or vertebrectomy; these procedures are widely used but are associated with a high failure rate. Although contemporary surgical series report a 70% to 80% rate of improvement, only about 50% of patients show satisfactory functional improvement or complete reversal of symptoms that is maintained for a long time. The efficacy of surgical decompression seems to have been established in these improved patients. The others show little or no improvement, and their condition may even become worse as a result of surgery. Sometimes, symptoms return and progress after immediate postoperative improvement. Sooner or later, an attempt will be made to standardize the collection of data to evaluate the outcome of these operations, and there might even be a therapeutic trial. Surgeons still contend that a controlled trial is neither feasible nor necessary. However, one randomized trial of corpectomy for single-level discdisease found that fusion added nothing to decompression alone. Commenting on the trial, orthopedist Jeremy Fairbank noted all the problems to be faced but nevertheless reaffirmed the need to document the advantages of surgery over nonsurgical management. In the absence of clear guidelines, management is tailored to the specific circumstances of individual patients and to the experiences of the treating physicians and surgeons. Conservative treatment with physical therapy for gait training and with neck immobilization with a firm collar is appropriate for patients with mild myelopathy. Surgery should be considered if the myelopathy progresses despite conservative treatment. SUGGESTED READINGS

Adams CBT, Logue V. Movement and contour of spine in relation to neural complications of cervical spondylosis. Brain 1971;94:569–586. Adams CBT, Logue V. Some functional effects of operations for cervical spondylotic myelopathy. Brain 1971;94:587–594. Arlien-Soborg P, Kjaer L, Praestholm J. Myelography, CT, and MRI of the spinal canal in patients with myelopathy: a prospective study. Acta Neurol Scand 1993;87:95–102. Barnes MP, Saunders M. The effect of cervical mobility on the natural history of cervical spondylotic myelopathy. J Neurol Neurosurg Psychiatry 1984;47:17–20. Bednarik J, Kadanka Z, Vohanka S, et al. The value of somatosensory and motor evoked potentials in spondylotic cervical cord compression. Eur Spine J 1998;493–500. Braakman R. Management of cervical spondylotic myelopathy and radiculopathy. J Neurol Neurosurg Psychiatry 1994;57:257–263. Caruso PA, Patel MR, Joseph J, Rachlin J. Primary intramedullary lymphoma of the spinal cord mimicking cervical spondylotic myelopathy. AJR 1998;171:526–527. Cooper PR, ed. Degenerative diseases of the cervical spine. Park Ridge, IL: AANS Publications, 1993. Crockard HA, Heilman AE, Stevens JM. Progressive myelopathy secondary to odontoid fractures: clinical, radiological and surgical features. J Neurosurg 1993;78:579–586. Ebara S, Yonenobu K, Fujiwara K, et al. Myelopathy hand characterized by muscle wasting: a different type of myelopathy hand in patients with cervical spondylosis. Spine 1988;13:785–791. Emery SE, Bohlman HH, Bolesta MJ, Jones PK. Anterior cervical decompression and arthrodesis for the treatment of cervical spondylotic myelopathy. Two- to seventeen-year follow-up. Surg Am 1998;80:941–951.

J Bone Joint

Fessler RG, Steck JC, Giovanni MA. Anterior cervical corpectomy for cervical spondylotic myelopathy. Neurosurgery 1998;43:257–265. Hirose G, Kadoya S. Cervical spondylotic radiculo-myelopathy in patients with athetoid-dystonic cerebral palsy: clinical evaluation and surgical treatment. J Neurol Neurosurg Psychiatry 1984;47:775–780. Kardon D. Cervical spondylotic myelopathy with reversible fasciculations in the lower extremities. Arch Neurol 1977;34:774–776. Lees F, Turner JWA. Natural history and prognosis of cervical spondylosis. BMJ 1963;2:1607–1610. Levine DN. Pathogenesis of cervical spondylotic myelopathy. J Neurol Neurosurg Psychiatry 1997;62:334–340. Lunsford LD, Bissonette DJ, Zorub DS. Anterior surgery for cervical disc disease. Part 2: treatment of cervical spondylotic myelopathy in 32 cases. J Neurosurg 1980;53:12–19. Moore AP, Blumhardt LD. A prospective survey of the causes of non-traumatic spastic paraparesis and tetraparesis in 585 patients. Spinal Cord 1997;5:361–367. Nakamura K, Kurokawa T, Hoshino Y, et al. Conservative treatment for cervical spondylotic myelopathy: achievement and sustainability of a level of “no disability”.

J Spinal Disord 1998;11:175–179.

Nurick S. The pathogenesis of the spinal cord disorder associated with cervical spondylosis. Brain 1972;95:87–100. Nurick S. The natural history and results of surgical treatment of the spinal cord disorder associated with cervical spondylosis. Brain 1972;95:101–108. Olive PM, Whitecloud TS 3rd, Bennett JT. Lower cervical spondylosis and myelopathy in adults with Down's syndrome. Spine 1988;13:781–784. Restuccia D, DiLazzaro V, Valeriani M, et al. Segmental dysfunctionof the cervical cord revealed by abnormalities of the spinal N13 poten-tial in cervical spondylotic myelopathy. 1992;42:1054–1063.

Neurology

Rowland LP. Surgical treatment of cervical spondylotic myelopathy: time for a controlled trial. Neurology 1992;42:5–13. Saunders RL, Bernini PM, eds. Cervical spondylotic myelopathy. Oxford: Blackwell Science, 1992. Saunders RL, Bernini PM, Shirreffs TG, Reeves AG. Central corpectomy for cervical spondylotic myelopathy: a consecutive series with long-term follow-up evaluation. Tavy DLJ, Wagner GL, Keunen RWM, et al. Transcranial magnetic stimulation in patients with cervical spondylotic myelopathy: clinical and radiological correlations. Wilkinson H, ed. Cervical spondylosis: its early diagnosis and treatment. Philadelphia: WB Saunders, 1971. Yu YL, Moseley IF. Syringomyelia and cervical spondylosis: a clinicoradiological investigation. Neuroradiology 1987;29:143–151.

J Neurosurg 1991;74:163–170. Muscle Nerve 1994;17:235–241.

CHAPTER 67. LUMBAR SPONDYLOSIS MERRITT’S NEUROLOGY

CHAPTER 67. LUMBAR SPONDYLOSIS LEWIS P. ROWLAND AND PAUL C. MCCORMICK Suggested Readings

The same pathologic changes that define cervical spondylosis may affect the lower spine. Here, however, the roots of the cauda equina are affected rather than the spinal cord. The spinal cord becomes narrow because of age-related degenerative changes that affect the vertebral column articulations, including disc bulging and spur formation, facet joint enlargement, and hypertrophy of the ligamenta flava and facet capsule. Encroachment is usually maximal at the disc spaces. Spinal stenosis is the term for this narrowing. Congenital stenosis makes a person more vulnerable to these changes. The stenosis caused by spondylosis may be diffuse, but it is usually confined to one or two lumbar levels. Isolated L4-5 disorder with unilateral or bilateral L-5 radiculopathy is the most common syndrome (Fig. 67.1). The L3-4 segment is less often affected either alone or in combination with L4-5 stenosis. Disorders at other levels are rare.

FIG. 67.1. A: Lumbar myelogram demonstrates focal high-grade stenosis at L4-5. B: Postmyelographic CT at the L4-5 interspace demonstrates circumferential stenosis caused by disc bulging, enlarged facets, and hypertrophy of the ligamenta flava.

The resulting syndrome differs from acute herniation in many respects. Most patients are older than 40 years, and many are older than 60. Progression of symptoms is likely to be gradual rather than acute. Twisting of the back, lifting, or falling are precipitating factors in fewer than one-third of cases, and back pain is not the dominant symptom but may be reported by more than 50% of patients. Leg pain, when present, is as often bilateral as unilateral. Weakness of the legs and urinary incontinence are symptoms in a minority of patients, but many show weakness of isolated muscles and loss of reflexes on examination. Straight leg raising is limited in a few patients. The characteristic symptom is pseudoclaudication, seen in almost all patients, and is defined as unilateral or bilateral discomfort in buttock, thigh, or leg on standing or walking that is relieved by rest. Patients use the words “pain,” “numbness,” or “weakness” to describe the discomfort, but there is often no objective sensory loss or focal muscle weakness. The discomfort is relieved by lying down, sitting, or flexing at the waist. Sometimes, pain persists in recumbency until the spine is flexed. Unlike vascular claudication, the pain persists if the patient stops walking without flexing the spine, and sometimes the discomfort is brought on by prolonged standing without walking. The pathogenesis of pseudoclaudication is uncertain. Sometimes, myelography shows that hyperextension of the spine increases the protrusion of intervertebral discs, with relief of nerve root compression in flexed postures. In addition, blood flow to the lumbar spinal cord may increase when leg muscles are exercised. As a result, vessels on nerve roots dilate, but are then confined by the bony changes and thus compress the nerve roots. This is relieved by cessation of activity. The diagnosis is made from the characteristic history, clinical findings, and radiography. Formerly, the syndrome was defined by changes in plain spine radiographs and by evidence of partial or complete subarachnoid block found by contrast myelography. Diagnosis was facilitated by the advent of computed tomography (CT), alone or with intrathecal contrast agents (see Fig. 67.1). Now, however, magnetic resonance imaging alone usually suffices to show the specific patterns and extent of compression. Electromyography can reveal that denervation is restricted to muscles innervated by lumbosacral roots. The cerebrospinal fluid protein level may be normal if the tap is performed above the level of the block, but values greater than 100 mg/dL may be found if there are multiple blocks. The differential diagnosis includes intermittent claudication caused by peripheral arterial occlusive disease, which is recognized by the loss of pulses and characteristic trophic changes in the skin of the feet. Aortoiliac occlusive disease may spare peripheral pulses, but the femoral pulse is usually affected; it may cause claudication and wasting of leg muscles but does not cause postural claudication. The pain of aortoiliac disease is localized to exercising muscles. The radicular pattern of spinal claudication is not seen. The pain of aortoiliac disease persists as long as exercise is continued, regardless of body position. Vascular sonography may be in order. Osteoarthritis of the hip joint may also cause activity-induced leg pain that is relieved by rest. The pain originates in the hip and usually radiates into the groin or anterior thigh, but does not extend below the knee. Pain and limitation of hip rotation are the usual findings. The diagnosis is confirmed radiographically. The treatment of lumbar stenosis varies according to the severity of the symptoms. Mild symptoms often respond to nonsteroidal antiinflammatory drugs and physical therapy. The symptoms of lumbar stenosis may be episodic; even severe pain should be treated conservatively because a prolonged remission may ensue. Surgical treatment consists of decompressive laminectomy with medial facetectomy and resection of the ligamenta flava at the stenosed levels. Epidural injection of steroids does not relieve the pain of spinal claudication. Surgery is reserved for patients who have pain and claudication severe enough to affect the quality of life and who do not respond to conservative therapy. Surgery is usually well tolerated and is highly effective; about two-thirds of the patients report considerable improvement that is sustained for years after surgery. In one study, the following features indicated a favorable prognosis for patients with weak legs: disc herniation, stenosis at one level, duration of leg weakness of less than 6 weeks, and age younger than 65. In another study, the radiographic severity of stenosis was the best predictor of long-term outcome regardless of therapy, surgical or nonsurgical. There have been no controlled trials of surgical treatment. SUGGESTED READINGS Bischoff RJ, Rodriguez RP, Gupta K, et al. Comparison of CT, MRI and myelography in the diagnosis of herniated nucleus pulposus and spinal stenosis. J Spinal Disord 1993;6:289–295. Caputy AJ, Lessenhup AJ. Long-term evaluation of decompressive surgery for degenerative lumbar stenosis. J Neurosurg 1992;77:669–678. DeVilliers JC. Combined neurogenic and vascular claudication. S Afr Med J 1980;57:650–654. Epstein NE, Maldonado VC, Cusick JF. Symptomatic lumbar spinal stenosis. Surg Neurol 1998;50:3–10. Fukusaki M, Kobayashi I, Hara T, Sumikawa K. Symptoms of spinal stenosis do not improve after epidural steroid injection. Clin J Pain 1998;14:148–151. Giugui P, Benoist M, Delecourt C, Delhoume J, Deburge A. Motor deficit in lumbar spinal stenosis: a retrospective study of a series of 50 patients. J Spinal Disorder 1998;11:283–288.

Hall S, Bartelson JD, Onofrio BM, et al. Lumbar spinal stenosis: clinical features, diagnostic procedures, and results of surgical treatment in 68 patients. Ann Intern Med 1985;103:271–275. Hurri H, Slatis P, Soini J, et al. Lumbar spinal stenosis: assessment of long-term outcome 12 years after operative and conservative treatment. J Spinal Disord 1998;11:110–115. Javid MJ, Hadar EJ. Long-term follow-up review of patients who underwent laminectomy for lumbar stenosis. J Neurosurg 1998;89:1–7. Lange M, Hamburger C, Waldhauser E, Beck OJ. Surgical treatment and results in patients with lumbar spinal stenosis. Neurosurg Rev 1993;16:27–33. Onel D, Sari H, Donmez C. Lumbar spinal stenosis: clinical-radiologic therapeutic evaluation in 145 patients: conservative treatment or surgery? Spine 1993;18:291–298. Sanderson PL, Wood PL. Surgery for lumbar spinal stenosis in old people. J Bone Joint Surg Br 1993;75:393–397. Silvers HR, Lewis PJ, Asch HL. Decompressive lumbar laminectomy for spinal stenosis. J Neurosurg 1993;78:695–701. Spivak JM. Degenerative lumbar spinal stenosis. J Bone Joint Surg Am 1998;80:1053–1066.

CHAPTER 68. PERIPHERAL AND CRANIAL NERVE LESIONS MERRITT’S NEUROLOGY

CHAPTER 68. PERIPHERAL AND CRANIAL NERVE LESIONS DALE J. LANGE, WERNER TROJABORG AND LEWIS P. ROWLAND Injury to Cranial and Peripheral Nerves Cranial Neuropathies Peripheral Nerves Nerves of the Leg Suggested Readings

INJURY TO CRANIAL AND PERIPHERAL NERVES The peripheral and cranial nerves are subject to trauma, infections, tumors, toxic agents, and vascular or metabolic disorders. Trauma is the most common cause of localized injury to a single nerve (mononeuropathy). Toxic and metabolic disorders usually affect many nerves (mononeuropathy multiplex or symmetric polyneuropathy). Pathology After nerve damage, the pathologic changes depend on the nature of the injury, which also affects the regenerative response and the prognosis for recovery. According to Seddon (1954), mechanical nerve injuries are classified as follows: (1) complete severing of a nerve ( neurotmesis), (2) axonal interruption with distal degeneration but an intact endoneurium ( axonotmesis), or (3) conduction block at the site of the lesion but normal distal conduction without degeneration of distal fibers (neurapraxia). Within the first 24 hours of injury, focal swelling occurs adjacent to the damaged site with fragmentation of endoplasmic reticulum, neurotubules, and neurofilaments, and accumulation of organelles. The axolemma becomes discontinuous; axons swell at some sites and narrow at others to give a beaded appearance. This process begins between the nodes of Ranvier and appears first in smaller fibers. Changes in myelin sheaths lag behind those in axons but progress in a similar way along the entire distal stump, again affecting small fibers first. The myelin surrounding the fragmented axons breaks up to form rows of elliptoids. Finally, Schwann cells and macrophages degrade the axon and myelin debris. In addition to these distal nerve changes, a retrograde axon reaction or chromatolysis is seen, with retraction of axons proximal to the lesion and alterations in the somata of neurons, such as cell body swelling, disruption of Nissl substance, migration of the cell nucleus, and increase in the size of the nucleolus. Presynaptic terminals gradually withdraw from the soma and dendrites; synaptic transmission is reduced until dorsal root stimulation fails to excite the motor neuron and evoke a reflex discharge in the ventral root. The pathologic distal changes of degeneration and retrograde axon reaction are similar in crush injury or complete nerve transection. If a nerve has been completely severed, the orderly process just described is interfered with in proportion to the length of the discontinuity between proximal and distal ends. If this distance is great, regeneration is not possible, unless the ends are apposed at operation. If the distance is small, the fine processes of the axon penetrate the fibrin and connective tissue in the scar and enter the distal end of the nerve. Some of these may be deflected from the proper path by the scar and become entangled to form a neuroma. Clinical Manifestations The symptoms and signs of nerve injury depend on the type of nerve affected. If the nerve is mainly motor, the result is flaccid paralysis with wasting of the muscles innervated by the nerve. If the nerve contains sensory fibers, the result is loss of sensation in an area that is usually smaller than the anatomic distribution of the nerve. Vasomotor disorders and “trophic disturbances” are more common when a sensory or mixed type of nerve is injured than when a motor nerve is damaged. Partial injury or incomplete division of a nerve may be accompanied by pain that may be stabbing in character, by dysesthesia in the form of a pins-and-needles sensation, or, rarely, by severe burning pain ( causalgia). Complete or incomplete interruption of a nerve may be followed by changes in the skin, mucous membranes, bones, and nails (trophic changes). Diagnosis The diagnosis of injury to one or more peripheral nerves can usually be made clinically by the distribution of the motor and sensory abnormalities. These patterns are considered later in connection with the description of isolated peripheral nerve lesions. The differentiation between lesions of the spinal roots and one or more peripheral nerves can be made by determining whether the muscular weakness and sensory loss are segmental rather than in the pattern of a nerve distribution. Electromyography (EMG) can be used to study the patterns of denervation and later reinnervation; nerve conduction studies can ascertain the site and the nature of the injury. The differential diagnosis between polyneuropathy and other causes of generalized weakness is reviewed in Chapter 105. Prognosis The prognosis after injury of peripheral nerves is related to the degree of axonal injury and, to some extent, to the site of the injury. As a rule, the nearer the injury is to the central nervous system (CNS), the lower the probability will be that a completely severed nerve will regenerate, particularly cranial nerves, which are part of the CNS. When injury to a peripheral nerve involves no loss of axons (i.e., conduction block) or little axonal loss, recovery is complete within a few days or weeks. If axonal loss is severe, recovery is slow, because axonal regeneration is required for recovery of function. If the nerve is severed or the damage is so great that axons regrow along appropriate tubules, recovery may not be complete or may fail to occur at all. In this circumstance, the neuronal dysfunction is permanent. Treatment When a peripheral nerve is severed by trauma, the ends should be surgically anastomosed. There is no agreement about the best time to explore and repair lesions of peripheral nerves if it cannot be determined whether there has been anatomic or physiologic interruption of the nerve. Most clinicians believe that surgery should be performed as soon as possible if there is any doubt about the state of the nerve. After surgical therapy, or in patients who do not need operative therapy, rehabilitation measures should commence immediately with passive range-of-motion exercises for paralyzed muscles and reeducative exercises for weak muscles. Electrical stimulation is of unproven value in preventing permanent weakness. Splints, braces, and other corrective devices should be used when the lesion produces a deformity, but should be removable for the regular application of physiotherapy.

CRANIAL NEUROPATHIES Olfactory Nerve and Tract The ability to smell is a special quality relegated to the olfactory cells in the nasal mucosa. The molecular biology of smell is uncertain, but transcription-activating factors, such as Olf-1, found exclusively in neurons with olfactory receptors, probably direct cellular differentiation. Smell may be impaired after injury of the nasal mucosa, the olfactory bulb or its filaments, or CNS connections. Lesions of the nerve cause diminution or loss of the sense of smell. Injury to the CNS connections usually is not accompanied by any detectable loss of olfactory sense. Occasionally, olfactory hallucinations of a transient and paroxysmal nature may occur with lesions in the temporal lobe. Loss of the sense of smell is often accompanied by impaired taste, depending on the volatile substances in the food and beverages. The sense of smell may be temporarily impaired in connection with the common cold. Inflammatory or neuritic lesions of the bulb or tract are uncommon, but these

structures are sometimes affected in meningitis or in multiple peripheral neuritis. Patients with diabetes mellitus may have impaired sensation of smell. Hyposmia or anosmia is common early in Refsum disease. The olfactory bulb or tract may be compressed by meningiomas, metastatic tumors, or aneurysms in the anterior fossa or by infiltrating tumors of the frontal lobe. The filaments of the olfactory nerve may be torn from the cribriform plate, or the olfactory bulb may be contused or lacerated in head injuries. Leigh and Zee (1991) reported altered olfactory sense in 7.2% of 1,000 patients with head injuries observed at a military hospital. The loss was complete in 4.1% and partial in 3.1%. Recovery of smell occurred in only 6 of 72 patients. Parosmia (perversion of sense of smell) was present in 12 patients. In a study of head injuries in civilians, Friedman and Merritt (1944) found that the olfactory nerve was damaged in 11 (2.6%) of 430 patients. In all patients, the anosmia was bilateral. In three, the loss was transient and disappeared within 2 weeks of injury. Parosmia is not accompanied by impairment of olfactory acuity and is most commonly caused by lesions of the temporal lobe, although it has been reported when the injury was probably in the olfactory bulb or tract. Hallucinations of smell may occur in psychotic persons or may be an aura in patients with convulsive seizures (hippocampal or uncinate gyrus fits). The aura in such cases is usually an unpleasant odor that is described with difficulty. Increased sensitivity to olfactory stimuli is rare, but cases have been reported in which the sense of smell is so acute that it is a source of discomfort. Such a symptom is usually psychogenic. Optic Nerve and Tract The retina, optic nerve, and optic tract are subject to injury from many causes with resulting loss of vision, impairment of pupillary light reflexes, and abnormalities in pupil size (Table 68.1).

TABLE 68.1. EFFECTS OF LESIONS OF THE OPTIC, OCULOMOTOR, AND SYMPATHETIC PATHWAYS ON THE PUPILS

Changes in the retina or optic nerve may result from direct trauma, damage by toxins, systemic diseases (e.g., chronic renal failure, diabetes mellitus, leukemia, anemia, polycythemia, nutritional deficiencies, syphilis, tuberculosis, the lipodystrophies, giant cell arteritis, or generalized arteriosclerosis), demyelinating hereditary diseases, local conditions (e.g., chorioretinitis, glaucoma, tumors, congenital anomalies, or thrombosis or embolism of the veins or arteries of the retina), infiltration or compression of the nerve (e.g., by glioma, meningioma, pituitary tumor, craniopharyngioma, metastatic tumor, or aneurysm), or increased intracranial pressure. Most of these conditions are considered elsewhere in this volume. Disorders of vision are also discussed in Chapter 7. Optic neuritis is a term used loosely to describe lesions of the optic nerve accompanied by diminution in visual acuity with or without changes in the peripheral fields of vision and caused by inflammatory, degenerative, demyelinating, or toxic disorders ( Fig. 68.1). On ophthalmoscopic examination, the disc may appear normal at first, or swelling and congestion of the nerve may be apparent. Later, the disc is pale and smaller than normal.

FIG. 68.1. Chart of visual fields in a patient with retrobulbar neuritis indicates large central scotoma in left eye. Visual acuity: OD 15/15, OS 1/400. (Courtesy of Dr. M. Chamlin.)

The optic nerve or retina may be injured by many toxic substances, including methyl alcohol, ethyl alcohol, tobacco, quinine, pentavalent arsenicals, thallium, lead, or mercury. Alcohol-Tobacco Amblyopia This term is used to describe the optic neuritis that is attributed to long and continued use of both tobacco and ethyl alcohol. The lesion could be an interstitial neuritis with destruction of the papillomacular bundle. A more reasonable hypothesis, however, is that the ganglion cells in the macular region of the retina are damaged. The neuritis is most common in middle-aged men who smoke a pipe and drink alcohol in large quantities. It usually affects both eyes. At the onset, a central or paracentral scotoma for colors exists that progresses to a complete central scotoma. The peripheral fields of vision are normal. Alcohol-tobacco amblyopia has been noted in association with pernicious anemia; malabsorption of vitamin B 12 may be a factor in causing alcohol-tobacco amblyopia. Many authorities believe that the condition is primarily a nutritional disorder in alcoholic persons who are not eating properly. Absolute withdrawal of all forms of alcohol and tobacco may improve vision, unless the disease has progressed to the point of complete atrophy of the retinal cells of the optic nerve. Oculomotor, Trochlear, and Abducens Nerves Injury to the nerves or nuclei that innervate the ocular muscles causes diplopia, deviation of the eyeball, and impairment of ocular movements ( Table 68.2).

TABLE 68.2. CAUSES OF THIRD AND SIXTH CRANIAL NERVE PALSIES

Complete lesions of the third nerve or its nucleus produce paralysis of the extrinsic muscles of the eye supplied by this nerve (medial rectus, superior rectus, inferior rectus, inferior oblique, and levator palpebrae superior), as well as the constrictor of the ciliary muscles. There is ptosis of the lid with loss of the ability to open the eye; the eyeball is deviated outward and slightly downward; the pupil is dilated, does not react to light, and loses the power of accommodation. Partial lesions of the third nerve or its nucleus produce fragments of the above picture according to the extent of involvement of the nerve fibers or neurons. Lesions of the fourth nerve or nucleus cause paralysis of the superior oblique muscle with impairment of the ability to turn the eye downward and inward. Deviation of the eyeball is slight, and diplopia is prevented by inclination of the head forward and to the side of the normal eye. Injury to the sixth nerve causes paralysis of the lateral rectus muscle. The eyeball is deviated inward, and diplopia is present in almost all ranges of movement of the eye, except on gaze to the side opposite the lesion. Lesions in the brainstem that involve the sixth nerve nucleus are accompanied by a paralysis of lateral gaze. On attempts to look toward the affected side, neither eyeball moves beyond the midline. An intact third nerve on the opposite side can be demonstrated by the ability of the patient to move the internal rectus muscle of that eye in accommodation窶田onvergence movements. Paralysis of the ocular muscles may result from injury to the corresponding motor nerves or cells of origin by many conditions, including trauma, neurosyphilis, multiple sclerosis (MS) and other demyelinating diseases, tumors or aneurysms at the base of the skull, acute or subacute meningitis, thrombosis of intracranial venous sinuses, encephalitis, acute anterior poliomyelitis, diphtheria, diabetes mellitus, syringobulbia, vascular accidents in the brainstem, lead poisoning, botulism, alcoholic polioencephalitis (Wernicke encephalitis), osteomyelitis of the skull, and following spinal anesthesia or simple lumbar puncture. Intraorbital lesions may cause ophthalmoplegia, proptosis, and local pain; retroorbital lesions may cause similar symptoms. Intracavernous inflammation is held to be responsible for a form of painful ophthalmoplegia known as the Tolosa-Hunt syndrome, but the pathology has been documented in few cases; most would also be considered examples of orbital myositis or orbital pseudotumor, in which swelling of the muscles within the orbit can be demonstrated by computed tomography (CT). Ocular palsies are frequently seen in myasthenia gravis, ocular myopathy, and, rarely, polyneuropathy. Discussion in this section is restricted to the disturbance of eye movements in patients with increased intracranial pressure. Paralysis of Eye Muscles Associated with Increased Intracranial Pressure The sixth nerve has a long course from its point of emergence from the brainstem to the lateral rectus muscle in the orbit. Although it lies in a fluid-cushioned channel for a portion of this course, it is peculiarly subject to injury by compression against the floor of the skull when intracranial pressure is increased from any cause. Thus, unilateral or bilateral paralysis of the lateral rectus muscle may develop in patients with increased intracranial pressure. In these patients, the paralysis is of no value in localizing the site of the lesion (see Table 68.2). Rarely, the third nerve is injured by increased intracranial pressure. The nerve may be damaged when the increase in pressure develops slowly, as with tumors of the brain, but it is more likely to be injured when the increased pressure is of sudden onset, with herniation of the uncinate gyrus through the tentorial notch and compression of the nerve. It is most commonly seen in patients with massive intracerebral hemorrhage or with extradural or subdural hematomas. Patients are usually comatose, and thus it is impossible to test eye movements, except by doll's eye or caloric tests, which may not suffice to show paresis of muscles innervated by the third cranial nerve. However, compression of the third nerve may be manifest by a dilated pupil nonresponsive to light ipsilateral to the herniation. Fifth (Trigeminal) Nerve Injury to the fifth cranial nerve causes paralysis of the muscles of mastication with deviation of the jaw toward the side of the lesion; loss of ability to appreciate soft tactile, thermal, or painful sensations in the face; and loss of the corneal and sneezing ( sternutatory) reflexes. The dorsal root ganglion for sensory fibers in the trigeminal nerve is the trigeminal (gasserian) ganglion in the middle cranial fossa. Sensory fibers pass into the brainstem at the midpons level and either ascend to terminate in the main sensory nucleus (subserving light touch) or descend to terminate in the nucleus of the spinal tract (pain and temperature sensation) or in the mesencephalic nucleus (subserving proprioception for jaw muscles). Lesions in the pons usually involve the motor and main sensory nuclei, causing paralysis of the muscles of mastication and loss of sensation of light touch in the face. Lesions in the medulla affect only the descending tract and cause loss of the sensation of light touch in the face. The fifth nerve may be injured by trauma, neoplasms, aneurysm, or meningeal infections. Occasionally, it may be involved in poliomyelitis and generalized polyneuropathy. The sensory and motor nuclei in the pons and medulla may be destroyed by intramedullary tumors or vascular lesions. In addition, an isolated lesion of the descending tract may occur in syringobulbia or MS. If no accompanying neurologic signs facilitate localization, isolated facial numbness ( idiopathic trigeminal neuropathy) may be a difficult problem to solve. Common causes of facial numbness are dental trauma, herpes zoster, cranial trauma, head and neck tumors, intracranial tumors, and idiopathic trigeminal neuropathy. Systemic sclerosis, mixed connective tissue diseases, amyloidosis, MS, and sarcoidosis are less common causes of facial numbness. Although restricted loss of sensation over the chin ( numb-chin syndrome) may result from dental trauma or even poorly fitting dentures, it may be the only manifestation of systemic malignancy, such as lymphoma, metastatic breast carcinoma, melanoma, or prostatic cancer. Magnetic resonance imaging (MRI) or CT of the mandible often identifies the disorder. Painful facial numbness may herald the presence of nasopharyngeal carcinoma or metastatic carcinoma. Severe facial pain in the absence of numbness or other objective findings (tic douloureux) is caused by fifth nerve dysfunction. Trigeminal Neuralgia (Tic Douloureux) This disorder of the sensory division of the trigeminal nerve is characterized by recurrent paroxysms of sharp, stabbing pains in the distribution of one or more branches of the nerve. The cause is unknown. In most cases, no organic disease of the fifth nerve or CNS can be identified. Degenerative or fibrotic changes in the gasserian ganglion have been found but are too variable to be considered causal. Some investigators believe that most patients with idiopathic trigeminal neuralgia have anomalous blood vessels that compress the nerve. Pain typical of trigeminal neuralgia occasionally affects patients with lesions in the brainstem as a result of MS or with vascular lesions that involve the descending root of the fifth nerve. Usually, trigeminal neuralgia follows other symptoms of MS. Of all patients with MS, however, 10% have facial pain first, and other symptoms of MS may not appear for 6 years. The attacks of facial pain in trigeminal neuralgia are attributed to discharges in the descending nucleus of the nerve, presumably because of excessive inflow of impulses to the nucleus. In support of this hypothesis is evidence that typical attacks of trigeminal neuralgia may be relieved by section of the greater auricular or

occipital nerves or that an episode of trigeminal neuralgia can be interrupted by intravenous injection of phenytoin sodium (Dilantin). Trigeminal neuralgia is the most common of all neuralgias. Onset is usually in middle or late life but may occur at any age. Typical trigeminal neuralgia occasionally affects children but rarely occurs before age 35. The incidence is slightly greater in women than in men. The pain occurs in paroxysms. Between attacks, the patient is free of symptoms, except for fear of an impending attack. The pain is searing or burning, coming in lightning like jabs. A paroxysm may last 15 minutes or more. The frequency of attacks varies from many times a day to a few times a month. The patient ceases to talk when the pain strikes and may rub or pinch the face; movements of the face and jaw may accompany the pain. Sometimes, ipsilateral lacrimation is prominent. No objective loss of cutaneous sensation is found during or after the paroxysms, but the patient may complain of facial hyperesthesia. A characteristic feature is the trigger zone, stimulation of which sets off a typical paroxysm of pain. This zone is a small area on the cheek, lip, or nose that may be stimulated by facial movement, chewing, or touch. The patient may avoid making facial expressions during conversation, may go without eating for days, or may avoid the slightest breeze to prevent an attack. The pain is limited strictly to one or more branches of the fifth nerve and does not spread beyond the distribution of that nerve. The second division is involved more frequently than the third. The first division is primarily affected in less than 5% of patients. Pain may spread to one or both of the other divisions. In cases of long duration, all three divisions are affected in 15%. The pain is occasionally bilateral (5%) but rarely occurs at the same time. Bilateral trigeminal neuralgia is encountered most often in patients with MS. The physical findings in patients with trigeminal neuralgia are normal. Hemifacial spasm, however, may accompany trigeminal neuralgia. The patient may be undernourished or emaciated if attacks are provoked by eating. There is no objective sensory loss, and motor functions are normal. The results of laboratory examinations are normal. The diagnosis of trigeminal neuralgia is usually made from the history without difficulty. Also characteristic is the method patients use to demonstrate the site of origin and mode of spread of the pain. They do not touch the area but hold the tip of the index finger a short distance from the face to point to areas of origin and spread. Trigeminal neuralgia must be differentiated from other types of pain that occur in the face or head, particularly from infections of the teeth and nasal sinus. The pains of dental and nasal sinus disease differ from those of trigeminal neuralgia in that they are usually steady and throbbing and persist for many hours. Nevertheless, many patients with trigeminal neuralgia have had numerous operations on the sinuses, and most of their teeth have been removed before the diagnosis is established. Conversely, many patients with diseased teeth are referred to neurologists with the diagnosis of trigeminal neuralgia. In these patients, the role of the diseased tooth in the production of pain can be demonstrated by syringing it and the surrounding gum with ice water. Patients with temporomandibular joint disease may have symptoms similar to those of trigeminal neuralgia, but the pain is not paroxysmal, is exacerbated by eating, and has no trigger point. Cluster headaches may be confused with trigeminal neuralgia, especially when the ipsilateral eye is red and watery. The pain of cluster headaches, however, is not paroxysmal, does not conform to the trigeminal distribution, and is accompanied by nasal stuffiness with Horner syndrome on the affected side. Atypical facial pain occurs in the territory of the trigeminal nerve, but the characteristics are different from those of trigeminal neuralgia. The pain may be as excruciating, but the individual paroxysm always last longer than a few seconds—usually minutes or even continuously. The pain itself is dull, aching, crushing, or burning. Surgical treatment is not effective in atypical facial pain, which may sometimes be a manifestation of depression. Treatment of trigeminal neuralgia with carbamazepine (Tegretol) is often successful. The effective dose is usually 200 mg four times daily. Larger doses may be needed, with monitoring of serum levels and clinical signs of toxicity. Toxicity is manifested as drowsiness, dizziness, unsteady gait, and nausea. A rare but serious complication is aplastic anemia. Unfortunately, tolerance to this medication frequently develops. Baclofen (Lioresal), 50 to 60 mg daily, also relieves symptoms. Phenytoin in a dose of 300 to 400 mg per day may help some patients unresponsive to carbamazepine or baclofen, but it is more commonly used as an adjunct to these medications. Surgical procedures to control pain are used in common practice. Techniques include microvascular decompression, radiofrequency and chemical gangliolysis using stereotactic techniques, and rhizotomy. One of the more popular procedures is radiofrequency surgery, which selectively interferes with pain-conducting small fibers but spares the large-diameter motor fibers. Some studies report 90% to 97% partial or complete relief. The rate of recurrence is uncertain. Increasing evidence indicates that many patients with trigeminal neuralgia have compression of the trigeminal nerve by arterial loops. Posterior fossa exploration is therefore recommended for patients whose symptoms are difficult to control. Other chronic masses, such as arteriovenous malformation, aneurysm, and cholesteatoma, may be found. Seventh (Facial) Nerve As the facial nerve leaves the brainstem, it has two divisions: the motor root and the nervus intermedius. The functions of the intermedius are much like those of the glossopharyngeal nerve. It conducts taste sensation from the anterior two-thirds of the tongue and supplies autonomic fibers to the submaxillary and sphenopalatine ganglia that innervate the salivary and lacrimal glands. Whether the seventh nerve has any somatic sensory function is debatable. It is thought to carry proprioceptive impulses from the facial muscles and cutaneous sensation from a small strip of skin on the posteromedial surface of the pinna and around the external auditory canal. In fact, however, sensory loss is only rarely detected in patients with lesions of the seventh nerve. Similarly, hearing is seldom impaired, although the ear may become more sensitive to low tones when the stapedius is paralyzed. Injuries to the facial nerve cause paralysis of the facial muscles with or without loss of taste on the anterior two-thirds of the tongue or altered secretion of the lacrimal and salivary glands, depending on the portion of the nerve involved. Lesions near the origin or in the region of the geniculate ganglion are accompanied by a paralysis of the motor, gustatory, and autonomic functions. Lesions between the geniculate ganglion and the origin of the chorda tympani produce the same dysfunction as that resulting from injury in the region of the geniculate ganglion, except that lacrimal secretion is not affected. Lesions near the stylomastoid foramen result only in facial paralysis. Lesions of the facial nucleus in the brainstem cause paralysis of all facial muscles. Lesions of the motor cortex or the connections between the cortex and the facial nucleus are accompanied by partial paralysis, usually most severe in muscles of the lower half of the face (supranuclear palsy). Asymmetric facial movements may follow voluntary or emotional stimuli. Because they are superficial, the peripheral branches of the seventh nerve are subject to injury by stab and gunshot wounds, cuts, and birth trauma. The nerve is occasionally injured in operations on the mastoid and parotid gland and in acoustic neuromas or trigeminal neuralgia. Damage to the seventh nerve is often found with fracture of the temporal bone and is usually evident immediately after injury. Occasionally, however, facial paralysis is delayed for several days after the accident. The mechanism of this delayed paralysis is not clear. Improvement is the rule when the nerve damage is associated with head trauma, but recovery may not be complete. Within the skull, the nerve may be affected by tumors, aneurysms, meningeal infections, leukemia, osteomyelitis, herpes zoster, Paget disease, and sarcomas or other tumors of bone. Occasionally, it is affected in the course of generalized polyneuritis, which is common in leprosy, Guillain-BarrÊ syndrome, or diphtheritic polyneuropathy, but seldom in diabetic or alcoholic neuropathy. The peripheral portion of the nerve may be compressed by tumors of the parotid gland. Facial palsy is rare in mumps but is common in sarcoidosis. Bilateral facial palsy may be caused by many of the conditions that produce unilateral paralysis, but is most often seen in sarcoidosis, Guillain-BarrÊ syndrome, leprosy, leukemia, and meningococcal meningitis. The facial nucleus may be damaged by tumors, inflammatory lesions, vascular lesions, acute poliomyelitis, and MS. Bell Palsy Paralysis of the seventh nerve may occur without any known cause. Bell palsy often follows exposure to cold (e.g., riding in an open car) and is thought to be caused by swelling of the nerve within the facial (fallopian) canal. It occurs at all ages but is slightly more common in the third to fifth decades. The frequency of involvement on the two sides is approximately equal. Paralysis occasionally recurs either on the same or on the opposite side. Familial occurrence of Bell palsy is occasionally seen. The onset of facial paralysis may be accompanied by a feeling of stiffness of the muscles. Pain is rare, however, except in the Ramsay Hunt syndrome, which is

caused by herpes zoster and includes pain in the ear ipsilateral to the facial paralysis. The signs of complete paralysis of the seventh nerve can be divided into motor, secretory, and sensory. When the damage is severe, facial paralysis is obvious, even when the face is at rest. Muscles of the lower half of the face sag. The normal folds and lines around the lips, nose, and forehead are ironed out, and the palpebral fissure is wider than normal. Absence of voluntary and associated movements of the facial and platysmal muscles is complete. When the patient attempts to smile, the lower facial muscles are pulled to the opposite side. This distortion of the facial muscles may give the false appearance of deviation of the protruded tongue or the open jaw. Saliva and food are likely to collect on the paralyzed side. The patient cannot close the eye, and with attempts to do so, the eyeball can be seen to divert upward and slightly inward (the Bell phenomenon). When the lesion is peripheral to the ganglion, the lacrimal fibers are spared and the collection of tears in the conjunctival sac is excessive because the tears are not expressed into the lacrimal duct by lid movements. The corneal reflex is absent as a result of paralysis of the upper lid; preservation of corneal sensation and the afferent portion of the reflex is manifested by blinking of the other lid. Secretion of tears is diminished only if the lesion is proximal to the geniculate ganglion. Decrease in salivary secretion and loss of taste in the anterior two-thirds of the tongue are found when the chorda tympani is affected. Although the seventh nerve presumably transmits proprioceptive sense from the facial muscles and cutaneous sensation from a small area of the pinna and the external auditory canal, loss of these sensations is rarely detected. Partial injury to the facial nerve causes weakness of the upper and lower halves of the face. Occasionally, however, the lower half is more severely affected than the upper half; rarely, the opposite is seen. Recovery from facial paralysis depends on the severity of the lesion. If the nerve is anatomically sectioned, the chances of complete or even partial recovery are remote. In most patients, especially those with Bell palsy, partial or complete recovery occurs. With complete recovery, no apparent difference can be detected between the two sides of the face at rest or in motion. When recovery is partial, “contracturesâ€? may develop on the paralyzed side; superficial inspection seems to reveal weakness of muscles on the normal side. The inaccuracy of this impression becomes obvious as soon as the patient smiles or attempts to move the facial muscles. Abnormal movement of facial muscles and lacrimation may follow facial palsy. A slight twitch of the labial muscles may occur whenever the patient blinks ( synkinesis), or an excess secretion of tears may result when the salivary glands are activated during eating. Paroxysmal clonic contractions of all facial muscles may simulate focal jacksonian seizures. These spasms are occasionally seen in patients who have never had any obvious lesion of the facial nerve. The cause of these sequelae is not known. They are attributed by some researchers to misdirection of the regenerated fibers or to the spread of impulses between fibers within the nerve ( ephaptic conduction). The differential diagnosis between facial paralysis caused by a cortical lesion and that resulting from a lesion of the nucleus or nerve can be made without difficulty, except when weakness is barely evident. Other signs of supranuclear cortical involvement include sparing of the muscles of the forehead and upper lid and preservation of electrical reactions. In addition, the weakness of a peripheral lesion is equal for all movements, whereas in supranuclear lesions volitional contractions may be greater or less than those in the emotional responses of smiling or laughing. The differentiation between lesions of the nucleus and those of the nerve is made by associated findings. Lesions in the tegmentum of the brainstem are accompanied by paralysis of lateral gaze because of concomitant injury to the sixth nerve nucleus and parapontine gaze center. Lesions in the basal part of the brainstem are accompanied by corticospinal signs. Lesions of the nerve as it emerges from the brainstem may be caused by tumors, meningitis, or other infections, resulting in concomitant paralysis of the facial nerve with abnormalities of the eighth, sixth, and, possibly, the fifth nerves. Attempts should be made to remove the lesion that causes the facial paralysis. Without formal therapeutic trials, some clinicians recommend massage or electrical stimulation of the paralyzed muscles to preserve tone. Surgical procedures may help when spontaneous recovery does not occur. Neurolysis or end-to-end suture may be indicated in extracranial lesions of the nerve or its branches. When the nerve is damaged proximal to the stylomastoid foramen, end-to-end suture is not possible, and innervation of the facial muscles can be restored only by suturing the distal portion of the seventh nerve to the central portion of the eleventh or the twelfth nerves. If the eleventh nerve is used, paralysis of the sternocleidomastoid and upper fibers of the trapezius is permanent. The resultant deformity is slight, but the facial muscles contract whenever the patient attempts to turn the head or elevate the shoulder. Sooner or later, a new motor pattern develops in the cerebral cortex, and movements of the facial muscles are dissociated from those of the shoulder. Conversely, anastomosis of the twelfth nerve with the seventh nerve is followed by atrophy and paralysis of one-half of the tongue. This outcome causes little discomfort, and control of the facial muscles returns without adventitious movement of other muscles. Anastomosis of the facial nerve with either the eleventh or the twelfth nerve should be performed as soon as possible if the nerve is cut in mastoid surgery or in removal of an acoustic neuroma. In other types of peripheral facial paralysis, surgery should be delayed for 6 months or more to determine whether spontaneous regeneration occurs. Steroid therapy has been recommended for Bell palsy to relieve edema in the nerve. Reports of this therapy have not been convincing; therapeutic trials have not been adequately controlled, because improvement is seen spontaneously in almost all cases. Acyclovir (Zovirax) therapy is also unproven. Decompression of the nerve in the canal is recommended by some otologists to expedite and enhance return of function in Bell palsy. No available evidence suggests that this treatment changes the course of the disorder, and the surgery itself is not without risk. Therefore, many surgeons have stopped performing this operation. Surgery may be necessary to alleviate the facial spasm that occurs spontaneously or after partial regeneration of the injured nerve. The nerve or one of its branches can be injected with alcohol or partially sectioned when the spasms are localized. These operations occasionally give permanent relief from the spasms, but the spasms usually recur when the nerve regenerates. Permanent relief can be obtained by anastomosing the seventh nerve with the eleventh or twelfth cranial nerve. Blepharospasm, Myokymia, and Hemifacial Spasm Blepharospasm is a state of forceful closure of the eye. Unilateral and repeated brief blepharospasm is a focal dystonia and may be part of hemifacial spasm. Bilateral blepharospasm may be seen in basal ganglia disorders, especially parkinsonism. The combination of blepharospasm and oromandibular dyskinesia is the Meige syndrome. Injections of botulinum toxin are effective and safe in treating of blepharospasm. Facial myokymia is characterized by fine rippling movements of facial muscles. EMG shows bursts of rapidly firing motor units that tend to recur in a regular fashion. Persistent facial myokymia is sometimes a manifestation of MS, brainstem glioma, or some other disorder of the brainstem. These CNS lesions presumably interrupt descending inhibitory impulses that act on motor neurons in the facial nucleus, thereby releasing the involuntary activity. Myokymia also can arise peripherally, especially in the acute phase of the Guillain-BarrĂŠ syndrome. Hemifacial spasm is characterized by clonic spasms of the facial muscles, usually starting around the eye and often spreading to other muscles of one side of the face. It increases in intensity during stress and may occur in sleep. The characteristic EMG findings include bursts of muscle action potentials that occur either regularly or irregularly at 5 to 20 per second. Synkinetic motor responses in muscles innervated by the facial nerve follow stimulation of the ipsilateral fifth nerve (blink reflex). Hemifacial spasm does not have the ominous implications of myokymia, but the cosmetic effects may be distressing. The cause is usually obscure, but it may follow facial nerve trauma. Treatment with anticonvulsant medication, such as carbamazepine, may be effective. Jannetta (1977) reported relief of the involuntary movements by exposing the facial nerve in the posterior fossa and decompressing vessels at the root entry zone. Botulinum toxin is also effective. Eighth (Acoustic) Nerve Eighth nerve disorders are described in Chapter 6. Ninth (Glossopharyngeal) Nerve The ninth cranial nerve contains both motor and sensory fibers. The motor fibers supply the stylopharyngeus muscle and the constrictors of the pharynx. Other efferent fibers innervate secretory glands in the pharyngeal mucosa. The sensory fibers carry general sensation from the upper part of the pharynx and the special sensation of taste from the posterior one-third of the tongue. Isolated lesions of the nerve or its nuclei are rare and are not accompanied by perceptible disability. Taste is lost on the posterior one-third of the tongue, and the gag

reflex is absent on the side of the lesion. Injuries of the ninth nerve by infections or tumors are usually accompanied by signs of involvement of the neighboring nerves. The tractus solitarius receives taste fibers from both the seventh and the ninth nerves and may be destroyed by vascular or neoplastic lesions in the brainstem. Because the ninth, tenth, and eleventh nerves exit the jugular foramen together, tumors here produce multiple cranial nerve palsies ( jugular foramen syndrome). The territory of the ninth nerve is the distribution also affected in glossopharyngeal neuralgia. Glossopharyngeal neuralgia (tic douloureux of the ninth nerve) is characterized by paroxysms of excruciating pain in the region of the tonsils, posterior pharynx, back of the tongue, and middle ear. The cause of glossopharyngeal neuralgia is unknown, and no significant pathologic changes occur in most cases. Pain in the distribution of the nerve occasionally follows injury of the nerve in the neck by tumors. Glossopharyngeal neuralgia is rare, with a frequency about 5% that of trigeminal neuralgia. The paroxysms are burning or stabbing in nature. They may occur spontaneously but are often precipitated by swallowing, talking, or touching the tonsils or posterior pharynx. The attacks last only a few seconds but sometimes last several minutes. The frequency of attacks varies from many times daily to once in several weeks. The diagnosis of glossopharyngeal neuralgia can be made from the description of the pain. The only differential diagnosis of any importance is neuralgia of the mandibular branch of the fifth nerve. The diagnosis of glossopharyngeal neuralgia is established when an attack of pain can be precipitated by stimulation of the tonsils, posterior pharynx, or base of the tongue or when the pain is relieved by spraying the affected area with local anesthetic. When the membrane becomes anesthetized, the pains disappear and cannot be precipitated by stimulation with an applicator. During this period, the patient can swallow food and talk without discomfort. There may be long remissions. During a remission the trigger zone disappears. The pains almost always recur, unless they are prevented by medical therapy or the nerve is surgically sectioned. The disease does not shorten life, but affected patients may become emaciated because of the fear that each morsel of food will precipitate a pain paroxysm. Carbamazepine, alone or in combination with phenytoin, is usually effective in producing a remission. If medical therapy is not effective, the nerve can be sectioned intracranially; the results of the operation are satisfactory. The patient is relieved of the pain, and there are no serious sequelae. The mucous membrane supplied by the ninth nerve is permanently anesthetized with loss of the gag reflex on that side. Taste is lost on the posterior one-third of the tongue. There are no motor symptoms, such as dysphagia or dysarthria, unless the tenth nerve is injured during surgery. Tenth (Vagus) Nerve The motor fibers of the tenth nerve arise from the nucleus ambiguus (to innervate the somatic muscles of the pharynx and larynx) and from the dorsal motor nucleus (to supply the autonomic innervation of the heart, lungs, esophagus, and stomach). The vagus nerve also carries sensory (visceral afferent) fibers from the mucosa in the oropharynx and upper part of the gastrointestinal tract; sensory fibers from the thoracic and abdominal organs send information into the tractus solitarius. Unilateral lesions of the nucleus ambiguus in the medulla cause dysarthria and dysphagia. Because the nucleus has a considerable longitudinal extent in the medulla, lesions in the brainstem may produce dysarthria without dysphagia, or vice versa, according to the site of the lesion. Lesions confined to the lower portion of the nucleus cause dysphagia, whereas lesions of the upper portions produce dysarthria. The dysphagia or dysarthria that follows unilateral lesions of the nucleus ambiguus is rarely severe. The voice may be hoarse, but speech is intelligible. Difficulty in swallowing solid food is usually only slight, but occasionally a transient aphagia necessitates the administration of food by tube for a few days or weeks. On examination, the palate on the affected side is lax, and the uvula deviates to the opposite side on phonation. The palatal reflex is absent on the affected side. Lesions of the nucleus ambiguus on both sides cause complete aphonia and aphagia. Bilateral destruction of this nucleus is rare, except in the terminal stages of amyotrophic lateral sclerosis (ALS). Selective destruction of cells in the nucleus ambiguus may occur in syringobulbia or intramedullary tumors, consequently causing paralysis of the vocal cords in adduction. The patient can talk and swallow without difficulty, but inspiratory stridor and dyspnea may be severe enough to require tracheotomy. Unilateral lesions of the dorsal motor nucleus are not accompanied by any symptoms of autonomic dysfunction. Bilateral lesions may be life-threatening. The nucleus of the tenth nerve may also be damaged by infections (especially acute poliomyelitis), intramedullary tumors, and vascular lesions. It may be involved in polyneuropathy, especially in the diphtheritic and Guillain-BarrĂŠ forms. Injury to the pharyngeal branches of the nerve results in dysphagia. Lesions of the superior laryngeal nerve produce anesthesia of the upper part of the larynx and paralysis of the cricothyroid muscle. The voice is weak and easily tires. Involvement of the recurrent laryngeal nerve, which is frequent with aneurysms of the aorta and occasionally occurs after operations in the neck, causes hoarseness and dysphonia as a result of paralysis of the vocal cords. Complete paralysis of both recurrent laryngeal nerves produces aphonia and inspiratory stridor. Partial bilateral paralysis may produce a paralysis of both abductors with severe dyspnea and inspiratory stridor; it does not cause any alteration in the voice, however. Unilateral lesions of the vagus nerve do not produce any constant disturbance of the autonomic functions of the nerve. The heart rate may be unchanged, slowed, or accelerated. The respiratory rhythm is not affected, and no significant disturbance in the action of the gastrointestinal tract results. Involuntary spasm of the vocal cords (spastic dysphonia or laryngeal dystonia) is of uncertain cause, but it interferes with speech. Injection of botulinum toxin is an effective treatment. Eleventh (Spinal Accessory) Nerve The spinal portion of the eleventh nerve innervates the sternocleidomastoid and part or all of the trapezius muscles. The fibers from the accessory portion of the nerve originate in the nucleus ambiguus, travel with the tenth nerve through the jugular foramen, and eventually merge with the axons from motor fibers from the upper four cervical levels. Fibers from the nucleus ambiguus portion innervate the larynx. Fibers from the spinal portion pass along the carotid artery, penetrate and innervate the sternocleidomastoid muscle, and emerge in the middle of that muscle at its posterior border, crossing the posterior triangle of the neck to innervate the upper portion of the trapezius. Lesions of the spinal portion produce weakness and atrophy of the trapezius muscle, impairing rotary movements of the neck and chin to the opposite side and weakness of shrugging movements of the shoulder. Weakness of the upper portion of the trapezius results in winging of the scapula, which must be differentiated from that produced by weakness of the serratus anterior. Scapular winging from weakness of the trapezius is present at rest (arms at side) and becomes worse on abduction of the shoulder. Scapular winging from weakness of the serratus anterior is negligible at rest and worsens during flexion of the shoulder. The nucleus of the eleventh nerve may be destroyed by infections and degenerative disorders in the medulla, such as syringobulbia or ALS; the peripheral portion of the nerve may be involved in polyneuropathy, meningeal infection, extramedullary tumor (e.g., meningioma and neurinoma), or destructive processes in the occipital bone. Because of its passage through the posterior triangle of the neck, the nerve is susceptible to damage during lymph node biopsy, cannulation of the internal jugular vein, or carotid endarterectomy. The muscles supplied by this nerve are frequently involved in myotonic muscular dystrophy, polymyositis, and myasthenia gravis. Twelfth (Hypoglossal) Nerve The hypoglossal nerve is the motor nerve to the tongue. The nucleus in the medulla or the peripheral nerve portion may be injured by all the disorders mentioned in connection with the tenth and eleventh nuclei. Occlusions of the short branches of the basilar artery that nourish the paramedian area of the medulla cause paralysis of the tongue on one side and of the arm and leg on the opposite side ( alternating hemiplegia). Unilateral injury to the nucleus results in atrophy and paralysis of the muscles of one-half of the tongue. When the tongue is protruded, it deviates toward the paralyzed side, and while it is protruded, movement toward the normal side is absent or weakly performed. When the tongue lies on the floor of the mouth, it deviates slightly toward the healthy side, and movement of the tongue toward the back of the mouth on this side is impaired. Fibrillation of the muscles is seen in chronic processes involving the hypoglossal nucleus (e.g., syringobulbia, ALS). Bilateral paralysis of the nucleus or nerve produces atrophy of both sides of the tongue and paralysis of all movements, with severe dysarthria and resultant difficulty in manipulating food in the process of eating. The tongue is only rarely affected by lesions in the cerebral hemispheres or corticobulbar connections. Homolateral weakness of the tongue may accompany severe

hemiplegia. Such weakness appears as a slight deviation of the tongue to the paralyzed side when it is protruded. Moderate weakness of the tongue may accompany pseudobulbar palsy but is never as severe as the weakness seen with destruction of both medullary nuclei. Tremor of the tongue is seen in chronic alcoholism. Apraxia of the tongue (i.e., inability to protrude the tongue on command but preservation of the associated movements in eating or licking of the lips) frequently accompanies motor aphasia.

PERIPHERAL NERVES The peripheral nerves are subject to injury by pressure, constriction by fascial bands, or trauma associated with injection of drugs, perforating wounds, fractures of the bones, or stretching of the nerves. Isolated or multiple nerve paralysis may also be associated with a reaction to the injection of serum or to some toxic or metabolic disorders. The radial, common peroneal, ulnar, and long thoracic nerves are subject to damage by external pressure. The median nerve is most frequently affected by constriction by fascial bands at the wrist. The axillary nerve is commonly affected in an allergic reaction to injections of serum. The sciatic nerve is affected by direct injection of drugs. Any peripheral nerve may be damaged by perforating wounds or fractures of the bones. The frequency of involvement of the peripheral nerves by trauma is shown in Table 68.3.

TABLE 68.3. INCIDENCE OF PERIPHERAL NERVE LESIONS BY TRAUMA

Nerves of the Arm Radial Nerve The radial nerve arises from the posterior secondary trunk of the brachial plexus (C-5 to C-8). It is predominantly a motor nerve and innervates the chief extensors of the forearm, wrist, and fingers (Table 68.4).

TABLE 68.4. MUSCLES INNERVATED BY THE RADIAL NERVE

The radial nerve may be injured by cuts, gunshot wounds, callus formation after fracture of the humerus, pressure of crutches, or pressure against some hard surface, especially in sleep ( “Saturday night palsy�). A complete lesion of the nerve in the axilla is characterized by paralysis of the triceps and abolition of the triceps reflex, in addition to the other signs of radial nerve palsy reviewed in the following. Lesions of the radial nerve in the axilla are usually accompanied by evidence of injury to other nerves in this region. When the nerve is injured in the posteromedial surface of the arm, one or more of the branches to the triceps may be spared so that weakness of extension of the forearm is minimal. The most common site of injury to the radial nerve is in the middle one-third of the arm proximal to the branch to the brachioradialis muscle. Lesions of the nerve at this level result in weakness of flexion of the forearm caused by paralysis of the brachioradialis muscle, which is a stronger flexor of the forearm than of the biceps, and paralysis of extension of the wrist, thumb, and fingers at the proximal joints. Extension at the distal phalanges is performed by the interosseus muscles. There is weakness of adduction of the hand as a result of loss of action of the extensor carpi ulnaris and loss of supination when the forearm is extended, because the supinating action of the biceps is evident only when the forearm is flexed. In addition, there is an apparent weakness of flexion of the fingers. This weakness is not real and is a result of faulty posture of the hand. When the wrist is passively extended, the fingers have normal power of flexion. Sensory loss associated with lesions of the radial nerve is slight and is confined in most cases to a small area on the posterior radial surface of the hand and of the first and second metacarpals of the thumb and the index and middle fingers. Lesions of the nerve or its branches in the forearm or wrist are accompanied by fragments of the syndrome previously described, according to the site of the lesion. Complete lesions of the radial nerve are followed by atrophy of the paralyzed muscles. Vasomotor or trophic disturbances are rare, unless there is an associated vascular lesion. Causalgia rarely follows partial injury to the nerve. Median Nerve The median nerve comprises fibers from the sixth, seventh, and eighth cervical nerves and first thoracic roots. It arises in two heads (lateral and medial cords), derived from the upper and lower trunks of the brachial plexus. It has important motor and sensory functions. The following movements are controlled by this nerve: pronation of the forearm by the pronator quadratus and pronator teres, flexion of the hand by the flexor carpi radialis and palmaris longus, flexion of the thumb and the index and middle fingers by the superficial and deep flexors, and opposition of the thumb ( Table 68.5). The sensory region of the median nerve comprises the radial side of the palm of the hand, the volar surface of the thumb and the index and middle fingers, the radial one-half of the ring finger, the dorsal surface of the distal phalanx of the thumb, and the middle and terminal phalanges of the index and middle fingers.

TABLE 68.5. MUSCLES INNERVATED BY THE MEDIAN NERVE

Injury to the median nerve in the arm is characterized by loss of ability to pronate the forearm, weakness of flexion of the wrist, paralysis of flexion of the thumb and the index finger, weakness of flexion of the middle finger, paralysis of opposition of the thumb, atrophy of the muscles of the thenar eminence, and loss of sensation in an area somewhat smaller than that of the anatomic distribution of the nerve. Lesions of the median nerve at the wrist cause paralysis and atrophy of the thenar muscles and sensory loss in the characteristic distribution. There is absolute paralysis of few movements of the wrist or fingers in isolated lesions of the median nerve because of the compensatory action of unparalyzed muscles. Pronation can be accomplished by the action of the deltoid in holding the arm outward when the forearm is flexed and by rotation of the arm inward by the subscapularis when the arm is extended. Flexion of the wrist can be performed by the action of the flexor carpi ulnaris with deviation of the hand toward the ulnar side of the arm. There is absence of flexion in the index and the middle fingers, although the middle finger is usually influenced by movements of the ring finger and its deep flexor may be supplied by the ulnar nerve. In addition, flexion of the proximal phalanx of the fingers, including the index finger in association with extension of the distal phalanges, is possible through the action of the interosseus muscles. Although the opponens pollicis is paralyzed, feeble movements of opposition can be made by energetic contraction of the adductors that causes the thumb to move to the ulnar edge of the hand by pressing against the base of the fingers. Partial lesions of the median nerve are more frequent than complete interruption, with dissociation in the degree of involvement of the various muscles supplied by the nerve and with little or no sensory loss. Flexion of the index finger and opposition of the thumb are the movements that are usually most affected in partial lesions. Vasomotor disturbances are common with median nerve lesions, probably because of associated lesions of blood vessels. The syndrome of causalgia is most commonly associated with lesions of the median nerve. A slowly developing atrophy limited to the muscles of the outer radial side of the thenar eminence has been described by the term partial thenar atrophy. The atrophy is often bilateral and exceeds the motor weakness. Pain, paresthesia, and a mild degree of impairment of sensation in the distribution of the nerves with or without motor weakness are fairly common as a result of compression of the nerve by the transverse carpal segment ( carpal tunnel syndrome). The pain is severe, often waking the patient from sleep. The pain is usually in the thumb and the index finger but may spread to other fingers or up the arm to the axilla. These symptoms most commonly occur in middle-aged persons and are often associated with arthritis or other changes in the tendons and connective tissues of the wrists in amyloid disease, myxedema, gout, or acromegaly. Surgical division of the transverse ligament results in relief of the pain and paresthesia and gradual decrease of the weakness. Ulnar Nerve The ulnar nerve is the main branch of the lower cord of the brachial plexus. The fibers arise from the eighth cervical and first thoracic segments. The motor fibers innervate the muscles listed in Table 68.6. The sensory portion of the nerve supplies the skin on the palmar and dorsal surfaces of the little finger, the inner one-half of the ring finger, and the ulnar side of the hand.

TABLE 68.6. MUSCLES INNERVATED BY THE ULNAR NERVE

The ulnar nerve is frequently injured by gunshot wounds, stab wounds, and fractures of the lower end of the humerus, olecranon, or head of the radius. The nerve may be compressed in the axilla by a cervical rib. More frequently, it is compressed at the elbow in sleep or as an occupational neuritis in workers who rest their elbows on hard surfaces for prolonged periods. Complete lesions of the ulnar nerve are characterized by weakness of flexion and adduction of the wrist and of flexion of the ring and the little fingers, paralysis of abduction and opposition of the little finger, paralysis of adduction of the thumb, and paralysis of adduction and abduction of the fingers. There is atrophy of the hypothenar muscles and the interossei. Atrophy of the first dorsal interosseous is especially obvious, seen on the dorsum of the hand between the thumb and the index finger. Sensory loss is greatest in the little finger and is present to a lesser extent on the inner side of the ring finger. There is clawing of the hand. Dissociated paralysis of the muscles supplied by the ulnar nerve may occur with partial lesions of the nerve in the arm or forearm. Trophic and vasomotor symptoms are not prominent after complete lesions of the nerve. There may be some hyperkeratosis or changes in the palmar fascia. Irritative lesions may be accompanied by pain, but injuries to the ulnar nerve are only rarely accompanied by causalgia. The diagnosis of ulnar palsy can usually be made without difficulty by the posture of the hand, which is always clawed, by atrophy of the hypothenar eminence and the first dorsal interosseous, and by the characteristic distribution of paralysis. One diagnostic sign of ulnar palsy, the Froment sign, is flexion of the terminal phalanx of the thumb when the patient attempts to hold a sheet of paper between the thumb and the index finger (because the thumb cannot be adducted). Musculocutaneous Nerve The musculocutaneous nerve is the main branch of the upper trunk of the brachial plexus. Its fibers arise in the fifth and sixth cervical segments. The musculocutaneous nerve is a mixed nerve, innervating the coracobrachialis, biceps brachii, and brachialis muscles and transmitting cutaneous sensation from the anterior outer part and a small area on the posterior outer surface of the forearm. Isolated injuries of the nerve are rare. It may be involved in traumatic lesions of the brachial plexus. Lesions of the musculocutaneous nerve produce weakness of flexion and supination of the forearm, a small area of hypesthesia or anesthesia on the anterior outer

surface of the forearm, atrophy of the muscles on the anterior surface of the arm, and loss of the biceps reflex. Flexor movements of the forearm can still be vigorously performed by the brachioradialis muscle, which is innervated by the radial nerve. If flexion is performed against resistance, palpation reveals that the biceps muscle is inactive. If the forearm is kept in supination, forearm flexion is impossible. Because the biceps is the chief supinator of the forearm, this movement is paralyzed. Loss of function of the coracobrachialis muscle is compensated for by the action of other adductor muscles of the arm. Axillary Nerve The axillary nerve is the last branch of the posterior cord of the brachial plexus, including fibers from the fifth and sixth cervical segments. It innervates the deltoid muscle and transmits cutaneous sensation from a small area on the lateral surface of the shoulder. Lesions of the axillary nerve caused by trauma or by fracture or dislocation of the head of the humerus are usually associated with injury to the brachial plexus. The axillary nerve may be involved alone or in combination with other nerves in the neuritis that follows serum (especially antitetanus) therapy. Lesions of the axillary nerve are characterized by loss of power in outward, backward, and forward movements of the arm because of paralysis of the deltoid muscle. The area of hypesthesia or anesthesia is inconstant and is much smaller than the anatomic distribution of the nerve. Long Thoracic Nerve The long thoracic nerve arises from the fifth, sixth, and seventh cervical roots. It is the motor nerve to the serratus anterior muscle. Lesions of the long thoracic nerve are most common in men who do heavy labor. The nerve may be injured by continued muscular effort with the arm extended or by the carrying of heavy sharp-cornered objects on the shoulder (“hod carrier's palsy”). Injury of the nerve following acute or chronic trauma is characterized by weakness in elevation of the arm above the horizontal plane. Winging of the scapula is a constant sign when the arm is fully abducted or elevated anteriorly ( Fig. 68.2). Winging is usually absent when the arm is held at the side.

FIG. 68.2. Paralysis of the serratus magnus muscle with winging of the scapula.

Brachial Cutaneous and Antebrachial Cutaneous Nerves The brachial and antebrachial cutaneous nerves, branches of the plexus (C8-T1), transmit sensory impulses from the inner surface of the arm and upper two-thirds of the forearm. These nerves are rarely affected, except in injuries of the medial cord of the brachial plexus. Lesions of these nerves produce hypesthesia on the inner surface of the arm and forearm. Suprascapular Nerve The suprascapular nerve arises from the upper trunk of the brachial plexus. Most of its fibers come from the fifth and sixth cervical roots. It is primarily motor and innervates the supraspinatus and infraspinatus muscles. Isolated lesions of the nerve are rare. It may be wounded directly, injured in falls, or stretched by muscular overaction. It may be involved in association with the axillary nerve in serum reactions, or it may be injured in traumatic lesions of the brachial plexus. Lesions of the nerve produce an atrophic paralysis of the supraspinatus and infraspinatus muscles. Weakness of movements performed by these muscles (i.e., abduction and external rotation of the shoulder) is masked by the action of the deltoid and teres minor muscles. Brachial Plexus The fifth, sixth, seventh, and eighth cervical roots and the first thoracic root contribute to the formation of the brachial plexus ( Fig. 68.3). The roots form three trunks: upper, middle, and lower. The upper is composed of fibers from C-5 and C-6, the middle receives fibers from C-7, and the lower receives fibers from C-8 and T-1. The redistribution of fibers from the trunks results in the formation of the cords (lateral, posterior, and medial) that contribute to the formation of the peripheral nerves as follows: lateral cord, the musculocutaneous and the lateral head of the median nerve; posterior cord, the axillary and radial nerves; the medial cord, the brachial and antebrachial cutaneous nerves, the ulnar nerve, and the medial head of the median nerve. In addition to these major nerves, which are formed by fibers in the secondary trunks, collateral branches from the roots and trunks form nerves that innervate the shoulder and scapular muscles and supply fibers to the interior cervical ganglion.

FIG. 68.3. Brachial plexus. (From Haymaker W, Woodhall B. Peripheal nerve injuries. Philadelphia: WB Saunders, 1945; with permission.)

The roots or trunks of the brachial plexus may be damaged by cuts, gunshot wounds, or direct trauma ( Fig. 68.4). They may be compressed by tumors or aneurysms or stretched and torn by violent movements of the shoulder in falls, dislocations of the shoulder, the carrying of heavy packs on the shoulder (“rucksack paralysis”), and traction in delivery at birth.

FIG. 68.4. Traumatic avulsion of lower cervical nerve roots. Iophendylate cervical myelogram (anteroposterior view) demonstrates contrast in avulsed right C-8 and T-1 root pouches. (Courtesy of Dr. S.K. Hilal and Dr. J.A. Bello.)

Unilateral or bilateral disorders of the brachial plexus may follow respiratory infections. The combination of local pain, weakness, and wasting of muscle had led to the popular terms neuralgic amyotrophy and brachial plexopathy. Weakness is maximal within a few days. The cerebrospinal fluid is normal. A similar disorder may affect the lumbosacral plexus. Myelography excludes intraspinal lesions. Nerve conduction studies may localize lesions of the brachial plexus. The condition remains stable for days or weeks and then improves. Some patients recover completely; others are left with moderate or severe disability. Various complex syndromes result from injuries to the plexus. Only the trunk syndromes are reviewed here. A minute examination of muscular and sensory disability must be made and studied in connection with anatomic charts of the plexus to determine the site of the lesion and whether the fibers have been injured at their point of emergence from the spinal cord or after the formation of the primary or secondary trunks ( Table 68.7, Table 68.8, and Table 68.9).

TABLE 68.7. INNERVATION OF THE MUSCLES OF THE SHOULDER GIRDLE

TABLE 68.8. INNERVATION OF MUSCLES OF THE ARM AND FOREARM

TABLE 68.9. INNERVATION OF THE MUSCLES OF THE HAND

Radicular Syndromes (Roots and Primary Trunks) The syndromes of the roots and primary trunks are essentially those of the roots involved, but partial paralysis and incomplete sensory loss are common because many muscles of the arm receive innervation from two or more roots and there are extensive substitutions among the various roots. Upper Radicular (Erb-Duchenne) Syndrome Lesions of the upper roots (fourth, fifth, and sixth cervical roots or upper trunk) are characterized by paralysis of the deltoid, biceps, brachialis anticus, brachioradialis, pectoralis major, supraspinatus, infraspinatus, subscapularis, and teres major muscles. If the lesion is near the roots, the serratus magnus, rhomboids, and levator anguli scapulae are also paralyzed. The motor disability resulting from lesions of the upper radicular group is essentially paralysis of flexion of the forearm and of abduction and internal and external rotation of the arm. There is also weakness or paralysis of apposition of the scapula and backward-inward movements of the arm. Sensory loss is incomplete and consists of hypesthesia on the outer surface of the arm and forearm. The biceps reflex is absent, and percussion of the styloid process of the radius produces flexion of the fingers instead of the normal flexion of the forearm.

Middle Radicular Syndrome Injury to the seventh cervical root or the middle trunk causes paralysis of the muscles supplied by the radial nerve with the exception of the brachioradialis, which is spared entirely. Weakness is essentially similar to that seen in paralysis of the radial nerve below the origin of the fibers to the brachioradialis or in lead palsy. Sensory loss is inconstant and, when present, is limited to hypesthesia over the dorsal surface of the forearm and the external part of the dorsal surface of the hand. Lower Radicular (Klumpke) Syndrome Injury to the lower primary trunk or eighth cervical and first thoracic root is characterized by paralysis of the flexor carpi ulnaris, the flexor digitorum, the interossei, and the thenar and hypothenar muscles. The motor disability is similar to that of a combined lesion of the median and ulnar nerves with a flattened or simian hand. The sensory disturbance is hypesthesia on the inner side of the arm and forearm and on the ulnar side of the hand. The triceps reflex is abolished. If the communicating branch to the inferior cervical ganglion is injured, there is paralysis of the sympathetic nerves, with resulting Horner syndrome. Cord Syndromes of the Brachial Plexus Lesions of the cords of the brachial plexus produce motor and sensory disturbances that resemble those seen after injuries to two or more peripheral nerves. The syndrome of the lateral cord is a combination of the signs and symptoms caused by injury to the musculocutaneous nerve and the lateral head of the median nerve. These injuries are accompanied by a paralysis of the pronator teres, almost complete paralysis of the flexor carpi radialis, and weakness of the flexor pollicis and opponens. Injury to the posterior cord produces paralysis similar to that resulting from injury to the radial and axillary nerves. The syndrome of the medial cord is the same as that of the ulnar nerve combined with a paralysis of flexion of the fingers as a result of injury to the medial head of the median nerve. Ischemic Paralysis of the Arm Paralysis of arm muscles may follow injury to large arteries. Ischemic paralysis may follow ligation of the major vessels when the collateral circulation is inadequate, or it may follow prolonged constriction of the arm by plaster casts. In the initial stages of ischemic paralysis, the distal part of the limb is cyanotic and edematous. Active movements of the finger and wrist muscles are possible but are of a limited range. There is diminution of cutaneous sensibility; all stimuli are poorly localized and have a painful quality. With the passage of time, the cyanosis and edema disappear, the skin becomes smooth and shiny, and the muscles undergo fibrotic changes; anesthesia extends in a glovelike distribution to the wrist or middle of the forearm. The hand is held extended, and the fingers are slightly flexed except when there are associated nerve lesions. Ischemic paralysis can be differentiated from paralysis caused by lesions of the nerves by the absence of pulsations in the radial artery, the glovelike distribution of sensory loss, which does not correspond to that of any peripheral nerve, the fibrous consistency of the tissues, and, in some cases, persistence of feeble imperfect movements of some of the muscles. Ischemic paralysis is frequently permanent. Improvement in some patients can be obtained by hot baths, massage, passive movements, and electrical stimulation.

NERVES OF THE LEG Obturator Nerve The obturator nerve is a mixed nerve that originates in the lumbar plexus from the second, third, and fourth lumbar roots. It transmits cutaneous sensation from a small area on the inner surface of the middle side of the hip, thigh, and knee joint. It innervates the obturator externus muscle, adductor longus, adductor brevis, gracilis, and adductor magnus muscles. Lesions of the obturator nerve are uncommon. It may be injured by pressure within the pelvis by tumors, obturator hernias, or the fetal head in difficult labor. Injuries to the obturator nerve result in severe weakness of adduction and, to a lesser extent, internal and external rotation of the thigh. Pain in the knee joint is sometimes caused by pelvic involvement of the geniculate branch of the obturator. Iliohypogastric Nerve The iliohypogastric nerve is a mixed nerve that originates from the uppermost part of the lumbar plexus and is derived from the twelfth thoracic and first lumbar roots. It transmits cutaneous sensation from the outer and upper parts of the buttocks and the lower part of the abdomen and supplies partial innervation to the internal oblique and transversalis muscles. Lesions of the iliohypogastric nerve are rare. It may be divided by incisions in kidney operations or together with the ilioinguinal nerve in operations in the inguinal region. Lesions of these nerves do not produce any significant motor loss, and there is only a small area of cutaneous anesthesia. Ilioinguinal Nerve The ilioinguinal nerve, a branch of the lumbar plexus, arises from the twelfth thoracic and first lumbar roots. It transmits cutaneous sensation from the upper inner portion of the thigh, the pubic region, and the external genitalia. Motor filaments are given off to the transversalis, internal oblique, and external oblique muscles. The ilioinguinal nerve is usually injured in connection with the iliohypogastric nerve. Genitofemoral Nerve This nerve originates from the second lumbar root and is primarily a sensory nerve. It transmits cutaneous sensation from an oval area on the thigh in the region of the Scarpa triangle and from the scrotum and the contiguous area of the inner surface of the thigh. Lesions of the genitofemoral nerve are rare. Irritative lesions of the nerve in the abdominal wall are accompanied by painful hyperesthesia at the root of the thigh and the scrotum. Lateral Cutaneous Nerve of Thigh This nerve is formed by fibers from the second and third lumbar roots. It crosses beneath the fascia iliaca to emerge at the anterosuperior iliac spine, descends in the thigh beneath the fascia lata, and divides into two branches. The posterior branch passes obliquely backward through the fascia lata and transmits cutaneous sensation from the superior external part of the buttocks. The anterior branch, which is more important clinically, pierces the fascia lata through a small fibrous canal about 10 cm below the ligament and transmits cutaneous fibrous sensation from the outer surface of the thigh. The anterior portion of the nerve is occasionally the site of meralgia paresthetica, which is a sensory neuritis with dysesthesia in the nature of tingling, burning, prickling, or pins-and-needles sensations with or without sensory loss in the cutaneous distribution of the nerve. The long superficial course exposes it to various forms of trauma, but in most patients there is no history of trauma to explain the onset of symptoms. Various factors said to play a contributing role include pressure of tight belts or corsets and intermittent stretching by extensor movements of the thigh during walking. The involvement is unilateral in most cases. Men are affected about three times as frequently as women. The diagnosis is not difficult when the dysesthesia is limited to the distribution of the anterior division of the nerve. Pains in the lateral surface of the thigh caused by spinal lesions or pelvic tumors must be excluded by appropriate diagnostic studies. The course of meralgia paresthetica is variable. Occasionally, symptoms spontaneously disappear after a few weeks. In most patients, they clear up by the removal of tight belts and avoidance of excessive walking. It is rarely necessary to split the fascia lata at the point of emergence of the nerve or correct the angulation of the

nerve at the iliac spine. Femoral Nerve The femoral nerve arises from the second, third, and fourth lumbar nerves. It innervates the iliacus, psoas magnus, pectineus, sartorius, and quadriceps femoris muscles. It also transmits cutaneous sensation from the anterior surface of the thigh and, by its internal saphenous branch, from the entire inner surface of the leg and the anterior internal surface of the knee. Traumatic lesions of the femoral nerve are uncommon. It may be compressed by tumors and other lesions in the pelvis, or it may be injured by fractures of the pubic ramus or femur. Often, there is no adequate explanation for the occurrence of an isolated femoral nerve palsy. In such cases, the nerve lesion is presumed to be a result of some toxic factor, such as diabetes, typhoid, or gout. Injury to the femoral nerve produces paralysis of extension of the leg and weakness of flexion of the thigh. When the patient stands erect, the leg is held stiffly extended by contraction of the tensor fasciae femoris and the gracilis. Walking on level ground is possible as long as the leg can be kept extended, but if the slightest flexion occurs, the patient sinks down on the suddenly flexed knee. Climbing stairs or walking uphill is difficult or impossible. The quadriceps reflex is lost on the affected side, and cutaneous sensation is impaired in an area somewhat smaller than the anatomic distribution of the nerve. Paralysis of the femoral nerve must be distinguished from hysterical paralysis and reflex muscular atrophies that follow fractures of the femur or lesions of the knee joint. Hysteric paralysis can be diagnosed by the presence of the knee jerk and by special tests. In hysteric paralysis, when the patient is in the recumbent position and attempts to elevate the “paralyzed� limb, there is an absence of the normal fixing movements (downward pressure of the heel) of the opposite leg ( Hoover sign). Orthopedic appliances that fix the knee joint in extension are of value in the treatment of femoral nerve paralysis. Transposition of tendons should be considered if paralysis persists. Sciatic Nerve The sciatic nerve is the largest nerve in the body. Its terminal branches consist of two distinct nerves, which are antagonists of each other: the common peroneal (external popliteal) and the tibial (internal popliteal) nerves. The common peroneal arises from the posterior and the tibial nerve from the anterior portion of the sacral plexus (i.e., L-4 to S-3). The main trunk of the sciatic nerve innervates the semitendinosus, the long and short heads of the biceps, the adductor magnus, and the semimembranosus muscles. The terminal branches of the nerve are considered separately in the following sections. Total paralysis of muscles innervated by the sciatic nerve is rare; even with a lesion in the thigh, the common peroneal nerve is often more severely damaged than the tibial nerve. The sciatic nerve is frequently injured by gunshot, shrapnel, or stab wounds, although it is rarely injured in civilian life. Partial rupture may result from violent muscular contractions, or the nerve may be injured by fractures of the pelvis or femur, dislocations of the hip, pressure of the fetal head on the plexus in the mother's pelvis, or pelvic tumors. The nerve is sometimes inadvertently injured by intramuscular injection of drugs, especially in infants. Total involvement of the sciatic nerve produces complete paralysis of all movements of the ankle and toes, as well as weakness or paralysis of flexion of the leg. The patient can stand, but the leg must be raised unduly high to correct for the footdrop when the patient walks (steppage gait). The ankle jerk is lost, and cutaneous sensation is lost on the outer surface of the leg, on the instep and sole of the foot, and over the toes. Vasomotor and trophic disturbances may also be present. Sciatica is a term used to describe pain in the low back and in the leg along the course of the nerve. The symptoms may be caused by involvement of any portion of the nerve, including the intraspinal roots. In the older literature, the list of causes of sciatica was long and included alcohol, arsenic, lead, diabetes, gout, syphilis, gonorrhea, phlebitis, tuberculosis, arthritis of the sacroiliac joint or of the hip, fibrositis, gluteal bursitis, osteitis deformans, pelvic tumors, and inflammatory neuritis. Although pain in the low back that extends down the posterior surface of the leg may be associated with pathologic processes in the pelvis or lower spine, in most patients sciatic pain is caused by a ruptured intervertebral disc. The distinctive features of ruptured intervertebral discs are considered more fully in Chapter 65. Sciatica is most common in the third to sixth decades of life and occurs about three times more frequently in men than in women. The pain of sciatica varies in severity. In some patients, there is a feeling of discomfort in the low back and down the posterior surface of the leg. In others, the pain may be so intense that it totally incapacitates the afflicted individual. The pain may be limited to the buttocks and sacroiliac region, it may extend only to the knee, or it may involve the calf and outer surface of the foot. There is usually no weakness, but the patient may keep the knee slightly flexed in walking to prevent stretching of the nerve. On examination, the nerve may be sensitive to pressure at any point along its course. Any movement of the leg that stretches the nerve is accompanied by pain and involuntary resistance to the movement. There is limitation of straight leg raising on the affected side, and complete extension of the leg is not possible when the hip is flexed. Similar movements of the unaffected limb can be performed more fully but may cause slight pain on the opposite side. Sensory loss and loss of the Achilles reflex are rarely found in sciatica associated with osteoarthritis of the spine or sacroiliac joint, and suggest involvement of the nerve roots in the spinal canal. The clinical course of sciatica depends on the nature of the underlying disorder. In most patients, the symptoms last for weeks or months and disappear, only to recur after a remission of months or years. Diagnosis of sciatic and low back pain may be difficult. Diagnosis rests on the history, findings on examination, and CT or MRI of the spine. Contrast CT-myelography may be needed. The results of these studies can determine whether the symptoms are caused by a ruptured intervertebral disc, primary or metastatic tumor of the spine, osteoarthritic changes, or other causes. The treatment of sciatica is essentially that of the underlying cause. The criteria for the operative removal of ruptured intervertebral discs are reviewed in Chapter 65. The treatment of causalgic pain after trauma to the sciatic nerve is reviewed in Chapter 70. Common Peroneal (External Popliteal) Nerve The common peroneal is a mixed nerve that innervates the extensor muscles of the ankle and toes and the evertor (abductor) muscles of the foot. It transmits cutaneous sensation from the outer side of the leg, the front of its lower one-third, the instep, and the dorsal surface of the four inner toes over their proximal phalanges. The common peroneal nerve is more frequently subjected to trauma than any other nerve of the body. It may be damaged by wounds near the knee or in the trunk of the sciatic nerve in the thigh. Because of its superficial position in close relation to the head and neck of the fibula, it is readily injured by pressure against hard objects while the patient is asleep, intoxicated, or under anesthesia. It may be stretched by prolonged squatting or compressed by crossing of the knees during sitting or by lying on a hard or uneven mattress during sleep, especially in acutely or chronically ill patients. Many cases of simple pressure neuropathy of the common peroneal nerve are falsely recorded as being caused by malarial, typhoid, or tuberculous neuritis. The nerve may be injured by ganglion cysts, which can usually be palpated at the head of the fibula. Compression of the nerve in this way leads to footdrop with burning pains on the lateral aspect of the leg and in the ankle or foot. Symptoms can be relieved by excision of the cyst. Paralysis of the common peroneal nerve results in footdrop and inversion of the foot. The patient cannot dorsiflex the ankle, straighten or extend the toes, or evert the foot. The gait is characterized by overflexion of the knee in the steppage gait. Sensation is lost in an area less extensive than the anatomic distribution of the nerve, or it may be entirely absent when the injury is caused by pressure. Vasomotor and trophic disturbances consisting of swelling, local cyanosis, and anhidrosis may also be present. Complete or partial recovery is the rule when the paralysis is caused by transient pressure. Treatment consists of physiotherapy and the use of a foot brace to overcome the footdrop. Tibial (Internal Popliteal) Nerve The tibial branch of the sciatic nerve innervates the muscles on the posterior surface of the leg and the plantar muscles. It transmits sensation from the entire sole of

the foot, the back and lower part to the middle one-third of the leg, the outer dorsal surface of the foot, and the terminal phalanges of the toes. Lesions of the tibial nerve are uncommon. It may be injured by gunshot wounds or fractures of the legs. A complete lesion of the nerve is characterized by paralysis of plantar flexion and adduction of the foot, flexion and separation of the toes, and sensory loss in an area less extensive than the anatomic distribution of the nerve. The ankle jerk and plantar reflex are lost. Causalgia is occasionally seen. Compression of the posterior tibial branch at the medial malleolus produces pain and paresthesia in the soles of the feet in a manner similar to compression of the median nerve at the wrist. Decompression results in the relief of symptoms. SUGGESTED READINGS General Aminofff MJ. Electromyography in clinical practice: clinical and electrodiagnostic aspects of neuromuscular disease, 3rd ed. New York: Churchill Livingstone, 1998. 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Phenomena due to misdirection of regenerating fibers of cranial, spinal and autonomic nerves: clinical observations. Arch Surg 1938;36:480–496. Friedman AP, Merritt HH. Damage to cranial nerves resulting from head injury. Bull Los Angeles Neurol Soc 1944;9:135–139. Furuta Y, Fukuda S, Chida E, et al. Reactivation of herpes simplex virus type 1 in patients with Bell's palsy. J Med Virol 1998;54:162–166. Geller BD, Hallett M, Ravits J. Botulinum toxin therapy in hemifacial spasm: clinical and electrophysiologic studies. Muscle Nerve 1989;12:716–722. Glocker FX, Krauss JK, Deuschl G, et al. Hemifacial spasm due to posterior fossa tumors: the impact of tumor location on electrophysiological findings. Clin Neurol Neurosurg 1998;100:104–111. Gouda JJ, Brown JA. Atypical facial pain and other pain syndromes: differential diagnosis and treatment. Neurosurg Clin N Am 1997;8:87–100. Jankovic J, Ford J. Blepharospasm and orofacial–cervical dystonia: clinical and pharmacological findings in 100 patients. Ann Neurol 1983;13:402–411. Jannetta P. Observations on the etiology of trigeminal neuralgia, hemifacial spasm, acoustic nerve dysfunction and glossopharyngeal neuralgia: definitive microsurgical treatment and results in 11 patients. Neurochirurgie 1977;20:145–154. Jitpimolmard S, Tiamkao S, Laopaiboon M. Long–term results of botulinum toxin type A (Dysport) in the treatment of hemifacial spasm: a report of 175 cases. 1998;64:751–757.

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Juncos JL, Beal MF. Idiopathic cranial polyneuropathy: a 5–year experience. Brain 1987;110:197–212. Kalovidouris A, Mancuso AA, Dillon W. A CT–clinical approach to patients with symptoms related to the V, VII, IX–XII cranial nerves and cervical sympathetics. Radiology 1984;151:671–676. Kondo A. Follow–up results of microvascular decompression in trigeminal neuralgia and hemifacial spasm. Neurosurgery 1997;40:46–51. Kondziolka D, Perez B, Flickinger JC, et al. Gamma knife radiosurgery for trigeminal neuralgia: results and expectations. Arch Neurol 1998;55:1524–1529. Lecky BRF, Hughes RAC, Murray NMF. Trigeminal sensory neuropathy. Brain 1987;110:1463–1486. Leigh RJ, Zee DS. The neurology of eye movements, 2nd ed. Philadelphia: FA Davis Co, 1991. Lossos A, Siegal T. Numb chin syndrome in cancer patients: etiology, response to treatment, and prognostic significance. Neurology 1992;42:1181–1184. Ludlow CL, Naunton RF, Fujita M, et al. Effects of botulinum toxin injections on speech in adductor spasmodic dysphonia. Neurology 1988;38:1220–1225. Majoie CB, Hulsmans FJ, Castelijns JA, et al. Symptoms and signs related to the trigeminal nerve: diagnostic yield of MR imaging. Radiology 1998;209:557–562. Murakami S, Nakashiro Y, Mizobuchi M, et al. Varicella–zoster virus distribution in Ramsay Hunt syndrome revealed by polymerase chain reaction. Acta Otolaryngol 1998;118:145–149. Nadeau SE, Trobe JD. Pupil sparing in oculomotor palsy: a brief review. Ann Neurol 1983;13:143–148. Nielsen VK. Electrophysiology of the facial nerve in hemifacial spasm: ectopic/ephaptic excitation. Muscle Nerve 1985;8:545–555.

Pearce JM. Melkersson's syndrome. J Neurol Neurosurg Psychiatry 1995;58:340. Pollock BE, Gorman DA, Schomberg PJ, Kline RW. The Mayo Clinic gamma knife experience: indications and initial results. Mayo Clin Proc 1999;74:5–13. Portenoy RK, Duma C, Foley KM. Acute herpetic and postherpetic neuralgia: clinical review and current management. Ann Neurol 1986;20:651–664. Rush JA, Younge BR. Paralysis of cranial nerves III, IV and VI: cause and prognosis in 1,000 cases. Arch Ophthalmol 1981;99:76–79. Ryu H, Yamamoto S, Sugiyama K, et al. Hemifacial spasm caused by vascular compression of the distal portion of the facial nerve: report of seven cases. J Neurosurg 1998;88:605–609. Searles RP, Mladinich K, Messner RP. Isolated trigeminal sensory neuropathy: early manifestations of mixed connective tissue disease. Neurology 1978;28:1286–1289. Spillane JD, Wells CEC. Isolated trigeminal neuropathy. Brain 1959;82:391–416. Stevens H. Melkersson's syndrome. Neurology 1965;15:263–266. Tankere F, Maisonobe T, Lamas G, et al. Electrophysiological determination of the site involved in generating abnormal muscle responses in hemifacial spasm. Muscle Nerve 1998;21:1013–1018. Taylor FH. Idiopathic Bell's facial palsy: natural history defies steroid and surgical treatment. Laryngoscope 1985;95:406–409. Tenser RB. Trigeminal neuralgia: mechanisms of treatment. Neurology 1998;51:17–19. Troost BT, Daroff RB. The ocular motor defects in progressive supranuclear palsy. Ann Neurol 1977;2:397–403. Van Zandycke M, Martin JJ, Vande Gaer L, Van den Heyning P. Facial myokymia in the Guillain–Barré syndrome: a clinicopathologic study. Neurology 1982;32:744–748. Victor M, Dreyfus PM. Tobacco–alcohol ambylopia: further comments on its pathology. Arch Ophthalmol 1965;74:649–657. Wang A, Jankovic J. Hemifacial spasm: clinical findings and treatment. Muscle Nerve 1998;21:1740–1747. Wartenberg R. Hemifacial spasm: a clinical and pathological study. London: Oxford University Press, 1952. Willoughby EW, Anderson NE. Lower cranial nerve motor function in unilateral vascular lesions of the cerebral hemisphere. BMJ 1984;289:791–794. Peripheral Nerves Bowsher D. The management of postherpetic neuralgia. Postgrad Med J 1997;73:623–629. Buchthal F, Rosenfalck A, Trojaborg W. Electrophysiological findings in entrapment of the median nerve at the wrist and elbow. J Neurol Neurosurg Psychiatry 1974;37:340–360. Choi PD, Novak CB, Mackinnon SE, Kline DG. Quality of life and functional outcome following brachial plexus injury. J Hand Surg [Am] 1997;22:605–612. D'Amour ML, Lebrun LH, Rabbat A, et al. Peripheral neurological complications of aortoiliac vascular disease. Can J Neurol Sci 1987;14:127–130. Dawson DM. Entrapment neuropathies of the upper extremities. N Engl J Med 1993;329:2013–2018. Dubuisson A, Kline DG. Indications for peripheral nerve and brachial plexus surgery. Neurol Clin 1992;10:935–951. Friedman AH, Nashold BS Jr, Ovelmen–Levitt J. Dorsal root entry zone lesions for the treatment of postherpetic neuralgia. J Neurosurg 1984;60:1258–1262. Gilliatt RW. Acute compression block. In: Sumner AJ, ed. The physiology of peripheral nerve disease. Philadelphia: WB Saunders, 1980. Gilliatt RW, Willison RG, Dietz V, et al. Peripheral nerve conduction in patients with a cervical rib and band. Ann Neurol 1978;4:124–129. Gossett JG, Chance PF. Is there a familial carpal tunnel syndrome? An evaluation and literature review. Muscle Nerve 1998;21:1533–1536. Kline DG, Kim D, Midha R, et al. Management and results of sciatic nerve injuries: a 24–year experience. J Neurosurg 1998;89:13–23. Kori SH, Foley KM, Posner JB. Brachial plexus lesions in patients with cancer: 100 cases. Neurology 1981;31:45–50. Liguori R, Krarup C, Trojaborg W. Determination of the segmental sensory and motor innervation of the lumbosacral spinal nerves. Brain 1992;115:915–934. Mastroianni PP, Roberts MP. Femoral neuropathy and retroperitoneal hemorrhage. 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Seddon HJ. Peripheral nerve injuries: Medical Research Council special report, series no. 282. London: Her Majesty's Stationery Office, 1954. Thomas JE, Pipegras DG, Scheithauer B, et al. Neurogenic tumors of the sciatic nerve: a clinicopathologic study of 35 cases. Mayo Clin Proc 1983;58:640–647. Trojaborg W. Rate of recovery in motor and sensory fibres of the radial nerve. J Neurol Neurosurg Psychiatry 1970;33:625–638. Trojaborg W. Early electrophysiological changes in conduction block. Muscle Nerve 1978;1:400–403. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50:1837–1841. Watson CP, Vernich L, Chipman M, et al. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 1998;51:1166–1171. Wiles CM, Whitehead S, Ward AB, Fletcher CDM. Not tarsal tunnel syndrome: a malignant “triton” tumour of the tibial nerve.

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CHAPTER 69. THORACIC OUTLET SYNDROME MERRITT’S NEUROLOGY

CHAPTER 69. THORACIC OUTLET SYNDROME LEWIS P. ROWLAND Pathology Symptoms and Signs Diagnosis and Management Suggested Readings

The term thoracic outlet syndrome encompasses different syndromes that arise from compression of the nerves in the brachial plexus or blood vessels (subclavian or axillary arteries, or veins in the same area). The compressing lesions are also diverse. How often these lesions are actually responsible for symptoms and how the symptoms should be treated are matters of intense debate. Studies done mainly by orthopedists, vascular surgeons, and neurosurgeons have included reports on several hundred patients who were treated surgically for this syndrome. When neurologists write about this neurologic disorder, however, the tone is always skeptical, and the syndrome is described as exceedingly rare, with an annual incidence of about 1 per 1 million persons. The debate warrants separate consideration,although this is actually another disorder of the peripheral nervous system.

PATHOLOGY The T-1 and C-8 nerve roots and the lower trunk of the brachial plexus are exposed to compression and angulation by anatomic anomalies that include cervical ribs and fibrous bands of uncertain origin. Among the more imaginative lesions are those ascribed to hypertrophy of the scalenus muscles. Cervical ribs are commonly found in asymptomatic people, and it is difficult to assume that the mere presence of a cervical rib automatically explains local symptoms. In addition to the neural syndromes, the same anomalies may compress local blood vessels and cause vascular syndromes.

SYMPTOMS AND SIGNS Patients have pain in the shoulder, arm, or hand, or in all three locations. The hand pain is often most severe in the fourth and fifth fingers. The pain is aggravated by use of the arm, and “fatigue” of the arm is often prominent. There may or may not be hypesthesia in the affected area. Critics have divided cases into two groups: those with the “true” neurogenic thoracic outlet syndrome and those with the “disputed” syndrome. In the true syndrome, there are definite clinical and electrodiagnostic abnormalities. This syndrome is rare but is almost always caused by a cervical band extending from a cervical rib and compressing the C-8 and T-1 roots or lower brachial plexus. There is unequivocal wasting and weakness of muscles in the hand that are innervated by these segments, and results of electromyography and nerve conduction studies are compatible with the site of the nerve lesion. In the “disputed” form, there are no objective signs and no consistent laboratory abnormalities. Attempts to reproduce the syndrome by abduction of the arm (Adson test) or other maneuvers have repeatedly been cited, but the same “abnormalities” can be demonstrated in normal persons and have no diagnostic value. Similarly, application of electrodiagnostic techniques has not been blinded or controlled, so different abnormalities have been reported, then refuted. The list includes low amplitude of the sensory evoked potential in the ulnar nerve, slowing of proximal conduction after stimulation at the Erb point, ulnar F-wave determination, and abnormality of somatosensory evoked potentials from the ulnar nerve. Magnetic resonance imaging (MRI) may show deviation or distortion of nerves or blood vessels, the presence of bands extending from the C-7 transverse process, or other causes of the syndrome. MR angiography and Doppler ultrasonography may help assess the possibility of vascular compression.

DIAGNOSIS AND MANAGEMENT In cases of “true” thoracic outlet syndrome, diagnosis must exclude entrapment syndromes in the arm and compressive lesions in the cervical spine. Arteriography may be indicated if there is any suggestion of an aneurysm of the subclavian artery. Surgery is indicated when the diagnosis is unequivocal. In the disputed form, when no objective findings are noted on neurologic examination, there is a problem. Each case must be evaluated separately, but in the absence of objective changes, it would seem reasonable to be cautious. Psychogenic factors should be considered. Conservative therapy should be given a trial; postural adjustments, manual therapy to increase mobility of the shoulder girdle, and an exercise program have all been advocated. The results of surgery are difficult to evaluate when there are no objective signs or diagnostic laboratory abnormalities; placebo effects are rarely considered in the evaluation of surgery. Success rates of 90% for a particular operation may be followed by equally enthusiastic reports for reoperation after the “failed operation.” Surgery is not without hazard; complications include causalgia, injury of the long thoracic nerve, infection, and laceration of the subclavian artery. SUGGESTED READINGS Aligne C, Barral X. Rehabilitation of patients with thoracic outlet syndrome. Ann Vasc Surg 1992;6:381–389. Campbell JN, Naff NJ, Dellon AL. Thoracic outlet syndrome: neurosurgical perspective. Neurosurg Clin N Am 1991;2:227–233. Cherington M, Cherington C. Thoracic outlet syndrome: reimbursement patterns and patient profiles. Neurology 1992;42:943–945. Cherington M, Harper I, Machanic B, Parry L. Surgery for thoracic outlet syndrome may be hazardous to your health. Muscle Nerve 1986;9:632–634. Cuetter AC, Bartoszek DM. Thoracic outlet syndrome: controversies, overdiagnosis, overtreatment, and recommendations for management. Muscle Nerve 1989;12:410–419. Gregoudis R, Barnes RW. Thoracic outlet arterial compression: prevalence in normal persons. Angiology 1980;31:538–541. Huffman JD. Electrodiagnostic techniques for and conservative treatment of thoracic outlet syndrome. Clin Orthop 1986;207:21–23. Kenny RA, Traynor GB, Withington D, Keegan DJ. Thoracic outlet syndrome: a useful exercise treatment option. Am J Surg 1993; 165:282–284. LeForestier N, Moulonguet A, Maisonobe T, Leger JM, Bouche P. True neurogenic thoracic outlet syndrome: electrophysiological diagnosis in six cases. Muscle Nerve 1998;21:1129–1134. Longley DG, Finlay DE, Letouorneau JG. Sonography of the upper extremity and jugular veins. AJR 1993;160:957–962. Novack CB, Mackinnon SE, Patterson GA. Evaluation of patients with thoracic outlet syndrome. J Hand Surg [Am] 1993;18:292–299. Ohkawa Y, Isoada H, Hasegawa S, et al. MR angiography of thoracic outlet syndrome. J Comput Assist Tomogr 1992;16:475–477. Panegyres PK, Moore N, Gibson R, Rushworth G, Donaghy M. Thoracic outlet syndromes and magnetic resonance imaging. Brain 1993;116:823–841. Roos DB. Thoracic outlet syndrome is underdiagnosed. Muscle Nerve 1999;22:126–129. Smith T, Trojaborg W. Diagnosis of thoracic outlet syndrome. Arch Neurol 1987;44:1161–1166. Veilleux M, Stevens JC, Campbell JK. Somatosensory evoked potentials: lack of value for diagnosis of thoracic outlet syndrome. Muscle Nerve 1988;11:571–575. Wilbourn AJ. Thoracic outlet syndrome: a plea for conservatism. Neurosurg Clin N Am 1991;2:235–245. Wilbourn AJ. Thoracic outlet syndrome is overdiagnosed. Muscle Nerve 1999;22:130–136.

Wilbourn AJ, Lederman RJ. Evidence for conduction delay in thoracic outlet syndrome is challenged. N Engl J Med 1984;310:1052–1053.

CHAPTER 70. NEUROPATHIC PAIN AND POSTTRAUMATIC PAIN SYNDROMES MERRITT’S NEUROLOGY

CHAPTER 70. NEUROPATHIC PAIN AND POSTTRAUMATIC PAIN SYNDROMES JAMES H. HALSEY Diagnosis Treatment Functional Component of Pain Suggested Readings

The term complex regional pain syndrome (CRPS) has been adopted by the International Association for the Study of Pain. CRPS type I was previously called reflex sympathetic dystrophy (RSD) when the syndrome was not associated with injury to a major nerve trunk. CRPS type II was previously causalgia for syndromes with a major nerve trunk injury. These disorders are characterized by continuous pain with combinations of aching, throbbing, burning, allodynia (pain in response to a stimulus that usually is not painful, such as light touch), sensitivity to cold, and temporal summation (increasing pain by repeated mild stimulation). Lancinating pain, as in trigeminal neuralgia, is rarely present. Sometimes, physical signs suggest autonomic dysfunction, with sweating, dry skin, vasomotor instability (edema, erythema, blotching, or blanching), atrophy of muscle, other soft tissues, and bone (Sudeck atrophy), and stiff joints. These signs occur in varying combinations. In some patients, the physical signs and the pain are abolished or greatly reduced by selective sympathetic blockade. However, failure of sympathetic block does not alter the classification, even if it excludes sympathetic activity in the pathogenesis of the particular case. These disorders may follow injuries involving a major peripheral nerve trunk (CRPS type II), especially a partial nerve injury rather than a complete transection. The nerves most often affected are the median nerve, the tibial division of the sciatic nerve, and portions of the brachial and lumbar plexuses from which these nerves originate. Often, more than one nerve is involved. The injury may follow stretch, missiles, injections, compression of roots or peripheral nerves, or inadvertent surgical damage. CRPS type I may follow a local crush injury of a hand or foot, without nerve trunk injury. However, it can also follow a less severe or even trivial injury, or no recognized injury at all. If untreated, the syndrome may progress and involve more proximal parts of the same limb. Rarely, it spreads to homologous parts of the other side or other parts of the body. Apparent progression may result from inappropriate immobilization brought on in part by the patient's desire to protect the painful area, a process that may be aggravated if the patient fears that progression is the natural history of the disorder. The same qualities of pain and sometimes the same physical signs can result from spinal cord or brain lesions, including hemiplegic cerebral infarction, or poliomyelitis. Rheumatoid arthritis and other collagen diseases, as well as osteoarthritis and traumatic arthritis, may produce similar physical signs and similar pain. Partial lesions of the spinothalamic tract, postherpetic neuralgia, and peripheral neuropathies involving small-diameter pain fibers but without complete loss of pain perception may result in neuropathic pain. A patient recovering from complete analgesia may pass through a phase of partial analgesia, with the appearance of pain that becomes progressively worse. In the face of increasing complaints, the physician must rely on quantitative documentation of reflexes, strength, and sensory perception thresholds to determine whether the condition is improving or getting worse. A corollary of this point is that pain without neurologic abnormality is unlikely to be due to an organic neurologic disorder.

DIAGNOSIS Neuropathic pain is defined by the clinical picture of continuous pain with or without nerve injury, sometimes associated with physical signs of sympathetic overactivity and relief by differential sympathetic block. The physiologic severity of the disorder is a function of allodynia, temporal summation, and (less objectively) sleep disturbance caused by the pain. The functional component is judged in large degree by observing pain behavior and signs of conversion reaction. If the pain is focal and involves one limb, it meets the criteria of CRPS.

TREATMENT Medical therapy of pain caused by damaged nerves, whether central or peripheral, trunk or terminal branches, is influenced more by the quality of the pain and the accompanying behavioral complications (e.g., insomnia, anxiety, agitation, or depression) than by the anatomic source or pathologic cause of the pain. In general, tricyclic antidepressants are most effective for burning and aching pain; phenytoin sodium (Dilantin) is intermediate, and carbamazepine (Tegretol) is least effective. For lancinating pain, as in trigeminal neuralgia but only rarely in the disorders described here, the reverse is usually true, and carbamazepine is favored. In individual patients, however, any of the three agents may be optimal. Gabapentin (Neurontin) may offer some additional opportunities for nonnarcotic pain control. Of the tricyclic agents, amitriptyline is particularly useful for its sedative effect in patients who cannot sleep because of the pain. Any of these drugs may be usefully supplemented in individual patients with benzodiazepines, other antidepressants, baclofen (Lioresal), or phenothiazines. Narcotics are sometimes appropriate and are underused in elderly patients, in whom the consequences of habituation are low. Transcutaneous electric nerve stimulation is sometimes a helpful adjuvant. Physical therapy is aimed specifically at minimizing the pathologic immobilization that seems to be responsible for many cases of progressive disability. Differential sympathetic and somatic nerve blocks may have diagnostic value and, when repeated, sometimes have cumulative therapeutic benefit with progressively longer intervals free of pain. In carefully selected patients with severe pain, effective treatments include surgical sympathectomy, dorsal column stimulation, and intrathecal administration of morphine.

FUNCTIONAL COMPONENT OF PAIN The chronic pain is debilitating and demoralizing, often leading to serious depression. Additionally, many patients guard the painful limb from tactile stimulation because they fear the pain. The behavioral pattern may suggest a conversion reaction with much “pain behavior”(grunting, panting, moaning, and tensing muscles) during an examination or even on simple observation. There is a considerable lay literature on RSD conveying a frightening prognosis and often aggravating the functional component of the disorder. The physician may facilitate or restrain this process by assessing the disorder in the context of the patient's total reaction to it. Not every hand or foot that tingles, burns, or aches should be labeled RSD, even if it follows an injury and seems to fit the definition of CRPS type I. Every effort should be exerted to reach a specific neurologic, vascular, orthopedic, or rheumatologic diagnosis for a specific treatment, without introducing or increasing the functional consequences of the labels “RSD” or “CRPS.” Behavioral pain control aims to teach the patient how to decrease the outward expression of pain behavior, decreasing the aggravating effects of increased muscle tension, the patient's anger, and the resulting guilt of family members and friends, all of which may feed back on the behavioral components of the suffering. Before a surgical sympathectomy or other permanently destructive or invasive procedure is undertaken, benefit may come from a multidisciplinary review of the problem, involving a physician interested in pain management, a physical therapist, and a psychotherapist. Some patients feel better when the physician acknowledges the severity of the pain without necessarily curing it. For a few, acknowledgment is even more important than cure, implying that the physician will stay with the patient while he or she continues to live with the pain. Many unsatisfactory outcomes of surgery for relief of pain result from failure to address the behavioral component. SUGGESTED READINGS Geertzen JH, Dijkstra PU, Groothoff JW, et al. Reflex sympathetic dystrophy of the upper extremity: a 5.5 year follow-up. Part I: impairments and perceived disability. 1998;279:12–18.

Acta Orthop Scand

Kozin F. Reflex sympathetic dystrophy syndrome: a review. Clin Exp Rheumatol 1992;10:401–409. Levine D. Burning pain in an extremity: breaking the destructive cycle of reflex sympathetic dystrophy. Postgrad Med 1991;90:175–185. Rowbotham M, Fields H. The relationship of pain, allodynia and thermal sensation in postherpetic neuralgia. Brain 1996;119:347–354. Schwartzman R. Reflex sympathetic dystrophy and causalgia. Neurol Clin 1992;10:953–973. Stanton-Hicks M, Janig W, Hassenbusch S, Haddox J, Boas R, Wilson P. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain 1995;63:127–133. Tsuruoka M, Willis WD. Descending modulation from the region of the locus coeruleus on nociceptive sensitivity in a rat model of inflammatory hyperalgesia.

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Veldman PH, Reynen HM, Arntz IE, Goris RJ. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet 1993;342:1012–1016. Zyluk A. The natural history of post-traumatic reflex sympathetic dystrophy. J Hand Surg [Br] 1998;23:20–23.

CHAPTER 71. RADIATION INJURY MERRITT’S NEUROLOGY

CHAPTER 71. RADIATION INJURY CASILDA M. BALMACEDA AND STEVEN R. ISAACSON Early Acute Effects Early Delayed Syndromes Late Delayed Syndromes Suggested Readings

Although irradiation is an essential treatment for many central nervous system (CNS) malignancies, injury to the brain or spinal cord is a feared complication. Healthy tissue may be exposed when the target of radiation is nearby in the brain or spinal cord or even after nonneural structures have been irradiated, if the peripheral or cranial nerves are within the field. Neurologic injury may follow scalp irradiation for tinea capitis, prophylactic whole-brain radiotherapy for small cell carcinoma of the lung or acute lymphocytic leukemia, or radiotherapy to the neck for systemic malignancy. There are three major categories: acute reactions (1 to 6 weeks after radiotherapy), early-delayed reactions (within 6 months afterward), and late-delayed reactions (months to years afterward).

EARLY (ACUTE) EFFECTS Radiotherapy is usually well tolerated during the treatment period. The only acute CNS injury is edema days or weeks after the start of radiation therapy. Headache, nausea, and vomiting may occur with high daily dose fractions. Fractions of 750 cGy generate a complication rate of 49%, but daily doses of 200 cGy or less are seldom toxic. The acute lesions appear on magnetic resonance imaging (MRI) as localized swelling without enhancement. Steroids may reduce symptoms and are commonly given during radiotherapy to reduce the likelihood of this complication. Tissues that have the fastest turnover rate are most often affected after CNS irradiation, causing alopecia and skin erythema. Otitis media or externa and pharyngitis may follow radiotherapy to the posterior fossa or brainstem because the eustachian tube is obstructed by swelling. Temporary hearing loss is seen, but deafness is rare. Marrow depression occurs with craniospinal radiotherapy, particularly in patients receiving concomitant chemotherapy, and may lead to infection or hemorrhage.

EARLY-DELAYED SYNDROMES Reactions occurring 1 month to several years after treatment have been divided into early and late categories, but there are no clearly defined time boundaries. Two main clinical syndromes are seen. Somnolence and headache may occur in children receiving prophylactic whole-brain radiotherapy for acute lymphocytic leukemia or tinea capitis. The syndrome appears 24 to 66 days after radiotherapy; recovery is spontaneous. Focal signs are uncommon but may simulate tumor progression. Rhombencephaly with ataxia, dysarthria, and nystagmus may follow irradiation to the middle ear area for glomus jugulare tumors. Severe leukoencephalopathy can occur within the first 6 months. Early-delayed radiation myelopathy takes the form of the Lhermitte symptom, a sensation of electrical current radiating down the back or limbs induced by flexing the neck; it is seen in up to 15% of patients receiving mantle irradiation for Hodgkin lymphoma. This symptom can be distinguished from delayed radiation myelopathy because it is transient and appears within 6 months of the completion of treatment. Other causes of the symptom are multiple sclerosis, vitamin B12 deficiency, and cisplatin (Platinol) chemotherapy. Epidural cord compression by tumor may also cause Lhermitte sign but is usually painful. The latent period for early-delayed effects is thought to correspond to the turnover time of myelin, and these syndromes are attributed to transient demyelination. Pathologic data are scarce because the syndrome is rarely lethal, but the few autopsies have showed areas of demyelination.

LATE-DELAYED SYNDROMES Radiation Necrosis It is not known how adverse effects relate to total dose of radiotherapy, fraction size, treatment time, volume of tissue irradiated, and host factors such as age. To standardize the biologic effects of different treatment regimens, Sheline and colleagues (1980) developed the concept of neuroret to specifically address brain tolerance to irradiation; the value is derived from a graph representing fractions (abscissa) and total dose (ordinate) to determine the threshold for necrosis. It occurs at doses greater than 1,000 to 1,100 neurorets (equivalent to 6,000 cGy given in 30 fractions for 6 weeks, a treatment commonly used for primary brain tumors). Necrosis develops in about 5% of patients given total doses greater than 5,000 cGy with daily fraction sizes greater than 200 cGy. It may also follow irradiation of extracranial malignancies, such as squamous cell carcinoma, or stereotactic radiosurgery, proton beam irradiation, or brachytherapy (implantation of radioactive sources into the tumor bed). The median time for onset of symptoms is 14 months after radiotherapy, but symptoms may occur as early as 6 months afterward. In 75% of the patients, symptoms appear within 3 years of the treatment but may be seen as late as 7.5 years. The clinical manifestations may simulate those of the original tumor, with lateralizing signs, headache, or increased intracranial pressure. Patients irradiated for nasopharyngeal carcinoma may have lesions in the temporal lobe with or without hypothalamic dysfunction. Radiation necrosis shows a predilection for the white matter. The underlying mechanisms are thought to be either loss of oligodendrocytes with demyelination and necrosis (glial hypothesis) or a vasculopathy with ischemia and infarction leading to necrosis. Contemporary views point to a vascular-mediated response resulting in delayed white matter necrosis. Glial cells, particularly oligodendrocytes, and the vascular endothelium are the major targets, not the neurons. Histologic changes include white matter necrosis, cystic cavitation with gliosis, and patchy demyelination. Vascular changes include endothelial proliferation, fibrinoid degeneration, perivascular lymphocytic infiltration, capillary occlusion, and intraluminal thrombosis of medium- and small-sized arteries. Vasogenic edema follows endothelial cell damage. The immunologic hypothesis speculates that irradiated glial cells release antigens that induce an autoimmune reaction. A mineralizing microangiopathy is seen at autopsy in up to 17% of patients who received cranial irradiation; it is usually asymptomatic. Radiographically, calcification may be seen at the gray–white matter junction, basal ganglia, or pons. Neuroradiologic abnormalities are of two types. The first is a mass lesion located at the original tumor site or within the path of radiation. Enhancement is usually seen, mimicking the original neoplasm; it may be ringlike or heterogeneous. Angiography shows that the lesion is avascular. Computed tomography (CT) or MRI indicates that the lesion may resolve with time. Neuroimaging can often differentiate between early, transient and more progressive, later injury. Imaging differentiates mild edema from significant edema and frank necrosis. Early changes are confined to white matter, but after 6 months to 1 or 2 years gray matter lesions may be evident. The second abnormality consists of diffuse white matter changes, appearing as areas of hypodensity on CT or increased signal intensity on MRI ( Fig. 71.1). The imaging abnormalities vary from mild to severe and are usually irreversible. Mild changes (grade 1) lie adjacent to the frontal and occipital horns of the lateral ventricles. Grade 2 (intermediate) change affects the centrum semiovale, and grades 3 to 4 show diffuse white matter lesions with a characteristic scalloped configuration. Mass effect is rare. Accompanying changes include cortical atrophy or ventricular dilatation. MRI is more sensitive than CT in detecting these white matter abnormalities. Imaging abnormalities correlate poorly with symptoms; many patients with severe white matter changes are asymptomatic.

FIG. 71.1. Radiation leukoencephalopathy. A: Axial T2-weighted MR scan shows diffuse increased signal intensity involving the periventricular white matter of both frontal lobes and parietal lobes, as well as the corona radiata and external capsules bilaterally. B: Axial T2-weighted MR scan at the level of the centrum semiovale demonstrates similar changes within the hemispheric white matter bilaterally. The known malignant glioma is identified in the posteromedial left frontal lobe ( arrow), for which the patient had received cranial radiation therapy. (Courtesy of Dr. S. Chan, Columbia University College of Physicians and Surgeons, New York, NY.)

Distinguishing tumor recurrence from radiation necrosis may be difficult. Provided that steroid dosage is not increasing, radiation effect is suggested by clinical improvement accompanied by a decrease of mass effect on CT or MRI. Although positron-emission tomography (PET) may show hypometabolic areas of radiation necrosis, a tissue biopsy is usually needed to establish the diagnosis. Single-photon emission computed tomography and PET are complementary. MR spectroscopy may document metabolic changes in brain N-acetylaspartate, choline, creatine, and lactate that appear after radiation and later return to normal. The changes include a reduction in choline levels with radiation, indicating the transformation of tumor to necrotic tissue, as well as an increase in choline levels with tumor recurrence. Steroid therapy may lead to clinical stabilization, but when there is marked mass effect, surgical resection can improve neurologic function and may be life-saving. Radiation necrosis can be progressive and fatal. Radiation Myelopathy Delayed injury to the spinal cord, radiation myelopathy, develops 1 to 3 years after radiotherapy, with one peak at 12 to 14 months and another at 24 to 28 months. The average latent period is 12 months, and in 75% of the patients, radiation myelopathy occurs within 30 months. In patients with shorter intervals, the total dose of radiation and the average dose per fraction were higher. The incidence is about 5% when doses between 57 Gy and 61 Gy are given to the spinal cord. Latency periods are shorter in children, after a second course of radiation, or for lumbar lesions. The latency bimodality is attributed to dual mechanisms of injury. Higher doses cause white matter necrosis and early myelopathy; lower doses preferentially cause vascular damage and delayed manifestations. A case report describes syrinx formation after radiation to the spinal cord in a patient with a cervical astrocytoma. The true incidence is not known. Wara and associates (1975) suggested a 5% risk in patients who received 4,500 cGy at fraction doses of 180 cGy, but the specifics of cord tolerance remain elusive. Symptoms are associated with increased fraction size, shorter treatment time, higher total dose, and cord exposure greater than 10 cm in length. Additional risk factors (e.g., diabetes mellitus, hypertension) may contribute to its development. The clinical syndrome includes painless subacute numbness and paresthesia followed by progression of spastic gait, sphincter symptoms, and limb weakness. MRI may be normal or show cord swelling, atrophy, or complete subarachnoid block. Low signal intensity on T1-weighted imaging, high signal on T2-weighted imaging, and focal enhancement may be seen as early as 1 month after the clinical manifestations. Diagnosis must exclude extra- or intramedullary tumors, leptomeningeal metastases, or vertebral body abnormalities causing cord compression. As early as 10 months after the onset of symptoms, one can see cord atrophy or resolution of contrast enhancement. There is no effective treatment, although steroids may transiently improve symptoms. Pathologically, spinal cord infarction is associated with necrosis, hemorrhage, and demyelination. After experimental radiation, asymptomatic animals showed spongy vacuolation of the spinal cord white matter only, whereas those with paralysis had large areas of tissue destruction and vascular changes, particularly in the posterior and lateral columns. Other rare syndromes attributed to radiation-induced cord damage are an acute paraplegia that progresses for hours to days (thought to be induced by vascular damage to the cord with infarction), anterior horn cell damage, and a delayed clinical syndrome that simulates motor neuron disease but is arrested spontaneously after 1 to 2 years. Radiation-induced Vasculopathy Both intra- and extracranial circulation can be affected. Most patients have had neck irradiation for head and neck cancer or for optic nerve or suprasellar tumors. The latent period can be up to 23 years. Angiography reveals localized stenosis, an irregular contour of the vessel involved, or even complete occlusion of the portion of the artery in the radiation portal. Extracranially, internal and common carotid artery occlusion can be seen, with premature atherosclerosis and endothelial proliferation compromising vessel patency and leading to thrombosis and infarction. Intracranially, the supraclinoid carotid is most commonly affected, and a moyamoya pattern may develop. Autopsy studies reveal myointimal proliferation, hyalinization, and occlusion. Clinically, radiation-induced vasculopathy causes transient ischemic attacks or ischemic stroke. Cerebrovascular malformations have also been observed in the irradiated field. Aneurysm formation is rare. Radiation-induced Plexopathy Either brachial or lumbar plexus may be affected; most commonly the arm is affected after radiotherapy for breast carcinoma. Three different syndromes are observed. Transient plexus injury occurs in 1.4% of the patients treated with doses of 5,000 cGy to the area, with paresthesia or, less commonly, pain or weakness. Median onset is 4.5 months after radiotherapy. Acute ischemic brachial neuropathy follows subclavian artery occlusion owing to prior irradiation. The lesion is acute, nonprogressive, and painless. Radiation fibrosis appears about 4 years after radiotherapy, with paresthesia or swelling of the arm; the signs are sensorimotor, most commonly affecting the upper plexus. Pathologically, local fibrosis or scarring entraps the plexus or nerves. Brachial plexopathy was reported in the treatment of breast cancer when the fraction size was greater than 2 Gy. Patients may have symptoms of paresthesia, hypesthesia, and weak hands. Lumbosacral plexopathy is a rare occurrence in patients treated for cervical or endometrial carcinoma, even when total doses approach 70 to 80 Gy, by a combination of brachytherapy and external-beam radiation. Clinically, the major difficulty lies in trying to differentiate radiation-induced plexopathy from tumor. Lymphedema, painless paresis and sensory loss, and upper plexus involvement suggest radiation plexopathy. Pain, lack of edema, and lower plexus involvement suggest recurrent tumor. Myokymia, when present on electromyography, strongly favors the diagnosis of radiation fibrosis. Typically, radiation fibrosis of the plexus appears on CT as diffuse involvement without a discrete mass. MRI may reveal radiation changes in the soft tissue or bone. Gadolinium enhancement of the irradiated area may occur and persist, even two decades after irradiation. Although the presence of enhancement is usually suggestive of recurrent tumor, the radiographic stability is more consistent with necrosis. When ancillary studies are ambiguous, surgical exploration of the plexus may be considered. Once the diagnosis of radiation plexopathy is established, attention should be given to preventing shoulder subluxation, treating lymphedema, and relieving pain. The plexopathy is usually irreversible. Endocrine Dysfunction Irradiation of the brain or neighboring sites can cause neuroendocrine disorders. These are primarily due to radiation effects on the hypothalamic–pituitary axis when this structure is included in the radiation field for treatment of primary brain tumors or head and neck cancer. For unknown reasons, the posterior pituitary is remarkably resistant to the effects of radiation. Several clinical syndromes may be evident. Growth hormone function is the most vulnerable. Growth arrest may occur in children treated with spinal radiotherapy because radiation impairs vertebral development and is exaggerated by endocrine deficiency. It is most visible in a growing child; the rate of growth slows and stature is short for age. Adults may exhibit a decrease in muscle mass and an increase in adipose tissue. These effects may become evident in children with doses of fractionated radiation as low as 18 Gy or single fractions of 9 to 10 Gy. Adults have a higher threshold. Among children treated for acute lymphoblastic leukemia with moderate doses of prophylactic cranial radiation (2,000 to 3,000 cGy), 65% have impaired growth hormone responses. Treatment includes growth hormone replacement. Modern treatment for chemosensitive tumors therefore emphasizes chemotherapy to reduce or avoid radiation. Gonadotropin deficiency (luteinizing hormone and follicle-stimulating hormone) may develop, with failure to enter puberty and amenorrhea. Adults may demonstrate infertility, sexual dysfunction, and decreased libido. The tolerance dose appears to be between 40 and 50 Gy. Thyrotropin deficiency may be manifested as weight gain and lethargy. Adrenocorticotropic hormone deficiency is rarely seen, with lethargy, decreased stamina, fasting, hypoglycemia, and dilutional hyponatremia. Hyperprolactinemia may cause delay in puberty, galactorrhea, or amenorrhea. Men may experience decreased libido and impotence. These findings may be found in 20% to 50% of patients receiving greater than 50 Gy of radiation. Neuropsychologic Sequelae Cognitive impairment is a delayed complication of radiation, especially in long-term survivors who have been cured of the original disease. There has usually been concomitant use of intrathecal chemotherapy, but radiation itself may be the culprit. Children younger than 5 years are particularly susceptible to cognitive sequelae. In the treatment of childhood brain tumors, survivors demonstrate a 40% to 100% incidence of cognitive dysfunction on formal neuropsychologic testing. Cranial irradiation in children may be associated with mild delayed IQ decline, learning disability, and academic failure. There is considerable pediatric literature, but little is

known about cognitive outcome in adults. However, in most studies, there were no controls, and often the most appropriate neuropsychologic procedures were not used. A syndrome of ataxia, cognitive disturbance, and urinary incontinence, sometimes ameliorated by ventriculoperitoneal shunting, has been described in adults treated with irradiation for brain tumors. Memory seems to be sensitive to radiotherapy. Local-field irradiation to the posterior fossa may also be accompanied by significant cognitive impairment. There have been few studies of the quality of life of patients surviving irradiation. Other Complications of Radiation Peripheral Nerves Peripheral nerves are seldom damaged with fractionated doses of less than 6,000 cGy. Fraction size appears to play a significant role as a causative factor. There may be two phases of injury to nerves following radiation. First, direct effects may cause changes in electrophysiology and histochemistry. Fibrosis may occur later and surround the nerve. Vascular injury to nutrient vessels may also occur. Radiation-induced Tumors As the survival of cancer patients increases, secondary tumors become an important treatment complication. Radiation has been implicated in the development of secondary tumors. The association between radiation and CNS tumors is especially strong for meningiomas, which may follow irradiation for brain or spinal cord tumors or doses of less than 850 cGy to the scalp for tinea capitis. The mean latency is 37 years if low-dose irradiation was given and 18 months for doses greater than 2,000 cGy. Compared with spontaneously arising tumors, radiation-induced meningiomas are more likely to recur after surgical excision and to undergo malignant degeneration. Radiation-induced sarcomas are seen in the third, fourth, or fifth decades after radiation for pituitary adenomas or gliomas. The latency period is 8 to 11 years with doses greater than 5,000 cGy. The possible role of cranial irradiation in the pathogenesis of CNS gliomas is controversial. The main diagnostic problem is differentiation of radiation-induced malignancy from recurrence of the original tumor. Peripheral nerve tumors, benign or malignant, arising within the radiation port are seen in up to 9% of patients, especially those treated for breast cancer or lymphoma. Tumors are most frequently located in the brachial plexus followed by spinal roots or nerve. Clinically, an enlarging painful mass causes progressive motor and sensory signs of plexopathy. The mean interval between irradiation and diagnosis of these tumors is 16 years. Patients with neurofibromatosis are particularly prone to radiation-induced peripheral nerve tumors. Treatment is surgical resection, but the prognosis for malignant tumors is poor. Radiation Optic Neuropathy Radiation optic neuropathy follows treatment directed to the orbit, sinuses, pituitary, or intracranial tumors. There is painless visual loss, usually monocular, but both eyes may be affected. Symptoms develop within 3 years. Findings include decreased visual acuity, abnormal visual fields (especially altitudinal defects), papilledema (or optic atrophy later), and hemorrhagic exudates. About 50% of the patients experience improvement of the condition, but some become blind. Steroids are ineffective. Measures to shield the optic nerve from the radiation portals may reduce the incidence of this rare but devastating complication. SUGGESTED READINGS Radiation: CNS Effects Al-Mefty O, Kersh JE, Routh A, et al. The long-term side effects of radiation therapy for benign brain tumors in adults. J Neurosurg 1990;73:502–512. Archibald Y, Lunn D, Ruttan L, et al. Cognitive functioning in long-term survivors of high-grade gliomas. J Neurosurg 1994;80:247–253. Armstrong C, Mollman J, Corn BW, et al. Effects of radiation therapy on adult brain behavior: evidence for a rebound phenomenon in a phase I trial.

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Burstein S. Poor growth after cranial irradiation. Pediatr Rev 1997;18:442–444. Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 1993;328:87–94. Duffner PK, Cohen ME, Voorhess ML, et al. Long-term effects of cranial irradiation on endocrine function in children with brain tumors: a prospective study. Cancer 1985;56:2189–2193. Mechanik JI, Hochberg FH, LaRocque A. Hypothalamic dysfunction following whole-brain irradiation. J Neurosurg 1986;65:490–494. Rappaport R, Brauner R. Growth and endocrine disorders secondary to cranial irradiation. Pediatr Res 1989;25:561–567. Shalet SM. Radiation and pituitary dysfunction. N Engl J Med 1993;238:131–133. Woo E, Lam K, Yu YL, Ma J, Wang C, Yeung RT. Temporal lobe and hypothalamic-pituitary dysfunctions after radiotherapy for nasopharyngeal carcinoma: a distinct clinical syndrome. Neurosurg Psychiatry 1988;51:1302–1307.

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Radiation: Neuropsychologic Effects Anderson V, Godber T, Smibert E, Ekert H. Neurobehavioural sequelae following cranial irradiation and chemotherapy in children: an analysis of risk factors. Pediatr Rehabil 1997;1:63–76. Armstrong C, Ruffer J, Corn B, De Vries K, Mollman J. Biphasic patterns of memory deficits following moderate-dose partial-brain irradiation: neuropsychologic outcome and proposed mechanisms. J Clin Oncol 1995;13:2263–2271. Crossen JR, Garwood D, Glatstein E, et al. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 1994;12:627–642. Duffey P, Chari G, Cartlidge NEF, et al. Progressive deterioration of intellect and motor function occurring several decades after cranial irradiation. Arch Neurol 1996;53:814–818. Glauser TA, Packer RJ. Cognitive deficits in long-term survivors of childhood brain tumors. Childs Nerv Syst 1991;7:2–12. Roman DD, Sperduto PW. Neuropsychological effects of cranial radiation: current knowledge and future directions. Int J Radiat Oncol Biol Phys 1998;31:983–998. Sklar CA, Copstine LS. Chronic neuropsychological sequela of radiation therapy. Int J Radiat Oncol Biol Phys 1995;31:1113–1121. Radiation Damage to Peripheral Nerves Giese WL, Kinsella TJ. Radiation injury to peripheral and cranial nerves. In: Gutin PH, Leibel SA, Sheline GE, eds. Radiation injury to the nervous system. New York: Raven Press, 1991:383–403. Gillette EL, Mahler PA, Powers BE, Gillette SM, Vujaskovic Z. Late radiation injury to muscle and peripheral nerves. Int J Radiat Oncol Biol Phys 1995;31:1309–1318. Radiation-induced Tumors Dweik A, Maheut-Lourmiere J, Lioret E, Jan M. Radiation-induced meningioma. Childs Nerv Syst 1995;11:661–663. Foley KM. Radiation-induced malignant and atypical peripheral nerve sheath tumors. Ann Neurol 1980;7:311–318. Harrison MJ, Wolfe DE, Lau TS, et al. Radiation-induced meningiomas: experience at the Mount Sinai Hospital and review of the literature. J Neurosurg 1991;75:564–574. Kumar PP, Good RR, Skultety FM, et al. Radiation-induced neoplasms of the brain. Cancer 1987;59:1274–1282. Nadeem SQ, Feun LG, Bruce-Gregorios JH, et al. Post-radiation sarcoma (malignant fibrous histiocytoma) of the cervical spine following ependymoma: a case report. J Neurooncol 1991;11:263–268. Ron E, Modan B, Boice JD Jr, et al. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 1988;319:1033–1039. Shapiro S, Mealey J, Sartorius C. Radiation-induced intracranial malignant gliomas. J Neurosurg 1989;71:77–82. Radiation Optic Neuropathy Piquemal R, Cottier JP, Arsene S, et al. Radiation-induced optic neuropathy 4 years after radiation: report of a case followed up with MRI. Neuroradiology 1998;40:439–441. McClellan RL, el Gammal T, Kline LB. Early bilateral radiation-induced optic neuropathy with follow-up MRI. Neuroradiology 1995;37:131–133.

CHAPTER 72. ELECTRICAL AND LIGHTNING INJURY MERRITT’S NEUROLOGY

CHAPTER 72. ELECTRICAL AND LIGHTNING INJURY LEWIS P. ROWLAND Pathology Epidemiology Symptoms and Signs Treatment Suggested Readings

PATHOLOGY High-voltage electric shock or lightning stroke may damage the central nervous system, motor neurons, or peripheral nerves. The lesions may involve either the brain or the spinal cord. In the spinal cord, myelomalacia may result without change in blood vessels, inflammation, or gliosis. Similarly, nonspecific lesions are found in the brain, and gray matter may be affected. In death from acute injury, cerebral lesions seem to be dominated by the effects of cardiac arrest and anoxia, with edema, perivascular hemorrhage, and neuronal loss. Pathogenesis The mechanism of injury is not clear. Investigators have stated that resistance to the flow of electric current is lower in neural tissue than in other organs and that the consequent syndromes result from the direct effects of high-voltage electricity on neural cells. Cerebellar injury has been attributed to heat injury as part of the insult. Demyelination does not seem to be the result of vascular injury, and it is not clear why symptoms are immediate in most patients but delayed in many. Nor is it clear why different parts of the nervous system are affected in different victims.

EPIDEMIOLOGY In earlier times, electrocution was the result of accidents at work or in the home. With technologic advances, these causes have become less common but still account for about 1,000 deaths per year in the United States; lightning strikes account for about 100 deaths per year. Lightning strikes may be occupational (farming, ranching, roofing) or recreational (especially water sports, hiking, camping, or other outdoor activities).

SYMPTOMS AND SIGNS Among survivors, the first signs occur immediately after the shock and may be transient. Unconsciousness and amnesia are common, and there may be transient limb paralysis or paresthesia. Cerebral infarction may result from cardiac arrhythmia and embolization. Days or weeks later, progressive disorders begin and resemble one or another of several syndromes, such as parkinsonism, cerebellar disorders, myelopathy, spinal muscular atrophy, or sensorimotor peripheral neuropathy. Because there are so few cases, it is not possible to determine whether all reported cases are consequences of the electric shock or are a coincidental occurrence of two conditions.

TREATMENT Acutely, attention is directed to the cardiac disorder. The delayed-onset syndromes can only be managed symptomatically because no specific treatment exists. SUGGESTED READINGS Cherington M, Yarnell P, Hallmark D. MRI in lightning encephalopathy. Neurology 1993;43:1437–1438. Cherington M, Yarnell P, Lammereste D. Lightning strikes: nature of neurological damage in patients evaluated in hospital emergency departments. Ann Emerg Med 1992;21:575–578. Critchley M. Neurological effects of lightning and electricity. Lancet 1934;1:68–72. Davidson GS, Deck JH. Delayed myelopathy following lightning strike: a demyelinating process. Acta Neuropathol 1988;77:104–108. Gallagher JP, Talbert OR. Motor neuron syndrome after electric shock. Acta Neurol Scand 1991;83:79–82. Fahmy FS, Brinsden MD, Smith J, Frame JD. Lightning: the multisystem group injuries. J Trauma 1999;46:937–940. Hawke CH, Thorpe JW. Acute polyneuropathy due to lightning injury. J Neurol Neurosurg Psychiatry 1992;55:388–390. Kleinschmidt-DeMasters DK. Neuropathology of lightning-strike injuries. Semin Neurol 1995;15:323–328. Panse F. Electrical trauma. In: Vinken PJ, Bruyn GW, Braakman R, eds. Injuries of the brain and skull. Handbook of clinical neurology, vol 23-24. Amsterdam: North-Holland Publishing, 1975:683–729. Sirdofsky MD, Hawley RJ, Manz H. Progressive motor neuron disease associated with electrical injury. Muscle Nerve 1991;14:977–980. Stanley LD, Suss RA. Intracerebral hematoma secondary to lightning stroke: case report and review of the literature. Neurosurgery 1985;16:686–688.

CHAPTER 73. DECOMPRESSION SICKNESS MERRITT’S NEUROLOGY

CHAPTER 73. DECOMPRESSION SICKNESS LEON D. PROCKOP Suggested Readings

In scuba diving, caisson work, flying, and simulated altitude ascents, rapid reduction in ambient pressure may allow the formation of bubbles from inert gases (nitrogen in particular) that are normally dissolved in body tissues. Resultant lesions involve the limbs, cardiopulmonary system, and central nervous system. In divers, most neurologic lesions affect the spinal cord. In fliers, cerebral damage is most common. The incidence of decompression sickness in divers is between 1% and 30%. Although the spinal cord is the most common site of neurologic lesions, encephalopathy is also well-described. Electrophysiologic studies, experimental models, and isolated postmortem examination of patients show predominant involvement of the posterolateral and posterior columns in the watershed areas of the thoracic, upper lumbar, and lower cervical cord. Ischemic perivascular lesions are usually confined to the white matter, but subsequent petechial hemorrhage may occur and extend into the gray matter. Lesions result from bubbles occluding vessels or directly disrupting tissue. Coincident intraarterial embolism may cause cerebral damage. With cord damage, back pain is followed by leg paresthesia, paresis, and urinary retention. When the brain is affected, neurologic signs and symptoms include visual impairment, vertigo, hemiparesis, loss of consciousness, and seizures. Unless recompression is achieved promptly, the signs, including paralysis, may become permanent. Serious manifestations of decompression sickness, including any neurologic signs, are a medical emergency. Current therapy consists of recompression in a hyperbaric chamber and the concurrent administration of high concentrations of inspired oxygen. Results of treatment vary, but the sooner recompression is begun, the better the outcome. For chamber locations, physicians should contact the local United States Coast Guard marine and air rescue centers listed in telephone directories in coastal areas. SUGGESTED READINGS Aharon-Peretz J, Adir Y, Gordon CR, et al. Spinal cord decompression sickness in sport diving. Arch Neurol 1993;50:753–756. Bond JP, Kirschner DA. Spinal cord myelin is vulnerable to decompression. Mol Chem Neuropathol 1997;30:273–288. Green RD, Leitch DR. Twenty years of treating decompression sickness. Aviat Space Environ Med 1987;58:362–366. Haymaker W, Johnston AD. Pathology of decompression sickness: comparison of lesions in airmen with those in caisson workers and divers. Mil Med 1955;117:285–306. James PB. Dysbarism: the medical problems from high and low atmospheric pressure. J R Coll Phyicians Lond 1993;27:367–374. Lambersten CJ. Concepts for advances in the therapy of bends in undersea and aerospace activity. Aerospace Med 1968;39:1086–1093. Leitch DR, Hallenbeck JM. Oxygen and pressure in the treatment of spinal cord decompression sickness. Undersea Biomed Res 1985;12:269–289. Macleod MA, Houston AS, Kemp PM, Francis TJ. A voxel-by-voxel multivariate analysis of cerebral perfusion defects in divers with “bends.”

Nucl Med Commun 1996;17:795–798.

Palmer AC, Calder IM, Yates PO. Cerebral vasculopathy in divers. Neuropathol Appl Neurobiol 1992;18:113–124. U.S. Navy diving manual, rev 3. Washington, DC: Naval Sea System Command, 1991. Weiss LD, Van Meter KW. The applications of hyperbaric oxygen therapy in emergency medicine. Am J Emerg Med 1992;10:558–568. Yiannikas C, Beran R. Somatosensory evoked potentials, electroencephalography and CT scans in the assessment of the neurological sequelae of decompression sickness. Clin Exp Neurol 1988;25:91–96. Zorpette G. Flying and the bends. Sci Am 1997;277:22–24.

CHAPTER 74. NEONATAL NEUROLOGY MERRITT’S NEUROLOGY

SECTION VIII. BIRTH INJURIES AND DEVELOPMENTAL ABNORMALITIES CHAPTER 74. NEONATAL NEUROLOGY M. RICHARD KOENIGSBERGER AND RAM KAIRAM Intracranial Hemorrhage Periventricular Intraventricular Hemorrhage Hypoxic Ischemic Encephalopathy Neonatal Infections Neonatal Seizures Suggested Readings

INTRACRANIAL HEMORRHAGE Gestational age is the best statistical indicator of the probable site of intracranial hemorrhage (ICH). Supratentorial subdural hemorrhage has become rare and occurs almost exclusively in full-term or large infants after difficult deliveries. Parenchymal cerebral hemorrhage originating in the periventricular area with or without secondary subarachnoid bleeding is common in infants of 32 weeks' gestation or less. Primary subarachnoid supratentorial hemorrhage of venous origin occurs in full-term newborns who have focal seizures and a benign clinical course. Subarachnoid hemorrhage may be found at autopsy in premature infants, but there is no recognized clinical syndrome. Posterior fossa hemorrhages are now more readily recognized in newborns, some needing only careful clinical observation, while others require surgical intervention.

PERIVENTRICULAR INTRAVENTRICULAR HEMORRHAGE Incidence With the advent of cranial ultrasonography, the incidence of parenchymal hemorrhage—more precisely, periventricular intraventricular hemorrhage (IVH)—used to be about 40% among newborns weighing less than 1,500 g. In the past few years, probably due to advances in pre- and perinatal care, the incidence is down to less than 20%, with very small premature infants (less than 900 g) still having a higher frequency. Pathology and Pathophysiology In most patients, the hemorrhage arises in the vascular germinal plate located in the region of the caudate near the foramen of Monro ( Fig. 74.1). Bleeding may be confined to this friable matrix area (grade I), but more than 50% of such hemorrhages rupture into the lateral ventricles (grade II), and these sometimes progressively enlarge (grade III). Grade IV, formerly attributed to parenchymal extension of grade III hemorrhage, is now thought to originate in the brain parenchyma itself; its location and size are main contributors to neonatal mortality and neurologic morbidity.

FIG. 74.1. Germinal matrix hemorrhage. Noncontrast axial CT shows small focal hemorrhage in the region of the left caudate head near the left thalamus with extension into the frontal horn of the left lateral ventricle. There is spread of hemorrhage into both occipital horns. This represents grade III germinal matrix hemorrhage. (Courtesy of Dr. S. Chan, Columbia University College of Physicians and Surgeons, New York, NY.)

It is not known whether IVH of grades I through III originates from an arterial source, the recurrent artery of Heubner, or from the thalamostriate veins. Proponents of the arterial theory cite hypotension followed by hypertension in an hypoxic brain that has lost autoregulation. The venous hypothesis suggests that increased venous pressure leads to stasis, thrombosis, and rupture of thin-walled vessels of the germinal plate. This mechanism of increased venous pressure is thought in some cases to produce a concurrent white matter parenchymal infarct, which may become bloody (grade IV). Pneumothorax is frequently encountered in coexistent hyaline membrane disease and is often associated with IVH. This complication usually occurs in the first 48 hours of life but may occur several days after birth. Signs and Symptoms Grade I hemorrhage is usually asymptomatic. In grade II, there is nonspecific irritability or lethargy. Some grade III hemorrhages are clinically silent with asymptomatic ventriculomegaly, whereas others produce hydrocephalic symptoms of varying severity. When observed in combination with grade IV hemorrhage, deterioration may ensue soon after onset, with at least a 50% chance of mortality; signs include severe apnea, bradycardia, extensor posturing and opisthotonos, ocular conversion or diversion, and pupillary fixation, usually in midposition. Many neonates become flaccid and unresponsive and die within minutes or hours. Clonic limb movements may occur concurrently. The posturing and movements have been called “seizures,” but there is little, if any, electroencephalographic (EEG) correlation. Less dramatic deterioration may occur over a few days. Diagnosis In preterm infants, gestation of less than 32 weeks places an infant at risk for periventricular IVH. A 20% or greater fall in the hematocrit suggests IVH. The cerebrospinal fluid (CSF) contains many red blood cells and has a protein content of 250 to 1,200 mg/dL. Lumbar puncture is not always diagnostic, because traumatic taps are common. Conversely, CSF may be normal, possibly because blood has not descended to the lumbar level. Days later, the CSF becomes xanthochromic with white and red blood cells and low glucose content; meningitis is ruled out by cultures. Sonography has replaced computed tomography (CT) as the cornerstone of diagnosis. This portable cribside technique delineates the site of blood in the parenchyma and ventricles, ventricular size, and shifts of major structures. White matter infarctions and cystic periventricular leukomalacia can also be identified. Prognosis and Therapy In grades I and II IVH, prognosis is good, with an 80% to 90% survival rate without obvious neurologic abnormality. Many of these children, however, may show later disorders of learning and behavior. Morbidity is attributed to coexisting hypoxic damage, the result of susceptibility of the premature infant's brain to decreases in the

partial pressure of oxygen. Grade III hemorrhage may develop into a static or reversible ventriculomegaly with normal pressure or may be followed by progressive hydrocephalus with at least a 40% incidence of cerebral palsy and mental retardation. Grade IV hemorrhage has a high mortality, particularly when large lesions occur. Morbidity can be predicted by the size of hemorrhage. Those with large, echodense parenchymal lesions have a universally poor outcome. Periventricular cysts develop in those with smaller lesions, with a high incidence of spastic diplegia. No treatment is necessary for grades I and II hemorrhages. In grade III, serial lumbar punctures are most effective when large volumes can be drained (e.g., 10 mL) or when sonography after lumbar puncture shows diminished ventricular size. If sonographic evidence of ventricular enlargement and signs of intracranial pressure persist, external ventriculostomy is used for periods not exceeding 5 days (because of the danger of infection). Lastly, a ventriculoperitoneal shunt may be installed, but this procedure has a high complication rate in small infants. Every attempt should be made to delay shunting until the infant attains as much somatic growth as possible. Although medical therapy with acetazolamide (Diamox) to decrease production of CSF is only sometimes efficacious, it may postpone shunt placement. Prevention Many treatments for the prevention of germinal hemorrhage have been attempted. Pharmacologic agents administered to small preterm infants include phenobarbital, ethamsylate, vitamin E, and indomethacin (Indocin). Of these, indomethacin appears to be most effective; however, late side effects remain to be delineated. Antenatal corticosteroids, primarily used to induce fetal lung maturation, clearly appear to reduce neonatal mortality, as well as the overall incidence and severity of IVH. Nursing techniques and pharmacotherapy that stabilizes systemic blood pressure with subsequent effects on cerebral blood flow may diminish the incidence of IVH and its spread. Among these, the technique of pancuronium bromide (Pavulon) paralysis while the infant is ventilated during the highest-risk first 48 hours of life has drawn much attention and controversy. The best prevention of ICH remains, when possible, the avoidance of premature birth.

HYPOXIC-ISCHEMIC ENCEPHALOPATHY Incidence After an era in which obstetric advances had lowered the frequency of asphyxia neonatorum, the incidence in the past decade has remained steady at 2 to 4 per 1,000 births; however, it is still a leading cause of static encephalopathy. Hypoxic-ischemic encephalopathy (HIE), the preferred term for asphyxia, probably occurs with equal frequency in pre- and full-term infants, but overt clinical patterns are seen mainly after 36 weeks' gestational age, often in the postmature baby. Pathology and Pathophysiology Hypoxic-ischemic insults had been thought to occur mainly during or immediately after labor. A majority of infants, however, suffer such insults in utero, and it is thought that congenital or metabolic abnormalities may increase susceptibility to peripartum stress. Therefore, neonatal HIE can occur despite optimal obstetric management. Concomitant anoxic cardiopulmonary and renal dysfunction may add to the cerebral insult. The resulting brain pathology depends on the maturity of the brain at the time of insult and its duration and location. The periventricular area is a vascular watershed region in premature infants and is especially vulnerable. Preterm infants experience periventricular leukomalacia in the centrum semiovale, which often affects the frontal myelinated fibers that project to the legs. This is the probable mechanism for spastic diplegia in these babies. After 36 weeks' gestation, lesions involve the cerebral gray matter, basal ganglia, brainstem, or cerebellar Purkinje cells. Acute neuronal necrosis is sometimes accompanied by edema and infarction. The chronic picture reveals neuronal loss and astrocytosis, along with ulegyria of the cortex, status marmoratus of the basal ganglia, or cerebellar atrophy (see Chapter 76). Severe, brief, total HIE results in diffuse deep and superficial lesions that may be incompatible with life. Experimentally, similar lesions can be induced in monkeys by complete intrauterine asphyxia for less than 13 minutes. In humans, these lesions can be caused by abruptio placentae, uterine rupture, or umbilical cord infarction. Partial HIE for minutes or hours results in predominantly supratentorial lesions, with generalized cerebral edema and laminar neuronal necrosis in the depths of the sulci. Some lesions have a parasagittal or watershed distribution, especially after fetal hypotension. These are the subacute variants most often recognized in the neonatal period. They are attributed to impaired placental exchange. Less severe episodes of hypoxic-ischemic insult of undetermined duration or timing may diffusely involve neurons or preferentially affect the hippocampal areas. At the cellular level, magnetic resonance spectroscopy, positron-emission tomography, and experimental animal studies have added to knowledge about the pathophysiology of HIE. The data suggest that all brain cells do not die at once following anoxia and energy failure. After the anoxic insult, many cells go through a reoxygenation and reperfusion period. This leads to neuronal leakage from the altered membranes of the edematous cells in the form of excitatory amino acids, particularly glutamate. This substance in turn causes other cells with NMDA ( N-methyl-d-aspartate) and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptors to be stimulated. The latter permit a large cytosolic accumulation of calcium, which in turn leads to a complex cascade of events resulting in secondary cell death. The excitotoxicity causes the release of nitric oxide, one of various free radicals that also contribute to further apoptotic cell death. This series of events caused by hypoxic-ischemic reperfusion takes place over 6 to 12 hours or longer after the original hypoxic-ischemic injury and leads to further neuronal destruction; however, it may also permit a therapeutic window in which pharmacologic therapy may limit the further injurious cascade set off by the original insult. Signs and Symptoms Infants who sustain hypoxic or ischemic insults weeks or months before birth may seem normal at birth but later show signs of static encephalopathy or seizures. Others, however, already exhibit signs of chronic cerebral disease at birth, with overt microcephaly and spasticity. In the perinatal period, HIE results in Apgar scores of less than 6 at 1 and 5 minutes. The infant may have poor color, reduced heart rate, and abnormal respiration, along with depressed muscle tone and reflexes. Low scores not only reflect HIE but also can be due to other causes, such as transplacental sedation or peripheral hypotonia due to lower motor neuron disease. The clinical pattern in infants of less than 34 weeks' gestation differs from that of full-term infants because the findings are nonspecific. Unless there is concurrent IVH (grade III or IV), preterm infants may show only poor response to stimulation, frequent apnea, and bradycardia. The more common clinical patterns of subacute HIE involving the cerebral cortex of infants of more than 36 weeks' gestation include three patterns: minimal lethargy and hypotonia; hyperalertness, often with hypertonia; or depression and severe hypotonia. Seizures are common in this last clinical pattern. Some children gradually show improvement in alertness and tone. Others have a few seizures before showing improvement. Infants with severe encephalopathy become more stuporous in the first 24 hours and have seizures, respiratory depression, brainstem abnormalities, and intermittent decerebration. They lose Moro and sucking reflexes and become unresponsive. Even with vigorous anticonvulsant and supportive therapy, 20% to 30% die. If an infant survives the first 48 to 72 hours, seizures usually stop. The patients remain hypotonic and stuporous for a variable period, depending on the severity of brain damage and the amount of drugs given to control the seizures. Laboratory Data At the time of labor, fetal heart tone records indicating late and variable deceleration of heart rate relative to uterine contractions, fixed intrauterine heart rate, and persistent fetal bradycardia may be evidence of placental insufficiency and fetal distress, which can lead to HIE. Although providing a warning for appropriate action, such as cesarean section, abnormal fetal heart tones do not necessarily correlate with subsequent brain damage. After birth, arterial blood gases show low partial pressure of oxygen, high partial pressure of carbon dioxide, and low pH. Serum glucose may be less than 40 Âľg/100 mL. Serum sodium may be decreased. Serum creatine kinase-BB isoenzyme activity may be elevated. CSF is usually normal, but the CSF lactic acid level is often increased. An EEG may reveal seizure activity that is clinically inapparent. In the interictal period, relatively inactive and burst-suppression patterns have been consistently correlated with poor outcome in infants of 36 weeks' gestational age or older. Impaired visual evoked responses and persistently abnormal brainstem auditory evoked responses may imply a poor prognosis. CT evidence of extensive areas of hypodensity of both gray and white matter suggests a guarded outlook. Magnetic resonance imaging (MRI), when not too risky to a patient's tenuous clinical state, may demonstrate early areas of hyperintensity, particularly in T2-weighted sequences, reflecting injury to the basal ganglia and other deep structures that is not evident on CT. Six months to 1 year later, the procedure may show delayed

myelination, as well as gray and white matter changes in the infant's brain. Treatment and Prognosis Because the hypoxic-ischemic insult involves several body systems, attention must be directed to the respiratory, cardiovascular, and renal systems, as well as the brain. Measures include respiratory support and maintenance of normal blood pressure and renal output while specific treatment of seizures and brain edema is undertaken. The treatment of seizures is discussed later. Steroids and osmotic agents have been used to treat brain edema in this setting with little success. In addition, given the therapeutic window during hypoxic-ischemic reperfusion described above, animal and early clinical trials with antiexcitotoxic amino acids (NMDA receptor antagonists), antioxidative substances, and nitric oxide inhibitors are being attempted in order to reduce neuronal death due to hypoxic-ischemic reperfusion. The prognosis is always guarded. The more rapid the recovery is from the initial depression, the better the outlook will be. Of infants with a benign neonatal course, 20% to 30% may still have neurologic sequelae ranging from intellectual impairment to spastic diplegia and seizures. At least 50% of those with neonatal seizures have serious morbidity. Prevention by rapid delivery (cesarean section) when there is evidence of intrauterine distress is still the best method of avoiding sequelae.

NEONATAL INFECTIONS Bacterial infections are commonly acquired perinatally. Viral or protozoan infections may be acquired in utero from the first trimester until delivery. Infections constituting the TORCH syndrome (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex) are discussed in Section III, Infections of the Nervous System. Only some particular features of perinatally acquired herpes simplex virus (HSV) infection are dealt with here. Neonatal Herpes Encephalitis Estimates of the incidence of active neonatal HSV infection are 1 per 15,000 live births. HSV infection may be acquired in utero or during passage through the birth canal. Most neonatal HSV infections are caused by HSV type 2 rather than HSV type 1. Some infants have only skin-eye-mouth disease, but 70% have either systemic or CNS disease. Infants with CNS involvement usually present in the second or third weeks of life. At presentation, infants with HSV septicemia may have respiratory disease, jaundice, fever, and CNS symptoms without evidence of skin or mucous membrane vesicles, much like those with only CNS involvement, who present with fever, irritability, and seizures. Laboratory investigation reveals lymphocytosis and increased protein in the CSF. Viral amplification with the polymerase chain reaction technique in the CSF has made diagnosis of HSV encephalitis quicker and more definite. Neuroimaging procedures, CT and MRI, may be normal but often show diffuse and, occasionally, focal abnormalities. Infants with suspected HSV infection should be treated with acyclovir (Zovirax), 30 mg/kg intravenously for 21 days. Mortality is in the neighborhood of 33%. Serious neurologic sequelae are frequent, particularly when multicystic encephalomalacia develops. Neonatal Meningitis Bacterial meningitis is usually seen in association with sepsis. The incidence of sepsis neonatorum is about 0.51 per 1,000 live births. In about 30% of patients with neonatal sepsis, there is spread to the meninges. At present in the United States, the predominant organism causing neonatal septicemia and meningitis is group B streptococci followed by gram-negative organisms, the most common being Escherichia coli, Proteus vulgaris, and Pseudomonas aeruginosa. Listeria monocytogenes and other organisms are sometimes encountered. Staphylococcus is now rare. Susceptibility to these organisms is attributed to immaturity of immune responses or of the blood–brain barrier. Pathologic changes in the newborn brain are similar to those in older children or adults. The clinical presentation of meningitis in the newborn is subtle. Meningeal signs are rarely elicited; lassitude and poor feeding may be the only abnormalities. Hypothermia, rather than fever, is a suggestive sign. Seizures may be the first sign. Only when the course is advanced does the fontanel bulge and the infant assumes a position of opisthotonos. Lumbar puncture shows CSF changes similar to those in older children, but CSF protein levels up to 150 µg/dL may be normal in newborns. The blood-to-CSF ratio is less valid, as newborns normally have blood glucose levels of 30 to 40 mg/dL. Cultures of the CSF may remain positive for 3 or 4 days, even after initiation of proper therapy. Because the disease may be advanced when it is clinically manifest, both mortality and morbidity remain high. Appropriate intravenous antibiotic therapy should be given for 3 weeks. Intrathecal and intraventricular therapy have not been effective. Parenchymal invasion and clinically significant subdural effusions are rare at this age. Gram-negative organisms, particularly Citrobacter, are most frequently implicated in neonatal abscess, which is rare.

NEONATAL SEIZURES Seizures in the neonatal period should always be considered symptomatic of serious underlying neurologic or systemic disease. Neonatal convulsions imply at least 17% mortality and 30% serious morbidity. The prognosis depends mainly on the cause of the seizures and on rapid establishment of the diagnosis and treatment; however, it is difficult to recognize the clinical expressions of abnormal cortical discharges, particularly in infants of less than 35 weeks' gestation in whom conventional clinical and EEG seizure patterns are infrequently seen. Classification Neonatal seizures occur in several forms. Focal and multifocal clonic seizures are the most frequent varieties that have clear electrical concomitants. They constitute 50% of neonatal convulsions and may begin as jerking of a limb, twitching on one side of the face, or rhythmic horizontal deviation of the eyes. More often than not, the convulsions become multifocal. Clonus or “jitteriness” may be misinterpreted as a seizure. The rhythm of a seizure is slow, three to four jerks per second; clonus or nonspecific tremor is about 6 to 12 jerks per second. Moreover, clonus or tremulousness can be started or stopped by altering the position of a limb. Tonic postures are the next most common kind of neonatal seizure. An arm may be extended with or without horizontal eye deviation or head turning. These seizures may not be recognized by nursery personnel and may look like yawning or stretching. Total-body extension with arm flexion or opisthotonic postures and vertical eye movements may be overinterpreted as seizures. These decerebrate or decorticate postures have no electrographic correlation and are likely to occur in infants of less than 34 weeks' gestational age with IVH. Classic grand mal seizures or infantile myoclonic seizures are rare in the newborn. Myoclonus is often stimulus-sensitive and suggests severe brain damage or drug withdrawal. Certain adventitious movements, frequently classified as “subtle seizures,” in most cases do not show evidence of an electrical-cortical genesis on video/EEG studies. These abnormal movements include mouthing, tongue thrusting, “pedaling” and “bicycling” of limbs, and chaotic eye shifting. The movements are attributed to brainstem or frontal release phenomena. Often seen in severe encephalopathy, these movements then imply a grave prognosis. Until their genesis is established, calling them “seizures” is not advised because this term implies benefit from anticonvulsant drug therapy. Apnea accompanied by bradycardia in the preterm infant is a frequent but poorly understood event. In infants of 36 weeks' gestation or older, apnea without bradycardia is often accompanied by other types of seizures and is an important type of convulsion to recognize. It responds to anticonvulsants, whereas depressant agents are contraindicated in the apnea of the premature. Diagnosis Once a seizure is identified, diagnostic evaluation should proceed as rapidly as possible. Family, pregnancy, delivery history, and physical examination may provide essential clues to etiology. The first laboratory tests should evaluate the common metabolic and infectious disorders that require specific treatment. A dipstick test for hypoglycemia and lumbar puncture to exclude meningitis or hemorrhage are essential. Then blood glucose, calcium, magnesium, sodium, and acid–base values should be obtained plus a blood culture. EEG studies must be promptly undertaken if abnormal movements are not clearly identified as seizures. Sonography provides information about large hemorrhages. CT will confirm these, other forms of ICH, calcifications, congenital anomalies, and ischemic damage. MRI is helpful for more subtle migration and myelinization defects. If a congenital infection is suspected, TORCH antibody titers should be drawn. If seizures do not respond to initial

treatment, pyridoxine, 50 mg, should be given intravenously to rule out rare pyridoxine dependency. Blood, urine, and CSF should then be analyzed for errors of inborn metabolism that present in the neonatal period: phenylketonuria, maple syrup urine disease, lactic or organic acidemias, ammonia cycle abnormalities, and nonketotic hyperglycinemia. Etiology and Prognosis The outcome of neonatal seizures is linked to etiology ( Table 74.1). In some metabolic disorders, prognosis is better the sooner treatment starts. Surveys of prognosis have given different estimates because some institutions see more neonatal seizures of benign etiology (e.g., late hypocalcemia), while others classify all adventitious movements as seizures.

TABLE 74.1. RELATIONSHIP OF NEUROLOGIC DISEASE TO PROGNOSIS IN NEONATAL SEIZURES

The EEG, judiciously interpreted, may help determine the prognosis. The proper time for an EEG is 24 to 72 hours, as in newborns the EEG often becomes normal in a few days and may lose prognostic significance. Five types of interictal EEG patterns are observed in infants of 36 to 42 weeks' gestation: normal, unifocal spike with normal background, multifocal spike, burst-suppression, and inactive or flat. The first two types suggest a 70% chance of a good outcome. A poor prognostic cause, however, is more important than any EEG pattern. Multifocal spikes, especially with abnormal backgrounds, imply only a 20% chance of a good prognosis. The burst-suppression pattern, not to be confused with the normal deep-sleep pattern, invariably implies a bad outcome. The inactive or low-voltage EEG has the same poor prognosis, although it may be hard to interpret when anticonvulsant drug levels are high. Treatment Treatment of neonatal seizures is either specific or symptomatic. Metabolic encephalopathies require specific therapy. Documented neonatal hypoglycemia (defined as a blood glucose level of less than 40 mg/dL in a full-term infant and less than 30 mg/dL in a premature infant) is usually treated with an intravenous bolus of 25% to 50% glucose followed by a maintenance infusion of 10% dextrose. Hypocalcemia (defined as a blood calcium level of less than 7 mg/dL) is of two varieties. The late-onset (after day 5) benign type is usually seen in full-term infants who are given high-phosphate formulas and who have multifocal seizures. When hypocalcemia is suspected, blood should be drawn for calcium levels. Treatment involves giving intravenous doses of calcium gluconate with electrocardiograph monitoring. When the blood calcium level does not rise in response to this therapy, it may respond to intramuscular therapy with magnesium sulfate. The seizures of infants with early-onset hypocalcemia may not respond to therapy because this type of hypocalcemia often accompanies severe ICH or HIE. Severe encephalopathy with inappropriate antidiuretic hormone secretion causes hyponatremia, which may also result from iatrogenic overhydration. It is controlled by fluid restriction. Other metabolic encephalopathies are difficult to treat and have a poor prognosis. General supportive care should not be forgotten; when possible, therapy should be carried out in a neonatal intensive care unit. An adequate airway should be ensured, and means for mechanical respiration should be available. A single seizure is treated with an intravenous loading dose of phenobarbital, 20 mg/kg, over 10 minutes followed by a maintenance dose of 5 mg/kg per day in two 12-hour doses. Blood phenobarbital levels of 20 to 40 µg/dL should be established and maintained. In status epilepticus, the same loading dose is given over 2 minutes. If seizures persist, two more 10 mg/kg doses can be administered over 1 or 2 hours. A blood level of 40 to 60 mg/kg for 1 or 2 days is justified in the attempt to suppress continuous epileptic activity. If phenobarbital fails, phenytoin sodium (Dilantin), 20 mg/kg, can be given intravenously over 15 minutes with cardiac monitoring. If status epilepticus continues, a 4% paraldehyde intravenous drip is titrated against seizure activity. Intravenous diazepam and lorazepam (Ativan) have increasingly been employed. Awareness of severe respiratory depression when benzodiazepines are combined with barbiturates is essential. In the newborn, maintenance dosage of phenobarbital is 3 to 5 mg/kg per day administered orally, intramuscularly, or intravenously in two 12-hour doses. Phenytoin should be given intravenously (because it has poor oral absorption) at 7 to 10 mg/kg per day in two 12-hour doses. In infants with single or easily controlled seizures, an anticonvulsant may be tapered on discharge. Others remain on phenobarbital maintenance (5 µg/kg per day) for 1 to 3 months, allowing the infant to self-taper by not increasing the dose with weight gain. SUGGESTED READINGS Intracranial Hemorrhage Allan WC. The IVH complex of lesions: cerebrovascular injury in the preterm infant. Neurol Clin 1990;8:529–551. Bergman I, Bauer RE, Barmada MH. Intracerebral hemorrhage in the full-term neonatal infant. Pediatrics 1985;75:488–496. Goddard-Finegold J, Mizrahi EM. Understanding and preventing perinatal peri- and intraventricular hemorrhage. J Child Neurol 1987;2:170–185. Guzzetta F, Shackelford GD, Volpe S, et al. Periventricular intraparenchymal echodensities in the premature newborn: critical determinant of neurologic outcome. Pediatrics 1986;78:995–1006. Horbar JD. Antenatal corticosteroid treatment and neonatal outcomes for infants 501 to 1500 gm in the Vernont-Oxford Trials Network. Am J Obstet Gynecol 1995;173:275–281. Ment LR, Oh W, Ehrenkranz RA, et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics 1994;93:543–550. Paneth N, Rudelli R, Monte W, et al. White matter necrosis in very low birth weight infants: neuropathologic and ultrasonographic findings in infants surviving six days or longer. 1990;116:975–984.

J Pediatr

Pape KE, Wigglesworth JS. Hemorrhage, ischemia and the perinatal brain. Philadelphia: JB Lippincott Co, 1979. Pearlman JM, Goodman S, Kreuser KL, et al. Reduction in intraventricular hemorrhage by elimination of fluctuating cerebral blood flow velocity in preterm infants with respiratory distress syndrome. Engl J Med 1985;312:1353–1356. Perrin RG, Rutha JT, Drake JM, et al. Management and outcome of posterior fossa subdural hematomas in neonates. Neurosurgery 1997;40:1190–1199. Roland EH, Hill A. Intraventricular hemorrhage and posthemorrhagic hydrocephalus: current and potential future interventions. Clin Perinatol 1997;24:589–605. Van de Bor M, den Ouden L, Guit GL. Value of cranial ultrasound and magnetic resonance imaging in predicting neurodevelopmental outcome in preterm infants. Pediatrics 1992;90:196–199. Volpe JJ. Neurology of the newborn, 3rd ed. Philadelphia: WB Saunders, 1995.

N

Welch K, Strand R. Traumatic parturitional intracranial hemorrhage. Dev Med Child Neurol 1986;28:156–164. Hypoxic-ischemic Encephalopathy Adsett DB, Fitz CR, Hill A. Hypoxic-ischemic injury in the term newborn: correlation of CT findings with neurological outcome. Dev Med Child Neurol 1985;27:155–160. Banker BA, Larroche JC. Periventricular leukomalacia of infancy. Arch Neurol 1962;7:386–410. Du Plessis AJ, Johnston MV. Hypoxic-ischemic brain injury in the newborn: cellular mechanisms and potential strategies for neuroprotection. Clin Perinatol 1997;24:627–654. Edwards AD, Yue X, Cox P, et al. Apoptosis in the brains of infants suffering intrauterine cerebral injury. Pediatr Res 1997;39:584–590. Gluckman PD, Williams CE. When and why do brain cells die? Dev Med Child Neurol 1992;34:1010–1014. Hanrahan JD, Sargentoni J, Azzopardi D, et al. Cerebral metabolism within 18 hours of birth asphyxia: a proton magnetic resonance spectroscopy study. Pediatr Res 1996;39:584–590. Lupton BA, Hill A, Roland EH, Whitfield MF, Flodmark O. Brain swelling in the asphyxiated term newborn: pathogenesis and outcome. Pediatrics 1988;82:139–146. Marin-Padilla M. Developmental neuropathology and impact of perinatal damage. I: hemorrhagic lesions of neocortex. J Neuropathol Exp Neurol 1996;55:758–773. Myers RE. Experimental models of periventricular brain damage: relevance to human pathology. In: Gluck L, ed. Intrauterine asphyxia and the developing brain. Chicago: Year Book Medical Publishers, 1977:337–397. Nelson KB, Ellenberg, JH. Antecedents of cerebral palsy. N Engl J Med 1986;315:81–86. Painter MJ. Fetal heart rate patterns, perinatal asphyxia, and brain injury. Pediatr Neurol 1989;5:137–144. Pasternak JF, Gorey MT. The syndrome of acute near-total intrauterine asphyxia in the term infant. Pediatr Neurol 1998;18:391–398. Rivkin MJ. Hypoxic-ischemic brain injury in the term newborn: neuropathology, clinical aspects, and neuroimaging. Clin Perinatol 1997;24:607–626. Roth SC, Edwards AD, Cady EB, et al. Relation of deranged neonatal cerebral oxidative metabolism asphyxia, with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol 1997;39:758–773. Infections Bale JF Jr, Murph JR. Infections of the central nervous system in the newborn. Clin Perinatol 1997;24:787–806. Bell WE, McCormick WF. Neurologic infections in children, 2nd ed. Philadelphia: WB Saunders, 1989. Edwards MS, Rench MA, Haffer AA, et al. Long-term sequelae of group B streptococcal meningitis in infants. J Pediatr 1985;106:717–722. Franco S, Cornelius V, Andrews B. Long-term outcome of neonatal meningitis. Am J Dis Child 1992;146:567–571. Kline M. Citrobacter meningitis and brain abscess in infancy: epidemiology, pathogenesis and treatment. J Pediatr 1988;113:430–434. Whitley R, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex viral infection.

N Engl J Med 1991;324:444–449.

Seizures Clancy RR, Legido A. Postnatal epilepsy after EEG-confirmed neonatal seizures. Epilepsia 1991;32:69–76. Holden KR, Mellitis ED, Freeman JM. Neonatal seizures I. Correlation of prenatal and perinatal events with outcome. Pediatrics 1982;70:165–176. Koenigsberger MR. Abnormal neonatal movements, intracranial hemorrhage, asphyxia. Pediatr Ann 1983;12:798–804. Koenigsberger MR, Caballar-Gonzaga FJ, Dierkes T. Neonatal seizures: initiation and discontinuation of therapy. REV NEUROL 1997;25: 706–708. Koivisto M, Blanco-Sequieros M, Krause U. Neonatal symptomatic hypoglycemia: a follow-up study of 151 children. Dev Med Child Neurol 1972;14:603–609. Legido A, Clancy RR, Berman PH. Recent advances in the diagnosis, treatment, and prognosis of neonatal seizures. Pediatr Neurol 1988;4:79–86. Lynch BJ, Rust RS. Natural history of neonatal hypocalcemic and hypomagnesemic seizures. Pediatr Neurol 1994;11:23–27. Maytal J, Novak GP, King KC. Lorazepam in the treatment of refractory neonatal seizures. J Child Neurol 1991;6:319–323. Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987;37:1837–1844. Painter MJ, Gaus LM. Neonatal seizures: diagnosis and treatment. J Child Neurol 1991;6:101–108. Rose AL, Lombroso CT. Neonatal seizures states: a study of clinical features in 137 full-term babies with long-term follow-up. Pediatrics 1970;45:404–425. Ryan SG, Wizniter M, Hollman C, et al. Benign familial neonatal convulsion: evidence for clinical and genetic heterogeneity. Scher MS. Seizures in the newborn infant: diagnosis, outcome and treatment. Clin Perinatol 1997;24:736–772. Volpe JJ. Neurology of the newborn, 3rd ed. Philadelphia: WB Saunders, 1995.

Ann Neurol 1991;29:469–473.

CHAPTER 75. FLOPPY INFANT SYNDROME MERRITT’S NEUROLOGY

CHAPTER 75. FLOPPY INFANT SYNDROME THORNTON B.A. MASON II AND DARRYL C. DE VIVO Focal Neonatal Hypotonia Dysgenetic Syndromes Neuromuscular Disorders Suggested Readings

When a normal infant is suspended in the prone position, the arms and legs move out, and the head is held in line with the body. In many different disorders, a child does not respond in this fashion. Rather, the limbs and head all hang limply—like a ragdoll. That is why the floppy infant syndrome has caught on as a popular term. In addition to children with these abnormal postures, some clinicians have extended the use of the term to include those with diminished resistance of limbs to passive movement and with abnormal extensibility of joints. The number of conditions that sometimes cause these manifestations seems endless, including disorders of the brain, spinal cord, peripheral nerves, neuromuscular junction, muscles, and ligaments, as well as some disorders of unknown origin. The number of possible causes of floppy infant syndrome makes diagnosis of the primary disorder seem impossible. There are almost always clues of some kind, however, that narrow the list of possible causes to a few choices. An essential division separates conditions found in the newborn infant from those occurring later ( Table 75.1). A second division separates conditions characterized by true limb weakness (often with no tendon reflexes) from those with clear neurologic signs or cerebral injury without true limb weakness. Among the latter, there are likely to be signs of mental retardation, dysmorphic physical evidence of chromosomal abnormality, or evidence of metabolic abnormality.

TABLE 75.1. FLOPPY INFANT SYNDROMES

A third diagnostic consideration concerns illness in the mother and the perinatal history. If the mother is known to have myotonic muscular dystrophy or myasthenia gravis, depressed movement in the infant is immediately recognized. The correct diagnosis in the child may be the first clue to explain previously unrecognized manifestations of illness in the mother. Similarly, maternal narcotic drug abuse, alcoholism, or use of anticonvulsant medications may affect the infant. Perinatal events may lead to suspicion of asphyxia or cerebral hemorrhage. A fourth consideration is the distribution of the abnormality. Are all four limbs, or only the legs, or one arm affected? Are sucking and swallowing impaired? The answers have different diagnostic implications. The most common causes of hypotonia are perinatal insult to the brain or spinal cord, spinal muscular atrophy, and dysgenetic syndromes. About 75% of cases fall into these categories. Spinal muscular atrophy, however, is only rarely evident immediately after birth. The neonatologist considers common perinatal insults such as birth asphyxia, hypoxic-ischemic insults, intracranial hemorrhage, bacterial or viral infections, metabolic disturbances, and extreme prematurity as principal causes of hypotonia in the newborn nursery. Congenital hypoglycemia or hypothyroidism may be suggested by hypothermia. Spinal cord injuries usually follow intrauterine malpositioning or traumatic birth. Severe asphyxia may also affect the lower motor neurons of the spinal cord. Autopsy studies of fatally asphyxiated neonates with flaccid tone and areflexia demonstrate prominent ischemic necrosis of anterior spinal cord gray matter in a radially oriented, watershed distribution consistent with hypoperfusion between the anterior spinal artery and the paired dorsal spinal arteries. In these conditions, the perinatal history is informative, and the hypotonic infant has associated behavioral alterations, including decreased responsiveness or seizures. Dysmorphic features are absent, and tendon reflexes are present.

FOCAL NEONATAL HYPOTONIA This disorder may be caused by trauma or developmental abnormality. A flaccid arm usually implies brachial plexus injury. Signs of injury to the upper brachial plexus may be associated with ipsilateral paralysis of the diaphragm; lower brachial plexus lesions may be accompanied by an ipsilateral Horner syndrome. Electromyography and spinal evoked potentials help define the severity of the nerve root injury. Spinal cord imaging may document nerve root avulsion. Hypotonia and weakness of the legs indicate spinal cord pathology. Spinal dysraphism and the caudal regression syndrome are obvious on inspection of the back. An arthrogrypotic leg deformity or gross maldevelopment of the legs is associated with sacral agenesis. Fifteen percent of patients with sacral agenesis are infants of diabetic mothers.

DYSGENETIC SYNDROMES These syndromes are often associated with distinctive dysmorphic physical features. The neurologic disorder may not be recognized until the infant fails to reach certain developmental stages. Common syndromes associated with hypotonia are Down syndrome, Prader-Willi syndrome, Lowe syndrome, Zellweger syndrome, Smith-Lemli-Opitz syndrome, and the Riley-Day (familial dysautonomia) syndrome. Environmental toxins may also produce hypotonia and dysmorphism. Common examples include fetal exposure to heroin, phenytoin sodium (Dilantin), trimethadione (Tridione), or alcohol. Strength is normal in these syndromes, but the tendon reflexes may vary from nondetectable to brisk.

NEUROMUSCULAR DISORDERS Neuromuscular disorders that cause infantile hypotonia do not impair mental alertness but are characterized by decreased limb movement (because of muscle weakness) and decreased tendon reflexes. Dysmorphic features accompany many congenital myopathies. After the immediate neonatal period, spinal muscular atrophy is the most common cause of infantile hypotonia. This autosomal-recessive disorder (Werdnig-Hoffmann disease) may sometimes be evident at birth. The characteristic findings include limb weakness, areflexia, and fasciculations of the tongue. Although most affected infants die before age 2 years, some survive for decades. Poliomyelitis is now uncommon as a cause of limb weakness. The neurologic findings are asymmetric and are accompanied by signs of meningeal irritation with cerebrospinal fluid (CSF) pleocytosis and elevated protein content. Infantile neuropathies are uncommon causes of weakness, areflexia, and hypotonia. Examples include metachromatic leukodystrophy, globoid cell leukodystrophy, infantile neuroaxonal dystrophy, giant axonal neuropathy, neonatal adrenoleukodystrophy, hypertrophic interstitial polyneuropathy, and peroneal muscular atrophy. Important clues may include a family history, palpably enlarged peripheral nerves, upper motor neuron signs, elevated CSF protein concentration, and slowed nerve conduction velocities. Guillain-Barré syndrome rarely presents in infancy. Diphtheria, caused by Corynebacterium diphtheriae, produces a generalized demyelinating

polyneuropathy clinically similar to Guillain-Barré syndrome. A protein exotoxin secreted by the organism inhibits myelin synthesis and may also activate cytotoxic mechanisms. Tick paralysis has a rapid onset, producing a hypotonic picture also similar to Guillain-Barré syndrome, and usually occurs in the spring and summer months. The paralysis is caused by a tick that is continuously attached and secreting toxin-laden saliva; removal of the tick is rapidly curative. Disturbances at the myoneural junction may cause limb weakness. Fluctuating signs intensified by vigorous crying or limb activity are important observations. Congenital myasthenia gravis often affects siblings and is thought to be inherited as an autosomal-recessive disorder. This condition is considered nonimmunologic. Clinically, the infant may display external ophthalmoplegia and generalized weakness; sudden respiratory failure rarely occurs. Autoimmune forms of myasthenia gravis in infancy include the transient neonatal form in infants of myasthenic mothers. The juvenile form ordinarily does not cause symptoms before age 2 years. Acetylcholine receptor antibodies, sensitivity to curare, and responsiveness to plasmapheresis distinguish these myasthenic syndromes from the inherited nonimmunologic forms. Another condition affecting neuromuscular transmission is infantile botulism, which results from ingestion of Clostridium botulinum spores that germinate in the intestinal tract. Manifestations include ileus, constipation, hypotonia, weakness, pupillary dilation, and apneic spells. The clinical picture is distinctive, and diagnosis can be confirmed by the recovery of the bacterium and the exotoxin in the feces. A facilitating response to repetitive stimulation (such as that of the Eaton-Lambert syndrome) can usually be demonstrated and may be an important diagnostic clue. Attention should be paid to avoiding any medications that might exacerbate the neuromuscular transmission deficit, in particular aminoglycoside antibiotics that are sometimes initiated empirically at presentation for possible sepsis. Complete recovery follows appropriate supportive care. Myopathies that cause infantile limb weakness include the congenital myopathies with specific structural abnormalities, myotonic muscular dystrophy, and metabolic myopathies. Although the term muscular dystrophy usually implies progressive disease, the term has been applied to apparently static congenital disorders in which the changes in muscle biopsy are myopathic but have no specific features. In Japan, the Fukuyama type of congenital muscular dystrophy is characterized by severe mental retardation in all cases and seizures in about 50%. Symptoms may start soon after birth, with difficulty nursing and impoverished movement. The children never walk but may live for decades. The cerebral pathology is distinctive, with polymicrogyria of the occipital lobes in a pattern that can be recognized by magnetic resonance imaging. Similar cases have been seen in the United States and Europe. The histochemically defined myopathies may be inherited as autosomal-dominant or autosomal-recessive traits or as a sex-linked recessive trait. These disorders share many phenotypic features that overlap with other syndromes. Examples include central core disease, multicore disease, nemaline myopathy, myotubular (centronuclear) myopathy, congenital fiber-type disproportion, sarcotubular myopathy, fingerprint-body myopathy, and reducing-body myopathy. Muscular weakness, decreased tendon reflexes, dysmorphic physical features, a predisposition to congenital hip dislocation, and later development of scoliosis characterize most of the histochemically defined myopathies. The similarities often outweigh the differences. Infantile acid maltase deficiency (Pompe disease) is the classic example of a metabolic myopathy and motor neuron disease that causes infantile hypotonia. The affected infant is mentally alert but weak and areflexic. As associated findings, the tongue and heart are enlarged; congestive heart failure is the cause of death before age 6 months. Other metabolic myopathies that may cause infantile hypotonia and weakness include cytochrome- c-oxidase deficiency (benign reversible and fatal forms), the mitochondrial DNA depletion syndrome, glycogenosis type IV (debrancher enzyme deficiency), and glycogenosis type V (myophosphorylase deficiency). Cytochrome-c-oxidase deficiency and mitochondrial DNA depletion syndrome are associated with lactic acidosis. A few hypotonic infants eventually develop normally after several years. The term essential hypotonia should be reserved to describe an otherwise healthy infant with unexplained hypotonia and normal strength, tendon reflexes, and general physical features. SUGGESTED READINGS Brooke MH, Carroll JE, Ringel SP. Congenital hypotonia revisited. Muscle Nerve 1979;2:84–100. DiMauro S, Hartlage PL. Fatal infantile form of muscle phosphorylase deficiency. Neurology 1978;28:1124–1129. DiMauro S, Mendell JR, Sahenk Z, et al. Fatal infantile mitochondrial myopathy and renal dysfunction due to cytochrome-C75-oxidase deficiency. Neurology 1980;30:795–804. DiMauro S, Nicholson JF, Hays AP, et al. Mitochondrial myopathy due to reversible cytochrome-C75-oxidase deficiency. Ann Neurol 1983;14:226–234. Dubowitz V. The floppy infant. London: Spastics International Medical Publications, 1969. Dubowitz V. Muscle disorders in childhood. Philadelphia: WB Saunders, 1978. Engel AG. Myasthenia gravis and myasthenic syndromes. Philadelphia: FA Davis, 1999. Gillessen-Kaesbach G, Gross S, Kaya-Westerloh S, et al. DNA methylation based testing of 450 patients suspected of having Prader-Willi syndrome. J Med Genet 1995;32:88–92. Hagberg B, Sanner G, Steen M. The dysequilibrium syndrome in cerebral palsy: clinical aspects and treatment. Acta Paediatr Scand Suppl 1972;226:1–63. Helbling-Leclerc A, Zhang X, Topaloglu H, et al. Mutations of the laminin a2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet 1995;11:216–218. Osawa M, Shishikura K. Werdnig-Hoffmann disease and variants. In: Vinken PJ, Bruyn GW, Klawans HL, De Jong JMBV, ed. Diseases of the motor system. Handbook of clinical neurology, vol 59. New York: Elsevier Science, 1991:51–80. Pickett J, Berg B, Chaplin E, Brunstetter-Shaffer MA. Syndrome of botulism in infancy: clinical and electrophysiological study. N Engl J Med 1976;295:770–772. Sarnat HB. Neuromuscular disorders in the neonatal period. In: Korobkin R, Guilleminault C, eds. Advances in perinatal neurology. New York: SP Medical & Scientific Books, 1979;1. Schaumburg HH, Kaplan JG. Toxic peripheral neuropathies. In: Asbury AK, Thomas PK, eds. Peripheral nerve disorders 2. Oxford: Butterworth-Heinemann, 1995:238–261. Toda T, Segawa M, Nomura Y, et al. Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33. Nat Genet 1993;5:283–286. Vu TH, Sciacco M, Tanji K, et al. Clinical manifestations of mitochondrial DNA depletion. Neurology 1998;50:1783–1790.

CHAPTER 76. STATIC DISORDERS OF BRAIN DEVELOPMENT MERRITT’S NEUROLOGY

CHAPTER 76. STATIC DISORDERS OF BRAIN DEVELOPMENT ISABELLE RAPIN Developmental Disorders of Motor Function Developmental Disorders of Higher Cerebral Functions Suggested Readings

The immature brain can be adversely affected at any time from fertilization to maturity because genetic or acquired disorders may disrupt developmental programs or inflict physical damage. Among the causes are cerebral malformations, intrauterine or extrauterine infections or strokes, and perinatal trauma or ischemic-anoxic insults that may or may not lead to gross motor impairments (cerebral palsy) or learning disorders. Genetic factors play a major etiologic role in developmental disabilities unassociated with detectable lesions or overt sensorimotor abnormalities.

DEVELOPMENTAL DISORDERS OF MOTOR FUNCTION Minor Motor Disability This term refers to subtle impairments of motor coordination, such as clumsiness, maladroitness, or developmental dyspraxia. Some of these impairments, such as reflex asymmetry or hyperactivity and minor dysmetria, are mild or “pastel” classic neurologic signs; others may be due to delayed acquisition of independent coordination of the two hands and maintenance of posture without adventitious movements. The neurologic basis of these “soft” signs is rarely known. They may occur in isolation but are often seen in children with specific learning disabilities or mild mental deficiency. Cerebral Palsy The term cerebral palsy (CP) has no etiologic specificity and refers to any nonprogressive motor disorder of cerebral or cerebellar origin. (CP does not apply to disorders of the spinal cord, peripheral nerves, or muscles.) The signs are present from early life and are evident on a standard neurologic examination. CP is often, though not invariably, an acquired lesion that is evident on neuroimaging ( Table 76.1). The type of CP depends on the location of the lesion.

TABLE 76.1. CLINICAL VARIANTS OF CEREBRAL PALSY (CP)

Spastic Hemiparesis (Hemiplegia) Spastic hemiparesis (hemiplegia) arises from a lesion of the corticospinal system of one cerebral hemisphere. A common cause is an intrauterine stroke that results in congenital porencephaly in the territory of the trunk or a branch of the middle cerebral artery. Strokes can also occur during the birth process and in infancy (acute infantile hemiplegia). Another common cause of hemiplegic CP is intraventricular hemorrhage complicated by intraparenchymal hemorrhage, which occurs in small, premature infants and starts as a germinal matrix hemorrhage. In late childhood, neuroimaging may reveal smallness of the entire hemisphere and an old infarct; the skull is thicker on the affected side, the sphenoid wing and petrous bone are elevated, and the frontal sinuses and mastoid air cells are larger. These changes are called the Davidoff-Dyke-Masson syndrome. Typically, the hemiparesis affects the arm and hand more than the leg. All children with hemiplegic CP walk, albeit often later and on the toes of the affected foot because of a tight heel cord that may necessitate surgical lengthening. Growth “arrest” of the arm and leg is frequent in lesions that involve the parietal lobe; the arm and leg are shorter and thinner, and there may be a compensatory scoliosis. In mild cases, decreased associated movements of the arm may be seen only in running or walking on the heels. Comparing fingernails on the two sides may demonstrate minor growth arrest. A purely motor hemiparesis may be due to a frontal lesion or one that affects the head of the caudate nucleus and adjacent internal capsule. Larger lesions are associated with cortical sensory loss involving position sense, stereognosis, neglect, and lack of use of the affected hand except as a prop. Tone in the hand may be decreased rather than increased, and there may be severe laxity of hand and finger ligaments, sometimes with joint deformities. Prognosis for habilitation of the hand is poor. Posterior lesions are associated with contralateral hemianopsia or spatial neglect. Hemiparesis may not be evident until the child starts to grab for objects and shows precocious handedness or failure of hand use; this delay does not imply that the lesion was acquired postnatally. Spasticity tends to increase in the first and second years and is more evident when the child is erect than supine. Seizures are frequent when the lesion affects the cortex. Children with large unilateral lesions, intractable seizures, and severe behavior disorders may be candidates for hemispherectomy or other excisional surgery. Speech may be delayed but competent in children with hemiplegic CP and a strictly unilateral lesion in either hemisphere. Intelligence may be spared despite subtle neuropsychologic differences between right and left lesions; children with right lesions tend to pay more attention to details of a visual display than to the overall pattern, whereas those with left lesions attend to the overall pattern but overlook details. Drawings of young children with right-sided lesions are more disorganized than those of children with left-sided lesions. As infants, children with right-sided lesions tend to be more irritable and cry more than those with left-sided lesions. Spastic Diplegia or Diparesis In spastic diplegia or diparesis, or Little disease, spasticity predominates in the legs and less severely affects the hands and face. Tendon reflexes are hyperactive and the toes upturning. The most common causes are prematurity with bilateral germinal matrix hemorrhage with or without intraventricular hemorrhage and hydrocephalus, and perinatal ischemia in the watershed parasagittal zone between the territories of the anterior and posterior cerebral arteries. Adductor spasm is responsible for “scissoring” of the legs, and marked spasticity may preclude ambulation without a walker and long-leg braces. Intelligence and language are often unimpaired, but there may be variable clumsiness of the hands. Spastic Quadriplegia Spastic quadriplegia is the most severe variant of CP, often associated with moderate to severe mental deficiency. It denotes diffuse malformation of or damage to the brain such as multicystic leukomalacia following severe ischemia, or lissencephaly. In some cases, bilateral porencephalies cause a double hemiplegia, with the

hands more severely affected than the legs. Severe limb spasticity may be associated with axial and neck hypotonia. Children with quadriparesis are rarely able to walk, and most are totally dependent and require wheelchairs, with neck and trunk supports. Pseudobulbar manifestations often preclude speech and severe dysphagia may lead to feeding gastrostomy. Seizures are frequent and difficult to control. Poor hand use almost always prevents the acquisition of sign language, making the assessment of cognition very difficult. Every effort must be made to provide an alternate means of expression, such as pointing. A child who understands that pointing means “I want� may learn to use a communication board and, potentially, a computer with voice. Even such a rudimentary means for communication greatly enhances the quality of life of these children and their caretakers. To relieve spasticity, dantrolene sodium (Dantrium) produces weakness, diazepam induces drowsiness, and oral baclofen (Lioresal) has a modest effect. Baclofen is more effective in spastic quadriplegia when administered by continuous intrathecal infusion. Injection of botulinum toxin into spastic muscles decreases spasticity for a number of months but requires reinjection. Selective dorsal rhizotomy relieves spasticity without causing weakness and may significantly enhance function. In most patients, ongoing physical therapy, orthoses, and orthopedic procedures are still needed. Hypotonic Cerebral Palsy Children with hypotonic CP are floppy, but most have hyperactive tendon reflexes, in contrast to those with lower motor neuron or primary muscle diseases. The pathophysiology of this syndrome is not understood, but there is usually severe mental deficiency with evidence of diffuse brain involvement, for example, a major malformation. Dyskinetic Cerebral Palsy In children with dyskinetic CP, basal ganglia lesions lead to abnormal involuntary movements, including athetosis, choreoathetosis, or dystonia. Most dyskinetic CP follows neonatal hyperbilirubinemia (kernicterus) and severe anoxia. The main cause of hyperbilirubinemia is neonatal blood group incompatibility, a preventable cause of CP that has become rare in the United States. Unconjugated bilirubin selectively damages the basal ganglia, central auditory and vestibular pathways, and the deep cerebellar nuclei, sparing the cortex. As a result, these children with dyskinetic CP, who may be unable to speak because of facial dyskinesia and hearing loss and have little or no hand use, may have normal intelligence. In contrast, children with dyskinetic CP following anoxia are likely to have both cortical and subcortical damage (status marmoratus of the basal ganglia) with intellectual as well as motor handicaps. It is crucial to test the hearing of all children with dyskinetic CP. The hearing loss of kernicterus is typically a high-tone loss; the children are not deaf but cannot discriminate the consonants that convey most of the meaning of speech. Assessment of cognitive skills is difficult because of the motor handicap and hearing loss, but it is crucial; it may have to rely on interest in the environment, development of nonverbal communication, and the views of parents. Athetosis is not present at birth; the movements emerge after age 1 year. In early infancy, the children are hypotonic with poor head and trunk control and little or no use of the hands. The first sign of athetosis may be tongue thrusting that makes spoon-feeding difficult. Severely affected children are helpless and unable to walk. Some gain sufficient control of a fist, a foot, or the head to manipulate a wand and communicate with a computer or a communication board. Some children walk but assume grotesque postures and have stigmatizing facial grimaces, dysarthria, and dysphagia. Many drugs have been tried in athetosis, but none is adequately effective. High doses of trihexyphenidyl pushed to tolerance may have a modest effect on dystonia; carbidopa is sometimes effective; chlorpromazine hydrochloride (Thorazine) is sedative and may have long-term side effects. The danger of irreversible anarthria following bilateral stereotactic surgery on the basal ganglia or thalamus has decreased with higher-resolution magnetic resonance imaging (MRI) and the making of smaller, better-targeted lesions. Ataxic Cerebral Palsy Ataxic CP is rare and usually denotes maldevelopment of the cerebellum or its pathways, which, if severe, may be associated with significant cognitive impairment. The differential diagnosis includes benign familial tremor, which may be seen in the preschool years, as well as a slowly progressive genetic metabolic disease rather than a static condition. Truncal and gait ataxia are more striking than limb ataxia, but some children take a long time to learn to feed themselves and have severe difficulty in writing. The children eventually learn to walk but fall frequently. Nystagmus is uncommon. Speech may be slow and scanning. Ataxic CP does not respond well to physical therapy or to any drug but may improve with age. Mixed Cerebral Palsy Mixed CP refers to the combination of dyskinetic and spastic CP, or ataxia and athetosis. It is also used for children who do not meet strict criteria for one of the major forms. Management of Cerebral Palsy Children with CP should be referred to a specialized assessment center as soon as they are identified. In the 1990s, most children with significant CP undergo neuroimaging to determine the basis of the motor disorder and to be sure that there is no remediable condition, such as hydrocephalus. Hearing must be tested early, with the use of brainstem evoked responses or cochlear emissions in children who cannot cooperate for audiometry. Vision must be assessed: Many children with CP have strabismus or a refractive error; myopia is particularly frequent in children born prematurely. Early evaluations of communication and cognitive skills, although essential, are descriptive and not necessarily predictive; response to intervention is a more reliable gauge of abilities than a one-shot test. Early intervention programs typically provide all required therapies in one center. Physical therapy is essential to train ambulation, stretch spastic muscles, and prevent deformities; it may not avoid the need for surgical procedures such as tendon releases or transplants, as well as for those described earlier. Occupational therapy focuses on self-help skills and language therapy on interpersonal communication. These centers teach parents to foster independence and help them get needed appliances and services, provide support groups for parents, and are often a source for baby-sitting and respite care. In severely affected children with CP and cognitive impairment, the thrust is to foster feeding, toileting, and dressing; most end up in a nursing home when their parents can no longer care for them. Less affected school-age children need an education tailored to their intellectual abilities. Sooner or later, they require counseling for adapting to the fact that they will always remain different from other people. Educated adults with CP provide excellent role models who can spur the child with CP to fight for independence and achievement.

DEVELOPMENTAL DISORDERS OF HIGHER CEREBRAL FUNCTIONS All of these disorders are defined behaviorally. Their severity varies greatly. Comorbidity (more than one developmental disorder in a given child, for example, dyslexia and Tourette syndrome) is frequent and may result from lack of selectivity of the underlying pathology, genetic linkage, or fuzzy boundaries because diagnostic criteria are quantitative rather than dichotomous. If general intelligence (cognition) is affected (mental deficiency), there is generally a diffuse disorder of neocortical (or cortical/subcortical) development and function, or multiple widespread lesions. Disorders selectively affecting cognitive abilities are considered specific developmental disorders and are generally classified according to their main functional consequence ( Table 76.2). Progress in functional brain imaging and electrophysiology, which are rapidly identifying brain regions selectively activated by particular cognitive tasks, indicates that the responsible circuits are both modular and distributed. A particularly striking discovery is the unanticipated participation of the cerebellum in many cognitive tasks.

TABLE 76.2. DEVELOPMENTAL DISORDERS OF HIGHER CEREBRAL FUNCTION

Etiology The label minimal brain damage (MBD), later replaced by minimal brain dysfunction (also MBD), was applied to clumsy, hyperkinetic, inattentive children with school problems when MBD was viewed as a global disorder with perinatal traumatic or ischemic-anoxic insult as its most common etiology. The Collaborative Perinatal Study of the 1960s and 1970s showed that, in contrast to severe prematurity, isolated perinatal insults account for fewer than 10% of the cases of CP and severe mental deficiency and play a minor role in milder cognitive impairments, such as learning disability. Mild mental subnormality is to a large degree attributable to environmental factors, such as poverty, social deprivation, inadequate nutrition or substance abuse during gestation, and low level of maternal education. Genetics rather than exogenous factors plays a major causal role in the developmental disorders. Some disorders, such as autism, are polygenic, with several genes required to produce the full phenotype. Polygenic causation provides an explanation for overlapping and borderline phenotypes. Some families with many dyslexic members have linkage to different chromosomes, which suggests that dyslexia is not linked to a single gene defect. The effects of genes responsible for developmental disorders on brain development are unknown. Perhaps some exert their effect by enhancing susceptibility to generally well tolerated environmental exposures. Mental Deficiency The term mental deficiency is preferred to the term mental retardation because it implies that it is unrealistic to expect catch-up and the achievement of normalcy. The best definition of mental deficiency is not a low score on an intelligence test but inability to function independently due to general incompetence. Before general incompetence is assumed, it is necessary to exclude specific impairments in sensorimotor, visual, auditory, language, and other specific cognitive and social skills that might account for failure to perform at a level commensurate with chronologic age and cultural opportunity. These impairments may make valid assessment difficult because there are few standardized tests for children with CP, deafness, blindness, or autism. Measurement of Intelligence and Neuropsychologic Skills A modular view of brain function negates the concept of a single construct, “intelligence;” it posits that intelligence or cognitive competence depends on the functional integrity of many discrete brain circuits whose coordinated activity gives rise to adaptive responses to unpredictable endogenous and exogenous conditions. Intelligence test batteries are used to predict likely success in school or in a particular vocation. These tests are generally well standardized for normal people of a particular culture and sample a range of verbal and nonverbal abilities, but the scores must be applied cautiously whenever they are used in other cultures or with handicapped persons. Brief screening tests, such as the Peabody Picture Vocabulary Test or the Raven Progressive Matrices, may be adequate for some limited purposes. For the practical purpose of assessing and predicting ability to function in real life, the Revised Vineland Adaptive Behavior Scales provide measures of communication, sociability, motor skills, and adaptive function. The data are derived from an interview with the parents or caretaker. These scales do not require the participation of the person being assessed and provide less culturally biased data than test data. The Revised Wechsler scales—Wechsler Preschool and Primary Scale of Intelligence, Wechsler Intelligence Scale for Children, and Wechsler Adult Intelligence Scale—and the Revised Stanford-Binet scale provide verbal and nonverbal summary scores, as well as an overall IQ score, and extend from preschool children to adults. The most commonly used test-based criterion for mental deficiency is departure from the mean score of 100 (standard deviation ±16) in the general population. Likely functional outcomes as a function of IQ score are listed in Table 76.3. IQ scores must be used cautiously: Tests in preschool and young school-age children may provide valid comparisons with peers and have satisfactory predictive validity when applied to groups, but they are not necessarily valid for long-term prediction in the individual child, especially in the face of a handicap.

TABLE 76.3. FUNCTIONAL ABILITY AND LEVEL OF COGNITIVE COMPETENCE

In addition to associated handicaps, what determines the functional level of a mentally deficient person with a particular IQ level are motivation, efficacy of habilitation, and a supportive environment. Adequate self-help and social skills, rather than academic skills, may determine outcome. Severe behavior disorders that worsen functional outcome increase with the severity of the mental deficiency. A quite different use of psychologic test data from the measure of “intelligence” is the identification of specific cognitive impairments. Neuropsychologic batteries incorporate tests to detect inadequacies in language; memory and learning; attention; visual, auditory, and somatosensory perception and processing; intersensory integration; fine motor abilities; planning; and even affect recognition, mood, and social cognition. Neuropsychologic tests generate a useful profile of strengths and weaknesses for planning remediation. Appropriately designed neuropsychologic measures are required to identify the neurologic basis of cognitively demanding tasks with the use of functional brain imaging and electrophysiology. Developmental Language Disorders (or Dysphasias) There is considerable variation in the manner and age at which normal children acquire various aspects of language. This makes the definition of developmental language disorders (DLDs) controversial because it depends on departure from some expected language age or on a discrepancy between verbal and nonverbal cognitive skills. The term developmental language delay is widely used because most children with a DLD learn to speak before school age; the term is inappropriate

for the many children who later have trouble learning to read or express themselves coherently orally or in writing. Neurologic Basis of the Dysphasias Focal brain lesions are rare, in part because unilateral focal lesions acquired in early life do not preclude the acquisition of language, which reflects the greater potential for reorganization in the immature than in the mature brain. Most people are genetically destined to develop language in the left hemisphere, regardless of handedness. Yet language can develop and be sustained in either hemisphere, as shown by adequate development of language in young children with large hemispheric lesions or following hemispherectomy, albeit with subtle but demonstrable differences in language and nonverbal skills in those with right and left pathology. Dysphasic children are therefore thought to have bilateral dysfunction in circuits critical to language development. Subtypes of Developmental Language Disorders There is no fully accepted classification of the dysphasias. Despite some similarities, models based on the acquired aphasias of adults do not fully apply to disorders of language acquisition, yet focal brain lesions in adults have provided crucial information on the localization of particular aspects of language. Some dysphasias, such as Broca aphasia in adults, are predominantly expressive and affect phonology (the production of the sounds of speech) and syntax (the grammar of language), whereas semantics (the meaning of language) and pragmatics (the communicative use of language) are spared. Receptive dysphasias preclude or severely jeopardize the processing of phonology and syntax and, consequently, semantics and the acquisition of expressive language; they are therefore always mixed (receptive and expressive), in contrast to Wernicke aphasia of adults, in which automatized speech continues unabated, albeit with abnormal content. The closest analogy between adult aphasia and childhood dysphasia is word deafness, or verbal auditory agnosia (VAA), the most severe variant of receptive DLD. The difference in this analogy is that adults with bilateral temporal lesions may speak quite normally and can read and write, whereas children with VAA are nonverbal because profound impairment of comprehension precludes all language skills, with the possible exception of nonverbal pragmatics (gestures). VAA is especially frequent in children with acquired epileptic aphasia ( Landau-Kleffner syndrome), which consists of chronic loss of speech (or failure to develop speech in the case of developmental VAA) associated with a seizure disorder or a frankly paroxysmal electroencephalogram (EEG) without clinical seizures. Children with VAA are often autistic with no sparing of pragmatics. A third type of DLD largely spares the development of receptive and expressive phonology and syntax but impairs semantic processing. Children with this type have difficulty understanding complex sentences, answering open-ended questions, retrieving vocabulary, and formulating coherent discourse. They may speak clearly but, when younger, often produced a fluent incomprehensible jargon with word approximations. Some have an excellent rote verbal memory and impaired pragmatic skills; they are likely to be chatterboxes who rely on overlearned scripts. They often perseverate and speak aloud to themselves without a conversational partner. This semantic-pragmatic syndrome is particularly frequent in verbal autistic children. Etiology and Pathophysiology DLD clearly does not have a single cause. Genetics plays a major but not exclusive role. A few known syndromes are associated with particular subtypes of dysphasia, such as hydrocephalus and Williams syndrome with the semantic-pragmatic syndrome. Dysphasia is significantly more frequent in boys than girls. Disorders of the acquisition of phonology may be linked to a more general impairment of rapid auditory processing that jeopardizes the detection of the brief acoustic stimuli that differentiate one consonant from another. VAA is linked to dysfunction in temporal auditory cortices. The pathophysiology of other dysphasic syndromes is not understood. Reading Disability (Dyslexia) Learning to read is learning to decode written (visually coded) language. It may be difficult to distinguish true dyslexia from poor reading attributable to impoverished language stimulation, poor teaching, lack of motivation, or borderline intellectual competence. As with dysphasia, there are subtypes of dyslexia. Visual perceptual problems play a minor pathophysiologic role in dyslexia, which is almost always the consequence of a language problem. The most prevalent subtype involves inadequate phonologic processing, such as difficulty in segmenting speech into component phonemes (speech sounds), sequencing them, learning the relationship between graphemes (letters) and phonemes, sounding out strings of letters (nonwords), and spelling. Occasionally, children have more difficulty learning to read whole words than analyzing them phonologically. Others have visual problems in association with phonologic deficits, making learning to read arduous or nearly impossible. Poor readers may be more generally learning disabled. Some are clumsy and have a poor handwriting, difficulty with mathematics, or an attention deficit with or without hyperactivity. Specific reading disability is virtually never the consequence of a detectable structural brain lesion. Galaburda and colleagues (1985) described minor migration cell defects and tiny scars located selectively in the perisylvian areas of the left hemisphere in dyslexics; he and others pointed out that dyslexia is statistically linked to lack of the expected asymmetry of the two hemispheres, associated with an atypically large planum temporale on the right. Genetics, including linkage to chromosomes 6 or 15 in some families, plays a major but not exclusive etiologic role. Outcome depends in part on the general intellectual level and adequacy of intervention. Most intelligent dyslexics eventually learn to read more or less efficiently, but they tend to be poor spellers, have difficulty reading nonwords, and may not read for pleasure. Other Learning Disabilities There are at least two clearly differentiable reasons for difficulty in writing ( dysgraphia): dysorthographia (the consequence of dyslexia) and poor handwriting (due to a minor motor or visuomotor disability). There are also several variants of dyscalculia: lack of understanding of the rules for calculation, spatial problems resulting in place errors while setting up written calculations and difficulty with geometry, higher-order language deficits interfering with the solving of word problems, and inadequate attention impairing short-term memory essential for mental arithmetic. Children with nonverbal learning disabilities have lower performance than verbal abilities and dyscalculia. Many have social deficits that place them on the autistic spectrum. Memory disorders for specific types of materials and tasks resemble those of adults. Executive and planning disorders have a profound impact on organizational and reasoning abilities, which, as in adults, depend on the integrity of prefrontal circuits. Disorders of Attention Attention deficit disorder (ADD) is reportedly more frequent in boys. This may be because it is actually more frequent in boys, because boys are more likely than girls to have attention deficit with hyperactivity disorder (ADHD), or because boys are generally more active and aggressive than girls and ADD is therefore more conspicuous and difficult to tolerate in boys. ADD may be evident in infancy by reduced need for sleep, later by difficulty in falling asleep, waking too early in the morning, or by multiple awakenings during the night. Children with ADD are restless, have a short attention span, go from one toy to another without getting engaged, and in school get up from their seat or wander in the classroom. They are impulsive, disorganized, and forgetful and may have a labile affect. Other features, such as clumsiness and learning disability, are associated rather than an intrinsic manifestations. Marked distractibility may interfere with the acquisition of reading and arithmetic, but most children of normal intelligence with ADHD are not learning disabled. ADD persists in adult life, but motor hyperactivity usually abates in adolescence. Prognosis varies: ADHD tends to abate with maturation, but distractibility, impulsivity, a disorganized lifestyle, accident-proneness, and a short temper may be lifelong liabilities; the high level of energy and curtailed need for sleep may be assets in otherwise well-functioning adults. The most widely used criterion for diagnosing ADD and gauging the efficacy of medication is Conner's questionnaire, administered to parents or teachers. Assessment of ADHD may include written or computerized tests of attention or direct recording of amount of movement. Management combines parental counseling, environmental manipulations such as removing distractions, providing the opportunity for frequent breaks and opportunities to move about, and, in some cases, medication. ADHD is disruptive because it affects family, peers, and teachers alike. Medication alone is rarely sufficient, and in severe cases counseling of the family, adjustments of school routines, and, in older children, teaching strategies to minimize the consequences of

ADD are necessary. Methylphenidate hydrochloride (Ritalin) is the safest and most frequently prescribed drug. Its short half-life is advantageous for gauging efficacy but requires divided doses. In a young child, one starts with a small dose given in the morning and at midday, progressively increasing the dose until the desired effect is achieved or sleeplessness, oversedation, increased hyperkinesia, or tics appear. A sustained-release form of methylphenidate is available, but release may be erratic and some children still require a short-acting tablet after school to avoid behavioral rebound. Drug holidays in the summer are reasonable to gauge whether the child can do without, but if the drug is truly effective, giving it only on school days risks committing the child to an emotional roller coaster. Pemoline (Cylert) has a long half-life so that a single pill in the morning suffices, but it requires 2 to 3 weeks for full effect and has recently been associated with rare cases of fatal liver damage. Dextroamphetamine sulfate (Dexedrine), especially time-release capsules, can also be tried, in doses one-half those of methylphenidate. Sedatives should be avoided because some, notably phenobarbital, may precipitate ADHD. There is no evidence that avoidance of sugar, foods with red dye or rich in salicylates, and megadoses of vitamins help either ADD or the learning disabilities. Drugs such as thioridazine (Mellaril), chlorpromazine, and haloperidol are contraindicated because they are sedating and have potential long-term, irreversible side effects. Autism Spectrum Disorders—Pervasive Developmental Disorders The term pervasive developmental disorder (PDD) is used in the Diagnostic and Statistical Manual of the American Psychiatric Association as an umbrella term for persons with classically autistic symptomatology referred to as “autistic disorder,” as well as for others with similar but fewer, less severe symptoms. Using PDD to avoid mentioning “autism,” which is considered stigmatizing because of the discredited theory that poor parenting was responsible and because it was erroneously thought to be hopeless, is confusing. Etiology Autism is a developmental disorder of brain function, and as with others, there are several causes. On the basis of twin and family studies, polygenic inheritance accounts for most cases with unknown causes. In some cases, there may be an inherited susceptibility to some environmentally determined stress. A minority of individuals with autism have tuberous sclerosis, hypomelanosis of Ito, fragile X, Rett or Angelman syndrome, phenylketonuria, congenital rubella, neonatal herpes simplex, hydrocephalus, a brain malformation, or other static encephalopathy. Perinatal brain injury does not cause autism as an isolated deficit. Symptoms There is great variability in severity and range of symptoms. The core problems involve sociability, verbal and nonverbal communication, and range of interests and activities. Intelligence is not a defining feature but strongly influences prognosis. There may be profound mental deficiency or superior ability, often with areas of major impairment coupled to normal or even prodigious rote memory, calculation, or music ability. Problems in sociability range from almost total lack of interest in others, inability to engage another person in play or conversation, and gaze aversion to inappropriate intrusiveness, failure to maintain appropriate interpersonal distance, and lack of empathy. Children with autism may not lack affection, but they may be selectively affectionate. They may be anxious or fearful, have a labile mood, and may laugh or cry without discernible cause. Temper tantrums and seemingly unprovoked aggressive outbursts create social problems. The second core problem, communicative incompetence, regularly presents as failure to learn to speak and limited comprehension of language. Nonverbal communication is affected, as young autistic children may not point to request or shake the head “yes” or “no.” The most severely affected preschoolers may understand little or nothing; they may remain nonverbal into adulthood, even when comprehension has improved. Others learn to speak after age 3 or 4 years, but with inadequate syntax and phonology. Still others, once they start to speak, progress rapidly to full, clearly articulated sentences. Echolalia, use of verbatim scripts, stilted or wooden prosody (melody of language), and a high-pitched or sing-song voice are frequent. A large and inappropriately sophisticated vocabulary may mask impaired comprehension. Many autistic children have better verbal skills for written than oral language. Some preschool autistic children are fascinated with letters and numbers and may learn to read without instruction, albeit often with limited comprehension (hyperlexia). The third core characteristic of autism is a narrow range of interests, unusual preoccupations and choice of activities, inadequate play, perseveration, rigidity, and resistance to change. Young children may look at the same video or book for hours, play with a string or spin wheels of a car, and prefer to line up or classify toys rather than play with them. Imaginative play is absent or minimal in early childhood. Older autistic children may become engrossed in studying timetables or collecting bottle caps or sports statistics. Frequent motor problems in autistic children include toe-walking, hypotonia, stereotypies, and apraxia (failure to imitate gestures and inadequate mastery of complex motor tasks). Stereotypies may be ticlike; they are most blatant in low-functioning autistic persons but may persist in miniature even in high-functioning adults. Stereotypies may consist of flapping the hands when excited, wringing or licking the hands, fiddling with clothing or a lock of hair, or twisting the fingers or gazing at them. There are few facts about the neurologic basis for self-injury, head-banging, or self-biting; failure to respond to sound but intolerance of certain sounds; withdrawal from tactile contact but enjoyment of tickling; excessive sniffing and licking; a narrow range of food choices; and enjoyment of staring at rotating objects, running around in circles, and antigravity play. Sleep disorders, overfocused attention or distractibility, labile mood, destructiveness, self-injury, and unprovoked aggression are frequent and troublesome complaints. Children with autism may have epileptic seizures of any type. The probability of epilepsy is highest in autistic children with mental deficiency or frank motor abnormality. It is high in infancy and early childhood and increases to a second peak in adolescence. Autism may follow infantile spasms or the Lennox-Gastaut syndrome. Course and Prognosis In retrospect, signs of autism may already have been present in infancy. In almost 50% of cases, signs of autism appear in the toddler or early preschool years, either in a perfectly normal or less severely developmentally affected child. Inadequate language is usually the presenting complaint. One-third of parents report language regression at a mean age of 21 months, together with regression of sociability and play, usually without regression of motor skills. Regression may be insidious or may follow an acute illness or environmental stress. Development resumes after a plateau lasting weeks or months, although complete recovery is exceptional. In some children, regression is associated with a paroxysmal EEG with or without clinical seizures and falls within the definition of acquired epileptic aphasia (Landau-Kleffner syndrome). “Disintegrative disorder” refers to autistic regression after age 2 years in completely normal, fully verbal children. The neurologic basis of autistic regression, including the potential role of subclinical epilepsy, is not known because autistic regression is often overlooked, precluding early investigation. No reliably effective medical treatment for autistic regression is known. Like other developmental disorders, autism is a lifelong condition, although sociability and language tend to improve. Unless an early history is available, autistic adults are likely to be diagnosed as mentally retarded, obsessive-compulsive, schizophrenic, or manic-depressive, or as having an antisocial or inadequate personality. Some intelligent verbal persons with autism lead independent lives. In general, they remain single and are likely to be underemployed but remarkably faithful workers. Less intelligent and multiply handicapped autistic persons need supervision throughout life, and the most severely affected require institutionalization. Pathology and Pathophysiology Information is scanty. Except in cases with a known cause, there is no evidence for gross malformation or destructive or inflammatory pathology. There may be developmental cellular anomalies in the limbic system, parts of the cerebellar cortex, and the inferior olive. Even high-resolution MRI is usually normal; therefore MRI is not indicated clinically unless the neurologic examination mandates it. In some autistic adults, MRI shows minor dysgenetic lesions of the type reported in dyslexia, as well as dysgenesis in vermal lobules VI and VII of the cerebellum. MRI morphometry indicates that autistic children may have larger, rather than smaller, cerebral hemispheres. Standard EEG and evoked potential studies are generally normal unless there are seizures. Recent loss of language mandates a prolonged sleep EEG to detect subclinical epilepsy. Research tools such as event-related potentials and functional imaging studies may be abnormal during the performance of cognitive and language tasks. Abnormalities in neurotransmitter metabolism, notably serotonin, may be present in some autistic persons. There is no unifying hypothesis about the neurochemical

basis of autism. Management Early individualized education that addresses both the behavioral and the communication needs of children with autistic spectrum disorders is the backbone of management. Parents need instruction in behavior management. Neurologists should discourage the squandering of resources on the many well meaning but unproven behavioral and dietary treatments offered to desperate parents. No drug cures autism, but psychotropic drugs can be targeted to specific behavioral problems. Serotonin-uptake inhibitors are widely used to decrease perseveration and, perhaps, enhance language acquisition. Aggressive outbursts may respond to large doses of propranolol given in progressive increments to tolerance and, in a crisis, to acute use of haloperidol or phenothiazines, which need to be avoided long-term because of their potentially irreversible side effects. Risperidone (Risperdal) and clonidine hydrochloride (Catapres) may mitigate prominent obsessive or self-injurious behaviors, for which naltrexone hydrochloride (ReVia) has been disappointing. Anxiolytic drugs and tricyclic antidepressants have their place, and methylphenidate may help in ADHD, although stimulants are generally contraindicated in autism. Anticonvulsants can be tried in children with a frankly paroxysmal EEG without clinical seizures and may also have mood stabilizing efficacy. SUGGESTED READINGS Developmental Disorders of Motor Function: Cerebral Palsy Arens LJ, Leary PM, Goldschmidt RB. Experience with botulinum toxin in the treatment of cerebral palsy. S Afr Med J 1997;87:1001–1003. Armstrong RW, Steinbok P, Cochrane DD, Kube SD, Fife SE, Farrell K. Intrathecally administered baclofen for treatment of children with spasticity of cerebral origin.

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Intrauterine growth retardation and premature delivery: the influence of maternal smoking and psychosocial factors. Am J Public Health 1996;86:347–354. Pennington BF, Smith SD. Genetic analysis of dyslexia and other complex behavioral phenotypes. Curr Opin Pediatr 1997;9:626–641. Pugh KR, Shaywitz BA, Shaywitz SE, et al. Cerebral organization of component processes in reading. Brain 1996;119:1221–1238. Rapin I. Developmental language disorders: a clinical update. J Child Psychol Psychiatry 1996;37:643–655. Rapin I. Autism. N Engl J Med 1997;337:97–104. Rutter M, Bailey A, Simonoff E, Pickles A. Genetic influences and autism. In: Cohen DJ, Volkmar FR, eds. Handbook of autism and pervasive developmental disorders, 2nd ed. New York: John Wiley and Sons: 370–387. Schmahmann JD, ed. The cerebellum and cognition. San Diego, CA: Academic Press, 1997. Shaywitz BA, Fletcher JM, Shaywitz SE. Attention-deficit/hyperactivity disorder. Adv Pediatr 1997;44:331–367. Shaywitz BA, Shaywitz SE, Pugh KR, et al. Sex differences in the functional organization of the brain for language. Nature 1995;373:607–609. Steinschneider M, Kurtzberg D, Vaughan GG Jr. Event-related potentials in developmental neuropsychology. In: Rapin I, Segalowitz SJ, eds. Child neuropsychology. Handbook of neuropsychology, vol 6. Amsterdam: Elsevier Science, 1992:239–299.

Temple CM. Developmental dyscalculia. In: Segalowitz SJ, Rapin I, eds. Child neuropsychology. Handbook of neuropsychology, vol 7. Amsterdam: Elsevier Science, 1992:211–222. Tuchman RF, Rapin I. Regression in pervasive developmental disorders: seizures and epileptiform electroencephalogram correlates. Pediatrics 1997;99:560–566. Weiss G, Trockenberg-Hechtman L. Hyperactive children grown up. New York: Guilford Press, 1986. Wilson BC. The neuropsychological assessment of the preschool child: a branching model. In: Rapin I, Segalowitz SJ, eds. Child neuropsychology. Handbook of neuropsychology, vol 6. Amsterdam: Elsevier Science, 1992:377–394.

CHAPTER 77. LAURENCE-MOON-BIEDL SYNDROME MERRITT’S NEUROLOGY

CHAPTER 77. LAURENCE-MOON-BIEDL SYNDROME MELVIN GREER Suggested Readings

A variable group of clinical features manifested primarily by obesity and hypogonadism was described in 1866 by Laurence and Moon. Subsequent redefinition of the syndrome by Bardet and Biedl may have established a new entity, but the clustering of manifestations appears similar. In essence, the features include obesity (85% to 95%); mental retardation (70% to 85%); retinal dystrophy and coloboma (92% to 95%); hypogenitalism and hypogonadism (74% to 86% of males and 45% to 53% of females); and polydactyly, syndactyly, or both (75% to 80%). Added to this are renal dysfunction and hypertension and, with lesser frequency, cardiac and hepatic defects. Isolated case reports include cranial nerve palsy, diabetes mellitus, diabetes insipidus, spinocerebellar degeneration, spastic quadriparesis with severe cervical stenosis, hydrocephalus, and facial dysostosis. The salient early characteristic is obesity ( Fig. 77.1). During the first decade of life, impaired night vision is the hallmark of retinitis pigmentosa, which progresses, and by age 20, 73% of the patients are blind.

FIG. 77.1. Laurence-Moon-Biedl syndrome. A 19-year-old patient with obesity, hypogenitalism, polydactyly (toes), retinitis pigmentosa, and mental retardation.

Testicular atrophy, decrease in the number of germinal cells, and spermatogenic arrest have been described, but no identifiable endocrine cause explains the gonadal dysfunction. Indeed, in adolescence, some patients improve spontaneously. Testosterone therapy is ineffective in treating hypogonadism or hypogenitalism. The mode of inheritance is autosomal recessive. Although the condition is compatible with a normal lifespan, a shortened longevity may occur because of renal or cardiac defects. No specific neuropathologic changes have been described. Several hereditary syndromes associated with pigmentary retinopathy have been described, including syndromes that loosely fit the Laurence-Moon-Biedl syndrome. The Alströ1m-Hallgren syndrome, transmitted as an autosomal recessive disorder, includes obesity, hypogonadism, nerve deafness, diabetes mellitus, and retinitis pigmentosa. The Biemond syndrome is characterized by hypogonadotropic hypogonadism, obesity, postaxial polydactyly, mental retardation, and coloboma of the iris rather than retinitis pigmentosa. The Prader-Willi syndrome is also manifested by obesity, hypogonadism, and mental retardation, but there are no visual problems. DNA samples from 29 families with such disorders have identified loci in chromosome regions 11q13, 15q22.3-q23, and 16q21. SUGGESTED READINGS Biedl A. Aduber das Laurence-Biedlsche Syndrome. Med Klin 1933;29:839–840. Buford EA, Riise R, Teague PW, et al. Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23 and 16q21. Genomics 1997;41:93–99. Cantani A, Bellioni P, Bamonte G, et al. Seven hereditary syndromes with pigmentary retinopathy. Clin Pediatr 1985;24:578–583. Koepp P. Laurence-Moon-Biedl syndrome associated with diabetes insipidus neurohormonalis. Eur J Pediatr 1975;121:59–62. Mehrotra N, Taub S, Covert RF. Hydrometrocolpos as a neonatal manifestation of the Bardet-Biedl syndrome. Am J Med Genet 1997;69:220. Pagon RA, Haas JE, Bunt AH, et al. Hepatic involvement in the Bardet-Biedl syndrome. Am J Med Genet 1982;13:373–381. Soliman AT, Rajab A, Al Salmi I, et al. Empty sellae, impaired testosterone secretion, and defective hypothalamic-pituitary growth and gonadal axes in children with Bardet-Biedl syndrome. Metabolism 1996;45:1230–1234. Verloes A, Temple IK, Bonnet S, Bottani A. Coloboma, mental retardation, hypogonadism, and obesity: critical review of the so-called Biemond syndrome type 2, updated nosology, and delineation of three “new” syndromes. Am J Med Genet 1997;69:370–379.

CHAPTER 78. STRUCTURAL MALFORMATIONS MERRITT’S NEUROLOGY

CHAPTER 78. STRUCTURAL MALFORMATIONS MELVIN GREER Malformations of Cerebral Hemispheres and Agenesis of Corpus Callosum Macrocephaly and Megalencephaly Malformations of Occipital Bone and Cervical Spine Premature Closure of Cranial Sutures Spina Bifida and Cranium Bifidum Arnold Chiari Malformation Suggested Readings

MALFORMATIONS OF CEREBRAL HEMISPHERES AND AGENESIS OF CORPUS CALLOSUM Before day 23 of human gestation, failure of cleavage of the telencephalon and diencephalon results in a single-lobed structure with an undivided ventricle. This is alobar holoprosencephaly or arhinencephaly. It is commonly associated with defects and anomalies of the skull base, dura, face, eyes, and olfactory apparatus. Semilobar and lobar holoprosencephaly are variations wherein the hemispheres are partly or completely separated and are invariably associated with multiple deformities of cerebral architecture, ranging from absence or primitive appearance of gyri ( lissencephaly) to heterotopias and migration defects. Perisylvian polymicrogyria may be familial, and in some families, mothers and daughters have band heterotropia and their sons have lissencephaly. Linkage to xq21.3-24 has been reported. Lissencephaly with malformations of muscle and eye have been identified in Fukuyama congenital muscular dystrophy and the Walker-Warburg syndrome. Common clinical manifestations noted early are facial dysmorphism, apneic episodes, seizures, and delayed psychomotor development. Causal mechanisms include chromosomal abnormalities and intrauterine acquired factors, such as maternal diabetes, toxoplasmosis, rubella, syphilis, or the fetal alcohol syndrome. Endocrine disorders include pituitary, thyroid, and adrenal hypoplasia. Septooptic dysplasia, another midline developmental defect, includes hypoplasia of the optic nerve, lateral geniculate, hypothalamic, or posterior pituitary in addition to cerebral and cerebellar dysplasia. Complete or partial agenesis of the corpus callosum is commonly noted in association with the holoprosencephalic brain. Callosal agenesis, unassociated with the major holoprosencephalic anomalies, is more common. This may be present in an otherwise clinically normal person and is attributed to impairment in development between gestation weeks 11 through 20. It may be partial or complete, familial or sporadic, and has been described as an autosomal dominant, autosomal recessive, or sex-limited recessive trait. Computed tomography (CT) or magnetic resonance imaging (MRI) shows that the lateral ventricles are widely separated and angular ( Fig. 78.1). The medial ventricular wall is convex, and the cavity is small. The septum pellucidum is superiorly displaced. When the agenesis is partial, the body and splenium are missing; the genu is present as a poorly formed anterior callosal rudiment. The third ventricle is wide and higher than normal.

FIG. 78.1. Agenesis of corpus callosum. Noncontrast computed tomography. Axial (A) and coronal (B) planes show high-riding third ventricle. C: Sagittal magnetic resonance imaging showing agenesis of the anterior portion of the corpus callosum ( multiple arrows). An associated anomaly, aplasia of the inferior portion of the cerebellat vermis, is indicated by the single arrow. (Courtesy of Dr. S.K. Hilal.)

Both microcephaly and macrocephaly in association with other cerebral malformations, including hydrocephalus, may be noted with agenesis of the corpus callosum. Seizures and mental retardation are seen in more than 50%of patients, and other anomalies seen with lesser frequency include defects of the skeleton, heart, craniofacial structures, gastrointestinal system, and genitourinary system. In some metabolic degenerative disorders, corpus callosum shrinkage may be postnatal in origin. This has been seen in the nonketotic hyperglycinemia, Menkes syndrome, Zellweger syndrome, adrenoleukodystrophy, pyruvate dehydrogenase deficiency, adenyl succinate deficiency, and glutaric aciduria type II. Structural changes within the affected corpus callosum may include a lipoma or, more rarely, a midline meningioma, dermoid cyst, or hamartoma. Chromosome defects, including trisomy 8, 9, 13, and 18, may be seen with agenesis of the corpus callosum. Syndrome complexes that include agenesis of the corpus callosum are listed in Table 78.1.

TABLE 78.1. SYNDROMES ASSOCIATED WITH AGENESIS OF THE CORPUS CALLOSUM

The acallosal but clinically normal person has alternative pathways of information transfer, probably via intercollicular connections and posterior commissure. Myelination of the corpus callosum is accomplished in large measure by age 6 years but may not be complete before age 10. Callosotomy as a treatment of refractory seizures in children did not result in the same psychologic changes identified as the disconnection syndrome in the adult callosotomy patient. This difference implies plasticity of neuronal pathways.

MACROCEPHALY AND MEGALENCEPHALY Head size enlargement greater than 2 standard deviations above the mean for age is macrocephaly. Progressive hydrocephalus and mass lesions are common causes of an enlarged head size in the infant and young child. Closure of the suture in the pubertal child prevents skull enlargement in the presence of these pressure-inducing disorders. Benign states of macrocephaly may be familial. Not infrequently, imaging studies reveal mildly dilated lateral ventricles and increase in subarachnoid fluid. Children who exhibit such features on CT or MRI have been identified as having hydrocephalus ex vacuo, but cerebrospinal fluid (CSF) shunts should be reserved for conditions in which there is progressive enlargement of the CSF spaces and, additionally, evidence of neurologic dysfunction. Megalencephaly is an enlarged brain. Brain weight 2.5 standard deviations above the mean for sex and age or brain weight greater than 1,600 g qualifies for the diagnosis. Primarily, megalencephaly may be an isolated finding. It has been described in families as an autosomal recessive trait and attributed to a disturbance of developmental cell proliferation. Progressive enlargement of the brain with deterioration of neurologic function is seen in children with neurocutaneous syndromes, neuronal storage, or degenerative diseases such as mucopolysaccharidoses or leukodystrophies. Pathologic changes include new growths, such as the tubers of tuberous sclerosis, which may occlude ventricular fluid flow to cause hydrocephalus. The degenerative diseases are associated with a myriad of pathologic changes associated with megalencephaly, including cystic changes and extensive gliosis. Developmental brain defects causing macrocephaly and megalencephaly may be associated with other organ system defects and are often noted at birth ( Table 78.2).

TABLE 78.2. MACROCEPHALY AND MEGALENCEPHALY

Unilateral megalencephaly is associated with unilateral hemisphere defects, such as an altered gyral pattern, including pachygyria and polymicrogyria, thickened cortex, and disorganization of gray matter. Such features are similar to the L'hermitte-Duclos syndrome, in which cerebellar granular cell hypertrophy and other cerebellar hamartomatous growths create a mass effect. Children with hemimegalencephaly commonly have seizures, hemiparesis, and mental retardation. MRI depicts the structural changes and may also identify the asymptomatic hemimegalencephalic child with white matter low attenuation features early in life that later disappear.

MALFORMATIONS OF OCCIPITAL BONE AND CERVICAL SPINE The defects in the development of the cervical spine and base of the skull may be divided into the following groups: 1. Basilar impression; 2. Malformation of the atlas and axis; 3. Malformation or fusion of other cervical vertebrae (Klippel- Feil anomaly) ( Table 78.3).

TABLE 78.3. UNCOMMON SYNDROMES ASSOCIATED WITH CERVICOMEDULLARY AND CERVICAL SPINE MALFORMATIONS

Any of these malformations may occur singly or together; they also may be associated with developmental defects in the skull, spine, CNS, or other organs. These deformities can be present without clinical symptoms, but symptoms may appear because of mechanical compression of the neuraxis or due to an associated malformation of the nervous system. Basilar Impression Platybasia, basilar impression, and basilar invagination are names frequently used interchangeably for the skeletal malformation in which the base of the skull is flattened on the cervical spine. Platybasia (flat base skull) is present if the angle formed by a line connecting the nasion, tuberculum sella, and anterior margin of the foramen magnum is greater than 143 degrees (Fig. 78.2). Basilar invagination refers to an upward indentation of the base of the skull, which may be present in Paget disease, osteomalacia, or other forms of bone disease associated with softening of the bones of the skull. An upward displacement of the occipital bone and cervical spine with protrusion of the odontoid process into the foramen magnum constitutes basilar impression. Compression of the pons, medulla, cerebellum, and cervical cord and stretching of the cranial nerves may result from the upward ascent of the occipital bone and cervical spine and from narrowing of the foramen magnum.

FIG. 78.2. Basilar impression with platybasia. The odontoid process is entirely above Chamberlain's line (hard palate to base of skull). Basal angle is flat. (Courtesy of Dr. Juan Taveras.)

Pathology and Pathogenesis Minor degrees of platybasia and basilar invagination may not produce symptoms. In most symptomatic cases, the deformity is due to a congenital maldevelopment or hypoplasia of the basiocciput, which causes basilar impression, platybasia, partial or complete atlantooccipital fusion, atlantoaxial dislocation, and a narrowed foramen magnum. The pons, medulla, and cerebellum may be distorted and the cranial nerves stretched. Vertebral artery obstruction may be significant in the production of brainstem symptoms (e.g., vertigo and drop attacks with head turning) in basilar impression. Symptoms and Signs Basilar impression is rare. Neurologic symptoms, when present, usually develop in childhood or early adult life. The head may appear to be elongated and its vertical diameter reduced. The neck appears shortened, and its movements may be limited by anomalies of the upper cervical vertebrae. Neurologic symptoms include spastic paraparesis, unsteady gait, cerebellar ataxia, nystagmus, and paralyses of the lower cranial nerves. Papilledema and signs of increased pressure may occur if the deformity interferes with the circulation of the CSF. Partial or complete subarachnoid block is present at lumbar puncture in most cases. CSF protein levels are increased in 50% of patients. Diagnosis The diagnosis of basilar impression is usually obvious from the general appearance of the patient. It can be established with certainty by the characteristic radiographic or CT appearance of the base of the skull. The clinical syndromes produced by the anomaly can simulate those of multiple sclerosis, syringomyelia, the Arnold-Chiari malformation, and posterior fossa tumors. These diagnoses are readily excluded CT and MRI. Treatment The treatment is surgical decompression of the posterior fossa and the upper cervical cord. Malformations of the Atlas and Axis Maldevelopments of the atlas and axis may be found with basilar impression or may occur independently. Congenital defects resulting in weakness or absence of the structures maintaining stability of the atlantoaxial joints predispose to subluxation and dislocation. These include dens aplasia, a condition in which part of the odontoid process remains on the body of the second cervical vertebra, thereby reducing the stability of the joint. Neurologic symptoms may be produced by anterior dislocation of the atlas and compression of the cord between the protruding odontoid process and the posterior rim of the foramen magnum. There may be mild or severe spastic quadriparesis, with or without evidence of damage to the lower cranial nerves. Head movement causes pain. Sensory loss may be mild. Transitory signs or symptoms of a progressive myelopathy may occur, often after exaggerated movements of the neck. Respiratory embarrassment is prominent when the thoracic muscles are affected. The diagnosis is made by finding anterior dislocation of the atlas in CT. When the bony changes are slight, and especially when there is little or no posterior dislocation of the odontoid process, the symptoms may be due to other congenital defects, such as syringomyelia or Arnold-Chiari malformation. Fusion of the Cervical Vertebrae Fusion of the upper thoracic vertebrae and the entire cervical spine into a single bony mass was reported by Klippel and Feil in 1912. Since that time, numerous cases have been reported with variations of this deformity. In most, the abnormality consists of the fusion of the cervical vertebrae into one or more separate masses (Fig. 78.3). This vertebral fusion is the result of maldevelopment in utero, and there is evidence of both autosomal dominant and recessive transmission. This anomaly is associated with a short neck, low hairline, and limitation of neck movement, especially in the lateral direction. Fusion of the vertebrae is not in itself of any great clinical importance except for the resulting deformity in the appearance of the neck. Clinical symptoms are usually due to the presence of syringomyelia or other developmental defects of the spinal cord, brainstem, or cerebellum. Congenital cardiovascular defects have been reported in 4% and genitourinary anomalies in 2% of patients. Congenital deafness due to faulty development of the osseous inner ear was estimated to occur in up to 30% of patients.

FIG. 78.3. Fusion of cervical vertebrae (Klippel-Feil syndrome).

More frequently, there may be fusion of only two adjacent cervical vertebrae causing only accentuation of symptoms in the presence of cervical osteoarthritis.

PREMATURE CLOSURE OF CRANIAL SUTURES Craniosynostosis or premature closure of cranial sutures occurs in childhood if cerebral growth is impaired. This is commonly manifested by a uniform closure of all sutures and microcephaly. True microcephaly is defined by a head circumference less than 3 standard deviations below the mean for age and sex. Rarely, early closure of the sutures may occur as a consequence of metabolic diseases, including rickets and hyperthyroidism. Craniosynostosis is usually a primary congenital disturbance of skull growth with no neurologic disorder. The frequency is about 1 in 1,900 births. In 10% to 20%,

there is a mendelian inheritance. Sixty-four mutations of six genes have been described in craniosynostosis syndromes commonly associated with limb malformations. Accompanying facial and other tissue deformities also may be seen in recognized syndromes ( Table 78.4).

TABLE 78.4. SYNDROMES ASSOCIATED WITH CRANIOSYNOSTOSIS

In essence, the skull deformity in primary craniosynostosis reflects the inhibition of growth perpendicular to the closed suture, with compensatory overgrowth in directions perpendicular to the unaffected sutures. Closure of a single suture is most common. Sagittal suture closure alone, seen in 55% of all patients with craniosynostosis, is clinically identified by a child with an oblong-shaped skull ( dolichocephalic or scaphocephalic), often with visible ridging of the closed suture ( Fig. 78.4).

FIG. 78.4. Acrocephalosyndactyly (Apert syndrome). Head is shortened in anterioposterior dimension, forehead is prominent, and occiput flat. Typical facies showing shallow orbits and proptosis of eyes, downward slanting palpebral fissures, small nose, and low-set ears. Osseous and cutaneous syndactyly of hands and feet.

Unilateral closure of the coronal suture is seen in about 24% of all patients, appearing as a misshapen and unilaterally flattened head (plagiocephaly). Metopic suture closure occurs in about 5% of all craniosynostosis patients, with a prominent midforehead brow appearance ( trigonencephaly). Single suture closure does not lead to compression of intracranial tissues. Multiple suture closure occurs commonly with other skull and facial defects and may lead to increased intracranial pressure because of interference with intracranial CSF flow. The optic and acoustic nerves may be compressed, especially in infants with bilateral coronal suture closure (about 9% of all patients with craniosynostosis). These infants have a broad biparietal diameter skull ( brachycephaly). Rarer forms of multiple suture disorder include some infants with closure of all sutures, resulting in a tower-shaped skull (oxycephaly) or a grossly distorted skull with an asymmetric, often bizarre clover-leaf shape ( Kleeblattsch채del). Early diagnosis of primary craniosynostosis is essential because the best cosmetic results from surgery are accomplished before the infant is 3 months old. The longer the delay, the greater the compensatory deformity in other areas of the skull and the more complex the surgery. Three-dimensional CT identifies the overall craniofacial contours and guides the surgical procedures needed for the complicated deformities of infants with more than one closed suture. In these infants, the cosmetic benefits are less important than prevention of intracranial hypertension and cranial nerve compression. Craniectomy to open up closed sutures is of no value in infants with craniostenosis and microcephaly in whom the injured brain has not grown adequately.

SPINA BIFIDA AND CRANIUM BIFIDUM Both environmental factors and genetics may produce structural malformations of the developing nervous system. Moreover, the damaged fetal brain may be more vulnerable to hypoxic perinatal insults. Teratogenetic factors including certain anticonvulsants probably cause malformations in 1 of every 400 births; genetic factors account for about a third of the malformations, and the cause is unknown in more than 50%. Pathogenesis and Diagnosis The neural tube begins to fuse on about day 27 and closes about day 28 of gestation. The primordium of the vertebrae forms from the mesoderm that, similar to the adjacent developing ectoderm, separates from the neural tube. Failure of closure of the neural tube and associated primitive mesodermal and ectodermal elements accounts for the appearance of congenital midline defects, termed dysraphism ( Table 78.5).

TABLE 78.5. NEURAL TUBE CLOSURE MALFORMATIONS

Severe malformations may be detected in utero by ultrasonography and by finding elevated maternal serum levels of alpha-fetoprotein (AFP). AFP is the major circulating protein of early fetal life, synthesized in the fetal liver and yolk sac. Peak levels are found about 16 weeks after the last menstrual period, making that the

optimum time for testing. The exposed fetal membranes and blood vessel surfaces increase the AFP levels in both maternal serum and amniotic fluid if there is an open neural tube. If results are ambiguous or in circumstances in which there is increased risk of a defect because of genetic factors, measurement of AFP and acetylcholinesterase by amniocentesis is warranted. Measurement of amniotic acetylcholinesterase activity helps to detect an open dysraphic state in utero because amniotic AFP levels may be high in gastroschisis, omphalocele, and nephrosis. Increased levels of amniotic AFP and acetylcholinesterase detect at least 90% of open spina bifida fetuses and almost all of the anencephalics, whereas maternal serum AFP levels detect 60% to 80% of open spina bifida fetuses and 90% of the anencephalics. The use of folic acid or vitamin supplements containing folic acid during the periconceptional period significantly decreases the risk of neural tube closure defects in the offspring. The risk of another child born with a neural tube defect in a family with two unaffected parents is 3% to 5%. Although familial clustering of neural tube defects has been identified, the pattern best fits a polygenic model of inheritance. The simplest defect, spina bifida occulta, is characterized by a lack of vertebral arch closure without any other associated defect. It is usually localized to L5-S1 and does not seem to have an increased risk of neural tube closure malformations in that individual's progeny. This is in contrast to anencephaly and other forms of spina bifida in which there is a close genetic relationship and in which the recurrence risk is equally distributed. Many severely affected fetuses are spontaneously aborted. Associated anomalies of other organ systems include congenital heart disorders, diaphragmatic defects, and esophageal atresia. Other central nervous system anomalies are common but may not be clinically apparent in the newborn infant with neural tube closure defect. Abnormalities of the basal ganglia, hippocampi, commissural pathways, brainstem, and cerebellum may be seen in infants born with occipital encephaloceles. Ventricular wall deformities, corpus callosum defects, and hydrocephalus may be noted with parietal encephaloceles. Basal ganglia and commissural anomalies may be seen with anterior encephaloceles that are most common in the frontoethmoidal junction. Spina bifida deformities commonly include other nervous system abnormalities: tethering of the cord ( Fig. 78.5), diastematomyelia, hydromyelia, and hydrocephalus usually associated with Arnold-Chiari type II malformation. Occult spinal dysraphic states reflect other defects of ectodermal and mesodermal origin, including pelvic meningoceles, hamartomas, lipomas, and dermoid tumors, and may be suspected if there are skin markers: skin tags, hair tufts, abnormal dimpling, or aplasia cutis congenita.

FIG. 78.5. Lumbosacral myelomeningocele. Sagittal magnetic resonance imaging shows spinal dysraphism and tethered cord.

The congenital syndromes associated with defects of neural tube closure include the Meckel-Gruber syndrome (posterior encephalocele, microcephaly, cerebral and cerebellar hypoplasia, and associated defects of face, neck, limbs, kidney, liver, and genitalia) and the Walker-Warburg syndrome (occipital encephalocele, Dandy-Walker cyst, hydrocephalus, cerebellar hypoplasia, and eye defects). Treatment MRI of the brain and spine has enhanced an understanding of the extent of the primary defect and the associated anomalies. MRI also guides treatment. Neurologic evaluation defines the level of function by evaluating anal reaction and sensory, reflex, and motor functions. Surgical excision of the meningocele and the encephalocele must include meticulous protection of the neural elements underlying and sometimes adherent to the tissue to be excised. Post-excision assessment is vital to detect complications or the emergence of secondary or associated abnormalities (e.g., hydrocephalus after closure of a spinal meningocele or tethering of the spinal cord). Orthopedic and urologic approaches are essential for maximizing functional ability and preventing skin, bone, and renal problems. Concomitant or resultant bone and joint changes include the Klippel-Feil syndrome, foot deformities, scoliosis, and hip dysplasia, which may point to an associated disorder, such as cord tethering, hydromyelia, adhesive arachnoiditis, or a lipoma. In a series of 286 patients who had surgical closure of a spinal defect within 48 hours of birth, 42% had a thoracic defect and 58% had a lumbar or sacral defect. With an average age at follow-up of 61.4 months, 11% had lost quadriceps function between birth and the most recent examination. This was attributed to the development of a tethered cord. Only 24% of the thoracic-level patients could walk, whereas 92% of the lumbosacral-level patients did so. Prevalence of quadriceps function was critical. Ninety-three percent of all patients had shunts placed for the treatment of clinically overt hydrocephalus; 74% had more than one shunt. Psychologic development depends on the extent of cerebral pathology due to associated congenital defects or the sequelae of an open spina bifida such as neonatal meningitis, hydrocephalus, and shunting plus the emotional impact of the multiplicity of treatment regimens.

ARNOLD-CHIARI MALFORMATION A congenital anomaly of the hindbrain characterized by a downward elongation of the brainstem and cerebellum into the cervical portion of the spinal cord was originally described by Arnold in 1894 and Chiari in 1895. Pathology Because of its common association with spina bifida occulta or the presence of a meningocele or meningomyelocele in the lumbosacral region, the downward displacement of the brainstem and cerebellum was attributed to fixation of the cord at the site of the spinal defect early in fetal life. This hypothesis is not applicable to the many cases in which there is no defect in the lower spine, and the theory fails to account for the other anomalies commonly associated with the hindbrain malformation (e.g., absence of the septum pellucidum, fusion of the thalami, hypoplasia of the falx cerebri, fusion of the corporea quadrigemina and microgyri). Some type of developmental arrest and overgrowth of the neural tube in embryonic life is a more plausible explanation of the anomaly. The gross description of the abnormality has been remarkably similar in all the reported cases. The inferior poles of the cerebellar hemispheres extend downward through the foramen magnum in two tonguelike processes and are often adherent to the adjacent medulla; more than half is usually below the level of the foramen magnum (Fig. 78.6). The medulla is elongated and flattened anteroposteriorly, and the lower cranial nerves are stretched.

FIG. 78.6. Arnold-Chiari malformation. Magnetic resonance imaging T1-weighted image of midsagittal section of brain and cervical cord. Note small and elongated fourth ventricle, low position of obex of fourth ventricle below plane of foramen magnum, cerebellar tonsillar ectopia, short clivus, wide foramen magnum, kinked cervical medullary junction, and prominent superior vermis. Large hydromyelia in cervical cord.

Incidence The Arnold-Chiari malformation is not as rare as would be expected from the small number of reported cases. Ingraham and Swan found 20 instances of this abnormality among 290 patients with myelomeningoceles. The defect is almost always, but not invariably, associated with a meningomyelocele or spina bifida occulta in the lumbosacral region. Hydrocephalus is present in most cases. Other associated defects of development include rounded defects in the bones of the skull (craniolacunia, Lückenschädel), defects in the spinal cord (hydromyelia, syringomyelia, double cord), and defects in the spinal column (basilar impression). Symptoms and Signs The neurologic signs and symptoms of the Arnold-Chiari malformation that appear in the first few months of life are usually due to hydrocephalus and other developmental defects in the nervous system. The prognosis is poor in these cases. The onset of symptoms may be delayed until adult life. There may be signs and symptoms of injury to the cerebellum, medulla, and the lower cranial nerves, with or without evidence of increased intracranial pressure. Progressive ataxia, leg weakness, and visual complaints are characteristic. Oscillopsia at rest and visual blurring of fixated targets are described. Downbeat nystagmus and seesaw nystagmus may be noted in lesions of the cervicomedullary region. Diagnosis The presence of an Arnold-Chiari malformation is probable when there is a coincidence of meningomyelocele, hydrocephalus, and craniolacunia in infancy. The diagnosis in adults should be considered whenever there are signs and symptoms of damage to the cerebellum, medulla, and lower cranial nerves. The signs and symptoms of the Arnold-Chiari malformation in adults may simulate the syndromes produced by tumors of the posterior fossa, multiple sclerosis, syringomyelia, or basilar impression. The diagnosis can be established by CT ( Fig. 78.7) and MRI (Fig. 78.8, Fig. 78.9, and Fig. 78.10).

FIG. 78.7. Arnold-Chiari malformation. Postmyelography computed tomography. At level of odontoid in high cervical region, spinal cord is flattened by cerebellar tonsils (arrows). (Courtesy of Drs. S.K. Hilal and M. Mawad.)

FIG. 78.8. Type I Arnold-Chiari malformation. Sagittal T1-weighted scan shows tonsillar herniation through foramen magnum. Fourth ventricle is of normal size and position as are aqueduct and brainstem. There is no hydrocephalus. (Courtesy of Drs. J.A. Bello and S.K. Hilal.)

FIG. 78.9. Chiari II malformation. A: T1-weighted sagittal magnetic resonance (MR) image shows significant inferior displacement of cerebellar tonsil with tip located posterior to cervical cord at C3 level. The fourth ventricle is typically small. Also note agenesis of the corpus callosum. This is a separate congenital lesion but is often seen in association with Chiari malformation. B and C: T2-weighted axial MR image demonstrates “beaking” of dorsal midbrain, or tectum, characteristic of Chiari II malformation. There is enlargement of the occipital horns of both lateral ventricles (with ventricular shunt in right lateral ventricle), consistent with colpocephaly, which

is often associated with agenesis of corpus callosum. (Courtesy of Dr. S. Chan, Columbia University College of Physicians and Surgeons, New York, NY.)

FIG. 78.10. Encephalocele with Chiari III malformation. A and B: T2-weighted sagittal and axial magnetic resonance images demonstrate a huge fluid-filled sac external to the skull posteriorly, with patent communication to intracranial structures. There is herniation of both cerebellar hemispheres into the extruded cerebrospinal fluid-filled sac, most consistent with occipital encephalocele. Distortion of the brainstem and absence of the corpus callosum are also apparent. (Courtesy of Dr. S. Chan, Columbia University College of Physicians and Surgeons, New York, NY.)

Treatment Treatment of the malformation in infants includes excision of the sac in the spinal region and a ventriculoperitoneal shunt to relieve the hydrocephalus. Early hindbrain decompression is needed in symptomatic neonates with vocal cord paralysis. In adults, the posterior fossa should be decompressed. The best results are obtained when there are few neurologic symptoms caused by the spinal defect or other congenital anomalies. SUGGESTED READINGS Agenesis of the Corpus Collosum Berg MJ, Sohifitto G, Powers JM, et al. X-linked female band heterotropia-male lissencephaly syndrome. Neurology 1998;50:1143–1146. Bertoni JM, von Loh S, Allen RJ. The Aicardi syndrome: report of 4 cases and review of the literature. Ann Neurol 1979;5:475–482. Dobyns WB. Agenesis of the corpus callosum and gyral malformations are frequent manifestations of nonketotic hyperglycinemia. Neurology 1989;39:817–820. Dobyns WB, Truwit CL. Lissencephaly and other malformations of cortical development. Neuropediatrics 1995;26:132–147. Faye-Peterson OM, Ward K, Carey JC, Kinsley AS. Osteochondrodysplasia with rhizomelia, platyspondyly, callosal agenesis, thrombocytopenia, hydrocephalus and hypertension. Am J Med Genet 1991;40:183–187. Guala A, Dellavecchia C, Mannarino S. Ring chromosome 13 with loss of the region D13S317-D13S285: phenotypic overlap with XK syndrome. Am J Med Genet 1997;72:319–323. Haltia M, Leivo I, Samer H, et al. Muscle-eye-brain disease: a neuropathological study. Ann Neurol 1997;41:173–180. Harding BN. Malformation of the nervous system. In: Adams JH, Duchen LW, eds. Greenfield's neuropathology, 5th ed. New York: Oxford University Press, 1992. Jeret JS, Serur D, Wisniewski KE, et al. Clinicopathological findings associated with agenesis of the corpus callosum. Brain Dev 1987;9:255–264. Jones KL. Smith's recognizable patterns of human malformation, 4th ed. Philadelphia: WB Saunders, 1988. Loeser JD, Alvord EC. Agenesis of the corpus callosum. Brain 1968;91:553–570. Pavlakis, SG, Frissora, CL, Giampietro PF, et al. Fanconi anemia a model for genetic causes of abnormal brain development. Dev Med Child Neurol 1992;34:1081–1084. Macrocephaly and Megalencephaly DeMeyer W. Megalencephaly: types, clinical syndromes, and management. Pediatr Neurol 1986;2:321–328. Dionisi-Vici C, Ruitenbeek W, Fariello G, et al. New familial mitochondrial encephalopathy with macrocephaly, cardiomyopathy, and complex I deficiency.

Ann Neurol 1997;42:661–665.

Fusco L, Ferracuti S, Fariello G, et al. Hemimegalencephaly and normal intellectual development. J Neurol Neurosurg Psychiatry 1992;55:720–722. Gontieres F, Boulloche J, Bourgeois M, Aicardi J. Leucoencephalopathy, megalencephaly, and mild clinical course. A recently individualized familial lecodystrophy. J Child Neurol 1996;11:439–444. Harding BN. Malformation of the nervous system. In: Adams JH, Duchen LW, eds. Greenfield's neuropathology, 5th ed. New York: Oxford University Press, 1992. Laubscher B, Deonna T, Uske A, et al. Primitive megalencephaly in children: natural history, medium term prognosis with special reference to external hydrocephalus. Eur J Pediatr 1990;149:502–507. Padberg GW, Schot JD, Vielvoye GJ, et al. L'hermitte-Duclos disease and Cowden disease: a single phakomatosis. Ann Neurol 1991;29:517–523. Malformations of Occipital Bone and Cervical Spine DeBarros MC, Farias W, Ataide L, et al. Basilar impression and Arnold-Chiari malformation. J Neurol Neurosurg Psychiatry 1968;31:596–605. Dehaene I, Pattyn G, Calliauw L. Megadolicho-basilar anomaly, basilar impression and occipitovertebral anastomosis. Clin Neurol Neurosurg 1975;78:131–138. Dunsker SB, Brown O, Thomson N. Craniovertebral anomalies. Clin Neurosurg 1980;27:430–439. Gunderson CH, Greenspan RH, Glaser GH. The Klippel-Feil syndrome: genetic and clinical reevaluation of cervical fusion. Medicine (Baltimore) 1967;46:491–512. Janeway R, Toole JF, Leinbach LB, et al. Vertebral artery obstruction with basilar impression. Arch Neurol 1966;15:211–214. Jones KL. Smith's recognizable patterns of human malformations, 4th ed. Philadelphia: WB Saunders, 1988. Kaplan JG, Rosenberg RS, DeSouza T, et al. Atlantoaxial subluxation in psoriatic arthropathy. Ann Neurol 1988;23:522–524. Norot JC, Stauffer ES. Sequelae of atlanto-axial stabilization in two patients with Down's syndrome. Spine 1981;6:437–440. Sakai M, Shinkawa A, Miyake H, et al. Klippel-Feil syndrome with conductive deafness: histological findings of removed stapes. Ann Otol Rhinol Laryngol 1983;92:202–206. Stevens JM, Chong WK, Barber C, Kendall BE, Cockard HA. A new appraisal of abnormalities of the odontoid process associated with atlanto-axial subluxation and neurological disability. Brain 1994;117:133–148.

Vangilder JC, Menezes AH, Dlan KD. The craniovertebral junction and its abnormalities. Mt. Kisco, NY: Futura Publishing Co, 1987. Premature Closure of Cranial Sutures Carmel PW, Luken MG III, Ascherl GF. Craniosynostosis: computed tomographic evaluation of skull base and calvarial deformities and associated intracranial changes. Neurosurgery 1981;9:366–372. Cohen MM. Craniosynostosis and syndromes with craniosynostosis: incidence, genetics, penetrance, variability, and new syndrome updating. Birth Defects 1979;15:13–63. Crouzon Q. Dysostose cranio-faciale hereditaire. Bull Mem Soc Med Hop Paris 1912;33:545. Gorlin RJ, Cohen MM Jr, Levin LS. Syndromes of the head and neck, 3rd ed. New York: Oxford University Press, 1990. Gripp KW, McDonald-McGinn DM, Gaudenz K, et al. Identification of a genetic cause for isolated unilateral coronal synostosis: a unique mutation in the fibroblast growth factor receptor 3. 1998;132:714–716.

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Hoffman HS, Epstein F. Disorders of the developing nervous system: diagnosis and treatment. Boston: Blackwell Scientific Publications, 1986. Jones KL. Smith's recognizable patterns of human malformation, 4th ed. Philadelphia: WB Saunders, 1988. Pellegrino JE, McDonald-McGinn DM, Schneider A. Further clinical delineation and increased morbidity in males with osteopathia striata with cranial sclerosis: an x-linked disorder? Am J Med Genet 1997;70:159–165. Shillito J Jr. A plea for early operation for craniostenosis. Surg Neurol 1992;37:182–188. Wilkie AOM. Craniosynostosis: genes and mechanisms. Hum Mol Genet 1997;6:1647–1656. Spina Bifida and Cranium Bifidum Czeizel AE, Duda I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832–1835. Gorlin RJ, Cohen MM Jr, Levin LS. Syndromes of the head and neck, 3rd ed. New York: Oxford University Press, 1990. Harding BN. Malformation of the nervous system. In: Adams JH, Duchen LW, eds. Greenfield's neuropathology, 5th ed. New York: Oxford University Press, 1992. Harper PS. Practical genetic counselling, 3rd ed. London: Wright, 1988. Hoffman HS, Epstein F. Disorders of the developing nervous system: diagnosis and treatment. Boston: Blackwell Scientific Publications, 1986. Patterson RS, Egelhoff JC, Crone KR, et al. Atretic parietal cephaloceles revisisted: an enlarging clinical and imaging spectrum. Am J Neuroradiol 1998;19:791–795. Robert E, Guiband P. Maternal valproic acid and congenital neural tube defects. Lancet 1982;2:934. Salonen R. The Meckel syndrome: clinicopathological findings in 67 patients. Am J Med Genet 1984;18:671–689. Arnold-Chiari Malformation Arnold J. Myelocyste. Transposition von Gewebskeimen und Sympodie. Beitr Pathol Anat 1894;16:1–28. Balagura S, Kuo DC. Spontaneous retraction of cerebellar tonsils after surgery for Arnold-Chiari malformation and posterior fossa cyst. Surg Neurol 1988;29:137–140. Banerji NK, Millar JHD. Chiari malformation presenting in adult life. Its relationship to syringomelia. Brain 1974;97:157–168. Brill CB, Gutierrez J, Mishkin MM. Chiari I malformation: association with seizures and developmental disabilities. J Child Neurol 1997;12:101–106. Caviness VS Jr. The Chiari malformations of the posterior fossa and their relation to hydrocephalus. Dev Med Child Neurol 1976;18:103–116. Chiari H. Adüber Veränderungen des Kleinhirns, des Pons und der Medulla oblongata in Folge von congenitaler Hydrocephalie des Grosshirns. Denkschr Akad Wiss Wien 1896;63:71–116. DeBarros MC, Farias W, Ataide L, et al. Basilar impression and Arnold-Chiari malformation. J Neurol Neurosurg Psychiatry 1968;31:596–605. Dehaene I, Pattyn G, Calliauw L. Megadolicho-basilar anomaly, basilar impression and occipito-vertebral anastomosis. Clin Neurol Neurosurg 1975;78:131–138. el Gammal T, Mark EK, Brooks BS. MR imaging of Chiari II malformation. AJR 1988;150:163–170. Elster AD, Chen MY. Chiari I malformations: clinical and radiologic reappraisal. Radiology 1992;183:347–353. Gilbert JN, Jones KL, Rorke LB, et al. Central nervous system anomalies associated with meningomyelocele hydrocephalus and the Arnold-Chiari malformation. Neurosurgery 1986;18:559–564. Levy WJ, Mason L, Hahn JF. Chiari malformation presenting in adults: a surgical experience in 127 cases. Neurosurgery 1983;12:377–390. Pollach IF, Dachling P, Albright AL, et al. Outcome following hindbrain decompression of symptomatic Chiari malformations in children previously treated with myelomeningocele closure and shunts. Neurosurg 1992;77:881–888. Salam MZ, Adams RD. The Arnold-Chiari malformation. In: Vinken P, Bruyn G, eds. Handbook of clinical neurology. Vol. 32. New York: American Elsevier-North Holland, 1978;99–110.

J

CHAPTER 79. MARCUS GUNN AND MÖBIUS SYNDROMES MERRITT’S NEUROLOGY

CHAPTER 79. MARCUS GUNN AND MÖBIUS SYNDROMES LEWIS P. ROWLAND Marcus Gunn Syndrome MÖBius Syndrome Suggested Readings

MARCUS GUNN SYNDROME Among the more bizarre and unexplained neurologic phenomena is jaw winking. The phenomenon was described by Marcus Gunn in 1863, and there have been many descriptions since then. The patient has congenital and unilateral ptosis. When the mouth is opened, the lid rises and there may even be retraction of the lid. Conversely, when the jaw closes, the lid comes down in a wink. Lateral movements of the jaw can substitute for opening. The patient can raise the lid voluntarily and on upward gaze, but the movements are exaggerated in response to movements of the jaw. There is also an inverted or reversed Marcus Gunn phenomenon: The eye closes when the jaw opens. This is known as Marin Amat syndrome, which may follow Bell palsy. How the Marcus Gunn syndrome arises is still not known; it is presumably a congenital error of neuronal wiring in the brainstem. In that respect, it is similar to the Duane retraction syndrome (retraction of the globe and narrowing of the palpebral fissure on attempted adduction). Another syndrome sometimes seen with the Marcus Gunn phenomenon and also attributed to neuronal miswiring is synergistic divergence, in which there is simultaneous abduction of both eyes on attempted gaze into the field of action of a paretic medial rectus; both eyes abduct on attempted lateral gaze. It is sometimes associated with other congenital anomalies that suggest an anomaly of tissues derived from the neural crest, or there may be restriction of all ocular movements in a pattern suggesting congenital fibrosis of ocular muscles. The Marcus Gunn syndrome is sometimes an autosomal-dominant familial trait. The risk is increased in infants after a pregnant woman has used misoprotol as an abortifacient. Abnormal brainstem auditory evoked responses suggest that the problem is in the brainstem, but the levator muscle of the eyelid may show neurogenic changes, suggesting that the oculomotor nerve is affected. There have not been enough anatomic, imaging, or physiologic studies, however, to come to any conclusion. The syndrome accounts for about 5% of all cases of congenital ptosis and may be so mild that it is of no functional consequence. The cosmetic distortion, however, has sometimes been sufficient to lead to surgical therapy in the form of operations on the levator or facial muscles. The Marcus Gunn syndrome should not be confused with the Marcus Gunn pupil, for he also described what is now known as the afferent pupillary defect. Jaw winking is an abnormal synkinesis, simultaneous movements effected by muscles innervated by different nerves. Formally, this is a trigeminooculomotor synkinesis.

MÖBIUS SYNDROME The usual definition of this syndrome is the combination of congenital facial diplegia and bilateral abducens palsies. Other cranial nerves, however, may be affected, with hearing loss, dysarthria, and dysphagia. Associated conditions include congenital anomalies of limbs or heart, Kallmann syndrome (hypogonadism and anosmia), or mental retardation. The syndrome is often evident in the neonatal period because the children have difficulty sucking and they lack facial expression when they cry. Vertical gaze and convergence are preserved; there is usually a convergent squint. If facial paralysis is incomplete, as in almost half the cases, the syndrome may not be recognized until later in childhood. Then, in contrast to other supranuclear or lower motor neuron causes of facial paralysis, the weakness is more severe in the upper face than below; there is more of a problem with eye closure than in moving the lips. There may be complete ophthalmoplegia, ptosis, lingual hemiatrophy, and, in a few cases, mental retardation. There is probably more than one mechanism in the pathogenesis of the facial paralysis. For instance, physiologic studies have shown cocontraction of the horizontal recti, but other cases have shown evidence of aplasia of ocular muscles or agenesis of motor neurons. In one autopsy, the facial muscles were absent but ocular muscles, nerves, and motor nerve cells were normal; there were, however, developmental anomalies of the brainstem, which may be evident on computed tomography or magnetic resonance imaging. In other autopsies, there was hypoplasia or degeneration of motor nuclei, but in some, no abnormality was seen in the central nervous system. Some cases later prove to be due to facioscapulohumeral muscular dystrophy. Congenital myotonic muscular dystrophy is another cause of facial diplegia. SUGGESTED READINGS Marcus Gunn Syndrome Brodsky MC, Pollock SC, Buckley EG. Neural misdirection in congenital ocular fibrosis syndrome; implications and pathogenesis. J Pediatr Ophthalmol Strabis 1989;26:159–161. Clausen N, Andersson P, Tommerup N. Familial occurrence of neuroblastoma, von Recklinghausen neurofibromatosis, Hirschsprung's agangliosis and jaw-winking syndrome. Acta Paediatr Scand 1989;78:736–741. Creel DJ, Kivlin JD, Wolfley DE. Auditory brain stem responses in Marcus-Gunn ptosis. Electroencephalogr Clin Neurophysiol 1984;59:341–344. Falls HF, Kruse WT, Cotterman CW. Three cases of Marcus Gunn phenomenon in two generations. Am J Ophthalmol 1949;32:53–59. Grant FC. The Marcus Gunn phenomenon. Arch Neurol Psychiatry 1936;35:487–500. Hamed LM, Dennehy PJ, Lingua RW. Synergistic divergence and jaw- winking phenomenon. J Pediatr Ophthalmol Strabis 1990;27:88–90. Lewy FH, Groff RA, Grant FC. Autonomic innervation of the eyelids and the Marcus Gunn phenomenon. Arch Neurol Psychiatry 1937;37:1289–1297. Lyness RW, Collin JR, Alexander RA, Garner A. Histologic appearances of the levator palpebral superioris muscle in the Marcus Gunn phenomenon. Br J Ophthalmol 1988;72:104–109. Meirez F, Standaert L, Delaey JJ, Zeng LH. Waardenberg syndrome, Hirschprung megacolon, and Marcus Gunn ptosis. Am J Med Genet 1987;27:683–686. Pratt SG, Beyer CK, Johnson CC. The Marcus Gunn phenomenon. A review of 71 cases. Ophthalmology 1984;91:27–30. MÖbius Syndrome Abid F, Hall R, Hudgson P, Weiser R. MÖbius syndrome, peripheral neuropathy and hypogonadotrophic hypogonadism. J Neurol Sci 1978;35:309–315. Bavinck JN, Weaver DD. Subclavian artery supply description sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and MÖbius anomalies. Am J Med Genet 1986;23:903–918. Brackett LE, Demers LM, Mamourian AC, et al. MÖbius syndrome in association with hypogonadotropic hypogonadism. J Endocrinol Invest 1991;14:599–607. Hanson PA, Rowland LP. MÖbius syndrome and facioscapulo-humeral muscular dystrophy. Arch Neurol 1971;24:31–39. Henderson JL. The congenital facial diplegia syndrome. Brain 1939;62:381–403. Hopper KD, Haas DK, Rice MM, et al. Poland-MÖbius syndrome: evaluation by computerized tomography. South Med J 1985;78:523–527.

Kumar D. MÖbius syndrome. J Med Genet 1990;27:122–126. Olson WH, Bardin CW, Walsh GO, Engel WK. MÖbius syndrome, lower motor neuron involvement and hypogonadotropic hypogonadism. Neurology 1970;20:1002–1008. Pastuszak AL, Schuler L, Speck-Martins CE, et al. Use of misoprostol during pregnancy and MÖbius syndrome in infants. N Engl J Med 1998;359:1553–1554. Pitner SE, Edwards JE, McCormick WF. Observations on the pathology of the MÖbius syndrome. J Neurol Neurosurg Psychiatry 1965;28: 362–374. Rojas-Martinez A, Garcia-Cruz D, Rodriguez-Garcia A, et al. Poland-MÖbius syndrome in a boy and Poland syndrome in his mother. Clin Genet 1991;40:225–228. Rubenstein AE, Lovelace RE, Behrens MM, Weisberg LA. Moebius syndrome in Kallmann syndrome. Arch Neurol 1975;32:480–482. Slee JJ, Smart RD, Viljoen DL. Deletion of chromosome 13 in MÖbius syndrome. J Med Genet 1991;28:413–414. Towfighi J, Marks K, Palmer E, Vanucci R. MÖbius syndrome. Neuropathologic observations. Acta Neuropathol (Berl) 1979;48:11–17. Ziter FA, Wiser WC, Robinson A. Three generation pedigree of a MÖbius syndrome variant with chromosome translocation. Arch Neurol 1977;34:437–442.

CHAPTER 80. CHROMOSOMAL DISEASES MERRITT’S NEUROLOGY

SECTION IX. GENETIC DISEASES OF THE CENTRAL NERVOUS SYSTEM CHAPTER 80. CHROMOSOMAL DISEASES CHING H. WANG Trisomy 21 (Down Syndrome) Prader-Willi and Angelman Syndromes Suggested Readings

Human chromosomal anomalies are manifest as change in the total number of chromosomes or as structural rearrangements. Examples of abnormal chromosome number (aneuploidy) are sex chromosomal aneuploidy such as 45,X (Turner syndrome) and autosomal aneuploidy such as 47,XX +21 (trisomy 21, Down syndrome). Structural abnormalities include regional deletions or insertions, segmental translocations (reciprocal or robertsonian) or inversions (pericentric or paracentric), duplications, and ring chromosomes. The chromosomal syndromes are many, but they primarily result from these chromosomal rearrangements, producing a functional monosomy or trisomy (one or three chromosomes instead of the normal two). The most common manifestation of these chromosomal anomalies is mental retardation. Congenital malformations are seen in variable frequencies and different severities. In the sex chromosome disorders, infertility is the most common feature. In this section, as examples, we discuss three chromosomal syndromes: trisomy 21, Prader-Willi, and Angelman syndromes.

TRISOMY 21 (DOWN SYNDROME) Down syndrome was named after the English physician John Langdon Down, who described the clinical features in 1866. The chromosomal abnormality, the first described in humans, was identified only 3 years after the normal human chromosome number was established in 1956. Down syndrome is also named trisomy 21 because there is usually an extra copy of chromosome 21. The syndrome is encountered in about 1 in 800 live births, with a male-to-female ratio about 3:2. The risk of occurrence increases sharply with increased maternal age: 1 in 350 at age 35 and 1 in 110 at age 40. A 45-year-old woman is 60 times more likely to have an affected child than is a 20-year-old woman. Clinical Features The typical facial features include a round face and a short nose with flat nasal bridge. The eyes show upward slanting of the lateral palpebral fissures with epicanthal folds. Brushfield spots are often seen arranged in a circular ring around the outer third of the iris. The mouth is small and kept open by a large protruding tongue. The palate is high-arched or cleft. Structural anomalies of the middle and inner ear lead to frequent bouts of otitis. Skeletal anomalies include short stature, stubby fingers and toes, an increased space between the first and second toes, and clinodactyly (inward curvature) of the fifth finger. The pelvis is small with diminished iliac and acetabular angles. Atlantoaxial or atlantooccipital instability is found in 15% to 20% of patients. Unique dermatoglyphic features include the simian crease in the palm and unusual hand- and footprints. There is an increased incidence of congenital heart diseases, such as septal and endocardial cushion defects. The genitalia are poorly developed in males, resulting in infertility. In women, ovarian defects and irregular menstruation commonly occur. Intestinal atresia, imperforate anus, and Hirschsprung disease are common. Hematologic abnormalities include an increased risk of leukemia. Infantile hypotonia and later mental retardation are the major neurologic signs. The IQ scores vary from 20 to 70 depending on the genetic background and environmental factors. Starting at ages 35 to 40, a further decline of cognitive function is attributed to dementia. Seizures are found more frequently in persons with Down syndrome, usually infantile spasms and tonic-clonic seizures with myoclonus in early life and partial simple or partial complex in the later years. Neuropathology The brain is spherical and small, with fewer secondary sulci than normal. The superior temporal lobes are hypoplastic, and the sylvian fissure is prominent. Microscopically, there is a reduction of neuronal density in diverse cortical areas. The pyramidal cells show a reduced number of apical dendrites and synapses. The cerebellum is small and includes an accumulation of undifferentiated fetal cells. There are striking microscopic similarities in the brains of those with Down syndrome and those with Alzheimer disease (AD), including degeneration of the cells in the nucleus basalis of Meynert with decreased choline acetyltransferase; pigmentary degeneration of neurons with accumulation of senile plaques and neurofibrillary tangles; and calcium deposits in hippocampus, basal ganglia, and cerebellar folia. Almost all Down syndrome adults over age 30 years have plaques and tangles, but because of the lifelong mental retardation, it is difficult to discern whether these neuropathologic findings contribute to clinical dementia. Cytogenetics and Molecular Genetics In 90% to 95% of cases, karyotype analysis showed trisomy 21, with a complete extra chromosome 21. In a few cases, trisomy is due to a translocation. Most free trisomy 21 results from meiotic nondisjunction in meiosis II, which correlates with advancing maternal age. Traditional cytogenetic techniques show maternal nondisjunction in about 80% and paternal in 20% of cases. With DNA analysis of polymorphisms, using highly informative markers and the polymerase chain reaction, the origin is paternal in only about 5% of cases. All of chromosome 21 need not be triplicated to produce the syndrome. In a few cases, the only extra chromosomal 21 material is the distal half of the long arm, specifically a region within bands q21.2 and q22.3. Many candidate genes have been isolated from this region. It is likely that multiple genes are responsible for the phenotypic variations in Down syndrome. The mosaic pattern (46/47, +21) occurs in 2% to 3%. The clinical features of these individuals range from virtually normal physical and intellectual characteristics to that of typical trisomy 21. Down Syndrome and Familial Alzheimer Disease In addition to the neuropathologic similarities of Down syndrome and AD, linkage studies indicate that one of the early-onset familial AD genes is linked to chromosome 21. In these families, a single base mutation in the amyloid precursor protein (APP) gene in 21q21.3 segregates with the disease. Mutations in the APP gene prevent the normal proteolytic breakdown of Ab core (a portion of APP) and result in accumulation of amyloid protein in the senile plaques. In one study, three copies of the amyloid gene were seen in three patients with AD and also in two patients with nontrisomy Down syndrome. This finding suggested a common genetic and pathophysiologic basis for the two diseases. There is genetic heterogeneity, however, in familial AD. Two other genes have been found to associate with early-onset AD: the presenilin 1 gene on chromosome 14 and the presenilin 2 gene on chromosome 1. The AD susceptibility locus apolipoprotein E (APOE4) allele on chromosome 19 and the recently identified a-2 M gene on chromosome 12 are associated with the late-onset AD. In Down syndrome, a triplicated region that includes the APP gene on chromosome 21 may be responsible for the increased APP production and the similar histopathology as seen in AD. Management There is no specific therapy for the neurologic or the cognitive impairment of Down syndrome. Several therapeutic trials using neurochemical (such as 5-hydroxytryptophan) or vitamin supplements have been unsuccessful. Management is addressed to the treatment of the medical and surgical conditions that accompany the syndrome. Computed tomography screening for atlantoaxial instability is indicated before a child participates in contact sports.

PRADER-WILLI AND ANGELMAN SYNDROMES These clinically distinct syndromes are both associated with a DNA deletion within chromosome 15q11-13. The clinical differences are attributed to the derangements of the genes preferentially expressed on either the maternally or paternally derived chromosome, which is called genomic imprinting. Prader-Willi Syndrome

First described by Prader in 1956, this syndrome is estimated to occur about 1 in 25,000 live births. It is usually sporadic, with an empiric risk of recurrence in siblings of less than 1:1,000. The clinical features can be divided into two stages. The first stage is characterized by neonatal hypotonia. A poor sucking reflex causes feeding problems that may lead to failure to thrive and requires tube feeding. The external genitalia are small. The hypotonia improves at ages 8 to 11 months. Electromyography, motor nerve conduction velocity, serum creatine kinase, and muscle biopsy are usually normal. The second stage, usually between ages 1 and 2 years, is characterized by delayed psychomotor development and childhood obesity. As the hypotonia improves, the infant becomes more alert. Increased appetite causes excessive weight gain. Speech delay and cognitive dysfunction are mild or moderately severe. Other typical features include short stature, small hands and feet, almond-shaped eyes, strabismus, and poor dentition. The syndrome is attributed to defective hypothalamic function. Thermoinstability, hyperphagia, hypogonadism, and growth hormone deficiency with short stature are clinical manifestations of hypothalamic dysfunction. However, no specific lesion of the hypothalamus has been identified at autopsy. Early death is occasionally caused by morbid obesity and cardiopulmonary complications. Angelman Syndrome In 1965, Angelman described three children with “flat heads, jerky movements, protruding tongues and bouts of laughter giving them a superficial resemblance to puppets.” The prevalence was estimated at 1 in 12,000. Most Angelman syndrome (AS) cases occur sporadically, but some familial cases have also been reported. There is no association with advanced maternal or paternal age. The infants are usually normal at birth. Feeding difficulty is noted at ages 1 to 2 months, with a period of failure to thrive. Head circumference stays at less than fifth percentile. The children may not sit alone until age 1 year and may walk at 3 to 5 years. There is no development of speech. The child is usually happy and smiling. Hyperactivity is common. The gait is wide-based and ataxic with tremulous movements. The face is round with a large mouth and protruding tongue. Electroencephalogram abnormalities and seizure of various severities occur frequently in early infancy. The child is usually unable to perform activities of daily living. Pubertal development is delayed, and the adult height is less than the third percentile. Molecular Basis More than 50% of Prader-Willi syndrome (PWS) patients studied with high-resolution banding techniques showed some chromosome 15 anomalies. More than 90% of the abnormalities involve a deletion in band 15q11-13, and an equal proportion of AS patients have a similar deletion at 15q11-13. Using both cytogenetic techniques and DNA polymorphisms, it is possible to identify the parental origin of the deleted chromosome; all PWS patients inherit a deleted chromosome 15 from the father and all AS patients inherit a similar chromosome 15 deletion from the mother. In PWS, maternal heterodisomy (two different chromosome 15 derived from the mother) is found in some of those without a cytogenetic deletion. Therefore, loss of the expressed paternal allele, due to interstitial deletion or uniparental disomy, may be responsible for the specific PWS phenotype. Six paternally expressed genes (SNRPN, IPW, ZNF127, PAR-1, PAR-5, and NDN) have been isolated from the PWS critical region. However, no mutation or deletion of any single gene can produce the full clinical phenotype of PWS. These findings suggest that PWS may be a contiguous gene syndrome. In AS, recent progress in the molecular genetics has led to the identification of a strong AS candidate gene UBE3A, located closely to but distal to the PWS critical region within chromosome 15q12. Mutations of UBE3A gene alone were sufficient to produce a full clinical AS phenotype. Using mouse model, the UBE3A gene is maternally expressed in the hippocampal and Purkinjie neurons. The other molecular causes of AS include de novo maternal deletions at 15q11-13 (about 70%), paternal uniparental disomy of chromosome 15 (about 2%), and mutations in the imprinting center (about 2% to 3%). Genomic Imprinting This epigenetic phenomenon illustrates an interesting non-Mendelian mode of inheritance in the mammalian genome. Several autosomal genes are inherited in a silent state on one parental allele and in an active state on the other parental allele. This parent-of-origin–specific gene expression is called genomic imprinting. The diseases that arise from these genes are mostly due to mutation of the active allele, duplication of the nonactive allele, or imprinting errors resulting in silencing of the active allele. Over 20 imprinted genes have now been identified in mouse genome; many of them have human homologues. For example, the insuline-like growth factor type 2 (IGF-2) gene is paternally active, and only when the gene defect is inherited from the father do the offspring express the dwarfing phenotype. In the cases of PWS and AS, deletions in the PWS critical region on the paternal chromosome or maternal uniparental disomy result in the silencing of the paternally active allele and the PWS phenotype, whereas deletion of the AS critical region on the maternal chromosome or paternal uniparental disomy result in the silencing of the maternal allele and the AS phenotype. The PWS and AS critical regions are physically very close to each other on chromosome 15q12. Evidence of other human genomic imprinting includes the following. First, in germline tumors such as hydatidiform moles, there are paternally derived haploid sets of chromosomes. Ovarian teratomas have two sets of maternal chromosomes. In fetal triploids, diandric triploids (two paternal chromosomes) are found in large cystic placentas. Conversely, in digynic fetus (two maternal chromosomes), fetal development is severely retarded, and the placentas are small and usually nonmolar. Second, in somatic cell tumors (such as retinoblastoma and Wilms tumor), inactivation of one allele by imprinting and a second step of chromosomal loss or mutation result in “loss of heterozygosity” and tumorogenesis. The molecular mechanism of genomic imprinting is largely unknown. The recent isolation of a cis-acting imprinting center located upstream to the promotor region of the SNRPN gene has helped us to understand the molecular basis of genomic imprinting. Deletions or mutations in this imprinting center have be shown to associate with PWS or AS depending on the origin of parental germlines. It is postulated that the imprinting center confers a male or female imprint by an “imprinting switch” during gametogenesis. In the female germline, the imprinting switch is needed to reset the male chromosome from the maternal grandfather to confer the charateristics of a female chromosome. In the male germline, the same process is needed to reset the female chromosome from the paternal grandmother to confer the characteristics of a male chromosome. This epigenetic mark is thought to be achieved by DNA methylation. In the case of PWS, the inactive allele on the maternal chromosome is hypermethylated, which suppresses gene transcription. The hypermethylated cytosine residues on the DNA sequences may repel the transcription factors needed for the activation of gene transcription. In other imprinted genes like IGF-2 receptor, DNA methylation is associated with the active allele on the maternal chromosome. Therefore, other factors in addition to DNA methylation may be involved in genomic imprinting. SUGGESTED READINGS Down Syndrome Antonarakis SE, Down syndrome collaborative group. Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. N Engl J Med 1991;324:872–876. Blacker D, Wilcox MA, Laird NM, et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 1998;19:357–360. Epstein CJ. Down syndrome. In: Rosenberg RN, Prusiner SB, DiMauro S, et al., eds. The molecular and genetic basis of neurological disease. Boston: Butterworth-Heinemann, 1997. Kallen B, Mastroiacovo P, and Robert E. Major congenital malformations in Down syndrome. Am J Med Genet 1996;65:160–166. Karlinsky H, Vaula G, Haines L, et al. Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer disease and a missense mutation in codon 717 of the b-amyloid precursor protein (APP) gene. Neurology 1992;42:1445–1453. St George-Hyslop P, Haines J, Rogaev E, et al. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nat Genet 1992;2:330–334. Prader-Willi and Angelman Syndromes Albrecht U, Sutcliffe JS, Cattanach BM, et al. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinjie neurons. Nat Genet 1997;17:75–78. Cassidy SB, Schwartz S. Prader-Willi and Angelman syndromes. Disorders of genomic imprinting. Medicine (Baltimore) 1998;77:140–151. Glenn CC, Saitoh S, Jong MTC, et al. Gene structure, DNA methylation, and imprinting expression of the human SNRNP gene. Am J Hum Genet 1996;58:335–346. Knoll JHM, Nicholls RD, Magenis RE, et al. Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of deletion. Am J Med Genet 1989;32:285–290.

Genomic Imprinting Bartolomei MS, Tilghman SM. Genomic imprinting in mammals. Annu Rev Genet 1997;31:493–525. Buiting K, Saitoh S, Gross S, et al. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet 1995;9:395–400. Dittrich B, Buiting K, Korn B, et al. Imprinting switch on human chromosome 15 may involve alternative transcripts of the SNRNP gene. Nat Genet 1996;14:163–170. Feinberg AP. Geomic imprinting and gene activation in cancer. Nat Genet 1993;4:110–113.

CHAPTER 81. DISORDERS OF AMINO ACID METABOLISM MERRITT’S NEUROLOGY

CHAPTER 81. DISORDERS OF AMINO ACID METABOLISM JOHN H. MENKES Phenylketonuria (Mim 261600) Maple Syrup Urine Disease (Mim 248600) Defects in the Metabolism of Sulfur Amino Acids Other Defects of Amino Acid Metabolism Disorders of Amino Acid Transport Suggested Readings

There has been an exponential growth in our understanding of the multiplicity of genetic defects that underlie the various disorders of amino acid metabolism. Rather than elaborate on the molecular biology of these disorders, this chapter focuses on their neurologic aspects and their diagnosis and management. Mass screening for disorders of amino acid metabolism has resulted in early biochemical diagnosis of phenylketonuria (PKU) and other aminoacidopathies. In one screening program, the incidence of PKU was 1:10,000 in New South Wales, Australia, the incidence of defects of amino acid transport was about 2:10,000, and the combined incidence of all other aminoacidopathies was less than 8:100,000. Although these conditions are rare, they are important because they provide information about the development and functions of the brain.

PHENYLKETONURIA (MIM 261600) PKU (phenylalanine hydroxylase deficiency) is an inborn error of metabolism transmitted as an autosomal recessive disorder and manifested by an impairment in the hepatic hydroxylation of phenylalanine to tyrosine. Untreated, the disorder causes a clinical picture highlighted by mental retardation, seizures, and imperfect hair pigmentation. Inasmuch as PKU is the prototype for demonstrating the interrelation between genetic alterations in intermediary metabolism and neurologic dysfunction, it deserves more space than its frequency in the panoply of neurologic disorders would otherwise warrant. The disease has been found in all parts of the world. The frequency in the general population of the United States, as determined by screening programs, is about 1:11,700. Pathogenesis and Pathology The hydroxylation of phenylalanine to tyrosine is an irreversible and complex reaction that requires phenylalanine hydroxylase and three other enzymes in addition to several nonprotein components. Phenylalanine hydroxylase is normally found in liver, kidney, and pancreas but not in brain or skin fibroblasts. In classic PKU, as a result of multiple and distinct mutations in the gene for phenylalanine hydroxylase, enzyme activity is completely or nearly completely abolished. Cloning of a full-length complementary DNA has enabled characterization of the normal and mutant genes. Over 300 different mutations have been identified to date, and the genetic heterogeneity of phenylalanine hydroxylase deficiency is immense. There is a broad continuum of phenotypes. In addition to classic PKU, less severe forms have been recognized, and based on their serum phenylalanine levels while on a free diet, patients have been arbitrarily subdivided into moderate PKU, mild PKU, and mild hyperphenylalaninemia. The different forms of PKU are allelic, and a high proportion of patients are compound heterozygotes rather than homozygotes. Dihydropteridine reductase, the second enzyme required for phenylalanine hydroxylation, is present in normal amounts in classic PKU but is absent or defective in a rare variant of the disease, which manifests itself by elevated serum phenylalanine levels and progressive neurologic dysfunction. The hydroxylation of phenylalanine also requires oxygen and tetrahydrobiopterin. Defects in the synthesis of tetrahydrobiopterin account for 1% to 3% of infants with phenylalanine elevation. These conditions lead to a syndrome of progressive neurologic deterioration, accompanied by a variety of involuntary movements. Children suffering from classic PKU are born with only slightly elevated phenylalanine blood levels, but because of the defect in phenylalanine hydroxylase, the amino acid derived from food proteins accumulates in serum and cerebrospinal fluid and is excreted in large quantities. In lieu of the normal degradative pathway, phenylalanine is converted to phenylpyruvic acid, phenylacetic acid, and phenylacetylglutamine. The transamination of phenylalanine to phenylpyruvic acid is sometimes deficient for the first few days of life, and the age when phenylpyruvic acid may be first detected ranges from 2 to 34 days. Alterations within the brain are nonspecific and diffuse and involve both gray and white matter. There are three types of alterations within the brain: 1. Interference with normal maturation of the brain. Brain growth is reduced; there is microscopic evidence of impaired cortical layering, delayed outward migration of neuroblasts, and heterotopic gray matter. These changes suggest a period of abnormal brain development during the last trimester of gestation. 2. Defective myelination. This may be generalized or limited to areas in which postnatal deposition of myelin is normal. Except in some older patients, products of myelin degeneration are not seen. Generally, there is relative pallor of myelin, sometimes with mild gliosis and irregular areas of vacuolation (i.e., status spongiosus). The vacuoles are usually seen in central white matter of the cerebral hemispheres and in the cerebellum. 3. Diminished or absent pigmentation of the substantia nigra and locus ceruleus. Symptoms and Signs Patients suffering from PKU exhibit a wide range of clinical and biochemical severity. In the classic form, caused by a virtual absence of phenylalanine hydroxylase activity, infants appear normal at birth. During the first 2 months, there is vomiting (sometimes projectile) and irritability. Delayed intellectual development is apparent by 4 to 9 months; mental retardation may be severe, precluding speech or toilet training. Seizures, common in more severely retarded infants, usually start before age 18 months and may cease spontaneously. In infants, seizures may appear as infantile spasms, later changing to grand mal attacks. The typical affected child is blond and blue-eyed with normal and often pleasant features. The skin is rough and dry, sometimes with eczema. A peculiar musty odor, attributable to phenylacetic acid, may suggest the diagnosis. Significant focal neurologic abnormalities are rare. Microcephaly may be present, and there may be a mild increase in muscle tone, particularly in the legs. A fine irregular tremor of the hands is seen in about 35% of subjects. The plantar response is often variable or extensor. Electroencephalogram abnormalities include hypsarrhythmia, recorded even in the absence of seizures, and single or multiple foci of spike and polyspike discharges. Magnetic resonance imaging (MRI) is almost invariably abnormal, even in early treated patients. On T2-weighted images, high signal areas are seen in white matter. These are mainly located in the posterior temporal and occipital periventricular regions, notably in the watershed between the posterior and middle cerebral arteries. They are probably caused by abnormalities of myelin formation and maintenance. Diagnosis Most PKU patients are identified through a newborn screening program. Although most infants whose blood phenylalanine levels are above the threshold value of 2 to 4 mg/dL do not have PKU, such patients will require prompt reevaluation by an appropriate laboratory to determine whether hyperphenylalaninemia is persistent and to determine whether it is due to phenylalanine hydroxylase deficiency. Because the urine of most newborns does not contain appreciable amounts of phenylpyruvic acid, the ferric chloride and 2,4- dinitrophenylhydrazine tests are inadequate during the neonatal period. If the diagnosis of a case of classic PKU is missed, the most likely reason is laboratory error rather than insufficient protein intake or too early testing of the infant. A combination of haplotype and mutation analysis has facilitated carrier detection and the prenatal diagnosis of PKU in families with at least one previously affected

child. The widespread screening programs that detect newborns with blood phenylalanine concentrations higher than normal have also uncovered other conditions in which blood phenylalanine levels are increased in the neonatal period. Patients with moderate and mild PKU and mild hyperphenylalaninemia, as these entities are termed, have phenylalanine levels that tend to be lower than those seen in classic PKU and have a less severe mutation in the gene for phenylalanine hydroxylase. Treatment On referral of an infant with a positive screening test, the first step is quantitative determination of serum phenylalanine and tyrosine levels. All infants whose blood phenylalanine concentration is greater than 10 mg/dL (606 µM/L) and whose tyrosine concentration is low or normal (1 to 4 mg/dL) should be started on a low-phenylalanine diet immediately. Infants whose blood phenylalanine concentrations remain in the range of 6.6 to 10.0 mg/dL should also be treated. The generally accepted therapy for classic PKU is restriction of the dietary intake of phenylalanine by placing the infant on one of several low-phenylalanine formulas. To avoid symptoms of phenylalanine deficiency, milk is added to the diet in amounts sufficient to maintain blood levels of the amino acid between 2 and 6 mg/dL (121 to 363 µM/L). Generally, patients tolerate this diet quite well, and within 1 to 2 weeks the serum concentration of phenylalanine becomes normal. Weekly serum phenylalanine determinations are essential to ensure adequate regulation of diet. Strict dietary control should be maintained for as long as possible, and most centers strive to keep levels below 6.0 mg/dL (360 µM/L) even in patients with moderate and mild PKU. Dietary lapses are frequently accompanied by progressive white matter abnormalities on MRI. Some workers have suggested supplementation of the low-phenylalanine diet with tyrosine, but there is no statistical evidence that this regimen results in a better intellectual outcome. Failure to treat subjects with mild hyperphenylalaninemias does not appear to produce either intellectual deficits or MRI abnormalities. The use of implanted microencapsulated genetically engineered cells to remove phenylalanine is under investigation. Vectors for efficient gene transfer have yet to be developed. Treatment of phenylalaninemia due to tetrahydrobiopterin deficiency involves administration of tetrahydrobiopterin or a synthetic pterin and replenishment of the neurotransmitters (levodopa, 5-hydroxytryptophan) because synthesis of these substances is also impaired. Early detection and dietary control of PKU has increased the number of homozygous PKU women who are of childbearing age. The harmful effects of maternal hyperphenylalaninemia on the heterozygous offspring include mental retardation, microcephaly, seizures, and congenital heart defects. Women who conceive while their blood phenylalanine levels are 15 mg/dL or above (greater than 900 µM/L) are at high risk for these malformations and should be offered termination of pregnancy. During pregnancy, phenylalanine levels should be monitored as closely as during infancy because the fetus is exposed to even higher phenylalanine concentrations than the mother. Prognosis When the patient with classic PKU is maintained on a low-phenylalanine diet, seizures disappear and the electroencephalogram tends to revert to normal. Abnormally blond hair regains natural color. The effects on mental ability are less clearcut. In most studies, some deficit in intellectual development has been found, even in infants who had been diagnosed and treated as neonates, and there appears to be no threshold below which phenylalanine has no effect on cognition. When the measured IQ is normal, children may exhibit impaired perceptual functions, and progress in school is poorer than expected from the IQ score. Neurologic deterioration during adult life has been seen in some patients. This is generally the consequence of dietary lapses. Failure to prevent mild mental retardation or cognitive deficits, even with optimal control, may be a consequence of prenatal brain damage induced by high phenylalanine levels in the fetus.

MAPLE SYRUP URINE DISEASE (MIM 248600) Maple syrup urine disease (MSUD) is a familial cerebral degenerative disease caused by a defect in branched-chain amino acid metabolism and marked by the passage of urine with a sweet maple syrup-like odor. Its incidence is 1:220,000 to 1:400,000 newborns. In the Mennonite population of Pennsylvania, the incidence of the classic form of the disease is 1:176 births. The disorder is characterized by accumulation of three branched-chain ketoacids: a-keto-isocaproic acid, a-keto-isovaleric acid, and a-keto-b-methylvaleric acid, which are the respective derivatives of leucine, valine, and isoleucine. Accumulation of these substances results from an autosomal recessively inherited deficiency in the mitochondrial branched-chain a-ketoacid dehydrogenase. This is a multienzyme complex comprising six proteins: E 1a and E1b, which form the decarboxylase; E2 and E3; and a branched-chain specific kinase and phosphatase. Mutations in the genes for E 1a, E 1b, E 2, and E3 have been described. These induce a continuum of disease severity that ranges from the severe classic form of MSUD to mild and intermittent forms. Patients with the severe classic phenotype can be compound heterozygote or homogygotes for defects in the genes for E 1a or E1b. Plasma levels of the corresponding amino acids are also elevated because the ketoacids are transaminated. In some cases, the branched-chain a-hydroxyacids, most prominently a-hydroxyisovaleric acid, are also excreted, and a sotolone derivative of a-ketobutyric acid, whose decarboxylation is impaired by accumulation of a-keto-b-methylvaleric acid, is responsible for the characteristic odor of the urine and sweat. Structural alterations in the brain are similar to, but more severe than, those in PKU. Also, the cytoarchitecture of the cortex is generally immature with fewer cortical layers, persistence of ectopic foci of neuroblasts, and abnormal dendritic development. Manifestations of the untreated classic form of the condition include opisthotonos, intermittent increase of muscle tone, seizures, and rapid deterioration of all cerebral functions. Some patients have presented with pseudotumor cerebri or with fluctuating ophthalmoplegia. About half the infants develop hypoglycemia. In the acute stage of the disease, MRI demonstrates both diffuse edema and a characteristic severe edema localized to the cerebellar deep white matter, the posterior part of the brainstem, the cerebral peduncles, the posterior limb of the internal capsule, and the posterior part of the centrum semiovale. The condition is suggested by the characteristic odor of the patient's urine and perspiration. It is confirmed by quantitation of plasma amino acids. Treatment is based on a commercially available diet that contains restricted amounts of leucine, isoleucine, and valine. For optimal results, dietary management must be initiated during the first few days of life. The regimen is complex and requires frequent quantitative measurement of serum amino acids. Children with the classic form of the disease who have been maintained on this regimen have achieved near-normal intellectual development. A subset of MSUD patients exhibits intermittent periods of ataxia, drowsiness, behavior disturbances, and seizures that appear between 6 and 9 months of age. In some of these subjects there is a defect in the gene coding for the E 2 subunit. In other children, there is only mild or moderate mental retardation. In yet another group of MSUD patients, the biochemical abnormality can be corrected by the administration of thiamin.

DEFECTS IN THE METABOLISM OF SULFUR AMINO ACIDS Of the several defects in the metabolism of sulfur-containing amino acids, the most common is homocystinuria (MIM 236200). This inborn error of methionine metabolism is manifested by multiple thromboembolic episodes, ectopia lentis, and mental retardation. It is transmitted by an autosomal recessive gene. The condition occurs in 1:45,000 newborns; it is second in frequency only to PKU among metabolic errors responsible for brain damage. In the most common form of homocystinuria, the metabolic defect affects cystathionine b-synthase, the enzyme that catalyzes the formation of cystathionine from homocysteine and serine. In most homocystinuric subjects, activity of this enzyme is completely absent, but there is residual enzyme activity in members of a significant proportion of affected families. In the latter group, about 25% to 50% of patients with homocystinuria, addition of pyridoxine stimulates enzyme activity and partially or completely abolishes the excretion of homocystine, the oxidized derivative of homocysteine. Such patients tend to have a milder phenotype of the disease. As a result of the enzymatic block, increased amounts of homocystine and its precursor, methionine, are found in urine and plasma.

Primary structural alterations are noted in blood vessels of all calibers. In most vessels, there is intimal thickening and fibrosis; in the aorta and its major branches, fraying of elastic fibers may be found. Both arterial and venous thromboses are common in different organs. In the brain, there are usually multiple infarcts of varying age. Dural sinus thrombosis has been recorded. The relationships between the metabolic defect and the predisposition to vascular thrombosis are multiple. Homocysteine is toxic to vascular endothelium, inhibiting intracellular protein transport; it potentiates the autooxidation of low-density lipoprotein cholesterol and promotes thrombosis by inhibiting the activation of anticoagulant protein C. Homocystinuric infants appear normal at birth, and early development is unremarkable until seizures, developmental slowing, or strokes occur between 5 and 9 months of age. Ectopia lentis has been recognized by age 18 months and is invariable in older children. The typical older homocystinuric child's hair is sparse, blond, and brittle. There are multiple erythematous blotches over the skin, particularly across the maxillary areas and cheeks. The gait is shuffling, the limbs and digits are long, and genu valgum is usually present. In about half, major thromboembolic episodes occur once or more. These include fatal thrombosis of the pulmonary artery or vein. Multiple major strokes may result in hemiplegia and, ultimately, in pseudobulbar palsy. Minor and unrecognized cerebral thrombi may be the direct cause of the mental retardation that occurs in more than 50% of homocystinuric patients. The observation that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor suggest that overstimulation of this receptor contributes to the pathogenesis of neurologic symptoms. The diagnosis of homocystinuria is suggested by the appearance of the patient and can be confirmed by a positive urinary cyanide-nitroprusside reaction, by the increased urinary excretion of homocystine, and by elevated levels of plasma homocystine and methionine. The diagnosis is further established by assays of cystathionine b-synthase in skin fibroblasts or liver. Administration of a commercially available low-methionine diet supplemented with cysteine lowers plasma methionine content and eliminates the abnormally high homocystine excretion. In some centers, the diet is further supplemented with betaine to use alternative pathways for removal of homocysteine. Pyridoxine (50 to 500 mg/day combined with folic acid) reduces the homocystine excretion of pyridoxine-responsive patients. Although the biochemical picture can be improved by these means, the variable clinical picture, particularly the thromboembolic episodes and mental retardation, has up to now rendered useless any evidence for clinical benefit. Heterozygotes for homocystinuria have an increased propensity to peripheral vascular disease and premature cerebrovascular accidents, and one-third of all patients with premature arterial thrombotic disease have elevated blood levels of homocysteine. The incidence of myocardial infarcts in this population, however, is no higher than normal. Several other genetic entities manifest themselves by increased excretion of homocystine. In some, the conversion of homocysteine to methionine is impaired. The most important of these entities is N 5,10-methylenetetrahydrofolate reductase deficiency. Children with this disorder can present with ataxia, spastic paraparesis, and mental retardation. Several conditions result from a deficiency of methyl cobalamine, the active cofactor for the conversion of homocysteine to methionine. These entities can present in infancy with lethargy and failure to thrive. Older children suffer from mental retardation, seizures, and spasticity. The characteristic biochemical feature of these diseases is that the excretion of homocystinuria is accompanied by methylmalonic aciduria.

OTHER DEFECTS OF AMINO ACID METABOLISM There have been numerous reports of a neurologic disorder apparently associated with some abnormality in the amino acid pattern of serum or urine. The frequency in the general population can be gauged by routine mass newborn screening, such as the one by Wilcken et al. (1980) ( Table 81.1). Other screening programs have found similar incidences.

TABLE 81.1. AMINOACIDURIAS DETECTED BY NEWBORN-INFANT URINE SCREENING

Neurologic complications are also common in disorders of the urea cycle. These are discussed in Chapter 86. The neurologic deficits reported in some of the other more common conditions (such as histidinemia, sarcosinemia, hyperprolinemia, and cystathioninuria) are considered to be unrelated to the metabolic defect, but the result of screening a selected population, namely mentally retarded individuals. Some of the less uncommon disorders are summarized in Table 81.2.

TABLE 81.2. SOME UNCOMMON ERRORS OF AMINO ACID METABOLISM

DISORDERS OF AMINO ACID TRANSPORT Renal amino acid transport is handled by five specific systems that have nonoverlapping substrate preferences. The disorders that result from genetic defects in each of these systems are listed in Table 81.3.

TABLE 81.3. DEFECTS IN AMINO-ACID TRANSPORT

Lowe Syndrome (MIM 309000) Lowe syndrome (oculocerebrorenal syndrome) is a sex-linked recessive disorder characterized clinically by severe mental retardation, delayed physical development, myopathy, and congenital glaucoma or cataract. The gene has been mapped to the long arm of the X chromosome and encodes a protein similar to inositol polyphosphate-5-phosphatase. Biochemically, there is generalized aminoaciduria of the Fanconi type, with renal tubular acidosis and rickets. There are no consistent neuropathologic findings. MRI shows various patterns of white matter involvement. The fundamental biochemical defect is unknown but is believed to be a defect in membrane transport due to a disorder in inositol metabolism. The urinary levels of lysine are more elevated than those of the other amino acids, and defective uptake of lysine and arginine by the intestinal mucosa has been demonstrated in two patients. Hartnup Disease (MIM 236200) This rare familial condition is characterized by photosensitive dermatitis, intermittent cerebellar ataxia, mental disturbances, and renal aminoaciduria. The name is that of the family in which the disorder was first detected. Symptoms are caused by an extensive disturbance in the transport of neutral amino acids. There are four main biochemical abnormalities: renal aminoaciduria, increased excretion of indican, increased excretion of nonhydroxylated indole metabolites, and increased fecal amino acids. Symptoms usually occur in mildly malnourished children. When present, they are intermittent and variable, tending to improve with age. They include a red scaly rash on the exposed areas of the body (resembling the dermatitis of pellagra), intermittent personality disorders, migrainelike headaches, photophobia, and bouts of cerebellar ataxia. Neuroimaging studies are nonspecific; MRI shows delayed myelination. There are no consistent neuropathologic findings. The similarity of Hartnup disease to pellagra has prompted treatment with nicotinic acid. The tendency, however, for symptoms to remit spontaneously and for general improvement to occur with improved dietary intake and advancing age makes such therapy difficult to evaluate. SUGGESTED READINGS General Cedarbaum SD, Scott CR, Wilcox WR. Amino acid metabolism. In: Rimoin DL, Connor JM, Pyeritz RE, eds. Principles and practice of medical genetics, 3rd ed. New York: Churchill Livingstone, 1996:1867–1895. Menkes JH. Metabolic diseases of the nervous system. In: Menkes JH, ed. Textbook of child neurology, 6th ed. Baltimore: Lippincott Williams & Wilkins, 2000. Phenylketonuria Baumeister AA, Baumeister AA. Dietary treatment of destructive behavior associated with hyperphenylalaninemia. Clin Neuropharmacol 1998;21:18–27. Green A. Neonatal screening: current trends and quality control in the United Kingdom. Jpn J Clin Pathol 1998;46:211–216. Guldberg P, Rey F, Zschocke J, et al. A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet 1998;63:71–79. Holtzman NA, Kronmal RA, van Doorninck W, et al. Effect of age at loss of dietary control of intellectual performance and behavior of children with phenylketonuria.

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Kaufman S, Kapatos G, Rizzo WB, et al. Tetrahydropterin therapy for hyperphenylalaninemia caused by defective synthesis of tetrahydrobiopterin. Ann Neurol 1983;14:308–315. Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia. N Engl J Med 1980;302:1202–1208. Lou HC, Toft PB, Andresen J, et al. An occipito-temporal syndrome in adolescents with optimally controlled hyperphenylalaninaemia. J Inher Metab Dis 1992;15:687–695. Malamud N. Neuropathology of phenylketonuria. J Neuropathol Exp Neurol 1966;25:254–268. MRC Working Party on Phenylketonuria. Recommendations on the dietary management of phenylketonuria. Arch Dis Child 1993;68:426–427. MRC Working Party on Phenylketonuria. Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding story. BMJ 1993;306:115–119. Partington MW. The early symptoms of phenylketonuria. Pediatrics 1961;27:465–473. Schneider AJ. Newborn phenylalanine tyrosine metabolism. Implications for screening for phenylketonuria. Am J Dis Child 1983;137:427–432. Smith I, Leeming RJ, Cavanagh NPC, et al. Neurologic aspects of biopterin metabolism. Arch Dis Child 1986;61:130–137. Smith ML, Hanley WB, Clarke JT, et al. Randomized controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria. Arch Dis Child 1998;78:116–121. Thompson AJ, Smith I, Brenton D, et al. Neurological deterioration in young adults with phenylketonuria. Lancet 1990;336:602–605. Waisbren SE, Mahon BE, Schnell RR, et al. Predictors of intelligence quotient and intelligence quotient change in persons treated for phenylketonuria early in life. Pediatrics 1987;79:351–355. Weglage J, Ullrich K, Pietsch M, et al. Intellectual, neurologic, and neuropsychologic outcome in untreated subjects with nonphenylketonuria hyperphenylalaninemia. German Collaborative Study on Phenylketonuria. Pediatr Res 1997;42:378–384. Wilcken B, Smith A, Brown DA. Urine screening for amino acidopathies: Is it beneficial? J Pediatr 1980;97:492–497. Maple Syrup Urine Disease Brismar J, Aqeel A, Brismar G, et al. Maple syrup urine disease: findings on CT and MR scans of the brain in 10 infants. AJNR 1990;11:1219–1228. Chuang DT. Maple syrup urine disease: it has come a long way. J Pediatr 1998;132:S17–S23. Kamei A, Takashima S, Chan F, et al. Abnormal dendritic development in maple syrup urine disease. Pediatr Neurol 1992;8:145–147.

Mantovani JF, Naidich TP, Prensky AL, et al. MSUD: presentation with pseudotumor cerebri and CT abnormalities. J Pediatr 1980;96:279–281. Menkes JH. Maple syrup disease: isolation and identification of organic acids in the urine. Pediatrics 1959;23:348–353. Menkes JH, Hurst PL, Craig JM. A new syndrome: progressive familial infantile cerebral dysfunction associated with unusual urinary substance. Pediatrics 1954;14:462–466. Podebrad F, Heil M, Reichart S, et al. 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone)-the odor of maple syrup urine disease. J Inherit Metab Dis 1999;22:107–114. Schadewaldt P, Wendel U. Metabolism of branched-chain amino acids in maple syrup urine disease. Eur J Pediatr 1997;156[Suppl 1]:S62–S66. Tsuruta M, Mitsubuchi H, Mardy S, et al. Molecular basis of intermitted maple syrup urine disease: novel mutations in the E2 gene of the branched-chain alpha-keto acid dehydrogenase complex. J Hum Genet 1998;43:91–100. Wynn RM, Davie JR, Chuang JL, et al. Impaired assembly of E1 decarboxylase of the branched-chain alpha-ketoacid dehydrogenase complex in type IA maple syrup urine disease. J Biol Chem 1998;273:13110–13118. Defects in the Metabolism of Sulfur Amino Acids Boers GHJ. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 1985;313:709–715. Dixon MA, Leonard JV. Intercurrent illness in inborn errors of intermediary metabolism. Arch Dis Child 1992;67:1387–1391. Lentz SR, Sadler JE. Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. Blood 1993;81:683–689. Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA 1997;94:5923–5928. Mitchell GA, Watkins D, Melancon SB, et al. Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria.

J Pediatr 1986;108:410–415.

Schimke RN, McKusick VA, Huang T. Homocystinuria: studies of 20 families with 38 affected members. JAMA 1965;193:711–719. Walter JH, Wraith JE, White FJ, et al. Strategies for the treatment of cystathionine beta-synthase deficiency: the experience of the Willink Biochemical Genetics Unit over the past 30 years. Pediatr 1998;157[Suppl 2]:S71–S76. Disorders of Amino Acid Transport Lowe Syndrome Charnas L, Bernar J, Pezeshkpour GH, et al. MRI findings and peripheral neuropathy in Lowe's syndrome. Neuropediatrics 1988;19:7–9. Charnas LR, Gahl WA. The oculocerebrorenal syndrome of Lowe. Adv Pediatr 1991;38:75–107. Demmer LA, Wippold FJ 2d, Dowton SB. Periventricular white matter cystic lesions in Lowe (oculocerebrorenal) syndrome. A new MR finding. Pediatr Radiol 1992;22:76–77. Kornfeld M, Synder RD, MacGee J, et al. The oculo-cerebral-renal syndrome of Lowe. Arch Neurol 1975;32:103–107. Lin T, Orrison BM, Leahey AM, et al. Spectrum of mutations in the OCR1 gene in the Lowe oculocerebrorenal syndrome. Am J Hum Genet 1997;60:1384–1388. Lowe CU, Terrey M, MacLachlan EA. Organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation. Am J Dis Child 1952;83:164–184. Martin MA, Sylvester PE. Clinico-pathological studies of oculo-cerebral-renal syndrome of Lowe, Terrey and MacLachlan. J Ment Defic Res 1980;24:1–16. Hartnup Disease Baron DN. Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal aminoaciduria, and other bizarre chemical features. Lancet 1956;2:421–428. Erly W, Castillo M, Foosaner D, et al. Hartnup disease: MR findings. AJNR 1991;12:1026–1027. Jepson JB. Hartnup disease. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, eds. The metabolic basis of inherited disease, 4th ed. New York: McGraw-Hill, 1978:1563–1577. Wilcken B, Yu JS, Brown DA. Natural history of Hartnup disease. Arch Dis Child 1977;52:38–40.

Eur J

CHAPTER 82. DISORDERS OF PURINE METABOLISM MERRITT’S NEUROLOGY

CHAPTER 82. DISORDERS OF PURINE METABOLISM LEWIS P. ROWLAND Lesch Nyhan Syndrome Mim 308000 Suggested Readings

LESCH-NYHAN SYNDROME (MIM 308000) In 1964, Lesch and Nyhan described two brothers with hyperuricemia, mental retardation, choreoathetosis, and self-destructive biting of the lips and fingers. All known cases have affected boys; the trait is inherited as an X-linked recessive trait, and the gene has been localized to the long arm of the X chromosome. The basic defect is the lack of hypoxanthine-guanine phosphoribosyltransferase (HPRT) in all body fluids. The gene was one of the first human genes to be cloned. Because of the enzyme deficiency, the rate of purine biosynthesis is increased, and the content of the end product of purine metabolism, uric acid, reaches high values in blood, urine, and cerebrospinal fluid. Deposits of urate are found in the kidneys and joints and may result in debilitating nephropathy and gout. The neurologic manifestations include severe mental retardation, spasticity, and choreoathetosis that start in the first year of life. The characteristic self-mutilating behavior appears in the second year. Death is usually due to renal failure and may occur in the second or third decade of life. The pathogenesis of the cerebral symptoms is not known. Although low levels of dopamine metabolites have been found in postmortem samples of tissue from the basal ganglia, it is not known how these abnormalities lead to the symptoms or how they relate to the enzyme disorder. Diagnosis depends on recognition of the clinical manifestations and can be made precisely by biochemical assay of the enzyme in erythrocyte hemolysates or cultured fibroblasts. Hair root analysis of HPRT has become a convenient way to analyze activity. Prenatal enzymatic diagnosis is possible in the first trimester with chorionic villus sampling. DNA analysis can be used for prenatal diagnosis and carrier detection but not yet to diagnose all individual cases. The gene, however, has been mapped to Xq26.1, and numerous point mutations have been found. Treatment is not satisfactory. Gout can be treated with allopurinol, but the neurologic disorder is daunting. Restraints may be needed to prevent the child from damaging himself or others; sometimes teeth must be removed. Enzyme replacement therapy with long-term erythrocyte transfusions in three patients gave only modest improvement of the neurologic symptoms, and drug therapy to modify dopamine metabolism has not yet been effective. Gene therapy is being evaluated in animals because the human gene has been introduced into transgenic mice and enzyme activity is expressed in the brain of the recipient animals. There is evidence of both clinical and biochemical heterogeneity. Hyperuricemia and cerebellar ataxia have been noted in individuals with normal HPRT activity. Patients with partial enzyme deficiency may have gout without neurologic symptoms or there may be varying severity of mental retardation, movement disorders, spastic tetraplegia, or seizures. The self-mutilating behavior may be restricted to the classic form, which lacks all enzyme activity. Neurologic abnormalities are also seen in patients without other enzymes of purine nucleoside metabolism. Adenosine deaminase deficiency (MIM 102700) causes severe combined immunodeficiency in infants; some patients have extrapyramidal or pyramidal signs and psychomotor development and may be retarded. Partial exchange transfusion may be clinically beneficial. Also, a few patients lacking purine nucleoside phosphorylase (MIM 164050), with impaired cellular immunity, have shown a form of spastic paraparesis in childhood. SUGGESTED READINGS Alford RL, Redman JB, O'Brien WE, Caskey CT. Lesch-Nyhan syndrome: carrier and prenatal diagnosis. Prenatal Diag 1995;15:329–338. Coleman MS, Danton MJ, Philips A. Adenosine deaminase and immune dysfunction. Ann N Y Acad Sci 1985;451:54–65. Edwards NL. Immunodeficiencies associated with errors in purine metabolism. Med Clin North Am 1985;69:505–518. Edwards NL, Jeryc W, Fox IH. Enzyme replacement in the Lesch-Nyhan syndrome with long-term erythrocyte transfusions. Adv Exp Med Biol 1984;165:23–26. Graham GW, Aitken DA, Connor JM. Prenatal diagnosis by enzyme analysis in 15 pregnancies at risk for the Lesch-Nyhan syndrome. Prenatal Diag 1996;16:647–651. Harris JC, Lee BR, Jinah HA, Wong Df, Yaster M, Bryan RN. Craniocerebral magnetic resonance imaging measurement and findings in Lesch-Nyhan syndrome. Arch Neurol 1998;55:547–553. Hirschhorn R. Complete and partial adenosine deaminase deficiency. Ann N Y Acad Sci 1985;451:20–25. Hirschhorn R, Ellenbogen A. Genetic heterogeneity in adenosine deaminase (ADA) deficiency: five different mutations in five new patients with partial ADA deficiency. 1986;38:13–25.

Am J Hum Genet

Jankovic J, Caskey TC, Stout JT, Butler IJ. Lesch-Nyhan syndrome: motor behavior and CSF neurotransmitters. Ann Neurol 1988;23:466–468. Kuehn MR, Bradley A, Robertson EJ, Evans MJ. A potential animal model for Lesch-Nyhan syndrome through introduction of HPRT mutations into mice. Nature 1987;326:295–298. Marcus S, Stern AM, Andersson B, et al. Mutation analysis and prenatal diagnosis in Lesch-Nyhan syndrome showing non-random C- inactivation interferes with carrier detection tests. Hum Genet 1992;89:395–400. Markert ML. Purine nucleoside deficiency. Immunodefic Rev 1991;3:45–81. Nyhan WL. The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. J Inherit Metabol Dis 1997;20:171–178. Nyhan WL, Parkman R, Page T, et al. Bone marrow transplantation in Lesch-Nyhan disease. Adv Exp Med Biol 1986;195:167–170. Rijksen G, Kuis W, Wadman SK, et al. A new case of purine nucleoside phosphorylase deficiency with neurologic disorder. Pediatr Res 1987;21:137–141. Rossiter BJF, Edwards A, Casket CT. HPRT mutations in Lesch-Nyhan syndrome. In: Brosis J, Frenau B, eds. Molecular genetic approach to neuropsychiatric diseases. New York: Academic Press, 1991. Scully DG, Dawson PA, Emerson BT, Gordon RS. Review of the molecular basis of HPRT deficiency. Hum Genet 1992;90:195–207. Shapira J, Ziberman Y, Becker A. Lesch-Nyhan syndrome: a nonextracting approach to prevent mutilation. Spec Care Dentist 1985;5:210–212. Silverstein FS, Johnson MV, Hutchinson RJ, Edwards NL. Lesch-Nyhan syndrome: CSF neurotransmitter abnormalities. Neurology 1985;35:907–911. Stout JT, Chen HY, Brennand J, et al. Expression of human HPRT in the central nervous system of transgenic mice. Nature 1985;317:250–251. Watson AR, Simmonds HA, Webster DR, et al. Purine nucleoside phosphorylase (PNP) deficiency: a therapeutic challenge. Adv Exp Med Biol 1984;165:53–59. Watts RWE, Spellacy E, Gibbs DA, et al. Clinical, postmortem, biochemical and therapeutic observations on the Lesch-Nyhan syndrome with particular reference to the neurological manifestations. J Med 1982;201:43–78. Wilson JM, Stout JT, Palella TD, et al. A molecular survey of hypoxanthine-guanine phosphoribosyltransferase deficiency in man. J Clin Invest 1986;77:188–195. Wu CL, Melton DW. Production of model for Lesch-Nyhan syndrome in hypoxanthine phosphoribosyl transferase-deficient mice. Nat Genet 1993;3:235–239.

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CHAPTER 83. LYSOSOMAL AND OTHER STORAGE DISEASES MERRITT’S NEUROLOGY

CHAPTER 83. LYSOSOMAL AND OTHER STORAGE DISEASES WILLIAM G. JOHNSON Lipidoses Gm2-Gangliosidoses Gm1 Gangliosidosis Fabry Disease Gaucher Disease Niemann-Pick Disease Farber Lipogranulomatosis Wolman Disease Cerebrotendinous Xanthomatosis (Cholestanol Storage Disease) Neuronal Ceroid Lipofuscinoses Leukodystrophies Mucopolysaccharidoses Mucolipidoses Free Sialic Acid Storage Diseases Fucosidosis Mannosidoses Aspartylglycosaminuria mucolipidoses ii and iii Mucolipidosis iv Suggested Readings

In the lysosomal diseases, storage material accumulates within lysosomes because of genetically determined deficiency of a catabolic enzyme. The stored material is usually of a complex lipid or saccharide nature; the nervous system is usually affected. The inheritance pattern is recessive and usually autosomal but occasionally X-linked. Carrier detection and prenatal diagnosis have been accomplished in most of these disorders, but there is as yet no specific treatment for any of the lysosomal storage diseases except for enzyme replacement therapy for Gaucher disease. Bone marrow transplantation is being tried experimentally for the mucopolysaccharidoses.

LIPIDOSES Lipid storage diseases involve all three major lipid classes: neutral lipids (i.e., cholesterol ester, fatty acid, and triglycerides), polar lipids (glycolipids and phospholipids), and very polar lipids (gangliosides). The largest group of stored lipids is the sphingolipids, based on sphingosine ( Fig. 83.1A). When a long-chain fatty acid is attached to the 2-amino group of sphingosine, the resulting compounds are called ceramides. Further hydrophilic residues are attached at the 1-hydroxyl group to give the sphingolipids ( Fig. 83.1B, Fig. 83.1C, Fig. 83.1D and Fig. 83.1E).

FIG. 83.1. A: Sphingosine. Addition of fatty acid in amide linkage gives ceramide (Cer). B: Structure of a ganglioside (here, a tetrasialoganglioside, GQ1a) containing sphingosine (Sph), fatty acid (FA), neutral hexoses (glucose, Glc; galactose, Gal), hexosamine (GalNAc, N-acetylgalactosamine), and sialic acid (NANA, N-acetylneuraminic acid). C: Structure of a glycolipid, globoside (GL4), containing sphingosine, fatty acid, neutral hexoses, and hexosamine. D: Structure of sulfatide (a major glycolipid of myelin) containing sphingosine, fatty acid, and galactose, which is sulfated on the 3-hydroxyl group. E: Structure of sphingomyelin or ceramide phosphorylcholine. Reactions 1-26 are illustrated in Fig. 83.1, Fig. 83.2 and Fig. 83.3. 1, Sialidase (sialidoses). 2, Beta-galactosidase (GM1-gangliosidoses, Morquio syndrome type B, secondarily deficient in galactosialidosis). 3, Hexosaminidase (GM2-gangliosidoses). 4, Alpha-galactosidase (Fabry disease). 5, Ceramide lactosidase. 6, b-Glucosidase (Gaucher disease). 7, Ceramidase (Farber disease). 8, Ganglioside sialidase. 9, Sulfatase A (metachromatic leukodystrophy, mucosulfatidosis, MSD). 10, Galactocerebrosidase (Krabbe disease). 11, a-L-Iduronidase (Hurler syndrome, Scheie syndrome, Hurler-Scheie compound). 12, Iduronate-2-sulfate sulfatase (Hunter syndrome, MSD). 13, Sulfamidase (Sanfilippo A, MSD). 14, a-N-acetylglucosaminidase (Sanfilippo B). 15, N-acetyl transferase (Sanfilippo D, MSD). 16, Galactose-6-sulfate sulfatase or N-acetylgalactosamine-6-sulfate sulfatase (Morquio syndrome type A, MSD). 17, N-acetylgalactosamine-4-sulfate sulfatase or sulfatase B (Maroteaux-Lamy syndrome, MSD). 18, b-Glucuronidase (Sly syndrome). 19, Acetylglucosamine-6-sulfate sulfatase (Sanfilippo D, MSD). 20, Dermatan sulfate N-acetylgalactosamine-6-sulfate sulfatase. 21, a-L-Fucosidase (fucosidosis). 22, a-Mannosidase (a-mannosidosis). 23, Mannosidase (b-mannosidosis). 24, Endoglucosaminidase. 25, Aspartylglucosaminidase (aspartylglucosaminuria). 26, Sphingomyelinase (Niemann-Pick disease, types A, B, and F).

GM2-GANGLIOSIDOSES Hexosaminidase-deficiency diseases result from a genetically determined deficiency of the enzyme hexosaminidase (reaction 3, Fig.83.1B and Fig.83.1C, Fig. 83.2 and Fig. 83.3), which causes accumulation in cells (especially in neurons) of GM2-ganglioside, certain other glycosphingolipids, and other compounds containing a terminal b-linked, N-acetylgalactosaminide or N-acetylglucosaminide moiety.

FIG. 83.2. Structure of three clinically important mucopolysaccharides: dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS). Each consists of repeating dimers of uronic acid (IdUA, iduronic acid; GlcUA, glucuronic acid), hexosamine (GlcNAc, N-acetylglucosamine; GalNAc, N-acetylgalactosamine), and sulfate (OSO3). In DS, the hexosamine is GalNAc. In HS, the hexosamine is a-linked glucosamine, sometimes N-acetylated, sometimes N-sulfated. In KS, uronic acid is replaced by galactose (Gal). The glycan portion is bound to protein (not shown).

FIG. 83.3. Structure of an asparagine-linked glycoprotein consisting of asparagine (Asn), neutral sugars (Man, mannose; Gal, galactose; L-Fuc, L-fucose), hexosamine (GlcNAc, N-acetylglucosamine), and sialic acid (NANA, N-acetylneuraminic acid). The mannose-6-phosphate recognition marker is formed by transfer of GlcNAc1P to the 6-hydroxyl groups of the a-linked mannose residues and subsequent removal of the phosphate-linked GlcNAc residues.

For full activity, hexosaminidase requires two different subunits: the a-subunit, coded for by the HEXA locus on chromosome 15, and the b-subunit, coded for by the HEXB locus on chromosome 5. Three isozymes of hexosaminidase have a defined subunit structure: hexosaminidase A (ab), hexosaminidase B (bb), and hexosaminidase S (aa). Hexosaminidase A is required for cleavage of GM2-ganglioside, but the true substrate is the ganglioside bound to a protein activator whose deficiency also causes a GM2-gangliosidosis (the so-called AB variant). The GM2-gangliosidoses are classified according to the phenotype, the genetic locus, and the allele involved. Progressive infantile encephalopathy was the most common clinical presentation in the past. The success of carrier screening among couples of Ashkenazi Jewish background dramatically reduced its incidence, and later onset variants are now seen more commonly. Hexosaminidase deficiencies present with a variety of phenotypes from infancy to adulthood. This diagnosis can reasonably be suspected with nearly any degenerative neurologic disorder except demyelinating neuropathy or myopathy. Sensory dysfunction, ocular palsies, neurogenic bladder, and extraneural involvement are not prominent features. The diagnosis is made by measuring the amount of hexosaminidase in blood serum and leukocytes. Rectal biopsy for electron microscopy of neurons is useful to confirm the diagnosis in variant phenotypes. DNA-based diagnosis is useful to specify the mutation involved. Infantile Encephalopathy with Cherry-red Spots Three disorders in this group are well known: classic infantile Tay-Sachs disease (a locus), infantile Sandhoff disease (b locus), and the so-called AB variant (activator locus). The a locus mutations occur with high frequency among people of Ashkenazi background (1 in 30 compared with 1 in 300 for the general population), accounting for the ethnic concentration of classic Tay-Sachs disease and genetic compounds containing a locus mutations. In all three conditions, the infants appear normal until 4 to 6 months of age. They learn to smile and reach for objects but do not sit or crawl. A myoclonic jerk reaction to sound (hyperacusis) and the macular cherry-red spot ( Fig. 83.4) are constant findings. The infants become floppy and weak but have hyperactive reflexes, clonus, and extensor plantar responses. Visual deterioration, apathy, and loss of developmental milestones lead to a vegetative state by the second year. Seizures and myoclonus are prominent for the first 2 years. The infants eventually become decorticate. They need tube feeding, have difficulty with secretions, and are blind. Head circumference enlarges progressively to about the 90th percentile from 1 to 3 years and then stabilizes. Death is due to intercurrent infection, usually pneumonia. The disease is confined to the nervous system.

FIG. 83.4. Macular cherry-red spot in Tay-Sachs disease. (Courtesy of Dr. Arnold Gold.)

By light microscopy, grossly ballooned neurons ( Fig. 83.5) are found throughout the brain, cerebellum, and spinal cord. The cytoplasm is filled with pale homogeneous-appearing material that pushes the nucleus and Nissl substrate to a corner of the cell. By electron microscopy, membranous cytoplasmic bodies (distended lysosomes) are seen with regularly spaced concentric dark and pale lamellae.

FIG. 83.5. Ballooned spinal cord ventral horn cells in Tay-Sachs disease. (Courtesy of Dr. Abner Wolf.)

GM2-ganglioside (Fig. 83.1B) content is markedly increased in the brain and, to a much lesser degree, in the viscera. Other glycosphingolipids with a terminal b-linked N-acetylgalactosamine moiety, such as asialo-GM2 ( Fig. 83.1B) and globoside (Fig. 83.1C), accumulate to a lesser degree. The storage results from deficiency of hexosaminidase (reaction 3). In classic Tay-Sachs disease, hexosaminidase A is absent and hexosaminidase B increased. Heterozygous carriers have a partial decrease of hexosaminidase A. In infantile Sandhoff disease, hexosaminidase A and B are deficient. Carriers have partially decreased hexosaminidase A and B. In one form of the AB variant, a hexosaminidase A activating protein is missing. Although levels of hexosaminidase A and B are increased, GM2-ganglioside cannot be cleaved. Diagnosis requires

use of the radiolabeled natural substrate, M2-ganglioside, or direct testing for the activator or activator mutations. In a second form of the AB variant, the residual hexosaminidase A cleaves artificial but not sulfated artificial or natural substrate. Although this is detected as an AB variant, it is an a-locus disorder. Late Infantile, Juvenile, and Adult GM2-Gangliosidoses These present with dementia and ataxia with or without macular cherry-red spots. Spasticity, muscle wasting due to anterior horn cell disease, and seizures are frequently seen. Hexosaminidase A deficiency or hexosaminidase A and B deficiency are found on biochemical study of serum, leukocytes, and cultured skin fibroblasts. Other late-onset forms of GM2-gangliosidosis present as cerebellar ataxia or spinocerebellar ataxia. Hexosaminidase A or hexosaminidase A and B deficiency are found on biochemical study. Motor neuron disease may be the presenting feature of late-onset GM2-gangliosidoses. Lower motor neuron disease may resemble Kugelberg-Welander or Aran-Duchenne syndrome. Upper motor neuron disease may be present, giving an amyotrophic lateral sclerosis-like phenotype. Many, perhaps most, of these late-onset cases are genetic compounds. Rectal biopsy for electron microscopy of autonomic neurons, natural substrate hexosaminidase assays, and DNA-based diagnosis are important diagnostic tests for late onset GM2-gangliosidosis.

GM1-GANGLIOSIDOSIS This group of disorders is characterized by deficiency of GM1-ganglioside b-galactosidase (reaction 2, Fig. 83.1B, Fig. 83.2 and Fig. 83.3) and storage of compounds that contain a terminal b-linked galactose moiety. These include GM1-ganglioside, asialo-M1, keratan sulfate-like oligosaccharides, and glycoproteins. Other b-galactosidases, such as those that cleave galactosylceramide (reaction 10, Fig. 83.1D) and lactosylceramide (reaction 5, Fig. 83.1B and Fig. 83.1C) are not deficient, and those compounds do not accumulate. There are at least three forms of deficiency of this enzyme: primary deficiency of b-galactosidase, causing infantile and late-infantile GM1-gangliosidosis and an adult form; combined neuraminidase and b-galactosidase deficiency, galactosialidosis; and combined deficiency of b-galactosidase and several other lysosomal enzymes in I-cell disease, mucolipidosis II. The latter two types are discussed under mucolipidoses. Infantile GM1-Gangliosidosis Infantile GM1-gangliosidosis is earlier in onset, more severe, and more rapidly progressive than infantile Tay-Sachs disease. Soon after birth, these infants become hypotonic, with poor sucking ability and slow weight gain. Their faces have frontal bossing, coarsened features, large low-set ears, and elongated philtrum. Gum hypertrophy, macroglossia, peripheral edema, and often faint corneal haze are noted. Strabismus and nystagmus may be seen. About half the patients develop macular cherry-red spots (Fig. 83.4). Development is slow, and they do not sit or crawl. By age 6 months, liver and spleen are enlarged; joint stiffness and claw-hand deformities may be seen, and the skin is coarse and thickened. Seizures may develop. The infants enter a vegetative state and die before age 2 of pneumonia or cardiac arrhythmias. Bone radiographs after 6 to 12 months show changes similar to those of Hurler syndrome, with anterior beaking of vertebral bodies and J-shaped sella turcica. Lymphocytes from peripheral smear are vacuolated, and histiocytes in the bone marrow are foamy. Diagnosis is made by the characteristic oligosaccharide pattern in urine, assay of GM1-ganglioside b-galactosidase (reaction 2, Fig. 83.1B and Fig 83.2) in blood leukocytes or cultured skin fibroblasts, and demonstration of partially decreased enzyme levels in the obligate carrier parents. It is important to exclude sialidosis and to be prepared for prenatal diagnosis. Specific mutations can be detected by DNA-based diagnosis. Late Infantile GM1-Gangliosidosis Onset is usually between 1 and 3 years with gait ataxia, hypotonia, hyperreflexia, dysarthria, and speech regression. Seizures, dementia, and spastic quadriplegia lead to death, usually by pneumonia. Optic atrophy and evidence of anterior horn cell disease may be found. Corneas are clear, organomegaly is absent, and bone changes are scanty. Diagnosis is made in the same manner as for the infantile form.

FABRY DISEASE Angiokeratoma corporis diffusum is an X-linked disorder affecting the skin, kidney, peripheral and autonomic nervous systems, and blood vessels with storage of trihexosylceramide, galactosyl galactosylglucosylceramide, a breakdown product of globoside ( Fig. 83.1C). Trihexosylceramide accumulates because of a deficiency of trihexosylceramide b-galactosidase (reaction 4, Fig. 83.1C), also known as b-galactosidase A. Fabry disease is the only sphingolipidosis that is X-linked. It is incompletely recessive; that is, some female heterozygotes are clinically affected. Symptoms usually begin in childhood or adolescence, with lancinating pains in the limbs, especially the feet and hands, often brought on by temperature changes, and accompanied by paresthesia or abdominal crises. Anhydrosis and unexplained fever are common. The characteristic skin lesions, which become more numerous with age, are purple, macular and maculopapular, hyperkeratotic, 1 to 3 mm in size with a predilection for the groin, buttocks, scrotum, and umbilicus. Glycolipid storage in the renal glomeruli and tubules begins with asymptomatic proteinuria in children; it progresses to renal failure and hypertension in the third or fourth decade. Glycolipid storage in blood vessel walls may cause stroke. Edema of the limbs, faint haziness of the cornea visible by slit lamp, and myocardial involvement may occur. There is no specific treatment. Renal transplant is life-saving when renal failure supervenes. The lancinating pains may respond to phenytoin. Heterozygous females may also be affected, but manifestations are less marked. Skin lesions are few or absent. Corneal opacity is more common. If renal or cardiac involvement occurs, they are later in onset and less severe. Diagnosis is by the finding of decreased b-galactosidase in plasma and leukocytes and by documentation of a specific mutation in the b-galactosidase gene.

GAUCHER DISEASE Gaucher disease is an autosomal recessive sphingolipidosis in which glucocerebroside ( Fig. 83.1B and Fig. 83.1C) is stored as a result of deficiency of glucocerebroside b-glucosidase (or glucocerebrosidase; reaction 6, Fig. 83.1B and Fig. 83.1C). At least four forms are known (Table 83.1): the infantile neuronopathic form, the juvenile neuronopathic form, the adult neuronopathic form, and the adult nonneuronopathic form. The adult (nonneuropathic) form is more common in persons of Ashkenazi background. Diagnosis of all forms is made by the characteristic clinical picture, finding of Gaucher cells in bone marrow, finding of reduced glucocerebroside b-glucosidase in cultured skin fibroblasts or blood leukocytes, and documentation of a mutation in the b-glucosidase gene.

TABLE 83.1. LIPIDOSES

Infantile Neuronopathic Gaucher Disease This disease occurs in the first year of life, often in the first 3 months. The course is rapid with developmental regression and death before age 2 years. Although the spleen and liver enlarge, the infants lose weight. They have stridor, difficulty in sucking and swallowing, strabismus, opisthotonic head retraction, spasticity, and hyperreflexia. Later, they enter a vegetative state, becoming flaccid and weak. Seizures may occur. Macular cherry-red spot and optic atrophy do not occur. Juvenile Neuronopathic Gaucher Disease This form is characterized by splenomegaly, Gaucher cells in bone marrow, mental deficiency (retardation or dementia), seizures, incoordination, and tics. Neurologic signs develop in childhood or adolescence. Adult Gaucher Disease Characteristics are splenomegaly and bone lesions but not neurologic disorders. It is most common in individuals of Ashkenazi background. Despite the name, the disease may be found even in young children. Although thrombocytopenia may be a problem, splenectomy should be avoided if possible; however, severe and prolonged thrombocytopenia is an indication for splenectomy. Lesions of long bones, pelvis, or vertebral bodies may be painful. Liver, skin, lymph nodes, and lungs may be involved. Multiple myeloma may be a late complication. Purified modified b-glucosidase, alglucerase, or recombinant b-glucosidase, imiglucerase, infused into patients with Gaucher disease, causes dramatic reduction in splenomegaly and improvement in other symptoms. Adult Neuronopathic Gaucher Disease Although resembling adult-onset Gaucher disease, symptoms also include seizures and dementia.

NIEMANN-PICK DISEASE This group of disorders is characterized by lysosomal storage of the glycosphingolipid sphingomyelin (ceramide phosphorylcholine) ( Fig. 83.1E). Two basic types have been described. Type I consists of the earlier types A and B deficiency. In type II, consisting of the earlier type C and D, a defect of intracellular cholesterol transport has been found. In type I patients, deficiency of a sphingomyelin-cleaving enzyme, sphingomyelinase (reaction 26, Fig. 83.1E), has been found. Diagnosis is made by the clinical evidence of hepatosplenomegaly, with or without cerebral symptoms, by finding characteristic “mulberry� storage cells (which appear different from Gaucher cells) in bone marrow and by demonstrating decreased sphingomyelinase activity in cultured skin fibroblasts, leukocytes, or tissue. Infantile Niemann-Pick Disease, Type A This is the most common and most severe form of Niemann-Pick disease and occurs more commonly in individuals of Ashkenazi background. Transient neonatal jaundice is followed by progressive hepatosplenomegaly; developmental regression and weight loss lead to death by age 2. Dementia and hypotonia are noted. About one-third of patients develop macular cherry-red spots ( Fig. 83.4). Seizures are uncommon. Bone involvement is mild. Skin often has a brownish-yellow tinge. Most patients have diffuse haziness or patchy infiltrates in the lungs. Diagnosis is made by the characteristic clinical picture, by the finding of foam cells in the bone marrow, and by demonstration of nearly total sphingomyelinase (reaction 26, Fig. 83.1E) deficiency in leukocytes and cultured skin fibroblasts. Juvenile Nonneuronopathic, Type B This form presents with asymptomatic splenomegaly or hepatosplenomegaly without neurologic disorder in infants, children, or adults. Foam cells appear in the bone marrow, and sphingomyelinase (reaction 26, Fig. 83.1E) is reduced in cultured skin fibroblasts and leukocytes. These patients have more residual sphingomyelinase (15% to 20% of normal) than those with type A (up to 10%). Niemann-Pick Disease Type C Patients are normal in infancy but after 1 to 2 years develop progressive dementia, seizures, spasticity, vertical gaze paresis, and ataxia. Hepatosplenomegaly is less prominent than in other types. Diagnosis is by demonstration of foam cells (sea-blue histiocytes) in bone marrow and the demonstration in cultured skin fibroblasts of deficient induction of cholesterol esterification and of intravesicular storage of cholesterol after filipin staining. The abnormal gene, NPC1, is located in the short arm of chromosome 18. In type D, found in Yarmouth County Acadians of Nova Scotia, the basic defect is also mutation in NPC1. Type E patients may simply be adult type B patients. Type F resembles type B except that sphingomyelinase is heat labile in type F.

FARBER LIPOGRANULOMATOSIS In the first few months of life, as early as 2 weeks of age, infants with this disease have painful swollen joints, hoarseness, vomiting, respiratory difficulty, or limb edema. Subcutaneous nodules are found near joints and tendon sheaths, especially on the hands, arms, and at pressure points such as the occiput or lumbosacral spine. Other findings include cardiac enlargement and murmurs, lymphadenopathy, hepatomegaly, splenomegaly, enlarged tongue, difficulty in swallowing, and pulmonary granulomata. Tendon reflexes may be hyperactive or hypoactive. Mental development may be normal or impaired. Seizures do not occur. Cerebrospinal fluid (CSF) protein may be elevated. Ceramide (Fig. 83.1B, Fig. 83.1C, Fig. 83.1D and Fig. 83.1E) and some related compounds accumulate in foam cells in affected tissues because of severe diminution of acid ceramidase (reaction 7, Fig. 83.1B, Fig. 83.1C, Fig. 83.1D and Fig. 83.1E), an enzyme that catabolizes ceramide to sphingosine and fatty acid. Neutral ceramidase is not decreased. Diagnosis is made by the clinical picture and finding of deficiency of acid ceramidase in cultured skin fibroblasts or leukocytes. Prenatal diagnosis and carrier testing are possible. Most patients die of pulmonary disease before age 2 years, but some survive into adolescence.

WOLMAN DISEASE Infants affected by Wolman disease are normal at birth but in the first few weeks of life have severe vomiting, abdominal distention, diarrhea, poor weight gain, jaundice, and unexplained fever. Hepatosplenomegaly may be massive, and there may be a papulovesiculopustular rash on face, neck, shoulders, and chest. The extent of neurologic disorder is not clear because the infants are so sick and die so early. Initially, they are active and alert, but activity decreases. Corticospinal signs have been found in some. Laboratory findings include anemia and foam cells in bone marrow. A distinctive finding is calcification of the adrenals on radiographic examination. The course is usually rapidly progressive. Death usually occurs within 3 to 6 months, but some survive into the second year. The lipid storage consists primarily of cholesterol ester and smaller amounts of triglyceride because there is severe deficiency of a lysosomal fatty acid ester acid hydrolase (acid lipase, acid esterase, or acid cholesteryl ester hydrolase), which cleaves cholesterol ester, triglycerides, and artificial substrates. Nearly total deficiency of this acid lipase is found in tissues, leukocytes, and

cultured fibroblasts from patients; carriers have been detected, and prenatal diagnosis is possible. The enzyme is coded for by a gene on the long arm of chromosome 10 (10q23.210q23). A milder allelic form of Wolman disease with deficiency of the same enzyme is called cholesterol ester storage disease. These patients have hepatomegaly (with or without splenomegaly), hypercholesterolemia, and foam cells in the bone marrow.

CEREBROTENDINOUS XANTHOMATOSIS (CHOLESTANOL STORAGE DISEASE) Although patients with cholestanol storage disease often have mental defect of early onset, the diagnosis is difficult in the first decade because cataracts, tendon xanthomas, and progressive spasticity, usually associated with ataxia, commonly do not begin before adolescence or young adulthood. The spasticity and ataxia are severe and progressive. Speech is affected. Neuropathy may appear with distal muscle wasting. Sensory deficits and Babinski signs are seen. Pseudobulbar palsy develops terminally. Death usually occurs in the fourth to sixth decade, caused by neurologic disease or myocardial infarction. Some patients have apparently normal mental function. Tendon xanthomas are almost always seen on the Achilles tendon and may occur elsewhere. The cerebellar hemispheres contain large (up to 1.5 cm), yellowish, granulomatous, xanthomatous lesions with extensive demyelination of white matter. Microscopically, cystic areas of necrosis and clear needle-shaped clefts contain birefringent material surrounded by macrophages with foamy vacuolated cytoplasm and multinucleated giant cells. The brainstem and spinal cord may be involved. Cholestanol is increased in plasma, brain, and tendon xanthomas. Cholesterol is increased in tendon xanthomas but is usually normal in plasma. Cholestanol is increased in bile, but chenodeoxycholic acid (a major component of normal bile) is virtually absent. Diagnosis is by the characteristic clinical picture, and biochemical findings and demonstration of mutations in the sterol 27-hydroxylase gene (CYP27). Treatment with certain bile acids may be beneficial.

NEURONAL CEROID LIPOFUSCINOSES The neuronal ceroid lipofuscinoses are defined by histologic and ultrastructural features. By light microscopy, neurons are engorged with periodic acid-Schiff–positive and autofluorescent material. Ultrastructurally, abnormal lipopigments resembling ceroid and lipofuscin are found in distinctive abnormal cytosomes such as curvilinear and fingerprint bodies. Although the signs and symptoms are confined to the nervous system, the abnormal cytosomes are widely distributed in skin, muscle, peripheral nerves, leukocytes, urine sediment, and viscera. Dolichol is elevated in tissue and urine sediment. The gene (CLN1) for infantile neuronal ceroid lipofuscinosis and those for the late infantile (CLN2) and juvenile (CLN3) forms have been cloned. CLN1 codes for the palmitoylprotein thioesterase enzyme; mutations in this gene also cause a juvenile form of neuronal ceroid lipofuscinosis with granular osmiophilic deposits. CLN2 also codes for a lysosomal enzyme, but the function of the CLN3 protein is not yet known. CLN4 and CLN5 have been mapped. CLN5 codes for a putative transmembrane protein. Diagnosis is made by the characteristic clinical picture, by abnormal electroretinogram (in the infantile, late-infantile, and juvenile forms), by electron microscopic examination of tissue (skin, nerve, muscle, or rectal biopsy for autonomic neurons) and by enzyme and mutation testing. Abnormal autofluorescence is seen on examination of frozen section of biopsied muscle, enabling rapid diagnosis. The neuronal ceroid lipofuscinoses are autosomal recessive. Infantile (Finnish) Variant (Santavuori Disease) This variant of neuronal ceroid lipofuscinosis begins at about 8 months with progressive visual loss, loss of developmental milestones, myoclonic jerks, and microcephaly. There is optic atrophy, macular and retinal degeneration, and no response in the electroretinogram. Progression is rapid, but infants may survive for several years. Late-infantile Variant (Jansky-Bielschowsky Disease) This begins between ages 1.5 and 4 years with seizures and ataxia. Seizures respond poorly to anticonvulsants. There is progressive visual deterioration with abolished electroretinogram and retinal deterioration. Progression is usually rapid to a vegetative state, but some affected children may survive several years. Juvenile Variant (Spielmeyer-SjÜgren Disease) This variant of neuronal ceroid lipofuscinosis begins with progressive visual loss between the ages of 5 and 10 years, with pigmentary degeneration of the retina. Seizures, dementia, and motor abnormalities occur later and progress to death by the end of the second decade. The storage material contains large amounts of the ATP synthase subunit C protein. Adult Variant (Kufs Disease) This begins in the third or fourth decade with progressive dementia, seizures, myoclonus, and ataxia. Blindness and retinal degeneration are not features of the adult form.

LEUKODYSTROPHIES The leukodystrophies are progressive genetic metabolic disorders affecting myelin metabolism ( Table 83.2). Krabbe leukodystrophy (globoid cell leukodystrophy) was initially defined by the presence of globoid cells in demyelinated portions of the brain. Metachromatic leukodystrophy (MLD) was set apart by abnormal tissue metachromasia. Adrenoleukodystrophy was set apart by involvement of adrenal glands and by X-linked inheritance (see Chapter 87 for a discussion of adrenoleukodystrophy). Classic Pelizaeus-Merzbacher disease was set apart by X-linked inheritance, early onset, a long course, and islands of preserved myelin in the demyelinated areas. This leaves a heterogeneous group of unclassified leukodystrophies, sometimes called orthochromatic or sudanophilic leukodystrophies.

TABLE 83.2. LEUKODYSTROPHIES

Metachromatic Leukodystrophy

MLD is a group of disorders with degeneration of central myelin ( Fig. 83.6) and peripheral myelin, striking metachromasia of the stored substances, primarily sulfatides, and deficiency of the sulfatide-cleaving enzyme, sulfatase A (reaction 9, Fig. 83.1D), also called arylsulfatase A. At least four forms are known, the late-infantile form being the most common. All have autosomal recessive inheritance.

FIG. 83.6. A: Standard CT projection through the center cerebrum. Open arrows indicate symmetrical lesions of markedly decreased absorption in white matter. Adult MLD, age 36. B: A more T2-weighted MRI scan of the same patient. Black arrow shows the confluent hyperintense signal in diseased white matter. So shrunken is this white matter that gyri now extend down next to the ventricle (open arrows).

Alleles causing sulfatase A deficiency and MLD have either absent or low residual enzyme activity. Patients with two alleles giving absent enzyme activity have the severe late-infantile MLD. Patients with two alleles giving low residual enzyme activity have the mildest, adult type MLD. Compound heterozygotes with one allele of each type have the intermediate juvenile form of MLD. The diagnosis of MLD is complicated by the existence of sulfatase A pseudodeficiency, an autosomal recessive condition in which sulfatase A activity is greatly diminished by the usual enzyme assays, but there is no neurologic disease. An additional complication is the requirement of sulfatase A for the sulfatide activator protein. Patients with genetic deficiency of sulfatide activator protein may have MLD, but the commonly used enzyme assays may fail to diagnosis this. Consequently, a high index of suspicion is required even if screening tests are apparently normal. Late-Infantile Metachromatic Leukodystrophy Affected infants have onset of difficulty in walking after the first year of life, usually between ages 12 and 30 months. Usually, flaccid paresis and diminished or absent tendon reflexes are seen. Occasionally, spastic paresis develops. Genu recurvatum may be noted. Mental functions deteriorate and dysarthria is noted. Tendon reflexes decrease and disappear. Intermittent pain in arms and legs may be seen. Later, patients become bedridden and quadriplegic, with feeding difficulties, bulbar and pseudobulbar palsies, and optic atrophy. Finally, the children become blind, enter a vegetative stage, and die usually in the first decade. CSF protein is increased. Gallbladder function may be impaired. Metachromatic lipids are seen on sural nerve biopsy. Urinary sulfatide excretion is increased. Sulfatide accumulates in brain and peripheral nerves and in some extraneural tissues (e.g., kidney) and is seen histologically as brown metachromasia with acetic acid-cresyl violet staining in glial cells, Schwann cells, myelin lamellae, and neurons. The characteristic “tuffstone� bodies are seen by electron microscopy. Sulfatide consists primarily of galactosylsulfatide ( Fig. 83.1D), although a smaller amount of lactosylsulfatide is found. The diagnosis is based on the clinical picture, demonstration of histologic and ultrastructural abnormalities in myelinated fibers of biopsied sural nerve or conjunctiva, the finding of severe deficiency of sulfatase A in leukocytes and cultured skin fibroblasts, and demonstration of a mutation in the sulfatase A gene. Juvenile Metachromatic Leukodystrophy These patients have later onset of symptoms (usually ages 3 to 10 years) and slower progression of the disease. The clinical features are similar to those late-infantile MLD. Juvenile MLD patients more frequently have emotional disturbance or dementia as the initial symptom, although they may present with gait disorder. Nystagmus and tremor may be noted. Nerve conduction velocities are slowed. CSF protein concentrations are elevated. Adult Metachromatic Leukodystrophy In adults, MLD commonly presents around age 30 years as a psychiatric disorder or progressive dementia. Other findings may include truncal ataxia, hyperactive reflexes, and seizures. CSF protein concentration is usually not elevated. The illness runs a protracted course, averaging 15 years. Multiple Sulfatase Deficiency This rare disorder, also known as sulfatidosis, Austin type or mucosulfatidosis, has clinical features of MLD and mucopolysaccharidosis, with excretion of both sulfatide and mucopolysaccharide in urine and deficiencies in at least nine sulfatases. Onset is usually earlier than with late-infantile MLD. Early development is slow. Patients do not achieve normal gait or speech, although they may walk or speak single words. Neurologic deterioration is noted at 1 to 2 years, and the disease proceeds much like late-infantile MLD. However, patients develop mildly coarsened facial features, ichthyosis, and sometimes hepatosplenomegaly and dystosis multiplex. The histologic changes in brain and peripheral nerve resemble those of late-infantile MLD. Metachromatic material is found in liver, spleen, and kidney. The diagnosis is based on the characteristic clinical picture and the findings of deficiencies of sulfatase A and other sulfatases in cultured skin fibroblasts. The biochemical basis for multiple sulfatase deficiency seems to be that all sulfatases require a posttranslational modification for sulfatase activity. This modification, conversion of a cysteine residue to 2-amino-3-oxopropionic acid, is believed to be defective in multiple sulfatase deficiency patients. Krabbe Leukodystrophy (Globoid Cell) Patients are normal at birth. Symptoms begin at ages 3 to 6 months with irritability, inexplicable crying, fevers, limb stiffness, seizures, feeding difficulty, vomiting, and slowing of mental and motor development. Later, mental and motor deterioration occur with marked hypertonia and extensor postures. Early tendon reflexes may be increased or already decreasing. Optic atrophy may be seen. Later, tendon reflexes decrease or disappear. Patients may develop flaccidity or flexor postures before death occurs at about age 2 years. Important diagnostic features are increased CSF protein and decreased nerve conduction velocities. On electron microscopy, sural nerve biopsy specimens show needlelike inclusions in histiocytes and Schwann cells, also seen in globoid cells in demyelinated brain regions ( Fig. 83.7).

FIG. 83.7. Globoid cells in white matter, Krabbe leukodystrophy (H&E stain)

Galactocerebrosidase (reaction 10, Fig. 83.1D) is deficient in serum, leukocytes, and cultured skin fibroblasts. Both galactosylcerebroside and galactosylsphingosine (psychosine) are substrates for that enzyme. Psychosine is increased at least 200-fold over levels in the normal brain, where it is barely detectable. Psychosine storage is probably the cause of the disease, because psychosine has been shown to be toxic to the brain. A few patients with juvenile onset and slower progression of dementia, optic atrophy, and pyramidal tract signs without neuropathy have had galactocerebrosidase deficiency. An adult-onset disorder with similar but more slowly progressive course has been described based on the pathologic findings of globoid cell leukodystrophy; however, the biochemical basis has not been established.

MUCOPOLYSACCHARIDOSES The mucopolysaccharidoses are defined by a characteristic phenotype and by the tissue storage and urinary excretion of acid mucopolysaccharide ( Table 83.3). They were originally regarded as a single disease, but eight clinical types and numerous subtypes are now known. Each is caused by deficiency of a lysosomal hydrolase enzyme required for degradation of one or more of three sulfated mucopolysaccharides: dermatan sulfate, heparan sulfate, and keratan sulfate ( Fig. 83.2).

TABLE 83.3. MUCOPOLYSACCHARIDOSES

Diagnosis is based on the clinical picture, excessive amounts of one or more acid mucopolysaccharides in urine, and the presence of the enzyme defect. Urine screening tests for excess mucopolysaccharide are useful but show both false-positive and false-negative results. Positive screening tests require confirmation by quantitative and qualitative determination of urinary mucopolysaccharides, radiographic and histologic evidence of tissue storage, and demonstration of the enzyme defect. Screening tests may be falsely negative, especially in Sanfilippo and Morquio syndromes. If clinical suspicion of mucopolysaccharidosis is strong, diagnostic evaluation should be pursued even with a negative urine screening test. Prenatal diagnosis of these disorders is possible. Hurler Syndrome This is the most severe of the mucopolysaccharidoses, characterized by onset in infancy, progressive disability, and death usually occurring before 10 years of age. Nearly all the features found in other types are present in Hurler syndrome. Corneal clouding and lumbar gibbus are noted in the first year of life. Patients develop stiff joints with periarticular swelling, short stubby hands and feet, claw hands, lumbar lordosis, chest deformity, and dwarfing, which are usually apparent by 2 or 3 years of age. The facial features become coarsened and grotesque, with thickened eyelids and lips, frontal bossing, bushy eyebrows, depressed nasal bridge, hypertelorism, enlarged tongue, noisy breathing, rhinorrhea, and widely spaced peglike teeth. Mental retardation and deterioration, but not seizures, are noted. Deafness is frequent. Few patients develop speech. Leptomeningeal thickening, arachnoid cysts, and hydrocephalus may occur. Cardiac murmurs due to valvular heart disease, coronary occlusion, and cardiac enlargement may occur and cause death. Abdominal distention is commonly noted, with inguinal and umbilical hernias and hepatomegaly. Corneal clouding becomes progressively more severe and, with retinal degeneration, impairs vision. Cervical cord compression with quadriplegia may occur. Radiographic changes are often helpful for the diagnosis of mucopolysaccharidosis but do not reliably distinguish the various types. These changes include ovoid or beaked lumbar vertebrae, peg-shaped metacarpals, a J-shaped sella turcica, and spatulate ribs. Peripheral leukocytes and bone marrow cells contain metachromatic granules. Clear vacuoles are seen in liver cells and cells of other tissues. Zebra bodies containing lipids occur in the brain. Both dermatan sulfate and heparan sulfate (Fig. 83.2) are stored. a-L-Iduronidase (reaction 11, Fig. 83.2), required for degradation of both, is deficient. The diagnosis is made by demonstrating severe deficiency of a-L-iduronidase in cultured skin fibroblasts and leukocytes. The a-L-iduronidase gene is located on the short arm of chromosome 4. Scheie syndrome (MPS IS), a milder allelic variant of Hurler syndrome, is characterized by juvenile onset of stiff joints with the development of claw hands and deformed feet. Corneal clouding causes visual impairment; corneal grafts may become opacified. Other features are pigmentary degeneration of the retina, glaucoma, coarse facial features, genu valgus, carpal tunnel syndrome, and involvement of the aortic valve. Deafness may occur. Stature and intelligence are normal. Psychologic disturbances have been noted. Lifespan may be normal unless cardiac involvement becomes severe. A phenotype intermediate between that of the Hurler and Scheie syndromes is referred to as the Hurler-Scheie compound. Distinction from other a-L-iduronidase deficiency disorders is solely on clinical grounds. Hunter Syndrome (MPS II) There are at least two forms, mild and severe. Both are X-linked recessive and show iduronate-2-sulfatase deficiency (reaction 12, Fig. 83.2). A Hunter-like phenotype in girls with iduronate-2-sulfatase deficiency is due to total sulfatase deficiency (MLD, Austin type). Boys with the severe form have juvenile onset of joint stiffness, coarse facial features, dysostosis multiplex, hepatosplenomegaly, diarrhea, dwarfing, and mental deterioration. Progressive deafness is prominent. Pigmentary retinal deterioration, papilledema, and hydrocephalus may be seen. Nodular or pebbled skin change over the scapulae and absence of corneal clouding are important features distinguishing Hunter from Hurler syndrome. Patients usually die by age 15 years. Patients with the mild form of Hunter syndrome may be asymptomatic. They have short stature, joint stiffness and limitation of motion, coarse features, and hepatosplenomegaly. They may have hernias and carpal tunnel syndrome. Intelligence is normal, but they may develop papilledema and neurologic deterioration late in the course. Lifespan may be normal.

Diagnosis is by finding excess urinary dermatan sulfate and heparan sulfate ( Fig. 83.2) and demonstration of iduronate-2-sulfatase deficiency (reaction 12, Fig. 83.2) in serum or cultured skin fibroblasts. Sanfilippo Syndrome (MPS III) Patients with this syndrome have prominent mental involvement, mild somatic involvement, and urinary excretion of heparan sulfate alone. Four biochemically distinct forms reflect four metabolic steps required for the degradation of heparan sulfate but not that of dermatan sulfate or keratan sulfate. These patients have the juvenile onset of mental deterioration with delay or deterioration of speech or school performance. On evaluation for psychiatric disorder, mental retardation, or dementia, the examiner notes mild coarsening of facial features, hepatosplenomegaly, hirsutism, joint stiffness, and radiographic changes of dysostosis multiplex. These patients deteriorate neurologically with progressive dementia, spastic quadriparesis, tetraballism, athetosis, incontinence, and seizures. Cardiac involvement may occur. Corneal clouding is absent. Bone changes, dwarfing, and organ enlargement are slight. Patients may die in adolescence or survive into the third decade. The diagnosis is made by the characteristic clinical picture, excess heparan sulfaturia, and demonstration of the enzyme defect. Urinary screening tests for mucopolysacchariduria may be negative in Sanfilippo syndrome. In Sanfilippo syndrome type A, the enzyme heparan sulfate N-sulfatase (sulfamidase; reaction 13, Fig. 83.2) is deficient. In type B, a- N-acetylglucosaminidase (reaction 14, Fig. 83.2) is lacking. In type C, an N-acetyltransferase is deficient (reaction 15, Fig. 83.2); this enzyme acetylates the amino group from which sulfamidase removes the sulfate (reaction 13, Fig. 83.2), thus allowing the (N-acetylglucosaminidase (reaction 14, Fig. 83.2) to act. In type D, an N-acetylglucosamine-6-sulfatase is deficient (reaction 19, Fig. 83.2); this enzyme removes the 6-sulfate from N-acetylglucosamine in heparan sulfate and keratan sulfate. Type A is by far the most common. Morquio Syndrome (MPS IV) This mucopolysaccharidosis is characterized by a severe skeletal disorder, little neurologic abnormality, and the urinary excretion of keratan sulfate ( Fig. 83.2). Two biochemically distinct forms are known, reflecting the two metabolic steps specifically required to degrade keratan sulfate. Skeletal manifestations appear in the first year, as in Hurler syndrome, but corneal clouding is not prominent (corneas usually become mildly cloudy). Patients develop severe dwarfing, pectus carinatum joint laxity, knock knees, short neck, sensorineural deafness, abnormal facies, and hepatosplenomegaly. Intelligence is normal. Because of odontoid process hypoplasia and joint laxity, atlantoaxial subluxation may cause cervical cord compression even in young children; this may be prevented by posterior spinal fusion. Cardiac or respiratory disease may cause death in the third or fourth decade. The diagnosis of type A is made by finding excess urinary keratan sulfate and that of type B by finding excess urinary oligosaccharides as well. Patients with type A Morquio syndrome lack an enzyme that cleaves 60 sulfate groups from galactose-6-sulfate (reaction 16, Fig. 83.2) and N-acetylgalactosamine-6-sulfate, causing the storage of keratan sulfate (which contains galactose-6-sulfate) and chondroitin-6-sulfate (which contains acetylgalactosamine-6-sulfate). The milder type B form of Morquio syndrome is caused by deficiency of b-galactosidase (reaction 2, Fig. 83.2), the same enzyme that is deficient in GM1-gangliosidosis. Presumably, the Morquio mutation severely affects the enzyme's ability to cleave the b-galactoside linkage in keratan sulfate but leaves sufficient activity against that linkage in GM1-ganglioside to prevent brain disease. Maroteaux-Lamy Syndrome (MPS VI) This syndrome resembles MPS type I syndrome because of the prominent skeletal disease, but intelligence is normal, and the predominant urinary mucopolysaccharide is dermatan sulfate. It is distinguished from Scheie syndrome by the affected patient's short stature. At least three forms of Maroteaux-Lamy syndrome are known, all with deficiency of N-acetylgalactosamine-4-sulfate sulfatase or arylsulfatase B (reaction 17, Fig. 83.2). In the severe form, growth retardation is noted by 2 or 3 years of age. Coarse facial features, marked corneal clouding, and severe skeletal disease develop. Valvular heart disease and heart failure develop. Intelligence is normal, but neurologic complications include hydrocephalus and cervical cord compression resulting from hypoplasia of the odontoid process. Patients may survive into the second or third decade. In milder forms, cervical cord compression and carpal tunnel syndrome may occur.

MUCOLIPIDOSES The mucolipidoses (Table 83.4) resemble the Hurler phenotype but lack excess urinary mucopolysaccharide, having instead excess urinary oligosaccharides or glycopeptides, most of which are fragments of more complex structures (Fig. 83.3). Urinary thin-layer chromatography for oligosaccharides is a useful screening test.

TABLE 83.4. MUCOLIPIDOSES

Sialidosis Patients with sialidoses have deficiency of a-L-neuraminidase, also known as sialidase (reaction 1, Fig. 83.1B and Fig. 83.3B). In most forms, sialic acid-containing glycoproteins, oligosaccharides, and glycolipids accumulate in tissue, and sialyloligosaccharides are excreted in urine. The diagnosis is based on clinical findings; the presence of abnormal sialyloligosaccharides in the urine; and deficiency of the appropriate sialidase in cultured skin fibroblasts, tissue, or leukocytes. There are at least two distinct lysosomal sialidases, one that cleaves the (a2,3)-linked sialic acid in monosialoganglioside (reaction 8, Fig. 83.1B) and the other that cleaves (a2,3)-linked and (a2,6)-linked sialic acid in polysialogangliosides, oligosaccharides, and glycoproteins (reaction 1, Fig. 83.1B and Fig. 83.3). The latter enzyme is deficient in the other sialidoses. In addition to the isolated sialidase deficiencies, two other groups of mucolipidoses have sialidase deficiency. In one, galactosialidosis and both sialidase and b-galactosidase are deficient because a stabilizing protein they share is defective. In the second group, mucolipidosis II and III, sialidase, and several other lysosomal hydrolases are deficient. Sialidoses with isolated sialidase deficiency have a highly variable clinical picture. Neonates with congenital sialidoses have hydrops fetalis, hepatosplenomegaly, and short survival times. They resemble infants with congenital lipidosis of Norman and Wood. Infants with nephrosialidosis resemble the Hurler phenotype and develop macular cherry-red spots and renal disease. Children with mucolipidosis I (lipomucopolysaccharidosis), a milder disorder, are similarly affected but develop ataxia, myoclonic jerks, and seizures. The mildest form is the cherry-red spot myoclonus disorder, in which adolescents, who are usually mentally normal, develop macular cherry-red spots, myoclonus, and myoclonic seizures. There is a predilection for individuals of Italian descent.

Galactosialidosis Sialidosis with combined sialidase and b-galactosidase deficiency (galactosialidosis) includes two forms: an infantile disorder with the clinical phenotype of GM1-gangliosidosis and the Goldberg syndrome. The first disorder should be considered in any patient who is suspected of having GM1-gangliosidosis or is found to have b-galactosidase deficiency. Goldberg syndrome resembles mucolipidosis I but is milder with a predilection for those of Japanese origin; there is an adult form as well.

FREE SIALIC ACID STORAGE DISEASES Onset of Salla disease is between ages 4 and 12 months with hypotonia, developmental delay, or both. Ataxia of trunk and limbs follows, and by age 2 years, there is mental and motor retardation. Patients are invariably severely mentally retarded and may never speak or walk. Usually, they develop spasticity, athetosis, dysarthria, and sometimes convulsions. They are short, often with strabismus and with thickened calvaria. Ultrastructural analysis of blood lymphocytes, skin, and liver reveals abnormal lysosomal morphology. Free sialic acid is markedly increased in urine; defective sialic acid egress has been noted from isolated fibroblast lysosomes. There is a predilection for those of Finnish descent.

FUCOSIDOSIS Some patients with fucosidosis have severe neurologic disease that resembles a leukodystrophy. Others with fucosidosis resemble the Hurler phenotype. Some have survived into the second or third decade. Fucose residues form part of the structure of oligosaccharides, glycoproteins, and glycolipids, including “fucogangliosides.” The diagnostic findings are excessive urinary abnormal oligosaccharides ( Fig. 83.3) and by demonstrating severely decreased levels of a-L-fucosidase (reaction 21, Fig. 83.3) in serum, leukocytes, and cultured skin fibroblasts.

MANNOSIDOSES a-Mannosidosis may be mild or severe. In severely affected patients, the diagnosis has been confused with mucolipidosis I. Other patients have slower progression of the disorder with greater dysmorphism, cataracts, and longer survival. Others have presented primarily with marked mental defect, striking gingival hyperplasia, and survival into the third decade or longer. Facial dysmorphism, skeletal involvement, and organ enlargement have been slight in these patients. Diagnosis requires a high index of suspicion and findings of excessive abnormal urinary oligosaccharides and decreased a-mannosidase (reaction 22, Fig. 83.3) in leukocytes and cultured skin fibroblasts. b-Mannosidosis, originally described in goats, was subsequently described in humans. One patient presented at 16 months with slowing of speech development and at 46 months had coarsened facial features, mild bone changes, speech delay, and mental retardation. Two brothers, aged 44 and 19 years, had angiokeratoma on the penis and scrotum; mental retardation from age 5 years or earlier; and no coarse features, organomegaly, or bone changes. Diagnosis was by lack of a-mannosidase in plasma, leukocytes, and fibroblasts and by presence of a mannose-containing disaccharide in urine. Interestingly, the first patient had absent sulfamidase, low sulfamidase in one parent, and urinary mucopolysaccharide excretion identical to that in Sanfilippo syndrome, type A, a clinically similar disorder.

ASPARTYLGLYCOSAMINURIA Aspartylglycosaminuria occurs almost solely in Finland. Patients have juvenile onset of somatic and mental changes. Somatic changes include coarse facial features, anteverted nostrils, short neck, and scoliosis. Intellectual deterioration leads to severe mental defect in the adult. Episodic hyperactivity, psychotic behavior, and seizures may occur. Patients excrete large amounts of aspartylglucosamine in their urine because of deficiency of N-aspartyl-b-glucosaminidase (reaction 25, Fig. 83.3). Diagnostic findings are aspartylglucosamine in the urine and deficiency of N-aspartyl-bglucosaminidase (reaction 25, Fig. 83.3) in cultured skin fibroblasts.

MUCOLIPIDOSES II AND III Mucolipidosis II (I-cell disease) is a severe disorder that resembles Hurler syndrome but the patient's corneas are clear. Cultured fibroblasts have coarse inclusions (I-cells). Diagnosis is made by finding excess sialo-oligosaccharides in the urine and deficiencies of multiple lysosomal enzymes in cultured skin fibroblasts with elevated levels of these enzymes in plasma. In brain and viscera, only b-galactosidase is consistently deficient. The basic defect is deficiency of the enzyme, UDP-N-acetylglucosamine: glycoprotein N-acetylglucosaminylphosphotransferase. This enzyme attaches the N-acetylglucosamine-1-phosphate of UDPGlcNAc1P to the 6-position of a-linked mannose residues of glycoproteins. The N-acetylglucosamine is subsequently removed to leave a mannose-6-phosphate residue, an important recognition marker for uptake of certain glycoproteins (including many lysosomal hydrolase enzymes) into the cell. Mucolipidosis III (pseudo-Hurler polydystrophy) is a milder clinical disorder than mucolipidosis II but is caused by a deficiency of the same enzyme. Diagnosis is made as for mucolipidosis II.

MUCOLIPIDOSIS IV Patients with mucolipidosis IV present with corneal clouding as early as 6 weeks of age. Mild retardation progresses to severe mental and motor defect. There is a predilection for those of Ashkenazi Jewish descent. Diagnosis is by the clinical picture, light microscopic findings (lipid-laden marrow histiocytes), and electron microscopic findings (vacuoles and membranous bodies in skin, conjunctiva, and cultured fibroblasts). Gangliosides GM3 and GD3 (Fig. 83.1B) accumulate in fibroblasts. Soluble ganglioside sialidase (reaction 8, Fig. 83.1B) is reportedly deficient but the basic defect is unknown. SUGGESTED READINGS Lysosomal Diseases Gieselmann V. Lysosomal storage diseases [Review]. Biochim Biophys Acta 1995;1270:103–136. Lipidoses and Leukodystrophies Berger J, Loschl B, Bernheimer H, et al. Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy. Am J Med Genet 1997;69:335–340. Beutler E. Enzyme replacement therapy for Gaucher's disease [Review]. Baillieres Clin Haematol 1997;10:751–763. Beutler E. Gaucher disease [Review]. Curr Opin Hematol 1997;4:19–23. Brady RO. Gaucher's disease: past, present and future [Review]. Baillieres Clin Haematol 1997;10:621–634. Chen W, Kubota S, Teramoto T, et al. Genetic analysis enables definite and rapid diagnosis of cerebrotendinous xanthomatosis. Neurology 1998;51:865–867. Crutchfield KE, Patronas NJ, Dambrosia JM, et al. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology 1998;50:1746–1749. Eng CM, Ashley GA, Burgert TS, et al. Fabry disease: thirty five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes. Mol Med 1997;3:174–182.

Goebel HH, Sharp JD. The neuronal ceroid-lipofuscinoses. Recent advances. Brain Pathol 1998;8:151–162. Grabowski GA, Horowitz M. Gaucher's disease: molecular, genetic and enzymological aspects [Review]. Baillieres Clin Haematol 1997;10:635–656. Greer WL, Riddell DC, Gillan TL, et al. The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097>T transversion in NPC1. Am J Hum Genet 1998;63:52–54. Jan MM, Camfield PR. Nova Scotia Niemann-Pick disease (type D): clinical study of 20 cases. J Child Neurol 1998;13:758. Kaye EM, Shalish C, Livermore J, et al. Beta-galactosidase gene mutations in patients with slowly progressive GM1 gangliosidosis [Review]. J Child Neurol 1997;12:24–27. Koch J, Gartner S, Li CM, et al. Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase (Farber disease). J Biol Chem 1996;271:33110–33115. Mitchison HM, Hofmann SL, Becerra CH, et al. Mutations in the palmitoylprotein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Hum Mol Genet 1998;7:291–297. Myerowitz R. Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene [Review]. Hum Mutat 1997;9:195–208. Nowaczyk MJ, Feigenbaum A, Silver MM, et al. Bone marrow involvement and obstructive jaundice in Farber lipogranulomatosis: clinical and autopsy report of a new case. J Inherit Metab Dis 1996;19:655–660. Pagani F, Pariyarath R, Garcia R, et al. New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease. J Lipid Res 1998;39:1382–1388. Schmidt B, Selmer T, Ingendoh A, et al. A novel amino acid modification in sulfatases that is defective in multiple sulfatase deficiency.

Cell 1995;82:271–278.

Tylki-Szymanska AT, Czartoryska B, Lugowska A. Practical suggestions in diagnosing etachromatic leukodystrophy in probands and in testing family members. Eur Neurol 1998;40:67–70. van Heijst AF, Verrips A, Wevers RA, et al. Treatment and follow-up of children with cerebrotendinous xanthomatosis. Eur J Pediatr 1998;157:31–36. Wenger DA, Rafi MA, Luzi P. Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications [Review]. Hum Mutat 1997;10:268–279. Mucopolysaccharidoses and Mucolipidoses Alkhayat AH, Kraemer SA, Leipprandt JR, et al. Human beta-mannosidase cDNA characterization and first identification of a mutation associated with human beta-mannosidosis. Hum Mol Genet 1998;7:75–83. Beck M, Barone R, Hoffmann R, et al. Inter and intrafamilial variability in mucolipidosis II (I-cell disease). Clin Genet 1995;47:191–199. Chen CS, Bach G, Pagano RE. Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease. Proc Natl Acad Sci USA 1998;95:637–638. Leppanen P, Isosomppi J, Schleutker J, et al. A physical map of the 6q14q15 region harboring the locus for the lysosomal membrane sialic acid transport defect (Salla disease and infantile free sialic acid storage disease). Genomics 1996;37:62–67. Nilssen O, Berg T, Riise HM, et al. Alpha-mannosidosis: functional cloning of the lysosomal alpha-mannosidase cDNA and identification of a mutation in two affected siblings. Hum Mol Genet 1997;6:717–726. Peltola M, Tikkanen R, Peltonen L, et al. Ser72Pro active-site disease mutation in human lysosomal aspartylglucosaminidase: abnormal intracellular processing and evidence for extracellular activation. Hum Mol Genet 1996;5:737–743. Pshezhetsky AV, Richard C, Michaud L, et al. Cloning, expression and chromosomal mapping of human lysosomal sialidase and characterization of mutations in sialidosis. Nat Genet 1997;15:316–320. Richard C, Tranchemontagne J, Elsliger MA, et al. Molecular pathology of galactosialidosis in a patient affected with two new frameshift mutations in the cathepsin A/protective protein gene. Mutat 1998;11:461–469. Umehara F, Matsumoto W, Kuriyama M, et al. Mucolipidosis III (pseudo-Hurler polydystrophy); clinical studies in aged patients in one family. J Neurol Sci 1997;146:167–172. Wraith JE. The mucopolysaccharidoses: a clinical review and guide to management [Review]. Arch Dis Child 1995;72:26–37.

Hum

CHAPTER 84. DISORDERS OF CARBOHYDRATE METABOLISM MERRITT’S NEUROLOGY

CHAPTER 84. DISORDERS OF CARBOHYDRATE METABOLISM SALVATORE DIMAURO Glycogen Storage Diseases Lafora Disease and Other Polyglucosan Storage Diseases Suggested Readings

GLYCOGEN STORAGE DISEASES Abnormal metabolism of glycogen and glucose may occur in a series of genetically determined disorders, each representing a specific enzyme deficiency ( Table 84.1). The signs and symptoms of each disease are largely determined by the tissues in which the enzyme defect is expressed. Virtually all enzymes of glycogen metabolism, including tissue-specific isoforms or subunits, have been assigned to chromosomal loci and the corresponding genes have been cloned and sequenced. Numerous mutations have been identified and a genotype-phenotype correlation is taking shape. The disorders affecting the neuromuscular system primarily are discussed in Section XVIII.

TABLE 84.1. CLASSIFICATION OF GLYCOGEN STORAGE DISEASE

Severe fasting hypoglycemia may result in periodic episodes of lethargy, coma, convulsions, and anoxic brain damage in glucose-6-phosphatase deficiency (glycogenosis type I) or in glycogen synthetase deficiency. The liver is enlarged in both diseases. Clinical manifestations tend to become milder in patients who survive the first few years of life. The nervous system is directly affected by the enzyme defect in generalized glycogen storage diseases, even though neurologic symptoms are lacking in some disorders and in others may be ascribed to liver rather than to brain dysfunction. The following enzyme defects seem to be generalized: acid maltase (type II), debrancher (type III), brancher (type IV), and phosphoglycerate kinase (type IX). In the infantile form of acid maltase deficiency (Pompe disease), pathologic involvement of the central nervous system (CNS) has been documented, with accumulation of both free and intralysosomal glycogen in all cells, especially spinal motor neurons and neurons of the brainstem nuclei. Peripheral nerve biopsy specimens show accumulation of glycogen in Schwann cells. The profound generalized weakness of infants with Pompe disease is probably due to combined effects of glycogen storage in muscle, anterior horn cells, and peripheral nerves. In the childhood form of acid maltase deficiency, increased glycogen deposition was seen in two children (one of whom was mentally retarded) but not in two other patients. No morphologic changes were seen in the CNS of a patient with adult-onset acid maltase deficiency despite marked decrease of enzyme activity. Patients with debrancher deficiency (glycogenosis type III) have hepatomegaly, fasting hypoglycemia, and seizures in infancy and childhood, which usually remit around puberty. Although overt signs of peripheral neuropathy are rare, abnormal deposits of glycogen have been documented both in axons and in Schwann cells and may explain, in part at least, the distal wasting and mixed electromyographic pattern observed in adult patients with neuromuscular involvement. In branching enzyme deficiency (glycogenosis type IV), the clinical picture is dominated by liver disease, with progressive cirrhosis and chronic hepatic failure causing death in childhood. Deposits of a basophilic intensely periodic acid-Schiff (PAS)-positive material that is partially resistant to b-amylase digestion have been found in all tissues; in the CNS, spheroids composed of branched filaments were present in astrocytic processes, particularly in the spinal cord and medulla. Ultrastructurally, the storage material was composed of aggregates of branched osmiophilic filaments, 6 nm in diameter, often surrounded by normal glycogen particles. In phosphoglycerate kinase (PGK) deficiency (glycogenosis type IX), type and severity of clinical manifestations vary in different genetic variants of the disease and are probably related to the severity of the enzyme defect in different tissues. In several families, the clinical picture was characterized by the association of severe hemolytic anemia with mental retardation and seizures.

LAFORA DISEASE AND OTHER POLYGLUCOSAN STORAGE DISEASES Myoclonus epilepsy with Lafora bodies (Lafora disease) is a hereditary neurologic disease transmitted as an autosomal recessive trait and affects both sexes equally. Clinically, the disease is characterized by the triad of epilepsy, myoclonus, and dementia. Inconstant other neurologic manifestations include ataxia, dysarthria, spasticity, and rigidity. Onset is in adolescence, and the course progresses rapidly to death, which in 90% of patients occurs between 17 and 24 years of age. Negative criteria or manifestations that imply some other disease include onset before 6 or after age 20, optic atrophy, macular degeneration, prolonged course, or normal intelligence. Epilepsy, with generalized seizures, is the first manifestation in most patients; status epilepticus is common in terminal stages. Myoclonus usually appears 2 or 3 years after the onset of epilepsy, may affect any area of the body, is sensitive to startle, and is absent during sleep. Intellectual deterioration generally follows the appearance of seizures by 2 or 3 years and progresses rapidly to severe dementia. Therapy is symptomatic and is designed to suppress seizures and reduce the severity of myoclonus; some control of myoclonus is achieved with benzodiazepines. Laboratory findings are normal except for electroencephalographic changes; bilaterally synchronous discharges of wave-and-spike formations are commonly seen in association with myoclonic jerks. Electroencephalographic abnormalities may be found in asymptomatic relatives. The pathologic hallmark of the disease is the presence in the CNS of the bodies first described by Lafora in 1911: round, basophilic, strongly PAS-positive intracellular inclusions that vary in size from “dustlike” bodies less than 3 nm in diameter to large bodies up to 30 nm in diameter. The medium and large bodies often show a dense core and a lighter periphery. Lafora bodies are seen only in neuronal perikarya and processe and are most numerous in cerebral cortex, substantia nigra, thalamus, globus pallidus, and dentate nucleus. Ultrastructurally, Lafora bodies are not limited by a membrane. They consist of two components in various proportions: amorphous electron-dense granules and irregular filaments. The filaments, which are about 6 nm in diameter, are often branched and frequently continuous with the granular material. Irregular accumulations of a material similar to that of the Lafora bodies are found in liver, heart, skeletal muscle, skin, and retina, suggesting that Lafora disease is a generalized storage disease. Both histochemical and biochemical criteria indicate that the storage material is a branched polysaccharide composed of glucose (polyglucosan) similar to the amylopectin-like polysaccharide that accumulates in branching enzyme deficiency. The activity of branching enzyme, however, was normal in several tissues, including brain, of patients with Lafora disease. Linkage analysis in nine families has localized the gene responsible for Lafora's disease to chromosome 6q, and by positional cloning, the gene product has been identified as a tyrosine phosphatase. Six mutations have been found in the nine families. A clinically distinct form of polyglucosan body disease ( adult polyglucosan body disease [APBD]) was described in patients with a complex but stereotyped chronic

neurologic disorder characterized by progressive upper and lower motor neuron involvement, sensory loss, sphincter problems, neurogenic bladder, and, in about half of the cases, dementia; there is no myoclonus or epilepsy. Onset is in the fifth or sixth decade of life, and the course ranges from 3 to 20 years. Electrophysiologic studies show axonal neuropathy. In some cases, the clinical picture simulates amyotrophic lateral sclerosis. Throughout the CNS, polyglucosan bodies are present in processes of neurons and astrocytes but not in perikarya. There are also polyglucosan accumulations in peripheral nerve and in other tissues, including liver, heart, skeletal, and smooth muscle. As in debranching enzyme deficiency and Lafora disease, the abnormal polysaccharide in APBD seems to have longer peripheral chains than normal glycogen. Branching enzyme activity was markedly decreased in leukocytes from Israeli patients, and this finding was confirmed in both leukocytes and peripheral nerve specimens from American Ashkenazi Jewish patients, whereas the activity was normal in both tissues from three non-Jewish white patients and from one African-American patient, suggesting genetic heterogeneity. A mutation in the gene encoding the branching enzyme has been found in five Ashkenazi Jewish families with APBD, confirming that APBD is a clinical variant of branching deficiency. Another form of polyglucosan is represented by corpora amylacea, which accumulate progressively and nonspecifically with age. They are more commonly seen within astrocytic processes in the hippocampus and in subpial and subependymal regions; however, they also occur in intramuscular nerves in patients older than 40. SUGGESTED READINGS Bigio EH, Weiner MF, Bonte FJ, White CL. Familial dementia due to adult polyglucosan body disease. Clin Neuropathol 1997;16:227–234. Bruno C, Servidei S, Shanske S, et al. Glycogen branching enzyme deficiency in adult polyglucosan body disease. Ann Neurol 1993;33:88–93. Coleman DL, Gambetti PL, DiMauro S. Muscle in Lafora disease. Arch Neurol 1974;31:396–406. DiMauro S, Servidei S, Tsujino S. Disorders of carbohydrate metabolism: Glycogen storage diseases. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, eds. The molecular and genetic basis of neurological disease. Boston: Butterworth-Heinemann, 1997:1067–1097. DiMauro S, Stern LZ, Mehler M, et al. Adult-onset acid maltase deficiency: a postmortem study. Muscle Nerve 1978;1:27–36. DiMauro S, Tsujino S, Shanske S, Rowland LP. Biochemistry and molecular genetics of human glycogenoses: an overview. Muscle Nerve 1995;3:S10–S17. Felice KJ, Grunnet ML, Rao KR, Wolfson LI. Childhood-onset spinocerebellar syndrome associated with massive polyglucosan body deposition. Acta Neurol Scand 1997;95:60–64. Gambetti PL, DiMauro S, Baker L. Nervous system in Pompe's disease. J Neuropath Exp Neurol 1971;30:412–430. Gambetti PL, DiMauro S, Hirt L, Blume RP. Myoclonic epilepsy with Lafora bodies. Arch Neurol 1971;25:483–493. Lafora GR. Uber das Vorkommen amyloider Korperchen in Innern der Ganglienzellen. Virchows Arch Pathol Anat 1911;205:295–303. Lossos A, Barash V, Soffer D, et al. Hereditary branching enzyme dysfunction in adult polyglucosan body disease: a possible cause in two patients. Ann Neurol 1991;30:655–662. Lossos A, Meiner Z, Barash V, et al. Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329 mutation in the glycogen branching gene. Ann Neurol 1998;44:867–872. McDonald ID, Faust PL, Bruno C, et al. Polyglucosan body disease simulating amyotrophic lateral sclerosis. Neurology 1993;43:785–790. McMaster KR, Powers JM, Hennigar GR, et al. Nervous system involvement in type IV glycogenosis. Arch Pathol Lab Med 1979;103:105–111. Minassian BA, Lee JR, Herbrick J-A, et al. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet 1998;20:171–174. Peress NS, DiMauro S, Roxburgh VA. Adult polysaccharidosis. Arch Neurol 979;36:840–845. Robitaille Y, Carpenter S, Karpati G, DiMauro S. A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes. Brain 1980;103:315–336. Sakai M, Austin J, Witmer F, Trueb L. Studies of corpora amylacea. Arch Neurol 1969;21:526–544. Sakai M, Austin J, Witmer F, Trueb L. Studies in myoclonus epilepsy (Lafora body form). II. Polyglucosans in the systemic deposits of myoclonus epilepsy and in corpora amylacea. Neurology 1970;20:160–176. Serratosa JM, Delgado-Escueta AV, Posada I, et al. The gene for progressive myoclonus epilepsy of the Lafora type maps to chromosome 6q. Hum Mol Genet 1995;4:1657–1663. Spencer-Peet J, Norman ME, Lake BD, et al. Hepatic glycogen storage disease. Q J Med 1971;40:95–114. Tarui S. Glycolytic defects in muscle: aspects of collaboration between basic science and clinical medicine. Muscle Nerve 1995;3:S2–S9. Ugawa Y, Inoue K, Takemura T, Iwamasa T. Accumulation of glycogen in sural nerve axons in adult-onset type III glycogenosis. Ann Neurol 1986;19:294–297.

CHAPTER 85. GLUCOSE TRANSPORTER PROTEIN SYNDROME MERRITT’S NEUROLOGY

CHAPTER 85. GLUCOSE TRANSPORTER PROTEIN SYNDROME DARRYL C. DE VIVO Clinical Syndrome Laboratory Data Molecular Genetics and Pathogenesis Diagnosis Treatment Suggested Readings

CLINICAL SYNDROME In 1991, De Vivo et al. described two children with infantile seizures, delayed motor and behavioral development, acquired microcephaly, ataxia, and hypotonia. Lumbar puncture revealed low cerebrospinal fluid glucose concentrations (hypoglycorrhachia) and low-normal to low cerebrospinal fluid lactate concentrations ( Table 85.1). Since 1991, 26 additional patients have been identified. The dominant clinical features are shown in Table 85.2.

TABLE 85.1. CSF GLUCOSE AND LACTATE VALUES (MEAN + S.E.M)

TABLE 85.2. GLUCOSE TRANSPORTER PROTEIN SYNDROME: CLINICAL FEATURES

Seizures begin in early infancy, and the seizure types vary with age of the patient. In infancy, the dominant seizure types include behavioral arrest, pallor and cyanosis, and eye deviation. The electroencephalographic correlates are focal spikes, commonly originating in the temporal and posterior cerebral quadrants. In childhood, the seizures change in character and typically include astatic seizures, atypical absence seizures, and generalized tonic-clonic seizures. The electroencephalogram shows a generalized spike-wave pattern. The seizures are refractory to antiepileptic drugs but respond promptly and dramatically to a ketogenic diet.

LABORATORY DATA Diagnosis requires awareness of the clinical manifestations and documentation of hypoglycorrhachia. A low or low-normal cerebrospinal fluid lactate concentration strengthens the presumptive diagnosis. Glucose uptake rates in vitro by intact washed erythrocytes are decreased by approximately 50% in patients. DNA studies may be diagnostic in 10% to 15% of cases.

MOLECULAR GENETICS AND PATHOGENESIS D-Glucose is the obligate fuel for brain metabolism under virtually all circumstances. With acute or chronic fasting, the brain adapts metabolically to use ketone bodies

(b-hydroxybutyrate and acetoacetate) in partial lieu of glucose. However, glucose is necessary as a permissive substrate for brain ketone body utilization under these extreme physiologic conditions. The transport of D-glucose across the blood–brain barrier and into brain cells is selectively mediated by a sodium-independent facilitative mechanism. The protein that facilitates glucose transport across these tissue barriers is glucose transporter-1 (GLUT-1), a member of a multigene family of protein transporters that facilitate the diffusion of sugar molecules across tissue barriers. GLUT-1 is present in high abundance in brain capillaries, astroglial cells, and erythrocyte membranes. The molecular basis of the syndrome is haploinsufficiency of the GLUT-1 protein. Haploinsufficiency has been determined in 18 patients by Wang and De Vivo (unpublished data). Three patients are hemizygous as determined by a positive fluorescent in situ hybridization study. The other 15 patients are heterozygous for nonsense mutations, missense mutations, frameshift mutations, or splice site mutations. These mutations are distributed throughout the gene, and each mutation is unique for the patient. The GLUT-1 cDNA is highly conserved across species, with 97% homology among humans, rats, mice, and rabbits. The highly conserved nature of the gene increases the likelihood of pathogenicity related to small-scale rearrangements. The GLUT-1 protein is responsible for the transport of glucose across both luminal and abluminal sides of the brain capillary endothelial cell and across the astroglial plasma membrane. GLUT-1 haploinsufficiency may cause a severe decrease in the concentration of glucose in the brain interstitial space and in the astroglial cell. This syndrome is the first genetically determined defect involving the blood–brain barrier, but it was not familial in any of the first 24 patients studied. One German family transmitted the disease through three successive generations as an autosomal dominant trait. The molecular basis has not yet been determined.

DIAGNOSIS The differential diagnosis includes cerebral palsy, Rett syndrome, hypoglycemia, infantile ataxia, and mitochondrial diseases. Seizures have been present in all cases, but this observation may represent an ascertainment bias. A lumbar puncture for measurement of glucose and lactate is a critical test in establishing the diagnosis.

TREATMENT Treatment is the ketogenic diet, which effectively controls the seizures but is less effective in improving cognition and behavior. Antiepileptic drugs have been uniformly ineffective. Thioctic acid may facilitate glucose transport and has been recommended as adjunctive therapy. SUGGESTED READINGS Bell IG, Burant CF, Takeda J, Gould GW. Structure and function of mammalian facilitative sugar transporters. J Biol Chem 1993;268:19161–19164. De Vivo DC, Garcia-Alvarez M, Roonen G, Trifiletti R. Glucose transport protein deficiency. An emerging syndrome with therapeutic implications. Int Pediatr 1995;10:51–56. De Vivo DC, Garcia-Alvarez M, Tritschler HJ. Deficiency of glucose transporter protein type I: possible therapeutic role for alpha-lipoic acid (thioctic acid).

Diabetes Stoffwech 1996;5:36–40.

De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991;325:703–709. Pardridge WM, Boado RJ, Farrell CR. Brain-type glucose transporter (Glut-1) is selectively localized to the blood-brain barrier. J Biol Chem 1990;265:18035–18040. Seidner G, Garcia-Alvarez M, Jeh J-I, et al. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 1998;18:188–191. Vannucci SJ, Maher F, Simpson IA. Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia 1997;21:2–21.

CHAPTER 86. HYPERAMMONEMIA MERRITT’S NEUROLOGY

CHAPTER 86. HYPERAMMONEMIA ROSARIO R. TRIFILETTI AND DOUGLAS R. NORDLI JR. Hyperammonemia in the Neonatal Period Older Children and Adults Suggested Readings

Hyperammonemia, an elevation in blood ammonia levels, has many causes ( Table 86.1). The hepatic urea cycle is the major mammalian system for the detoxification of ammonia (Fig. 86.1), and defects have been described in all six urea cycle enzymes. An additional pathway from arginine to citrulline generates the putative second messenger and neurotransmitter, nitric oxide, catalyzed by nitric oxide synthetase. The enzyme is found in many tissues, including brain. The significance of this pathway is not yet clear, but it may be perturbed in urea cycle disorders.

TABLE 86.1. MAJOR CAUSES OF HYPERAMMONEMIA

FIG. 86.1. The urea cycle.

The differential diagnosis of hyperammonemia differs considerably according to the age of the patient ( Table 86.1).

HYPERAMMONEMIA IN THE NEONATAL PERIOD Transient hyperammonemia of the newborn is occasionally seen in otherwise well premature infants and is attributed to metabolic immaturity, analagous to physiologic hyperbilirubinemia of the newborn. Transient hyperammonemia of the newborn is mild and reversible and rarely requires treatment. Hyperammonemia also may result from liver damage associated with birth asphyxia or congenital hepatic disease; the birth history may help to establish the diagnosis. The ill newborn child with hyperammonemia (especially marked hyperammonemia) without other explanation often has an inborn error of metabolism that, directly or indirectly, affects the urea cycle. The newborn infant with marked hyperammonemia, whatever the cause, has a constellation of symptoms, including progressive lethargy, vomiting, poor feeding, apneic episodes, and seizures. These symptoms are not specific for hyperammonemia, and other possible explanations should also be considered, for instance, sepsis. The age at onset of these symptoms is a useful differential diagnostic point. Infants with hyperammonemia due to urea cycle enzymopathies or organic acidurias typically are well for the first 24 hours of life but become symptomatic after 24 to 72 hours of protein feeding. In contrast, infants with hyperammonemia secondary to impaired pyruvate metabolism are symptomatic within the first 24 hours. Pyruvate dehydrogenase and (type B) pyruvate carboxylase deficiencies feature lactic acidosis, and these diagnoses can be confirmed by assay of enzyme activities in fibroblasts. Organic acidurias usually (but not invariably) lead to ketoacidosis, which distinguishes them from urea cycle enzymopathies. Specific diagnosis of organic acidurias requires study of the urine organic acid profile, usually by gas-liquid chromatography. Lack of any one of the urea cycle enzymes listed in Figure 86.1, other than arginase, causes similar clinical syndromes. The affected child is well for the first 24 hours of life, but signs of hyperammonemia appear as protein feedings continue. There is no lactic acidosis or ketoacidosis, but there may be respiratory alkalosis with hyperventilation. Measurement of plasma citrulline and urinary orotic acid levels is most helpful in rapid determination of the site of block ( Table 86.2). Confirmatory enzyme assays may then be performed; ornithine carbamyl transferase and carbamyl phosphate synthase activities can be measured only in liver, but other enzymes can be assayed in fibroblasts. All these enzymopathies are autosomal recessive diseases except for ornithine carbamyl transferase deficiency, which is X-linked. Prenatal screening is available for some of these disorders.

TABLE 86.2. PLASMA AMINO ACID AND URINARY OROTIC ACID FINDINGS IN UREA CYCLE DEFECTS

Management of Neonatal Hyperammonemia It is not known how elevated ammonia levels damage the brain, but the outcome is worse the higher the ammonia level and the longer the exposure to elevated blood ammonia levels. For this reason, acute hyperammonemic coma in the newborn is a medical emergency, and rapid reduction in ammonia levels is necessary. Peritoneal dialysis is more effective than exchange transfusion; hemodialysis may also be effective. Useful adjuncts include intravenous administration of sodium benzoate (250 mg/kg body weight), followed by a constant infusion of 250 to 500 mg/kg body weight every 24 hours. The rationale for benzoate therapy is outlined in Figure 86.1. An important metabolic consequence of a block in the urea cycle (other than at arginase) is that arginine is rendered an essential amino acid. Therefore, patients with hyperammonemia due to urea cycle enzymopathies should be given supplemental arginine. A loading dose of 0.8 mg/kg body weight of arginine hydrochloride is administered as a loading dose, followed by 0.2 mg/kg/day ( N-acetyl-glutamate synthetase, carbamyl phosphate synthetase, or ornithine transcarbamoylase [OTC] deficiencies) or 0.8 mg/kg/day (argininosuccinate synthetase or argininosuccinate lyase deficiencies). Protein catabolism should be minimized by temporarily deleting protein from the diet and by ensuring adequate caloric intake. Long-term management depends on the specific cause of the disorder.

OLDER CHILDREN AND ADULTS As compared with the newborn, primary metabolic disease is much less likely a cause of hyperammonemia in an older child or adult. Incomplete urea cycle defects (as seen in female OTC-deficiency heterozygotes) may cause episodic hyperammonemia during periods of metabolic stress and should be considered, especially if there are affected relatives. Dibasic amino acidurias and primary systemic carnitine deficiency ( Table 86.1) are rare. More likely, the older child or adult with hyperammonemia has severe liver disease or drug-induced hyperammonemia. Valproate-associated Hyperammonemia Valproate therapy is one of the most common causes of hyperammonemia in clinical neurologic practice. This silent dose-related side effect may occur without hepatic dysfunction. The pathogenesis is obscure but may involve increased renal production of ammonia and decreased function of carbamyl phosphate synthetase. Inhibition of this enzyme may be a direct effect of the drug or may be related to reduced amounts of N-acetylglutamate because valproate depresses fatty acid metabolism. It is unclear whether patients sometimes become symptomatic from the increased ammonia under these circumstances. Lethargy may be associated with elevated ammonia values, but the encephalopathy may be due to other substances, including known toxic metabolites of valproate or other organic acids. Laboratory studies suggest that L-carnitine supplementation can prevent the development of hyperammonemia in animals receiving valproate and in cultured rat hepatocytes. Supplementation with carnitine also reduces the elevated levels of ammonia in patients treated with valproate. The clinical significance of this reduction is unclear. Some authorities routinely measure serum carnitine levels in patients with marked hyperammonemia. If there is evidence of carnitine deficiency, the patient is given supplementary L-carnitine. SUGGESTED READINGS Batshaw ML. Hyperammonemia. Curr Probl Pediatr 1984;14:1–69. Batshaw ML, Brusilow SW. Asymptomatic hyperammonemia in low birth weight infants. Pediatr Res 1978;12:221–224. Batshaw ML, Brusilow SW. Valproate-induced hyperammonemia. Ann Neurol 1982;11:319–321. Brusilow SW, Batshaw ML, Waber L. Neonatal hyperammonemic coma. Adv Pediatr 1982;29:69–103. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CS, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited disease, 7th ed. New York: McGraw-Hill, 1995:1187–1232. Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996;43:127–170. Dawson TD, Dawson VL, Snyder SH. A novel neuronal messenger molecule in the brain: the free radical, nitric oxide. Ann Neurol 1992;32:297–311. De Vivo DC, Bohan TP, Coulter DL, et al. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998;39:1216–1225. Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehyrogenase gene. N Engl J Med 1998;338:1352–1357.

CHAPTER 87. PEROXISOMAL DISEASES: ADRENOLEUKODYSTROPHY, ZELLWEGER SYNDROME, AND REFSUM DISEASE MERRITT’S NEUROLOGY

CHAPTER 87. PEROXISOMAL DISEASES: ADRENOLEUKODYSTROPHY, ZELLWEGER SYNDROME, AND REFSUM DISEASE MIA MACCOLLIN AND DARRYL C. DE VIVO Zellweger Syndrome Adrenoleukodystrophy (MIM 300100) Refsum Disease (MIM-266510) Suggested Readings

Peroxisomes are ubiquitous cellular organelles that participate in a variety of essential biochemical functions. Peroxisomes are contained by a single membrane and contain no DNA, implying that all peroxisomal-associated proteins are encoded by nuclear genes. A complex shuttle system transports peroxisomal enzymes and structural proteins from the cytosolic polyribosomes where they are made to the peroxisome. This system involves at least two recognition sequences (peroxisomal targeting sequences) that are embedded in the protein products themselves and several receptors or transporters; the system is ATP-dependent. Peroxisomes participate in both anabolic and catabolic cellular functions, especially in the metabolism of lipids. For example, peroxisomes contain a complete series of enzymes for the beta oxidation of fatty acids. These enzymes are distinct from the mitochondrial enzymes of beta oxidation in both genetic coding and substrate specificity. Because mitochondrial enzymes of beta oxidation cannot metabolize carbon chain lengths greater than 24, the peroxisomal system is required for the degradation of endogenous and exogenous very-long-chain fatty acids (VLCFA). The peroxisome is also the site of the initial and rate-limiting steps of the synthesis of plasmalogens, ether-linked lipids that constitute the major portion of the myelin sheath. Other key functions include cholesterol and bile acid biosynthesis, degradation of pipecolic and phytanic acids, and transamination of glyoxalate. Human diseases caused by disruption of peroxisome function are divided into two broad categories ( Table 87.1). The first is characterized by abnormalities in more than one metabolic pathway, often accompanied by morphologic changes of the peroxisome. The prototype of this class is Zellweger syndrome discussed below, although patients with milder phenotypes have been described under various names such as neonatal adrenoleukodystrophy, infantile Refsum disease, and hyperpipecolic acidemia. This overlapping range of phenotypes is referred to as the Zellweger spectrum. A second phenotype, distinct from the Zellweger spectrum and termed rhizomelic chondrodysplasia punctata (RCDP), is associated with severe growth failure, profound developmental delay, cataracts, rhizomelia, epiphyseal calcifications, and ichthyosis. Patients with RCDP have decreased plasmalogens and elevated phytanic acid, but unlike the Zellweger spectrum patients, the beta oxidation pathway and VLCFA levels are normal. In recognition of the similar cellular pathophysiology in these phenotypes, peroxisome biogenesis disorder (PBD) is now the preferred term for all Zellweger spectrum and RCDP conditions.

TABLE 87.1. HUMAN GENETIC DISEASES DUE TO PEROXISOMAL DYSFUNCTION

The second class of human peroxisomal diseases shows the genetic and biochemical features of single enzyme defects. In addition to X-linked adrenoleukodystrophy (ALD) and Refsum disease discussed below, this category includes defects in the beta oxidation pathway of VLCFA, which cause a Zellweger-like phenotype, and defects in plasmalogen synthesis, which result in an RCDP-like phenotype.

ZELLWEGER SYNDROME The Zellweger syndrome (cerebrohepatorenal syndrome) is an autosomal recessive disease with no ethnic or racial predilection. Affected newborns are strikingly floppy and inactive; they lack the Moro, stepping, and placing reflexes. The characteristic facial appearance includes a high narrow forehead, round cheeks, flat root of the nose, wide-set eyes with shallow orbits, puffy eyelids, pursed lips, narrow high-arched palate, and small chin. The head circumference is normal, but the fontanels and sutures are widely open. Ophthalmologic findings include pigmentary retinopathy, retinal arteriolar attenuation, and optic atrophy. The pinnas may be abnormal and posteriorly rotated. Affected infants suck and swallow poorly and often require tube feeding. Some have congenital heart disease, notably patent ductus arteriosus or septal defects. The liver is cirrhotic and either enlarged or shrunken; some children are jaundiced, and some develop splenomegaly and a bleeding diathesis. Cystic dysplasia of the kidneys may be palpable and may cause mild renal failure. Genital anomalies include an enlarged clitoris, hypospadias, and cryptorchidism. Minor skeletal anomalies include contractures of large and small joints, polydactyly, low-set rotated thumbs, and clubfeet; there are also stippled calcifications of the patella and epiphyseal cartilage. The children are apathetic, poorly responsive to environmental stimuli, and limp. Tendon reflexes are absent or hypoactive. Many children have seizures and fail to thrive or develop; most succumb within the first few months of life. Typical but nonspecific laboratory findings include elevated bilirubin levels, abnormal liver function tests, elevated serum iron, saturated iron binding capacity, and transferrin. The cerebrospinal fluid (CSF) protein content may be elevated. The electroencephalogram is abnormal, and magnetic resonance imaging (MRI) shows poor myelination, brain atrophy, pachygyria, polymicrogyria, and neuronal heterotopias. The hallmark of Zellweger syndrome is dysfunction in multiple enzymatic pathways, including the following: 1. 2. 3. 4.

Levels of VLCFA—those with 24 or more carbons—are increased in plasma, fibroblasts, and chorionic villus; In plasma and urine, increased content of intermediates of bile acid metabolism includes trihydroxycholestanoic acid and dihydroxycholestanoic acid; Levels of pipecolic and phytanic acids increase; Plasmalogen levels decrease.

In addition, levels of cholesterol and the fat-soluble vitamins may be low. PBD patients, including those with Zellweger syndrome, can be divided into at least 11 complementation groups, based on the ability of their cells to reconstitute peroxisomal structure and function in fusion experiments. These groups do not correspond to the clinical phenotypes but rather to the underlying molecular defect ( Table 87.2).

TABLE 87.2. MOLECULAR BASIS OF PEROXISOMAL BIOGENESIS DISORDERS (PBD)

Pathologically, the absence of functional peroxisomes in hepatocytes is a pathognomonic feature of Zellweger syndrome and one that helps distinguish it from other PBDs and from single enzyme disorders such as pseudo-Zellweger disease. Membrane proteins may assemble with membrane lipids to form rudimentary “ghosts� of peroxisomes that seem unable to import enzymes. For reasons not well understood, secondary abnormalities are seen in mitochondria that show an abnormally dense matrix and distorted cristae. Lipid leaflets resembling those in adrenoleukodystrophy are found in several tissues, including the adrenal gland. The brain is dysgenic, with signs of disordered cell migration resulting in areas of pachygyria or micropolygyria and neuronal ectopias. The inferior olive is grossly disorganized. Myelination is severely affected. Neutral fat accumulates in fibrous astrocytes, hepatocytes, renal tubules and glomeruli, and muscle. Therapy for Zellweger syndrome is primarily supportive and limited because of the multisystem impairment already present at birth. Therapeutic trials of the polyunsaturated fatty acid docohexaenate have shown some success in improving visual function of mildly affected patients. Other potential therapies, including the peroxisomal proliferator clofibrate and bile acids, are of less clear benefit. Reliable prenatal diagnosis is available by enzymatic assays in chorionic villus or amniotic fluid cells.

ADRENOLEUKODYSTROPHY (MIM 300100) ALD is an X-linked incompletely recessive disorder with variable expressivity; it is well defined genetically, clinically, and pathologically. The most common phenotype is the childhood cerebral form, which appears in boys who have normal early development. Behavioral change is the most common initial feature, with abnormal withdrawal, aggression, poor memory, or difficulties in school. Ultimately, progressive dementia is evident. Visual loss with optic atrophy is a consistent feature due to demyelination along the entire visual pathway. The outer retina is notably spared. Progressive gait disturbance with pyramidal tract signs is an important feature. Dysphagia and deafness may occur. Seizures are common late in the disease but are occasionally the first manifestation. Some patients have overt signs of adrenal failure, including fatigue, vomiting, salt craving, and hyperpigmentation that is most prominent in skin folds. The course is relentlessly progressive. Patients enter a vegetative state and die from adrenal crisis or other causes 1 to 10 years after onset. Several other clinical phenotypes have been described ( Table 87.3). Adrenomyeloneuropathy (AMN) is the most common of the variant phenotypes. Typical features are spastic paraparesis, peripheral neuropathy, and adrenal insufficiency, beginning in the second decade. Hypogonadism, impotence, and sphincter disturbance are also seen. Cerebellar dysfunction and dementia have been reported. A similar syndrome is found in about 15% of women who are heterozygous for mutation at the ALD gene. MRI frequently reveals cortical demyelinating lesions in AMN patients, even in those without signs or symptoms of cortical involvement. Pathologic findings in AMN include demyelination and dying-back changes in the cord and lamellar cytoplasmic inclusions in brain, adrenal, and testis; the findings are similar to those of ALD.

TABLE 87.3. PHENOTYPES ASSOCIATED WITH MUTATION AT THE ALD LOCUS

A cerebral form of ALD is occasionally seen that is similar to the childhood form, but starts in adolescence. In adults, X-linked ALD may show symptoms of dementia, schizophrenia, or focal cerebral syndromes such as aphasia, Kluver-Bucy syndrome, or hemianopia; usually there is also evidence of adrenal insufficiency. Adult ALD includes spastic paraparesis, cerebellar dysfunction, or olivopontocerebellar atrophy. Female heterozygotes may become symptomatic with adult ALD. Adrenal insufficiency can be seen without neurologic disorder; ALD should be considered in any boy with unexplained Addison disease. Finally, children and adults with the biochemical defect may be asymptomatic or presymptomatic. Phenotypic heterogeneity is the rule within families with multiple affected individuals; the disparate manifestations are probably the result of modifying genetic loci or environmental factors. Laboratory evaluation of the patient with ALD reveals several abnormalities. The CSF protein content is often elevated. Computed tomography shows characteristic hyperdense and hypodense bandlike regions in parietooccipital white matter; if found, these are virtually diagnostic of ALD. MRI abnormalities are more diffuse and always predate clinical findings. Adrenal function tests, especially the corticotropin stimulation test, usually show adrenal insufficiency even in the absence of clinical signs. In the zona fasciculata and reticularis, adrenal biopsy shows many ballooned cortical cells and striated cytoplasm and microvacuoles, findings specific for ALD. Characteristic inclusions, accumulations of lamellar lipid profiles, may also be seen in the brain, sural nerve biopsy, or testis. The primary finding in the brain is extensive diffuse demyelination, sparing U-fibers in the centrum semiovale and elsewhere. In involved areas of white matter, perivascular infiltration of lymphocytes and plasma cells is prominent. Diagnosis is suggested by the characteristic clinical findings of neurologic deterioration, demonstration of adrenal hypofunction, and MRI abnormalities. Definite diagnosis is made by finding elevated VLCFA levels in plasma and cultured skin fibroblasts without disruption of other peroxisomal functions. To date, elevated VLCFA levels in both tissues have been found only in patients with ALD, PBDs, and single enzyme defects involving the VLCFA oxidation pathway. Unlike ALD patients, patients on the ketogenic diet may show elevated VLCFA levels in plasma but not cultured skin fibroblasts. Prenatal diagnosis of ALD is made by assay of VLCFA oxidation in amniotic fluid cells or chorionic villus sampling. Eighty-five percent of female carriers of ALD have elevated VLCFA levels in plasma and cultured skin fibroblasts. The ALD gene has been cloned and encodes a member of the ATP binding cassette transporter class of proteins. Mutations at this locus have proven to be mostly private, limiting the usefulness of molecular analysis for diagnosis. Several approaches have been taken to the rational treatment of ALD. Steroid replacement therapy is given during stressful periods, such as intercurrent illness, or if there is evidence of adrenal insufficiency. Dietary avoidance of VLCFA alone does not lead to biochemical change because of endogenous synthesis. Efforts to lower endogenous synthesis using glycerol trierucate oil and glycerol trioleate oil (Lorenzo oil) in conjunction with dietary restriction do produce a fall in VLCFA levels in both affected individuals and female carriers. Unfortunately, this striking biochemical change does not have an equally striking clinical correlate; its use is most likely

limited to presymptomatic boys. Bone marrow transplantation cures the biochemical defect in ALD, but the morbidity and mortality are high, and neither neurologic defects nor radiologic abnormalities revert. In all cases, radiologic abnormalities and progression almost invariably precede neurologic progression; it is therfore imperative that every child whose family might consider bone marrow transplantation is closely followed radiographically. Immunotherapy has been considered in X-ALD because of the inflammatory component of the central lesions, but beta interferon and thalidomide have not been effective. Finally, the cloning and characterization of the ALD locus may lead to a gene or protein product replacement therapy.

REFSUM DISEASE (MIM-266510) This autosomal recessive disease (also known as heredopathia atactica polyneuritiformis) is unique among the lipidoses because the stored lipid (phytanic acid) is not synthesized in the body but is exclusively dietary in origin. This has enabled successful therapy by dietary management. Symptoms begin in early childhood in some patients but may be delayed until the fifth decade in others. Progressive night blindness usually appears in the first or second decade, followed by limb weakness and gait ataxia. Symptoms are progressive, but abrupt exacerbations and gradual remissions may occur with intercurrent illness or pregnancy. There are no seizures, but some patients have psychiatric symptoms. Peripheral neuropathy is manifest by loss of tendon reflexes, weakness and wasting, and distal sensory loss. Ataxia may be seen. A granular pigmentary retinopathy is universally present. Other findings include ichthyosis, nerve deafness (often severe), cataracts, miosis and pupillary asymmetry, pes cavus, and bone deformities with shortening of the metatarsal bones, epiphyseal dysplasia, and, in some, kyphoscoliosis. CSF protein content is elevated. Nerve conduction velocities are slowed. Electrocardiographic changes may be seen, including conduction abnormalities. Peripheral nerves may feel thickened and, on histologic study, may show hypertrophic interstitial changes and onion-bulb formation. The course is generally progressive with exacerbations and remissions. Peripheral visual fields may ultimately be lost, with resulting telescopic vision. Sudden death may result from cardiac arrhythmia. The biochemical defect in Refsum disease has been identified as phytanoyl-coenzyme A hydroxylase deficiency; the responsible gene has been cloned. Diagnosis is made by the characteristic clinical picture and elevation of phytanic acid levels in the plasma. Therapy limits dietary phytanic acid and its precursor, phytol. When dairy products, ruminant fat, and chlorophyll-containing foods are eliminated, plasma phytanic acid levels are reduced and tissue stores are mobilized, with improvement of symptoms. Paradoxically, symptoms may worsen and plasma phytanic acid levels may rise shortly after institution of dietary therapy, especially if patients reduce caloric intake and lose weight. Increased plasma phytanic acid causes anorexia, increased weight loss, and still more severe symptoms. Adequate caloric intake helps prevent weight loss and abrupt fat mobilization. Plasmapheresis helps to prevent or treat exacerbations. SUGGESTED READINGS Peroxisomal Biogenesis and Biochemistry Waterham H, Cregg J. Peroxisome biogenesis. BioEssays 1997;19:57–66. Peroxisomal Biogenesis Disorders Braverman N, Dodt G, Gould S, Valle D. Disorders of peroxisome biogenesis. Human Mol Genet 1996;4:1791–1798. Martinez M, Vazquez E. MRI evidence that docosahexaenoic acid ethyl ester improves myelination in generalized peroxisomal disorders. Neurology 1998;51:26–32. Moser A, Rasmussen M, Naidu S, et al. Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr 1995;127:13–22. Reuber B, Germain-Lee E, Collins C, et al. Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders. Nat Genet 1997;17:445–452. Santos MJ, Imanaka T, Shio H, et al. Peroxisomal membrane ghosts in Zellweger syndrome—aberrant organelle assembly. Science 1988; 239:1536–1538. Setchell K, Bragetti P, Zimmer-Nechemias L, et al. Oral bile acid treatment and the patient with Zellweger syndrome. Hepatology 1992;15:198–207. Volpe JJ, Adams RD. Cerebro-hepato-renal syndrome of Zellweger: an inherited disorder of neuronal migration. Acta Neuropathol (Berl) 1972;20:175–198. Adrenoleukodystrophy Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, et al. A two-year trial of oleic and erucic acids (“Lorenzo's oil”) as treatment for adrenomyeloneuropathy. N Engl J Med 1993;329:745–752. Aubourg P, Blanche S, Jambaque I, et al. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 1990;322:1860–1866. Bezman L, Moser H. Incidence of X-linked adrenoleukodystrophy and the relative frequency of its phenotypes. Am J Med Genet 1998;76:415–419. Mosser J, Douar A, Sarde C, et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 1993;361:726–730. Panegyres P, Goldswain P, Kakulas B. Adult-onset adrenoleukodystrophy manifesting as dementia. Am J Med 1989;87:481–482. Sadeghi-Nejad A, Senior B. Adrenomyeloneuropathy presenting as Addison's disease in childhood. N Engl J Med 1990;322:13–16. Shapiro E, Aubourg P, Lockman L et al. Bone marrow transplant for adrenoleukodystrophy: 5 year follow-up of 12 engrafted cases. Ann Neurol 1997;42:498. Refsum Disease Djupesland G, Flottorp G, Refsum S. Phytanic acid storage disease; hearing maintained after 15 years of dietary treatment. Neurology 1983;33: 237–239. Masters-Thomas A, Bailes J, Billimoria J, et al. Heredopathia atactica polyneuritiformis (Refsum's disease). 1. Clinical features and dietary management. J Hum Nutr 1980;34:245–250. Mihalik S, Morrell J, Kim D, et al. Identification of PAHX, a Refsum disease gene. Nat Genet 1997;17:185–189. Refsum S. Heredopathia atactica polyneuritiformis. Acta Psychiatr Scand (suppl) 1946;38:9–303. Other Single Enzyme Defects Schram AW, Goldfischer S, van Roermund CWT, et al. Human peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency. Proc Natl Acad Sci USA 1987;84:2494–2496. Wanders R, Schumacher H, Heikoop H, Schutgens R, Tager J. Human dihydroxyacetonephsphate acyltransferase deficiency: a new peroxisomal disorder. J Inherit Metab Dis 1992;15:389–391. Watkins P, McGuinness M, Raymond G, et al. Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies. Ann Neurol 1995;38:472–477.

CHAPTER 88. ORGANIC ACIDURIAS MERRITT’S NEUROLOGY

CHAPTER 88. ORGANIC ACIDURIAS STEFANO DI DONATO AND GRAZIELLA UZIEL Clinical Manifestations and Diagnosis Neuroimaging Therapy Suggested Readings

The organic acidurias are inborn errors of metabolism that are characterized by abnormal accumulation of one or more organic acids in the urine. Although individually rare, these diseases comprise more than 50 specific disorders and collectively are the most frequent cause of acute encephalopathy in early infancy. They may appear later in life with more complex features of chronic brain disorder, including dystonia, seizures, or myopathy, sometimes with liver and heart pathology. The acute and frequently life-threatening manifestations in the newborn or young infant demand rapid differential diagnosis of the many acute encephalopathies of infancy, such as cerebral infection, hypoxia, space-occupying lesions, and ingestion of drugs or toxins. The issue is urgent because a few organic acidurias can be effectively cured, including multiple carboxylase deficiency responsive to biotin, methylmalonic aciduria responsive to vitamin B 12, and glutaric aciduria type II responsive to riboflavin. Early diagnosis is also important because treatment may prevent acute metabolic attacks and therefore mental retardation, epilepsy, severe brain damage, or death. The most common inherited organic acidurias involve enzymes of two principal biochemical pathways. One is the stepwise degradation of amino acids, including methionine and threonine; the branched-chain amino acids valine, leucine, and isoleucine; tryptophan; and the basic amino acid lysine. The other is the b-oxidation of straight-chain fatty acid. Some of the final degradative pathways are the same in both amino acid and fatty acid catabolism, such as the funneling of flavin adenine dinucleotide-linked reducing equivalents to the respiratory chain through the electron transferring flavoproteins. Lactic acidemia also results in an organic aciduria. Pyruvate dehydrogenase deficiency and respiratory chain defects, however, are the major causes of familial lactic acidosis of infancy, so lactic acidemia is discussed in Chapter 96. In fact, most organic acidurias are mitochondrial disorders, caused by genetic deficiencies of enzymes that catalyze the oxidative degradation of some amino acids and the b-oxidation of straight-chain fatty acids. The organic acidurias that cause acute encephalopathy include multiple carboxylase deficiency, maple syrup urine disease, methylmalonic aciduria, propionic aciduria, isovaleric aciduria, fumaric aciduria, glutaric aciduria types I and II, methylcrotonic aciduria, hydroxymethylglutaric aciduria, dicarboxylic acidurias, and 3-hydroxydicarboxylic aciduria (Table 88.1).

TABLE 88.1. ORGANIC ACIDURIAS

CLINICAL MANIFESTATIONS AND DIAGNOSIS The signs and symptoms of organic acidurias in the newborn or infant are usually nonspecific. Acute episodes of nausea and vomiting, hypotonia, drowsiness, and coma do not discriminate acquired from inherited conditions. The presence of hypoglycemia, however, with glucose blood concentrations less than 2.5 mmol/L or metabolic acidosis with blood pH less than 7.30 and, in some instances, such as in propionic and methylmalonic acidurias, hyperammonemia with plasma ammonia values of 100 mmol/L or more are suggestive of organic acidurias. Acute hypoglycemia, particularly with acidosis, may be fatal. Some infants with these diseases die abruptly without any evident prodromal or accompanying symptoms. Similar features are also part of two relatively common but pathogenetically ill-defined disorders of infancy: Reye hepatic encephalopathy and the sudden infant death syndrome. Both syndromes, currently viewed as nongenetic disorders, have much in common with inherited disorders of fatty acid metabolism because dicarboxylic aciduria has been reported in Reye syndrome and sudden infant death syndrome has been observed in a few patients with b-oxidation defects such as medium-chain acyl-CoA dehydrogenase deficiency. Clinical manifestations seldom discriminate these diseases. The only conclusive way to reach a definite diagnosis is laboratory examination, including the analysis of body fluids for accumulating metabolites and study of the patients' cells for the specific enzymes listed in Table 88.1. Molecular genetic analysis of mutations of the corresponding genes usually follows biochemical diagnosis and is of less importance for early diagnosis. Together with analysis of amniotic fluid and enzyme assay in chorionic villi and amniocytes, however, DNA analysis is useful for prenatal diagnosis. Molecular diagnosis can be a first-choice diagnostic tool in case of prevalent mutations such as the A985G transition in medium-chain acyl-CoA dehydrogenase deficiency. Because most of these acids are effectively cleared from the blood by the kidneys, detection of abundant organic acids in urine is facilitated by gas chromatography mass spectrometry of a 24-hour urine specimen, which generally reveals the pattern of urinary metabolites characteristic of one disease. Some infants with organic aciduria survive the acute metabolic attack but show poor growth, macrocephaly, and impaired psychomotor development. Dystonia, spastic tetraplegia, and intractable seizures may also mark the devastating effects of acidosis, acute energy shortage, and the accumulation of toxic metabolites on the developing brain. A few organic acidurias may not damage the human brain acutely but result in chronic neurologic disorder. In general, early-onset forms are devastatingly lethal, whereas late-onset forms are more benign. Different amounts of residual enzyme activity may account for the clinical heterogeneity. Therefore, in addition to acute acidosis, chronic neurologic disorders of infancy or early childhood without evident etiology should lead to a search for metabolic disease. Mental retardation, ataxia, and behavioral changes suggest maple syrup urine disease but are also seen in 4-hydroxybutyric aciduria. Spasticity, ataxia, mental retardation, and seizures are present in L-2-hydroxyglutaric aciduria. Severe hypotonia, epilepsy, spastic tetraparesis, and early death are features of fumaric aciduria. Dystonia and spasticity, often with normal intellectual development, may underlie glutaric aciduria type I. Choreoathetosis and dystonic posture are signs of 3-hydroxy-3-methylglutaric aciduria. Seizures and ataxia are classically seen with alopecia and skin rash in late-onset multiple carboxylase deficiency. Ataxia, optic atrophy, and retinitis pigmentosa may be associated with 3-methylglutaconic aciduria. Some patients with mitochondrial trifunctional protein deficiency (type II) in addition to retinitis pigmentosa show peripheral neuropathy. Infantile spinal muscular atrophy with mental retardation can suggest 3-methylcrotonic aciduria. Lipid myopathy and cardiomyopathy develop in patients with the rare late-onset b-oxidation defects associated with dicarboxylic aciduria, such as carnitine translocase deficiency, mitochondrial trifunctional protein deficiency, very-long-chain acyl-CoA dehydrogenase deficiency, and the riboflavin-responsive form of glutaric aciduria type II.

NEUROIMAGING Brain magnetic resonance imaging (MRI) and computed tomography (CT) help in the diagnosis of organic acidurias, although they often lack specificity. In maple syrup urine disease, CT and MRI show the leukoencephalopathic features of white matter, particularly involving the pallidum. In glutaric aciduria type I, CT shows

dilated insular cisterns, temporal lobe shrinkage, and hypodensity of the lenticular nuclei. MRI demonstrates abnormal signal intensity in the white matter in glutaric aciduria type II. In methylmalonic aciduria, MRI shows symmetric abnormalities in the pallidum that may subsequently involve the whole basal ganglia. Progressive leukoencephalopathy starting in subcortical areas are characteristic of L-2-hydroxyglutaric aciduria.

THERAPY Management of organic acidurias caused by defects in amino acid metabolism is based on accurate early dietary treatment with protein-modified diets that restrict the appropriate amino acids: leucine, valine, and isoleucine in maple syrup urine disease; leucine in 3-hydroxymethylglutaric aciduria; isoleucine, valine, threonine, and methionine in propionic and methylmalonic aciduria; and lysine and tryptophan in glutaric aciduria type I. Patients with methylmalonic aciduria and propionic acidemia may also benefit from oral carnitine supplementation, which increases urinary excretion of propionylcarnitine. Carnitine and medium-chain triglycerides have been also used to treat b-oxidation disorders such as long-chain acyl-CoA dehydrogenase deficiency, long-chain b-hydroxyacyl-CoA dehydrogenase deficiency, and trifunctional protein deficiency; the use of carnitine in these disorders has been questioned because of possible cardiotoxicity. SUGGESTED READINGS Barth PG, Hoffmann GF, Jaeken J, et al. L-2-Hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol 1992;32:66–71. Chalmers RA. Current research in the organic acidurias. J Inherit Metab Dis 1989;12:225–239. DiDonato S. Diseases associated with defects of beta-oxidation. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, eds. The molecular and genetic basis of neurological disease, 2nd ed. Boston: Butterworth-Heineman, 1997:939–956. Gellera C, Uziel G, Rimoldi M, et al. Fumarase deficiency in an autosomal recessive encephalopathy affecting both mitochondrial and cytosolic enzymes.

Neurology 1990;40:495–499.

Pollit RJ. Disorders of mitochondrial b-oxidation: prenatal and early postnatal diagnosis and their relevance to Reye syndrome and sudden infant death. J Inherit Metab Dis 1989;12:215–230. Roe C, Coates P. AcylCoA dehydrogenase deficiency. In: Scriver CR, Beaudet AR, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited disease, 7th ed. New York: McGraw-Hill, 1995. Thomas E. Dietary management of inborn errors of amino acid metabolism with protein modified diets. J Child Neurol 1992;7:92–111. Uziel G, Savoiardo M, Nardocci N. CT and MRI in maple syrup urine disease. Neurology 1988;38:486–488.

CHAPTER 89. DISORDERS OF METAL METABOLISM MERRITT’S NEUROLOGY

CHAPTER 89. DISORDERS OF METAL METABOLISM JOHN H. MENKES Hepatolenticular Degeneration (Wilson Disease) (MIM 277900) Menkes Disease (Kinky Hair Disease) (MIM 309400) Suggested Readings

HEPATOLENTICULAR DEGENERATION (WILSON DISEASE) (MIM 277900) Wilson disease is an inborn error of copper metabolism that is associated with cirrhosis of the liver and degenerative changes in the basal ganglia. During the second half of the 19th century, a condition termed pseudosclerosis was distinguished from multiple sclerosis by the lack of nystagmus and visual loss. In 1902, Kayser observed green corneal pigmentation in one such patient; Fleischer commented on the association of the corneal rings with pseudosclerosis in 1903 and fully required it in 1912. In 1912, Wilson gave the classic description of the disease and its pathologic anatomy. The worldwide prevalence of the disease is about 30 in 1 million, with a gene frequency of 1:180. Pathogenesis and Pathology Wilson disease is an autosomal recessive disorder with the gene being located on the long arm of chromosome 13. The gene has been cloned. It encodes a copper-transporting P-type ATPase that is expressed in liver and kidney. The protein is present in two forms: one is localized to the cellular trans-Golgi network and the other, probably representing a cleavage product, to mitochondria. A large number of mutations have been characterized. Some are large deletions that completely destroy function of the gene and result in an early onset of symptoms, whereas others that reduce but not eliminate copper transport are consistent with a late onset of symptoms. Most patients are compound heterozygotes. The genetic mutation induces extensive changes in copper homeostasis. Normally, the amount of copper in the body is kept constant through excretion of copper from the liver into bile. In Wilson disease, the two fundamental defects are reduced biliary transport of copper and an impaired formation of plasma ceruloplasmin. Because ceruloplasmin is present in the liver of patients with Wilson disease, a posttranslational defect appears to be responsible for the absence of ceruloplasmin from both bile and serum. In addition to these abnormalities, levels of nonceruloplasmin (free) copper in serum are increased and plasma iron-binding globulin is low to low normal. These abnormalities occur in asymptomatic carriers and suggest that Wilson disease may also encompass a disorder of iron metabolism. This may result from the deficiency of ceruloplasmin that is directly involved in the transfer of iron from tissue cells to plasma transferrin. Another metabolic feature is a persistent aminoaciduria. This is most marked during the later stages but may be noted in some asymptomatic patients. The presence of other tubular defects (e.g., impaired phosphate resorption in patients without aminoaciduria) suggests that a toxic action of the metal on renal tubules causes the aminoaciduria. A defect in the gene encoding a different copper transporting P-type ATPase is responsible for Menkes disease. Although the gene for Menkes disease is located on the X chromosome, there is more than 60% identity between the two proteins. The similarities and differences between the two diseases are listed in Table 89.1.

TABLE 89.1. MOLECULAR BIOLOGY OF MENKES DISEASE AND WILSON DISEASE

The abnormalities in copper metabolism that occur in Wilson disease lead to accumulation of the metal in liver and consequently to progressive liver damage. Anatomically, the liver shows focal necrosis that leads to a coarsely nodular postnecrotic cirrhosis; the nodules vary in size and are separated by bands of fibrous tissue of different width. Some hepatic cells are enlarged and contain fat droplets, intranuclear glycogen, and clumped pigment granules; other cells are necrotic, and there are regenerative changes in the surrounding parenchyma. Electron microscopic studies have shown that copper is sequestered by lysosomes that become more than normally sensitive to rupture and therefore lack normal alkaline phosphatase activity. Copper probably initiates and catalyzes oxidation of the lysosomal membrane lipids, resulting in lipofuscin accumulation. Subsequent overflow of copper from the liver produces accumulation in other organs, mainly brain, kidney, and cornea. Within the kidneys, the tubular epithelial cells may degenerate, and the cytoplasm may contain copper deposits. In brain, the basal ganglia show the most striking alterations ( Fig. 89.1). They have a brick-red pigmentation; spongy degeneration of the putamen frequently leads to the formation of small cavities. Microscopic studies reveal a loss of neurons, axonal degeneration, and large numbers of protoplasmic astrocytes, including giant forms known as Alzheimer cells. The cortex of the frontal lobe may also show spongy degeneration and astrocytosis. Copper is deposited in the pericapillary area and within astrocytes, where it is located in the subcellular soluble fraction and bound not only to cerebrocuprein but also to other cerebral proteins. Copper is uniformly absent from neurons and ground substance. Lesser degenerative changes are seen in the brainstem, the dentate nucleus, the substantia nigra, and the convolutional white matter. Copper is also found throughout the cornea, particularly the substantia propria.

FIG. 89.1. Wilson disease. Ventricular dilation, atrophy of caudate nucleus. Cyst in lower half of putamen.

In the cornea, the metal is deposited in the periphery where it appears in granular clumps close to the endothelial surface of the Descemet membrane. The deposits in this area are responsible for the appearance of the Kayser-Fleischer ring. The color of this ring varies from yellow to green to brown. Copper is deposited in two or more layers, with particle size and distance between layers influencing the ultimate appearance of the ring. Symptoms and Signs Wilson disease is a progressive condition with a tendency toward temporary clinical improvement and arrest. The condition occurs in all races, with a particularly high incidence among Eastern European Jews, Italians from southern Italy and Sicily, and people from some of the smaller islands of Japan—groups in which there is a high rate of inbreeding. In most patients, symptoms begin between the ages of 11 and 25 years. Onset as early as age 3 and as late as the fifth decade has been recorded. The signs and symptoms of hepatolenticular degeneration are generally those of damage to the liver and brain. Signs of liver damage, ascites, or jaundice may occur at any stage of the disease. They have been observed in some cases several or many years before the onset of neurologic symptoms. The neurologic manifestations are so varied that it is impossible to describe a clinical picture that is characteristic. In the past, texts have distinguished between pseudosclerotic and dystonic forms of the disease: the former dominated by tremor, the latter by rigidity and contractures. In actuality, most patients, if untreated, ultimately develop both types of symptoms. In essence, Wilson disease is a disorder of motor function; despite often widespread cerebral atrophy, there are no sensory symptoms or reflex alterations. Symptoms at onset are shown in Table 89.2. Symptoms of basal ganglia damage usually predominate, but cerebellar symptoms may occasionally be in the foreground. Tremors and rigidity are the most common early signs. The tremor may be of the intention type or it may be the alternating tremor of Parkinson disease. More commonly, however, it is a bizarre tremor, localized to the arms and best described by the term “wing beating” ( Fig. 89.2). This tremor is usually absent when the arms are at rest; it develops after a short latent period when the arms are extended. The beating movements may be confined to the muscles of the wrist, but it is more common for the arm to be thrown up and down in a wide arc. The movements increase in severity and may become so violent that the patient is thrown off balance. A change in the posture of the outstretched arms may alter the severity of the tremor. The tremor may affect both arms but is usually more severe in one. The tremor may occasionally be present even when the arm is at rest. Many patients have a fixed open-mouth smile.

TABLE 89.2. CLINICAL MANIFESTATIONS AT ONSET OF WILSON DISEASE

FIG. 89.2. Wilson disease. Open mouth, athetoid posture of arms, and wing-beating movements of left hand.

Rigidity and spasms of the muscles are often present. In some cases, a typical parkinsonian rigidity may involve all muscles. Torticollis, tortipelvis, and other dystonic movements are not uncommon. Spasticity of the laryngeal and pharyngeal muscles may lead to dysarthria and dysphagia. Drooping of the lower jaw and excess salivation are common. Other symptoms include convulsions, transient periods of coma, and mental changes. Mental symptoms may dominate the clinical course for varying periods and simulate an affective disorder or a psychosis. Tendon reflexes are increased, but extensor plantar responses are exceptional. Somatosensory evoked potentials are abnormal in most patients with neurologic symptoms. The prevalence of epileptic seizures is 10 times higher in patients with Wilson disease than in the general population. Seizures can occur at any stage of the disease, but most begin after the initiation of treatment. Behavioral or personality disorders were noted in the original description of the disease by Wilson. In the experience of Akil and Brewer (1995), the first symptoms of one-third of patients are psychiatric abnormalities. These include impaired school performance, depression, labile moods, and frank psychosis. In those patients who show primarily neurologic symptoms, about two-thirds have had psychiatric problems before the diagnosis was made. Symptoms in about one-half of patients were sufficiently severe to require treatment by a psychiatrist or a hospital admission. The intracorneal ring-shaped pigmentation first noted by Kayser (1902) and Fleischer (1912) may be evident to the naked eye or may be seen only by slit-lamp examination. The ring may be complete or incomplete and is present in 75% of patients who present with hepatic symptoms and in all patients with cerebral symptoms alone or both cerebral and hepatic symptoms. The Kayser-Fleischer ring may antedate overt symptoms and has been detected even with normal liver functions. In the larger clinical series of Arima and colleagues (1977), it was never present before age 7 years. Magnetic resonance imaging (MRI) usually reveals ventricular dilatation and diffuse atrophy of the cortex, cerebellum, and brainstem. The basal ganglia is usually abnormal with the putamen, thalamus, the head of the caudate, and the globus pallidus the most likely areas to be involved in patients presenting with neurologic symptoms (Fig. 89.3). Most patients with hepatic symptoms have increased signal in the basal ganglia on T1-weighted images. Abnormalities are also seen in the tegmentum of the midbrain, the substantia nigra, and pons. In a few subjects there are focal white matter lesions. On compured tomography (CT), increased density due to copper deposition is not observed. As a rule, MRI correlates better with the clinical symptoms than CT.

FIG. 89.3. Wilson disease. Coronal T2-weighted magnetic resonance images of a 22-year-old woman with Wilson disease. A: Three months after the disease has been diagnosed and at start of penicillamine therapy, there are bilateral hyperintense thalamic lesions that were hypointense on T1-weighted images. B: The same patient after 13 months of penicillamine therapy shows a significant regression of the thalamic lesions. Spin-echo sequences TR 2.5 ms, TE 90 ms, using Siemens Magneton 63 operating at 1.5 T. (Courtesy of Dr. I. Prayer, Zentral Institut fur Radiodiagnose und Ludwig Boltzmann Institut, University of Vienna, Austria; and Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL. Molecular and genetic basis of neurological disease. Boston: Butterworth-Heinemann, 1997.)

Diagnosis The clinical picture of Wilson disease is fairly clearcut when the disease is advanced. The Kayser-Fleischer ring is the most important diagnostic feature; absence of corneal pigmentation in untreated patients with neurologic symptoms rules out the diagnosis. The ring is not seen in most presymptomatic patients or in some children with hepatic symptoms. A low serum ceruloplasmin and elevated urinary copper support the diagnosis. Although 96% of patients with Wilson disease have low or absent serum ceruloplasmin, some cases have been reported with normal ceruloplasmin levels. In affected families, the differential diagnosis between heterozygotes and presymptomatic homozygotes is of utmost importance because homozygotes should be treated preventively. Low ceruloplasmin levels in an asymptomatic patient suggest the presymptomatic stage of the disease. Because 6% of heterozygotes also have low ceruloplasmin levels, further studies are indicated. An elevation of urinary copper is diagnostic of a presymptomatic patient if the patient is 15 years or older. In children, urinary copper is not always elevated, and in such cases a liver biopsy to measure hepatic copper content is indicated to confirm the diagnosis. A screening test using penicillamine to stimulate urinary excretion of copper has not been standardized and is therefore of little value. When a liver biopsy has been decided upon, both histologic studies with stains for copper and copper-associated proteins and chemical quantitation for copper are performed. In all confirmed cases of Wilson disease, hepatic copper is greater than 3.9 Âľmol/g dry weight (237.6 Âľg/g) compared with a normal range of 0.2 to 0.6 Âľmol/g. Because of the large number of mutations causing the disease, a combination of mutation and linkage analysis is required for prenatal diagnosis and as a rule is not useful in the diagnosis of an individual patient. A variant of Wilson disease begins in adolescence and is marked by progressive tremor, dysarthria, disturbed eye movements, and dementia. Biochemically, it is characterized by low serum levels of copper and ceruloplasmin. Kayser-Fleischer rings are absent, and liver copper concentrations are low. Metabolic studies using labeled copper suggest a failure in copper absorption from the lower gut. In familial apoceruloplasm deficiency, the clinical presentation is dementia, retinal degeneration, and a variety of movement disorders. MRI and neuropathologic examinations demonstrate iron deposition in the basal ganglia. The clinical and pathologic findings confirm the essential role of ceruloplasmin in iron metabolism and in brain iron homeostasis. The relationship between this condition and Hallervorden-Spatz syndrome is unclear. Treatment All patients with Wilson disease, whether symptomatic or asymptomatic, require treatment. The aims of treatment are initially to remove the toxic amounts of copper and secondarily to prevent tissue reaccumulation of the metal. Treatment can be divided into two phases: the initial phase, when toxic copper levels are brought under control, and maintenance therapy. There is no currently agreed on regimen for the treatment of the new patient with neurologic or psychiatric symptoms. In the past, most centers recommended starting patients on penicillamine (600 mg to 3,000 mg/day). Although this drug is effective in promoting urinary excretion of copper, adverse reactions during both the initial and maintenance phases of treatment are seen in about 25% of patients. These include worsening of neurologic symptoms during the initial phases of treatment, seen in up to 50% of patients and frequently irreversible. Skin rashes, gastrointestinal discomfort, and hair loss are also encountered. During maintenance therapy, one may see polyneuropathy, polymyositis, and nephropathy. Some of these adverse effects can be prevented by giving pyridoxine (25 mg/day). Because of these side effects, many institutions now advocate initial therapy with ammonium tetrathiomolybdate (60 to 300 mg/day, administered in six divided doses, three with meals and three between meals). Tetrathiomolybdate forms a complex with protein and copper and when given with food blocks the absorption of copper. The major drawback to using this drug is that it still has not been approved for general use in this country. Triethylene tetramine dihydrochloride (trientine) (250 mg four times a day, given at least 1 hour before or 2 hours after meals) is also a chelator that increases urinary excretion of copper. Its effectiveness is less than that of penicillamine, but the incidence of toxicity and hypersensitivity reactions is lower. Zinc acetate (50 mg of elemental zinc acetate three times a day) acts by inducing intestinal metallothionein, which has a high affinity for copper and prevents its entrance into blood. Zinc is far less toxic than penicillamine but is much slower acting. Diet does not play an important role in the management of Wilson disease, although Brewer (1995) recommended restriction of liver and shellfish during the first year of treatment. Zinc is the optimum drug for maintenance therapy and for the treatment of the presymptomatic patient. Trientine in combination with zinc acetate has been suggested for patients who present in hepatic failure. Liver transplantation can be helpful in the patient who presents in end-stage liver disease. The procedure appears to correct the metabolic defect and can reverse neurologic symptoms. Improvement of neurologic symptoms and signs and fading of the Kayser-Fleischer rings can be expected from therapy. As a rule, patients with the predominantly pseudosclerotic form of the disease fare better than those with dystonia as the main manifestation. Improvement of neurologic symptoms starts 5 to 6 months after therapy has begun and is generally complete in 24 months. Serial neuroimaging studies demonstrate progressive reduction of the abnormal areas in the basal ganglia (Fig. 89.3). Survival of patients who have completed the first few years of treatment is within the range of normal.

MENKES DISEASE (KINKY HAIR DISEASE) (MIM 309400) Menkes disease (kinky hair disease [KHD]) is a focal degenerative disorder of gray matter that is transmitted by a gene mapped to the long arm of the X chromosome. The gene codes for a copper-transporting ATPase that has been localized to the Golgi complex. This transporter is required to mobilize copper from the intestinal mucosa cells and to transfer copper into apoenzymes. Numerous mutations have been documented. Partial gene deletions are seen in some 15% to 20% of patients. About half of the mutations lead to splicing abnormalities. Other mutations that have been encountered include small duplications, nonsense mutations, and missense mutations. To date, all mutations detected have been unique for each given family, and almost all have been associated with a decreased level of the mRNA for the copper-transporting ATPase. These observations explain the considerable variability in the severity of clinical manifestations. The result of this gene defect is maldistribution of body copper. The metal accumulates to abnormal levels in a form or location that makes it inaccessible for the synthesis of various copper enzymes. These include cytochrome c oxidase, lysyl oxidase, superoxide dismutase, and tyrosinase. Cytochrome c oxidase (complex IV) is a copper-containing enzyme located in the mitochondrial inner membrane. It is the terminal oxidase of the respiratory chain. In KHD there is a marked reduction in the enzyme in all portions of the central nervous system. Lysyl oxidase normally deaminates lysine and hydoxylysine as the first step in collagen cross-link formation.

Several groups of workers have found that lysyl oxidase activity is markedly reduced in children with KHD. Tyrosinase, an enzyme involved in melanin biosynthesis, is considered to be responsible for reduced pigmentation and hair and skin. Copper levels are low in liver and all areas of the brain but are elevated in some other tissues, notably intestinal mucosa and kidney. Patients absorb little or no orally administered copper, but when the metal is given intravenously, there is a prompt rise in serum copper and ceruloplasmin. In fibroblasts, the copper content is markedly elevated as is metallothionein; synthesis of metallothionein is increased as a consequence of abnormally high intracellular copper levels. As a consequence of tissue copper deficiency, a large number of pathologic changes is set into motion. Cerebral and systemic arteries are tortuous with irregular lumens and frayed and split intimal linings. In brain, there is extensive focal degeneration of cortical gray matter with neuronal loss and gliosis. Cellular loss is prominent in the cerebellum, where many Purkinje cells are lost; others show grotesque proliferation of the dendritic network. In the thalamus, there is primary cellular degeneration that spares the smaller inhibitory neurons. The incidence is thought to be as high as 2 in 100,000 male live births. Symptoms appear in the neonatal period. Most commonly, hypothermia, poor feeding, and impaired weight gain are observed. Seizures soon become apparent with progressive deterioration of all neurologic functions. The most striking finding is the appearance of the hair, which is colorless and friable. On microscopic examination, a variety of abnormalities is evident, most often pili torti (twisted hair) and trichorrhexis nodosa (fractures of the hair shaft at regular intervals). Radiographs of long bones reveal metaphyseal spurring and a diaphyseal periosteal reaction. On arteriography, the cerebral vessels are markedly elongated and tortuous. Similar changes are seen in systemic blood vessels. CT or MRI may reveal areas of cortical atrophy or tortuous and enlarged intracranial vessels. Subdural effusions are not unusual ( Fig. 89.4).

FIG. 89.4. Axial T1-weighted magnetic resonance image in patient with kinky hair disease. Patient was a 2-year-old girl with psychomotor retardation, seizures, and characteristic hair. No family history of neurologic disease. Chromosomal analysis revealed X/2 translocation. There is considerable periventricular and cortical atrophy. Fluid collection over left cortical margin represents and old subdural hematoma.

The clinical history and appearance of the infant suggest the diagnosis. Serum ceruloplasmin and copper levels are normally low in the neonatal period and do not reach adult levels until age 1 month. Thus, these determinations must be performed serially to demonstrate that the expected rise does not occur. The increased copper content of fibroblasts permits intrauterine diagnosis. Even though copper infusions raise serum copper and ceruloplasmin, neurologic symptoms are neither alleviated nor prevented. Early treatment with copper-histidine could be beneficial in some instances. Several variants of Menkes syndrome have been recognized based on the low serum copper concentrations. Symptoms include ataxia, mild mental retardation, and extrapyramidal movement disorders. In occipital horn syndrome, a condition allelic with KHD, the characteristic picture includes a hyperelastic and bruisable skin, hyperextensible joints, hernias, bladder diverticula or rupture, and multiple skeletal abnormalities, including wormian bones in the skull. SUGGESTED READINGS Aisen AM, Martel W, Gabrielsen TO, et al. Wilson disease of the brain. MR imaging. Radiology 1985;157:137–141. Akil M, Brewer GJ. Psychiatric and behavioral abnormalities in Wilson's disease. Adv Neurol 1995;65:171–178. Arima M, Takeshita K, Yoshino K, et al. Prognosis of Wilson's disease in childhood. Eur J Pediatr 1977;126:147–154. Brewer GJ. Practical recommendations and new therapies for Wilson's disease. Drugs 1995;50:240–249. Brewer GJ, Hill GM, Prasad AS, et al. Oral zinc for Wilson's disease. Ann Intern Med 1983;99:314–320. Brewer GJ, Yuzbasian-Gurkan V. Wilson disease. Medicine (Baltimore) 1992;71:139–164. Chelly J, Monaco AP. Cloning the Wilson disease gene. Nat Genet 1993;5:317–318. Danks DM, Campbell PE, Stevens BJ, et al. Menkes' kinky hair syndrome: An inherited defect in copper absorption with widespread effects. Pediatrics 1972;50:188–201. Davis W, Chowrimootoo GF, Seymour CA. Defective biliary copper exretion in Wilson's disease: the role of caeruloplasmin. Eur J Clin Invest 1996;26:893–901. Fleischer, B. Über einer der “Pseudosklerose” nahestehende bisher unbekannte Krankheit (gekennzeichnet durch Tremor, psychische Störungen, bräunliche Pigmentierung bestimmter Gewebe, insbesondere auch der Hornhautperipherie, Lebercirrhose). Deutsch Z Nervenheilk 1912;44: 179–201. Francis MJ, Jones EE, Levy ER, et al. A Golgi localization signal identified in the Menkes recombinant protein. Hum Mol Genet 1998;7:1245–1252. Gitlin J. Aceruloplasminemia. Pediatr Res 1998;44:271–276. Glass JD, Reich SG, Delong MR. Wilson's disease. Development of neurologic disease after beginning penicillamine therapy. Arch Neurol 1990;47:595–596. Grover WD, Johnson WC, Henkin RI. Clinical and biochemical aspects of trichopoliodystrophy. Ann Neurol 1979;5:65–71. Heckmann J, Saffer D. Abnormal copper metabolism: another “non-Wilson's” case. Neurology 1988;38:1493–1496. Hefter H, Rautenberg W, Kreuzpaintner G, et al. Does orthoptic liver transplantation heal Wilson's disease? Clinical follow-up of two liver-transplanted patients. Acta Neurol Scand 1991;84:192–196. Kayser, B. Ueber einen Fall von angeborener grünlicher Verfärbung der Cornea. Klin Monatsbl Augenheilkd 1902;40:22–25. Lutsenko S, Cooper MJ. Localization of the Wilson's disease protein product to mitochondria. Proc Natl Acad Sci USA 1998;95:6004–6009. Menkes JH, Alter M, Steigleder GK, et al. A sex-linked recessive disorder with growth retardation, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 1962;29:764–779. Royce PM, Camakaris J, Danks DM. Reduced lysyl oxidase activity in skin fibroblasts from patients with Menkes' syndrome. Biochem J 1980;192:579–586. Scheinberg IH, Sternieb I. Wilson's disease, 2nd ed. Philadelphia: WB Saunders, 1999. Shah AB, Chernov I, Zhang HT, et al. Identification and analysis of mutation in the Wilson disease gene ATP 7B. Am J Hum Genet 1997;61:317–339. Starosta-Rubenstein S, Young AB, Kluin K, et al. Clinical assessment of 31 patients with Wilson's disease. Arch Neurol 1987;44:365–370.

Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper-transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993;5:344–350. Thomas GR, Forbes JR, Roberts EA, et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet 1995;9:210–217. Vulpe C, Levinson B, Whitney S, et al. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nat Genet 1993;3:7–13. Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain 1912;34:295–509.

CHAPTER 90. ACUTE INTERMITTENT PORPHYRIA MERRITT’S NEUROLOGY

CHAPTER 90. ACUTE INTERMITTENT PORPHYRIA LEWIS P. ROWLAND Pathogenesis Molecular Genetics Pathology Incidence Symptoms and Signs Laboratory Data Diagnosis Treatment Suggested Readings

Excessive excretion of porphyrins makes the urine appear bright red. The change is so dramatic that one form of genetic porphyria was among the first inborn errors of metabolism when that class of disease was identified by Garrod. We now recognize both acquired and heritable forms; the genetic categories are further divided into hepatic and erythropoietic types, depending on the site of the enzymatic disorder. Neurologic manifestations are encountered in two classes of porphyria. Acute intermittent porphyria (AIP; MIM 176000) occurs worldwide; variegate porphyria (MIM 176200) occurs in Sweden and South Africa. These two forms differ primarily in that a rash occurs in the variegate form but not in AIP. Both are inherited as autosomal dominant traits, with low penetrance.

PATHOGENESIS There are eight steps in the biosynthesis of heme. The crucial steps in understanding porphyria are as follows: delta aminolevulinic acid (ALA) is formed from succinyl CoA and glycine under the influence of ALA synthetase; two molecules of ALA are joined by ALA-dehydratase to form a monopyrrole, porphobilinogen (PBG); four molecules of PBG are linked to form a porphyrin by uroporphyrinogen-1 synthase—rearrangements of the side chains of this tetrapyrrole follow under the action of a series of other enzymes, including protoporphyrinogen oxidase; and the process culminates in the formation of heme by the addition of an iron molecule. In AIP, there is excessive urinary excretion of ALA, PBG, and several porphyrins. Suggestions of a block in an alternate pathway of ALA metabolism have not been confirmed. It is still not certain how this pattern of metabolite excretion arises. The dominant theory is of a block in the activity of PBG deaminase in AIP and of protoporphyrinogen oxidase in the variegate form; this causes decreased amounts of heme to be formed downstream, and the lack of normal inhibitory feedback from heme on ALA synthetase releases that enzyme, accounting for the overproduction of ALA and PBG. However, there is no deficiency of heme compounds in blood or tissues, and the activity of PBG deaminase is about 50% of normal. This is the usual level of enzyme activity in asymptomatic heterozygote carriers of autosomal recessive diseases; it is not clear why the same level of activity should be linked to symptoms in AIP but not in so many other conditions. Moreover, the decreased activity of PBG deaminase has been demonstrated in liver biopsy specimens, cultured skin fibroblasts, amniotic cells, and erythrocytes. Inexplicably, the enzyme activity is normal in some unequivocally affected individuals. Neurologic symptoms do not appear in other genetic disorders of porphyrin synthesis. It has not been possible to attribute the characteristic neuropathy of AIP to the increased amounts of circulating ALA or PBG. Clinical symptoms of porphyria are similar to those of lead poisoning, in which ALA excretion also increases, but PBG excretion is normal in lead intoxication. Whatever the abnormality, clinical symptoms seem to be caused by the interaction of genetic and environmental factors. Porphyric crises result most often from ingestion or administration of drugs that adversely affect porphyrin metabolism, especially barbiturates taken for sedation or for general anesthesia. Attacks are also attributed to menses, starvation, emotional stress, intercurrent infections, or other drugs.

MOLECULAR GENETICS Genetic heterogeneity was evident even before DNA analysis was possible. For instance, using antibodies to PBG deaminase, 74% to 85% of families show cross-reacting immunologic material, whereas others do not. In most families, the enzyme in red blood cells has about half of normal activity; in others, the erythrocyte enzyme is normal. The enzyme has been mapped to 11q24.1-q24.2. DNA studies have revealed 14 different mutations in the gene. In Sweden, about half of all families had the same point mutation. Fifteen of 49 Dutch families and 1 of 33 French families showed a single base mutation. There has been no convincing documentation of a homozygous individual, but one child was a “compound” of two different mutations at the same locus on the two chromosomes. DNA analysis is important in family studies, identifying people at risk more reliably than assays of erythrocyte PBG deaminase activity, which, in one study, missed 28% of those who carried the mutation and therefore might be susceptible to symptoms if exposed to responsible drugs.

PATHOLOGY The functional disorder is not due to structural change. Even in fatal cases, it may be difficult to demonstrate any histologic lesions. Demyelinating lesions of central and peripheral nerves have been observed, but modern electrophysiologic studies show normal or nearly normal conduction velocities with signs of denervation in muscle, the pattern of an axonal neuropathy. This view has been supported by morphometric studies of peripheral nerves and nerve roots, with evidence also of a dying-back process. Large and small fibers are affected in peripheral nerves, and autonomic fibers are also attacked.

INCIDENCE In South Africa, Dean and Barnes traced most current cases to a single colonist who arrived there in 1688. In Sweden, the prevalence varies from 1:1,000 in the north to 1:100,000 population in other parts. Prevalence figures for other countries are also about 1:100,000. In one psychiatric hospital, the prevalence was 2:1,000. Acute symptoms are rare, however, and in major academic medical centers in New York, new cases are seen less often than once a year. All races seem to be affected. In most series, women are more often affected than men. Symptoms are rare in childhood and are most likely to affect adolescents or young adults.

SYMPTOMS AND SIGNS Asymptomatic individuals with acute porphyria or variegate porphyria are identified by biochemical tests. Symptoms of either disease occur in attacks that may be induced by commonly used drugs; these are described subsequently. The symptoms of an attack are most commonly gastrointestinal (attributed to autonomic neuropathy), psychiatric, and neurologic ( Table 90.1). Abdominal pain is most common and may occur alone or with a neurologic or psychiatric disorder. There is usually no abdominal rigidity, but fever, leukocytosis, and diarrhea or constipation often lead to laparotomy. Patients with acute porphyria may actually have appendicitis or some other visceral emergency. The psychiatric disorder may suggest conversion reaction, acute delirium, mood change, or an acute or chronic psychosis. Symptoms of the neuropathy are like those of any peripheral neuropathy except that the signs may be purely motor and are almost always associated with abdominal pain. In one series, 18% of the cases with neuropathy were fatal, 25% recovered completely, and the others were left with some neurologic disability. Survivors may have recurrent attacks. Cerebral manifestations are unusual except for the syndrome of inappropriate secretion of antidiuretic hormone. Unexplained transient amblyopia has been reported. Autonomic abnormalities include hypertension and tachycardia.

TABLE 90.1. CLINICAL MANIFESTATIONS OF ACUTE INTERMITTENT PORPHYRIA

LABORATORY DATA Routine laboratory tests usually give normal results, including cerebrospinal fluid. Electromyogram shows signs of denervation, but motor and sensory nerve velocities are normal or only slightly slow. Even between attacks, affected individuals can be identified by a qualitative test for PBG in the urine. The Watson-Schwartz test depends on the action of the monopyrrole with diaminobenzaldehyde to form a reddish compound that is soluble in chloroform. The test can be performed in a few minutes, and there are few false-positive or false-negative results. Quantitative measurement of urinary PBG and ALA can be achieved by column chromatography, now available in commercial laboratories in the United States. The most reliable test is assay of PBG-deaminase activity in red blood cell membranes, which is about 50% of control values in affected individuals with AIP, between and during attacks. The assay also identifies family members who are at risk even if they are asymptomatic, and DNA analysis is even more accurate. Variegate porphyria cannot be distinguished from AIP clinically, unless there is a rash, which may be lacking in almost half of symptomatic individuals. The acute attacks are virtually identical to those of AIP. The difference is biochemical; excretion of PBG and ALA is increased during attacks but not between attacks. In contrast to AIP, there is increased fecal excretion of protoporphyrin, but even this may be normal, and measurement of the porphyrin in bile seems more accurate. The affected enzyme is protoporphyrinogen oxidase.

DIAGNOSIS Clinical diagnosis is not difficult if there is a family history of the disease, but the condition is so rare in the United States that physicians often do not recognize the source of unexplained abdominal pain and personality disorder. If peripheral neuropathy is added to the syndrome, however, and the appropriate biochemical tests are made, the diagnosis is ascertained. These tests are more important than looking for red urine or measurement of porphyrins in urine. Neurologically, the major disorder to be considered is the Guillain-Barré syndrome, but the characteristic rise in cerebrospinal fluid protein content of that disease is not found in AIP; the cerebrospinal fluid protein rises so rarely in AIP that when the protein does rise, it may be a sign of Guillain- Barré syndrome in a person with porphyria.

TREATMENT The fundamental biochemical abnormality cannot be corrected, but the autonomic manifestations of an acute attack may be reversed by propanolol. Doses up to 100 mg every 4 hours may reverse tachycardia, abdominal pain, and anxiety. The neuropathy and abdominal symptoms may respond dramatically to hematin given intravenously in amounts from 200 to 1,000 mg in attempts to suppress the activity of ALA dehydratase. The optimal dosage is uncertain; one recommendation is to use 4 mg hematin/kg body weight twice daily for 3 days. The wholesale price of hemin in 1996 was $120 to $475 daily. This may still be the most effective treatment, but some advocate the use of cimetidine orally, 800 mg daily. Treatment of seizures is a problem because most commonly used anticonvulsants have been held responsible for porphyric attacks in human patients or they are porphyrogenic in experimental animals or cultured hepatic cells. In acute attacks of porphyria, seizures may be treated with diazepam or paraldehyde, whereas hematin and propanolol are used to abort the attacks. Between attacks, conventional anticonvulsants may be evaluated cautiously, monitoring urinary excretion of ALA and PBG. Gabapentin is said to be safe and effective. Other drugs that are suitable for symptomatic relief include codeine and meperidine for pain, chlorpromazine and other psychoactive drugs, and almost all antibiotics. The major drugs to avoid are barbiturates in any form, including pentobarbital for general anesthesia ( Table 90.2). Barbiturates may be especially hazardous when given for sedation or anesthesia in the early stages of an attack. It is otherwise difficult to prevent attacks, but some women have symptoms only and regularly in relation to menses; both suppression of ovulation and prophylactic use of hematin have been reported to be effective. In case of accident, patients should wear warning bracelets to identify the drug problem. Prophylactic care requires identification of gene carriers so that they can avoid drugs that precipitate attacks in susceptible people.

TABLE 90.2. PORPHYROGENIC DRUGS IN ACUTE PORPHYRIA*

SUGGESTED READINGS Becker DM, Kramer S. The neurological manifestations of porphyria: a review. Medicine (Baltimore) 1977;56:411–423. Bottomley SS, Bonkowsky HL, Birnbaum MK. The diagnosis of acute intermittent porphyria. Usefulness and limitations of the erythrocyte uroporphyrinogen-1 synthase assay. Am J Clin Pathol 1981;76:133–139. Brezis M, Ghanem J, Weiler-Ravell O, et al. Hematin and propanolol in acute intermittent porphyria. Full recovery from quadriplegic coma and respiratory failure.

Eur Neurol 1979;18:289–294.

Dean G. The porphyrias. A story of inheritance and the environment, 2nd ed. London: Pitman, 1971. Delfau MH, Picat C, DeRooij F, et al. Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in CRIM-negative subtype of the disease.

Am J Hum

Genet 1991;49:421–428. Eales L. Porphyria and the dangerous life-threatening drugs. S Afr Med J 1979;2:914–917. Flugel KA, Druschky KF. EMG and nerve conduction in patients with acute intermittent porphyria. J Neurol 1977;214:267–279. Grandchamp B. Acute intermittent porphyria. Semin Liver Dis 1998;18:17–24. Gu XF, deRooij F, Voortman G, et al. Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis. Hum Genet 1994;93:47–52. Herick AL, McColl KEL, Moore MR, Cook A. Controlled trial of haem arginate in acute hepatic porphyria. Lancet 1989;1:1295–1297. Hindmarsh JT. Variable pheotypic expression of genotypic abnormalities in the porphyrias. Clin Chim Acta 1993;217:29–38. King PH, Bragdon AC. MRI reveals multiple reversible lesions in an attack of acute intermittent porphyria. Neurology 1991;41:1300–1302. Laiwah ACY, Moore MR, Goldberg A. Pathogenesis of acute porphyria. Q J Med 1987;63:377–392. Lee JS, Anvret M. Identification of the most common mutation within the porphobilinogen deaminase gene in Swedish patients with acute intermittent porphyria. Proc Natl Acad Sci USA 1991;88:10912–10915. Lee J-S, Anvret M, Lindsten J, et al. DNA polymorphisms within the porphobilinogen deaminase gene in acute intermittent porphyria. Hum Genet 1988;79:379–381. Llewellyn DH, Smyth SJ, Elder GH, et al. Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene. Hum Genet 1992;89:97–98. Loftus CS, Arnold WN. Vincent Van Gogh's illness: acute intermittent porphyria? Br Med J 1991;303:1585–1591. McEneaney D, Hawkins S, Trimble E, Smye M. Porphyric neuropathy—a rare and often neglected differential diagnosis of Guillain-Barré syndrome. J Neurol Sci 1993;114:231–233. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: pathogenesis of neurological manifestations. Semin Liv Dis 1998;18:43–52. Moore MR. The biochemistry of heme synthesis in porphyria and in the porphyrinurias. Clin Dermatol 1998;16:203–223. Moore MR, Disler PB. Drug induction of the acute porphyrias. Adverse Drug React Acute Poison Rev 1983;2:149–189. Mustajoki P, Desnick RJ. Genetic heterogeneity in acute intermittent porphyria: characterisation and frequency of porphobilinogen deaminase mutations in Finland. Br Med J 1985;291:505–509. Muthane UB, Vengamma B, Bharathi KC, Mamatha P. Porphyric neuropathy: prevention of progression using haeme-arginate. J Intern Med 1993;234:611–613. Pierach CA, Weimer MK, Cardinal RA, et al. Red blood cell porphobilinogen deaminase in the evaluation of acute intermittent porphyria. JAMA 1987;257:60–61. Reynolds NC, Miska RM. Safety of anticonvulsants in hepatic porphyrias. Neurology 1981;31:480–484. Ridley A. The neuropathy of acute intermittent porphyria. Q J Med 1969;38:307–333. Rogers PD. Cimetidine in the treatment of acute intermittent porphyria. Ann Pharmacother 1997;31:365–367. Rowland LP. Acute intermittent porphyria: search for an enzymatic defect with implications for neurology and psychiatry. Dis Nerv Sys 1961;22[Suppl]:1–12. Sadeh H, Blatt I, Martonovits G, et al. Treatment of porphyric convulsions with magnesium sulfate. Epilepsia 1991;32:712–715. Suarez JI, Cohen ML, Larkin J, Kernich CA, Hricik DE, Daroff RB. Acute intermittent porphyria: clinicopathologic correlation. Report of a case and review of the literature. 1997;48:1678–1683.

Neurology

Suzuki A, Aso K, Ariyoshi C, Ishimaru N. Acute intermittent porphyria and epilepsy: safety of clonazepam. Epilepsia 1992;33:108–111. Thorner PA, Bilbao JM, Sima AAF, Briggs S. Porphyric neuropathy: an ultrastructural and quantitative study. Can J Neurol Sci 1981;8:261–287. Tishler PV, Woodward B, O'Connor J, et al. High prevalence of intermittent acute porphyria in a psychiatric patient population. Am J Psychiatry 1985;142:1430–1436. Yamada M, Kondo M, Tanaka M, et al. An autopsy case of acute porphyria with a decrease of both uroporphyrinogen I synthetase and ferrochetalase activities. Acta Neuropathol (Berl) 1984;64:6–11. Yeung AC, Moore MR, Goldberg A. Pathogenesis of acute porphyria. Q J Med 1987;163:377–392.

CHAPTER 91. NEUROLOGICAL SYNDROMES WITH ACANTHOCYTES MERRITT’S NEUROLOGY

CHAPTER 91. NEUROLOGICAL SYNDROMES WITH ACANTHOCYTES TIMOTHY A. PEDLEY AND LEWIS P. ROWLAND Abetalipoproteinemia Neuroacanthocytosis Mcleod Syndrome Suggested Readings

Several neurologic syndromes are associated with abnormal erythrocytes that are called acanthocytes because of the spiny projections from the cell surface. Acantho is derived from a Greek word meaning thorns. Acanthocytes are seen in four neurologic disorders: abetalipoproteinemia, hypolipoproteinemia, neuroacanthocytosis, and McLeod syndrome.

ABETALIPOPROTEINEMIA Abetalipoproteinemia, the Bassen-Kornzweig syndrome, is an autosomal recessive disease characterized by inability of the liver and intestine to secrete apolipoprotein B. It is caused by mutations in the microsomal triglyceride transfer protein gene, not the one for apolipoprotein B. Abetalipoproteinemia was originally defined clinically as a neurologic disorder resembling Friedreich ataxia in patients with chronic steatorrhea and acanthocytes. There have been few autopsy examinations, but the neuropathologic findings account for the clinical syndrome. There is demyelination of the posterior columns, spinocerebellar tracts, and corticospinal tracts. Neuronal changes are seen in the Purkinje cells and molecular layer of the cerebellum and the anterior horn cells. Peripheral nerves show mainly axonal loss with focal areas of demyelination, especially in large myelinated nerves. There is no clear explanation, however, for the clinically evident ophthalmoplegia. Interstitial myocardial fibrosis may be seen. Muscle shows signs of denervation with accumulation of lipopigment. Pathogenesis Abetalipoproteinemia is caused by mutations in the microsomal triglyceride transfer protein, a heterodimer composed of a multifunctional protein, protein disulfide isomerase, and a unique 97-kDa subunit. Mutations that functionally inactivate the 97-kDa subunit lead to defects in the assembly and secretion of apolipoprotein B-containing lipoproteins, probably because apolipoprotein B requires microsomal triglyceride transfer protein to enter the endoplasmic reticulum, where lipoproteins are assembled. Neuropathologic findings and the clinical phenotype result from a nearly complete absence of apolipoprotein B-containing lipoproteins in the plasma. Beta-lipoproteins are an essential component of plasma chylomicrons and very-low-density lipoproteins. Apolipoprotein B is needed for the normal transport of lipids from intestinal mucosa to plasma, but in these patients, it is lacking from intestinal mucosa and plasma. As a result, there is intestinal malabsorption of lipids, and the serum content of lipids is drastically reduced, including cholesterol, triglycerides, and phospholipids. (Serum cholesterol levels, normally 135 to 335 mg/dL, are 25 to 61 mg/dL in affected individuals.) Low-density and very-low-density lipoproteins are also much reduced, as are chylomicrons. Levels of high-density lipoproteins are about 50% of normal. As a consequence of the malabsorption, there is severe deficiency of the fat-soluble vitamins, A, D, E, and K. Vitamin A levels are 0 to 37 µg/dL (normal, 20 to 87), and this deficiency probably plays a role in the retinitis pigmentosa. Vitamin E levels are 0.06 to 0.1 µg/mL (normal, 0.5 to 1.5), a depletion held responsible for the neurologic disorder that resembles the spinocerebellar syndrome seen in other malabsorption states, including cholestatic liver disease and Crohn disease. The abnormal shape of the erythrocytes also seems to be secondary to the hypolipidemia; the red cell membranes show abnormal distribution of lipid constituents. Symptoms and Signs Fatty diarrhea is evident from infancy, with abdominal distention and retarded growth. The children are typically small and underweight, with delayed bone age. The first neurologic abnormality is loss of tendon jerks at about age 5 years. At about age 10, ataxic gait is noted, then limb ataxia, tremor of the head and hands, and evidence of sensorimotor neuropathy: distal limb weakness, distal paresthesias, and glove-stocking and proprioceptive sensory loss. There is also proximal limb weakness with scoliosis in 25% of patients and pedal abnormalities such as pes cavus. Babinski signs are inconsistent ( Table 91.1).

TABLE 91.1. NEUROLOGIC ABNORMALITIES IN A SERIES OF PATIENTS WITH ABETALIPOPROTEINEMIA

Eye movements become progressively restricted, but before ophthalmoplegia is complete, nystagmus may be prominent. Concomitantly, as retinitis pigmentosa develops in adolescence, night-blindness (nyctalopia), with constriction of the visual fields and loss of visual acuity, occurs. The fundi show macular degeneration, with pigmentary degeneration in the midperiphery of the retina, arteriolar narrowing, bone spicules, and angioid streaks. The syndrome is fully developed by age 20. Vitamin K deficiency may lead to subdural or retroperitoneal hemorrhage, or there may be excessive blood loss after surgery. Laboratory Data In addition to the plasma changes mentioned previously, the erythrocyte sedimentation rate is inordinately low, usually 1 mm/hr. Nerve conduction studies and electromyography indicate that the neuropathy is primarily axonal. Sensory evoked responses imply abnormality in the posterior columns; brainstem auditory responses are normal. Abnormalities of visual evoked potentials and electroretinography reflect the retinal degeneration and optic neuropathy. Electrocardiographic abnormalities, cardiac enlargement, and murmurs imply a cardiomyopathy, but heart block and symptomatic congestive heart failure are not part of the picture. Diagnosis The neurologic disorder resembles Friedreich ataxia, spinocerebellar degeneration, sensorimotor peripheral neuropathy, and progressive external ophthalmoplegia. The first clue to the diagnosis of abetalipoproteinemia is the finding of low values for serum cholesterol. Identifying acanthocytes usually requires a fresh blood smear (without ETDA) and even then may go unrecognized unless the technician has been asked to look for them specifically. Measurement of serum beta-lipoprotein and plasma lipids confirms the diagnosis.

Treatment The essential element of treatment is dietary supplementation with vitamin E in doses of 10,000 to 25,000 units daily; blood levels should be monitored to avoid liver damage. In addition, adults should be given vitamin K, at least 5 mg daily. Supplemental corn oil has been recommended to correct or prevent deficiency of essential fatty acids. With adequate tocopherol therapy, progression of the neurologic and retinal abnormalities ceases, and some patients even improve. Treatment is most effective when given early, preferably before neurologic signs are apparent. Under these circumstances, the neurologic syndrome may be prevented. Replacement therapy in adults with established symptoms is usually only partially successful. Hypobetalipoproteinemia is an autosomal dominant disorder caused by different mutations in the gene for apolipoprotein B (apoB100), all of which seem to result in production of truncated forms of beta-lipoprotein that cannot be secreted by hepatocytes and enterocytes. In heterozygous patients, plasma levels of lipoproteins are about 50% of normal. An animal model has been created by gene targeting. Levels of low-density-lipoprotein cholesterol and triglycerides are also low. Heterozygous individuals usually have no neurologic symptoms. In contrast, homozygous patients usually have prominent steatorrhea, adult-onset ataxia, retinitis, and neuropathy with acanthocytosis, as in abetalipoproteinemia.

NEUROACANTHOCYTOSIS Neuroacanthocytosis (Levine-Critchley syndrome or chorea-acanthocytosis) is a multisystem neurodegenerative disorder characterized by acanthocytes, normal plasma lipids and lipoproteins, and variable neurologic manifestations. Onset is usually in the fourth or fifth decade, but both juvenile and elderly forms are known. The most consistent clinical feature is a hyperkinetic movement disorder (chorea, orofacial dyskinesias, and dystonia). In many patients, dementia follows psychiatric features, including obsessive-compulsive disorder and personality changes. An axonal neuropathy with muscle wasting, weakness, and absent deep tendon reflexes occurs in most patients. About 40% of patients have epileptic seizures. The course is one of progressive disability, with a mean duration of illness of about 14 years. Only symptomatic therapy is available, but response of the involuntary movements to drug treatment is generally poor. The clinical picture correlates with neuronal degeneration and astrocytic proliferation within the basal ganglia and substantia nigra. Despite the dementia and psychiatric symptoms, the cerebral cortex is histologically normal. The axonal neuropathy involves primarily large-diameter myelinated fibers, and muscle biopsy shows findings consistent with denervation. Magnetic resonance imaging findings are similar to those of Huntington chorea, including prominent atrophy of the caudate nuclei and increased T2 signal within the striatum. Neuroacanthocytosis is typically familial, although sporadic cases occur. Most affected families exhibit an autosomal dominant pattern of inheritance; in others, however, autosomal recessive inheritance seems likely The disease has been linked to chromosome 9q21.

MCLEOD SYNDROME The McLeod syndrome is an X-linked disorder defined by abnormal expression of the Kell blood group antigens and absence of the Kx erythrocyte surface antigen. The first cases were found in asymptomatic people who were donating blood and had blood typing carried out. When they were studied hematologically, the acanthocytes were recognized, and so were high serum levels of creatine kinase, high enough to suggest a true myopathy. Later, some people with the condition were found to have a symptomatic myopathy, amyotrophy, or involuntary movements, and a permanent hemolytic state. In some patients, the clinical features are similar to those of neuroacanthocytosis. The McLeod syndrome results from a point mutation in the XK gene, which encodes a membrane transport protein. The XX protein corresponds to the Kx antigen and is associated with a marked reduction in all Kell antigens. Mutations in the XK gene result in premature termination of translation, so that the aberrant protein has only 128 amino acids instead of 444 and lacks 7 of the normal 10 transmembrane segments. Because several patients with a clinical diagnosis of McLeod syndrome have lacked any abnormality in the XK gene and because at least two point mutations have been found in normal subjects, it is unclear how often mutations in the McLeod gene lead to neurologic disease. The triad of creatine kinase myopathy, acanthocytosis, and neurologic disorder may be caused by mutations in contiguous genes. SUGGESTED READINGS Brin MF. Acanthocytosis. Handb Clin Neurol 1993;19(Part 1):271–299. Du EZ, Wang SL, Kayden HJ, et al. Translocation of apolipoprotein B across the endoplasmic reticulum is blocked in abetalipoproteinemia. J Lipid Res 1996;37:1309–1315. Feinberg TE, Cianci CD, Morrow JS, et al. Diagnostic tests for choreoacanthocytosis. Neurology 1991;41:1000–1006. Hardie AE, Pullon HW, Harding AE, et al. Neuroacanthocytosis;a clinical, haematological, and pathological study of 19 cases. Brain 1991;114:13–49. Harding AE. Vitamin E and the nervous system. Crit Rev Neurobiol 1987;3:89–103. Higgins JJ, Patterson MC, Papadopoulos NM, et al. Hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome). Neurology 1992;42:194–198. Ho MF, Chalmers RM, Davis MB, Harding AE, Monaco AP. A novel point mutation in the McLeod syndrome gene in neuroacanthocytosis. Ann Neurol 1996;39:672–675. Kim E, Cham CM, Veniant MM, Ambroziak P, Young SG. Dual mechanisms for the low plasma levels of truncated apolipoprotein B proteins in familial hypobetalipoproteinemia. Analysis of a new mouse model with a nonsense mutation in the Apob gene. J Clin Invest 1998;101:1468–1477. Levine IM, Estes JW, Looney JM. Hereditary neurological disease with acanthocytosis. A new syndrome. Arch Neurol 1968;19:403–409. Levy E. The genetic basis of primary disorders of intestinal fat transport. Clin Invest Med 1996;19:317–324. Lodi R, Rinaldi R, Gaddi A, et al. Brain and skeletal muscle bioenergetic failure in familial hypolipoproteinemia. J Neurol Neurosurg Psychiatry 1998;62:574–580. MacGilchrist AJ, Mills PR, Noble M, et al. Abetalipoproteinemia in adults: role of vitamin therapy. J Inherit Metab Dis 1988;11:184–190. Muller DPR, Lloyd JK, Wolff OH. The role of vitamin E in the treatment of the neurological features of abetalipoproteinemia and other disorders of fat absorption. 1]:88–92.

J Inherit Metab Dis 1985;8[Suppl

Rader DJ, Brewer HB Jr. Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease. JAMA 1993;270:865–869. Rehberg EF, Samson-Bouma ME, Kienzle B, et al. A novel abetalipoproteinemia genotype. Identification of a missense mutation in the 97-kDa subunit of the microsomoal triglyceride transfer protein. J Biol Chem 1996;271:29945–29952. Rinne J, Daniel SE, Scaravilli F, et al. The neuropathological features of neuroacanthocytosis. Mov Disord 1994;9:297–304. Ross RS, Gregg RE, Law SW. Homozygous hypobetalipoproteinemia: a disease distinct from abetalipoproteinemia at the molecular level. J Clin Invest 1988;81:590–595. Rubio JP, Danek A, Stone C, et al. Chorea-acanthocytosis: genetic linkage to chromosome 9q21. Am J Hum Genet 1997;61:899–908. Runge P, Muller DP, McAllister J, et al. Oral vitamin E supplements can prevent the retinopathy of abetalipoproteinemia. Br J Ophthalmol 1986;70:166–173. Sakai T, Iwashita H, Kakugawa M. Neuroacanthocytosis syndrome and choreoacanthocytosis (Levine-Critchley syndrome). Neurology 1985;35:1679. Satya-Murti S, Howard L, Krohel G, Wolf B. The spectrum of neurologic disorder from vitamin E deficiency. Neurology 1986;36:917–921. Schwartz JF, Rowland LP, Eder H, et al. Bassen-Kornzweig syndrome: deficiency of serum B-lipoprotein. Arch Neurol 1963;8:438–454.

Shizuka M, Watanabe M, Aoki M, et al. Analysis of the McLeod syndrome gene in three patients with neuroacanthocytosis. J Neurol Sci 1997;150:133–135. Shoulders CC, Brett DJ, Bayliss JD, et al. Abetalipoproteinemia is caused by defects of the gene encoding the 97-kDa subunit of a microsomal triglyceride transfer protein. Hum Mol Genet 1993;2:2109–2116. Sokol RJ. Vitamin E and neurologic deficits. Adv Pediatr 1990;37:119–148. Vance JM, Pericak-Vance BA, Bowman MH, et al. Chorea-acanthocytosis: a report of three new families and implications for genetic counselling. Am J Med Genet 1987;28:403–410. Welterau PJ, Aggerbeeli LP, Bouma ME, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 1992;258:999–1001. Witt TN, Danek A, Reiter M, et al. McLeod syndrome: a distinct form of neuroacanthocytosis. Report of two cases and literature review with emphasis on neuromuscular manifestations. J Neurol 1992;349:302–306.

CHAPTER 92. XERODERMA PIGMENTOSUM MERRITT’S NEUROLOGY

CHAPTER 92. XERODERMA PIGMENTOSUM LEWIS P. ROWLAND Suggested Readings

Xeroderma pigmentosum (MIM 278700) is a rare condition that is not a metabolic disorder in the conventional sense. Rather, cultured cells from affected patients are hypersensitive to being killed or to undergoing mutagenesis by ultraviolet light and chemical carcinogens. Autosomal-recessive inheritance results in lack of a gene product responsible for the excision of damaged deoxyribonucleic acid (DNA) or for replication past the damaged site of DNA. The mutations affect subunits of the transcription/repair factor TFIIH as modified by interaction with several tumor suppressor genes. Some patients have features of both xeroderma pigmentosum and Cockayne syndrome. The syndrome was first described by Kaposi in 1874, but it is also known as the DeSanctis-Cacchione syndrome. Affected individuals show marked cutaneous hypersensitivity to sunlight beginning in early childhood. Erythema and blisters are followed by freckling, keratosis, and skin cancers. Dwarfism is common. Neurologic disorders include microcephaly, mental retardation, chorea, ataxia, corticospinal signs, and either motor neuron disorders or segmental demyelination of peripheral nerves. Hearing loss and supranuclear ophthalmoplegia have been prominent in some patients. In others, the neurologic disorder is more disabling than the cutaneous problems (see Chapter 107). In one autopsy case, the outstanding change was selective neuronal loss in the cerebral cortex, basal ganglia, olivary nuclei, and cerebellum. In another, the findings resembled olivopontocerebellar atrophy. Management includes avoidance of sunlight. One patient with a spinal cord glioma was effectively treated with radiotherapy, without evidence of abnormal responses to x-irradiation. Antenatal diagnosis is possible because cultured amniotic cells show the abnormal patterns of excision repair of DNA. There is no effective treatment for the neurologic disorders. SUGGESTED READINGS Coin F, Marinoni JC, Rodolfo C, Fribourg S, Pedrini AM, Egly JM. Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH. Nat Genet 1998;20:184–188. Ellison AR, Nouspikel T, Jaspers NG, Clarkson SG, Gruenert DC. Complementation of transformed fibroblasts from patients with combined xeroderma pigmentosum-Cockayne syndrome. Exp Cell Res 1998; 243:22–28. Greenhaw GA, Hecht JT, Herbert AA, et al. Xeroderma pigmentosum with severe neurological involvement without significant DNA repair defect. Am J Hum Genet 1989;45:447. Hakamada S, Watanbe K, Sobue G, et al. Xeroderma pigmentosum: neurological, neurophysiological and morphological studies. Eur Neurol 1982;21:69–76. Hwang BJ, Ford JM, Hanawalt PC, Chu G. Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. Proc Natl Acad Sci U S A 1999;96:424–428. Kanda T, Oda M, Gonezawa M, et al. Peripheral neuropathy in xeroderma pigmentosum. Brain 1990;119:1025–1044. Kenyon GS, Booth JB, Prasher DK, Rudge P. Neuro-otological abnormalities in xeroderma pigmentosum with particular reference to deafness. Brain 1985;108:771–784. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum: cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987;123:241–250. Roytta M, Amttinen A. Xeroderma pigmentosum with neurological abnormalities: clinical and neuropathological study. Acta Neurol Scand 1986;73:191–199. Takeda N, Shibuya M, Maru Y. The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein. Proc Nat Acad Sci U S A 1999;96:203–207. Woods CG. DNA repair disorders. Arch Dis Child 1998;78:178–184.

CHAPTER 93. CEREBRAL DEGENERATIONS OF CHILDHOOD MERRITT’S NEUROLOGY

CHAPTER 93. CEREBRAL DEGENERATIONS OF CHILDHOOD EVELINE C. TRAEGER AND ISABELLE RAPIN Spongy Degeneration of the Nervous System (Canavan Disease) Infantile Neuroaxonal Dystrophy Hallervorden-Spatz Disease Pelizaeus-Merzbacher Disease Alexander Disease Cockayne Syndrome Suggested Readings

SPONGY DEGENERATION OF THE NERVOUS SYSTEM (CANAVAN DISEASE) This autosomal-recessive illness (MIM 271900) is one of the more common cerebral degenerative diseases of infancy. Although van Bogaert and Bertrand should be credited with the nosologic identification, it is often called Canavan disease in the United States. It affects all ethnic groups but is especially prevalent among Ashkenazi Jews from eastern Poland, Lithuania, and western Russia, and among Saudi Arabians. A characteristic feature that it shares with Alexander disease and classic Tay-Sachs disease is megalencephaly. The clinical picture is often sufficiently distinctive to suggest the diagnosis. It is prenatal in onset with variable progression; at least 50% of children are symptomatic by 4 months of age. Extremely poor control of the enlarged head, lack of psychomotor development, spasticity, and optic atrophy are the main features. Affected children may achieve smiling, but they are characteristically quiet and apathetic. Few progress far enough to reach for objects or sit, and except for children with a rare protracted variant, none ever walks independently. Seizures occur in more than 50% of patients. By age 2 years, head growth plateaus as progressive parenchymal destruction leads to hydrocephalus ex vacuo. The children eventually become decerebrate and die of intercurrent illness; survival into the second or third decades is not uncommon. Computed tomography (CT) and magnetic resonance imaging (MRI) show increased lucency of the white matter, poor demarcation of gray and white matter ( Fig. 93.1), and, later, severe brain atrophy with ventricular enlargement and gaping sulci. Cerebrospinal fluid (CSF) and nerve conduction velocities are usually normal. The pathology includes two characteristic abnormalities: intramyelinic vacuolation of the deep layers of the cortex, and superficial layers of the white matter and gigantic abnormal mitochondria containing a dense filamentous granular matrix and distorted cristae in the watery cytoplasm of hypertrophied astrocytes. Sponginess eventually becomes diffuse and involves the centrum semiovale, brainstem, cerebellum, and spinal cord. As the disease progresses, the vacuoles enlarge and split the myelin sheath to form cysts that communicate with the extracellular space. This leads to extensive demyelination and tissue destruction with loss of neurons, axons, and oligodendroglia; extensive gliosis follows. Chemical analysis of the brain reveals markedly increased N-acetylaspartic acid (NAA) and water content, and nonspecific loss of myelin and other tissue constituents.

FIG. 93.1. A and B:Axial noncontrast CT in an 11-month-old boy with spongy degeneration. Note the diffuse low density of white matter with occipital preponderance and poor demarcation between gray and white matter. Sulci are mildly widened.

Deficiency of aspartoacylase in skin fibroblasts is diagnostic and is associated with elevated levels of NAA in blood and urine, as well as brain. Carrier detection based on aspartoacylase activity in cultured skin fibroblasts is possible; aspartoacylase activity in amniotic fluid, chorionic villi, or amniocytes is unreliable for prenatal diagnosis. The gene for Canavan disease has been cloned and is located on chromosome 17p. Two mutations account for 97% of the alleles in Ashkenazi-Jewish patients. In non-Jewish patients, the mutations are different and more diverse. Carrier detection and prenatal diagnosis by DNA analysis are available in most but not all high-risk families. Spongy degeneration of the brain also occurs in other conditions, notably intoxication by triethyl tin or hexachlorophene, some neonatal acidurias, some mitochondrial disorders, and the Aicardi-GoutiĂŠres syndrome (leukodystrophy with CSF lymphocytosis and basal ganglia calcification). In fact, prior to DNA analysis, some cases labeled juvenile spongy degeneration that started in childhood with external ophthalmoplegia and pigmentary degeneration of the retina, with or without other neurologic or systemic abnormalities, may have been Kearns-Sayre syndrome or some other mitochondrial disorder.

INFANTILE NEUROAXONAL DYSTROPHY Infantile neuroaxonal dystrophy (Seitelberger disease) (MIM 256600) is an autosomal-recessive disease of unknown etiology that typically becomes manifest between 6 and 18 months of age and leads to death before the end of the first decade, usually after a variable period of purely vegetative existence. The first symptom is arrest of motor development, followed by loss of skills. The children may be floppy, spastic, or both. Most never achieve independent walking or speaking. In some, the motor disorder progresses from the legs, to the arms, and finally to the cranial muscles, causing severe dysphagia. There may be loss of sensation in the legs and urinary retention. Ataxia, nystagmus, and optic atrophy are common, but seizures are rare. The degree of dementia is difficult to ascertain because of anarthria; at first, affected children appear alert and seem to understand some language, but intellectual deterioration eventually becomes severe. A newly described lysosomal storage disease due to alpha- N-acetylgalactosaminidase deficiency has been found in patients with a phenotype similar to that of infantile neuroaxonal dystrophy but differing by the presence of prominent generalized or myoclonic seizures. Atypical variants are seen. A few infants are symptomatic from birth, whereas others experience a later onset and more protracted course, some with prominent myoclonus, others with dystonic features. The relationship of these more chronic cases to Hallervorden-Spatz disease is controversial. Some authorities consider neuroaxonal dystrophy and Hallervorden-Spatz disease to be the same nosologic entity because spheroid formation is seen in both and because there are clinical similarities. Spheroids, however, are not pathognomonic of either disease, and the distribution of these lesions differs in the two disorders; brown discoloration of the globus pallidus occurs only in Hallervorden-Spatz disease. The linkage of Hallervorden-Spatz disease to chromosome 20 in 10 families will help resolve the question of the relationship of the two conditions. The characteristic pathologic picture of neuroaxonal dystrophy is the profusion of axonal spheroids in the brain, spinal cord, and peripheral nerves. Spheroids are eosinophilic, argyrophilic ovoid inclusions that distend axons and myelin sheaths. They may be found anywhere along axons but are especially numerous in axon terminals, including those at the neuromuscular junction. Electron microscopy shows that they contain tubular structures, vesicles, and masses of smooth membranes arranged in stacks or, less often, in circular concentric arrays. The relation of these structures to synaptic vesicles or smooth endoplasmic reticulum is speculative. Spheroids also contain membrane-bound clefts and accumulations of mitochondria. Spheroids are particularly prevalent in the cerebellum, basal ganglia, thalamus, cuneate, gracile, and the brainstem nuclei. The cerebellum is strikingly atrophic because of loss of Purkinje and granular cells. The basal ganglia show neuronal loss and may appear spongy, with demyelinated axons and spheroid deposition. Although lipopigment granules are found in basal ganglia, there is no discoloration visible

to the naked eye. The long tracts of the visual system, corticospinal system, spinocerebellar pathways, and posterior columns are degenerated, and there is pallor of the myelin. No characteristic lesions have been described in the viscera. Biochemical changes in the brain are viewed as nonspecific. Laboratory tests are not helpful. The CSF is usually normal; electroencephalographic (EEG) changes are absent or nonspecific. Nerve conduction velocities may be normal or slow. Electromyography (EMG) usually suggests denervation. T2-weighted MRI shows diffuse cerebellar atrophy with hyperintensity of the cerebellar cortex. Definite diagnosis requires autopsy. Nerve, muscle, rectal, or conjunctival biopsy is confirmatory when spheroids are found in nerves or at the neuromuscular junction, but because of sampling problems normal peripheral nerve or even cortical biopsy does not exclude the diagnosis. There is no chemical or enzymatic test available; intrauterine diagnosis is not feasible. Treatment is limited to symptomatic measures and to support and genetic counseling for the child's family.

HALLERVORDEN-SPATZ DISEASE Hallervorden-Spatz disease (MIM 234200) is an insidiously progressive, autosomal-recessive disease of childhood and adolescence in which motor symptoms predominate. It usually starts with stiffness of gait and is eventually associated with distal wasting, pes cavus or equinovarus, and toe-walking. The arms are held stiffly with hyperextended fingers; the hands may become useless when the child is still ambulatory. The children often have a characteristically frozen, pained expression with risus sardonicus and contracted platysma muscles. They speak through clenched teeth and have difficulty eating. Eventually, they become anarthric, although they continue to understand language. Muscle tone is both spastic and rigid, often with painful spasms, yet passive movement with the patient supine reveals an underlying hypotonia. Reflexes are hyperactive, including facial reflexes, and the toes are usually, but not always, upgoing. Some children become dystonic and assume bizarre postures that suggest dystonia musculorum deformans. Ataxia, tremor, nystagmus, and facial grimacing are seen in some patients, usually early in the illness. Pigmentary degeneration of the retina occurs in some families; in others the eyegrounds are normal or show primary optic atrophy. Assessing intellectual function is difficult; affected children remain alert, and if dementia occurs, it may not be severe. The course of the illness typically spans several decades. Therapy is limited to symptomatic measures. Once the illness is full-blown, the clinical picture is sufficiently characteristic to suggest the diagnosis. T2-weighted MRI demonstrates striking hypointensity in the globus pallidus, so-called eye-of-the-tiger sign. Rare patients have osmiophilic deposits in lymphocytes and bone marrow macrophages resembling sea-blue histiocytes. Definite diagnosis requires autopsy because the biochemical basis of the illness is unknown. Linkage of Hallervorden-Spatz disease to chromosome 20p12.3-p13 has been reported in 10 families. Evidence for locus heterogeneity in other families does exist. The pathology is so restricted in distribution that biopsy diagnosis is not practical. Olive or golden brown discoloration of the medial segment of the globus pallidus is the macroscopic hallmark of Hallervorden-Spatz disease. Less striking discoloration occurs in the red nucleus and zona reticulata of the substantia nigra. This appearance is due to granules of an iron-containing lipopigment (similar to neuromelanin) located inside and outside the neurons and hyperplastic astrocytes. Irregular mulberry concretions, some calcified, lie free in the tissue. Increased amounts of iron and other metals (e.g., zinc, copper) and calcium are found in the affected tissue, which contains axonal spheroids identical to those seen in neuroaxonal dystrophy. Neuronal loss and thinning of myelin sheaths are prominent in the globus pallidus, less severe in the rest of the basal ganglia, and uncommon elsewhere, although mild cerebellar atrophy does occur. In contrast to infantile neuroaxonal dystrophy, only small numbers of spheroids are found in the cortex and cerebral white matter. Variants (Hallervorden-Spatz syndrome) include mid- or late-adult onset. Symptoms include acanthocytosis with or without hypoprebetalipoproteinemia.

PELIZAEUS-MERZBACHER DISEASE The two clinical forms of Pelizaeus-Merzbacher disease (PMD) (MIM 312080) are both X-linked recessive and linked to the proteolipid protein (PLP) gene. One form is present at birth, the so-called connatal variant of Seitelberger, and the other is an infantile variant with a more protracted course, which is the classic form. A prominent, irregular nystagmus and head tremor or head rolling from birth or the first few months of life are the most striking features of both forms. In the connatal form, these symptoms are associated with floppiness, head lag, grayness of the optic discs, and stridor. Meaningful development does not occur. Boys develop ataxia, severe spasticity, and optic atrophy. Seizures, microcephaly, and failure to thrive supervene, and most infants succumb in the first years of life. Others survive for 8 to 12 years but are mute with limited intellect, despite apparent alertness. In the classic form, slow motor development may enable the children to reach for objects, roll over, crawl, and say a few words. Independent walking is rarely achieved; even these few developmental milestones are lost as increasing ataxia, spasticity with hyperreflexia, and choreoathetotic movements develop. By school age, the affected boy is often mute and confined to a wheelchair. Patients are likely to develop kyphoscoliosis and joint contractures; they become incontinent. Sensory loss does not occur. Dementia is difficult to assess but may not be profound. Optic atrophy is not severe. Hearing is preserved. Despite severe growth failure and small muscle mass, there is little further deterioration until the patient dies of an intercurrent illness, usually in late adolescence or early adulthood. Normal nerve conduction velocities and usually normal CSF protein help differentiate the connatal variant from Krabbe disease and metachromatic leukodystrophy. Prominent nystagmus is the main differentiating symptom from infantile neuroaxonal dystrophy and early-onset Hallervorden-Spatz disease. EEG is normal or mildly slow. CT shows ventricular dilatation, decreased differentiation of gray and white matter, and cerebellar atrophy. T2-weighted MRI shows diffuse elongation in the white matter with atrophy, findings similar to those of other leukodystrophies. At autopsy, the brain, cerebellum, brainstem, and spinal cord of children with the connatal variant are essentially devoid of myelin. In the late infantile variant, characteristic changes are limited to brainstem and cerebellar white matter. The hallmark of PMD is a tigroid appearance of the white matter on myelin stains because of perivascular islands of spared myelin against a nonmyelinated background. There is no sparing of U fibers. Axons are spared but are almost devoid of oligodendroglia. The cerebral cortex is preserved, although large pyramids in layer V of the motor cortex (Betz cells) may be lacking in the connatal form. Neuronal dropout is not severe, with the possible exception of granular cell loss in the cerebellum. Areas of cerebral dysgenesis and micropolygyria have been observed too often to be coincidental. Peripheral nerves are characteristically well myelinated. Missense mutations of the X-linked PLP gene, a component of myelin, have been documented in 10% to 25% of patients with PMD. Tight linkage to the PLP gene has been documented in most others; recent studies suggest that duplications of the gene may be a frequent cause of the disease in this group. Differences in trafficking of the two PLP gene products, PLP and and its smaller isoform DM20, correlate with the phenotypic variability of the connatal and classic forms of disease. A clinically distinct disease, X-linked spastic paraplegia type 2, in which demyelination spares most of the central white matter but selectively affects the spinal tracts, is also linked to PLP.

ALEXANDER DISEASE Two main variants of Alexander disease (MIM 203450), which appears to affect astrocytes primarily, occur in children. The first is a rapidly progressive infantile variant that causes megalencephaly, severe motor and developmental deficits, and seizures. The large head is usually due to an enlarged brain, but some children develop hydrocephalus owing to an obstruction of the aqueduct of Sylvius by Rosenthal fibers. The children are usually but not invariably spastic. Most die in a vegetative state in infancy or during the preschool years. A few children survive into the second decade. Neuroimaging suggests the diagnosis when there is marked demyelination with frontal predominance, especially if there are enlarged ventricles with a zone of increased density in the subependymal region ( Fig. 93.2). Occasionally, the basal ganglia appear necrotic on CT, as in the infantile variant of Leigh disease. The main differential diagnosis is spongy degeneration, suggested by the enlarged head, early dementia, and decreased density of white matter, although optic atrophy is not characteristic of Alexander disease. Autosomal-recessive inheritance is suggested by some pedigrees.

FIG. 93.2. A and B:Axial contrast CT in a 29-month-old girl with Alexander disease. Note the low density of the white matter with frontal-to-occipital gradient and increased periventricular density.

The juvenile variant (or variants) has a more indolent, protracted course (usually without seizures), or it may present in adults with signs of bulbar palsy and ataxia with or without intellectual deterioration and spasticity. Few of these late-onset cases are familial. Alexander disease is defined by the principal histologic characteristic, the so-called Rosenthal fibers, which are hyaline, eosinophilic, and argyrophilic inclusions found exclusively in astrocytic footplates. Rosenthal fibers contain small stress proteins: alpha B-crystallin and heat shock protein 27 (HSP27). The relationship of these proteins to the pathogenesis of the disease is not understood. Rosenthal fibers are characteristically distributed in subpial, subependymal, and perivascular locations. In some patients, especially infants, the fibers are found diffusely in the brain and spinal cord, especially the floor of the fourth ventricle. Rosenthal fibers are not pathognomonic of this illness; they occur in pilocytic astrocytomas, are rarely associated with multiple sclerosis plaques, and have been reported in adolescents and adults without known neurologic symptoms. Demyelination with loss of oligodendroglia and sparing of axons occurs in regions rich in Rosenthal fibers. In infantile cases, demyelination of the centrum semiovale is so severe that it may lead to cavitation; loss of myelin is most severe frontally and has a characteristic frontal-to-occipital gradient. The myelin of peripheral nerves is spared. Neurons are also spared, with the exception of brainstem motor neurons in some juvenile and adult patients with bulbar symptoms, and of basal ganglia neurons in some infantile cases. No characteristic biochemical abnormality has been reported except for the loss of myelin constituents in patietns with severe demyelination. The fibers are proteinaceous, but whether they are derived from degraded glial filaments is not certain. Presumptive diagnosis may be made clinically, aided by neuroimaging and elevated levels of alpha B-crystallin and HSP27 in the CSF. Prenatal diagnosis is not yet possible. Therapy remains purely symptomatic.

COCKAYNE SYNDROME Cockayne syndrome (MIM 216400) is a progressive multisystem disease with autosomal-recessive inheritance characterized by extreme dwarfing, a characteristic cachectic appearance, and neurologic deterioration. The children are of normal size at birth. Failure to thrive with progressive decrease in height, weight, and head circumference becomes apparent before the child reaches age 2 years. These growth measures are many standard deviations below the mean by midchildhood or adolescence. Affected children have an arresting facies with large ears, long aquiline nose, deep-set eyes, thin lips, and jutting chin; the appearance is often accentuated by the loss of severely carious teeth. Some children have atrophic or hyperpigmented skin changes over exposed areas, especially the face. Body proportions, although miniature, are appropriate for the child's age. Signs of maturation, such as the shedding of deciduous teeth and puberty, occur on time, although testes and breasts are usually underdeveloped. The children may suffer from carbohydrate intolerance and anomalies of renal function. Most survive at least into the second decade. Intellectual development is extremely limited, but affected children remain alert and have pleasant personalities. Most do not speak, and many do not walk independently because of progressive spasticity, widespread joint contractures, and deformities of the feet. Some have signs of a peripheral neuropathy and are ataxic. Many become deaf, and vision is impaired as the result of variable combinations of corneal opacity, cataract, pigmentary degeneration of the retina, and optic atrophy. The pupils are meiotic and respond poorly to mydriatics. Tearing is reduced or absent. Plain radiographs of the skull and CT typically show stippled calcification in the basal ganglia. Nerve conduction velocities are slow, and CSF protein may be elevated. The diagnosis is suggested by the clinical features. The main differential diagnosis is Seckel (bird-headed) dwarfism, in which dwarfing is invariably present at birth, with extremely low weights for gestational age. The children do not suffer from progressive physical and neurologic deterioration; they learn to walk and speak, despite their extreme microcephaly; they are less retarded than children with Cockayne syndrome but share similar dysmorphic features. Children with progeria are usually of normal intelligence and have much more prominent signs of premature aging than children with Cockayne syndrome, who do not lose their hair, for example, even though mild, early graying may occur. The brains of children with Cockayne syndrome (and of Seckel dwarfs) are tiny, weighing 500 to 700 g. A prominent feature is extreme thinness of the white matter, which has a tigroid appearance on myelin stains because of islands of myelinated fibers amid areas without myelin, a pattern reminiscent of that seen in PMD. Calcification of the basal ganglia and cerebellar atrophy are typical. Developmental anomalies include areas of deficient gyration of the neocortex and hippocampus, defective cell migration and cortical lamination, and evidence of diffuse neuronal and axonal loss. These findings indicate that the disease starts prenatally, despite allegedly normal head circumference and development in infancy. Other pathology features include grotesque dendrites of Purkinje cells and multinucleate astrocytes. Cockayne fibroblasts and amniocytes are unable to recover their ribonucleic acid synthesis after ultraviolet irradiation. They are defective in the preferential repair of transcriptionally active genes. Cockayne syndrome is genetically heterogeneous, and so far two genes have been cloned. A few children suffer from both Cockayne syndrome and xeroderma pigmentosum (XP), another disease affecting DNA repair mechanisms resulting in extreme sensitivity to ultraviolet light. There are atypical Cockayne and Cockayne/XP cases, including both neonatal and adult variants. The complexities of the genetics of these related disorders and the pathophysiology of the Cockayne phenotype are not fully understood. SUGGESTED READINGS Spongy Degeneration of the Nervous System (Canavan Disease) Banker BQ, Robertson JT, Victor M. Spongy degeneration of the central nervous system in infancy. Neurology 1964;14:981–1001. Cardenas-Mera N, Campos-Castello J, Lucas F, et al. Progressive familial encephalopathy in infancy with calcification of the basal ganglia and cerebrospinal fluid lymphocytosis. Acta Neuropediatr 1995;1:207–213. Gascon GG, Ozand PT, Mahdi A, et al. Infantile CNS spongy degeneration—14 cases: clinical update. Neurology 1990;40:1876–1882. Matalon R, Michals-Matalon K. Molecular basis of Canavan disease. Eur J Paediatr Neurol 1998;2:69–76. Matalon R, Michals K, Sebesta D, et al. Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet 1988;29:463–471. McAdams H, Geyer C, Done S, et al. CT and MR imaging of Canavan disease. AJNR 1990;11:397–399. Toft PB, Geiss-Holtorff R, Rolland MO, et al. Magnetic resonance imaging in juvenile Canavan disease. Eur J Pediatr 1993;152:750–753. Traeger EC, Rapin I. The clinical course of Canavan disease. Pediatr Neurol 1998;18:207–212. Van Bogaert L, Bertrand I. Spongy degeneration of the brain in infancy. Springfield, IL: Charles C Thomas, 1967.

Infantile Neuroaxonal Dystrophy Dorfman LJ, Pedley TA, Tharp BR, Scheithauer BW. Juvenile neuroaxonal dystrophy: clinical, electrophysiological, and neuropathological features. Ann Neurol 1978;3:419–428. Gilman S, Barrett RE. Hallervorden-Spatz disease and infantile neuroaxonal dystrophy. J Neurol Sci 1973;19:189–205. Scheithauer BW, Forno LS, Dorfman LJ, Lane CA. Neuroaxonal dystrophy (Seitelberger's disease) with late onset, protracted course and myoclonic epilepsy. J Neurol Sci 1978;36:247–258. Tanabe Y, Iai M, Ishii M, et al. The use of magnetic resonance imaging in diagnosing infantile neuroaxonal dystrophy. Neurology 1993; 43:110–113. Taylor TD, Litt M, Kramer P, et al. Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. Nat Genet 1996;14:479–481. Erratum: Nat Genet 1997;16:109. Wolfe DE, Schindler D, Desnick RJ. Neuroaxonal dystrophy in infantile alpha- N-acetylgalactosaminidase deficiency. J Neurol Sci 1995;132:44–56. Hallervorden-Spatz Disease Jankovic J, Kirkpatrick JB, Blomqvist KA, et al. Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism. Neurology 1985;35:227–234. Orrell RW, Amrolia PJ, Heald A, et al. Acanthocytosis, retinitis pigmentosa, and pallidal degeneration: a report of three patients, including the second reported case with hypoprebetalipoproteinemia (HARP syndrome). Neurology 1995;45:487–492. Porter-Grenn L, Silbergleit R, Mehta BA. Hallervorden-Spatz disease with bilateral involvement of globus pallidus and substantia nigra: MR demonstration. J Comput Assist Tomogr 1993;17:961–963. Taylor TD, Litt M, Kramer P, et al. Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. Nat Genet 1996;14:479–481. Erratum: Nat Genet 1997;16:109. Wigboldus JM, Bruyn GW. Hallervorden-Spatz disease. In: Vinken PJ, Bruyn GW, eds. Diseases of the basal ganglia. Handbook of clinical neurology, vol 6. New York: Wiley Interscience, 1968:604–631. Zupane M, Chun R, Gilbert-Barnes E. Osmiophilic deposits in cytosomes in Hallervorden-Spatz syndrome. Pediatr Neurol 1990;6:349–352. Pelizaeus-Merzbacher Disease Gow A, Lazzarini RA. A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. Nat Genet 1996;13:422–427. Koepper AH, Ronca NA, Greenfield EA, Hans MB. Defective biosynthesis of proteolipid protein in Pelizaeus-Merzbacher disease. Ann Neurol 1987;21:159–170. Saugier-Veber P, Munnich A, Bonneau D, et al. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet 1994;6:257–262. Seitelberger F. Pelizaeus-Merzbacher disease. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, vol 10. New York: Elsevier-North Holland, 1970:150–202. Seitelberger F. Neuropathology and genetics of Pelizaeus-Merzbacher disease. Brain Pathol 1995;5:267–273. Sistermans EA, de Coo R, De Wijs IJ, et al. Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology 1998;50:1749–1754. Takanashi J, Sugita K, Osaka H, Ishii M, Niimi H. Proton MR spectroscopy in Pelizaeus-Merzbacher disease. AJNR 1997;18:533–535. Alexander Disease Borrett D, Becker LE. Alexander disease: a disease of astrocytes. Brain 1985;108:367–385. Head MW, Corbin E, Goldman JE. Overexpression and abnormal modification of the stress proteins alpha B-crystallin and HSP27 in Alexander disease. Am J Pathol 1993;143:1743–1753. Holland IM, Kendall BE. Computed tomography in Alexander's disease. Neuroradiology 1980;20:103–106. Shah M, Ross J. Infantile Alexander disease: MR appearance of a biopsy-proved case. AJNR 1990;11:1105–1106. Takanashi J, Sugita K, Tanabe Y, Niimi H. Adolescent case of Alexander disease: MR imaging and MR spectroscopy. Pediatr Neurol 1998;18:67–70. Cockayne Syndrome Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1946;21:52–54. Friedberg EC. Xeroderma pigmentosum, Cockayne syndrome, helicases and DNA repair. Cell 1992;128:1233–1237. Goldstein S. Human genetic disorders which feature accelerated aging. In: Schneider EL, ed. The genetics of aging. New York: Plenum Publishing, 1978. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum: cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987;123:241–250. Lehmann AR, Francis AJ, Giannelli P. Prenatal diagnosis of Cockayne's syndrome. Lancet 1985;1:486–488. Moriwaki S, Stefanini M, Lehmann A, et al. DNA repair and ultraviolet mutagenesis in cells from a new patient with xeroderma pigmentosum group G and Cockayne syndrome resemble xeroderma pigmentosum cells. J Invest Dermatol 1996;107:647–653. Seckel HPG. Birdheaded dwarfism. Basel: Karger, 1960. Sofer D, Grotsky HW, Rapin I, Suzuki K. Cockayne syndrome: unusual pathological findings and review of the literature. Ann Neurol 1979;6:340–348. Venema J, Mullenders LH, Natarajan AT, et al. The genetic defect in Cockayne syndrome is associated with a defect in repair of UV-induced DNA damage in transcriptionally active DNA. Proc Natl Acad Sci U S A 1990;87:4707–4711.

CHAPTER 94. DIFFUSE SCLEROSIS MERRITT’S NEUROLOGY

CHAPTER 94. DIFFUSE SCLEROSIS LEWIS P.ROWLAND Suggested Readings

Some eponyms have lasted for more than 100 years; some come and go. Schilder disease has had its day and seems to be disappearing. Part of the problem was Schilder's genius for recognizing what were then new syndromes. In 1912, 1913, and 1924, he described three different patients with diffuse demyelination of the brain. Each of the cases was dramatic, and his contribution was recognized; diffuse sclerosis was called Schilder disease. Unfortunately for the eponym, later advances identified the 1913 description as one of adrenoleukodystrophy, and the 1924 patient had subacute sclerosing panencephalitis. Nevertheless, the 1912 case delineated a clinical and pathologic syndrome that is still seen, even though cases of uncomplicated diffuse sclerosis are so few that each encounter results in a case report. In 1994, Afifi and colleagues counted 12 cases since 1912. The situation was not helped by introduction of the term myelinoclastic as a tongue-twisting way of denoting demyelination in children; it was intended to distinguish the disorder from dysmyelination or loss of myelin because of an inherited biochemical abnormality in the myelin. Schilder disease was and is regarded as a variant of multiple sclerosis, but the etiology and pathogenesis are not known. At autopsy, there are large areas of demyelination in the centrum ovale ( Fig. 94.1), with relative preservation of axons. Subcortical U fibers are often spared. In acute lesions, there is perivascular infiltration by lymphocytes and giant cells. There may be actual necrosis. The lesions are similar to those of multiple sclerosis. In fact, in most cases that include large areas of demyelination, there are also smaller, more typical lesions of multiple sclerosis. For these cases, the term transitional sclerosis has been used. It is assumed that the small lesions coalesce to form the large ones.

FIG. 94.1. Diffuse myelinoclastic sclerosis. On myelin sheath staining, there is almost complete loss of myelin in occipital white matter. U fibers are irregularly involved. (Courtesy of Dr. H. Shiraki, Tokyo.)

The clinical syndrome is a leukoencephalopathy, with progressive dementia, psychosis, corticospinal signs, and loss of vision caused by either optic neuritis with papilledema or cerebral blindness. Brainstem signs may include nystagmus and internuclear ophthalmoplegia. The disease is relentlessly progressive, with average survival of about 6 years but sometimes as long as 45 years. Diagnosis depends on imaging. Computed tomography shows large areas of ring-enhancing lucency. Magnetic resonance imaging shows gadolinium enhancement. There may be cerebrospinal fluid pleocytosis with evidence of intrathecal synthesis of gamma globulin and oligoclonal bands. Brain biopsy may be needed to identify the few cases that simulate mass lesions. The differential diagnosis includes other childhood leukoencephalopathies (see Chapter 95). Most important is the exclusion of adrenoleukodystrophy, which is achieved by measurement of very-long-chain fatty acids. In areas where measles vaccination has not been practiced, subacute sclerosing panencephalitis must be considered. Steroid therapy is ineffective; management is therefore symptomatic. SUGGESTED READINGS Afifi AK, Bell WE, Menezs AH, Moore SA. Myelinoclastic diffuse sclerosis (Schilder's disease): report of a case and review of the literature. J Child Neurol 1994;9:398–403. Anselmi G, Masdeu JC, Macaluso C, Donnenfeld H. Disseminated-diffuse sclerosis: a variety of multiple sclerosis with characteristic clinical, neuroimaging, and pathological findings. J Neuroimaging 1993;3:143–145. Bonsack TA, Robertson RL, Lacson A, Casadonte JA, Buonomo C. Pediatric case of the day: myelinoclastic diffuse sclerosis (MDS) (Schilder disease). Radiographics 1996;16:1509–1511. Dresser LP, Tourian AY, Anthony DC. A case of myelinoclastic diffuse sclerosis in an adult. Neurology 1991;41:316–318. Eblen F, Premba M, Grodd W, et al. Myelinoclastic diffuse sclerosis (Schilder's disease): cliniconeuroradiologic correlations. Neurology 1991;41:589–591. Hainfellner JA, Schmidbauer M, Schmitahard E, et al. Devic's neuromyelitis optica and Schilder's myelinoclastic diffuse sclerosis. J Neurol Neurosurg Psychiatry 1992;55:1194–1196. Poser CM, Foutieres F, Carpentier MA, Aicardi J. Schilder's myelinoclastic diffuse sclerosis. Pediatrics 1986;77:107–112. Schilder P. Zur Kenntnis der sogennanten diffusen Sklerose. Z Gesamte Neurol Psychiatrie 1912;10:1–60. Sewick LA, Lingele TG, Burde RM, et al. Schilder's (1912) disease: total cerebral blindness due to acute demyelination. Arch Neurol 1986;43:85–87. Stachniak JB, Mickle JP, Ellis T, Quisling R, Rojiani AM. Myelinoclastic diffuse sclerosis presenting as a mass lesion in a child with Turner's syndrome. Pediatr Neurosurg 1995;22:266–269.

CHAPTER 95. DIFFERENTIAL DIAGNOSIS MERRITT’S NEUROLOGY

CHAPTER 95. DIFFERENTIAL DIAGNOSIS EVELINE C.TRAEGER AND ISABELLE RAPIN

Although most of the degenerative diseases of infancy and childhood are not treatable today, neurologists are obligated to make as definite a diagnosis as possible. This allows them to provide the parents with a prognosis and genetic counseling. Of course, physicians are on the alert for the few treatable conditions, but there is also responsibility to advance knowledge, and precise diagnosis is the first step toward unraveling the chemical pathology of the illness and devising therapy. Clinicians' first concern is to determine that the illness is in fact progressive and to review the genetic evidence. Findings on physical and neurologic examination almost always narrow the diagnostic possibilities and guide the selection of laboratory tests. The most powerful diagnostic resource is Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/Omin), which can be searched by phenotype and provides an extensive and up-to-date differential diagnosis of all currently identified genetic diseases. This database is authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins University and elsewhere and was developed for the World Wide Web by the National Center for Biotechnology Information. Deterioration is usually obvious when a disease affects an adult or adolescent, but in infancy and early childhood, the slope of the developmental curve is so steep that it can mask functional decay, as a child's symptoms represent the net difference between the two opposing trends ( Fig. 95.1). An early sign of insidious dementia may be slowing of development rather than loss of milestones. As long as a child continues to acquire new skills, even too slowly, the illness is likely to be misinterpreted as a static condition. When the disease is already advanced at birth, dementia can masquerade as total failure to develop, suggesting an unrecognized intrauterine or perinatal catastrophe. In these situations, the correct diagnosis may not be contemplated until after the birth of an affected sibling.

FIG. 95.1. Theoretical curves show the possible effects of progressive brain dysfunction on behavior, depending on time of onset and rapidity of course. The curve depicting observed behavior ( ) is the difference between the curves indicating expected development (---) and brain function ( ). A: Prenatal onset with damage at birth so advanced that no development is observed, suggesting a severe static encephalopathy. B: Prenatal onset with damage at birth somewhat less severe than in A. Development is minimal and markedly delayed but does appear to take place initially. C,D: Onset at birth with a less acute course. E: Onset in adulthood. Note that in B, C, and D loss of milestones may not appear until months or years after the onset of the illness, which therefore does not appear progressive unless it is realized that deceleration of development or developmental standstill implies deteriorating function. When a progressive disease starts after adolescence (E), loss of function should be less delayed and the disease recognized as progressive virtually from its start. F: A severe static lesion acquired postnatally may produce total regression acutely, but development may be expected to resume until the time of puberty. (From Rapin I. Progressive genetic metabolic diseases. In: Rudolph AM, ed. Pediatrics, 16th ed. New York: Appleton-Century-Crofts, 1977; with permission.)

A family history of similar disease or consanguinity is a strong clue, but neither is frequent. Most of these diseases are recessive, and the birth of the first affected child occurs as a sporadic event. It is important to detect X-linked diseases ( Table 95.1) because even in the absence of a specific method for intrauterine diagnosis, sex identification of the fetus can limit the birth of affected children. Knowing that certain diseases are particularly frequent in children of particular ethnic backgrounds is also helpful (Table 95.2).

TABLE 95.1. UNUSUAL PATTERN OF INHERITANCE OTHER THAN AUTOSOMAL RECESSIVE

TABLE 95.2. PREDOMINANT ETHNIC BACKGROUND IN CERTAIN DISEASES

The age at onset may be a lead to the diagnosis ( Table 95.3). Genetically homogeneous syndromes tend to run a predictable course and appear at about the same age, but what is considered to be genetically homogeneous today is likely to prove to be nonhomogeneous tomorrow because phenocopies are common. As a general rule, the younger a child is when the symptoms appear, the more rapid is the deterioration, but there are exceptions. For example, when Pelizaeus-Merzbacher disease is manifest before age 1 year, the patient may survive into the third decade. Two diseases of midchildhood or adolescence can

progress rapidly to death from liver failure (Wilson disease) or adrenal insufficiency (adrenoleukodystrophy).

TABLE 95.3. TYPICAL AGE AT ONSET

The general physical examination may provide helpful clues ( Table 95.4). The neurologic symptoms and signs indicate which systems are most affected. Intractable seizures, abnormal involuntary movements, and myoclonus are more typical of diseases of gray matter than of white matter ( Table 95.5), whereas spasticity appears early in diseases of white matter. Spasticity may also be the result of diffuse neuronal dropout; it then occurs in later stages of the disease. Hypotonia suggests involvement of peripheral nerves, anterior horn cells, or cerebellum ( Table 95.6). The combination of hypotonia and increased reflexes, seen in Tay-Sachs disease, suggests that both upper and lower motor neurons are affected. Ataxia and abnormal involuntary movements are particularly useful diagnostic signs. Sensory abnormalities are rarely detectable; lack of sensitivity to pain suggests dysautonomia and is reported in some cases of infantile neuroaxonal dystrophy.

TABLE 95.4. HELPFUL CLUES IN THE PHYSICAL EXAMINATION

TABLE 95.5. DISEASES WITH PROMINENT SEIZURES OR MYOCLONUS

TABLE 95.6. MOTOR SIGNS HELPFUL TO DIAGNOSIS

The eyes are so likely to provide information of diagnostic importance that detailed examination is mandatory ( Table 95.7). Dilating the pupil is required to afford an adequate view of the peripheral retina, macula, and disc. The mild corneal haze of some of the mucolipidoses and mucopolysaccharidoses and the detection of early Kayser-Fleischer rings call for slit-lamp examination. Electroretinography may disclose pigmentary degeneration of the retina before it is visible with the ophthalmoscope.

TABLE 95.7. EYE FINDINGS

Repeated neuropsychologic testing may be needed to document progressive dementia. Lack of dementia, at least early, in the face of motor deterioration suggests a disease that spares the cortex and selectively affects the basal ganglia, brainstem, or cerebellar pathways. In children with an undiagnosed disease, laboratory investigations are screening devices. How many are used depends partly on accessibility and cost ( Table 95.8). “New” diseases are often discovered serendipitously rather than after a directed diagnostic endeavor.

TABLE 95.8. USEFUL LABORATORY TESTS

Electrical studies may yield clues ( Table 95.9). The plain electroencephalogram rarely provides decisive information. However, photomyoclonus suggests Lafora disease, and action myoclonus suggests sialidosis, ceroid lipofuscinosis, myoclonic epilepsy with ragged-red fibers (MERRF) syndrome, Gaucher disease type III, and Baltic myoclonus.

TABLE 95.9. ELECTRODIAGNOSIS

Radiologic tests are crucial in some cases. Adrenal calcification is virtually pathognomonic of Wolman disease. The diagnostic yield of plain radiographs of the skull is extremely low, in contrast to the efficiency of computed tomography (CT) or magnetic resonance imaging (MRI). Even if CT or MRI shows only nonspecific atrophy, this is helpful if it is progressive. Adrenoleukodystrophy and Canavan, Alexander, and Krabbe diseases show characteristic patterns of lucency of white matter. A tiger's-eye pattern of the basal ganglia points to Hallervorden-Spatz disease, and lucency of the basal ganglia to acute mitochondrial encephalopathy. Lack of radioactive copper absorption into the liver can be shown in Menkes disease. The need for a biopsy arises when noninvasive tests fail ( Table 95.10). A skin biopsy specimen is examined under the electron microscope for abnormal inclusions and is also used for tissue culture. Cultured fibroblasts may yield an enzymatic or deoxyribonucleic acid (DNA) diagnosis. Equally important, the cultures can be kept viable indefinitely in the frozen state, and tissue will be available when new data suggest further study, especially as molecular techniques enable detection of additional mutations. Cell lines in federally funded repositories provide invaluable resources for such future studies. Conjunctival biopsies are helpful when storage in connective tissue is suspected and enzymatic diagnosis is unavailable (e.g., in mucolipidosis IV), or when axonal spheroids are being evaluated. Muscle biopsy to identify mitochondrial encephalomyopathies requires special histochemical, biochemical, and DNA studies.

TABLE 95.10. DISEASES IN WHICH BIOPSIES FOR HISTOLOGY ARE LIKELY TO HELP

Brain biopsy is rarely needed today and is reserved for patients in whom diagnosis remains elusive despite thorough peripheral investigation. It is imperative to sample the white matter, as well as the cortex. Routine histologic examination of the tissue is not sufficient because brain biopsy is reserved for disorders that are biochemical enigmas; therefore, brain biopsy should be carried out in a center that has the resources necessary for many avenues of investigation. Under these conditions, the informational yield of brain biopsy is sufficiently high and its morbidity sufficiently low to make it a rewarding procedure both clinically and scientifically. Biopsy is not a substitute for autopsy because it may not be diagnostic and because some studies can be done only on biopsy tissue or only on autopsy tissue. When all diagnostic methods have failed, the physician must broach the subject of an autopsy. This can be done when the parents are informed of the likelihood of a fatal outcome. Parents who understand how little is known about their child's illness are likely to want an autopsy; they will also be spared the unnecessary hurt of being pressed for an autopsy when the child actually dies and they are most distressed. A planned and speedy autopsy maximizes the probability of obtaining useful data. Viscera, peripheral nerves, muscle, and retina, as well as the brain, must be investigated. Tissue samples should be removed and frozen at -70°C for chemical analysis; other samples are fixed for electron microscopy before the organs are placed in formalin. If autopsy does not yield a diagnosis, brain tissue stored in

federally funded brain banks remains available for later diagnosis or research. In the interim, the physician must explain to the parents that the child's illness may be one that is as yet unrecognized and that data of scientific importance may yet emerge from the study of their child, who will thus have made a unique contribution to other children and their families.

CHAPTER 96. MITOCHONDRIAL ENCEPHALOMYOPATHIES: DISEASES OF MITOCHONDRIAL DNA MERRITT’S NEUROLOGY

SECTION X. DISORDERS OF MITOCHONDRIAL DNA CHAPTER 96. MITOCHONDRIAL ENCEPHALOMYOPATHIES: DISEASES OF MITOCHONDRIAL DNA SALVATORE DIMAURO AND ERIC A. SCHON AND MICHIO HIRANO AND LEWIS P. ROWLAND Principles of Mitochondrial Genetics and Pathogenesis of Mitochondrial Diseases Progressive External Ophthalmoplegia Multisystem Neurologic Diseases Without Ophthalmoplegia Depletion of mtDNA Suggested Readings

Mitochondria are uniquely interesting organelles not only because they serve a variety of functions but also because they are under the control of two genomes: their own (mitochondrial deoxyribonucleic acid [mtDNA]) and that of the nucleus (nDNA). Therefore, mitochondrial diseases, that is, genetic diseases resulting in mitochondrial dysfunction, can be due to mutations in either genome ( Table 96.1). Diseases caused by nDNA mutations are transmitted by mendelian inheritance (see Chapter 98). In this chapter, we consider diseases caused by mutations in mtDNA and also a group of disorders (defects of intergenomic signaling; see Table 96.1) characterized by mutations in nDNA that in turn alter mtDNA integrity or replication.

TABLE 96.1. GENETIC CLASSIFICATION OF MITOCHONDRIAL DISEASES

The ubiquitous nature of mtDNA and the peculiar rules of mitochondrial genetics (more akin to population genetics than to mendelian genetics) contribute to explaining the extraordinary clinical heterogeneity of mitochondrial disorders, which, due to the frequent involvement of brain and muscle tissues, are generally labeled mitochondrial encephalomyopathies. The first human disease attributed to mitochondrial dysfunction was a hypermetabolic state in a patient with normal thyroid function and an excessive number of abnormally large mitochondria in skeletal muscle. Biochemical studies showed “loose coupling' of oxidative phosphorylation. The syndrome was named after Rolf Luft, the endocrinologist who led the studies (Luft et al., 1962). In the 36 years since then, however, there has been only one other known case of Luft syndrome. Mitochondrial diseases were brought to prominence by Shy and coworkers (1966) in the 1960s, when they set about assigning different myopathies to different organelles. They defined one category by the electron microscopic appearance of overabundant or enlarged mitochondria with paracrystalline inclusions. Soon, Olson and colleagues (1972) found that these abnormal mitochondria could be identified under the light microscope as ragged-red fibers (RRF) with a modified Gomori trichrome stain. For the next two decades, this observation was the basis for recognizing mitochondrial diseases, while biochemical tests were being developed and applied, eventually leading to a biochemical classification (see Table 96.1). Throughout this period, there were vigorous debates between those who thought that there were identifiable clinical syndromes and those who thought there was too much overlap of the clinical features (a foreshadowing of mitochondrial genetics). Ophthalmoplegia plus became a popular term for the lumpers. The splitters, however, recognized the constancy of clinical manifestations in the Kearns-Sayre syndrome (KSS) and noted that it was never familial, in contrast to the often familial nature of two other syndromes: mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS) and myoclonic epilepsy with ragged-red fibers (MERRF), both described in the early 1980s. The pattern of inheritance in these disorders was maternal, suggesting mtDNA involvement. A revolution commenced in 1988 with the demonstration by Holt and colleagues (1990) of mtDNA single deletions in patients with mitochondrial myopathies, and with the simultaneous recognition by Wallace and associates (1988) of a point mutation in Leber hereditary optic neuropathy (see Chapter 97). Single deletions were found by Zeviani and associates (1988) to be characteristic of KSS and sporadic progressive external ophthalmoplegia (PEO), but not of familial PEO. In families with autosomal-dominant PEO (adPEO), they found multiple rather than single deletions of mtDNA. Demonstration soon followed that there were different point mutations of mtDNA in MELAS and MERRF syndromes. In the ensuing years, more than 50 pathogenic point mutations and myriad rearrangements in mtDNA have been associated with a bewildering array of clinical presentations ( Fig. 96.1). A new lexicon was developed to encompass the new acronyms for multisystem diseases and for new concepts to deal with problems of pathogenesis.

FIG. 96.1. Morbidity map of human mtDNA. The map of the 16.5-kbp mtDNA shows differently shaded areas representing the structural genes for the seven subunits of complex I (NADH-ubiquinone oxidoreductase [ND]), the three subunits of cytochrome-c oxidase (COX), cytochrome b (Cyt b), the two subunits of ATP synthetase (ATPase 6 and 8), the 12S and 16S ribosomal RNAs (rRNA), and the 22 transfer RNAs (tRNA) identified by one-letter codes for the corresponding amino acids (FBSN, familial bilateral striatal necrosis; LHON, Leber hereditary optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke; MERRF, myoclonus epilepsy with ragged-red fibers; MILS, maternally inherited Leigh syndrome; NARP, neuropathy, ataxia, retinitis pigmentosa; PEO, progressive external ophthalmoplegia). (Modified from DiMauro and Bonilla, 1997; with permission.)

PRINCIPLES OF MITOCHONDRIAL GENETICS AND PATHOGENESIS OF MITOCHONDRIAL DISEASES Human mtDNA is a small (16.6 kilobase pairs [kbp]) circle of double-stranded DNA, comprising only 37 genes (see Fig. 96.1). Of these, 13 encode polypeptides, all subunits of the respiratory chain: seven subunits of complex I (NADH-ubiquinone oxidoreductase), one subunit of complex III (ubiquinone-cytochrome -c

oxidoreductase), three subunits of complex IV (cytochrome- c oxidase [COX]), and two subunits of complex V (ATP synthetase). The other 24 genes encode 22 transfer ribonucleic acids (tRNAs) and two ribosomal RNAs (rRNAs) that are required for translation of messenger RNAs on mitochondrial ribosomes. The subunits of complex II (succinate dehydrogenase-ubiquinone oxidoreductase) and two small electron carriers, coenzyme Q10 (ubiquinone) and cytochrome c, are encoded exclusively by nDNA. Mendelian versus Mitochondrial Genetics The following main principles distinguish mitochondrial genetics from mendelian genetics and help explain many of the clinical peculiarities of mtDNA-related disorders. 1. Polyplasmy. Most cells contain multiple mitochondria, and each mitochondrion contains multiple copies of mtDNA, so that there are hundreds or thousands of mitochondrial genomes in each cell. 2. Heteroplasmy. When an mtDNA mutation affects some but not all genomes, a cell, a tissue, indeed a whole individual will harbor two populations of mtDNA, normal (or wild-type) and mutant, a condition known as heteroplasmy. In normal tissues, all mtDNAs are identical, a situation of homoplasmy. Usually, neutral mutations (or polymorphisms) are homoplasmic. In contrast, most (but not all) pathogenic mtDNA mutations are heteroplasmic. 3. Threshold effect. Functional impairment associated with a pathogenic mtDNA mutation is largely determined by the degree of heteroplasmy, and a minimum critical number of mutant genomes must be present before tissue dysfunction becomes evident (and related clinical signs become manifest), a concept aptly termed the threshold effect. However, this is a relative concept: Tissues with high metabolic demands, such as brain, heart, and muscle, tend to have lower tolerance for mtDNA mutations than metabolically less active tissues. 4. Mitotic segregation. Both organellar division and mtDNA replication are apparently stochastic events unrelated to cell division; thus, the number of mitochondria (and mtDNA) can vary not just in space (i.e., among cells and tissues) but also in time (i.e., during development or aging). Moreover, at cell division, the proportion of mutant mtDNAs in daughter cells may drift, allowing relatively rapid changes in genotype that can translate into changes in phenotype, including the clinical picture, if and when the threshold is crossed. 5. Maternal inheritance. At fertilization, all mitochondria (and all mtDNA) are contributed to the zygote by the oocyte. Therefore, a mother carrying an mtDNA mutation will pass it on to all of her children, males and females, but only her daughters will transmit it to their progeny in a “vertical,' matrilinear line. When maternal inheritance is evident in a clinical setting, it provides conclusive evidence that an mtDNA mutation must underlie the disease in question. However, the other features of mitochondrial genetics (e.g., heteroplasmy and the threshold effect) often mask maternal inheritance by causing striking intrafamilial clinical heterogeneity. Thus, when an mtDNA-related disorder is suspected, it is crucial to collect the family history meticulously, with special attention to “soft' signs (e.g., short stature, hearing loss, migrainous headache) in potentially oligosymptomatic maternal relatives. Clinical Manifestations Although specific syndromes can be identified by particular combinations of symptoms and signs ( Table 96.2), several clinical manifestations seem to be prevalent among different syndromes, especially short stature, neurosensory hearing loss, and diabetes mellitus. Lactic acidosis, often detected in blood and cerebrospinal fluid (CSF), is the most common laboratory sign. Perhaps as a result of impaired respiration, mitochondria in muscle proliferate and enlarge, which is the basis for finding RRF (Fig. 96.2). Neuropathologic and neuroradiologic changes fall into five main patterns:

FIG. 96.2. Histochemistry detects ragged-red fibers in serial sections of human skeletal muscle. A: Succinate dehydrogenase enzyme activity shows an intensely staining ragged-red fiber ( white asterisk). B: Cytochrome c oxidase shows that the ragged-red fiber ( black asterisk) as well as other muscle fibers are deficient in this enzyme activity. (Courtesy of Dr. E. Bonilla, Columbia University College of Physicians and Surgeons, New York, N.Y.)

TABLE 96.2. CLASSIFICATION OF PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA (PEO)

1. 2. 3. 4. 5.

Microcephaly and ventricular dilatation, sometimes associated with agenesis of the corpus callosum, are seen in infants with severe congenital lactic acidosis. Bilateral, symmetric lesions of basal ganglia, thalamus, brainstem, and cerebellar roof nuclei are the signature of Leigh syndrome. Multifocal encephalomalacia, usually involving the cortex of the posterior cerebral hemispheres, corresponds to the “strokes' of the MELAS syndrome. Spongy encephalopathy, predominantly in white matter, is characteristic of KSS. Calcification of the basal ganglia can be seen in all of these disorders, but in a minority of patients with any syndrome.

Diagnosis of a mitochondrial disease is based on five crucial elements: (1) recognition of an appropriate clinical syndrome, (2) presence of lactic acidosis in blood or CSF, (3) demonstration of RRF in muscle biopsy, (4) documentation of impaired respiration in biochemical assays of muscle extracts or isolated mitochondria, or (5) identification of a pathogenic mutation in mtDNA. Not all of these criteria, however, are necessarily present in an individual syndrome. Unfortunately, there is no effective treatment for any of these diseases.

PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA PEO is defined clinically as a slowly progressive limitation of eye movements until there is complete immobility ( ophthalmoplegia). It is usually accompanied by eyelid droop (ptosis) because the eyelids cannot be held in the normal position by the levator palpebrae muscles. There may or may not be weakness of muscles of the face, oropharynx, neck, or limbs. It is not known whether the ophthalmoplegia is myopathic, neurogenic, or both, because neither electromyography of ocular muscles nor autopsy findings suffice to make this determination. This condition is clearly heterogeneous, but several distinct syndromes can be recognized, some related to primary abnormalities of mtDNA

(with sporadic single deletions or maternally inherited point mutations), others related to autosomal genes directly affecting mtDNA (defects of intergenomic signaling with multiple deletions of mtDNA). For convenience, a separation can be made into a mitochondrial group, a presumably myopathic group of PEO alone or with myopathic findings in limb muscles, and a third group, presumably neurogenic, associated with disease of the central nervous system or peripheral neuropathy ( Table 96.2). Sporadic PEO with Single mtDNA Deletions PEO with or without Limb Weakness This is a relatively benign condition, often compatible with a normal life span. Symptoms usually begin in childhood but may be delayed to adolescence or adult years. Ptosis is often the first symptom, followed by ophthalmoparesis. The disorder is bilateral and symmetric, so diplopia is exceptional. Some patients also have pharyngeal and limb weakness. Kearns-Sayre Syndrome This syndrome is identified by an invariant triad: onset before age 20 years, PEO, and pigmentary retinopathy. In addition, there must be one of the following: heart block (usually needing a pacemaker), cerebellar syndrome, or CSF protein content of 100 mg/dL or more. Seizures are distinctly infrequent and are usually associated with electrolyte disturbances, as may occur in hypoparathyroidism, one of several endocrine disorders sometimes associated with KSS. The course is relentlessly downhill, and patients rarely survive past the second decade. Molecular Genetics In both sporadic PEO and KSS, patients harbor a single deletion in their mtDNA that is identical in all tissues in any patient, although the number of deleted genomes varies from tissue to tissue (heteroplasmy). The single mtDNA deletions arise spontaneously early in oogenesis or embryogenesis. Although the molecular defect is the same in both conditions, intermediate cases are surprisingly few. Laboratory Abnormalities In both conditions, muscle biopsy shows RRFs that are devoid of histochemically demonstrable COX activity. Raised levels of lactate and pyruvate are usually found in blood in both sporadic PEO and KSS; increased lactate in the CSF is seen only in KSS. At postmortem examination, typical cases of KSS show spongy degeneration of the brain. Correspondingly, computed tomography or magnetic resonance imaging (MRI) shows evidence of leukoencephalopathy, and there may be calcification of basal ganglia. Treatment It is crucial to recognize KSS because sudden death as a result of the cardiac conduction disorder is a threat that can be prevented. Episodic coma may result from the combination of diabetes mellitus and encephalopathy. The cerebellar syndrome can be severe enough to be disabling. Because of their severe disabilities and hormonal problems, patients with KSS are not expected to have children, but the few women who have reproduced have had normal children. Treatment with coenzyme Q10 may reverse some electroencephalogram abnormalities but has not reversed heart block, ophthalmoplegia, or the neurologic syndrome. Maternally Inherited PEO with Point Mutations of mtDNA A substantial number of patients with mitochondrial PEO (i.e., PEO and RRF in the muscle biopsy) show maternal inheritance of their syndrome. PEO predominates in this syndrome but is often associated with various combinations of other symptoms, including hearing loss, endocrinopathy, heart block, cerebellar ataxia, or pigmentary retinopathy. The most common mutation in these patients is the typical A3243G MELAS mutation, but other mutations have also been described, including the A8344G mutation typically seen in MERRF syndrome. The reason for the appearance of PEO in patients with the MELAS mutation is not known, but it may be related to a selective accumulation of mutant mtDNA in muscle. There is usually lactic acidosis, and muscle biopsies show RRF. Autosomal PEO with Multiple Deletions of mtDNA PEO has been described in numerous families with autosomal-dominant (adPEO) or autosomal-recessive (arPEO) inheritance. Generally, adPEO syndromes are dominated by myopathic symptoms, while arPEO syndromes tend to be multisystemic. Autosomal-dominant PEO The clinical syndrome is characterized by ophthalmoplegia, although hearing loss, tremor, cataracts, and psychiatric disorders are variably present and suggest multisystemic involvement. Onset is usually in adult age, and there may be weakness of facial, pharyngeal, and respiratory muscles in addition to slowly progressive proximal limb weakness. Autosomal-recessive PEO with Cardiomyopathy Severe hypertrophic cardiomyopathy, proximal weakness, and PEO were the clinical hallmarks of two unrelated families from the eastern seaboard of the Arab peninsula. Onset was in childhood, and cardiac transplantation was needed to prevent early death. Mitochondrial Neurogastrointestinal Encephalomyopathy Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) starts in childhood or adolescence with chronic intractable diarrhea, loud borborygmi, and recurrent intestinal pseudoobstruction, causing severe emaciation. There is also PEO, both proximal and distal limb weakness, and sensory neuropathy. MRI shows diffuse leukodystrophy, although patients are rarely frankly demented. Death usually occurs in the fourth or fifth decade. Laboratory Abnormalities In all these conditions, muscle biopsy shows RRF and COX-negative fibers; these are more abundant in arPEO than in adPEO syndromes. Lactic acidosis is usually present but may not be very marked. In MNGIE, nerve conduction studies and nerve biopsies have shown features of both axonal and demyelinating neuropathy. Molecular Genetics Southern blot analyses of muscle mtDNA in these conditions show multiple bands representing species of mtDNA molecules harboring deletions of different sizes (more abundantly in arPEO than in adPEO patients). The autosomal nature of these disorders suggests that defects of nuclear genes either facilitate an intrinsic propensity of mtDNA to undergo rearrangements or cause a failure to eliminate spontaneously occurring rearrangements. The heterogeneous nature of these disorders is exemplified by the different modes of transmission and the variety of clinical phenotypes, and has been confirmed by linkage analyses. Two distinct loci (one on chromosome 3, the other on chromosome 10) have been linked to adPEO in some but not all families, and a locus on chromosome 22 has been linked to MNGIE in four families of different ethnic origins. In MNGIE, several mutations have been identified in the gene encoding

thymidine phosphorylase, and the diagnosis can be established by enzyme assay in leukocytes. Other Forms of Mitochondrial PEO Ophthalmoplegia is often seen in patients with the congenital or the infantile myopathic variants of mtDNA depletion, which are transmitted as autosomal-recessive traits (see below). Ptosis, PEO, or both can also accompany the late-onset mitochondrial myopathies, often associated with multiple mtDNA deletions, that have been described in sporadic elderly individuals and have been interpreted as an exaggerated manifestation of the normal aging process.

MULTISYSTEM NEUROLOGIC DISEASES WITHOUT OPHTHALMOPLEGIA MELAS Syndrome The distinguishing features of this syndrome are the strokes with hemiparesis, hemianopia, or cortical blindness that almost invariably occur before age 40 years, and often in childhood. Common additional features are focal or generalized seizures, recurrent migrainelike headaches and vomiting, and dementia. The course is one of gradual deterioration. Laboratory abnormalities include elevated blood and CSF lactate and MRI evidence of encephalomalacic foci, usually involving the occipital cortex and not conforming to the distribution of major vessels. Muscle biopsy shows RRF, which are uncharacteristically COX-positive, rather than COX-negative as in most other mtDNA-related diseases. In about 80% of patients, the molecular defect is a point mutation (A3243G) in the tRNA Leu(UUR) gene of mtDNA. In the remaining patients, a handful of mutations have been described, some of which affect protein-encoding genes rather than tRNA genes. A3243G is the most frequent pathogenic mtDNA mutation, and it has been associated not only with MELAS and maternally inherited PEO but also with diabetes mellitus alone or in combination with deafness. MERRF Syndrome Typical clinical features include myoclonus, generalized seizures, cerebellar ataxia, myopathy, and, in some families, multiple symmetric lipomas. Onset may occur in childhood or in adult life, and the course may be slowly progressive or rapidly downhill. As the acronym denotes, muscle biopsy shows RRF, which are COX-negative. Most patients with MERRF have a mutation (A8344G) in the tRNA Lys gene of mtDNA. Neuropathy, Ataxia, and Retinitis Pigmentosa The combination of neuropathy, ataxia, and retinitis pigmentosa (NARP) is a maternally transmitted multisystem disorder of young adult life, comprising, in various combinations, sensory neuropathy, ataxia, seizures, dementia, and retinitis pigmentosa. Lactic acid in blood may be normal or slightly elevated, and muscle biopsy does not show RRF. The molecular defect is a point mutation (T8993G) in the gene that encodes ATPase 6. When this mutation approaches homoplasmic levels, onset is in infancy, and the clinical and neuropathologic features are those of Leigh syndrome (maternally inherited Leigh syndrome [MILS]). A different mutation at the very same nucleotide (T8993C) causes a phenotype similar to MILS but generally milder. A few other mutations in the ATPase 6 gene have been associated with Leighlike syndromes or with familial bilateral striatal necrosis. Leber hereditary optic neuropathy is discussed in Chapter 97.

DEPLETION OF mtDNA Depletion of mtDNA is the other major defect of intergenomic signaling, together with multiple mtDNA deletions described above. As the name implies, this is a quantitative rather than qualitative mtDNA abnormality, consisting of markedly decreased levels of mtDNA in one or more tissues. The clinical spectrum of mtDNA depletion has been incompletely characterized and is probably more heterogeneous than was initially thought. Three syndromes stand out, all inherited as autosomal-recessive traits: congenital myopathy, infantile myopathy, and hepatopathy. Congenital Myopathy At or soon after birth, there is generalized weakness (sometimes including PEO) with lactic acidosis and markedly elevated serum creatine kinase. Some children also have renal involvement with Fanconi syndrome. Muscle biopsy shows abundant RRF that are COX-negative. Due to intractable respiratory failure, these children do not live more than a few months. Southern blot analysis shows a profound defect of mtDNA in muscle (less than 10% of normal). Infantile Myopathy In some children, weakness starts a little later but is usually evident by age 1 year and may cause PEO. Progression is rapid, leading to flaccid paralysis, respiratory insufficiency, and death within 1 or 2 more years. There is only partial mtDNA depletion in muscle (about 30% of normal), with some fibers virtually devoid of mtDNA while others look normal. Recognizing this entity is especially difficult because the clinical presentation is nonspecific, lactic acidosis initially may not be present and is generally mild, and early biopsies may show nonspecific myopathic features rather than mitochondrial proliferation with RRF (which do appear in later biopsies). Hepatopathy Infants with severe mtDNA depletion in liver experience intractable liver failure soon after birth and die within months. Liver biopsy shows mitochondrial proliferation in hepatocytes, and biochemical analysis shows very low activities of all respiratory chain complexes containing mtDNA-encoded subunits. It is likely that the genetic errors underlying the different variants of mtDNA depletion all involve one or more nDNA-encoded factors involved in the control of mtDNA replication. These factors, however, are unknown. Acquired mtDNA Depletion An iatrogenic form of mtDNA depletion has been recognized in patients with acquired immunodeficiency syndrome in whom a mitochondrial myopathy developed during treatment with zidovudine (Retrovir). The myopathy is reversible upon discontinuation of the drug. SUGGESTED READINGS Arnaudo E, Dalakas M, Shanske S, et al. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 1991;337:508–510. Berenberg RA, Pellock JM, DiMauro S, et al. Lumping or splitting? “ophthalmoplegia plus' or Kearns-Sayre syndrome? Ann Neurol 1977;1:37–54. Bohlega S, Tanji K, Santorelli FM, et al. Multiple mtDNA deletions associated with autosomal recessive ophthalmoplegia and severe cardiomyopathy. Neurology 1996;46:1329–1334. Carrozzo R, Hirano M, Fromenty B, et al. Multiple mtDNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses. Neurology 1998;50:99–106. Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol 1992;31:391–398. Dalakas M, Illa I, Pezeshkpour GH, et al. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990;322:1098–1105. DiMauro S, Bonilla E. Mitochondrial encephalomyopathies. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, eds. The molecular and genetic basis of neurological disease. Boston:

Butterworth-Heinemann, 1997:201–235. DiMauro S, Schon EA. Mitochondrial DNA and diseases of the nervous system: the spectrum. Neuroscientist 1998;4:53–63. Engel WK, Cunningham CG. Rapid examination of muscle tissue: an improved trichrome stain method for fresh-frozen biopsy specimens. Neurology 1963;13:919–923. Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T. Myoclonus epilepsy associated with ragged red fibers (mitochondrial abnormalities): disease entity or syndrome? J Neurol Sci 1980;47:117–133. Goto YI, Nonaka I, Horai S. A mutation in the tRNA Leu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990;348:651–653. Hirano M, Silvestri G, Blake DM, et al. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical and genetic features of an autosomal-recessive disorder. 1994;44:721–727.

Neurology

Hirano M, Yebenes J, Jones AC, et al. Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32qter. Am J Hum Genet 1998;63:526–533. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathy. Nature 1988;331:717–718. Holt IJ, Harding AE, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990;46:428–433. Johnston W, Karpati G, Carpenter S, Arnold D, Shoubridge EA. Late-onset mitochondrial myopathy. Ann Neurol 1995;37:16–23. Kaukonen JA, Amati P, Suomalainen A, et al. An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p. Am J Hum Genet 1996;58:763–769. Kearns TP, Sayre G. Retinitis pigmentosa, external ophthalmoplegia, and complete heart block. Arch Ophthalmol 1958;60:280–289. Luft R, Ikkos D, Palmieri G, et al. Severe hypermetabolism of nonthyroidal origin with a defect in the maintenance of mitochondrial respiratory control.

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Moraes CT, Ciacci F, Silvestri G, et al. Atypical presentation associated with the MELAS mutation at position 3243 of human mitochondrial DNA. Neuromuscul Disord 1993;3:43–50. Moraes CT, DiMauro S, Zeviani M, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 1989;320:1293–1299. Moraes CT, Shanske S, Tritschler HJ, et al. mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am J Hum Genet 1991;48:492–501. Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999;283:689–692. Olson W, Engel WK, Einaugler R. Oculocraniosomatic neuromuscular disease with ragged red fibers. Arch Neurol 1972;26:193–211. Pavlakis SG, Phillips PC, DiMauro S, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Ann Neurol 1984;16:481–487. Rowland LP. Progressive external ophthalmoplegia. In: Vinken PJ, Bruyn G, eds. System disorders and atrophies. Handbook of clinical neurology, vol 22. New York: American Elsevier, 1975. Rowland LP, Blake DM, Hirano M, et al. Clinical syndromes associated with ragged red fibers. Rev Neurol (Paris) 1991;290:457–465. Santorelli FM, Shanske S, Macaya A, et al. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann Neurol 1993;34:827–834. Shy GM, Gonatas NK, Perez M. Childhood myopathies with abnormal mitochondria. I. Megaconial myopathy; II. Pleoconial myopathy. Brain 1966;89:133–158. Silvestri G, Ciafaloni E, Santorelli FM, et al. Clinical features associated with the A®G transition at nucleotide 8344 of mtDNA (“MERRF mutation').

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Suomalainen A, Kaukonen JA, Amati P, et al. An autosomal locus predisposing to deletions of mitochondrial DNA. Nat Genet 1995;9:146–151. Tatuch Y, Christodoulou J, Feigenbaum A, et al. Heteroplasmic mtDNA mutation (T®G) at 8993 can cause Leigh disease when the percentage of mtDNA is high. Am J Hum Genet 1992;50:852–858. Vu TH, Sciacco M, Tanji K, et al. Clinical manifestations of mitochondrial DNA depletion. Neurology 1998;50:1783–1790. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic atrophy. Science 1988;242:1427–1430. Wallace DC, Zhang X, Lott MT, et al. Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. 1988;55:601–610. Zeviani M, Moraes CT, DiMauro S, et al. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988;38:1339–1346. Zeviani M, Servidei S, Gellera C, et al. An autosomal-dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region.

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CHAPTER 97. LEBER HEREDITARY OPTIC NEUROPATHY MERRITT’S NEUROLOGY

CHAPTER 97. LEBER HEREDITARY OPTIC NEUROPATHY MYLES M. BEHRENS AND MICHIO HIRANO Clinical Manifestations Pathology and Molecular Genetics Differential Diagnosis Treatment Suggested Readings

Leber hereditary optic neuropathy (LHON; MIM 535600) is a maternally inherited disorder characterized by loss of central vision and occurring more often in males. It was named for Leber because he reported 15 patients in four families in 1871, following von Graefe's initial description in 1858. Maternal inheritance was recognized by Wallace in 1970 in a large pedigree residing in Queensland, Australia, with LHON plus other neurologic manifestations. Nikoskelainen studied patients with more typical LHON and in 1984 proposed that mutations in mitochondrial DNA (mtDNA) might be responsible. A major breakthrough came in 1988 when Wallace, Nikoskelainen, and colleagues described the first mtDNA point mutation in a human disease. This accounted for the maternal inheritance, that is, transmission by women to all their progeny (male and female), but not by men.

CLINICAL MANIFESTATIONS Onset usually occurs in adolescence or early-adult years but may occur from ages 5 to 80 years. Cloudiness of central vision progresses painlessly over weeks, usually first in one eye, to a larger, denser centrocecal scotoma, occasionally breaking out peripherally to a minor extent. Both eyes are usually affected within weeks or months, sometimes simultaneously; it is only rarely unilateral. Color vision is affected, and acuity drops to 20/200 or finger counting. Residual visual loss may be severe and generally remains stationary. Sometimes, there is later improvement, infrequently striking and occasionally sudden. The fundus may appear normal until optic atrophy supervenes, but at onset, as first described by Smith, Hoyt, and Susac (1973), the disc often appears blurred and suggestive of edema, as in papillitis. However, the findings are due to swelling of the nerve fiber layer around the disc, with circumpapillary telangiectatic microangiopathy and without evidence of abnormal vascular permeability (leakage) on fluorescein angiography. The vascular abnormalities may be seen in presymptomatic and asymptomatic relatives and do not invariably predict imminent visual loss, which may never occur. As the acute stage approaches, vessels dilate and undulate in and out of the thickening peripapillary nerve fiber layer, with increased arteriovenous shunting. This subsides after a few weeks or months. Optic atrophy follows, starting in the temporal portion of the disc, then usually generalized. In most patients with LHON, visual disturbance is the only symptom, but cardiac preexcitation is frequently associated. Neurologic examination, however, may reveal subtle neurologic abnormalities, including postural tremor, dystonia, motor tics, parkinsonism with dystonia, or peripheral neuropathy. Several patients (mostly women) with LHON have had multiple sclerosis–like manifestations. The Uhthoff symptom has been reported by a few patients with LHON itself. Two patients had ataxia and optic neuropathy with a mtDNA point mutation of LHON. At least three Leber-plus syndromes have been reported: optic neuropathy and dystonia, optic neuropathy and spastic dystonia, and the Queensland variant with optic neuropathy, athetosis, tremor, corticospinal tract signs, posterior column dysfunction, psychiatric disturbances, and acute encephalopathy.

PATHOLOGY AND MOLECULAR GENETICS Prior to the identification of molecular genetic defects, several autopsy studies of LHON patients revealed atrophy of the retinal ganglion cells and nerve fiber layers and optic nerve. The clinical manifestations of LHON are similar regardless of the specific genotype, but the molecular genetic features of LHON are complex and unique. First, there are mtDNA primary mutations that are thought to be pathogenic. Secondary mutations may be synergistically pathogenic in combination with each other or with primary mutations. Second, about 85% of patients with LHON harbor primary mutations that are usually homoplasmic, in contrast to the mitochondrial encephalomyopathies, which typically show heteroplasmic mutations. The first and most common primary mtDNA mutation associated with LHON was found in the gene for subunit 4 of NADH-ubiquinone oxidoreductase, or complex I, of the mitochondrial respiratory chain. The A-to-G transition mutation at nucleotide 11778 (A11778G) in the mtDNA genome changes amino acid 340 in the ND4 gene from arginine to histidine. Two additional mtDNA mutations in complex I (ND) subunits have been identified: G3460A in ND1 and T14484C in ND6; both result in amino acid substitutions. Isolated LHON patients or individual families have had other mtDNA mutations thought to be pathogenic ( Table 97.1). The penetrance rates of the LHON mutations are uncertain; however, some reports estimate that symptoms appear in 20% to 83% of men and 4% to 32% of women at risk. Sixty percent to 90% of LHON patients are men. The molecular basis for male predominance is not known. An unknown X-linked factor may interact with a LHON mtDNA mutation, but linkage studies have failed to identify such a locus.

TABLE 97.1. MITOCHONDRIAL DNA MUTATIONS ASSOCIATED WITH LHON

Distinct mtDNA mutations have been associated with LHON-plus phenotypes. In the Queensland LHON-plus variant, two primary coexisting mutations were identified, T4160C in ND1 and T14484C in ND6. Two distinct mitochondrial genotypes have been identified in pedigrees with LHON and dystonia, G14459A in ND6 and a combination of A11696G in ND1 plus T14596A in ND6.

DIFFERENTIAL DIAGNOSIS The diagnosis of LHON is usually made when the typical course of visual loss occurs with an appropriate family history or with observation of the typical acute fundus appearance in a patient or compatible fundus changes in close maternal relatives. Now, it can be diagnosed, even without family history and even with optic neuropathy with less typical features, by genetic analysis of a blood sample. Other forms of bilateral optic neuropathies with centrocecal scotomas include demyelinating, toxic-nutritional optic neuropathy (including tobacco—alcohol amblyopia), other types of hereditary optic atrophy, occasionally glaucoma or ischemic optic neuropathy, and only rarely compressive lesions. To help exclude tumors, computed tomography or magnetic resonance imaging includes axial and coronal orbital views with and without contrast to include the optic nerves and chiasm. The dominant variety of hereditary optic atrophy as initially categorized by Kjer (1972) is the most common form of hereditary optic atrophy and must be distinguished

from LHON. It is also characterized by centrocecal scotomas, dyschromatopsia, and temporal pallor but is generally milder, usually beginning insidiously between ages 4 and 8 years and slowly progressing with visual acuity from 20/30 to no worse than 20/200. It has been mapped to chromosome 3q27-3q28. Other forms of hereditary optic atrophy may occur as part of complex neurologic disorders, including the lipidoses, spinocerebellar ataxias, and polyneuropathies, including Charcot-Marie-Tooth polyneuropathies. Autosomal-recessive Behr complicated optic atrophy may be a transitional form between the ataxias and isolated hereditary optic atrophy. Other autosomal-recessive forms of optic atrophy include the rare but severe simple optic atrophy beginning in early infancy and that associated with diabetes insipidus, diabetes mellitus, and hearing defect (DIDMOAD or Wolfram syndrome). A source of confusion in nomenclature is the severe congenital visual loss known as Leber congenital amaurosis. This is an autosomal-recessive degeneration of the retina rather than of the optic nerve and is usually characterized by retinal arteriolar narrowing and retinal pigmentary degeneration. Occasionally, the fundus appears normal at first. The electroretinogram is extinguished, whereas it is normal with optic neuropathy.

TREATMENT No treatment is of proven value, including corticosteroids, hydroxycobalamin (suggested because of evidence that cyanide toxicity might be a factor), optic nerve sheath fenestration, or craniotomy with lysis of optic nerve chiasm–arachnoidal adhesions. Given the usual sequential involvement of the two eyes, however, it may be possible to prevent loss of vision in the second eye. With the new insights into pathogenesis, it can be hoped that an effective therapy will be found, perhaps one that enhances or preserves mitochondrial respiratory enzyme function. Products that might enhance mitochondrial respiratory enzymes (coenzyme Q10, idebenone, and thiamine) have been used but are not of proven value. Antioxidants have also been used to reduce possible damage from free radicals generated by the impaired oxidative metabolism. According to consensus, tobacco and alcohol should be avoided in family members at risk. SUGGESTED READINGS Brown JJ, Fingert JH, Taylor CM, et al. Clinical and genetic analysis of a family affected with dominant optic atrophy (OPA1). Arch Ophthalmol 1997;115:95–99. Chalmers RM, Harding AE. A case-control study of Leber's hereditary optic neuropathy. Brain 1996;119:1481–1486. Harding AE, Sweeney MG, Miller DH, et al. Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain 1992;115:979–989. Howell N, Bogolin C, Jamieson R, et al. mtDNA mutations that cause optic neuropathy: how do we know? Am J Hum Genet 1998;62:196–202. Huoponen K, Vilkki J, Aula P, et al. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 1991;48:1147–1153. Johns DR, Heher KL, Miller NR, Smith KH. Leber's hereditary optic neuropathy: clinical manifestations of the 14484 mutation. Arch Ophthalmol 1993;111:495–498. Johns DR, Neufeld MJ, Park RD. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Comm 1992;187:1551–1557. Johns DR, Smith KH, Miller NR. Leber's hereditary optic neuropathy: clinical manifestations of the 3460 mutation. Arch Ophthalmol 1992;110:1577–1581. Johnston RL, Burdon MA, Spalton DJ, et al. Dominant optic atrophy, Kjer type: linkage analysis and clinical features in a large British pedigree. Arch Ophthalmol 1997;115:100–103. Kjer P. Infantile optic atrophy with dominant mode of inheritance. In: Vinken PJ, Bruyn GW, eds. Neuroretinal degenerations. Handbook of clinical neurology, vol 13. New York: American Elsevier Publishing, 1972:111–123. Kline LB, Glaser JS. Dominant optic atrophy: the clinical profile. Arch Ophthalmol 1979;97:1680–1686. Leber TH. Über hereditäre und congenital-angelegte Sehnervenleiden. Graefes Archiv Ophthalmol 1871;17:249–291. McLeod JG, Low PA, Morgan JA. Charcot-Marie-Tooth disease with Leber optic atrophy. Neurology 1978;28:179–184. Merritt HH. Hereditary optic atrophy (Leber's disease). Arch Neurol Psychiatry 1930;24:775–781. Mojon DS, Herbert J, Sadiq SA, Miller JR, Madonna M, Hirano M. Leber's hereditary optic neuropathy mitochondrial DNA mutations at nucleotides 11778 and 3460 in multiple sclerosis. Ophthalmologica 1999;213:171–175. Newman NJ. Leber's hereditary optic neuropathy: new genetic considerations. Arch Neurol 1993;50:540–548. Newman NJ. Hereditary optic neuropathies. In: Miller NR, Newman NJ, eds. Walsh and Hoyt's clinical neuro-ophthalmology, 5th ed. Baltimore: Williams & Wilkins, 1998:741–773. Nikoskelainen EK. New aspects of the genetic, etiologic, and clinical puzzle of Leber's disease. Neurology 1984;34:1482–1484. Nikoskelainen EK, Hoyt WF, Nummelin KU. Ophthalmoscopic findings in Leber's hereditary optic neuropathy. I. Fundus findings in asymptomatic family members. 1982;100:1597–1602.

Arch Ophthalmol

Nikoskelainen EK, Hoyt WF, Nummelin KU. Ophthalmoscopic findings in Leber's hereditary optic neuropathy. II. The fundus findings in the affected family members. 1983;101:1059–1068.

Arch Ophthalmol

Nikoskelainen EK, Hoyt WF, Nummelin KU, Schatz H. Fundus findings in Leber's hereditary optic neuropathy. III. Fluorescein angiographic studies. Arch Ophthalmol 1984;102:981–989. Nikoskelainen EK, Marttila RJ, Huoponen K, et al. Leber's “plus”: neurological abnormalities in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 1995;59:160–164. Novotny EJ, Singh G, Wallace DC, et al. Leber's disease and dystonia: a mitochondrial disease. Neurology 1986;36:1053–1060. Polymeropoulos MH, Swift RG, Swift M. Linkage of the gene for Wolfram syndrome to markers on the short arm of chromosome 4. Nat Genet 1994;8:95–97. Scolding NJ, Keller-Wood HF, Shaw C, et al. Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy. Ann Neurol 1996;39:352–360. Shoffner JM, Brown MD, Stugard C, et al. Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. Ann Neurol 1995;38:163–169. Smith JL, Hoyt W, Susac JO. Ocular fundus in acute Leber optic neuropathy. Arch Ophthalmol 1973;90:349–354. Von Graefe A. Ein ungewöhnlicher Fall von hereditären Amaurose. Arch Ophthalmol 1858;4:266–268. Votruba M, Fitzke FW, Holder GE, Carter A, Bhattacharya SS, Moore AT. Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy.

Arch Ophthalmol 1998;116:351–358.

Wallace DC. A new manifestation of Leber's disease and a new explanation for the agency responsible for its unusual pattern of inheritance. Brain 1970;93:121–132. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988;242:1427–1430.

CHAPTER 98. MITOCHONDRIAL DISEASES WITH MUTATIONS OF NUCLEAR DNA MERRITT’S NEUROLOGY

CHAPTER 98. MITOCHONDRIAL DISEASES WITH MUTATIONS OF NUCLEAR DNA DARRYL C. DE VIVO AND MICHIO HIRANO Disorders of Substrate Transport and Utilization Disorders of the Citric Acid Cycle Disorders of the Respiratory Chain Leigh Syndrome Alpers Syndrome Impaired Mitochondrial Transport Suggested Readings

The vast majority of polypeptides in mitochondria are encoded in nuclear deoxyribonucleic acid (nDNA); therefore, nDNA mutations are likely to be the cause of many mitochondrial diseases. Most of these disorders are autosomal-recessive and lack ragged-red fibers (RRF) or other structural abnormalities of mitochondria. Exceptions are defects of intergenomic signaling (see Chapter 96) and an X-linked form of pyruvate dehydrogenase deficiency. These diseases can be classified biochemically (Table 98.1) and are beginning to be defined at the molecular genetic level. As a rule, symptoms begin in infancy or childhood, when the metabolic demands of growth and development are the greatest. Clinical manifestations may be tissue-specific or generalized. Diagnosis depends on the clinical syndrome plus biochemical and DNA analyses.

TABLE 98.1. CLASSIFICATION OF MITOCHONDRIAL DISEASES ASSOCIATED WITH MUTATIONS OF NUCLEAR DNA

DISORDERS OF SUBSTRATE TRANSPORT AND UTILIZATION Abnormalities of fatty acid oxidation provide examples of both substrate transport defects (e.g., carnitine disorders) and substrate utilization defects (e.g., abnormalities of beta-oxidation). These conditions are discussed in Chapter 88. Impaired fatty acid oxidation leads to periods of metabolic decompensation during fasting. Liver, myocardium, and limb muscle are particularly vulnerable; the brain is affected secondarily, a result of nonketotic hypoglycemia and increased fatty acid levels in serum. In infants, the disorder may mimic Reye syndrome (see Chapter 32) and may cause sudden infant death. The most common disorders of fatty acid metabolism are medium-chain acyl-CoA dehydrogenase deficiency (a Reye-like syndrome) and carnitine palmityltransferase deficiency (DiMauro syndrome), manifested by recurrent myoglobinuria. Impaired substrate utilization is best illustrated by pyruvate carboxylase deficiency, which interferes with the synthesis of oxaloacetate. The syndrome includes congenital hypotonia, psychomotor retardation, failure to thrive, seizures, and metabolic acidosis. About 50% of all reported cases have what is called the French phenotype, with lactic acidosis, citrullinemia, hyperlysinemia, and hyperammonemia. Aspartate depletion impairs urea cycle activity, and oxaloacetate depletion limits Krebs cycle activity. Ketoacidosis, a prominent metabolic feature, results from the accumulation of acetyl-CoA. A North American phenotype may seem less severe at first but is ultimately fatal in late infancy or early childhood. The two phenotypes parallel the amount of residual enzyme activity. Deficiencies of the pyruvate dehydrogenase (PDH) complex account for most cases of congenital lactic acidosis. The PDH complex comprises five enzymes encoded by at least nine nuclear genes. Most patients have an abnormality in the E1a subunit with a gene mutation on the short arm of the X-chromosome, with a male predominance. Female involvement is determined by the random pattern of inactivation of the X-chromosome. The disorder may be symptomatic in the newborn period with hypotonia, convulsions, episodic apnea, weak sucking, dysmorphic features, low birthweight, failure to thrive, and coma. The distinctive neuropathology includes cystic degeneration of subcortical white matter, basal ganglia, and brainstem. Less common features include agenesis of the corpus callosum, ectopic olivary nuclei, hydrocephalus, optic atrophy, spongy degeneration, and other nonspecific abnormalities. A similar phenotype may become symptomatic later in life. In addition, girls and women may manifest as carriers with mental retardation and ataxia. In these milder forms, lactic acidosis may be minimal.

DISORDERS OF THE CITRIC ACID CYCLE Congenital lactic acidosis can be due to one of several enzymes of the Krebs cycle: dihydrolipoyl dehydrogenase, alpha-ketoglutarate dehydrogenase, or fumarase. Symptoms begin at birth or early infancy with failure to thrive, hypotonia, seizures, microcephaly, and optic atrophy. Diagnosis can be made by analysis of urinary organic acids, with patterns distinctive for each condition.

DISORDERS OF THE RESPIRATORY CHAIN These conditions are another cause of congenital lactic acidosis. In contrast to the previously cited autosomal or X-linked conditions, respiratory enzyme disorders can result from mutations of either nDNA or mtDNA. Pathogenic mutations in two nDNA-encoded subunits of complex I have been identified. A homozygous five-base-pair duplication in the 18-kDa (AQDQ) subunit was found in an infant with recurrent vomiting, psychomotor retardation, seizures, hypotonia, and cardiopulmonary failure leading to death at 16 months. The second patient died of Leigh syndrome at age 11 weeks and harbored compound heterozygous mutations in the NDUFS8 (TYKY) subunit. Deficiency of succinate dehydrogenase, which functions as complex II of the respiratory chain, was attributed to a homozygous mutation in the flavoprotein subunit in two infants with Leigh syndrome. Coenzyme Q10 deficiency leads to an encephalomyopathy with recurrent myoglobinuria and RRF that responds to replacement therapy. Cytochrome-c oxidase (COX) deficiency, as mentioned previously, may be associated with a fatal infantile myopathy or a relatively benign condition.

LEIGH SYNDROME The most common form of complex IV deficiency (COX) is subacute necrotizing encephalomyelopathy (Leigh syndrome). The condition was first described in 1951 in a 7-month-old infant who showed necrotizing lesions in the brainstem that resembled those of Wernicke encephalopathy. The lesions are found in the periaqueductal region of the midbrain and pons and in the medulla adjacent to the fourth ventricle ( Table 98.2). Other parts of the central nervous system and peripheral nerves may also be affected. The lesions are a combination of cell necrosis, demyelination, and a vascular proliferation. The topology and vascular lesions are distinctive ( Fig. 98.1). Pathologically, the condition differs from Wernicke disease because the hypothalamus and mammillary bodies are spared in Leigh syndrome.

TABLE 98.2. COMPARISON OF DISTRIBUTION OF BRAIN LESIONS IN SUBACUTE NECROTIZING ENCEPHALOMYELOPATHY (SNE) AND WERNICKE DISEASE (WD)

FIG. 98.1. A 2-year-old-girl with cytochrome- c-oxidase deficiency and Leigh syndrome. Heavily T2-weighted MRI shows prominent signal abnormality with bilaterally symmetric involvement of basal ganglia. Putaminal involvement is characteristic of Leigh syndrome.

The condition may be inherited in an autosomal-recessive, X-linked, or maternal pattern. In adults, it is usually sporadic. Infants may develop normally for months; others may show signs of encephalopathy in early infancy. Poor feeding, feeble crying, and respiratory difficulty may be early symptoms. This is followed by impaired vision and hearing, ataxia, limb weakness, intellectual deterioration, and seizures. Nystagmus is common. In patients with later onset, there may be progressive external ophthalmoplegia, dystonia, or ataxia. Once affected, the child may die in infancy or childhood; some live until the third decade. Laboratory Abnormalities Cerebrospinal fluid (CSF) protein content is mildly elevated in 25% of patients. Lactate and pyruvate levels are almost always increased in CSF and, to a lesser degree, in blood and urine. These findings and the histopathology lead to a search for an abnormality of pyruvate metabolism. Electroencephalogram changes and abnormal evoked responses are nonspecific. Computed tomography may show symmetric lucencies in basal ganglia and the thalamus; the ventricles may be enlarged. Magnetic resonance imaging (MRI) demonstrates the distinctive topography in detail (see Fig. 98.1). Pathogenesis The biochemical lesions are diverse but impair cerebral oxidative metabolism. Affected enzymes include PDH, biotinidase, or complex I, II, or IV (COX) of the respiratory chain. In most autosomally inherited cases, the mutations are in nDNA-encoded subunits of the enzymes; however, in COX-deficient Leigh syndrome, the first pathogenic mutations were identified in SURF1, a putative assembly or maintenance factor for COX. Point mutations of mtDNA, particularly the T8993G mutation in ATPase 6, have been associated with maternally inherited Leigh syndrome (see Chapter 96). There are no RRF in any of these conditions. Leigh syndrome is usually fatal before age 1 year when associated with the neuropathy, ataxia, and retinitis pigmentosa (NARP) mutation or PDH complex deficiency.

ALPERS SYNDROME In 1931, Bernard Alpers described an infant girl with progressive poliodystrophy. The pathology had anoxic features, but in retrospect some authorities have ascribed the changes to status epilepticus and hypoxia-ischemia. Later, Huttenlocher described an autosomal-recessive condition with the same neuropathology and hepatic cirrhosis. The relation of this condition to mitochondrial dysfunction is at best uncertain.

IMPAIRED MITOCHONDRIAL TRANSPORT In one patient with methylmalonic aciduria, a point mutation within the mitochondrial targeting sequence of methylmalonyl-CoA mutase led to failure of protein importation into mitochondria. One family with X-linked pyruvate dehydrogenase E1a deficiency harbored a point mutation that altered the structure of the polypeptide mitochondrial targeting sequence in affected individuals. The protein was not effectively transported across the mitochondrial membranes into the matrix. Finally, in hyperoxaluria type I, the enzyme is misdirected to the mitochondrial matrix rather than its normal location, the peroxisome. Identification of gene mutations—frataxin in Friedreich ataxia (see Chapter 107 and a copper-transporting P-type ATPase in Wilson-Duchene (see Chapter 89)— has revealed defects in metal-transporting proteins located in mitochondria. SUGGESTED READINGS Alpers BJ. Diffuse progressive degeneration of the grey matter of the cerebrum. Arch Neurol Psychiatry 1931;25:469–505. Atkin BM, Buist NR, Utter MF, et al. Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's disease. Pediatr Res 1979;13:109–116. Babcock M, de Silva D, Oaks R, et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin.

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Bourgeron T, Rustin P, Chretien D, et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 1995;11:144–149. De Vivo DC. The expanding clinical spectrum of mitochondrial diseases. Brain Dev 1993;15:1–21. De Vivo DC. Complexities of the pyruvate dehydrogenase complex. Neurology 1998;51:1247–1249. De Vivo DC, Haymond MW, Leckie MP, Bussman YL. The clinical and biochemical implications of pyruvate carboxylase deficiency.

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De Vivo DC, Hirano M, DiMauro S. Mitochondrial disorders. In: Moser H, ed. Neurodystrophies and neurolipidoses. Amsterdam: Elsevier Science, 1997:389–446. DiMauro S, Hirano M, Bonilla E, et al. Cytochrome oxidase deficiency: progress and problems. Oxford: Butterworth-Heinemann, 1994;1:91–115. DiMauro S, Schon EA. Nuclear power and mitochondrial diseases. Nat Genet 1998;19:214–215.

Farrell DF, Clark AF, Scott CR, Wennberg RP. Absence of pyruvate decarboxylase activity in man: a cause of congenital lactic acidosis. Science 1975;187:1082–1084. Feigin I, Wolf A. A disease in infants resembling chronic Wernicke's encephalopathy. J Pediatr 1954;45:243–263. Gellera C, Uziel G, Rimoldi M, et al. Fumarase deficiency is an autosomal-recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. Neurology 1990;40:495–499. Hale DE. Fatty acid oxidation disorders: a new class of metabolic disorders. J Pediatr 1992;121:1–11. Harding BN. Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review. J Child Neurol 1990;5:273–289. Hommes FA, Polman HA, Reerink JD. Leigh's encephalomyelopathy: an inborn error of gluconeogenesis. Arch Dis Child 1968;43:423–426. Huttenlocher PR, et al. Arch Neurol 1976;33:186–192. Jellinger K, Zimprich H, Muller D. Relapsing form of subacute necrotizing encepalomyelopathy. Neuropediatrics 1973;4:314–321. Ledley FD, Jansen R, Nham SU, et al. Mutations eliminating mitochondrial leader sequence of methylmalonyl-CoA cause mut

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methylmalonic acidemia. Proc Natl Acad Sci U S A 1990;87:3147–3150.

Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951;14:216–221. Loeffen J, Smeitink J, Triepels R, et al. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet 1998;63:1598–1608. Lutsenko S, Cooper MJ. Localization of the Wilson's disease protein product to mitochondria. Proc Natl Acad Sci U S A 1998;95:6004–6009. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343–351. Santorelli FM, Shanske S, Macaya A, et al. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh syndrome. Ann Neurol 1993;34:827–834. Stanley CA, De Leeuw S, Coates PA, et al. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol 1991;30:709–716. Takakubo F, Cartwright P, Hoogenraad N, et al. An amino acid substitution in the pyruvate dehydrogenase E1 alpha gene, affecting mitochondrial import of the precursor protein. Am J Hum Genet 1995;57:772–780. Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper-transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993;5:344–350. Tiranti V, Hoertnagel K, Carrozzo R, et al. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 1998;63:1609–1621. Van Coster R, Fernhoff PM, De Vivo DC. Pyruvate carboxylase deficiency: a benign variant with normal development. Pediatr Res 1991;30:1–4. Van Coster R, Lombes A, De Vivo DC, et al. Cytochrome c oxidase-associated Leigh syndrome: phenotypic features and pathogenetic speculations. J Neurol Sci 1991;104:97–111. van den Heuvel L, Ruitenbeek W, Smeets R, et al. Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. Am J Hum Genet 1998;62:262–268. Zhu S, Yao J, Johns T, et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 1998;20:337–343. Zinn AB, Kerr DS, Hoppel CL. Fumarase deficiency: a new cause of mitochondrial encephalomyopathy. N Engl J Med 1986;315:469–475.

CHAPTER 99. NEUROFIBROMATOSIS MERRITT’S NEUROLOGY

SECTION XI. NEUROCUTANEOUS DISORDERS Several genetic diseases involve both the skin and nervous system. These are called neurocutaneous disorders or neuroectodermatoses. In the past, they were referred to as the “phakomatoses” (phakos is the Greek word for lentil, flat plate, or spot). Retinal lesions are seen in tuberous sclerosis and sometimes in neurofibromatosis. Other distinct disorders are Sturge-Weber-Dimitri syndrome, linear nevus sebaceous, and incontinentia pigmenti. Any portion of the central and peripheral nervous system may be affected by these heredodegenerative diseases, and different portions may be involved in various combinations. Some families breed true and show a remarkable consistency with regard to location and extent of the pathologic changes; other families demonstrate great discrepancies among individual members of the family. The clinical spectrum ranges from frequent abortive forms ( formes frustes) to a severe, potentially lethal condition with highly protean clinical manifestations.

CHAPTER 99. NEUROFIBROMATOSIS ARNOLD P GOLD Genetics and Incidence Molecular Genetics and Pathogenesis Neuropathology Symptoms and Signs Diagnosis Laboratory Data Treatment Suggested Readings

Neurofibromatosis (NF) was first described by von Recklinghausen in 1882; it is one of the most common single-gene disorders of the central nervous system (CNS). The two cardinal features are multiple hyperpigmented marks on the skin ( café-au-lait spots) and multiple neurofibromas; other symptoms may result from lesions in bone, the CNS, the peripheral nervous system, or other organs. Two forms are recognized. Neurofibromatosis type 1 (NF-1) is also known as von Recklinghausen disease or peripheral NF (MIM 162200). It is one of the most common hereditary diseases, with a prevalence of 1 per 3,000 population. Neurofibromatosis type 2 (NF-2) is also known as central NF or bilateral acoustic neuroma syndrome (MIM 101000). The two conditions differ genetically, pathogenetically, and clinically. Many of the clinical features, neurofibromas, and CNS lesions affect structures that originate in the neural crest. Other disorders include altered synthesis and secretion of melanin, disturbed cellular organization with hamartomatous collections, and abnormal production and distribution of nerve growth factors. In both syndromes, gene products seem to act as oncogenes.

GENETICS AND INCIDENCE Both NF-1 and NF-2 are autosomal-dominant conditions; penetrance of NF-1 is almost 100%, but expressivity varies. Mutations are thought to account for 50% of new cases. Both sexes are affected equally, and the condition is found worldwide in all racial and ethnic groups. Incidence figures must be a minimal estimate because abortive cases are often unrecognized clinically.

MOLECULAR GENETICS AND PATHOGENESIS The NF1 gene has been mapped to chromosome 17q11.2. The gene product is called neurofibromin. Since individuals with NF-1 are at increased risk for benign and malignant tumors, neurofibromin is considered a tumor-suppressor gene. Five different types of NF1 gene mutations are known: translocations, large megabase deletions, large internal deletions, small rearrangements, and point mutations. Although the genotypes differ, the phenotypes are indistinguishable. The marked clinical variability within families having an identical NF1 gene mutation equals the variability among families with different NF1 gene mutations. The only exception is the syndrome of large megabase deletions, where affected people are typically mentally retarded. Mutation inactivates the gene, and, by analogy with other oncogenes, loss of the allelic gene later in life could result in tumor formation. It is not known, however, how the other manifestations of the disease arise. Neurofibromin is expressed in neurons, but it is not known why some affected people have neurologic disorders and others do not. Modifying genes in other locations may play a role. The NF2 gene maps to chromosome 22q12. The gene product is similar to that of moesin-, ezrin-, and radixin-like gene; for this reason, it is called merlin. Deletions of the gene have been found in schwannoma and meningioma cells, the major tumors in NF-2 patients.

NEUROPATHOLOGY The neuropathologic changes result from changes in neural supporting tissue with resultant dysplasia, hyperplasia, and neoplasia. These pathologic changes may involve the central, peripheral, and autonomic nervous systems. Visceral manifestations result from hyperplasia of the autonomic ganglia and nerves within the organ. In addition to neural lesions, dysplastic and neoplastic changes affect skin, bone, endocrine glands, and blood vessels. Developmental anomalies include thoracic meningocele and syringomyelia. Patients affected by NF are more likely than others to have neoplastic disorders, including neuroblastoma, Wilms tumor, leukemia, pheochromocytoma, and sarcomas. Neoplasms involving the peripheral nervous system and spinal nerve roots include schwannomas and neurofibromas. Intramedullary spinal cord tumors include ependymomas (especially of the conus medullaris and filum terminale) and, less often, astrocytomas. The most common intracranial tumors are hemispheral astrocytomas of any histologic grade from benign to highly malignant. Pilocytic astrocytic gliomas of the optic nerve and optic chiasm are also characteristic. Bilateral acoustic neuromas and solitary or multicentric menigiomas commonly occur in adults with NF-2.

SYMPTOMS AND SIGNS There are at least four forms of NF. Peripheral NF (NF-1) as described by von Recklinghausen is most commonly encountered. Central NF (NF-2) is manifest by bilateral acoustic neuromas at about age 20 years. Cutaneous changes are mild, and there are only a few café-au-lait spots or neurofibromas. Antigenic activity of nerve growth factor is increased. Segmental NF probably arises from a somatic cell mutation; it is characterized by café-au-lait spots and neurofibromas that are limited, usually affecting an upper body segment. The lesions extend to the midline and include the ipsilateral arm but spare the head and neck. Cutaneous NF is limited to pigmentary changes; there are numerous café-au-lait spots but no other clinical manifestations. NF-1 often presents with protean and progressive manifestations. Not uncommonly, once the diagnosis is established, a fate like that of the grotesque John Merrick (the Elephant Man) is anticipated by parents or physicians. In reality, many patients with this disease are functionally indistinguishable from normal. Often, they have only cutaneous lesions and are diagnosed when They see a physician because of a learning disability, scoliosis, or another problem. Cutaneous Symptoms The café-au-lait macule is the pathognomonic lesion, being present in almost all patients ( Fig. 99.1). Six or more café-au-lait spots larger than 5 mm in diameter before puberty and greater than 15 mm in diameter after puberty are diagnostic. The spots are usually present at birth but may not appear until age 1 or 2 years. Increasing in both size and number during the first decade of life, the macules tend to be less evident after the second decade because they blend into the surrounding hyperpigmented skin. These discrete, tan macules involve the trunk and limbs in a random fashion but tend to spare the face.

FIG. 99.1. Neurofibromatosis. CafĂŠ-au-lait macule (abdomen) and larger pigmented lesion in the perineal area associated with an underlying plexiform neuroma and elephantiasis of the left labia.

Other cutaneous manifestations may include freckles over the entire body, but freckles usually involve the axilla and other intertriginous areas. Larger, darker hyperpigmented lesions are often associated with an underlying plexiform neurofibroma ( Fig. 99.2); if this involves the midline, it may indicate the presence of a spinal cord tumor.

FIG. 99.2. Neurofibromatosis. Large pigmented lesion with associated progressive scoliosis.

Ocular Symptoms Pigmented iris hamartomas (Lisch nodules), when present, are pathognomonic and consist of small translucent yellow or brown elevations on slit-lamp examination. The nodules increase in number with age and are present in almost all patients older than 20 years. They are observed only in NF-1 and are not seen in the normal eye. Neurologic Symptoms Neurofibromas are highly characteristic lesions and usually become clinically evident at ages 10 to 15 years. They always involve the skin, ultimately developing into sessile, pedunculated lesions. The nodules are found on deep peripheral nerves or nerve roots and on the autonomic nerves that innervate the viscera and blood vessels. The lesions increase in size and number during the second and third decades. There may be a few or many thousands. These benign tumors consist of neurons, Schwann cells, fibroblasts, blood vessels, and mast cells. They rarely give rise to any symptoms other than pain as a result of pressure on nerves or nerve roots, but may undergo sarcomatous degeneration in the third and fourth decades of life ( Fig. 99.3). Neurofibromas involving the terminal distribution of peripheral nerves form vascular plexiform neurofibromas that result in localized overgrowth of tissues or segmental hypertrophy of a limb ( elephantiasis neuromatosa). Spinal root or cauda equina neurofibromas are often asymptomatic when they are small, but large tumors may compress the spinal cord, causing the appropriate clinical signs.

FIG. 99.3. Neurofibromatosis. Sarcomatous degeneration of a neurofibroma at 35 years.

Optic gliomas, astrocytomas, acoustic neuromas, neurilemmomas, and meningiomas have a combined frequency of 5% to 10% in all patients with NF. Optic nerve gliomas and other intracranial neoplasms are often evident before age 10; acoustic neuromas become symptomatic at about age 20. When optic glioma is associated with NF, it commonly involves the optic nerve or is multicentric; less frequently, it involves the chiasm ( Fig. 99.4 and Fig. 99.5). Optic nerve glioma must be distinguished from the commonly observed nonneoplastic optic nerve hyperplasia. The optic glioma of NF is slowly progressive and has a better prognosis than similar tumors without this association.

FIG. 99.4. Neurofibromatosis. Lateral skull radiograph shows a J-shaped sella secondary to an optic chiasm glioma.

FIG. 99.5. Neurofibromatosis. Optic canal view shows an enlarged optic foramen secondary to an optic nerve glioma.

NF-2 is clinically evident at about age 20; symptoms include hearing loss, tinnitus, imbalance, and headache. Only a few café-au-lait spots and neurofibromas are seen. Intracranial and intraspinal neoplasms include meningiomas, schwannomas, and gliomas. CNS involvement in NF is highly variable. Macrocephaly, a common clinical manifestation of postnatal origin, is an incidental finding with no correlation with academic performance, seizures, or neurologic function. Specific learning disabilities or attention deficit disorder, with or without impaired speech, is the most common neurologic complication of NF. Intellectual retardation or convulsive disorders each occur in about 5% of the patients. Brainstem tumors associated with NF-1 have a more indolent course than those without NF. Occlusive cerebrovascular disease is rare but is sometimes seen in children, resulting in acute hemiplegia and convulsions. Magnetic resonance angiography or conventional angiography may demonstrate occlusion of the supraclinoid portion of the internal carotid artery at the origin of the anterior and middle cerebral arteries with associated telangiectasia (moyamoya). Symptoms of the Skull, Spine, and Limbs Skeletal anomalies characteristic of NF include (1) unilateral defects in the posterosuperior wall of the orbit, with pulsating exophthalmos; (2) a defect in the lambdoid with underdevelopment of the ipsilateral mastoid; (3) dural ectasia with enlargement of the spinal canal and scalloping of the posterior portions of the vertebral bodies (also seen in connective tissue disorders such as Marfan and Ehlers-Danlos syndromes); (4) kyphoscoliosis, seen in 2% to 10% of patients with NF, most commonly involving the cervicothoracic vertebrae; unless corrected, it can be rapidly progressive, characterized by a short-segment angular scoliosis that typically involves the lower thoracic vertebrae; (5) pseudarthrosis, especially involving the tibia and radius; (6) “twisted ribbon” rib deformities; and (7) enlargement of long bones. Miscellaneous Symptoms Pheochromocytoma, an unusual complication of NF, is never seen in children. Hypertension may be due to a pheochromocytoma or a neurofibroma of a renal artery. Malignant tumors not uncommonly complicating NF include sarcoma, leukemia, Wilms tumor, ganglioglioma, and neuroblastoma. Medullary thyroid carcinoma and hyperparathyroidism rarely occur. Precocious puberty and, less commonly, sexual infantilism result from involvement of the hypothalamus by glioma or hamartoma. Cystic lesions, malignancy, and interstitial pneumonia are pulmonary complications.

DIAGNOSIS Diagnosis of NF-1 or NF-2 is based on clinical, radiologic, and pathologic findings, as well as the family history. Diagnostic criteria have been established by the National Institutes of Health Consensus Conference ( Table 99.1).

TABLE 99.1. DIAGNOSTIC CRITERIA FOR NEUROFIBROMATOSIS

LABORATORY DATA Molecular genetic studies are now available but are not always specific or diagnostic. Therefore, all patients and those at risk should receive an extensive clinical evaluation aimed at diagnosis and identification of possible complications. Ancillary laboratory studies, however, should be individualized, determined by the clinical manifestations. Complete evaluation may include psychoeducational and psychometric testing; electroencephalogram; ophthalmologic and audiologic testing; cranial computed tomography (CT), including orbital views; CT of the spine and internal auditory foramina; magnetic resonance imaging of brain and spine; and quantitative measurement of 24-hour urinary catecholamines.

TREATMENT There is no specific treatment for NF, but complications may be ameliorated with early recognition and prompt therapeutic intervention. Learning disabilities should be considered in all children with NF and may be complicated by behavioral problems (hyperkinesis or attention deficit disorder) that warrant educational therapy or behavioral modification, psychotherapy, and pharmacotherapy. Speech problems require a language evaluation and formal speech therapy, and seizures indicate the need for anticonvulsant medication. Progressive kyphoscoliosis usually requires surgical intervention. Surgery may be necessary for removal of pheochromocytomas and intracranial or spinal neoplasms; cutaneous neurofibromas require extirpation when they compromise function or are disfiguring. Radiation therapy is reserved for some CNS neoplasms, including optic glioma. Genetic counseling and psychotherapy with family counseling are important. SUGGESTED READINGS

1Neurofibromatosis. Conference Statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988;45:575–578. Crowe FW, Schull WJ, Neel JV. A clinical, pathological and genetic study of multiple neurofibromatosis. Springfield, IL: Charles C Thomas, 1956. Easton DF, Ponder MA, Huson SM, et al. Analysis of variation in expression of neurofibromatosis (NF1): evidence for modifying genes. Am J Hum Genet 1993;53:305–313. Es SV, North KN, McHugh K, Silva MD. MRI findings in children with neurofibromatosis type I: a prospective study. Pediatr Radiol 1996:26;478–487. Evans DGR, Huson SM, Donnai D, et al. A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling. J Med Genet 1992;29:847–852. Gutmann DH. Recent insights into neurofibromatosis type 1: clear genetic progress. Arch Neurol 1998;55:778–780. Gutmann DH, Collins FS. Recent progress toward understanding the molecular biology of von Recklinghausen neurofibromatosis. Ann Neurol 1992;31:555–561. Gutmann DH, Collins FS. The neurofibromatosis type 1 gene and its protein product, neurofibromin. Neuron 1993;10:335–343. Karmes PS. Neurofibromatosis: a common neurocutaneous disorder. Mayo Clin Proc 1998;73:1071–1076. Korf BR. Neurocutaneous syndromes: neurofibromatosis 1, neurofibromatosis 2, and tuberous sclerosis. Curr Opin Neurol 1997;10:131–136. Levinsohn PM, Mikahel MA, Rothman SM. Cerebrovascular changes in neurofibromatosis. Dev Med Child Neurol 1978;20:789–792. Listernick R, Louis DN, Packer RJ, Gutmann DH. Optic pathway gliomas in neurofibromatosis I. Optic Pathway Glioma Taskforce. Ann Neurol 1997;41:143–149. Martuza RL, Eldridge R. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 1988;318:684–688. Mulvihill JJ, Pavory DM, Sherman JL, et al. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis): an update. Ann Intern Med 1990;113:39–52. North K. Neurofibromatosis type 1 in childhood. London: MacKeith Press, 1997. Pollack IF, Mulvihill JJ. Neurofibromatosis 1 and 2. Brain Pathol 1997;7:823–836. Riccardi VM. Neurofibromatosis: phenotype, natural history, and pathogenesis, 2nd ed. Baltimore: Johns Hopkins University Press, 1992. Romanowski CA, Cavallin LI. Neurofibromatosis types I and II: radiological appearance. Hosp Med 1998;59:134–139. Rubenstein AE, Bunge RP, Housman DE, eds. Neurofibromatosis. Ann N Y Acad Sci 1986;486:1–414. Smirniotopoulos JG, Murphy FM. The phakomatoses: neurofibromatosis. AJNR 1992;13:737–744. Stern HJ, Saal HM, Lee JS, et al. Clinical variability of type 1 neurofibromatosis: is there a neurofibromatosis-Noonan syndrome? J Med Genet 1992;29:184–187. Tibbles JAR, Cohen MM. The proteus syndrome: the Elephant Man diagnosed. BMJ 1986;293:683–685. Trofatter JA, MacCollin MM, Rutter JL, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for neurofibromatosis 2 tumor suppressor. Cell 1993;72:1–20. Upadhyaya M, Fryer A, MacMillan J, et al. Prenatal diagnosis and presymptomatic detection of neurofibromatosis type 1. J Med Genet 1992;29:180–183.

CHAPTER 100. ENCEPHALOTRIGEMINAL ANGIOMATOSIS MERRITT’S NEUROLOGY

CHAPTER 100. ENCEPHALOTRIGEMINAL ANGIOMATOSIS ARNOLD P GOLD Genetics Neuropathology Symptoms and Signs Laboratory Data Diagnosis Treatment Suggested Readings

Encephalotrigeminal angiomatosis (Sturge-Weber-Dimitri syndrome) (MIM 185300) is manifested by a cutaneous vascular port-wine nevus of the face, contralateral hemiparesis and hemiatrophy, glaucoma, seizures, and mental retardation. In 1847, Sturge described the clinical picture and attributed the neurologic manifestations to a nevoid lesion of the brain similar to the facial lesion. In 1923, Dimitri showed the gyriform pattern of calcification. Weber described the radiographic findings of intracranial calcification.

GENETICS Most cases are sporadic, but affected siblings suggest autosomal-recessive inheritance in some families. Others cases suggest an autosomal-dominant pattern. As with other neurocutaneous disorders, there is incomplete penetrance with marked variability of the clinical manifestations. The gene locus has not yet been mapped.

NEUROPATHOLOGY The occipital lobe is most often affected, but lesions may involve the temporal and parietal lobes or the entire cerebral hemisphere. Atrophy is characteristically unilateral and ipsilateral to the facial nevus. Leptomeningeal angiomatosis with small venules fills the subarachnoid space. Calcification of the arteries on the surface of the brain and intracerebral calcifications of small vessels are seen. The trolley-track or curvilinear calcifications seen on skull radiographs are due to calcification of the outer cortex rather than of blood vessels.

SYMPTOMS AND SIGNS Facial nevus and a neurologic syndrome of seizures, hemiplegia, retardation, and glaucoma are characteristic. Typically, other than the facial nevus, the child has normal function for months or years. Subsequent clinical course is highly variable; a clinical classification has recently been proposed by Roach (1992) ( Table 100.1).

TABLE 100.2. ENCEPHALOFACIAL ANGIOMATOSIS

Cutaneous Symptoms The port-wine facial nevus flammeus is related to the cutaneous distribution of the trigeminal nerve ( Fig. 100.1). Most commonly involving the forehead, the nevus may involve one-half of the face and may extend to the neck. The nevus may cross or fall short of the midline. Rarely, bilateral facial lesions are seen.

FIG. 100.1. Encephalotrigeminal angiomatosis. Facial nevus flammeus involves the cutaneous distribution of all three branches of the trigeminal nerve on one side and the mandibular branch on the contralateral side.

Only when the entire ophthalmic sensory area (forehead and upper eyelid) is covered by the nevus flammeus (with or without involvement of the maxillary and mandibular areas) is there a high risk of glaucoma or neurologic complications. Neuroocular disease is rare when only part of the ophthalmic area has a port-wine stain. There is little or no risk when the nevus is localized to the maxillary or mandibular trigeminal sensory areas without involving the ophthalmic area. Neurologic Symptoms Epilepsy is the most common neurologic manifestation, usually starting in the first year of life with focal motor, generalized major motor, or partial complex convulsions. Often refractory to anticonvulsants, the focal motor seizures, hemiparesis, and hemiatrophy are contralateral to the facial nevus. Onset of seizures before age 2 years and refractory epilepsy have prognostic significance; these patients are more likely to be intellectually impaired. Intellectual retardation often becomes more marked with age. Ophthalmologic Symptoms Raised intraocular pressure with glaucoma and buphthalmos occurs in approximately 30% of patients. Buphthalmos, which is more common than glaucoma, is due to

antenatal intraocular hypertension. Homonymous hemianopia, a common visual-field complication, is invariable when the occipital lobe is affected. Other congenital anomalies include coloboma of the iris and deformity of the lens.

LABORATORY DATA The highly characteristic calcifications are rarely seen on radiographs before age 2 years ( Fig. 100.2). They appear as paired (trolley-track) curvilinear lines that follow the cerebral convolutions. Cerebral atrophy may be implied by asymmetry of the calvarium, with elevated petrous pyramid, thickening of the calvarial diploë, and enlargement of the paranasal sinuses and mastoid air cells on the side of the lesion. Computed tomography (CT) documents the intracranial calcification and unilateral cerebral atrophy ( Fig. 100.3). Magnetic resonance imaging (MRI) with gadolinium defines the extent of the leptomeningeal angioma, whereas functional imaging with positron-emission tomography or single-photon emission computed tomography with underperfusion delineates the involved area of the brain. Combining these procedures enhances the effectiveness of precise functional neurosurgery. Cerebral angiography may demonstrate capillary and venous abnormalities. The capillaries over the affected hemisphere are homogeneously increased, the superficial cortical veins are markedly decreased, and the superior sagittal sinus may be diminished or not seen.

FIG. 100.2. Encephalotrigeminal angiomatosis. A: Lateral skull radiograph shows characteristic calcifications consisting of paired curvilinear lines localized mostly to the occipital and parietal lobes. B: Posteroanterior view shows calcifications outlining an atrophic right cerebral hemisphere.

FIG. 100.3. Noncontrast CT shows subcortical calcification conforming to the gyral pattern of calcification in the Sturge-Weber-Dimitri syndrome. (Courtesy of Dr. S.K. Hilal and Dr. M. Mawad.)

Electroencephalography shows a wide area of low potentials over the affected areas, and this electrical silence correlates with the degree of intracranial calcification. The remainder of the hemisphere may show epileptiform activity. Visual-field studies document the homonymous hemianopia.

DIAGNOSIS The diagnosis is based on the facial vascular port-wine nevus flammeus and one or more of the following: seizures, contralateral hemiparesis and hemiatrophy, mental retardation, and ocular findings of glaucoma or buphthalmos. The appearance of calcifications on skull radiographs or CT reinforces the diagnosis. Rarely, Sturge-Weber-Dimitri syndrome may occur with the neurologic syndrome and the typical intracranial calcifications but without the facial nevus.

TREATMENT The facial nevus rarely requires early cosmetic therapy. Later, this blemish can be covered with cosmetics or permanently treated with laser therapy. Seizures may be difficult to control with anticonvulsants; lobectomy or hemispherectomy may be efficacious. Physical and occupational therapy are indicated for the hemiparesis. Educational therapy and placement in a special school are important in the learning-disabled or intellectually impaired patient; vocational training is essential in affected older children and young adults. Behavioral problems are common and may include attention deficit disorder or overt psychopathology that warrants psychotropic drug therapy and psychotherapy. Prophylactic daily low-dose aspirin to prevent venous thrombosis is controversial but can be considered if there are recurrent transient ischemic attacks. Yearly monitoring for glaucoma is recommended for all patients and, if present, should be treated aggressively. SUGGESTED READINGS Aicardi J, Arzimanoglou A. Sturge-Weber syndrome. Int Pediatr 1991;6:129–134. Alexander GL. Sturge-Weber syndrome. In: Vinken PJ, Bruyn GW, eds. The phakomatoses. Handbook of clinical neurology, vol 14. New York: American Elsevier Publishing, 1972:223–240. Griffiths PD, Boodram MB, Blaser S, Armstrong D, Gilday DL, Harwood-Nash D. 99m Technetium HMPAO imaging in children with the Stuge-Weber syndrome: a study of nine cases with CT and MRI correlation. Neuroradiology 1997;39:219–224. Poser CM, Taveras JM. Cerebral angiography in encephalotrigeminal angiomatosis. Radiology 1957;68:327–336. Roach ES. Encephalofacial angiomatosis. Pediatr Clin North Am 1992;39:606–613. Romanowski CA, Cavallin LI. Tuberous sclerosis, von Hippel-Lindau disease, Sturge-Weber syndrome. Hosp Med 1998;59:226–231. Sturge WA. A case of partial epilepsy, apparently due to a lesion of one of the vaso-motor centres of the brain. Trans Clin Soc Lond 1879;12:162–167. Sujansky E, Conradi S. Outcome of Sturge-Weber syndrome in 52 adults. Am J Med Genet 1995;57:35–45. Sujansky E, Conradi S. Sturge-Weber syndrome: age of onset of seizures and glaucoma and the prognosis for affected children. J Child Neurol 1995;10:49–53. Tallman B, Tan OT, Morelli JG, et al. Location of port-wine stains and the likelihood of ophthalmic and/or central nervous system complications. Pediatrics 1991;87:323–327. Vogl J, Stemmler J, Bergman C, et al. MRI and MR angiography of Sturge-Weber syndrome. AJNR 1993;14:417–425. Weber FP. Right-sided hemi-hypertrophy resulting from right-sided congenital spastic hemiplegia, with a morbid condition of the left side of the brain, revealed by radiograms. 1922;3:134–139.

J Neurol Psychopathol

CHAPTER 101. INCONTINENTIA PIGMENTI MERRITT’S NEUROLOGY

CHAPTER 101. INCONTINENTIA PIGMENTI ARNOLD P.GOLD Incontinentia Pigmenti Incontinentia Pigmenti Achromians Suggested Readings

INCONTINENTIA PIGMENTI Incontinentia pigmenti (MIM 308300), described by Bloch and Sulzberger, is a genetic disorder affecting the skin in a characteristic manner and also involving the brain, eyes, nails, and hair. Genetics The disorder is thought to be an X-linked dominant condition that is lethal in males. The evidence includes high female-to-male ratio, female-to-female transmission, increased incidence of miscarriages, and affected males having a 47,XXY karyotype (Klinefelter syndrome). Incontinentia pigmenti has been mapped to Xq28 by linkage analysis, but some families show recombination with probes to this locus, so there must be other loci for the inherited form. The disease has also appeared in girls with no family history of the disease. In these cases, there is a translocation with a breakpoint at Xp11.21; this is the sporadic form. Some patients and some families do not map to either site, so there must be locus heterogeneity, with still more gene loci to be discovered. A related condition is incontinentia pigmenti achromians (hypomelanosis of Ito) (MIM 146150), which also maps to Xp11; this condition and sporadic incontinentia pigmenti may be different disorders (contiguous gene syndromes) or allelic forms of mutation in the same gene. A pregnant woman with incontinentia pigmenti runs a 25% risk of a spontaneous miscarriage (the affected male); 50% of her female children will be affected and will have the disease. Daughters are likely to be more severely affected than their mothers. Neuropathology The neuropathologic findings are nonspecific and include cerebral atrophy with microgyria, focal necrosis with formation of small cavities in the central white matter, and focal areas of neuronal loss in the cerebellar cortex. Symptoms and Signs Cutaneous Symptoms One-half of affected infants have the initial linear vesicobullous lesions at birth, and most of the remaining children show the lesions in the first 2 weeks of life. About 10% are delayed, appearing as late as age 1 year. The skin lesions can recur and ultimately may undergo a characteristic change to linear verrucous and dyskeratotic growth, usually between the second and sixth weeks of life; pigmentary changes appear between 12 and 26 weeks. Some infants may show the pigmentary lesions at birth without further cutaneous progression. The pigmentation involves the trunk and extremities, is slate-gray blue or brown, and is distributed in irregular marbled or wavy lines. With age, the pigmentary lesions fade and become depigmented with atrophic skin changes. Neurologic, Ophthalmic, and Other Symptoms About 20% of affected children have a neurologic syndrome that may include slow motor development; pyramidal-tract dysfunction with spastic hemiparesis, quadriparesis, or diplegia; mental retardation; and convulsive disorders. Strabismus, cataracts, and severe visual loss occur in about 20% of affected children. Retinal vascular changes may result in blindness with ectasia, microhemorrhages, avascularity, and, later, retinal pigmentation and atrophy. Partial or total anodontia and peg-shaped teeth are characteristic of incontinentia pigmenti. Partial or complete diffuse alopecia with scarring and nail dystrophy may also occur. Laboratory Data Eosinophilia as high as 65% is often seen in infants younger than 1 year, together with an associated leukocytosis. Eosinophils are also found in the vesicobullous lesions and in affected dermis. Treatment There is no specific treatment for incontinentia pigmenti, and management is directed at complicating problems, such as anticonvulsants for seizures. Awareness of the ocular manifestations is essential because laser coagulation in retinal ectasia prevents blindness.

INCONTINENTIA PIGMENTI ACHROMIANS This neurocutaneous entity was originally described by Ito ( hypomelanosis of Ito) and is distinctive in both clinical manifestations and pathologic features. Etiology The pathogenesis of this disease is similar to that of other neurocutaneous disorders. Migration of neural cells to the brain and melanoblasts to the skin from the neural crest occurs between 3 and 6 months' gestational age. A disturbance of this migration results in both brain and cutaneous pigmentary disease. Genetics Incontinentia pigmenti achromians is found in all races and sexes and is inherited as an autosomal-dominant trait with variable penetrance. At least one form maps to Xp11, suggesting that different mutations at that locus give rise to the pigmented or hypomelanotic classes of incontinentia pigmenti. Clinical Manifestations In infancy, hypopigmented skin lesions appear as whorls or streaks on any part of the body ( Fig. 101.1) and tend to progress onto uninvolved areas. This lesion is the negative image of incontinentia pigmenti. In later childhood, affected areas tend to return to normal skin color. The cutaneous lesion is often associated with developmental and neurologic abnormalities with hypotonia, pyramidal-tract dysfunction, mental retardation (approximately 80%), and seizures. Ophthalmologic disorders, including strabismus, optic atrophy, microophthalmia, tessellated fundus, eyelid ptosis, and heterochromia iridis, are also present. The hair, teeth, and musculoskeletal system may be affected.

FIG. 101.1. Incontinentia pigmenti achromians. Hypopigmented skin lesions show streaks or whorls.

Pathology The hypopigmented skin lesions are characterized by a decrease in the number of dopa-positive melanocytes and decreased pigment production in the basal layer of the epidermis. Diagnosis and Laboratory Data Because there is no pathognomonic laboratory test, diagnosis must be based solely on the characteristic hypomelanosis. Treatment The whorled, marble-cake hypopigmented skin lesions do not require any treatment. Therapy is directed toward the associated complications, such as anticonvulsants for seizures and specialized educational facilities for the learning-disabled or retarded child. SUGGESTED READINGS Aydingoz U, Midia M. Central nervous system involvement in incontinentia pigmenti: cranial MRI of two siblings. Neuroradiology 1998;40:364–366. Donat JF, Walsworth DM, Turk LL. Focal cerebral atrophy in incontinentia pigmenti achromians. Am J Dis Child 1980;134:709–710. Hyden-Gramskog C, Salonen R, von Koskull H. Three Finnish incontinentia pigmenti (IP) families with recombinations with the IP loci at Xq28 and Xp11. Hum Genet 1993;91:185–189. Jelinek JE, Bart RS, Schiff GM. Hypomelanosis of Ito (incontinentia pigmenti achromians). Arch Dermatol 1973;107:596–601. Koiffmann CP, deSouza DH, Diament A, et al. Incontinentia pigmenti achromians (hypomelanosis of Ito, MIM 146150): further evidence of localtization at Xp11.

Am J Med Genet 1993;46:529–533.

Landy SJ, Domani D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet 1993;30:53–59. Larsen R, Ashwal S, Peckham N. Incontinentia pigmenti: association with anterior horn cell degeneration. Neurology 1987;37:446–450. Lee AG, Goldberg MF, Gillard JH, Barker PB, Bryan RN. Intracranial assessment of incontinentia pigmenti using magnetic resonance imaging, angiography, and spectroscopic imaging. Arch Pediatr Adolesc Med 1995;149;573–580. O'Brien JE, Feingold M. Incontinentia pigmenti: a longitudinal study. Am J Dis Child 1985;139:711–712. Pascual-Castroviejo I, Roche C, Martinez-Bermejo A, et al. Hypomelanosis of Ito: a study of 76 infantile cases. Brain Dev 1998;20: 36–43. Scheuerle AF. Male cases of incontinentia pigmenti: a case report and review. Am J Med Genet 1998;77:201–218. Schwartz MF, Esterly NB, Fretzin DF, et al. Hypomelanosis of Ito (incontinentia pigmenti achromians): a neurocutaneous syndrome. J Pediatr 1977;90:236–240. Sulzberger MB. Incontinentia pigmenti (Bloch-Sulzberger): report of an additional case, with comment on possible relation to a new syndrome of familial and congenital anomalies. Arch Dermatol 1938;38:57–69. Wald KJ, Mehta MC, Katsumi O, et al. Retinal detachments in incontinentia pigmenti. Arch Ophthalmol 1993;111:614–617.

CHAPTER 102. TUBEROUS SCLEROSIS MERRITT’S NEUROLOGY

CHAPTER 102. TUBEROUS SCLEROSIS ARNOLD P.GOLD Genetics and Incidence Pathology and Pathogenesis Symptoms and Signs Cutaneous Symptoms Laboratory Data Diagnosis Course and Prognosis Treatment Suggested Readings

Tuberous sclerosis was first described by von Recklinghausen in 1863. In 1880, Bourneville coined the term sclérose tubéreuse for the potato-like lesions in the brain. In 1890, Pringle described the facial nevi, or adenoma sebaceum. Vogt later emphasized the classic triad of seizures, mental retardation, and adenoma sebaceum. Eponymically, tuberous sclerosis is called Pringle disease when there are only dermatologic findings, Bourneville disease when the nervous system is affected, and West syndrome when skin lesions are associated with infantile spasms, hypsarrhythmia, and mental retardation. Tuberous sclerosis (MIM 191100) is a hereditarily determined progressive disorder characterized by the development in early life of hamartomas, malformations, and congenital tumors of the nervous system, skin, and viscera.

GENETICS AND INCIDENCE Tuberous sclerosis is inherited as an autosomal-dominant trait, with a high incidence of sporadic cases and protean clinical expressivity. These features are attributed to modifier genes, for which the homozygous condition results in a phenotypically normal individual despite the presence of the gene for tuberous sclerosis; when heterozygous, the modifier gene results in a mildly affected patient. The defective gene has been mapped to chromosome 9q34 (TSC1) in some families and to chromosome 16p13.3 (TSC2) in others. Hamartin is the gene product for TSC1, and tuberin is the gene product for TSC2. Both are involved in the regulation of cell growth and are considered tumor suppressor genes. As in other hereditary tumor syndromes, a second somatic mutation may be involved in pathogenesis. Incidence figures must be considered minimal because milder varieties are often unrecognized. Autopsy data gave an incidence of 1 in 10,000 people; clinical surveys gave a prevalence between 1 in 10,000 and 1 in 170,000. Although all races are affected, the disease is thought to be uncommon in blacks, and there may be a greater frequency in males.

PATHOLOGY AND PATHOGENESIS The pathologic changes are widespread and include lesions in the nervous system, skin, bones, retina, kidney, lungs, and other viscera. The brain is usually normal in size, but several or many hard nodules occur on the surface of the cortex. These nodules are smooth, round, or polygonal and project slightly above the surface of the neighboring cortex. They are white, firm to the touch, and of various sizes. Some involve only a small portion of one convolution; others encompass the convolutions of one whole lobe or a major portion of a hemisphere. In addition, there may be developmental anomalies of the cortical convolutions in the form of pachygyria or microgyria. On sectioning of the hemispheres, sclerotic nodules may be found in the subcortical gray matter, the white matter, and the basal ganglia. The lining of the lateral ventricles is frequently the site of numerous small nodules that project into the ventricular cavity ( candle gutterings) (Fig. 102.1). Sclerotic nodules are less frequently found in the cerebellum. The brainstem and spinal cord are rarely involved.

FIG. 102.1. Tuberous sclerosis. Nodules (candle gutterings) on the surface of ventricles. (Courtesy of Dr. Leon Roizin.)

Histologically, the nodules are characterized by a cluster of atypical glial cells in the center and giant cells in the periphery. Calcifications are relatively frequent. Other features include heterotopia, vascular hyperplasia (sometimes with actual angiomatous malformations), disturbances in the cortical architecture, and, occasionally, development of subependymal giant-cell astrocytomas. Intracranial giant aneurysm and arterial ectasia are uncommon findings. The skin lesions are multiform and include the characteristic facial nevi ( adenoma sebaceum) and patches of skin fibrosis. The facial lesions are not adenomas of the sebaceous glands but rather small hamartomas arising from nerve elements of the skin combined with hyperplasia of connective tissue and blood vessels ( Fig. 102.2). In late childhood, lesions similar to those on the face are found around or underneath the fingernails and toenails ( ungual fibroma). Circumscribed areas of hypomelanosis or white nevi are common in tuberous sclerosis and are often found in infants. Although these depigmented nevi are less specific than the sebaceous adenoma, they are of importance in raising suspicion for the diagnosis in infants with seizures. Histologically, the skin appears normal except for the loss of melanin, but ultrastructural studies show that melanosomes are small and have reduced content of melanin.

FIG. 102.2. Tuberous sclerosis. Facial adenoma sebaceum over the butterfly area of the face spares the upper lip.

The retinal lesions are small congenital tumors ( phakomas) composed of glia, ganglion cells, or fibroblasts. Glioma of the optic nerve has been reported. Other lesions include cardiac rhabdomyoma; renal angiomyolipoma, renal cysts, and, rarely, renal carcinoma; cystic disease of the lungs and pulmonary lymphangioleiomyomatosis; hepatic angiomas and hamartomas; skeletal abnormalities with localized areas of osteosclerosis in the calvarium, spine, pelvis, and limbs; cystic defects involving the phalanges; and periosteal new bone formation confined to the metacarpals and metatarsals.

SYMPTOMS AND SIGNS The cardinal features of tuberous sclerosis are skin lesions, convulsive seizures, and mental retardation. The disease is characterized by variability and expressivity of the clinical manifestations.

CUTANEOUS SYMPTOMS Depigmented or hypomelanotic macules are the earliest skin lesion ( Fig. 102.3). They are present at birth, persist through life, and may only be found with a Wood's-lamp examination. The diagnosis is suggested if there are three or more macules measuring 1 cm or more in length. Numerous small macules sometimes resemble confetti or depigmented freckles. Most macules are leaf-shaped, resembling the leaf of the European mountain ash tree and sometimes following a dermatomal distribution. Facial adenoma sebaceum ( facial angiofibroma) is never present at birth but is clinically evident in more than 90% of affected children by age 4 years. At first, the facial lesion is the size of a pinhead and red because of the angiomatous component. It is distributed symmetrically on the nose and cheeks in a butterfly distribution. The lesions may involve the forehead and chin but rarely involve the upper lip. They gradually increase in size and become yellowish and glistening. Shagreen patches, a connective tissue hamartoma, are also characteristic. Rarely present in infancy, the patches become evident after age 10. Usually found in the lumbosacral region, shagreen plaques are yellowish-brown elevated plaques that have the texture of pig skin. Other skin lesions include cafĂŠ-au-lait spots, small fibromas that may be tiny and resemble coarse goose flesh, and ungual fibromas that appear after puberty.

FIG. 102.3. Tuberous sclerosis. Hypomelanotic or ash leaf macules on the skin.

Neurologic Symptoms Seizures and mental retardation indicate a diffuse encephalopathy. Infantile myoclonic spasms with or without hypsarrhythmia are the characteristic seizures of young infants and, when associated with hypopigmented macules, are diagnostic of tuberous sclerosis. The older child or adult has generalized tonic-clonic or partial complex seizures. There is a close relationship between the onset of seizures at a young age and mental retardation. Mental retardation rarely occurs without clinical seizures, but intellect may be normal, despite seizures. Other than a delayed acquisition of developmental milestones, intellectual impairment, or nonspecific language or coordinative deficiencies, a formal neurologic examination is typically nonfocal. Ophthalmic Symptoms Hamartomas of the retina or optic nerve are observed in about 50% of patients. Two types of retinal lesions are seen on funduscopic examination: (1) the easily recognized calcified hamartoma near or at the disc with an elevated multinodular lesion that resembles mulberries, grains of tapioca, or salmon eggs ( Fig. 102.4); and (2) the less distinct, relatively flat, smooth-surfaced, white or salmon-colored, circular or oval lesion located peripherally in the retina ( Fig. 102.5). Nonretinal lesions may range from the specific depigmented lesion of the iris ( Fig. 102.6) to nonspecific, nonparalytic strabismus, optic atrophy, visual-field defects, or cataracts.

FIG. 102.4. Tuberous sclerosis. Central calcified hamartoma, or so-called &147;mulberry phakoma,&148; at the optic nerve.

FIG. 102.5. Tuberous sclerosis. Phakoma or retinal hamartoma involves the peripheral retina.

FIG. 102.6. Tuberous sclerosis. Depigmented or hypomelanotic lesions of the iris.

Visceral Symptoms Renal lesions include hamartomas ( angiomyolipomas) and renal cysts. Typically, both are multiple, bilateral, and usually innocuous and silent. Renal cell carcinoma is a rare complication in the older child or adult. In one series, there was a 50% incidence of tuberous sclerosis in patients with cardiac rhabdomyoma. This cardiac tumor may be symptomatic at any age, even infancy, and can result in death. Pulmonary hamartomatous lesions consisting of multifocal alveolar hyperplasia associated with cystic lymphangioleiomyomatosis occur in fewer than 1% of patients. These become symptomatic (often with a spontaneous pneumothorax) in the third or fourth decade and are progressive and often fatal. Sclerotic lesions of the calvaria and cystic lesions of the metacarpals and phalanges are asymptomatic. Hamartomatous hemangiomas of the spleen and racemose angiomas of the liver are rare and usually asymptomatic. Enamel pitting of the deciduous teeth may aid in diagnosis.

LABORATORY DATA Unless renal lesions are present, routine laboratory studies are normal. Renal angiomyolipomas are usually asymptomatic and rarely cause gross hematuria, but they may show albuminuria and microscopic hematuria. Sonography ( Fig. 102.7), angiography, and computed tomography (CT) are often diagnostic. Multiple or diffuse renal cysts may be associated with albuminuria or azotemia and hypertension. Intravenous pyelography is diagnostic.

FIG. 102.7. Tuberous sclerosis. Renal sonogram demonstrates a renal angiomyolipoma.

Chest radiographs may reveal pulmonary lesions or rhabdomyoma with cardiomegaly. Electrocardiogram findings are variable, but the echocardiogram is diagnostic. Skull radiographs usually reveal small calcifications within the substance of the cerebrum ( Fig. 102.8). Cerebrospinal fluid is normal, except when a large intracerebral tumor is present. The electroencephalogram is often abnormal, especially in patients with clinical seizures. Abnormalities include slow-wave activity and epileptiform discharges such as hypsarrhythmia, focal or multifocal spike or sharp-wave discharges, and generalized spike-and-wave discharges. CT is diagnostic when calcified subependymal nodules encroach on the lateral ventricle (often in the region of the foramen of Monro); there may also be calcified cortical or cerebellar nodules ( Fig. 102.9). A few nodules appear isodense on CT and are better visualized on magnetic resonance imaging (MRI). Fluid-attenuated inversion recovery (FLAIR) MRI images allow more accurate delineation of cortical and subcortical tubers. Calcified paraventricular and cortical lesions have been visualized shortly after birth. The number of cortical tubers often correlates with the severity of cortical dysfunction. There is enough variation in clinical outcome that prognosis cannot be based on cortical tuber count alone.

FIG. 102.8. Tuberous sclerosis. Calcified nodules in the cerebrum. (Courtesy of Dr. P.I. Yakovlev.)

FIG. 102.9. Tuberous sclerosis. A: Noncontrast axial CT demonstrates a calcific density adjacent to the right foramen of Monro, a typical location for tubers. B:

Postcontrast, this lesion enhances, as do additional noncalcified lesions on the contralateral side. (Courtesy of Dr. J.A. Bello and Dr. S.K. Hilal.)

DIAGNOSIS Clinical diagnosis is possible at most ages. In infancy, three or more characteristic depigmented cutaneous lesions suggest the diagnosis, and this is reinforced in the presence of infantile myoclonic spasms. In the older child or adult, the diagnosis is made by the triad of tuberous sclerosis: facial adenoma sebaceum, epilepsy, and mental retardation. Retinal or visceral lesions may be diagnostic. The disease, however, is noted for protean manifestations, and a family history may be invaluable in establishing the diagnosis, which is often reinforced by CT or MRI evidence of calcified subependymal nodules. The differential diagnosis includes other diseases that involve skin, nervous system, and retina. Neurofibromatous and encephalotrigeminal angiomatosis are differentiated by the characteristic skin lesions of those disorders. Multisystem involvement may result in difficulties in establishing a diagnosis of tuberous sclerosis. The National Tuberous Sclerosis Association has developed a classification of diagnostic criteria ( Table 102.1). Prenatal diagnosis is not currently available.

TABLE 102.1. DIAGNOSTIC CRITERIA FOR TUBEROUS SCLEROSIS COMPLEX (TSC)

COURSE AND PROGNOSIS Mild or solely cutaneous involvement often follows a static course, whereas patients with the full-blown syndrome have a progressive course with increasing seizures and dementia. The child with infantile myoclonic spasms is at great risk of later intellectual deficit. Brain tumor, status epilepticus, renal insufficiency, cardiac failure, or progressive pulmonary impairment can lead to death.

TREATMENT There is no specific treatment. The cutaneous lesions do not compromise function, but cosmetic surgery may be indicated for facial adenoma sebaceum or large shagreen patches. Infantile myoclonic spasms previously responded to corticosteroid or corticotropin therapy, and currently vigabatrin is the drug of choice; focal and generalized seizures are treated with anticonvulsants. Progressive cystic renal disease often responds to surgical decompression, but with renal failure, dialysis or renal transplantation may be necessary. Intramural cardiac rhabdomyoma and complicating congestive heart failure are managed medically with cardiotonics, diuretics, and salt restriction. Whole obstructive intracavity tumors and congestive heart failure require surgical extirpation of the tumor. Progressive pulmonary involvement is an indication for respiratory therapy, but response is poor and most patients die a few years after the onset of this complication. SUGGESTED READINGS Bourneville DM. Sclerose tubereuse des circonvolutions cerebrales: idotie et epilepsie hemiplegique. Arch Neurol 1880;1:81–91. Castro M, Shepherd CW, Gomez MR, Lie JT, Ryu JM. Pulmonary tuberous sclerosis. Chest 1995;107:189–195. Gold AP, Freeman JM. Depigmented nevi: the earliest sign of tuberous sclerosis. Pediatrics 1965;35:1003–1005. Goodman M, Lamm SH, Engle A, Shepherd CW, Houser OW, Gomez MR. Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. 1997;12:85–90.

J Child Neurol

Inoue Y, Nemoto Y, Murata R, et al. CT and MR imaging of cerebral tuberous sclerosis. Brain Dev 1998;20:209–221. Johnson WG, Gomez MR, eds. Tuberous sclerosis and allied disorders: clinical, cellular and molecular studies. Ann N Y Acad Sci 1991;615:1–385. Kandt RS, Gebarski SS, Geotting MG. Tuberous sclerosis with cardiogenic cerebral embolism: magnetic resonance imaging. Neurology 1985;35:1223–1225. Korf BR. Neurocutaneous syndromes: neurofibromatosis 1, neurofibromatosis 2, and tuberous sclerosis. Curr Opin Neurol 1997;10:131–136. Kwiatkowska J, Wigowska-Sowinska J, Napierala, D et al. Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis. N Engl J Med 1999;340:703–707. Lucchese NJ, Goldberg MF. Iris and fundus pigmentary changes in tuberous sclerosis. J Pediatr Ophthalmol Strabismus 1981;18:45–46. Nixon JR, Houser OW, Gomez MR, Okazaki H. Cerebral tuberous sclerosis: MR imaging. Radiology 1989;170:869–873. Roach ES. Tuberous sclerosis. Pediatr Clin North Am 1992;39:591–620. Roach ES, Smith M, Huttenlocher P, et al. Diagnostic criteria: tuberous sclerosis complex. Report of the diagnostic criteria committee of the National Tuberous Sclerosis Association. J Child Neurol 1992;7:221–224. Romanowski CA, Cavallin LI. Tuberous sclerosis, von Hippel-Lindau disease, Sturge-Weber syndrome. Hosp Med 1998;59:226–231. Smirniotopoulos JG, Murphy FM. The phakomatoses: tuberous sclerosis. AJNR 1992;13:732–737. Weiner DM, Ewalt DH, Roach ES, et al. The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg 1998;187:548–561. Wielderhold WC, Gomez MR, Kurland LT. Incidence and prevalence of tuberous sclerosis in Rochester, Minnesota, 1950 through 1982. Neurology 1985;35:600–603. Young J, Povey S. The genetic basis of tuberous sclerosis. Mol Med Today 1998;4:313–319.

CHAPTER 103. GENERAL CONSIDERATIONS MERRITT’S NEUROLOGY

SECTION XII. PREIPHERAL NEUROPATHIES CHAPTER 103. GENERAL CONSIDERATIONSx NORMAN LATOV Symptoms and Signs Etiology and Diagnosis Treatment Course Suggested Readings

The peripheral nervous system is composed of multiple cell types and elements that subserve diverse motor, sensory, and autonomic functions. The clinical manifestations of neuropathies depend on the severity, distribution, and functions affected. Peripheral neuropathy and polyneuropathy are terms that describe syndromes resulting from diffuse lesions of peripheral nerves, usually manifested by weakness, sensory loss, and autonomic dysfunction. Mononeuropathy indicates a disorder of a single nerve and is often due to a local cause such as trauma or entrapment. Mononeuropathy multiplex signifies focal involvement of two or more nerves, usually as a result of a generalized disorder such as diabetes mellitus or vasculitis. Neuritis is typically reserved for inflammatory disorders of nerves resulting from infection or autoimmunity.

SYMPTOMS AND SIGNS Polyneuropathy may occur at any age, although particular syndromes are more likely to occur in certain age groups. Charcot-Marie-Tooth (CMT) disease, for example, begins in childhood or adolescence, whereas neuropathy associated with paraproteinemia is seen in adults. The onset and progression differ; the Guillain-Barré syndrome (GBS), tick paralysis, and porphyria begin acutely and may remit. Others, such as vitamin B 12 deficiency or carcinomatous neuropathy, begin insidiously and progress slowly. Still others, such as chronic inflammatory demyelinating polyneuropathy, may begin acutely or insidiously and then progress with remissions and exacerbations. The myelin sheaths or the motor or sensory axons themselves may be predominantly affected, or the neuropathy may be mixed, axonal, or demyelinating. Most polyneuropathies, especially those with primary demyelination, affect both motor and sensory functions. A predominantly motor polyneuropathy is seen in lead toxicity, dapsone or hexane intoxication, tick paralysis, porphyria, in some cases of GBS, and in association with multifocal conduction block or anti-GM 1 antibodies. Sensory neuropathy, sometimes with concomitant autonomic dysfunction, is seen in thallium poisoning, acute idiopathic sensory neuronopathy or ganglioneuritis, pyridoxine (vitamin B6) deficiency, inherited sensory neuropathies, primary biliary cirrhosis, and, occasionally, with diabetes mellitus, amyloidosis, carcinoma, or lepromatous leprosy. Predominant involvement of the autonomic system can be seen in acute or chronic autonomic neuropathy or in amyloidosis. Symptoms of polyneuropathy include acral (distal) pain, paresthesia, weakness, and sensory loss. Pain may be spontaneous (parathesias) or elicited by stimulation of the skin (dysthesias) and may be sharp or burning. Paresthesia is usually described as numbness (a dead sensation), tingling, buzzing, stinging, burning, or a feeling of constriction. Lack of pain perception may result in repeated traumatic injuries with degeneration of joints ( arthropathy or Charcot joints) and in chronic ulcerations. Weakness is greatest in distal limb muscles in most neuropathies; there may be paralysis of the intrinsic foot and hand muscles with footdrop or wristdrop. Tendon reflexes are often lost, especially in demyelinating neuropathy. In severe polyneuropathy, the patient may become quadriplegic and respirator-dependent. The cranial nerves may be affected, particularly in GBS and diphtheritic neuropathy. Cutaneous sensory loss appears in a stocking-and-glove distribution. All modes of sensation may be affected, or there may be selective impairment of “large” myelinated fiber functions (position and vibratory sense) or “small” unmyelinated fiber functions (pain and temperature perception). Often, there is a rise in the threshold of perception of painful stimuli, but with a delayed and greater than normal reaction. Involvement of autonomic nerves may cause miosis (small pupil), anhidrosis (impaired sweating), orthostatic hypotension, sphincter symptoms, impotence, and vasomotor abnormalities; these may occur without other evidence of neuropathy, but autonomic neuropathy is more commonly seen in association with symmetric distal polyneuropathy. The most common cause of predominantly autonomic neuropathy in the United States is diabetes mellitus. Amyloidosis is another cause. Tachycardia, rapid alterations in blood pressure, flushing and sweating, and abnormalities in gastrointestinal motility are sometimes prominent in thallium poisoning, porphyria, or GBS. In mononeuropathy or mononeuropathy multiplex, focal motor, sensory, and reflex changes are restricted to areas innervated by specific nerves. When multiple distal subcutaneous nerves are affected in mononeuropathy multiplex, the stocking-and-glove pattern of symmetric distal sensory loss may suggest polyneuropathy. The most frequent causes of mononeuropathy multiplex are diabetes mellitus, periarteritis nodosa, human immunodeficiency virus type 1 infection, rheumatoid arthritis, brachial neuropathy, leprosy, nerve trauma, or sarcoid. Asymmetric motor neuropathy is also seen in multifocal neuropathy with motor conduction block, sometimes with increased titers of anti-GM 1 antibodies. Superficial cutaneous nerves may be thickened and visibly enlarged secondary to Schwann cell proliferation and deposition of collagen as a result of repeated episodes of segmental demyelination and remyelination or to deposition of amyloid or polysaccharides in the nerves. Hypertrophic nerves may be observed in the demyelinating form of CMT disease (type I), Dejerine-Sottas neuropathy, Refsum disease, von Recklinghausen disease (neurofibromatosis), leprous neuritis, amyloidosis, chronic demyelinative polyneuritis, sarcoid, and acromegaly. Fasciculations, or spontaneous contractions of individual motor units, are visible twitches of limb muscles under the skin and may be seen in the tongue. They are characteristic of anterior horn cell diseases but are also seen in motor neuropathy with multifocal motor conduction block and, occasionally, in chronic motor neuropathies involving axons.

ETIOLOGY AND DIAGNOSIS Peripheral nerve disorders may be divided into hereditary and acquired forms. The most common hereditary disorder is CMT syndrome type 1A (peroneal muscular atrophy), associated with duplication of the peripheral myelin protein 22 (PMP22) gene region on chromosome 17. A deletion in the same region is seen in hereditary neuropathy with a liability to pressure palsies. The most common acquired neuropathies in the United States are associated with diabetes mellitus and alcoholism; other causes of polyneuropathy are listed in Table 103.1. Trauma and entrapment are considered in the differential diagnosis of mononeuropathies, particularly if the median nerve is affected at the wrist, the ulnar nerve at the elbow, or the peroneal nerve at the knee. Patients with any form of polyneuropathy seem to be more vulnerable to mechanical injury of nerves; in cachectic or immobile patients, neuropathy may result from pressure or trauma rather than from underlying disease.

TABLE 103.1. CLASSIFICATION AND EVALUATION OF POLYNEUROPATHIES

In the evaluation of a patient with peripheral neuropathy, a detailed family, social, and medical history; neurologic examination; and electrodiagnostic, laboratory, and nerve biopsy studies are usually necessary for diagnosis. A classification of the most common acquired and hereditary polyneuropathies and their laboratory evaluation are presented in Table 103.1.

TREATMENT Treatment of patients with peripheral nerve disorders can be divided into two phases: removal or treatment of the condition responsible for the disorder and symptomatic therapy. Specific treatments will be considered in discussions of the individual disorders. Symptomatic treatment of polyneuropathy consists of general supportive measures, amelioration of pain, and physiotherapy. Tracheal intubation and respiratory support may be needed in GBS. The corneas are protected if there is weakness of eye closure. The bed is kept clean and the sheets are kept smooth to prevent injury to the anesthetic skin; a special mattress can be used to prevent pressure sores. Chronic compression of vulnerable nerves (ulnar at the elbow and common peroneal at the knee) is avoided. Paralyzed limbs are splinted to prevent contractures. Physical therapy includes massage of all weak muscles and passive movement of all joints. When voluntary movement begins to return, muscle training exercises are done daily. Patients should not attempt to walk before muscle testing indicates that they are ready. In chronic polyneuropathy with footdrop, an orthosis for the foot often helps the patient's gait. Patients with postural hypotension are instructed to rise gradually. Treatment includes the use of body stockings to minimize blood pooling in the legs and, if necessary, dietary salt supplementation or mineralocorticoid therapy to expand blood volume.

COURSE The polyneuropathy may be progressive or remitting, and the prognosis is affected by the extent of destruction of nerves before treatment begins. With removal or treatment of the cause of the neuropathy, recovery is more rapid if macroscopic continuity of the nerves has not been interrupted. Conversely, recovery may be delayed for months if axons are destroyed. Axonal regeneration proceeds at a rate of 1 to 2 mm per day and may be delayed where the axons have to penetrate focally damaged segments of nerve. Aberrant growth of axonal sprouts may lead to formation of persistent neuromas. After severe wallerian degeneration, there may be permanent weakness, muscular wasting, diminution of reflexes, and sensory loss. In demyelinating neuropathies, recovery may sometimes be more rapid and complete. SUGGESTED READINGS Asbury AK, Thomas PK. Peripheral nerve disorders 2. London: Butterworths, 1995. Dyck PJ, Thomas PK, Griffin JW, et al, eds. Peripheral neuropathy, 3rd ed. Philadelphia: WB Saunders, 1993. Latov N, Wokke JHJ, Kelly JJ Jr, eds, Immunological and infectious diseases of the peripheral nerves. New York: Cambridge University Press, 1998. Schaumberg HH, Berger AR, Thomas PK. Disorders of peripheral nerves, 2nd ed. Philadelphia: FA Davis Co, 1991. Stewart JD. Focal peripheral neuropathies, 2nd ed. New York: Raven Press, 1993.

CHAPTER 104. HEREDITARY NEUROPATHIES MERRITT’S NEUROLOGY

CHAPTER 104. HEREDITARY NEUROPATHIES ROBERT E.LOVELACE AND LEWIS P.ROWLAND Charcot-Marie-Tooth Diseases Hereditary Sensory and Autonomic Neuropathy Familial Amyloidotic Polyneuropathy Suggested Readings

Hereditary diseases of peripheral nerves have been classified by different criteria through the years. At first, the distinctions were clinical, then by different combinations of histopathology, associated diseases, and patterns of inheritance ( Table 104.1). In the 1960s, nerve conduction velocity became a major determinant (Table 104.2). Now, molecular genetics is a force, especially because the affected gene products are being identified ( Table 104.3).

TABLE 104.1. HEREDITARY PERIPHERAL NEUROPATHIES

TABLE 104.2. CHARCOT-MARIE-TOOTH DISEASES (CMT): HEREDITARY MOTOR AND SENSORY NEUROPATHIES (HMSN)

TABLE 104.3. GENETIC MAPPING OF CHARCOT-MARIE-TOOTH (CMT) AND RELATED NEUROPATHIES

The most common of these hereditary peripheral nerve diseases are the ones originally called Charcot-Marie-Tooth (CMT) disease or peroneal muscular atrophy. Dyck introduced the term hereditary motor and sensory neuropathy as the formal designation, but the McKusick catalog still lists the diseases as CMT, which accounts for about 90% of all hereditary neuropathies. The prevalence of CMT in the United States is about 40 per 100,000 population, or about 125,000 affected people. This is more common than myasthenia gravis and twice the rate of Duchenne dystrophy. A second important group of these diseases is formed by purely sensory neuropathies, some with autonomic disorders. A third group comprises the familial amyloid polyneuropathies. There are still others and new syndromes are still emerging. The focus of this chapter is on the major categories.

CHARCOT-MARIE-TOOTH DISEASES Classification and Molecular Genetics The most common form is type 1 (CMT-1), a demyelinating neuropathy with slow conduction velocity, histologic evidence of demyelination with remyelination in the form of “onion bulb” formations, and autosomal-dominant inheritance. CMT-1 was first linked to the Duffy blood group on chromosome 1, and the encoded gene product was identified as peripheral nerve protein (Po). This proved to be an uncommon form, however, because most families with type 1 features are linked to chromosome 17p12-p11.2, and the affected gene product is peripheral myelin protein 22 (PMP22). This became CMT type 1A; the disorder linked to chromosome 1 is type 1B (see Table 104.2 and Table 104.3). Ionasescu and associates found that CMT-1A accounted for about 60% of hereditary neuropathies and CMT-1B was found in fewer than 2% (Table 104.4).

TABLE 104.4. RELATIVE FREQUENCY OF AUTOSOMAL-DOMINANT NEUROPATHIES IN 63 FAMILIES DETERMINED BY DNA ANALYSIS

CMT-2 is clinically similar, including sensory loss. However, nerve conduction velocity is normal, and there is no histologic evidence of demyelination; therefore the disorder is considered neuronal. Some families show an autosomal-dominant pattern, others an autosomal-recessive. This category is therefore heterogeneous. Four types of the autosomal-dominant type have been mapped: 2A to chromosome 1, 2B at chromosome 3q, 2C (unmapped but includes vocal cord paralysis), and 2D to chromosome 7. Recessive infantile forms have also been described. CMT type 3, the most severe form, is called the Dejerine-Sottas syndrome (DSS). Onset is usually in early childhood, and there is extreme disability from a hypertrophic demyelinating disorder, with extremely slow conduction velocity in the vicinity of 10 meters per second (mps). It was long thought to be autosomal recessive. In fact, deoxyribonucleic acid (DNA) analysis has shown that some patients are homozygous for the mutation, while the parents are consanguineous, heterozygous, and not affected clinically or subclinically because conduction velocity is normal in them. This pattern is consistent with recessive inheritance. Most patients, however, are heterozygous for the mutation, and the disorder must be autosomal-dominant. Remarkably, the affected gene may be myelin protein zero (MPZ), PMP22, or EGR2 (early growth response protein). It has become difficult to separate DSS from severe CMT-1A. Two forms have been mapped. There is at least one other version, and there are perhaps more because some cases are not linked to any of the known genes. One child with abnormal Po had been previously identified as having congenital hypomyelination. The McKusick catalog lists a severe autosomal-recessive form as CMT-4, which maps to chromosome 8q (see Table 104.2). CMT-5 comprises rare families with combinations of spastic paraplegia and amyotrophy, some autosomal dominant, others autosomal recessive. X-linked CMT syndromes, including some large families with X-dominant inheritance but only female transmission. CMT-X dominant is the second most common demyelinating CMT after CMT-1A. CMT-X results from point mutations in the connexin32 gene (Cx32) at Xq13; more than 200 mutations have been found in all domains of the protein. Still other types of CMT are identified by companion disorders, such as pigmentary retinopathy, optic atrophy, hearing loss, or mental retardation. Even before the advent of DNA analysis, this classification gave reasonably consistent results. Among 430 families studied by Lovelace and colleagues ( Table 104.5), CMT-1 and CMT-2 were almost equally represented at first, but now CMT-1 is almost twice as prevalent. There were atypical manifestations in some families, however, and others showed features of more than one type (see Table 104.3). DNA analysis should resolve these unsettled diagnoses; direct DNA diagnosis is now reliable.

TABLE 104.5. RELATIVE FREQUENCY OF CHARCOT-MARIE-TOOTH (CMT) SYNDROMES

At first, it seemed that the only heterogeneity was locus heterogeneity; that is, CMT-1A and CMT-1B were linked to different chromosomes, and different gene products were involved. Moreover, the disorder in CMT-1A seemed to be related to allelic heterogeneity (mutations within the same gene) and also to gene dosage; if there are two copies of the PMP22 gene (normal state), there are no symptoms. If there is a duplication (triple dose), CMT-1A results. Remarkably, if there is a point mutation (one dose of the gene), a different peripheral nerve syndrome results, hereditary neuropathy with liability to pressure palsies (HNPP). How this comes about (the pathogenesis) is not known. The same gene product is implicated in the trembler mouse. Many sporadic cases prove to be new mutations of CMT1A, CMT1B, or CMTX. The merits of the cinical classification have been demonstrated by the remarkable allelic heterogeneity ( Table 104.6). The only phenotype with a consistent genotype is HNPP, with mutations only in the PMP22 gene. In contrast, CMT-1A has been found with Po, PMP22, Cx32, and EGR2 mutations. Cx32 mutations have been found in both CMT-1 and CMT-2. Similarly, EGR2 mutations are found in CMT-1, DSS, and congenital hypomyelination. It is a continuing challenge to determine how these clinical differences arise from alterations of the same gene.

TABLE 104.6. GENES IMPLICATED IN PERIPHERAL MYELINOPATHIES

Clinical Features Most forms of hereditary peripheral neuropathy begin in childhood or adolescence. The first signs may be skeletal, with pes cavus or other deformity of the feet, or

with scoliosis. Disproportionate thinness of the lower legs (“stork legs� ) may be evident before there is footdrop and steppage gait. Weakness and wasting are usually symmetric, and progression is usually slow. Ultimately, the hands are also affected, and that may be more disabling than the gait disorder. The motor disorder is usually more impressive than any sensory loss. Cranial nerves are generally spared. Even within the same family, the severity varies; some of those who carry the mutant gene are asymptomatic but have abnormal feet or slow conduction velocities. Others may be totally without clinical manifestations, whereas some use crutches or wheelchairs. Laboratory Studies Nerve conduction studies are essential for classification. In CMT-1, conduction velocity is much reduced, from a normal value of about 50 mps to 20 mps or less. Conduction block is not seen. Nerve biopsy is useful in excluding other hereditary neuropathies in which there is deposition of metabolic products, as in Refsum disease, or in excluding lymphocytic infiltration or vasculitis seen in autoimmune neuropathies. DNA analysis is now also essential. Cerebrospinal fluid (CSF) is usually normal, except for modest increase in protein content. Antenatal diagnosis is increasingly reliable. Diagnosis Diagnosis is facilitated if there is a family history of CMT-1. Other familial neuropathies, such as familial amyloidotic polyneuropathy, can be distinguished clinically to some extent and also by DNA analysis. In sporadic cases, the diagnosis is usually evident if the patient is a child or adolescent. In adults, however, it may be difficult to distinguish CMT from chronic inflammatory demyelinating polyneuropathy (CIDP), which differs in later onset, more rapid course, high CSF protein content, and therapeutic response to prednisone. This distinction may be difficult to make because some individuals in CMT families may show abrupt exacerbations, high CSF protein content, or even a therapeutic response to prednisone. People with CMT could be more susceptible to CIDP. CMT-2, the neuronal form, can be identified if conduction velocities are normal and there is sensory loss in stocking distribution. If the disorder is purely motor, however, the condition could be considered a disease of the perikaryon of motor neurons, that is, distal spinal muscular atrophy. HNPP was originally considered a different disease because the clinical manifestations are intermittent. In affected families, individuals suffer transient paralysis of muscles innervated by specific peripheral nerves (especially the median and ulnar nerves) or by components of the brachial plexus. The symptoms are usually transient, with complete or partial recovery from each bout. The condition is linked to CMT because nerve conduction velocities are often slow between attacks. In contrast to CMT, there may be conduction block. The hypertrophic component may be so dramatic that it was called tomaculous neuropathy (from the Latin word for sausage). DNA analysis established these conditions as allelic to CMT. Treatment and Prognosis There is not yet any specific drug or gene therapy. Treatment is therefore directed to mechanical assistance for leg weakness (orthoses), surgical correction of joint deformities and scoliosis, and physical therapy. The course of CMT-1 or CMT-2 is normally so slowly progressive that most affected people can enjoy a productive, satisfying life. Children with the DSS form, however, have serious problems and may never walk.

HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY Disorders in this category are defined by clinical, genetic, physiologic, and pathologic criteria. No DNA information is available yet. The dominant clinical disorder is sensory loss, which may be so profound that there are mutilating deformities of the hands and feet, a condition called sensory neurogenic arthropathy or mutilating acropathy. There may be weakness or skeletal changes similar to those in CMT disease. Hereditary sensory and autonomic neuropathy type 1 (HSAN-1) is autosomal-dominant and begins in adolescence with pedal deformity and burning pain. HSAN types 2, 3, and 4 are all autosomal-recessive forms of congenital indifference to pain. HSAN-2 is similar to HSAN-1 in mutilation but begins earlier. HSAN-3 is the Riley-Day syndrome or familial dysautonomia. HSAN-4 is similar to HSAN-2, with the addition of anhidrosis to congenital pain insensitivity. As in CMT disease, there are sporadic forms and other forms identified by associated abnormalities of vision or hearing.

FAMILIAL AMYLOIDOTIC POLYNEUROPATHY History and Molecular Genetics In 1952, Andrade described an autosomal-dominant neuropathy characterized by deposition of amyloid in peripheral nerves. Identified first in Portugal, it was soon found in other countries visited by Portuguese sailors, especially former colonies, neighboring countries, and Japan. The disease has been found in non-Portuguese populations, including the United States. In 1979, Costa found immunologically that the amyloid contained a serum protein, then called prealbumin because of its electrophoretic characteristics and now known as transthyretin. More than 20 different mutations in the gene have been found by DNA analysis, with little correlation between different mutations and clinical manifestations. The number of mutations and the lack of evidence of a founder effect suggest that there is a high incidence of new mutations. The gene for transthyretin and familial amyloidotic polyneuropathy maps to 18q11.2-q12,1, and direct DNA diagnosis is feasible. Clinical Manifestations In Portugal, onset is between ages 20 and 35 years, with acral sensory loss, chronic diarrhea, and impotence ( Table 104.7). Weakness follows the severe sensory symptoms by several years and becomes disabling. Neurogenic acropathy is common. The autonomic disorder may include sphincter symptoms and orthostatic hypotension. Cardiomyopathy may lead to heart block and pacemaker insertion. Nephrosis is a later manifestation. Inexorably progressive, the condition is fatal 7 to 15 years after onset. Similar patterns are seen in Majorca, Brazil, Sweden, and Japan. In Sweden, onset is after age 40, and later onset also characterizes many sporadic cases.

TABLE 104.7. CLASSIFICATION OF FAMILIAL AMYLOIDOTIC POLYNEUROPATHIES (MIM 176300)

Variants include forms that are primarily neuropathic, predominantly cardiomyopathic, or both. As in Huntington disease, there is no clinical difference between homozygous and heterozygous individuals. Pathology and Pathogenesis

Amyloid is found in extracellular spaces of many organs, infiltrating blood vessels. The central nervous system is spared, but amyloid deposits are found in autonomic and myelinated or unmyelinated peripheral nerves. The disorder is both demyelinating and axonal. Transthyretin is a serum protein involved in the transport of thyroid hormones and vitamin A. The main site of production is the liver, but the choroid plexus is also a source of the protein in CSF; it is also produced in the eye. It is not known how abnormalities of the protein lead to the clinical neuropathy. The abnormal gene has been introduced into transgenic mice; amyloid accumulates in serum and liver but not in peripheral nerves. Treatment The disease cannot be arrested. Symptomatic relief can ameliorate the gastrointestinal and cardiac symptoms, but little can be done about the sensorimotor neuropathy. Plasmapheresis has been used with limited success. Immunoabsorption of the abnormal protein may prove useful. Liver transplantation has been used to replace the abnormal transthyretin with the normal donor protein; in early trials, progression seemed to be arrested, but there was no functional improvement of the neuropathy. Antenatal diagnosis is feasible. The question of presymptomatic diagnosis is a problem for a disease that cannot be cured. SUGGESTED READINGS Charcot-Marie-Tooth Diseases Ben Othmane K, Hentati F, Lennon F, et al. Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum Mol Genet 1993;2:1625–1628. Ben Othmane K, Middleton LT, Laprest LJ, et al. Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics 1993;17:370–375. Bone LJ, Deschenes SM, Balice-Gordon RJ, Fischbeck KH, Scherer SS. Connexin32 and X-linked Charcot-Marie-Tooth disease. Neurobiol Dis 1997;4:221–230. Chance PF, Alderson MK, Lepig KA, et al. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 1993;72:143–152. Chance PF, Bird TD, Matsunami N, et al. Trisomy 17p associated with Charcot-Marie-Tooth neuropathy type 1A phenotype: evidence for gene dosage as a mechanism in CMT1A. Neurology 1992;42:2295–2299. Chance PF, Dyck PJ. Hereditary neuropathy with liability to pressure palsies: a patient's point mutation in a mouse model. Neurology 1998;51:664–665. DeJonghe P, Timmerman V, Van Broeckhoven C. Workshop report: classification and diagnostic guidelines for CMT2-HMSN II and distal hereditary motor neuropathy (distal HMN-spinal CMT). Neuromuscul Disord 1998;8:426–431. Dyck PJ. Inherited neuronal degeneration and atrophy affecting peripheral motor, sensory and autonomic neurons. In: Dyck PJ, Thomas PK, Griffin JW, et al., eds. Peripheral neuropathy, 3rd ed. Philadelphia: WB Saunders, 1993. Goebel HH. Hereditary metabolic neuropathies. Zentralbl Allg Pathol 1990;136:503–515. Haites NE, Nelis E, Van Broeckhoven C. Workshop report: gentotype/phenotype correlations in CMT1 and HNNP. Neuromuscul Disord 1998;8:591–603. Hannemann CO, Muller HW. Pathogenesis of CMT1A neuropathy. Trends Neurosci 1998;21:282–286. Ionasescu VV, Ionasescu R, Searby C. Screening of dominantly inherited Charcot-Marie-Tooth neuropathies. Muscle Nerve 1993;16:1232–1238. Ionasescu VV, Searby C, Ionasescu R. Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy. Hum Mol Genet 1994;3:355–358. Ionasescu VV, Searby CC, Ionasescu R, et al. Dejerine-Sottas neuropathy in mother and son with the same point mutation of PMP22 gene. Muscle Nerve 1997;20:97–99. Lovelace RE. Charcot-Marie-Tooth disorders and other hereditary neuropathies. In: Younger DS, ed. Textbook of motor disorders. Philadelphia: Lippincott Williams &038; Wilkins, 1999:205–211. Lovelace RE, Shapiro HK, eds. Charcot-Marie-Tooth disorders: pathophysiology, molecular genetics and therapy. New York: Wiley-Lee, 1990. Lupski JR. Charcot-Marie-Tooth disease: lessons in genetic mechanisms. Mol Med 1998;4:3–11. Malandrini A, Villanova M, Dotti MT, Federico A. Acute inflammatory neuropathy in Charcot-Marie-Tooth disease. Neurology 1999;52:859–861. Nelis E, Haites N, Van Broeckhoven C. Mutations in peripheral myelin genes and associated genes in inherited peripheral neuropathies. Hum Mutat 1999;13:11–28. Nicholson GA, Yeung L, Corbett A. Efficient neurophysiologic selection of X-linked Charcot-Marie-Tooth families: ten novel mutations. Neurology 1998;51:1412–1416. Oda K, Miura H, Shibasaki H, et al. Hereditary pressure-sensitive neuropathy: demonstration of “tomacula” in motor nerve fibers. J Neurol Sci 1990;98:139–148. Parman Y, Plante-Bordeneuve V, Guiochon-Mantel A, Eraksoy M, Said G. Recessive inheritance of a new point mutation of the PMP22 gene in Dejerine-Sottas diseae. Ann Neurol 1999;45:518–522. Rouger H, LeGuerne, Birouk N, et al. CMT disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families. Hum Mutat 1997;10:443–452. Saito M, Hayashi Y, Suzuki T, et al. Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and clinical features of CMT2A. Neurology 1997;49:1630–1635. Sambuughin N, Sivakumar K, Selenge B, et al. Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15. J Neurol Sci 1998:161:23–28. Sghirlanzoni A, Pareyson D, Balestrini MR, et al. HMSN III phenotype due to homozygous expression of a dominant HMSN II gene. Neurology 1992;42:2201–2203. Shy ME, Arroyo E, Dladky J, et al. Heterozygous Po knockout mice develop a peripheral neuropathy that resembles chronic inflammataory demyelinating polyneuropathy. J Neuropathol Exp Neurol 1997;56:811–821. Silander K, Meretoja P, Juvonen V, et al. Spectrum of mutations in Finnish patients with Charcot-Marie-Tooth and related neuropathies. Hum Mutat 1998;12:59–68. Teunissen LL, Notermans NC, Franssen H, et al. Differences between hereditary motor and sensory neuropathy type 2 and chronic idiopathic axonal neuropathy: a clinical and electrophysiological study. Brain 1997;120:955–962. Thomas PK, Ormerod JEC. Hereditary neuralgic amyotrophy associated with a relapsing multifocal sensory neuropathy. J Neurol Neurosurg Psychiatry 1993;56:107–109. Verhagen WIM, Gabreels-Festen AAWM, van Wensen PJM, et al. Hereditary neuropathy with liability to pressure palsies: a clinical, electroneurophysiological and morphological study. J Neurol Sci 1993;116:176–184. Warner LE, Garcia CA, Lupski JR. Hereditary peripheral neuropathies: clinical forms, genetics and molecular mechanisms. Annu Rev Med 1999;50:263–275. Warner LE, Mancias P, Butler IJ, et al. Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 1998;18:382–384. Wicklein EM, Orth U, Gal A, Kunze K. Missense mutation (R15W) of the connexin32 gene in a family with X chromosomal Charcot-Marie-Tooth neuropathy with only female members affected. Neurol Neurosurg Psychiatry 1997;63:379–381.

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Hereditary Sensory Neuropathies Bejaoui K, McKenna-Yasek D, Hoisler BA, et al. Confirmation of linkage of type 1 hereditary sensory neuropathy to human chromosome 9q22. Neurology 1999;52:510–515. DeJonghe P, Timmerman V, Fitzpatrick D, et al. Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family. J Neurol Neurosurg Psychiatry 1997;62:570–573.

Dyck PJ, Mellinger JF, Reagan TJ, et al. Not “indifference to pain” but varieties of hereditary sensory and autonomic neuropathy. Brain 1983;106:373–390. Nicholson GA, Dawkins JL, Blair IP, et al. The gene for hereditary sensory neuropathy type 1 (HSN-1) maps to chromosome 9q22.1-q22.3. Nat Genet 1996;13:101–104. Familial Amyloid Polyneuropathy Andrade C. A peculiar form of peripheral neuropathy: familial atypical generalized amyloidosis with special involvement of the peripheral nerves.

Brain 1952;75:408–427.

Coelho T. Familial amyloid polyneuropathy: new developments in genetics and treatment. Curr Opin Neurol 1996;9:355–359. Costa PP, Figueira AS, Bravo FR. Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy. Proc Natl Acad Sci U S A 1978;75:4499–4503. Plante-Bordeneuve V, Lalu T, Misrahi M, et al. Genotypic-phenotypic variations in a series of 65 patients with familial amyloidotic polyneuropathy. Neurology 1998;51:708–714. Reilly MM, King RHM. Familial amyloid polyneuropathy. Brain Pathol 1993;3:165–176. Saraiva MJM, Birken S, Costa PP, et al. Amyloid fibril protein in familial amyloid polyneuropathy, Portuguese type: definition of molecular abnormality in transthyretin (prealbumin). 1984;74:104–119. Suhr OB, Holmgren G, Ando Y. Improvement in the polyneuropathy associated with familial amyloid polyneuropathy after liver transplantation [Letter].

J Clin Invest

Neurology 1998;51:926–927.

Takaoka Y, Tashiro F, Yi S, et al. Comparison of amyloid deposition in two lines of transgenic mouse model of familial amyloidotic polyneuropathy type 1.

Transgenic Res 1997;6:261–269.

CHAPTER 105. ACQUIRED NEUROPATHIES MERRITT’S NEUROLOGY

CHAPTER 105. ACQUIRED NEUROPATHIES DALE J.LANGE,NORMAN LATOV AND WERNER TROJABORG Guillain Barré Syndrome and Variants Chronic Inflammatory Demyelinating Polyneuropathy Multifocal Motor Neuropathy Sensory Neuronopathy and Neuropathy Idiopathic Autonomic Neuropathy Vasculitic and Cryoglobulinemic Neuropathies Neuropathies Associated With Myeloma and Nonmalignant Igg or Iga Monoclonal Gammopathies Neuropathies Associated With Igm Monoclonal Antibodies that React with Peripheral Nerve Glycoconjugate Antigens Amyloid Neuropathy Neuropathy Associated with Carcinoma (Paraneoplastic Neuropathy) Hypothyroid Neuropathy Acromegalic Neuropathy Hyperthyroid Neuropathy Uremic Neuropathy Neuropathy Associated with Hepatic Disease Neuropathies Associated with Infection Sarcoid Neuropathy Polyneuropathy Associated with Dietary States Critical Illness Polyneuropathy Neuropathies Caused by Heavy Metals Neuropathies Caused by Therapeutic Drugs Diabetic Neuropathy Brachial Neuropathy Radiation Neuropathy Lyme Neuropathy Suggested Readings

GUILLAIN BARRÉ SYNDROME AND VARIANTS The Guillain-Barré syndrome (GBS; acute inflammatory demyelinating neuropathy) is characterized by acute onset of peripheral and cranial nerve dysfunction. Viral respiratory or gastrointestinal infection, immunization, or surgery often precedes neurologic symptoms by 5 days to 3 weeks. Symptoms and signs include rapidly progressive symmetric weakness, loss of tendon reflexes, facial diplegia, oropharyngeal and respiratory paresis, and impaired sensation in the hands and feet. The condition worsens for several days to 3 weeks, followed by a period of stability and then gradual improvement to normal or nearly normal function. Early plasmapheresis or intravenous infusion of human gamma globulins accelerates recovery and diminishes the incidence of long-term neurologic disability. Etiology The cause of the GBS is unknown. It is thought to be immune-mediated because a disease with similar clinical features (i.e., similar pathologic, electrophysiologic, and cerebrospinal fluid [CSF] alterations) can be induced in experimental animals by immunization with whole peripheral nerve, peripheral nerve myelin, or, in some species, peripheral nerve myelin P2 basic protein or galactocerebroside. Although there is no evidence of sensitization to these antigens in humans with spontaneous GBS, activity of the disease seems to correlate with the appearance of serum antibodies to peripheral nerve myelin. When GBS is preceded by a viral infection, there is no evidence of direct viral infection of peripheral nerves or nerve roots. Electrophysiology and Pathology Nerve conduction velocities are reduced in GBS, but values may be normal early in the course. Distal sensory and motor latencies are prolonged. As a result of demyelination of nerve roots, F-wave conduction velocity is often slowed. Conduction slowing may persist for months or years after clinical recovery. In general, the severity of neurologic abnormality is not related to the degree of slowing of conduction but is related to the extent of conduction block. Long-standing weakness is most apt to occur when there is electromyographic (EMG) evidence of muscle denervation early in the course. Histologically, GBS is characterized by focal segmental demyelination ( Fig. 105.1) with perivascular and endoneurial infiltrates of lymphocytes and monocytes or macrophages (Fig. 105.2). These lesions are scattered throughout the nerves, nerve roots, and cranial nerves. In particularly severe lesions, there is both axonal degeneration and segmental demyelination. During recovery, remyelination occurs, but the lymphocytic infiltrates may persist.

FIG. 105.1. Focal demyelination in acute GBS. (Courtesy of Dr. Arthur Asbury.)

FIG. 105.2. Diffuse mononuclear infiltrate in peripheral nerve in GBS. (Courtesy of Dr. Arthur Asbury.)

Incidence GBS is the most frequent acquired demyelinating neuropathy, with an incidence of 0.6 to 1.9 cases per 100,000 population. The incidence increases gradually with age, but the disease may occur at any age. Men and women are affected equally. The incidence increases in patients with Hodgkin disease, as well as with

pregnancy or general surgery. Symptoms and Signs GBS often appears days to weeks after symptoms of a viral upper respiratory or gastrointestinal infection. Usually, the first neurologic symptoms are due to symmetric limb weakness, often with paresthesia. In contrast to most other neuropathies, proximal muscles are sometimes affected more often than distal muscles at first. Occasionally, facial, ocular, or oropharyngeal muscles may be affected first; more than 50% of patients have facial diplegia, and dysphagia and dysarthria develop in a similar number. Some patients require mechanical ventilation. Tendon reflexes may be normal for the first few days but are then lost. The degree of sensory impairment varies. In some patients, all sensory modalities are preserved; others have marked diminution in perception of joint position, vibration, pain, and temperature in stocking-and-glove distribution. Patients occasionally exhibit papilledema, sensory ataxia, transient extensor plantar responses, or evidence of autonomic dysfunction (orthostatic hypotension, transient hypertension, or cardiac arrhythmia). Many have muscle tenderness, and the nerves may be sensitive to pressure, but there are no signs of meningeal irritation such as nuchal rigidity. Variants Acute motor axonal neuropathy (AMAN) is a variant of GBS. There is motor axonal degeneration and little or no demyelination or inflammation. AMAN may follow infection with Campylobacter jejuni or parenteral injection of gangliosides. The Miller-Fisher syndrome is characterized by gait ataxia, areflexia, and ophthalmoparesis; pupillary abnormalities are sometimes present. It is considered a variant of GBS because it is often preceded by respiratory infection, it progresses for weeks and then improves, and CSF protein content is increased. There is no limb weakness, however, and nerve conductions are normal. Sometimes, magnetic resonance imaging shows brainstem lesions. Other GBS variants include acute motor and sensory axonal neuropathy, acute sensory neuropathy or neuronopathy, and acute autonomic neuropathy or pandysautonomia. Laboratory Data The CSF protein content is elevated in most patients with GBS but may be normal in the first few days after onset. The CSF cell count is usually normal, but some patients with otherwise typical GBS have 10 to 100 mononuclear cells/ÂľL of CSF. Antecedent infectious mononucleosis, cytomegalovirus (CMV) infection, viral hepatitis, human immunodeficiency virus (HIV) infection, or other viral diseases may be documented by serologic studies. Increased titers of immunoglobulin (Ig) G or IgA antibodies to GM 1 or GD1a gangliosides may be found in the axonal form of GBS; anti-GQ 1b antibodies are closely associated with the Miller-Fisher syndrome. Course and Prognosis Symptoms are usually most severe within 1 week of onset but may progress for 3 weeks or more. Death is uncommon but may follow aspiration pneumonia, pulmonary embolism, intercurrent infection, or autonomic dysfunction. The rate of recovery varies. In some, it is rapid, with restoration to normal function within a few weeks. In most, recovery is slow and not complete for many months. Recovery is accelerated by early institution of plasmapheresis or intravenous immunoglobulin (IVIG) therapy. In untreated series, about 35% of patients have permanent residual hyporeflexia, atrophy, and weakness of distal muscles or facial paresis. A biphasic illness, with partial recovery followed by relapse, is present in fewer than 10% of patients. Recurrence after full recovery occurs in about 2%. Diagnosis and Differential Diagnosis The characteristic history of subacute development of symmetric motor or sensorimotor neuropathy after a viral illness, delivery, or surgery, together with slowing of conductions and a high CSF protein content with normal CSF cell count, define GBS. In the past, the principal diseases to be differentiated from GBS were diphtheritic polyneuropathy and acute anterior poliomyelitis. Both are now rare in the United States. Diphtheritic polyneuropathy can usually be distinguished by the long latency period between the respiratory infection and onset of neuritis, the frequency of paralysis of accommodation, and the relatively slow evolution of symptoms. Acute anterior poliomyelitis was distinguished by asymmetry of paralysis, signs of meningeal irritation, fever, and CSF pleocytosis. Occasionally, patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex have a disorder identical to GBS, sometimes but not always due to CMV infection. Porphyric neuropathy resembles GBS clinically but is differentiated by normal CSF protein, recurrent abdominal crisis, mental symptoms, onset after exposure to barbiturates or other drugs, and high urinary levels of d-aminolevulinic acid and porphobilinogen. Development of a GBS-like syndrome during prolonged parenteral feeding should raise the possibility of hypophosphatemia-induced neural dysfunction. Toxic neuropathies caused by hexane inhalation or thallium or arsenic ingestion occasionally begin acutely or subacutely. These can be distinguished from GBS by history of toxin exposure or, in thallium or arsenic intoxication, by later alopecia. Botulism may be difficult to discriminate on clinical grounds from purely motor forms of GBS, but ocular muscles and the pupils are frequently affected. Electrophysiologic tests in botulism reveal normal nerve conduction velocities and a facilitating response to repetitive nerve stimulation. Tick paralysis should be excluded by careful examination of the scalp. Treatment Early plasmapheresis has proved useful in patients with GBS. IVIG therapy is also reported to be beneficial. Glucocorticoid administration does not shorten the course or affect the prognosis. Mechanically assisted ventilation is sometimes necessary, and precautions against aspiration of food or stomach contents must be taken if oropharyngeal muscles are affected. Exposure keratitis must be prevented in patients with facial diplegia.

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY Chronic inflammatory demyelinating polyneuropathy (CIDP) may begin insidiously or acutely, as in GBS, and then follow a chronic progressive or relapsing course. As in GBS, it often follows nonspecific viral infections, segmental demyelination and lymphocytic infiltrates are present in peripheral nerves, and a similar disease can be induced in experimental animals by immunization with peripheral nerve myelin. The CSF protein content is often increased but less consistently than in GBS. An infantile form of CIDP begins with hypotonia and delayed motor development. Optic neuritis has been noted in some patients. Nerves may become enlarged because of Schwann cell proliferation and collagen deposition after recurrent segmental demyelination and remyelination. In contrast to GBS, glucocorticoid therapy is often beneficial. CIDP is also responsive to plasmapheresis or IVIG therapy, and immunosuppressive drug therapy may be effective in resistant cases. Research criteria for the diagnosis of CIDP have been recommended, but there is no specific test, and the diagnosis is often made on clinical grounds. A predominantly sensory form of CIDP and an axonal form have been described; it is likely that CIDP is heterogeneous, including several different chronic immune-mediated diseases that affect peripheral nerves. Tests for HIV-1, monoclonal paraproteins, antibodies to myelin-associated glycoprotein (MAG) and, occasionally, Charcot-Marie-Tooth disease type 1 or hereditary neuropathy with liability to pressure palsy are carried out in suspected patients to evaluate possible causes of demyelinating neuropathy.

MULTIFOCAL MOTOR NEUROPATHY Multifocal motor neuropathy (MMN) is manifested by a clinical syndrome restricted to signs of a lower motor neuron disorder. Typically, there is weakness, wasting, and fasciculation with active or absent tendon reflexes. The findings are often asymmetric and affect the arms and hands more than the legs. Electrophysiologic evidence of denervation is accompanied by the defining abnormality, physiologic evidence of multifocal motor conduction block. MMN is associated with increased titers of IgM anti-GM 1 in about one-third of the patients; less frequently, anti-GD 1a antibodies are found. It is important to recognize these patients and to distinguish them from patients with typical motor neuron disease because the weakness of MMN is reversible with IVIG or immunosuppressive drug therapy.

SENSORY NEURONOPATHY AND NEUROPATHY Sensory neuropathy may result from primary involvement of the sensory root ganglia, as in ganglioneuritis or sensory neuronitis, or the nerve may be directly affected as in distal sensory neuropathy. Ganglioneuritis may be acute or subacute in onset and is characterized by numbness, paresthesia, and pain that can be distal or

radicular or involve the entire body including the face. Ataxia and autonomic dysfunction may be evident. Small-fiber sensation alone or all sensory modalities may be affected to varying degrees. Tendon reflexes may be present or absent, and strength is normal. The disease may be self-limiting or chronic, with relapses or slow progression. Motor nerve conduction velocities are normal or near normal, but sensory potentials are reduced in amplitude or absent. Routine electrophysiologic studies may be normal if the disease is mild or if only small fibers are affected, but spinal somatosensory evoked responses and quantitative sensory testing are usually abnormal. CSF protein content is normal or slightly elevated. Response to glucocorticoids or immunosuppressive therapy is variable. Pathologic studies of spinal root ganglia show inflammatory infiltrates with a predominance of T cells and macrophages. Some patients have sicca or Sjรถgren syndrome with anti-Ro and anti-La antibodies. Several autoantibodies to peripheral nerve antigens have been reported to be associated with sensory neuropathy. Some patients with sensory axonal neuropathies have monoclonal or polyclonal IgM anti-sulfatide antibodies and monoclonal IgM autoantibodies with anti-GD 1b and disialosyl ganglioside antibody activity have been associated with large-fiber sensory neuropathy. Other causes of sensory neuropathy include HIV-1 infection, vitamin B 6 deficiency, paraneoplastic neuropathy, amyloidosis, and toxic neuropathy.

IDIOPATHIC AUTONOMIC NEUROPATHY This condition is characterized by acute or subacute onset of hypofunction of sympathetic and parasympathetic nerve functions. Symptoms include postural syncope, diminished tear and sweat production, impaired bladder function, constipation, and diminished sexual potency. The autonomic preganglionic or postganglionic efferent neurons are thought to be affected. It may follow viral infection, as in GBS, and CSF protein concentration may be elevated. The disease is frequently self-limiting, and gradual partial or complete recovery occurs without specific therapy.

VASCULITIC AND CRYOGLOBULINEMIC NEUROPATHIES Vasculitic neuropathy is manifested as mononeuritis multiplex or distal symmetric polyneuropathy. Nerve conduction studies may show electrical inexcitability of nerve segments distal to an infarct caused by vascular occlusion. If some fascicles in the nerves are spared, they conduct at a normal rate, but the amplitude of the evoked response is diminished. The diagnosis of peripheral nerve involvement may be established by nerve and muscle biopsies ( Fig. 105.3), which typically show inflammatory cell infiltrates and necrosis of the walls of blood vessels. The biopsy specimen, however, may show only axonal degeneration if vasculitis has caused a nerve infarct that is proximal to the site of biopsy, or if no affected vessels are encountered in the specimen.

FIG. 105.3. Polyarteritis in large proximal nerve trunk. Three small epineurial arteries show inflammation in the vessel wall and adventitia, as well as luminal narrowing and fibrosis. Surrounding nerve fascicles are not involved in this section. (Courtesy of Dr. Arthur Asbury.)

The vasculitis may be confined to the peripheral nerves or may be associated with systemic disease, such as polyarteritis or cryoglobulinemia. The most common systemic cause of vasculitic neuropathy is polyarteritis nodosa, which may cause purpuric skin lesions, renal failure, Raynaud phenomenon, constitutional symptoms, and, sometimes, mixed polyclonal cryoglobulinemia; hepatitis B or C virus (HBV or HCV) infection may be found. Cryoglobulins are immunoglobulins that precipitate in the cold and are classified as types I through III. Type I contains a monoclonal immunoglobulin only, type II contains both monoclonal and polyclonal immunoglobulins, and type III contains mixed polyclonal immunoglobulins. Types I and II are associated with plasma cell dyscrasia, and type III may be associated with polyarteritis nodosa and HBV or HCV infection. Other causes of vasculitic neuropathy include the Churg-Strauss syndrome with asthma and eosinophilia; Sjรถgren syndrome with xerophthalmia, xerostomia, and anti-Ro and anti-La antibodies; and Wegener granulomatosis with necrotizing granulomatous lesions in the upper or lower respiratory tracts, glomerulonephritis, and antineutrophilic cytoplasmic antigen antibodies. Less commonly, vasculitic neuropathy is seen in rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Vasculitis may respond to therapy with prednisone and cyclophosphamide. Plasmapheresis is also useful in the treatment of cryoglobulinemia.

NEUROPATHIES ASSOCIATED WITH MYELOMA AND NONMALIGNANT IgG OR IgA MONOCLONAL GAMMOPATHIES Peripheral neuropathy is found in approximately 50% of patients with osteosclerotic myeloma and IgG or IgA monoclonal gammopathies. Some patients have the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, myeloma, and skin changes) or Crow-Fukase syndrome with hyperpigmentation of skin, edema, excessive hair growth, hepatosplenomegaly, papilledema, elevated CSF protein content, hypogonadism, and hypothyroidism. POEMS syndrome is sometimes associated with nonosteosclerotic myeloma or with nonmalignant monoclonal gammopathy. The IgG or IgA light-chain type is almost always lambda. Electrophysiologic and pathologic abnormalities are consistent with demyelination and axonal degeneration; the patterns may resemble those of CIDP. Malignant or nonmalignant IgG or IgA monoclonal gammopathy may also be associated with neuropathy in primary amyloidosis, in which fragments of the monoclonal light chains are deposited as amyloid in peripheral nerve, and in types I and II cryoglobulinemia, in which the monoclonal immunoglobulins are components of the cryoprecipitates. The significance of IgG or IgA monoclonal gammopathies is uncertain in the absence of myeloma, POEMS syndrome, amyloidosis, or cryoglobulinemia. Nonmalignant monoclonal gammopathies are found more frequently in patients with neuropathy of otherwise unknown etiology; however, they are also present in approximately 1% of normal adults, and the frequency increases with age or in chronic infections or inflammatory diseases, so the association with neuropathy in some cases could be coincidental. Other causes of neuropathy, particularly inflammatory conditions such as CIDP, should be considered. In cases of myeloma, irradiation, chemotherapy, or bone marrow transplantation may be beneficial.

NEUROPATHIES ASSOCIATED WITH IgM MONOCLONAL ANTIBODIES THAT REACT WITH PERIPHERAL NERVE GLYCOCONJUGATE ANTIGENS In several syndromes, peripheral neuropathy is associated with polyclonal or monoclonal IgM autoantibodies that react with glycoconjugates in peripheral nerve. IgM antibodies that react with MAG are associated with a chronic demyelinating sensorimotor neuropathy. Pathologic studies show deposits of the monoclonal IgM and complement on affected myelin sheaths, and passive transfer of the autoantibodies in experimental animals reproduces the neuropathy. Treatment consisting of plasmapheresis and chemotherapy to reduce autoantibody concentrations, or IVIG, frequently results in clinical improvement. Increased titers of polyclonal or monoclonal anti-GM 1 ganglioside antibodies are associated with a clinical syndrome of motor neuropathy or motor neuron disease. Typically, there is weakness, wasting, and fasciculation with active or absent tendon reflexes. The condition is associated with electrophysiologic evidence of denervation and conduction block. Conduction block is not always present, however, in patients with increased antibody titers. The same clinical syndrome may also occur in patients with normal titers of anti-GM 1 antibodies. It is important to recognize these patients and to distinguish them from patients with typical motor neuron

disease because the weakness may be reversed by immunosuppressive chemotherapy or IVIG. Other syndromes associated with monoclonal or polyclonal IgM autoantibodies include: multifocal motor neuropathy or lower motor neuron syndrome associated with anti-GM1 or anti-GD1a ganglioside antibodies, large-fiber sensory neuropathy with anti-GD 1b and disialosyl ganglioside antibodies, and axonal sensory neuropathy associated with antisulfatide antibodies.

AMYLOID NEUROPATHY Amyloid is an insoluble extracellular aggregate of proteins that forms in nerve or other tissues when any of several proteins is produced in excess. The two principal forms of amyloid protein that cause neuropathy are immunoglobulin light chains in patients with primary amyloidosis and plasma cell dyscrasias, and transthyretin in hereditary amyloidosis. The syndrome is often that of a painful, small-fiber sensory neuropathy with progressive autonomic dysfunction, symmetric loss of pain and temperature sensations with spared position and vibratory senses, carpal tunnel syndrome, or some combination of these symptoms. The diagnosis of amyloid neuropathy can be established by histologic demonstration of amyloid in nerve ( Fig. 105.4), followed by immunocytochemical characterization of the deposits with the use of antibodies to immunoglobulin light chains or transthyretin. Mutation of the transthyretin gene is detected by DNA analysis. Electrophoresis of serum and urine with immunofixation can assist in the diagnosis of primary amyloid neuropathy. Prognosis is generally poor. Liver transplantation has been reported to be beneficial for hereditary amyloidosis, and high-dose chemotherapy followed by bone marrow transplantation has been reported to help some patients with primary amyloidosis.

FIG. 105.4. Amyloid neuropathy. Massive deposits of endoneurial amyloid compress nerve fiber bundles. (Courtesy of Dr. Arthur Asbury.)

NEUROPATHY ASSOCIATED WITH CARCINOMA (PARANEOPLASTIC NEUROPATHY) Both direct and indirect effects of malignant neoplasms on the peripheral nervous system are recognized. In some patients, the nerves or nerve roots are compressed or infiltrated by neoplastic cells. In others, there is no evidence of damage to the nerves by the neoplasm, and dietary deficiency or metabolic, toxic, or immunologic factors may be responsible. The most characteristic paraneoplastic disorder is a sensory neuropathy of subacute onset, associated with small-cell carcinoma of the lung. Electrodiagnostic studies reveal loss of sensory evoked responses. Autoantibodies against the Hu antigen in neuronal nuclei are characteristic, and postmortem studies show loss of neurons, deposition of antibodies, and inflammatory cells in dorsal root ganglia. Less consistently associated with carcinoma is a distal sensorimotor polyneuropathy without specific features. Nerve biopsy may reveal infiltration by tumor cells, axonal degeneration, or demyelination. A primarily motor syndrome of subacute onset occurs in Hodgkin disease and other lymphomas. In these patients, the predominant lesion is degeneration of anterior horn cells, but demyelination, perivascular mononuclear cell infiltrates, and alterations in Schwann cell morphology in ventral roots are also observed. Some patients also have probable or definite upper motor neuron signs in life, and corticospinal tract degeneration is found at autopsy; that is, they have clinical and pathologic evidence of amyotrophic lateral sclerosis (ALS). The diagnosis of malignancy should be suspected in a middle-aged or elderly patient with a subacute sensory neuropathy or polyradiculopathy of obscure cause, particularly with weight loss. The course is usually progressive until the primary malignancy is cured or until it causes death. CSF examination for malignant cells is valuable in the diagnosis of infiltration of the meninges by cancer. In some instances of meningeal infiltration, radiotherapy or intrathecal chemotherapy may be valuable.

HYPOTHYROID NEUROPATHY Entrapment neuropathies are relatively common in patients with hypothyroidism, probably because acid mucopolysaccaride protein complexes (mucoid) are deposited in the nerve. Painful paresthesia in the hands and feet is the most common symptom of hypothyroidism. Weakness is not a feature. Tendon reflexes are reduced or absent, and, when present, may show the characteristic delayed or “hung-up� response. Direct percussion of muscle produces transient mounding of the underlying skin and muscle (myoedema). Nerve conduction studies show mild slowing of motor nerve conduction and decreased amplitude of the sensory evoked response. Morphologic studies show evidence of demyelination, axonal loss, and excessive glycogen within Schwann cells. CSF protein content is often more than 100 mg/dL. Rarely, dysfunction of cranial nerves IX, X, and XII causes hoarseness and dysarthria, probably as a result of local myxedematous infiltration of the nerves. Some hearing loss is reported in as many as 85% of hypothyroid patients. The peripheral neuropathy may occur before there is laboratory evidence of hypothyroidism. Once identified, thyroid replacement causes clinical, electrophysiologic, and morphologic improvement.

ACROMEGALIC NEUROPATHY Entrapment neuropathy is also relatively common in patients with acromegaly. Rarely, acromegalic patients note distal paresthesia, but in contrast to myxedematous patients, weakness may be severe, and peripheral nerves may be palpable. There is a significant correlation between total exchangeable body sodium and the severity of the neuropathy. The nerves are enlarged because there is increased endoneurial and perineurial connective tissue, perhaps stimulated by increased levels of somatomedin C (insulin-like growth factor). Tendon reflexes are reduced. Nerve conduction velocities are mildly slow with low evoked response amplitudes. Morphologic changes suggest segmental demyelination.

HYPERTHYROID NEUROPATHY Hyperthyroidism can produce a syndrome consisting of diffuse weakness and fasciculations with preserved or hyperactive tendon reflexes, resembling ALS. However, the symptoms and signs disappear with treatment of the toxic state. GBS is also seen with hyperthyroidism. No convincing pathologic studies have established the presence of chronic sensorimotor neuropathy with hyperthyroidism.

UREMIC NEUROPATHY Peripheral neuropathy is only one of the neuromuscular syndromes associated with chronic renal failure. Restless legs, cramps, and muscle twitching may be early manifestations of peripheral nerve disease. Some 70% of patients with chronic renal failure have neuropathy, but most are subclinical and are identified by conduction studies. Symptoms include painful dysesthesia and glove-stocking loss of sensation, as well as weakness of distal muscles. Electrodiagnostic studies show a sensorimotor neuropathy with axonal features. Pathologic studies confirm the axonopathy. Segmental demyelination may result from axonal loss. Dialysis rarely reverses the neuropathy but may stabilize symptoms; peritoneal dialysis is more effective than hemodialysis. Serial nerve conduction studies can measure the effectiveness of hemodialysis. Renal transplantation often resolves the neuropathy shortly after surgery. Mononeuropathy, particularly the carpal tunnel syndrome, often appears distal to an implanted arteriovenous fistula, suggesting ischemia as a possible mechanism.

Distal ischemia from implanted bovine shunts may cause a more severe ischemic neuropathy in the median, ulnar, and radial nerves, possibly from excessive arteriovenous shunting. Chronic hemodialysis (more than 10 years) causes excessive accumulation of b 2-microglobulin (generalized amyloidosis), another possible cause of carpal tunnel syndrome and peripheral uremic neuropathy. The cause of uremic neuropathy is uncertain. An accumulation of a toxic metabolite is most likely, but its identity is unknown. A 2- to 60-kDa molecular weight compound in the plasma of uremic patients induced an axonal neuropathy in experimental animals.

NEUROPATHY ASSOCIATED WITH HEPATIC DISEASE Peripheral neuropathy is rarely associated with primary diseases of the liver. A chronic demyelinating neuropathy with chronic liver disease is usually subclinical. A painful sensory neuropathy is seen with primary biliary cirrhosis, probably caused by xanthoma formation in and around nerves. Electrodiagnostic studies may be normal, or the amplitude of the sensory evoked response may be low or absent. Nerve biopsy shows loss of small-diameter nerve fibers. Sudanophilic material is seen in cells of the perineurium. Treatment is directed at pain control. Tricyclic antidepressants or anticonvulsants may relieve paresthesia. Infectious diseases of the liver may also be associated with peripheral neuropathy. Viral hepatitis (especially hepatitis C associated with cryoglobulinemia), HIV or CMV infection, and infectious mononucleosis may be associated with acute demyelinating neuropathy (GBS), chronic demyelinating neuropathy, or mononeuropathy multiplex. Immunologically mediated diseases such as polyarteritis and sarcoidosis may also cause liver abnormalities and mononeuropathy multiplex. Peripheral neuropathy is often seen with toxic liver disease or hepatic metabolic diseases such as acute intermittent porphyria (see Chapter 90) and abetalipoproteinemia (see Chapter 91).

NEUROPATHIES ASSOCIATED WITH INFECTION Neuropathy of Leprosy Direct infiltration of small-diameter peripheral nerve fibers by Mycobacterium leprae causes the neuropathy of leprosy. It is the most common treatable neuropathy in the world. In the United States, the disease is less endemic but is seen in immigrants from India, Southeast Asia, and Central Africa. Peripheral nerves are affected differently in tuberculoid and lepromatous forms. In tuberculoid leprosy, there are small hypopigmented areas with superficial sensory loss, and the underlying subcutaneous sensory nerves may be visibly or palpably enlarged. Large nerve trunks, such as the ulnar, peroneal, facial, and posterior auricular nerves, may be enmeshed in granulomas and scar tissue. Endoneurial caseation necrosis may occur. The clinical picture is one of mononeuritis or mononeuritis multiplex. In lepromatous leprosy, Hansen bacilli proliferate in large numbers within Schwann cells and macrophages in the endoneurium and perineurium of subcutaneous nerve twigs (Fig. 105.5), particularly in cool areas of the body (pinnae of the ears and dorsum of the hands, forearms, and feet). Loss of cutaneous sensibility is observed in affected patches; these may later coalesce to cover large parts of the body. Position sense may be preserved in affected areas, whereas pain and temperature sensibility is lost, a dissociation similar to that in syringomyelia. Tendon reflexes are preserved.

FIG. 105.5. Lepromatous leprous neuritis. Few myelinated fibers are scattered in fibrotic endoneurium. Abundant foam cells (arrows) contain M. leprae bacilli when viewed at higher magnification. (Courtesy of Dr. Arthur Asbury.)

Acute mononeuritis multiplex may appear during chemotherapy of lepromatous leprosy in conjunction with erythema nodosum. This complication is treated with thalidomide. Treatment is designed to eradicate the bacterium using dapsone and to prevent secondary immune reactions that may damage nerves. Because of the dense sensory loss, painless and inadvertent traumatic injuries, such as self-inflicted burns, may occur without extreme caution to avoid trauma to the anesthetic areas. Diphtheritic Neuropathy Although diphtheria itself is rare, diphtheritic neuropathy is seen in approximately 20% of infected patients. Corynebacterium diphtheriae infects the larynx and pharynx, as well as cutaneous wounds. The organisms release an exotoxin that causes myocarditis and, later, symmetric neuropathy. The neuropathy often begins with impaired visual accommodation and paresis of ocular and oropharyngeal muscles, and quadriparesis follows. Nerve conduction velocities are slow, reflecting the underlying demyelinating neuropathy. Diphtheria and its neuropathy may be prevented by immunization, and if infection occurs, antibiotic therapy may be used. Recovery may be slow, and physiologic measures resolve after the clinical syndrome. HIV-related Neuropathies Several neuropathies afflict patients infected with HIV, depending on the stage of the illness and the immunocompetence of the patient. An acute demyelinating neuropathy resembling GBS occurs early in the course of infection, often with no signs of immunodeficiency or at the time of seroconversion. This form of GBS with HIV infection differs from sporadic GBS in greater incidence of generalized lymphadenopathy, more frequent involvement of cranial nerves, and a higher frequency of other sexually transmitted diseases. Subacute demyelinating neuropathy, clinically indistinguishable from idiopathic CIDP, is usually found in HIV-positive patients before there is evidence of immunodeficiency (AIDS). The CSF protein content is increased in both idiopathic CIDP and HIV-associated demyelinating neuropathy. The HIV syndrome, however, includes CSF pleocytosis, which is not seen in CIDP. Steroids, plasmapheresis, and IVIG therapy have been reported to be effective treatments. Patients who fulfill diagnostic criteria for AIDS rarely have demyelinating neuropathy. Instead, there is a distal sensorimotor polyneuropathy with axonal features. The syndrome is dominated by severe painful paresthesia that affects the feet first and most intensely. This painful neuropathy can be the most functionally disabling manifestation of AIDS. The exact mechanism is uncertain, but one form is the diffuse infiltrating lymphocystosis syndrome, a hyperimmune reaction to HIV infection. No treatment reverses the symptoms, but carbamazepine (Tegretol) and amitriptyline may help. Mononeuropathy multiplex occurs in HIV-infected patients at any stage of the disease, sometimes with hepatitis. When CD4 cells number less than 50/mm 3, the likely cause of the mononeuropathy is CMV, and prompt treatment with ganciclovir sodium (Cytovene) may be life-saving. CMV infection is also associated with

polyradiculopathy or GBS. Neuropathy of Herpes Zoster Varicella-zoster virus infection of the dorsal root ganglion produces radicular pain that may precede or follow the appearance of the characteristic skin eruption. Although primarily a sensory neuropathy, weakness from motor involvement occurs in 0.5% to 5% of infected patients, more often in elderly patients or those with a malignancy and usually in the same myotomal distribution as the dermatomal rash. Zoster infections are also associated with GBS and CSF pleocytosis. Because zoster infection often occurs in patients with HIV infection and CSF pleocytosis is seen in both conditions, the combination of herpes infection and focal weakness in a young person should alert the clinician to the possibility of HIV infection. Herpes zoster may affect any level of the neuraxis, but it most often involves thoracic dermatomes and cranial nerves with sensory ganglia (V and VII). Ophthalmic herpes infection in the gasserian ganglion characteristically involves the first division of the trigeminal nerve. There may be weakness of ocular muscles and ptosis. Infection of the geniculate ganglion of the facial (VII) nerve causes a vesicular herpetic eruption in the external auditory meatus, vertigo, deafness, and facial weakness (Ramsay Hunt syndrome). Treatment with acyclovir (Zovirax), 4 g per day in five doses for 5 days, decreases the incidence of segmental motor neuritis and sensory axonopathy but does not reduce the incidence of postherpetic neuralgia.

SARCOID NEUROPATHY Neurologic symptoms appear in 4% of patients with sarcoidosis. Most commonly, there are single or multiple cranial nerve palsies that fluctuate in intensity. Of the cranial nerves, the seventh is most commonly affected, and, as in diabetes mellitus, the facial nerve syndrome in sarcoidosis is indistinguishable from idiopathic Bell palsy. Some cranial neuropathies in sarcoidosis result from basilar meningitis. One distinguishing feature of sarcoid mononeuropathy is a large area of sensory loss on the trunk. Patients with sarcoidosis occasionally experience symmetric polyneuropathy months or years after the diagnosis is established. The neuropathy may be the first manifestation before the diagnosis of sarcoidosis is made. The clinical syndromes may include GBS, lumbosacral plexopathy, mononeuritis multiplex, or pure sensory neuropathy. Almost all patients, however, have cranial nerve symptoms. Nerve biopsy shows a mixture of wallerian degeneration and segmental demyelination with sarcoid granulomas in endoneurium and epineurium. Sarcoid neuropathy may respond to steroid therapy.

POLYNEUROPATHY ASSOCIATED WITH DIETARY STATES The peripheral neuropathy of alcoholic abusers is well known, but the cause is still debated. No unequivocal evidence supports the concept that alcohol is toxic to peripheral nerve. A widely held belief is that the neuropathy of alcoholism is due to nutritional deficiency, particularly of vitamin B 1 (thiamine). Thiamine deficiency may cause two different clinical syndromes: wet beriberi, in which congestive heart failure is the predominant syndrome, and dry beriberi, in which peripheral neuropathy is the predominant symptom. The signs and symptoms of this neuropathy closely resemble those observed in alcoholics. Patients with thiamine deficiency have severe burning dysesthesia in the feet more than the hands, weakness and wasting of distal more than proximal muscles, trophic changes (shiny skin, hair loss), and sensory loss that is worse in distal portions of the legs. EMG and nerve conduction studies reveal the presence of a diffuse sensorimotor peripheral neuropathy that is axonal in nature. Axonal degeneration is also the principal finding seen on nerve biopsy specimens. Treatment of both beriberi and alcoholic neuropathy should be initiated with parenteral B-complex vitamins followed by oral thiamine. Recovery is slow; there may be residual muscular weakness and atrophy. Niacin (nicotinic acid) deficiency causes pellagra characterized by hyperkeratotic skin lesions. Peripheral neuropathy is usually present in patients deficient in niacin, but the neuropathy does not improve with niacin supplementation. Symptoms improve only when thiamine and pyridoxine are added to the diet. Vitamin B12 deficiency causes the classic clinical syndrome of subacute combined degeneration of the spinal cord. Separation of the peripheral neuropathic symptoms from spinal cord involvement is difficult. Painful paresthesia accompanies vitamin B 12 deficiency, probably as a result of spinal cord involvement. Vitamin B6 (pyridoxine) deficiency produces a peripheral neuropathy, and the most common cause of pyridoxine deficiency is ingestion of the antituberculous drug, isoniazid. Isoniazid increases the excretion of pyridoxine. The resulting neuropathy affects sensory more than motor fibers and is caused by axonal loss. Treatment consists of administering excessive amounts of pyridoxine to compensate for the added excretion. The neuropathy can be prevented by prophylactic pyridoxine administration. Occasionally, isoniazid also elicits a vasculitic mononeuropathy multiplex. Vitamin E deficiency contributes to neuropathy in fat malabsorption syndromes (e.g., chronic cholestasis). The clinical syndrome of vitamin E deficiency resembles spinocerebellar degeneration with ataxia, severe sensory loss of joint position and vibration, and hyporeflexia. Motor nerve conduction studies are normal, but sensory evoked responses are of low amplitude or absent. Somatosensory evoked responses show a delay in central conduction. EMG is usually normal. Vitamin E deficiency occurs in most fat malabsorption disorders including abetalipoproteinemia, congenital biliary atresia, pancreatic dysfunction, and surgical removal of large portions of the small intestine.

CRITICAL ILLNESS POLYNEUROPATHY Severe sensorimotor peripheral neuropathy is seen in many patients who are critically ill, suffering from sepsis and multiple organ failure. Although this disorder may be suggested by other clinical manifestations, the diagnosis may arise when a patient experiences difficulty being weaned from a ventilator. Electrodiagnostic studies show a severe sensorimotor axonal neuropathy, but some pathologic studies have shown little axonal loss and extensive type 1 and 2 fiber atrophy disorder, a pattern attributed to pharmacologic denervation or treatment with drugs that interfere with neuromuscular transmission. A disorder of nerve terminals has been proposed. Recovery of neuronal function may occur if the underlying cause of multiple organ failure is treated successfully. The cause is unknown, but dietary deficiency is not likely. Many respirator-dependent patients with critical illness neuropathy have received neuromuscular blocking agents, which may be the main cause. Mononeuritis or mononeuritis multiplex occurs in 2% of patients with bacterial endocarditis because of septic emboli to peripheral nerves. Some patients with bacterial endocarditis may experience a severe axonal neuropathy, thought to be similar to the axonopathy seen in patients with critical illness polyneuropathy.

NEUROPATHIES CAUSED BY HEAVY METALS Arsenic Neuropathy may follow chronic exposure to small amounts of arsenic or ingestion or parenteral administration of a large amount. Chronic exposure may occur in industries in which arsenic is released as a byproduct, such as the copper smelting industry. Because of the prevalence of these byproducts, arsenic neuropathy is the most common of all heavy metal–induced neuropathies. Gastrointestinal symptoms, vomiting, and diarrhea occur when a toxic quantity of arsenic is ingested, but these symptoms may be absent if the arsenic is given parenterally or taken in small amounts over long periods. In acute arsenic poisoning, the onset of symptoms is delayed 4 to 8 weeks; once symptoms develop, they reach maximum intensity within a few days. The evolution of polyneuropathy is much slower in chronic arsenic poisoning. Sensory symptoms are prominent in the early stages. Pain and paresthesia in the legs may be present for several days or weeks before onset of weakness. The weakness progresses to complete flaccid paralysis of the legs and sometimes the arms. Cutaneous sensation is impaired in a stocking-and-glove distribution, with vibration and position sensation being most affected. Tendon reflexes are lost. Pigmentation and hyperkeratosis of the skin and changes in the nails (Mees lines) are frequently present. Arsenic is present in the urine in the acute stages of poisoning and, later, in the hair and nails. Nerve conduction velocities may be normal or mildly diminished; the amplitude of sensory evoked responses may be reduced. Pathologic examination of nerves shows axonal degeneration. Arsenic polyneuropathy should be treated with a chelating agent. Effectiveness of chelation therapy can be monitored by measuring arsenic excretion rates in 24-hour samples.

Lead Most toxic neuropathies cause a symmetric weakness and loss of sensation in distal more than proximal regions, feet worse than legs. In contrast to most other toxic neuropathies, lead poisoning causes focal weakness of the extensor muscles of the fingers and wrist. Pure motor bilateral arm weakness and wasting may be caused by chronic lead intoxication. Lead neuropathy occurs almost exclusively in adults. Infants poisoned with lead usually experience encephalopathy. Lead may enter the body through the lungs, skin, or gut. Occupational lead poisoning is encountered in battery workers, painters, and pottery glazers. Accidental lead poisoning follows ingestion of lead in food or beverages, or occurs in children who ingest lead paint. Lead poisoning may cause abdominal distress (lead colic). By its effect on renal tubules, lead poisoning often causes urate retention and gout. Weakness usually begins in distinct muscles innervated by the radial nerve, sparing the brachioradialis; it is often bilateral. Later, the weakness may extend to other muscles in the arms and, occasionally, to the legs. Sensory symptoms and signs are usually absent. Rarely, upper motor neuron signs occur with the lower motor neuron disorder and mimic ALS. Laboratory findings include anemia with basophilic stippling of the red cells, increased serum uric acid, and slight elevation of CSF protein content. Nerve conduction velocities are usually normal, raising the possibility that the disorder may be an anterior horn cell disorder rather than a neuropathy. Urinary lead excretion is elevated, particularly after administration of a chelating agent. Urinary porphobilinogen excretion is also elevated, but b-aminolevulinic acid is normal. Primary therapy is prevention of further exposure to lead. With termination of exposure and use of chelation therapy, recovery is gradual over several months. Mercury Mercury is used in the electrical and chemical industries. There are two forms of mercury: elemental and organic. The organic form of mercury (methyl and ethylmercury) is most toxic to the central nervous system (CNS), although distal paresthesia is a prominent symptom (presumably secondary to dorsal root ganglion degeneration). Ventral roots are spared. Inorganic mercury may be absorbed through the gastrointestinal tract, and elemental mercury may be absorbed directly through the skin or lungs (it is volatile at room temperature). Elemental mercury exposure primarily causes weakness and wasting more than sensory symptoms. However, electrophysiologic studies reveal axonal affection of both motor and sensory fibers. Because of the prominent motor manifestations, confusion with ALS may occur. Thallium This element is used as a rodenticide and in other industrial processes. As with lead, children exposed to thallium are more likely to experience encephalopathy, whereas neuropathy develops in adults. In contrast to lead poisoning, however, thallium neuropathy is primarily sensory and autonomic. Severe disturbing dysesthesia appears acutely, and diffuse alopecia is a characteristic feature of thallium poisoning. Signs of cardiovascular autonomic neuropathy are sometimes delayed and recover slowly. Electrophysiologic findings are consistent with an axonal neuropathy. Other Chemicals Triorthocresyl phosphate (Jamaican ginger or “jake� ), an adulterant used in illegal liquor (moonshine) and as a cooking oil contaminant, has been responsible for epidemics of neuropathy. A symmetric distal motor polyneuropathy progresses for 2 to 3 weeks and may be confused with ALS. In later stages, upper motor neuron findings appear. Electrophysiologic studies, however, show axonal loss in sensory nerves, as well as motor fibers. Nerve biopsy shows distal axonal fragmentation. As the neuropathy clears, evidence of previously unrecognized irreversible damage to corticospinal tracts may become apparent, and late spasticity becomes a problem. Acrylamide monomer is used to prepare polyacrylamide. It is used in chemical laboratories and for the treatment of liquid sewerage. Exposure produces a distal sensorimotor neuropathy that may be associated with trophic skin changes and a mild organic dementia. Nerve biopsy shows axonal degeneration with accumulations of neurofilaments in affected axons. Many solvents used in manufacturing artificial materials or for polishing and dry cleaning are neurotoxic, as are many substances used in insecticides and rodenticides. The clinical and electrophysiologic features are similar to those of neuropathies caused by chemotherapeutics. Some, however, affect the CNS, as well as peripheral nerves, and some have certain specific features. For instance, dimethylaminopropionitrile, which is used to manufacture polyurethane foam, causes urologic dysfunction and sensory loss localized to sacral dermatomes. Exposure to methylbromide, an insecticide, results in a mixture of pyramidal tract, cerebellar, and peripheral nerve dysfunction. Accidental ingestion of pyriminil, a rat poison marketed under the name Vacor, gives rise to an acute severe distal axonopathy with prominent autonomic involvement accompanied by acute diabetes mellitus secondary to necrosis of pancreatic beta cells.

NEUROPATHIES CAUSED BY THERAPEUTIC DRUGS A distal axonopathy is a common reaction to toxic chemicals, antineoplastic drugs, other medicaments, or industrial agents. Most of these neuropathies are dose-related, presenting with predominantly sensory symptoms and signs or with a combination of sensory and motor involvement. Numerous substances causing neuropathy have been described, and the interested reader should consult comprehensive reviews cited in the suggested readings. Here, we mention only a few to illustrate typical clinical features. The most commonly used antineoplastic agents are vincristine and cisplatin (Platinol). Vincristine causes a symmetric progressive sensorimotor distal neuropathy that begins in the legs and is associated with areflexia. In contrast, cisplatin neuropathy is a pure sensory distal neuropathy with paresthesia, impaired vibration sense, and loss of ankle jerks. Motor and sensory conduction velocities are normal or mildly slowed in both conditions, but the most conspicuous finding is a marked reduction of the sensory action potential amplitude, implying loss of large myelinated fibers. Paclitaxel (Taxol) is used to treat cancers of the breast, ovary, and lung. It causes a predominantly sensory neuropathy, but administration of a single high-dose may affect motor fibers, as well. Long-term administration of other therapeutic drugs, such as nitrofurantoin for treatment of pyelonephritis and amiodarone hydrochloride (Cordarone) for cardiac arrhythmias, may cause a severe symmetric distal sensorimotor neuropathy. Long-lasting therapy with phenytoin sodium (Dilantin) may give rise to distal sensory impairment and areflexia. A predominantly motor neuropathy has been related to disulfiram (Antabuse) used to treat alcoholism, or to dapsone for leprosy.

DIABETIC NEUROPATHY The broad diversity of neurologic complications in patients with diabetes mellitus can be considered to consist of two distinct types. In one form, the symptoms and signs are transient; in the other, they progress steadily. The transient category includes acute painful neuropathies, mononeuropathies, and radiculopathies. The painful type starts abruptly with a disabling and continuous pain, often a burning sensation in a stocking distribution. Sometimes, the pain is localized to the thighs as a femoral neuropathy. The pain may last for months. Recovery from severe pain, however, is usually complete within 1 year, and the disorder does not necessarily progress to a conventional sensory polyneuropathy. The progressive type comprises sensorimotor polyneuropathies with or without autonomic symptoms and signs. Although the actual cause of diabetic neuropathies is unknown, focal nerve involvement is considered to be vascular; and progressive symmetric polyneuropathy is probably due to a metabolic disorder. There may be as many causal factors as there are different clinical pictures. However, it seems that hyperglycemic hypoxia is mainly responsible for the conduction changes seen in damaged diabetic nerves. Dysfunction of ion conductances, especially voltage-gated ion channels, could contribute to abnormalities in the generation and conduction of action potentials. A syndrome recognized by a triad of pain, severe asymmetric muscle weakness, and wasting of the iliopsoas, quadriceps, and adductor muscles is named diabetic amyotrophy. Onset is usually acute, but it may evolve over weeks. It occurs primarily in older noninsulin-dependent diabetics and is often accompanied by severe weight loss and cachexia. Knee jerks are absent, but there is little or no sensory loss. The condition resolves spontaneously but may last 1 to 3 years.

Mononeuropathies It is generally believed but has never been proved that focal neuropathies are more frequent in diabetic patients than in the general population. The syndromes are usually localized to the common sites of nerve entrapment or external compression and may imply an increased liability to pressure palsies. This applies to the median nerve at the carpal tunnel, the ulnar at the elbow, and the peroneal at the fibular head. The electrophysiologic features are similar to those seen in nondiabetic patients with pressure palsies, except that abnormalities outside the clinically affected areas sometimes indicate that the palsies are superimposed on a generalized neuropathy. Cranial nerve palsies are most often localized to the third and sixth nerves. They start abruptly and usually spontaneously resolve completely within 6 months; relapses are rare. Generalized Polyneuropathies The most common diabetic neuropathy is a diffuse distal symmetric and predominantly sensory neuropathy with or without autonomic manifestations. Distal limb weakness is usually minor. The neuropathy develops slowly and is related to the duration of the diabetes, but not all patients are so afflicted. Once present, it never remits or recovers. Whether strict diabetic control or other measures can alter the course is still a matter of debate. Most evidence suggests that small nerve fibers, both myelinated and unmyelinated, are affected first. Thus, pain and temperature sensation transmitted through the smallest fibers may be affected before the large-fiber modalities (vibration, light touch, position sense). Small-fiber function can be evaluated by determining thresholds for warming and cooling or by a pinprick threshold technique using weighted needles. Perception of cooling and pinprick is conveyed by small myelinated fibers; the sense of warming is carried by unmyelinated fibers. The prevalence of diabetic autonomic neuropathy may be underestimated because nonspecific symptoms are undiagnosed or the condition may be asymptomatic. Symptoms appear insidiously, long after the onset of diabetes. They progress slowly and are usually irreversible. It is essential to screen for autonomic involvement in diabetics because those who have abnormal cardiovascular reflexes have an excess mortality risk of 56% compared with 11% for the general diabetic population, when followed up to 5 years. Autonomic function tests include determination of the heart rate at rest, during deep breathing, and during standing by measuring the electrocardiographic RR intervals (predominantly parasympathetic function); the change in mean arterial blood pressure from supine to standing position also tests the sympathetic function. Slowing of motor and sensory conduction is a common finding in diabetics even among those without overt neuropathy. It is generally attributed to axonal degeneration with secondary demyelination. Therapeutic attempts, including continuous subcutaneous insulin infusion to correct hyperglycemia to prevent the diabetic complications, have been unsuccessful in most instances. Although combined pancreas and kidney transplantation may halt the progression of diabetic polyneuropathy, the long-term effect is still doubtful. Patients with burning pain may benefit from amitriptyline, but side effects often preclude treatment. Desipramine, which acts by blocking norepinephrine reuptake, may be a better choice.

BRACHIAL NEUROPATHY This syndrome, also known as neuralgic amyotrophy, is characterized by acute onset of severe pain localized to the shoulder region and followed shortly by weakness of the shoulder girdle or arm muscles ipsilateral to the pain. It may be bilateral and asymmetric. Paresthesia and sensory loss may also be noted. In about 50% of patients, the clinical pattern is a mononeuropathy multiplex, followed by mononeuropathy in 33% and plexopathy in 20%. Autoimmune or infectious causes have been suggested, but the etiology is obscure. Some cases have occurred in small epidemics among military personnel, and the disorder may follow intravenous administration of heroin. The typical EMG findings, including motor and sensory nerve studies, are consistent with a predominantly axonal neuropathy, but demyelination occasionally plays a role. The diversity of physiologic disorders in different nerves or even within the same nerve is attributed to involvement of the terminal nerve twigs or to patchy damage of discrete bundles of fibers within the cords or trunks of the brachial plexus or its branches. Recovery depends on the severity of the initial insult. It is considered good in about 66%, fair in 20%, and poor in 14%. Clinical recovery may take 2 months to 3 years.

RADIATION NEUROPATHY Irradiation for carcinoma may damage nervous tissue, especially since the introduction of high-voltage therapy. Lesions of the brachial plexus are seen after radiotherapy for breast cancer; caudal roots and lumbosacral plexus are sometimes affected by radiation therapy for testicular cancer or Hodgkin disease. The first symptom is usually severe pain, followed by paresthesia and sensory loss. There may be a latent period of 12 to 20 months; in milder cases, several years may elapse before symptoms appear. Limb weakness peaks many months later. Latency intervals of up to 20 years have been reported. The damage may affect a single peripheral nerve initially and then progress slowly to involve others. Clinically, tendon reflexes disappear before weakness and atrophy become obvious; fasciculation and myokymia may be prominent. EMG and conduction studies reveal changes consistent with axonal damage; myokymic discharges are thought to be helpful in differentiating plexopathy caused by radiation from plexopathy caused by infiltration by malignancy.

LYME NEUROPATHY Lyme disease is increasingly diagnosed in the United States and Europe. It is caused by a tick-borne spirochete, Borrelia burgdorferi. The most common clinical feature of neuroborreliosis is a painful sensory radiculitis, which may appear about 3 weeks after the erythema migrans. Pain intensity varies from day to day and is often severe, jumping from one area to another and often associated with patchy areas of unpleasant dysesthesia. Focal neurologic signs are common and may present as cranial neuropathy (61%), limb paresis (12%), or both (16%). The facial nerve is most frequently affected; involvement is unilateral twice as often as bilateral. Abducens and oculomotor paresis occasionally occurs. Myeloradiculitis and chronic progressive encephalomyelitis are rare. In some, the disorder is associated with dilated cardiomyopathy. Arthralgia is common among patients in the United States but rare among Europeans (6%). The triad of painful radiculitis, predominantly cranial mononeuritis multiplex, and lymphocytic pleocytosis in the CSF is known as Bann- warth syndrome in Europe. Peripheral nerve biopsy shows perineurial and epineurial vasculitis and axonal degeneration, consistent with the electrophysiologic findings. The diagnosis of neuroborreliosis is based on the presence of inflammatory CSF changes and specific intrathecal B. burgdorferi antibodies. In some infected patients, however, no free antibodies are detectable. Antigen detection in CSF could then be helpful. Polymerase chain reaction technique for detecting spirochetes or spirochetal DNA turned out to be less specific. The prognosis is good after high-dose penicillin treatment. Disabling sequelae are rare and occur mainly in patients with previous CNS lesions. SUGGESTED READINGS General Dyck PJ, Thomas PK, Griffin JW, eds. Peripheral neuropathy. Philadelphia: WB Saunders, 1993. Maravilla KR, Bowen BC. Imaging of the peripheral nervous system: evaluation of peripheral neuropathy and plexopathy. AJNR 1998;19:1011–1023. Guillain-Barré Syndrome and Variants Feasby TE, Gilbert JJ, Brown WP, et al. An acute axonal form of Guillain-Barré polyneuropathy. Brain 1986;109:1115–1126. Feasby TE, Hughes RAC. Campylobacter jejuni, antiganglioside antibodies, and Guillain-Barré syndrome. Neurology 1998;51:340–342. Gorson KC, Allam G, Ropper AH. Chronic inflammatory demyelinating polyneuropathy: clinical features and response to treatment in 67 consecutive patients with and without a monoclonal gammopathy. Neurology 1997;48:321–328. Hadden RDM, Cornblath DR, Hughes RAC, et al. Electrophysiological classification of Guillain-Barré syndrome: clinical associations and outcome. Ann Neurol 1998;44:780–788. Hainfellner JA, Kristoferitsch W, Lassman H, et al. T-cell mediated ganglioneuritis associated with acute sensory neuronopathy. Ann Neurol 1996;39:543–547. Hartung HP, Pollard JD, Harvey GK, Tokya KV. Immunopathogenesis and treatment of the Guillain-Barré syndrome—part 1. Muscle Nerve 1995;18:137–153.

Hartung HP, Pollard JD, Harvey GK, Tokya KV. Immunopathogenesis and treatment of the Guillain-Barré syndrome—part 2. Muscle Nerve 1995;18:154–164. Ho TW, Willison HJ, Nachamkin I, et al. Anti GD1a antibody is associated with axonal but not demyelinating forms of Guillain-Barré syndrome.

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CHAPTER 106. ALZHEIMER DISEASE AND RELATED DEMENTIAS MERRITT’S NEUROLOGY

SECTION XIII. DEMENTIAS CHAPTER 106. ALZHEIMER DISEASE AND RELATED DEMENTIAS SCOTT A. SMALL AND RICHARD MAYEUX Degenerative Diseases Vascular Diseases Infectious Diseases Inherited Metabolic Diseases Suggested Readings

The defining features of dementia have evolved since the term was first introduced over 300 years ago. In this era of standardized criteria, those of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) are most commonly used. According to DSM-IV, the diagnosis of dementia requires “the development of multiple cognitive deficits that are sufficiently severe to cause impairment in occupational or social functioning.” The cognitive deficits must involve memory and other cognitive domains, must represent a decline from premorbid function, and cannot be attributed to delirium (see Chapter 1). The cellular and molecular mechanisms underlying the pathogenesis of various forms of dementia have been elaborated in the last decade. Although there are many similarities, there are also important differences. Thus, the need for a classification system remains. Dementia can be grouped into four major categories: degenerative,vascular, infectious, and metabolic diseases.

DEGENERATIVE DISEASES Alzheimer Disease The most frequently encountered dementia was named after Alois Alzheimer by Kraeplin. Alzheimer described the clinical features and the pathologic manifestations of dementia in a 51-year-old woman at the turn of the century. For many years Alzheimer disease was considered a presenile form of dementia, limited to individuals with symptoms beginning before the age of 65. However, subsequent clinical, pathologic, ultrastructural, and biochemical analyses indicated that Alzheimer disease is identical to the more common senile dementia beginning after age 65. Clinical Syndrome The manifestations of Alzheimer disease evolve uniformly from the earliest signs of impaired memory to severe cognitive loss. The clinical course is progressive, terminating inevitably in complete incapacity and death. Plateaus sometimes occur; cognitive impairment does not change for a year or two, but progression then resumes. Memory impairment for newly acquired information is the usual initial presenting complaint, whereas memory for remote events is relatively unimpaired at the beginning of the illness. As the disease progresses, deficits in language, abstract reasoning, and executive function can be elicited on specific probing. Major depression with insomnia or anorexia occurs in 5% to 8% of patients with Alzheimer disease unrelated to severity. Delusions and psychotic behavior increase with progression of Alzheimer disease and remain persistent in 20%. Agitation may coexist in up to 20%, increasing with advanced disease. Hallucinations occur with similar frequency and may be either visual or auditory. Except for the mental state, the neurologic examination is usually normal, but extrapyramidal features, including rigidity, bradykinesia, shuffling gait, and postural change, are relatively common in later stages of the disease. Primary motor and sensory functions are otherwise spared. Oculomotor, cerebellar, or peripheral nerve abnormalities on physical examination strongly raise the possibility of some other form of dementia. Diagnosis Criteria for the clinical diagnosis of Alzheimer disease were established by a joint effort of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association in 1984 and are referred to as the NINCDS-ADRDA criteria. These include a history of progressive deterioration in cognitive ability in the absence of other known neurologic or medical problems. Psychologic testing, brain imaging, and other criteria establish three levels of diagnostic certainty. The designation of “definite” Alzheimer disease is reserved for autopsy-confirmed disease. If there is no associated illness, the condition is called “probable” Alzheimer disease; “possible” refers to these who meet criteria for dementia but have another illness that may contribute, such as hypothyroidism or cerebrovascular disease. Comparing the clinical with the pathologic diagnosis, the NINCDS-ADRDA criteria provide 90% sensitivity for the diagnosis of probable or possible Alzheimer disease and 60% specificity. The designation of definite Alzheimer disease has been reserved only for autopsy-confirmed disease. There are no specific changes in routine laboratory examinations. Cerebrospinal fluid (CSF) is normal, but there may be a slight increase in the protein content. Generalized slowing is seen regularly on the electroencephalogram (EEG). Neuropsychological testing can detect minimal or subtle cognitive impairment early in the disease, can document global impairment, or can follow the course of the disease. Dilatation of the lateral ventricles and widening of the cortical sulci, particularly in the frontal and temporal regions, can be observed using either computed tomography or magnetic resonance imaging (MRI), especially late in the disease. Mild cortical atrophy, however, is seen in some older individuals who function normally by clinical and psychologic testing. Functional brain imaging studies, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), or functional MRI, show hypometabolism in the temporal and parietal areas of patients with moderate to severe symptoms. Genetic tests may be useful in the diagnosis of Alzheimer disease in families with early-onset autosomal dominant forms of the disease. For sporadic or familial late-onset Alzheimer disease, the e4 polymorphism of the apolipoprotein E gene has been associated with a higher risk of the disease but does not provide sufficient sensitivity or specificity to be used for diagnosis and is not recommended. Epidemiology Before age 65, the prevalence, or proportion, of individuals with Alzheimer disease is less than 1%, but this rapidly increases to between 5% and 10% at age 65 years and to as high as 30% to 40% at age 85 and older. The age-specific incidence, or the number of new cases arising over a specific period of time, also rises steeply from less than 1% per year before age 65 years to 6.0% per year for individuals aged 85 and older. The average duration of symptoms until death may be 10 years, with a range of 4 to 16 years. Disease duration tends to be longer for women than for men. Rates of Alzheimer disease are slightly higher among women than in men, partly because affected women generally live longer than men do. However, the incidence rates for Alzheimer disease are also slightly higher in women, especially after age 85 years. In families with at least one affected individual, women who are first-degree relatives have a higher lifetime risk of developing Alzheimer disease than men. Genetic Basis of Alzheimer Disease Many families with autosomal dominant Alzheimer disease have been described. Siblings of patients have twice the expected lifetime risk of developing the disease. Also, monozygotic twins have significantly higher concordance of Alzheimer disease than do dizygotic twins. Mutations in three genes, the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PS1) on chromosome 14, and the presenilin 2 (PS2) on chromosome 1, result in an autosomal dominant form of the disease beginning as early as the third decade of life. The existence of over 50 different mutations in PS1 suggests that this may be the most common form of familial early-onset Alzheimer disease. APP mutations can lead to enhanced generation or aggregation of amyloid-beta, indicating a pathogenic role. On the other hand, PS1 and PS2 are distinct from the immediate regulatory and coding regions of the APP gene, indicating that defects in molecules other than APP can also lead to cerebral

amyloidogenesis and familial Alzheimer disease. Mutations in these genes may be considered deterministic because of nearly complete correspondence between the genotype and phenotype. The e4 polymorphism of the apolipoprotein E (APOE) gene on chromosome 19 has been associated with the more typical sporadic and familial forms of Alzheimer disease, usually beginning after age 65. In contrast to the disease-causing mutations in the APP and PS1/2 genes, the e4 polymorphism of APOE is a normally occurring variant of the gene that appears to significantly increase susceptibility to the disease. In some families with late-onset Alzheimer disease, in a few families with mutations in the APP gene, and in patients with Down syndrome, each APOE e4 allele can lower the age at onset of dementia. The association between the APOE e4 polymorphism and Alzheimer disease is weaker among African-Americans and Caribbean Hispanics. Consistent with other genes involved in Alzheimer disease, apolipoprotein E may also act through a complex and poorly understood relationship with amyloid. The apolipoprotein E protein is an obligatory participant in amyloid accumulation, and different apolipoprotein E protein isoforms corresponding to polymorphisms exert at least some of their effects by controlling accumulation. A genetic locus on chromosome 12 has pointed to the possibility of yet another susceptibility gene for Alzheimer disease. At least two polymorphisms in the gene encoding the a2-macroglobulin protein have been associated with Alzheimer disease in these families. This candidate gene has also been implicated in amyloid clearance. Thus, mutations in at least three genes are associated with familial Alzheimer disease beginning before age 65, and polymorphisms in two genes are associated with susceptibility to Alzheimer disease after age 65 ( Table 106.1).

TABLE 106.1. GENETIC LOCI IN ALZHEIMER DISEASE

Other Risk Factors Though inconsistent, Alzheimer disease has also been associated with traumatic head injury, lower educational achievement, parental age at the time of birth, smoking, and Down syndrome in a first-degree relative. In several observational studies, the use of estrogen replacement therapy in postmenopausal women and the regular use of anti-inflammatory agents in both men and women have been associated with lower risks of Alzheimer disease and are currently being investigated in randomized clinical trials ( Table 106.2).

TABLE 106.2. RISK FACTORS MOST CONSISTENTLY ASSOCIATED WITH ALZHEIMER DISEASE

Pathology Alzheimer disease is characterized by atrophy of the cerebral cortex. At autopsy, the process is usually diffuse, but it may be more severe in the frontal, parietal, and temporal lobes (Fig. 106.1). On microscopic examination, there is loss of both neurons and neuropil in the cortex; sometimes, secondary demyelination is seen in subcortical white matter. Quantitative morphometry suggests that the earliest cell loss occurs in the entorhinal region of the medial temporal lobe. The most characteristic histopathologic markers are the argentophilic senile plaques and neurofibrillary tangles.

FIG. 106.1. Alzheimer disease. Diffuse atrophy of brain, especially severe in frontal, temporal, and parietal lobes with sparing of precentral and postcentral gyri. (Courtesy of Dr. Robert Terry.)

The senile neuritic plaques are spherical microscopic lesions that are best seen with Bielschowsky stain; a core of extracellular amyloid is surrounded by enlarged axonal endings (neurites). The major protein in amyloid is beta-peptide, which is derived from APP—a transmembrane protein. This protein undergoes proteolysis, resulting in the accumulation of beta-amyloid peptide in brain, a key step in the pathogenesis of the disease. Amyloid is a generic description applied to a heterogeneous group of protein precipitates that may be deposited in a general manner throughout the body (systemic amyloids) or confined to a particular organ (e.g., cerebral amyloid, renal amyloid). In Alzheimer disease, amyloid is deposited around meningeal and cerebral vessels and in gray matter. The gray matter deposits are multifocal, coalescing into miliary structures known as plaques ( Fig. 106.2). Parenchymal amyloid plaques are distributed in brain in a characteristic fashion, differentially affecting the various cerebral and cerebellar lobes and cortical laminae. A region of the APP molecule resides within an intramembranous domain of the neuron, and it is believed that proteases, termed g-secretases, are responsible for cleavage of a site residing within a membranous domain. At least one of these g-secretases may be under the control of PS1/2. The generation of highly aggregatable peptides is believed to initiate the accumulation of amyloid in all

forms of the disease.

FIG. 106.2. Alzheimer disease. Left: Prominent senial plaques. Right: Several neurons with neurofibrillary tangles. Note also disruption of cortical organization. (Courtesy of Dr. Robert Terry.)

Neurofibrillary tangles are fibrillary intracytoplasmic structures within the neurons and are, like the plaques, also seen with the Bielschowsky stain. Electron microscopy shows paired helical filaments. Among the proteins within affected neurons are beta-amyloid and the tau protein, a microtubule protein. Although neurofibrillary tangles are not specific to Alzheimer disease, they occur first in the hippocampal formation; later, neurofibrillary tangles may be seen throughout the cerebral cortex (Table 106.3).

TABLE 106.3. PATHOLOGIC CHANGES IN ALZHEIMER DISEASE

Other features of Alzheimer disease include granulovacuolar degeneration of pyramidal cells of the hippocampus and amyloid angiopathy. The Hirano body, a rodlike body containing actin in a paracrystalline array, was first described in the Guam–parkinsonism–dementia complex; these neuronal inclusions are also found in Alzheimer disease. Some investigators believe that cognitive decline correlates, not with increased number of plaques but with a decrease in the density of presynaptic boutons from the pyramidal neurons in lamina III and IV, especially in the midfrontal neocortex. Arteriosclerotic changes are absent or inconspicuous in most cases. Biochemically, the most consistent change is a 50% to 90% reduction of the activity of choline acetyltransferase, the biosynthetic enzyme for acetylcholine, in the cerebral cortex and hippocampus. This enzyme is found in cholinergic neurons, and there is a selective loss of cholinergic neurons, particularly of the cholinergic projection pathway, from deep nuclei in the septum near the diagonal band of Broca to the hippocampus and from the nearby basal nucleus of Meynert to the cerebral cortex. Among the cholinergic receptor subtypes, M2—a presynaptic muscarinic receptor—displays decreased binding in the brains of Alzheimer patients. The severity of cognitive loss is roughly proportional to the loss of choline acetyltransferase. There is decreased content of corticotropin-releasing factor and somatostatin, both of which are found within degenerating neurites of the neuritic plaque. Glutaminergic neurons account for many large neurons lost in the cerebral cortex and hippocampus, and there is variable loss of ascending and descending serotoninergic and adrenergic systems. Treatment Anticholinesterases are currently the only U.S. Food and Drug Administration–approved treatments for Alzheimer disease and, at present, are considered palliative treatments. Anticholinesterases decrease the hydrolysis of acetylcholine released from the presynaptic neuron into the synaptic cleft by inhibiting acetylcholinesterase, resulting in stimulation of the cholinergic receptor. At the maximum dosages of the two approved drugs, tacrine improves cognitive test performance slightly more than donepezil. Donepezil scored slightly better in the clinicians' rating scales, had fewer side effects, did not alter liver transaminases, and could be given once a day. Though currently unavailable in the United States, rivastigmine and metrifonate compare with donepezil on cognitive performance, but adverse effects have been slightly more frequent. Other drugs are also used. Both alpha tocopherol and selegiline are said to delay the later stages of Alzheimer disease. Unlike selegiline, alpha tocopherol does not interact with other medications, allowing it to be used in most patients without concern. Psychotropic drugs are frequently used to treat agitation, delusions, and psychosis in Alzheimer disease. For depression, nearly all drugs are similar in efficacy, but there are only a handful of randomized controlled studies upon which to make therapeutic decisions. Frontotemporal Dementias Pick disease is a progressive form of dementia characterized by personality change, speech disturbance, inattentiveness, and sometimes extrapyramidal signs. In contrast to Alzheimer disease, Pick disease is rare. The disease can be familial. Atrophy of the frontal and temporal poles and argyrophilic round intraneuronal inclusions (Pick bodies) are the characteristic morphologic changes. Glial reaction is often pronounced in affected cerebral gray and white matter. Tau-immunoreactive glial inclusions and neuritic changes are recognized. Biochemical and immunocytochemical studies demonstrate that abnormal tau proteins are the major structural components of Pick bodies and differ from those seen in Alzheimer disease. As with other frontotemporal dementias, Pick disease shows filamentous tau pathology that has been associated with mutations in tau protein. Tau is a microtubule-associated protein found mainly in axons; it is involved in microtubule assembly and stabilization. Frontotemporal dementias other than Pick disease are also rare and have been associated with mutations on chromosome 17 in the tau gene. Several different mutations account for a diverse array of clinical manifestations in addition to contributing to a characteristic pathologic change observed in Alzheimer disease: the neurofibrillary tangle. Table 106.4 lists the diseases associated with mutation in tau. Frontotemporal dementias are also characterized by personality change, deterioration of memory and executive functions, and stereotypical behavior. Extrapyramidal signs are usually prominent. Standard neuropsychologic tests and conventional brain imaging such as MRI and SPECT may not be sensitive to the early changes in the ventromedial frontal cortex. This suggests difficulty in distinguishing this form of dementia from other dementias early in the illness. Over time, however, there are abnormalities on SPECT, frontal atrophy on MRI, or a neuropsychologic profile more typical of frontotemporal dementia.

TABLE 106.4. DEGENERATIVE DISEASES ASSOCIATED WITH DEMENTIA AND WITH SPECIFIC TAU MUTATIONS

Although there is clinical and neuropathologic variability among and within families, the consistency of the syndrome led investigators to name the disease frontotemporal dementia and parkinsonism linked to chromosome 17 . The pathologic changes include atrophy of frontal and temporal cortex and the basal ganglia and substantia nigra. In most cases, these features are accompanied by neuronal loss, gliosis, and deposits of microtubule-associated protein tau in both neurons and glial cells. The distribution and structural and biochemical characteristics of the tau deposits differentiate them from those of Alzheimer disease, corticobasal degeneration, progressive supranuclear palsy, and Pick disease. No beta-amyloid deposits are present. Other degenerative diseases that may include dementia and are associated with tau mutations include progressive supranuclear palsy, familial progressive subcortical gliosis, and corticobasal ganglionic degeneration. Familial multiple-system tauopathy with presenile dementia shows abundant filamentous tau protein pathology. Parkinson Disease and Lewy Body Dementia As many as 40% of patients with Parkinson disease (see Chapter 114 can develop dementia. The risk of dementia with Parkinson disease is about four times that of other people of the same age. The risk of dementia increases with age at the time of the diagnosis of Parkinson disease and with depression or advanced motor disease. Neither computed tomography nor MRI reliably distinguishes demented from nondemented patients with Parkinson disease. Compared with patients with Parkinson disease who are not demented, those with dementia may show hypometabolism in the frontal lobes and the basal ganglia on PET or SPECT. Dementia associated with Parkinson disease is the third most common form of dementia overall. In addition, the presence of dementia limits the usefulness of nearly all forms of treatment for the motor manifestations because adverse effects such as delusions are more frequent. Dementia is often superimposed on a mild degree of cognitive loss that is specific to Parkinson disease. Impairment in mental speed and visuospatial functions are impaired in most patients with Parkinson disease in the absence of dementia. With the onset of dementia, impaired memory, verbal fluency, and language compound these manifestations. New dementia occurs at the rate of 7% per year among patients with Parkinson disease. With increasing age, the cumulative risk of dementia by age 85 may be over 65%, suggesting that dementia is an inevitable consequence of Parkinson disease. Three distinct neuropathologic changes are associated with dementia in Parkinson disease: coincident Alzheimer disease (senile plaques and neurofibrillary tangles), Lewy bodies (in cortical and subcortical structures), and primary nigral degeneration. Dementia associated with Lewy bodies is considered clinically distinct from dementia associated with Parkinson disease and Alzheimer disease. Features include cognitive decline, visual hallucinations, parkinsonism, repeated falls, and sensitivity to neuroleptic medications. A “Lewy body variant” of Alzheimer disease characterized by a greater degree of impairment in attention, verbal fluency, and visuospatial function than typically seen in Alzheimer disease has been described in retrospective postmortem studies. Although criteria for dementia associated with cortical Lewy bodies have been proposed by the Nottingham Group for the Study of Neurodegenerative Diseases, they require the presence of parkinsonism, which is an inconsistent finding. Some patients with cortical Lewy bodies and dementia have no history or clinical evidence of rigidity, tremor, bradykinesia, or postural change. A fluctuating decline in cognitive function, characterized by episodes of confusion and lucid intervals, is believed by some to distinguish between senile dementia of the Lewy body type and Alzheimer disease. Depression, complex visual hallucinations, and delusions are also part of the clinical spectrum. Yet none of these clinical manifestations is specific for any single form of dementia. The first described cases had only Lewy bodies on histologic analysis. Nevertheless, most subsequent cases showed both Lewy bodies and histologic markers of Alzheimer disease. Unique histologic findings include ubiquitin immunostaining in the CA2 subregion of the hippocampal formation. Huntington Disease This disorder is described in Chapter 108. In addition to chorea and other motor manifestations, memory loss and difficulty performing complex or sequential mental activities are seen early in the disease. After several years, chorea, postural instability, and frank dementia are evident, contributing to functional decline. In a mildly impaired patient, metabolic activity is reduced in the striatum and frontoparietal areas bilaterally. With progression, glucose metabolism is reduced at the junction of temporal and occipital regions. The severity of chorea correlates with subcortical metabolic activity, and the severity of dementia is linked to cortical metabolic rates. The pathologic correlates of dementia in Huntington disease have not been established. There is atrophy of the caudate nucleus and putamen with extensive nerve cell loss and astrocytosis. Neurons containing gamma-aminobutyric acid, enkephalin, substance P, and dynorphin are reduced in number, with low brain concentrations of gamma-aminobutyric acid and glutamic acid decarboxylase.

VASCULAR DISEASES Cerebrovascular Disease and Dementia Dementia in association with stroke is the second most frequent cause of dementia overall. As many as 15% to 20% of patients with acute ischemic stroke over age 60 years have dementia at the time of the stroke, and 5% per year become demented thereafter. Risk factors include advancing age, diabetes, history of prior stroke, and the size and location of the stroke. There is a complex interaction between stroke, vascular risk factors, and Alzheimer disease, although the exact nature of this interaction remains unknown. Dementia and intellectual impairment can result from brain injury caused by stroke, either hemorrhagic or ischemic. The manifestations of dementia after stroke include loss of memory and impairment in at least two other cognitive domains: orientation, attention, language-verbal skills, visuospatial abilities, calculation, executive functions, motor control, praxis, abstraction, and judgment. The impairment must be severe enough to impair “functioning in daily living” or “to interfere broadly with the conduct of the patient's customary affairs of life.” Although stroke increases the risk of dementia, the definition of vascular dementia remains unsettled despite numerous attempts at clarification. Dementia after stroke may be predominantly of the mixed type, a combination of Alzheimer disease and stroke, and the etiology is likely to be multifactorial. High blood pressure is associated with both Alzheimer disease and dementia after stroke and can be associated with leukoaraiosis found on brain imaging. Severe leukoaraiosis, cerebral hypoperfusion, fluctuations in systemic blood pressure, hypotension induced by medication or systemic conditions, ischemia, carotid atherosclerosis, and diabetes may each increase the risk of dementia after stroke. Although APOE may influence the risk of Alzheimer disease, its role in dementia after stroke is unsettled. Different clinical subtypes of cerebrovascular dementia are described. A cortical syndrome is generally characterized by repeated atherothrombotic or cardioembolic strokes, obvious focal sensorimotor signs, more severe aphasic disturbance when present, and an abrupt onset of cognitive failure. A subcortical syndrome accompanied by deep white matter lesions is characterized by pseudobulbar signs, isolated pyramidal signs, depression or emotional lability, “frontal” behavior, mildly impaired memory, disorientation, poor response to novelty, restricted field of interest, decreased ability to make associations, difficulty passing from one idea to

another, inattention, and perseveration. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is an autosomal dominant form of cerebrovascular dementia with onset in the third and forth decades of life and has been related to mutations in the notch3 gene on chromosome 19. In patients with multiple deep infarcts resulting in etat lacunaire, pseudobulbar palsy is often a central feature with emotional and urinary incontinence, dysarthria, bilateral pyramidal signs, and gait imbalance with marche a petit pas. Regardless of the clinical syndrome, the survival of patients with cerebrovascular dementia is less than that of other forms of dementia, including Alzheimer disease. Control of hypertension reduces the risk of recurrent cerebral infarction and may secondarily reduce the risk of subsequent dementia. Any effective measure that prevents stroke recurrence could be applied to patients with vascular dementia: antiplatelet therapy, anticoagulants, carotid endarterectomy, and, for most patients, aspirin.

INFECTIOUS DISEASES Prion-related Diseases Dementia related to prion disease is rare. The worldwide incidence of sporadic Creutzfeldt-Jakob disease, the most common prion disease, is 0.5 to 1.5 per million population per year and less than 1 death per million per year. There are no established risk factors for contracting the disease. The transmissible spongiform encephalopathies are a group of disorders characterized by similar histopathology consisting of spongy degeneration, neuronal loss, and astrocytic proliferation. In all prion disorders, an abnormal protease-resistant prion protein accumulates in the brain (see Chapter 33). There are several forms of prion diseases in humans ( Table 106.5): Creutzfeldt-Jakob, Gerstmann-Sträussler-Scheinker, fatal familial insomnia, and Kuru. Prion disorders are inherited, acquired, or sporadic. The familial forms, which include Gerstmann-Sträussler-Scheinker and fatal familial insomnia, and 15% to 20% of patients with Creutzfeldt-Jakob disease are associated with mutations in the prion protein (PrP). The most frequent mutations are at codons 178 and 200, both of which cause an alteration in the folding pattern of the protein to produce a beta-pleated configuration that polymerizes into amyloid fibrils.

TABLE 106.5. PRION-RELATED DEMENTIAS

The most common form is Creutzfeldt-Jakob disease. The diagnosis is usually made in individuals aged 50 to 70 years. A progressive dementia with myoclonus, pyramidal signs, periodic sharp waves on EEG, and cerebellar or extrapyramidal signs suffices for the diagnosis of probable Creutzfeldt-Jakob disease. Progression is subacute, with significant decline noted in weeks or months; most die within 1 year of onset. “Variant Creutzfeldt-Jakob disease” begins before age 40 years and the course is more prolonged than the familial form. These patients are more likely to have psychiatric manifestations, to have paresthesias and sensory loss, and to develop cerebellar ataxia. They usually lack the periodic complexes on EEG and have no genetic mutations. These patients and cows with bovine spongiform encephalopathy share a unique glycosylation pattern of the PrP res protein. Fifteen percent to 20% of persons with Creutzfeldt-Jakob disease have an autosomal dominant inheritance pattern on family history. Point mutations, deletions, or insertions are found in the PRP gene on chromosome 20. In contrast to the sporadic form, these patients typically have a younger age at onset and a more protracted course; they are less likely to have the periodic EEG findings. The Gerstmann-Sträussler-Scheinker disease is a familial form of prion disease with autosomal dominant ataxia, spastic paraplegia, and dementia. Multicentric prion plaques are found in the cerebellar and cerebral hemispheres. Deposition of PrP plaques is most marked in this form of prion disease. At least four distinct mutations in the PrP gene have been found. Fatal familial insomnia is associated with mutations in the PrP gene at codon 178. The average age at onset varies from 20 to 60 years, and the duration is less that 2 years. Severe loss of weight, insomnia, autonomic dysfunction, and motor abnormalities can be present. The brain shows widespread cortical astrogliosis and brainstem degeneration. Deposition of the PrP in the form of plaques is found in the cerebellum and brainstem. Kuru is sporadic prion disease that was associated with cannibalism among natives of New Guinea. The disease disappeared once cannibalism was halted. The CFS in prion disease is typically normal, although the protein level can be mildly elevated. Immunoassays of CSF show the presence of a normal brain protein, “14-3-3.” If recent stroke or viral menigoencephalitis can be ruled out, this assay is highly sensitive and specific for Creutzfeldt-Jakob disease. Early, EEG may be normal or show nonspecific slowing. Later, periodic bi- or triphasic complexes may be evident. With repeated recordings, most patients manifest these EEG findings and myoclonus occurs with the periodic complexes. Typically, neuroimaging studies are normal, but late in the disease generalized atrophy may be detected. Hyperintense signals in the basal ganglia have been described. Human Immunodeficiency Virus Type 1-associated Dementia Complex Human immunodeficiency virus type 1 dementia complex, a frequent sequela of acquired immunodeficiency syndrome is characterized by apathy, memory loss, and cognitive slowing often before there are other neurologic abnormalities. Diagnosis is established by clinical features and laboratory tests. The differential diagnosis includes cerebral toxoplasmosis, cerebral lymphoma, progressive multifocal leukoencephalopathy, neurosyphilis, cytomegalovirus encephalitis, and cryptococcal and tuberculous meningitis. Examination of the CSF and brain imaging are essential to rule out these treatable diseases. Subcortical hypermetabolism on PET characterizes the early stages of the dementia. There is predominantly frontotemporal atrophy; multinucleated giant cells, microglial nodules, and perivascular infiltrates are evident microscopically.

INHERITED METABOLIC DISEASES These disorders rarely cause dementia in adults but are important because some are potentially treatable. Young onset of dementia or involvement of other areas of the nervous system (e.g., cerebellar, visual, peripheral nerve, muscle) and body (e.g., skin, skeletal, and visceral organs) should prompt and guide investigation into these disorders (Table 106.6). Most of these diseases are described elsewhere in this book. Wilson disease, Hallervorden-Spatz disease, and the Fahr syndrome are dementias associated with abnormal metal metabolism. X-linked adrenoleukodystrophy and adrenomyeloneuropathy are due to a defect in the peroxisomal enzyme, lignoceroyl-CoA ligase mapped to the gene Xq28. Dementia is one of several manifestations in late-onset forms of these diseases. Cerebrotendinous xanthomatosis, Kufs disease, and membranous lipodystrophy are disorders of lipid metabolism that can cause dementia in adults. Several mitochondrial disorders are associated with dementia, especially MELAS and MERRF (see Chapter 96).

TABLE 106.6. LABORATORY INVESTIGATIONS OF INHERITED METABOLIC DEMENTIAS

Lysosomal disorders can cause dementia in adults. The most common lysosomal disease with adult-onset dementia is metachromatic leukodystrophy. Other rare lysosomal diseases include mucopolysaccharidosis III (Sanfilippo disease) with alpha- N-acetyl-glucosaminidase deficiency, Gaucher disease with glucocerebrosidase (glucosylceramide-beta-glucosidase) deficiency, Niemann-Pick disease type C with sphingomyelinase deficiency, Fabry disease with alpha-galactosidase deficiency, Krabbe disease (globoid cell leukodystrophy) with galactocerebrosidase deficiency, GM 2 gangliosidosis with hexosaminidase A deficiency, and GM 1 gangliosidosis with beta-galactosidase deficiency. Adult polyglucosan body disease and Lafora disease are disorders of carbohydrate metabolism associated with dementia. Neuronal intranuclear hyaline inclusion disease, an autosomal dominant adult-onset leukodystrophy of unknown origin; Alexander disease; and Mast syndrome are rare causes of dementia. SUGGESTED READINGS American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994:143–147. Backman L, Ahlbom A, Winblad B. Prevalence of Alzheimer's disease and other dementias in an elderly urban population,relationship with age, sex and education. Neurology 1991;41:1886–1892. Baker M, Litvan I, Houlden H, et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 1999;8:711–715. Bales KR, Verina T, Dodel RC, et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet 1997;17:263–264. Beaudry P, Cohen P, Brandel JP, et al. Alpha-2-macroglobulin is genetically associated with Alzheimer disease. Nat Genet 1998;19:357–360. Borchelt DR, Thinakaran G, Eckman CB, et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.

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Nature

CHAPTER 107. HEREDITARY ATAXIAS MERRITT’S NEUROLOGY

SECTION XIV. ATAXIAS CHAPTER 107. HEREDITARY ATAXIAS SUSAN B. BRESSMAN, TIMOTHY LYNCH AND ROGER N. ROSENBERG Classification Early Onset Ataxias Late Onset Ataxias Drpla Episodic or Paroxysmal Ataxias Sporadic Cerebellar Ataxia of Late Onset Congenital and Acquired Cerebellar Ataxias Management of Hereditary Ataxias Suggested Readings

CLASSIFICATION The hereditary ataxias comprise heterogenous disorders that share three features: ataxia, an inherited genetic basis, and pathology involving the cerebellum or its connections. In most of these conditions, the pathology affects more than the cerebellum, especially the posterior columns, pyramidal tracts, pontine nuclei, and basal ganglia, and there are corresponding neurologic signs. Within a family, there may be a broad range of clinical and pathologic features; the heterogeneity has created problems for classification. In 1983 Harding proposed a scheme based on age at onset, mode of inheritance, and specific biochemical abnormality when known. Harding's classification has been widely adopted, especially for autosomal dominant cerebellar ataxia (ADCA) and its three subtypes. In the last decade loci for the ADCA subtypes have been mapped and assigned spinocerebellar ataxia (SCA) numbers (SCA1, 2, 3, etc.). In this chapter we concentrate on genetic causes of ataxia, excluding those due to inborn errors of metabolism, which are discussed in Sections IX and X.

EARLY-ONSET ATAXIAS Friedreich Ataxia (MIM *2293000) Friedreich ataxia (FRDA), described in 1863, is an autosomal recessive disorder and the most common early-onset ataxia. The essential clinical features are juvenile onset (between puberty and age 25) with progressive ataxia of gait and limbs, absent tendon reflexes, and extensor plantar responses. Other common features are dysarthria, corticospinal tract clumsiness, proprioceptive sensory loss in the legs, scoliosis, and cardiopathy. Onset before age 25 and absence of tendon reflexes in the legs separated FRDA from “FRDA-like” syndromes, including late-onset FRDA and other early-onset cerebellar ataxias such as FRDA with retained reflexes. Once the FRDA gene was cloned (see below), it became clear that some FRDA-like syndromes are also the result of FRDA mutations. Epidemiology The prevalence of FRDA in North America and Europe is about 2 per 100,000, with a carrier frequency of about 1:120. Boys and girls are equally affected. Because the disorder is autosomal recessive, parents are asymptomatic, and the rate of consanguinity is high, from 5.6% to 28% in different populations. The risk for siblings to be affected is 25%. In populations with small families, most patients are the only ones affected in the family. Neuropathology The spinal cord may be thinner than normal. Degeneration and sclerosis are seen in the posterior columns, spinocerebellar tracts, and corticospinal tracts. Nerve cells are lost in the dorsal root ganglia and Clarke column. Peripheral nerves are involved, with fewer large myelinated axons. The brainstem, cerebellum, and cerebrum are normal except for mild degenerative changes of the pontine and medullary nuclei, optic tracts, and Purkinje cells in the cerebellum. Cardiac muscle, nerves, and ganglia are also involved. Genetics The gene for FRDA (X25) maps to 9q and codes for a highly conserved protein, frataxin. More than 95% of FRDA patients are homozygous for an expansion of a GAA triplet repeat in the first intron of X25. A few FRDA patients harbor compound heterozygous mutations, with one GAA intronic expansion and a truncating or missense mutation in the other allele. Some, but not all, individuals who are compound heterozygotes have an atypical and milder disease. Normal chromosomes have fewer than 42 triplets, and disease chromosomes have 66 to more than 1,700 repeats. Repeats in normal chromosomes are stable when transmitted from parent to child, but expanded GAA repeats show meiotic instability, usually contracting after paternal transmission and either expanding or contracting with maternal transmission. There is also mitotic instability of the expansion that varies in different tissues, including different brain regions. FRDA is due to a deficiency of frataxin caused by the GAA intronic expansion, which interferes with the transcription of frataxin. As a result of the expansion, one DNA strand has a long segment of purines and the other has pyrimidines; these sequences adopt an abnormal helical structure that inhibits transcription. Larger repeats more profoundly inhibit frataxin transcription and cause earlier onset and more severe symptoms (see below). Expression of the FRDA gene is tissue specific, highest in the sites most affected in FRDA such as heart, liver, skeletal muscle, and pancreas. In the central nervous system, the highest levels are found in the spinal cord, with lower levels in the cerebellum. Frataxin is localized to the inner mitochondrial membranes. Yeast cells deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. Iron deposits and iron-sulfur enzyme deficiencies have also been found in the hearts of FRDA patients. The pathogenesis of FRDA may be mitochondrial dysfunction and free radical toxicity. Clinical Expression and Genotype-Phenotype Correlations Symptoms usually begin between ages 8 and 15 years; it may start in infancy or after age 25, even in the fifth decade. Like other triplicate repeat disorders, there is a correlation between the GAA repeat size and clinical features, particularly age at onset and rate of progression. However, the age at onset correlates with the shorter of the two alleles because FRDA, unlike the other triplicate repeat disorders, is recessive (with expanded repeats in both alleles) and due to loss of frataxin function. The GAA size, however, does not entirely account for the variability in age at onset or clinical progressions; other factors, including somatic mosaicism and other genetic or environmental modifiers, play a role. Ataxia of gait is the most common symptom and is usually the first. The gait disorder may be seen in children who have been walking normally; more commonly, children are slow in learning to walk, the gait is clumsy and awkward, and they are less agile than other children. Within a few years, ataxia appears in the arms and trunk, a combination of cerebellar asynergia and loss of proprioceptive sense. Movements are jerky, awkward, and poorly controlled. Intention tremor, most common in the arms, may affect the trunk (titubation). Frequent repositioning or pseudoathetosis and true generalized chorea may occur. Speech becomes explosive or slurred and finally unintelligible. Limb weakness is common, sometimes leading to paraplegia in flexion. Loss of appreciation of vibration is an early sign. Frequently, position sense is impaired in the legs and later in the arms. Loss of two-point discrimination; partial astereognosis; and impaired appreciation of pain, temperature, or tactile sensation are occasionally seen. Loss of lower limb reflexes and the presence of Babinski signs were once considered necessary for diagnosis; they are characteristic, and almost all patients with typical recessive or sporadic early-onset ataxia with these features have the X25 hyperexpansion. Ocular movements are usually abnormal; fixation instability and square wave jerks are the most common abnormalities. Also frequent are jerky pursuit, ocular

dysmetria, and failure of fixation suppression of the vestibular ocular reflexes. Nystagmus and optic atrophy are each seen in about 25% of patients, but severely reduced visual acuity is rare. Deafness is also rare. Sphincter impairment occasionally occurs when patients are bedridden; dementia and psychosis are unusual, and the condition is not incompatible with a high degree of intellectual development. Skeletal abnormalities are common. Scoliosis or kyphosis, usually in the upper thoracic region, affects more than 75%. Pes cavus and equinovarus deformities occur in more than 50%. Heart disease is found in more than 85%. The electrocardiogram most commonly shows ST segment changes and T-wave inversions. Ventricular hypertrophy, arrhythmia, and murmurs are less common. Congestive heart failure occurs late and may be precipitated by atrial fibrillation. Diabetes mellitus is found in 10% to 20%. With the advent of FRDA testing in large ataxia populations, the spectrum of FRDA is wider than previously thought and includes late onset, retained reflexes, or absence of pyramidal signs. In one study of ataxic individuals thought on clinical grounds not to have FRDA, 10% of those with recessive disease and 5% with sporadic disease had homozygous GAA hyperexpansions. To some extent this variability, especially between families, is explained by the length of the GAA expansion. However, GAA expansion cannot explain all the variation, particularly with repeat sizes above 500. For example, Acadian FRDA patients descend from a single founder and have the typical homozygous hyperexpansion, with no other identified change in the gene. Nevertheless, they have milder symptoms and cardiopathy is rare. Other inherited factors, including possible differences in frataxin regulation, may play a role. Laboratory findings include characteristic electrocardiogram changes and echocardiographic evidence of concentric ventricular hypertrophy or less commonly asymmetric septal hypertrophy. Normal peripheral nerve conduction studies with absent or markedly reduced sensory nerve action potentials distinguish FRDA from Charcot-Marie-Tooth disease. Other common abnormalities are reduced amplitude of visual evoked responses and small or absent somatosensory evoked potentials recorded over the clavicle and delayed dispersed potentials at the sensory cortex. Computed tomography and magnetic resonance imaging (MRI) of the brain are usually normal, but there may be mild cerebellar atrophy. Cervical spinal cord atrophy can often be detected on MRI. The cerebrospinal fluid is normal. The course is progressive; most patients cannot walk 15 years after onset of symptoms, although variability rate of progression varies. The mean age at death is between 40 and 60 and results from infection or cardiac disease. No medical treatment influences the course, and treatment that modulates oxidative stress or directly affects frataxin expression may be expected. Other Early-onset Ataxias Another early-onset recessive ataxia is the Marinesco-Sjögren syndrome characterized by ataxia, bilateral cataracts, mental retardation, and short stature. Other rare autosomal recessive conditions include ataxia with pigmentary retinopathy, ataxia with deafness, and ataxia with hypogonadism. One rare infantile-onset autosomal recessive disorder in Finnish families was mapped to chromosome 10q23. These children develop ataxia, athetosis, and loss of tendon reflexes before age 2. This is followed by hypotonia, optic atrophy, ophthalmoplegia, deafness, and sensory neuropathy. One early-onset ataxia, the Ramsay Hunt syndrome, is etiologically heterogeneous. The syndrome consists of myoclonus and progressive ataxia, which may be produced by several diseases, including MERRF (mitochondrial encephalomyopathy with ragged red fibers) and the autosomal recessive disorderUnverricht-Lundborg disease or progressive myoclonus epi-lepsy type 1, which maps to chromosome 2lq (MIM254800). The gene encodes cystatin B, which acts within cells to block the action of cathepsins, proteases that degrade other cell proteins. The Ramsay Hunt syndrome is most commonly caused by MERRF. Clinical features include ataxia, myoclonus, seizures, myopathy, and hearing loss. Maternal relatives maybe asymptomatic or have partial syndromes, including acharacteristic “horse collar” distribution of lipomas (see Chapter 96). The pathogenesis of another autosomal recessive early-onset ataxia, ataxia telangiectasia (MIM208900), is defective DNA repair. Clinical symptoms and signs vary, but typically there is truncal ataxia in infancy, obvious when the child learns to walk, and motor development is delayed. Growth retardation, delayed sexual development, and mild mental retardation may be seen. Prominent oculomotor abnormalities include difficulty generating saccades, dependence on head thrusts to fixate, ocular dysmetria, and nystagmus. Facial hypomimia, drooling, dysarthria, dystonia, myoclonus, chorea, and peripheral neuropathy may appear around age 10 or in adolescence. Cutaneous telangiectases are characteristic but are not always present and generally do not appear in the first years of life. Telangiectases involve the conjunctivae, face, ears, and flexor creases (Fig. 107.1). Immune dysfunction is typical and includes recurrent respiratory and cutaneous infections, lymphopenia, and decreased concentrations of IgA and IgG. There may be progeria, including premature graying. About 20% of patients develop malignancies, most frequently acute lymphocytic leukemia or lymphoma. The rate of cancer in heterozygote carriers is also increased.

FIG. 107.1. Ataxia telangiectasia. Telangiectases in the bulbar conjunctiva. (Courtesy of Dr. G. Gaull.)

The disease is progressive with a median age at death at about 20 years. The two major causes of death are cancer and pulmonary disease. Rarely, the course is protracted and benign; ataxia telangiectasia may account for progressive ataxia of adult onset. Pathologically, loss of Purkinje cells is seen in the cerebellum with less prominent changes in the granule cell layer, dentate and inferior olivary nuclei, ventral horns, and spinal ganglia. Aside from decreased serum concentrations of IgA and IgG, laboratory abnormalities include cytogenetic abnormalities, abnormal sensitivity to ionizing radiation, and an elevation in alpha-fetoprotein. Cultured cells from ataxia telangiectasia patients show an excess of chromosome breaks and rearrangements, and there is much greater cell death than expected after exposure to ionizing radiation. Almost all ataxia telangiectasia patients show high serum content of alpha-fetoprotein, which is positively correlated with age. A clinical picture consistent with ataxia telangiectasia and an elevated alpha-fetoprotein level suffice to make the diagnosis. The gene maps to chromosome 11 and is named ATM (for “ataxia telangiectasia mutated”) ( Table 107.1). Coding sequence mutations include deletions leading to sequence changes with premature truncation and in-frame deletions. The ATM protein belongs to a family of protein kinases. ATM is a key regulator of multiple signaling cascades that respond to DNA strand breaks induced by damaging agents or by normal processes, such meiotic recombination. The altered responses involve activation of cell checkpoints, DNA repair, and apoptosis. Approximately 1% of the population is heterozygous for ATM; however, population screening for the mutation is difficult because the gene is large and there are many different mutations.

TABLE 107.1. GENETIC ASPECTS OF THE HEREDITARY ATAXIAS

The diagnostic workup of a patient with early-onset ataxia depends on the constellation of clinical features in the family. If FRDA genetic testing is not diagnostic, other causes of sporadic or recessive ataxia need to be considered. Evaluation includes blood lipids, vitamin E, alpha-fetoprotein, lysosomal analysis, very-long-chain fatty acids, lactate and pyruvate, ceruloplasmin, and thyroid function. Abetalipoproteinemia and isolated vitamin E deficiency, in particular, can mimic the spinocerebellar findings of FRDA. If there is no FRDA mutation, the vitamin E level is measured because a treatment may improve or prevent progression of signs. In addition to abetalipoproteinemia and cholestatic liver disease, vitamin E deficiency may be an isolated abnormality, with no lipid malabsorption. This condition, known as isolated vitamin E deficiency or ataxia/vitamin E deficiency (MIM 277460), is autosomal recessive. Clinical features usually mimic FRDA, but late onset in the sixth decade has been reported, and prominent titubation may be more common with isolated vitamin E deficiency. The disease is due to frameshift or missense point mutations in the alpha-tocopherol transfer protein gene, which maps to chromosome 8q13. The result impairs incorporation of alpha-tocopherol into very low density lipoprotein (VLDL), which is needed for the efficient recycling of vitamin E.

LATE-ONSET ATAXIAS In 1893, Marie applied the term hereditary cerebellar ataxia to syndromes that differed from FRDA in later onset of symptoms, autosomal dominant inheritance, hyperactive tendon reflexes, and, frequently, ophthalmoplegia. Classification has been the subject of controversy because nosology was based on pathology, leading to eponyms named for Marie, Menzel, and Holmes, but with poor clinical-pathologic correlation, even within a single family. Harding challenged these confusing pathology-based schemes, lumping ADCA and then dividing them into clinical groups ( Table 107.2). With the mapping and cloning of autosomal dominant ataxia genes, emphasis has shifted to a genetic classification, leading to a numbering system of autosomal spinocerebellar ataxia loci (SCA1, 2, 3,...7). This classification has the advantage of defining causally related groups, but the numerous loci lack a connection to clinical or pathologic features. We try to bridge the clinical-genetic gap, incorporating both the ADCA and SCA classifications.

TABLE 107.2. INHERITED ATAXIAS

Autosomal Dominant Cerebellar Ataxia Type I Many kindreds with ADCA I (SCA1-4, +1SCA8) share clinical features, although clinical differences are still being defined. Symptoms usually begin in the third or fourth decade, but the age at onset varies from childhood to the seventh decade ( Table 107.3). The first and generally most prominent sign is gait ataxia. Sudden falls may come first. Limb ataxia and dysarthria are early symptoms. Hyperreflexia may be present initially, but tendon reflexes may later be depressed and vibration and proprioception may be lost. Eye signs include nystagmus, slow saccades, and abnormal pursuit. Dementia, dystonia, facial fasciculations, and distal wasting may occur. Anticipation and potentiation, earlier onset, and more severe symptoms in succeeding generations are often observed. Most affected individuals are severely disabled 10 to 20 years after symptom onset (Table 107.3).

TABLE 107.3. CLINICAL FEATURES OF THE HEREDITARY ATAXIAS

All cloned ADCA I except SCA8 genes share the same type of mutation, an unstable expansion of a CAG trinucleotide repeat in the protein-coding region of the gene. As in other dominant disorders with trinucleotide expansions (e.g., Huntington disease, dentatorubropallidoluysian atrophy), there is an inverse relation between repeat size and age at onset. Another feature of the trinucleotide expansion in ADCA I is meiotic instability. In a parent窶田hild transmission, the size of the repeat changes. Also, paternal and maternal transmission differ, with a greater tendency for an increase in repeat size in paternally transmitted disease chromosomes. As a result, anticipation is greater in paternally transmitted disease. The CAG expansions all result in an expanded polyglutamine tract, because CAG codes for glutamine. Unlike the FRDA triplet expansion, which causes a disease by inducing a loss of normal function (frataxin deficiency), the dominant SCA triplet expansions cause disease by altering the protein, which acquires a new activity that is toxic to the cell, a toxic gain of functions. The pathogenic mechanism of the polyglutamine proteins is not yet clarified. However, each polyglutamine disorder has distinctive clinical-pathologic features, so some other feature of the protein, in addition to the polyglutamine, must play a role. Possible toxic mechanisms include

nuclear targeting of protein fragments that contain the polyglutamine stretches and the formation of intranuclear filamentous inclusions. SCA1 (MIM 164400) Genetics The first ADCA locus, SCA1, was mapped to the short arm of chromosome 6 in 1974, based on linkage to the human leukocyte antigen. In 1991, highly polymorphic DNA markers flanking the SCA1 gene were identified, and in 1993, the SCA1 mutation was identified. A trinucleotide expansion was specifically sought because of the known anticipation in SCA1 families and the earlier finding of expanded trinucleotide repeats and anticipation in Huntington disease. Abnormal alleles have 40 or more repeats; normal alleles have fewer than 38. Normal alleles differ from abnormal repeats not only in size but also by the presence of one or more CAT repeats. The CAT repeats serve as anchors during replication and prevent slippage, which is presumably the mechanism reasonsible for repeat instability. The protein coded by SCA1 is called ataxin-1, a novel protein of unknown function. It is expressed ubiquitously. Ataxin-1 is located in the nucleus in all cells except Purkinje cells where there is cytoplasmic and nuclear localization. In affected neurons of SCA1 patients and transgenic mice, mutant ataxin-1 aggregates and forms a ubiquitin-positive nuclear inclusion. However, studies in transgenic mice suggest that nuclear localization of mutant ataxin-1 may be necessary for the disease to occur, but nuclear aggregation is not. Epidemiology The prevalence of SCA1 (or any of the other ADCA genetic subtypes) is not known. However, the proportion of ADCA families with SCA1 (as determined by the CAG repeat) in different populations varies widely. In the United States and Germany, the proportion is low (1% to 9%), whereas in Italy and England the number is higher (30% to 35%), and even more so in some regions of Japan. In all series, SCA1 rarely if ever accounts for ataxia in singleton cases or those that seem to be recessive. Clinical and Pathologic Features Typically, SCA1 starts in the fourth decade, but the range of age at onset is 6 to 60 years. Gait ataxia always predominates and is often the first sign, accompanied by hypermetric saccades and nystagmus. Hyperreflexia, Babinski signs, ophthalmoparesis, (particularly upgaze), dysarthria, dysphagia, and sensory loss are common later (Table 107.3). Sphincter symptoms, optic atrophy, dementia, personality change, dystonia (torticollis), chorea, and fasciculations are less common. The pathology includes neuronal loss in the cerebellum, brainstem, spinocerebellar tracts, and dorsal columns with rare involvement of the substantia nigra and basal ganglia. Purkinje cell loss and severe neuronal degeneration in the inferior olive are seen; degeneration is also seen in the cranial nerve nuclei, restiform body, brachium conjunctivum, dorsal and ventral spinocerebellar tracts, posterior columns, and rarely the anterior horn cells. SCA2 (MIM 183090) This autosomal dominant locus was mapped to chromosome 12q23-24 in 1993. It was first localized in ataxic patients originating from the Holguin province of Cuba and descended from an Iberian founder. Subsequently, SCA2 families were found in Italy, Germany, French-Canada, Tunisia, and Japan. In 1996, three independent groups identified the SCA2 gene using different techniques: positional cloning, using antibody for polyglutamine repeats, and the direct identification of repeat and cloning technique. Normal individuals have 14 to 32 CAG repeats (with most containing 22) interrupted by one to three CAAs within the CAG repeat. SCA2 patients have CAG expansions of 35 or more and no CAAs within the repeat. There is an inverse correlation between age at onset and CAG number. When the CAG expansion is large, manifestations are more likely to include dementia, chorea, myoclonus, and dystonia. The function of ataxin-2, the protein encoded by SCA2, is not known but it is localized in the cytoplasm of neurons, especially Purkinje cells. Epidemiology SCA2 is a relatively frequent cause of ADCA (excluding those with retinopathy) worldwide, varying from 10% in German families to 13% to 15% in U.S. families to 37% to 47% in Italian and English families. It is rarely a cause in families with apparent recessive inheritance or in sporadic cases. Clinical and Pathologic Features The disease usually begins in the fourth decade, but onset ranges from early childhood to the seventh decade. The most common clinical features are gait and limb ataxia and dysarthria. Other common features include depressed or absent tendon reflexes (especially in the arms), slow saccades, fasciculations, ophthalmoplegia, and vibratory and position sensory loss. Less common features are action tremor, cramps, staring gaze, dementia, leg hyperreflexia, and chorea. Nystagmus may be present at onset but tends to disappear as slow saccades emerge. Although there is considerable overlap among the different ADCA I subtypes, SCA2 patients are most likely to have slow saccades and hyporeflexia. Many show electrophysiologic evidence of axonal neuropathy, with severe involvement of sensory fibers. The highly variable phenotype occasionally seems to “breed true� in families (e.g., kindreds with dementia and extrapyramidal signs, or with moderate ataxia, facial fasciculations, and prominent eye signs that include lid lag). Pathology, like clinical signs, varies. Usually there is olivopontocerebellar atrophy with severe neuronal loss in the inferior olive, pons, and cerebellum. However, there may also be degeneration of the substantia nigra, dorsal columns, andanterior horn cells. Rarely, degeneration is restricted to the cerebellum. SCA3/Machado-Joseph Disease (MIM 109150 Genetics and Clinical-Genetic Correlation Machado-Joseph disease (MJD) was first described in families of Azorean Portuguese descent. Common signs, regardless of age at onset, include gait and limb ataxia, dysarthria, and progressive ophthalmoplegia. Findings more dependent on age at onset include pyramidal signs, dystonia and rigidity, amyotrophy, facial and lingual fasciculations, and lid retraction with bulging eyes. Four clinical subclasses were proposed: 1. 2. 3. 4.

Adolescent/young adult-onset: rapidly progressive, with spasticity, rigidity, bradykinesia, weakness, dystonia, and ataxia; Mid-adult onset (ages 30 to 50): moderate progression of ataxia; Late adult onset (ages 40 to 70): slower progression of ataxia, prominent peripheral nerve signs, and few extrapyramidal findings; Adult onset: parkinsonism and peripheral neuropathy.

The pathology was considered distinct with primarily spinopontine atrophy and involvement of pontine nuclei, spinocerebellar tracts, Clarke column, anterior horn cells, substantia nigra, and basal ganglia; the inferior olives and cerebellar cortex were spared. With mutation screening, however, it is now evident that the olives and cerebellar cortex may be involved. In addition to families of Portuguese descent, a similar disorder has been described in German, Dutch, African-American, and Japanese families. In 1993, Takiyama and colleagues mapped a gene in several Japanese families to chromosome 14q24.3-32. This locus then was confirmed in MJD families of Azorean descent. In 1994, linkage to the same region was found in French families that were not considered clinically different from SCA1 or 2 and the locus was numbered SCA3. Because these French families were not of Azorean descent and because of several clinical differences (lack of dystonia and facial fasciculation), it was uncertain whether MJD and SCA3 were due to different genes, different mutations in the same gene, or the varying phenotypic expressions of the same mutation in individuals with different ancestry. In 1994, an expanded and unstable CAG repeat was found in the coding region of the MJD gene. Subsequently, all 14q-linked families have been found to have the same unstable CAG repeat within the SCA3/MJD gene, so that SCA3 and MJD are a single genetic disorder with a wide clinical spectrum. As with

the other ADCA genes, there may be intrafamilial genetic modifiers (including differences within the SCA3/MJD gene) that influence the phenotype. Unlike SCA1 and SCA2, there is a wide gap between normal and disease repeat size, with normal ranging from 12 to 41 and disease alleles ranging from 61 to 89. As in all CAG repeat diseases, there is a strong inverse correlation between the length of the repeat and age at onset. Greater instability in paternal meioses seems to be true for SCA3, as in the other ADCA genes. Unlike Huntington disease and other dominant CAG repeat diseases, homozygous SCA3 individuals have early-onset severe disease, suggesting a gene-dosage effect. The SCA3/MJD gene encodes ataxin-3, a protein of unknown function that is not related to ataxin-1 or -2. It is ubiquitously expressed in the cytoplasm of cell bodies and processes. In SCA3/MJD brain there is aberrant nuclear localization and accumulation of ubiquitinated nuclear inclusions. Epidemiology SCA3 is a common cause of ADCA in many but not all populations. In the United States, about 21% of families with ataxia have SCA3; in a study of mixed populations, 41% were SCA3, but this dropped to 17% when Portuguese families were excluded. SCA3 seems to be common in Germany (accounting for 50% of ADCA cases), India, and Japan but rare in Italy and uncommon in England. SCA4 (MIM 600223) This ADCA is based on linkage in a large U.S. family to chromosome 16q. The phenotype consists of late-onset (19 to 59 years) ataxia, prominent sensory axonal neuropathy, normal eye movements in most, and pyramidal tract signs. The gene is not yet identified. The earliest symptom is unsteadiness of gait. Dysarthria is present in 50%, absent ankle jerks in 100%, decreased sensation in 100%, extensor plantar responses in 20%, and saccadic pursuit eye movements in only 15%. Nerve conduction studies indicate an axonal sensory neuropathy. SCA8 This is the most recently identified ADCA; it is based on the cloning of an untranslated CTG expansion as the mutation in eight families. This expansion maps to chromosome 13q, and the mechanism seems similar to that of myotonic dystrophy. There appears to be expansion of the CTG repeat in maternal transmission and deletion in paternal transmission; penetrance is reduced and depends on repeat size. Normal alleles have 16 to 37 repeats and affected alleles have 107 to 127 repeats. Initial clinical features include dysarthria and gait instability. Age at onset averages 39 years (range, 18 to 65). In addition to limb and gait ataxia and dysarthria, the findings include nystagmus, limb spasticity, and diminished vibration sense. The course is slowly progressive, and the most severely affected are not able to walk by the fourth decade. SCA8 is estimated to account for 3% of ADCA families and 6% of those characterized as recessive. Autosomal Dominant Cerebellar Ataxia Type III Harding reserved this ADCA group for families with “pure” cerebellar features, usually of later onset and generally after age 50. It is unclear whether any genetically described families completely fulfill these criteria. Three mapped SCA genes, one cloned, differ from ADCA I in that the clinical picture is dominated by cerebellar features, with other signs contributing little to overall phenotype. Therefore, they are categorized separately from ADCA I. However, the clinical differences between ADCA I and III are not absolute, and an alternate classification may properly include all SCA subtypes without retinopathy under the SCA1 heading. SCA5 (MIM 600224) This locus was mapped to the pericentromeric region of chromosome llq in a kindred descended from the paternal grandparents of President Abraham Lincoln. Symptoms of this relatively benign, slowly progressive, cerebellar syndrome appear at 10 to 68 years, with anticipation ( Table 107.3). All four juvenile-onset patients (10 to 18 years) resulted from maternal transmission rather than the paternal pattern seen in the other SCA syndromes. The juvenile-onset patients showed cerebellar and pyramidal tract signs, as well as bulbar dysfunction. The gene is not yet identified. SCA6 (MIM 183086) Genetics SCA6 was the designation for families excluded from linkage to previously identified loci. In 1996, SCA6 was mapped and the gene identified. The pathogenic mechanism of SCA6 may differ from the others, and mutations in this gene may underlie some sporadic cases. The SCA6 gene maps to chromosome 19p13 and encodes for an alpha IA voltage-dependent calcium channel subunit (CACNA1A, previously named CACNLIA4). Different mutations have distinct phenotypes. The SCA6 symbol is reserved for a phenotype dominated by a late-onset progressive cerebellar syndrome associated with coding sequence CAG repeat expansions; the expansions are smaller than other SCA mutations. SCA6 CAG repeats are 21 to 29 (normal expansions are 4 to 18), in contrast to other SCA repeat expansions that range from 35 to 100 or more. Missense mutations in the same gene are found in familial hemiplegic migraine, and mutations causing premature termination of the coding sequence are found in families with episodic (or paroxysmal) ataxia type 2. As with the other ADCA repeat disorders, there is a correlation between the number of SCA6 repeats and age at onset. However, unlike the other ADCA repeat disorders, the repeat is stable during transmission and anticipation is generally not observed. Like MJD, the phenotype is more severe in homozygous individuals. New mutations underlie some sporadic cases. The molecular basis of disease in SCA6 may differ from the other repeat ataxias. First, the expansion in SCA6 is small; as few as 20 repeats can cause disease. Second, there is clinical overlap between episodic ataxia type 2 and SCA6; some family members with episodic ataxia have progressive ataxia and some SCA6 family members have episodic symptoms. This suggests a related pathogenesis despite the different mutations within CACNA1A. Third, homozygous individuals have a more severe phenotype, suggesting a dose effect. All three findings suggest loss of a normal function or a dominant negative effect in which a heterozygous mutation alters normal function. This contrasts with the “gain” or new toxic function that is intrinsic to the expanded CAG repeat in the SCA1, 2, 3, or 7. Clinical and Pathologic Features The clinical picture of SCA6 is fairly uniform. The average age at onset is about 45 years (range, 20 to 75). The first symptom is usually unsteady gait. Dysarthria, leg cramps, and diplopia can also be early symptoms. Occasionally, patients describe positional vertigo or nausea. Cerebellar signs include gait and limb ataxia (especially leg), cerebellar dysarthria, saccadic pursuit, and dysmetric saccades. Horizontal and downbeat nystagmus (most prominent on lateral gaze) are common eye signs. Noncerebellar signs occur with less frequency and less clinical impact than other SCA disorders but include decreased vibration and position sense, peripheral neuropathy, and impaired upgaze. Long tract signs, parkinsonism, and chorea are rare. Onset of ataxia is occasionally episodic or apoplectic and may resemble episodic ataxia type 2 with attacks of unsteadiness, vertigo, and dysarthria that last for hours; between attacks there are few if any symptoms or signs. The attacks may occur for years before progressive cerebellar signs emerge. The course is slowly progressive, but after 10 to 15 years most affected individuals are no longer able to walk without assistance. MRI shows cerebellar atrophy but little brainstem or cortical atrophy. Pathologically, there is cerebellar atrophy with loss of Purkinje and granule cells and limited involvement of the inferior olives. Epidemiology SCA6 accounts for 2% to 30% of dominantly inherited ataxia, depending on the population. In the United States and Germany, SCA6 accounts for 10% to 15% of ADCA families. It is more common in regions of Japan (30%) and is uncommon in France, where only 1% of ADCA families harbor the mutation. Five percent to 6% of sporadic ataxia patients demonstrate SCA6 expansions. Some are due to new mutations, but it is also likely that some appear sporadic because of the late age at

onset and relatively indolent course. SCA10 In 1999, two independent groups mapped this locus to chromosome 22q; the phenotype is marked by pure cerebellar signs and seizures. Both families are of Mexican ancestry and it is suspected that they descend from a common ancestor. Age at onset ranged from adolescence to 45 years with evidence of anticipation. There was gait and limb ataxia, dysarthria, and nystagmus in all affected individuals. Also, unlike the other SCA syndromes, partial complex and generalized motor seizures occurred in 20% of members of one family and 67% of the other. Autosomal Dominant Cerebellar Ataxia type II SCA7 (MIM 164500) This type was first distinguished from other forms of ADCA in 1937 by the presence of retinal degeneration. The locus was mapped to chromosome 3p in 1995; the gene was cloned in 1997. As with most of the other ADCA genes, SCA7 is due to the expansion of a coding sequence CAG repeat. Normal alleles have 4 to 35 repeats. In affected individuals, the repeat contains 37 to more than 200. Dramatic examples of anticipation, especially with paternal transmission, were described before the gene was cloned and is due to repeat instability, which is greater in SCA7 than any other SCAs. There is a correlation between age at onset and repeat length. The rate of clinical progression and constellation of clinical signs also correlate with repeat size. Ataxin-7 is expressed ubiquitously, is present in the nuclear fraction of lymphoblasts, and contains a nuclear localization signal, suggesting that it may be a transcription factor. SCA7 age at onset ranges from infancy to the seventh decade and averages around 30 years. The clinical course varies with age at onset. A severe infantile form occurs with large expansions (more than 200) that are paternally inherited. These infants have hypotonia, dysphagia, visual loss, cerebellar and cerebral atrophy, and congestive heart failure with cardiac anomalies. This differs from childhood and adult forms that are marked by early visual loss, moderately progressive limb and gait ataxia, dysarthria, ophthalmoparesis (especially upgaze), and Babinski signs and rarely include dementia, peripheral neuropathy, hearing loss, dyskinesias, parkinsonism, or psychosis. In late-onset cases (fourth to sixth decade), ataxia may occur in isolation or it may precede visual symptoms ( Table 107.3). Affected individuals all have abnormal yellow-blue color discrimination (which in the mildest forms may be asymptomatic) and clinically there is often optic disc pallor with granular and atrophic changes in the macula. Pathology Degeneration affects the cerebellum, basis pontis, inferior olive, and retinal ganglion cells. Neuronal intranuclear inclusions containing the expanded polyglutamine tract are found in many brain regions, most frequently in the inferior olive. Epidemiology SCA7 accounts for all or almost all families with both ADCA and retinal degeneration. Among 86 ADCA families of diverse ethnic background, 11.6% of the families were due to SCA7.

DRPLA This condition, first described in 1946, is most common in Japan where it constitutes about 20% of ADCA families. Rare cases have been described in African-Americans, North American whites, and Europeans. The pathology involves the dentate, red nucleus, subthalamic nucleus, and the external globus pallidus; the posterior columns may be involved. The phenotype varies, even within a family, and depends to some extent on the age at onset. Early-onset cases tend to show severe and rapid progression of myoclonus, epilepsy, and cognitive decline (myoclonic epilepsy), whereas late-onset cases display ataxia, chorea, and dementia (resembling Huntington disease) (Table 107.3). Anticipation is evident, and paternal transmission is associated with more severe early-onset disease. One clinical variant, the Haw River syndrome, was described in an African-American family in North Carolina. This variant includes all the above symptoms except for myoclonic seizures, and additional features include basal ganglia calcification, neuroaxonal dystrophy, and demyelination of the central white matter. MRI may show atrophy of the cerebral cortex, cerebellum, and pontomesencephalic tegmentum, with increased signal in white matter of the cerebrum and brainstem. The disorder is due to an expansion of a CAG repeat in the DRPLA gene, which maps to chromosome 12p. There is an inverse relationship between repeat size and age at onset; normal subjects have up to 35 repeats and disease alleles have 49 or more ( Table 107.1). The gene is expressed in all tissues, including brain. The DRPLA gene product, atrophin, is found mainly in neuronal cytoplasm. Ubiquinated intranuclear inclusions are found in neurons and to a lesser extent in glia. The neuronal inclusions are concentrated in the striatum, pontine nuclei, inferior olive, cerebellar cortex, and dentate. Other Unmapped Autosomal Dominant Cerebellar Ataxias The mapped and cloned SCA genes account for most ADCAs, up to 90% in some series. Other loci for ADCA, however, remain to be identified. In several families, all known ADCA loci have been excluded.

EPISODIC OR PAROXYSMAL ATAXIAS Episodes of ataxia can be the first manifestation of metabolic disorders such as multiple carboxylase deficiencies or amino acidurias. However, the term episodic or paroxysmal ataxia is generally applied to a condition in which the major expressions are self-limited episodes of cerebellar dysfunction with little fixed or progressive neurologic dysfunction. Two major clinical-genetic subtypes of this rare condition are described: episodic ataxia with myokymia (EA1/myokymia) and episodic ataxia with nystagmus (EA2/nystagmus). A third type is marked by paroxysmal choreoathetosis with spasticity and episodic ataxia (Table 107.3). In EA1/myokymia, the attacks usually last a few minutes; they are provoked by startle, sudden movement, or change in posture and exercise (especially if the subject is excited or fatigued). Usually, these are one or a few attacks each day, but up to 15 may occur. Onset is in childhood or adolescence; the disorder is not associated with neurologic deterioration, but myokymia appears around the eyes and in the hands. The Achilles tendon may be shortened and there may be a tremor of the hands. The attacks are often heralded by an aura of weightlessness or weakness; an attack comprises ataxia, dysarthria, shaking tremor, and twitching. In some families, acetazolamide reduces the frequency of attacks; phenytoin and other anticonvulsants may reduce myokymia. This disorder is caused by missense point mutations in the potassium voltage-gated channel gene KCNAI on chromosome 12p ( Table 107.1). EA2/nystagmus attacks last longer, usually hours or even days. Attacks are provoked by stress, exercise, fatigue, and alcohol and do not generally occur more than once per day. Age at onset varies from infancy to 40 years. Unlike EA1/myokymia, the cerebellar syndrome may progress with increasing ataxia and dysarthria. Even when there is no progressive cerebellar syndrome, interictal nystagmus is often seen ( Table 107.3). During an attack, associated symptoms include headache, diaphoresis, nausea, vertigo, ataxia, dysarthria, ptosis, and ocular palsy. Acetazolamide is usually effective in reducing attacks. The gene maps to chromosome 19p and encodes a brain-specific alpha 1A voltage-dependent calcium channel subunit (CACNAIA). Different disease-causing point mutations result in premature termination of the coding sequence. CAG repeat expansion is responsible for SCA6. A third form of episodic ataxia associated with spasticity and paroxysmal choreoathetosis maps to lp.

SPORADIC CEREBELLAR ATAXIA OF LATE ONSET Many patients with ataxia beginning after age 40 have noaffected relatives. Some apparent sporadic cases with late-onset ataxia are due to SCA mutations. Compared with ADCA, sporadic cases begin later in life (in the sixth decade), have a more rapid course, and are less likely to have ophthalmoplegia, amyotrophy, retinal degeneration, or optic atrophy. However, many of these patients have parkinsonism and upper motor neuron signs. Some also have autonomic dysfunction and are classified as having multisystem atrophy of the olivopontocerebellar atrophy (OPCA) type; the cause of multi-system atrophy is not known, but a distinct pathologic

finding of multisystem atrophy is the oligodendroglial cytoplasmic inclusion.

CONGENITAL AND ACQUIRED CEREBELLAR ATAXIAS The cerebellum and spinocerebellar tracts are the primary sites involved in several developmental, metabolic, infectious, neoplastic, and vascular disorders ( Table 107.2). Most of these syndromes are discussed elsewhere in this book. Two acquired cerebellar syndromes are common causes of subacute and chronic ataxia in adults, paraneoplastic (see Chapter 153).

MANAGEMENT OF HEREDITARY ATAXIAS No specific treatments influence the course of most hereditary ataxias. Vitamin E replacement can prevent or improve the ataxia of familial isolated vitamin E deficiency. In FRDA, orthopedic procedures are indicated for the relief of foot deformity. In the SCAs, especially MJD/SCA3, levodopa may bring symptomatic relief of rigidity or other parkinsonian features; baclofen or trizanidene may help spasticity. Acetazolamide controls the attacks of the episodic paroxysmal cerebellar ataxias (EA1 and EA2), and phenytoin ameliorates the facial and hand myokymia associated with EA1. Amantadine and buspirone may improve different forms of cerebellar ataxia, but any effect is moderate at best. Genetic counseling should be offered to patients and families with these disorders and should always accompany genetic testing. We can hope for novel specific therapies based on our increasing knowledge of the molecular mechanisms underlying the hereditary ataxias. SUGGESTED READINGS Early-Onset Inherited Ataxias Friedreich Ataxia Ackroyd RS, Finnegan JA, Green SH. Friedreich ataxia: a clinical review with neurophysiological and echocardiographic findings. Arch Dis Child 1984;59:217–221. Campuzano V, Montermini L, Lutz Y, et al. Frataxin is reduced in Fried-reich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 1997;6:1771–1780. Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic triplet repeat expansion. Science 1996;271:1374–1375. Chamberlain S, Shaw S, Rowland S, et al. Mapping of the mutation causing Friedreich's ataxia to human chromosome 9. Nature 1988;334:248–250. Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 1996;335:1222–1224. Friedreich N. Uber Ataxic mit besonderer Berucksichtigung der hereditaren Formen. Virchows Arch Pathol Anat 1863;26:391–419, 433–459, 27:1–26. Harding AE. Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features.

Brain 1981;104:589–620.

Harding AE. Clinical features and classification of inherited ataxias. Adv Neurol 1993;61:1–14. Lamont PJ, Davis MB, Wood NW. Identification and sizing of the GAA trinucleotide repeat expansion of Friedreich's ataxia in 56 patients. Clinical and genetic correlates.

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Montermini L, Richter A, Morgan K, et al. Phenotypic variability in Friedreich ataxia:role of the associated GAA triplet repeat expansion. Ann Neurol 1997;41:675–682. Moseley ML, Benzow KA, Schut LJ, et al. Dominant cerebellar and Fried-reich triplet repeats among 361 ataxia families. Neurology 1998;51:1603–1607. Pandolfo M, Montermini L. Molecular genetics of the hereditary ataxias. Adv Genet 1998;51:31–68. Schols L, Amoiridis G, Przuntek H, et al. Friedreich ataxia: revision of the phenotype according to molecular genetics. Brain 1997;120:2131–2140. Ragno M, De Michele G, Cavalcanti F, et al. Broadened Friedreich ataxia phenotype after gene cloning: minimal GAA expansion causes late-onset spastic ataxia. Neurology 1997;49:1617–1620. Other Early-onset Ataxias Ben Hamida C, Doerflinaer N, Belal S, et al. Localization of Friedreich ataxia phenotype with selective Vitamin E deficiency to chromosome 8q by homozygosity mapping.

Nat Genet 1993;5:195–200.

Gatti RA, Berkel L, Boder E, et al. Localization of an ataxia-telangiectasia gene to chromosome I lq-22-23. Nature 1988;336:577–580. Gotoda T, Arita M, Arai H, et al. Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha tocopheral transfer protein. N Engl J Med 1995;333:1313–1318. Pennacchio LA, Lehesjoki AE, Stone NE, et al. Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPMJ). Science 1996;27:1731–1734. Yokota T, Shicjiri T, Gotoda T, et al. Friedreich-like ataxia with retinitis pigmentosa caused by the His101 Gln mutation of the alpha-tocopherol transfer protein gene. Ann Neurol 1997;41:826–832. Late-Onset Autosomal Dominant Cerebellar Ataxia Banfi S, Servadio A, Chung MY, et al. Identification and characterization of the gene causing type I spinocerebellar ataxia. Nat Genet 1994;7:513–520. Benomar A, Krols L, Stevanin G, et al. The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3pl2-p2l.l. Nat Genet 1995;10:84–88. Benton CS, de Silva R, Rutledge SL, Bohlega S, Ashizawa T, Zoghbi HY. Molecular/clinical studies in SCA 7 define a broad clinical spectrum and infantile phenotype. Neurology 1998;51:1081–1085. Burke JR, Wingfield MS, Lewis KE, et al. The Haw River syndrome: dentatorubropallidoluysian atrophy in an African-American family. Nat Genet 1994;7:521–524. David G, Abbas N, Stevanin G, et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 1997;17:65–70. Davies SW, Turmaine M, Cozens BA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation.

Cell 1997;90:537–548.

Flanigan K, Gardner K, Alderson K, et al. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 1996;59:392–399. Geshwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst S. Spinocerebellar type 6: frequency of the mutation and genotype phenotype correlations. Neurology 1997;49:1247–1251. Geshwind DS, Perlman H, Figueroa CP, Treiman J, Pulst SM. The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia. Am J Hum Genet 1997;60:842–850. Giunti P, Sabbadini M, Sweeney MG, et al. The role of SCA2 trinucleotide repeat expansion in 89 autosomal dominant ataxia families. Brain 1998;121:459–467. Grewel RP, Tayag E, Figueroa KP, et al. Clinical and genetic analysis of a distinct autosomal dominant spinocerebellar ataxia. Neurology 1998;51:1423–1426. Holmberg M, Duyckaerts C, Durr A, et al. Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 1998;7:913–918. Jodice C, Mantuano E, Veneziano L, et al. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA I A gene on chromosome l9p. Hum Mol Genet 1997;11:1973–1978. Johansson J, Forsgren L, Sandgren O, Brice A, Holmgren G, Holmberg M. Expanded CAG repeats in Swedish spinocerebellar ataxia type 7 (SCA7) patients: effect of CAG repeat length on the clinical manifestation. Hum Mol Genet 1998;7:171–176. Koeppen AH. The hereditary ataxias. J Neuropathol Exp Neurol 1998;57:531–543. Koob MD, Moseley ML, Schut LJ, et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia. Nat Genet 1999;4:379–384.

Matsuura T, Achari M, Khajavi M, Bachinski LL, Zoghbi HY, Ashizawa T. Mapping of the gene for a novel spinocerebellar ataxia with pure cerebellar signs and epilepsy. Ann Neurol 1999;45:407–411. Nagafuchi S, Yanagisawa H, Ohsaki E, et al. Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidolysian atrophy (DRPLA). Nat Genet 1994;8:177–182. Nakano K, Dawson D, Spence A. Machado disease: hereditary ataxia in Portuguese immigrants to Massachusetts. Neurology 1972;22:49–59. Paulson HL, Perez MK, Trottier PY, et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 1997;19:333–344. Ranurn LP, Schut LJ, Lundgren JK, Orr HT, Livingston PM. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 1994;8:280–284. Rosenberg RN, Nyhan WL, Bay C, Shore P. Autosomal dominant striatonigral degeneration: a clinical, pathologic and biochemical study of a new genetic disorder. Neurology 1976;26:703–714. Sanpei K, Takano H, Igarashi S, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 1996;14:277–284. Stevanin G, Durr A, David G, et al. Clinical and molecular features of spinocerebellar type 6. Neurology 1997;49:1243–1246. Tuite PJ, Rogaeva EA, St. George-Hyslop PH, Lang AE. Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: confirmation of 14q CAG expansion. Ann Neurol 1995;38:684–687. Woods BT, Schaumburg HH. Nigro-spinodentatal degeneration with nuclear ophthalmoplegia. A unique and partially treated clinico-pathologic entity. J Neurol Sci 1972;17:149–166. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha IA-voltage-dependent calcium channel. Nat Genet 1997;15:62–69. Zu L, Figueroa KP, Grewel R, Pulst SM. Mapping a new autosomal dominant spinocerebellar ataxia to chromosome 22. Am J Hum Genet 1999;64:594–599. Episodic Ataxia Auburger G, Ratzlaff T, Lunkes A, et al. A gene for autosomal dominant paroxysmal choreoathetosis/spasticity (CSE) maps to the vicinity of a potassium gene cluster on chromosome I p. probably within 2 cM between DIS443 and DIS197. Genomics 1996;31:90–94. Baloh RW, Qing Y, Furman JM, Nelson SF. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p.

Ann Neurol 1997;41:8–16.

Baloh RW, Winder A. Acetazolamide-responsive vestibulocerebellar syndrome: clinical and oculographic features. Neurology 1991;41:429–432. Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia-myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA 1. Nat Genet 1994;8:136–140. Brunt EP, Van Weerden TW. Familial paroxysmal ataxia and continuous myokymia. Brain 1990;113:1361–1382. Gancher ST, Nutt JG. Autosomal dominant episodic ataxia: a heterogenous syndrome. Mov Dis 1986;1:239–253. Griggs RC, Moxley RT, Lafrance R-A, McQuillen J. Hereditary paroxysmal ataxia: responsive to acetazolamide. Neurology 1978;28:1259–1264. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type 2 are caused by mutations in the CA 21 channel gene CACNLIA4. Cell 1996;87:543–552. Vahedi K, Joutel A, Van Bogaert P, et al. A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. Ann Neurol 1995;7:289–293. Treatment Trouillas P, Jing X, Adeleine P, et al. Buspirone, a 5-hydroxy-tryptamine 1 A agonist, is active in cerebellar ataxia. Arch Neurol 1997;54:749–752.

CHAPTER 108. HUNTINGTON DISEASE MERRITT’S NEUROLOGY

SECTION XV. MOVEMENT DISORDERS CHAPTER 108. HUNTINGTON DISEASE STANLEY FAHN Pathology Biochemistry Prevalence Genetics Signs and Symptoms Choreic Movements Mental Symptoms Other Neurologic Manifestations Laboratory Data Diagnosis and Differential Diagnosis Treatment Suggested Readings

Huntington disease (HD; MIM 143100) is a progressive hereditary disorder that usually appears in adult life. It is characterized by a movement disorder (usually chorea), dementia, and personality disorder. It was first recognized clinically by Waters in 1842 and became accepted as a clinical entity with the comprehensive description and interpretation of the mode of transmission by George Huntington in 1872.

PATHOLOGY At postmortem examination, the brain is shrunken and atrophic; the caudate nucleus is the most affected structure ( Fig. 108.1). Histologically, the cerebral cortex shows loss of neurons, especially in layer 3. The caudate nucleus and putamen are severely involved, with loss of neurons, particularly the medium-sized spiny neurons, and their GABAergic striatal efferents. Those lost earliest are the efferents (containing GABA and enkephalin) projecting to the lateral globus pallidus, which is thought to account for chorea. With progression of the disease, the striatal efferents projecting to the medial pallidum are lost; their loss is thought to account for the later developing rigidity and dystonia. Dementia is attributed to changes in both the cerebral cortex and deep nuclei (i.e., subcortical dementia).

FIG. 108.1. Brain slices. Top: Huntington disease. Atrophy of caudate nucleus and lentiform nuclei with dilatation of lateral ventricle. Bottom: Normal brain.

Less marked changes occur in other structures, such as the thalamus and brainstem. A reactive gliosis is apparent in all affected areas. In advanced cases, the striatum may be completely devoid of cells and replaced by a gliotic process, at which time choreic movements abate and are replaced by dystonia and an akinetic-rigid state. Progressive striatal atrophy is the basis for staging the severity of the disease. The age at onset is inversely correlated to the severity of striatal degeneration.

BIOCHEMISTRY There is loss of striatal and nigral GABA and its synthesizing enzyme glutamic acid decarboxylase, whereas the cholinergic and somatostatin striatal interneurons are relatively spared. The receptors for dopamine and acetylcholine are decreased in the striatum. N-methyl-D-aspartate receptors are reduced severely in the striatum and cerebral cortex. These defects can be duplicated experimentally in animals by striatal injection of excitotoxins, such as kainic acid, and an excitotoxic hypothesis has been proposed as the pathogenesis of the disease. The neurochemical changes have not yet been translated into effective therapy because trials with GABA and acetylcholine agonists have not been beneficial. A defect in mitochondrial energy metabolism is considered to be present in HD. This in turn can lead to oxidative stress, which has been measured in the vulnerable regions of brain of caudate and putamen.

PREVALENCE HD occurs worldwide and in all ethnic groups, especially whites. The prevalence rate in the United States and Europe ranges from 4 to 8 per 100,000, whereas in Japan the rate is 10% of this figure. The highest incidence rates have been reported from geographically somewhat isolated regions where affected families have resided for many generations (e.g., the Lake Maracaibo region in Venezuela).

GENETICS A major discovery was the identification and characterization of the HD gene near the tip of the short arm of chromosome 4 (4p16.3). Studies on HD families of different ethnic origins and countries found that despite the marked variability in phenotypic expression, there does not seem to be any genetic heterogeneity. The abnormal gene contains extra copies of trinucleotide repeats of CAG (cytosine-adenine-guanine). Normal individuals have 11 to 34 repeats; those with HD have 37 to 86 repeats. This trinucleotide repeat is unstable in gametes; change in the number of repeats is transmitted to the next generation, sometimes with a decrease in number but more often with an increase. Spontaneous mutations occur from expansion of repeats from parents who have repeat lengths of 34 to 38 units, which span the gap between the normal and HD distributions, the so-called intermediate alleles. Spontaneous mutations in HD previously were considered rare, but this concept has changed as more sporadic (simplex) cases are evaluated by DNA analysis. Affected mothers tend to transmit the abnormal gene to offspring in approximately the same number of trinucleotide repeats, plus or minus about three repeats. Affected fathers often transmit a greater increase in the length of trinucleotide repeats to offspring, thus resulting in many more juvenile cases of HD when an individual inherits the gene from the father. The trinucleotide repeat is stable over time in lymphocyte DNA but is unstable in sperm DNA. This characteristic may account for the occasional marked increase in the number of trinucleotide repeats in offspring of affected fathers, leading to a 10:1 ratio of juvenile HD when the affected parent is the father. This is because an inverse correlation exists between the number of trinucleotide repeats and the age at onset of symptoms. Knowing the number of repeats in an at-risk offspring can fairly well predict the age at onset of symptoms. The rate of pathologic degeneration also correlates with the number of repeats. HD is a true autosomal dominant disease in that homozygotes do not differ clinically from heterozygotes. Overexpression of the normal protein could explain why an individual with a double dose of the gene (i.e., the HD gene was transmitted to the offspring by each affected parent) does not differ phenotypically from

heterozygotes with only one abnormal gene. The protein product of the normal gene is called huntingtin. The trinu- cleotide CAG codes for glutamine, and the increase in polyglutamine appears to prevent the normal turnover of the protein, resulting in aggregation of the protein with accumulation in the cytoplasm and the nucleus. Other genetic disorders with expanded trinucleotide repeats of CAG include the Kennedy syndrome (X-linked spinal and bulbar muscular atrophy), myotonic dystrophy, many of the spinocerebellar atrophies, and dentatorubral-pallidoluysian atrophy. A similar pathogenesis for these disorders has been proposed. One-third of individuals with HD share a common haplotype, thus implying a common ancestor. The other two-thirds appear to derive HD through a spontaneous mutation in the distant or near past. For the time being, without directly testing for the gene, lack of a positive family history raises questions of paternity or misdiagnosis. A diagnosis of HD can be established by testing for the gene in patients with adult-onset chorea without a clear positive family history. Preclinical and prenatal testing can also be carried out, but appropriate genetic counseling is required. Diagnosis is still uncertain in those with a borderline number of trinucleotide repeats (i.e., between 34 and 37); for them, the diagnosis is “inconclusive.” Disclosure of positive results of the HD gene in asymptomatic individuals often leads to transient symptoms of depression, but suicidal ideation has been rare. Because of the ethical and legal implications that arise with DNA identification of a gene carrier, predictive testing must be performed by a team of clinicians and geneticists who not only are knowledgeable about the disease and the genetic techniques but also are sensitive to the psychosocial issues and counseling that precede and follow testing.

SIGNS AND SYMPTOMS Symptoms usually appear between 35 and 40 years of age. The range of age at onset is broad, however, with cases recorded as early as age 5 and as late as age 70. The three characteristic manifestations of the disease are movement disorder, personality disorder, and mental deterioration. The three may occur together at onset or one may precede the others by a period of years. In general, the onset of symptoms is insidious, beginning with clumsiness, dropping of objects, fidgetiness, irritability, slovenliness, and neglect of duties, progressing to frank choreic movements and dementia. Overt psychotic episodes, depression, and irresponsible behavior may occur. The disease tends to run its course over a period of 15 years, more rapidly in those with an earlier age at onset.

CHOREIC MOVEMENTS The most striking and diagnostic feature of the disease is the appearance of involuntary movements that seem purposeless and abrupt but less rapid and lightning-like than those seen in myoclonus. The somatic muscles are affected in a random manner, and choreic movements flow from one part of the body to another. Proximal, distal, and axial muscles are involved. In the early stages and in the less severe form, there is slight grimacing of the face, intermittent movements of the eyebrows and forehead, shrugging of the shoulders, and jerking movements of the limbs. Pseudopurposeful movements ( parakinesia) are common in attempts to mask the involuntary jerking. As the disease progresses, walking is associated with more intense arm and leg movements, which cause a dancing, prancing, stuttering type of gait, an abnormality that is particularly characteristic of HD. Motor impersistence or inhibitory pauses during voluntary contraction probably account for “milkmaid grips,” dropping of objects, and inability to keep the tongue steadily protruded. Ocular movements become impaired with reduced saccades and loss of smooth pursuit. The choreic movements are increased by emotional stimuli, disappear during sleep, and become superimposed on voluntary movements to the point that they make volitional activity difficult. With increased severity, the routine daily activities of living become difficult, as do speech and swallowing. Terminally, choreic movements may disappear and be replaced by muscular rigidity and dystonia.

MENTAL SYMPTOMS Characteristically, there is an organic dementia with progressive impairment of memory, loss of intellectual capacity, apathy, and inattention to personal hygiene. Early in the disease, less profound abnormalities consist of irritability, impulsive behavior, and bouts of depression or fits of violence; these are not infrequent. In some patients, frank psychotic features that are schizophrenic predominate, and the underlying cause is not evident until choreic movements develop. The dementing and psychotic features of the disease usually lead to commitment to a mental institution.

OTHER NEUROLOGIC MANIFESTATIONS Cranial nerves remain intact except for rapid eye movements, which are impaired in a large percentage of patients. Patients often blink during the execution of a saccadic eye movement. Sensation is usually unaffected. Tendon reflexes are usually normal but may be hyperactive; the plantar responses may be abnormal. Muscle tone is hypotonic in most patients except for those with the so-called akinetic-rigid variety ( Westphal variant). With childhood onset (approximately 10% of cases), the akinetic-rigid state usually occurs instead of chorea and in conjunction with mental abnormalities and convulsive seizures. This form of the disease is rapidly progressive with a fatal outcome in less than 10 years. The observation that 90% of all patients with childhood onset inherit the disease from their father stems from the greater likelihood of a large increase in the number of CAG repeats in sperm cells. In the terminal stages of the more classic form of HD, muscular rigidity and dystonia tend to replace chorea, and seizures are not unusual.

LABORATORY DATA Routine studies of blood, urine, and cerebrospinal fluid show no abnormalities. Diffuse abnormalities are seen in the electroencephalogram. Radiographs of the skull are normal, but computed tomography and magnetic resonance imaging show enlarged ventricles with characteristic butterfly appearance of the lateral ventricles, a result of degeneration of the caudate nucleus ( Fig. 108.2). Patients with the akinetic-rigid form of HD are likely to show striatal hyperintensity on T2-weighted magnetic resonance imaging. Positron emission tomography using fluorodeoxyglucose has shown hypometabolism in the caudate and the putamen in affected patients. Abnormalities in striatal metabolism may precede caudate atrophy, but positron emission tomography is not sufficiently sensitive to detect the disease in presymptomatic persons.

FIG. 108.2. T1-weighted magnetic resonance imaging of Huntington disease brain showing ventricular enlargement with atrophy of the head of the caudate nucleus.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS HD can be diagnosed without difficulty in an adult with the clinical triad of chorea, dementia, and personality disorder and family history of the disease. Difficulties arise when the family history is lacking. The patient may be ignorant of the family history or may deny that history. Other conditions in which choreic movements are a major manifestation can often be excluded on clinical grounds. The most common other adult-onset choreic disorder is neuroacanthocytosis. It is manifested by mild chorea, tics, tongue biting, peripheral neuropathy, feeding dystonia, increased serum creatine kinase, and

red cell acanthocytes. It is also common for these patients to have had a few seizures. Dentatorubral-pallidoluysian atrophy can also mimic HD. Besides chorea, it can present with myoclonus, ataxia, seizures, and dementia. Differentiation is by gene testing. Sydenham chorea has an earlier age at onset, is self-limited, and lacks the characteristic mental disturbances. Chorea and mental disturbances occurring as manifestations of lupus erythematosus are usually more acute in onset, the chorea is more localized and often periodic, and there are characteristic serologic and clinical abnormalities. Involuntary movements occurring in psychiatric patients on long-term treatment with neuroleptic agents (the so-called tardive dyskinesia) occasionally pose a diagnostic problem. Such movements, however, are usually repetitive (stereotypy), in contrast to the nonrepetitive and random nature of chorea. Oral-lingual-buccal dyskinesia is the most common feature of tardive dyskinesia. Gait is usually normal in tardive dyskinesia and is abnormal in HD (see Table 116.1 for more distinguishing differences). The presenile dementias (Alzheimer and Pick diseases) are similar in the mental disorder, but language is more often involved; aphasic abnormalities are not seen early in HD. Myoclonus, rather than chorea, occasionally occurs. The peculiarities of the childhood disorder with rigidity, convulsive seizures, and mental retardation require differentiation from other heritable disorders, such as the leukodystrophies and gangliosidosis. Tics, particularly those of the Gilles de la Tourette syndrome, usually pose little problem in view of the complex nature of the involuntary movements, the characteristic vocalizations, and their suppressibility. Hereditary nonprogressive chorea begins in childhood, does not worsen, and is not associated with dementia or with personality disorder.

TREATMENT There is at present no known means of altering the disease process or the fatal outcome. Attempts to replace the deficiency in GABA by using GABA-mimetic agents or inhibitors of GABA metabolism have been unsuccessful. Symptomatic treatment of depression and psychosis can be achieved with antidepressants and typical or atypical (i.e., clozapine and quetiapine) antipsychotic agents. The choreic movements can be controlled by the use of neuroleptic agents, including dopamine receptor blockers, such as haloperidol and perphenazine, and presynaptic dopamine depleters, such as reserpine and tetrabenazine. Using these drugs combined with supervision of the patient's daily activities allows management at home during the early stages of the disorder. As the disease advances, however, confinement to a psychiatric facility is often necessary. SUGGESTED READINGS Albin RL, Reiner A, Anderson KD, et al. Striatal and nigral neuron subpopulations in rigid Huntington's disease: implications for the functional anatomy of chorea and rigidity-akinesia. Ann Neurol 1990;27:357–365. Alford RL, Ashizawa T, Jankovic J, Caskey CT, Richards CS. Molecular detection of new mutations, resolution of ambiguous results and complex genetic counseling issues in Huntington disease. Am J Med Genet 1996;66:281–286. Bamford KA, Caine ED, Kido DK, Cox C, Shoulson I. A prospective evaluation of cognitive decline in early Huntington's disease: functional and radiographic correlates. Neurology 1995;45:1867–1873. Brandt J, Bylsma FW, Gross R, Stine OC, Ranen N, Ross CA. Trinucleotide repeat length and clinical progression in Huntington's disease. Neurology 1996;46:527–531. Brinkman RR, Mezei MM, Theilmann J, Almqvist E, Hayden MR. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. 1997;60:1202–1210.

Am J Hum Genet

Browne SE, Bowling AC, MacGarvey U, et al. Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. Ann Neurol 1997;41:646–653. Davies SW, Beardsall K, Turmaine M, DiFiglia M, Aronin N, Bates GP. Are neuronal intranuclear inclusions the common neuropathology of triple-repeat disorders with polyglutamine-repeat expansions? Lancet 1998;351:131–133. Duyao M, Ambrose C, Myers R, et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet 1993;4:387–392. Feigin A, Kieburtz K, Bordwell K, et al. Functional decline in Huntington's disease. Mov Disord 1995;10:211–214. Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72:971–983. Myers RH, MacDonald ME, Koroshetz WJ, et al. De novo expansion of a (CAG)(n) repeat in sporadic Huntington's disease. Nat Genet 1993;5:168–173. Myers RH, Vonsattel JP, Stevens TJ, et al. Clinical and neuropathologic assessment of severity in Huntington's disease. Neurology 1988;38:341–347. Penney JB, Vonsattel JP, MacDonald ME, Gusella JF, Myers RH. CAG repeat number governs the development rate of pathology in Huntington's disease. Ann Neurol 1997;41:689–692. Penney JB, Young AB, Shoulson I, et al. Huntington's disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals. Mov Disord 1990;5:93–99. Thompson PD, Berardelli A, Rothwell JC, et al. The coexistence of bradykinesia and chorea in Huntington's disease and its implications for the theories of basal ganglia control of movement. Brain 1988;111:223–244.

CHAPTER 109. SYDENHAM AND OTHER FORMS OF CHOREA MERRITT’S NEUROLOGY

CHAPTER 109. SYDENHAM AND OTHER FORMS OF CHOREA STANLEY FAHN Sydenham Chorea Other Immune Choreas Vascular Chorea and Ballism Neuroacanthocytosis Dentatorubral-Pallidoluysian Atrophy Hereditary Nonprogressive Chorea (Mim 118700) Senile Chorea Suggested Readings

Choreic movements can be associated with many disorders; the most common are listed in Table 109.1.

TABLE 109.1. COMMON CAUSES OF CHOREA

SYDENHAM CHOREA In 1686, Thomas Sydenham described the chorea now known by his name but originally called St. Vitus dance. His description was of children with a halting gait and jerky movements. Sydenham chorea (acute chorea, St. Vitus dance, chorea minor, rheumatic chorea) is a disease of childhood characterized by rapid, irregular, aimless, involuntary movements of the muscles of the limbs, face, and trunk that resemble continuous restlessness. There is also muscular weakness, hypotonia, and emotional lability. Once fairly common, it now is encountered infrequently in developed countries. The course is self-limited and fatalities are rare except as a result of cardiac complications. Etiology and Pathology Sydenham chorea is considered an autoimmune disorder, a consequence of infection with group A beta-hemolytic streptococcus. Chorea may be delayed for 6 months or longer after the infection. The incidence of Sydenham chorea had fallen dramatically with the introduction of antibiotics and with better sanitary conditions. The streptococcus is thought to induce antibodies that cross-react with neuronal cytoplasmic antigens of caudate and subthalamic nuclei, which apparently account for the symptoms characteristic of rheumatic chorea. These antineuronal antibodies are found in nearly all patients with Sydenham chorea. Antibodies to cardiolipin, which have been found in chorea associated with lupus erythematosus, have not been found in Sydenham chorea. Pathologic studies are rare in this nonfatal disease. Postmortem changes in fatal cases can be attributed to embolic phenomena and terminal changes. A mild degree of inflammatory reaction has been found in a few patients. Knowledge of the etiology and immunology of Sydenham chorea has spawned the concept of other pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. This diagnostic appellation is being applied to children or adolescents who develop tic disorders or obsessive-compulsive disorder after group A beta-hemolytic streptococcal infections. Incidence Acute chorea is almost exclusively a disease of childhood; over 80% of the cases occur in patients between the ages of 5 and 15. Onset before the age of 5 is rare, and the occurrence of the first attack after the age of 15 is uncommon, except during pregnancy or the use of oral contraceptives in the late teens and early twenties. All races are affected. Girls are affected more than twice as frequently as boys. The disease occurs at all times of the year but is less common in summer. Symptoms and Signs In addition to the choreic movements and accompanying motor impersistence, Sydenham chorea is associated with irritability, emotional lability, obsessive-compulsive symptoms, attention deficit, and anxiety. Neurologic manifestations other than chorea are speech impairment and, more rarely, encephalopathy, reflex changes, weakness, gait disturbance, headache, seizures, and cranial neuropathy. Chorea is generalized in about 80% and unilateral in 20% of cases. The clinical features of the chorea in Sydenham chorea differ from those of Huntington chorea. In Sydenham chorea, the movements are usually more flowing, with a restless-appearing quality. In Huntington chorea, the movements tend to be more individualistic and jerky and become more flowing when the chorea worsens. Physiologic recordings in Sydenham chorea reveal the bursts of electromyographic activity to last more than 100 ms and to occur asynchronously in antagonistic muscles. These findings are in contrast to Huntington chorea, in which more frequent bursts of 10 to 30 ms and 50 to 100 ms occur. Complications Other manifestations of the rheumatic infection may occur during the course of the chorea or may precede or follow it. Cardiac complications, usually endocarditis, occur in approximately 20% of patients. Myocarditis and pericarditis are less common. Vegetative endocarditis and embolic phenomena may occur but are rare. A previous history of rheumatic polyarthritis is common, but involvement of the joints during the course of the chorea is rare. Other infrequent complications include subcutaneous rheumatic nodules, erythema nodosum, and purpura. Persistent mental and behavioral effects can also result from Sydenham chorea. Diagnosis The diagnosis is made without difficulty from the appearance of the characteristic choreic movements in a child. Helpful for diagnosis are the presence of behavioral changes and diffuse slowing on the electroencephalogram. Often, a history of prior streptococcal infection is not elicited, and tests for rheumatoid factor, antinuclear antibodies, antistreptolysin titers, and cerebrospinal fluid oligoclonal bands are often negative. Cerebrospinal fluid is usually normal, but pleocytosis has been reported in a few cases. Magnetic resonance imaging is usually normal except for selective enlargement of the caudate, putamen, and globus pallidus. In contrast to many other types of choreic disorders, positron emission tomography (PET) in Sydenham chorea reveals striatal hypermetabolism that returns to normal when the

symptoms abate. Some other causes of symptomatic chorea in childhood are presented in Table 109.2; some are reviewed here. The withdrawal emergent syndrome, occurring in children when neuroleptic agents are suddenly discontinued, closely resembles the type of chorea seen in Sydenham, but a history of having taken these drugs should enable this diagnosis to be made.

TABLE 109.2. OTHER CAUSES OF SYMPTOMATIC CHOREA IN CHILDHOOD

Other dyskinesias in childhood also could present a problem in differential diagnosis, but the distinctions between these and choreic movements should lead to the correct diagnosis. Tics may offer some difficulty, but these movements are stereotyped and localized always to the same muscle or groups of muscles. Idiopathic torsion dystonia often begins in childhood, but the sustained and twisting movements are quite distinct from choreic movements. On the other hand, some dystonic movements are more rapid, but repetitive and twisting, and could be mistaken for chorea. Dystonic movements affect the same body parts repetitiously, so-called patterning, in contrast to chorea. Also, childhood dystonia persists and does not have the self-limiting characteristic of Sydenham chorea. Essential hereditary myoclonus can begin in childhood and sometimes could be difficult to distinguish from chorea. Athetosis in childhood often is seen with static encephalopathy or some metabolic diseases and usually occurs in the first few years of life, not at the ages commonly encountered with Sydenham chorea. Course and Prognosis Sydenham chorea often is a benign disease, and complete recovery is the rule in uncomplicated cases. The mortality rate of approximately 2% is due to associated cardiac complications. The duration of the symptoms is quite variable. In the average case, they persist for 3 to 6 weeks. Occasionally, the course may be prolonged for several months, and it is not unusual for involuntary movements of a mild degree to persist for many months after recrudescence of the more severe movements. Recurrences after months or several years are reported in approximately 35% of the cases. A rare patient may have persistent chorea throughout life. Residual behavioral and electroencephalographic changes are not uncommon in Sydenham chorea. Susceptibility to chorea gravidarum, chorea from oral contraceptives and topical vaginal creams containing estrogen, and even increased sensitivity to levodopa-induced chorea are sequelae of Sydenham chorea. The end of pregnancy and the discontinuation of oral contraceptives or estrogen provide relief from the involuntary movements. A postmortem examination of a case of chorea gravidarum revealed neuronal loss and astrocytosis in the striatum. Treatment There is no specific treatment for the disease. Symptomatic therapy may be of great value in the control of the movements. In the mild form, bedrest during the period of active movements is sufficient. The room should be quiet, and all external stimuli should be reduced to a minimum. When the severity of the movements interferes with proper rest, sedatives in the form of barbiturates, chloral hydrate, or paraldehyde may be needed. If further treatment is necessary, a benzodiazepine, valproate, or corticosteroids may be effective. Although antidopaminergic drugs can suppress choreic movements, a dopamine-receptor blocking agent, such as a phenothiazine, should not be administered because of its potential to produce tardive dyskinesia or tardive dystonia. A dopamine-depleting drug (e.g., reserpine) could be used if milder drugs are ineffective. Prophylactic administration of penicillin for at least 10 years is recommended to prevent other manifestations of rheumatic fever, of which Sydenham chorea may be its sole manifestation.

OTHER IMMUNE CHOREAS Chorea in systemic lupus erythematosus (SLE) has been associated with the presence of antiphospholipid antibodies (lupus anticoagulant), a heterogeneous group of antibodies that can cause platelet dysfunction and result in thrombosis. Chorea is intermittent in SLE. PET has not found caudate hypometabolism in SLE in contrast to many other choreas. Treatment with antidopaminergic agents has been successful. The primary antiphospholipid antibody syndrome also causes chorea, particularly in young women. Systemically, patients have migraine, spontaneous abortions, venous and arterial thromboses, thickened cardiac valves, livedo reticularis, and Raynaud phenomenon. The central nervous system is involved with strokes, multiinfarct dementia, and chorea. Activated partial thromboplastin time is prolonged because of the presence of lupus anticoagulant, and high titers of anticardiolipin antibodies exist. Anticoagulation, immunosuppressive drugs, and plasmapheresis have had variable success; it is difficult to interpret the effectiveness of therapeutic interventions because spontaneous remission occurs frequently. Striatal hypermetabolism is seen in PET.

VASCULAR CHOREA AND BALLISM Choreic movements confined to the arm and leg on one side of the body (hemichorea, hemiballism) may develop abruptly in middle-aged or elderly patients. Ballistic movements are a more violent form of chorea and are characterized by large amplitude uncoordinated activity of the proximal appendicular muscles, so vigorous that the limbs are forcefully and aimlessly thrown about. Padding of the limbs is necessary to prevent injury. The movements are present at rest and may be suppressed during voluntary limb movement. The sudden onset suggests a vascular basis; indeed, it may be preceded by hemiplegia or hemiparesis. In such instances, the choreic or ballistic movements appear when return of motor function occurs. This type of movement disorder is the result of a destructive lesion of the contralateral subthalamic nucleus or its connections. It has also been seen with scattered encephalomalacic lesions involving the internal capsule and basal ganglia. Vascular lesions, hemorrhagic or occlusive in nature, are the most common cause, but hemiballism has been found in association with tumors and plaques from multiple sclerosis in the subthalamic nucleus and has occasionally followed attempted thalamotomy when the target was missed. In general, the movements tend to diminish over time, but they may be persistent and require therapeutic intervention. The agents noted previously for the control of choreic movements in general have proved effective. Chorea-ballism is a common feature of hyperosmolar hyperglycemic nonketotic syndrome, which appears related to hypoperfusion in the striatum (see Chapter 51). Choreoathetosis as a sequela to surgery for congenital heart disease appears to be associated with prolonged time on pump, deep hypothermia, and circulatory arrest. In most cases of postpump syndrome, the chorea persists, and fewer than 25% improve with antidopaminergic therapy.

NEUROACANTHOCYTOSIS Perhaps the most common hereditary chorea after Huntington disease is neuroacanthocytosis (MIM 100500), formerly called chorea-acanthocytosis, which is also described in Chapter 91. The chorea is typically less severe than that seen with Huntington disease but occasionally can be just as severe. In addition to chorea, patients with neuroacanthocytosis usually have tics, occasional seizures, amyotrophy, absent tendon reflexes, high serum creatine kinase, feeding dystonia (tongue pushes food out of the mouth), and self-mutilation with lip and tongue biting. Age at onset is typically in adolescence and young adulthood, but the range is wide (8 to 62 years). Like Huntington disease, a young age at onset is more likely to produce parkinsonism or dystonia rather than chorea. The diagnosis depends on finding more than 15% spiky erythrocytes (acanthocytes) in blood smears. Some authorities have proposed that detection of acanthocytes can be enhanced if a wet smear of blood is diluted 1:1 with normal saline. The cerebral pathology is similar to that of Huntington disease, with striatal degeneration causing caudate atrophy and hypometabolism in the caudate nucleus in the PET. PET also reveals reduced fluorodopa uptake and decreased dopamine receptor binding in the striatum. Erythrocyte membrane lipids are altered. Tightly bound palmitic acid (C16:0) is increased, and stearic acid (C18:0) is decreased. Choline acetyltransferase and glutamic acid decarboxylase are normal in basal ganglia and cortex, substance P levels are low in the substantia nigra and striatum, and norepinephrine is elevated in the putamen and pallidum. Both autosomal dominant and recessive transmission have been proposed for this condition, and the exact genetic mechanism is not known; recently, linkage in 11 families has been found on chromosome 9q21. A rare patient may have the McLeod phenotype, an X-linked (Xp21) form of acanthocytosis associated with chorea, seizures, neuropathy, liver disease, hemolysis, and elevated creatine kinase.

DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY Once thought to be found mainly in the Japanese population, this autosomal dominant disorder is now known to be more widespread thanks to discovery of an expanded CAG repeat on a gene on chromosome 12p12. Dentatorubral-pallidoluysian atrophy clinically overlaps with Huntington disease and manifests combinations of chorea, myoclonus, seizures, ataxia, and dementia. The phenotype varies according to repeat length, and anticipation and excess of paternal inheritance in younger onset cases with longer repeat lengths are seen. The neuropathologic spectrum is centered around the cerebellifugal and pallidofugal systems, but neurodegenerative changes can be found in many nuclei.

HEREDITARY NONPROGRESSIVE CHOREA (MIM 118700) This rare disorder is not associated with dementia or other neurologic problems aside from chorea, which is nonprogressive and usually lessens in severity over time. It follows an autosomal dominant transmission pattern and usually begins in childhood. The glucose PET shows striatal hypometabolism. In the absence of a family history, a benign nonprogressive chorea without other neurologic features can be rarely encountered, so-called essential chorea.

SENILE CHOREA Senile chorea is characterized by the presence of late-onset generalized chorea with no family history and no dementia. As a rule, the movements begin insidiously, are mild, and usually involve the limbs. More complex movements of the lingual-facial-buccal regions, however, are on occasion encountered. Slow progression in the intensity and extent of the movements may occur. With molecular genetic testing, half the patients show the CAG expansion in the HD gene. Most other cases have been shown to have other diagnoses, such as the antiphospholipid antibody syndrome, hypocalcemia, tardive dyskinesia, and basal ganglia calcification. Still, a rare patient can remain undiagnosed despite extensive investigation and is left with the diagnosis of senile chorea. In such a case, pathologic changes are found in the caudate nucleus and putamen but not to the degree seen in Huntington disease. Significantly, degenerative changes in the cerebral cortex are absent. In general, the symptoms are mild and there is little need to resort to therapeutic measures. In those instances in which oral–facial and neck muscle involvement occurs, however, drugs used to control chorea as indicated previously may prove useful. SUGGESTED READINGS Aron AM, Freeman JM, Carter S. The natural history of Sydenham's chorea. Am J Med 1965;38:83–95. Cardoso F, Eduardo C, Silva AP, Mota CCC. Chorea in fifty consecutive patients with rheumatic fever. Mov Disord 1997;12:701–703. Emery ES, Vieco PT. Sydenham chorea: Magnetic resonance imaging reveals permanent basal ganglia injury. Neurology 1997;48:531–533. Garvey MA, Giedd J, Swedo SE. PANDAS: The search for environmental triggers of pediatric neuropsychiatric disorders. Lessons from rheumatic fever. J Child Neurol 1998;13:413–423. Gibb WRG, Lees AJ, Scadding JW. Persistent rheumatic chorea. Neurology 1985;35:101–102. Giedd JN, Rapoport JL, Kruesi MJP, et al. Sydenham's chorea: magnetic resonance imaging of the basal ganglia. Neurology 1995;45:2199–2202. Gledhill RF, Thompson PD. Standard neurodiagnostic tests in Sydenham chorea. J Neurol Neurosurg Psychiatry 1990;53:534–535. Goldman S, Amrom D, Szliwowski HB, et al. Reversible striatal hypermetabolism in a case of Sydenham's chorea. Mov Disord 1993;8:355–358. Hallett M, Kaufman C. Physiological observations in Sydenham's chorea. J Neurol Neurosurg Psychiatry 1981;44:829–832. Husby G, Vande Rijn I, Zabriskie JB, et al. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med 1976;144:1094–1110. Ichikawa K, Kim RC, Givelber H, Collins GH. Chorea gravidarum. Report of a fatal case with neuropathological observations. Arch Neurol 1980;37:429–432. Weindl A, Kuwert T, Leenders KL, et al. Increased striatal glucose consumption in Sydenham's chorea. Mov Disord 1993;8:437–444. Other Immune Choreas Cervera R, Asherson RA, Font J, et al. Chorea in the antiphospholipid syndrome: clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature. (Baltimore) 1997;76:203–212.

Medicine

Furie R, Ishikawa T, Dhawan V, Eidelberg D. Alternating hemichorea in primary antiphospholipid syndrome: evidence for contralateral striatal hypermetabolism. Neurology 1994;44:2197–2199. Vascular Chorea-Ballism Holden KR, Sessions JC, Cure J, Whitcomb DS, Sade RM. Neurologic outcomes in children with postpump choreoathetosis. J Pediatr 1998;132:162–164. Lai PH, Tien RD, Chang MH, et al. Choreaballismus with nonketotic hyperglycemia in primary diabetes mellitus. Am J Neuroradiol 1996;17:1057–1064. Vidakovic A, Dragasevic N, Kostic VS. Hemiballism: report of 25 cases. J Neurol Neurosurg Psychiatry 1994;57:945–949. Neuroacanthocytosis Hardie RJ, Pullon HWH, Harding AE, et al. Neuroacanthocytosis—a clinical, haematological and pathological study of 19 cases. Brain 1991;114:13–49. Rubio JP, Danek A, Stone C, et al. Chorea acanthocytosis: genetic linkage to chromosome 9q21. Am J Hum Genet 1997;61:899–908. Sakai T, Antoku Y, Iwashita H, et al. Chorea-acanthocytosis: abnormal composition of covalently bound fatty acids of erythrocyte membrane proteins. Ann Neurol 1991;29:664–669. Tanaka M, Hirai S, Kondo S, et al. Cerebral hypoperfusion and hypometabolism with altered striatal signal intensity in chorea-acanthocytosis: a combined PET and MRI study. Mov Disord

1998;13:100–107. Dentatorubral-Pallidoluysian Atrophy Becher MW, Rubinsztein DC, Leggo J, et al. Dentatorubral and pallidoluysian atrophy (DRPLA): clinical and neuropathological findings in genetically confirmed North American and European pedigrees. Mov Disord 1997;12:519–530. Hereditary Nonprogressive Chorea Kuwert T, Lange HW, Langen KJ, et al. Normal striatal glucose consumption in 2 patients with benign hereditary chorea as measured by positron emission tomography. J Neurol 1990;237:80–84. Senile Chorea Friedman JH, Ambler M. A case of senile chorea. Mov Disord 1990;5:251–253. Ruiz PJG, Gomez-Tortosa E, Delbarrio A, et al. Senile chorea: a multicenter prospective study. Acta Neurol Scand 1997;95:180–183. Warren JD, Firgaira F, Thompson EM, Kneebone CS, Blumbergs PC, Thompson PD. The causes of sporadic and “senile” chorea. Aust N Z J Med 1998;28:429–431.

CHAPTER 110. MYOCLONUS MERRITT’S NEUROLOGY

CHAPTER 110. MYOCLONUS STANLEY FAHN Suggested Readings

Myoclonus refers to brief lightning-like muscle jerks due to brief electromyographic bursts of 10 to 50 ms, rarely more than 100 ms in duration. The jerks are usually due to positive muscle contractions but can also be due to sudden brief lapses of contraction (i.e., so-called negative myoclonus) such as is seen in asterixis. Asterixis is a tremorlike phenomenon of the extended wrists due to brief lapses of muscle contraction. It is usually encountered in the metabolic encephalopathies that accompany severe hepatic, renal, and pulmonary disorders. Agonists and antagonists usually fire (or are inhibited in negative myoclonus) synchronously. Clinically, there is a wide expression of myoclonus. The jerks may occur singly or repetitively. They may be focal, segmental, or generalized. The amplitude ranges from mild contractions that do not move a joint to gross contractions that move limbs, the head, or the trunk. Myoclonic jerks range in frequency from rare isolated events to many events each minute; they may occur at rest, with action, or with intention movements. Commonly, myoclonic jerks are stimulus sensitive (reflex myoclonus); they can be induced by sudden noise, movement, light, visual threat, or pinprick. Most often, myoclonic jerks occur irregularly and unpredictably. But some occur in bursts of oscillations, and some are very rhythmic, as in palatal myoclonus. They resemble tremor in this last situation. Myoclonus arising from the cerebral cortex (cortical myoclonus) is usually focal and reflex-induced. Epilepsia partialis continua can be considered within the cortical myoclonus family. The cortical origin can be ascertained by enlarged somatosensory evoked potentials or by spikes in the electroencephalogram associated with electromyographic correlated jerks that are revealed by a back-averaging technique. Rasmussen encephalitis is a disorder of childhood and adolescence in which there is a unilateral focal seizure disorder, including epilepsia partialis continua, and a progressive hemiplegia due to focal cortical inflammation and destruction. Myoclonus originating from the brainstem can be either generalized (reticular myoclonus) or segmental (e.g., oculo-palatal-pharyngeal myoclonus). Palatal myoclonus is rhythmical (approximately 2 Hz) and can be primary or secondary. The latter is more common and is the result of a lesion within the Guillain-Mollaret triangle encompassing the dentate, red, and inferior olivary nuclei. This results in an interuption of the dentatoolivary pathway, leading to denervation of the olives, which become hypertrophic. Vascular lesions and multiple sclerosis are common causes of secondary palatal myoclonus that persists during sleep. This disorder is commonly associated with vertical rhythmical ocular movements, also occurring at 2 Hz, so-called ocular myoclonus. Primary myoclonus is of unknown etiology and is often associated with annoying constant clicking sounds in the ear caused by contractions of the tensor veli palatini muscles, which open the eustachian tubes. Primary palatal myoclonus disappears during sleep. Myoclonus arising from the spinal cord is of two clinical types. Spinal segmental myoclonus is rhythmic and persists during sleep, whereas propriospinal myoclonus causes truncal flexion jerks, usually triggered by a stimulus, such as when eliciting the knee jerk. In propriospinal myoclonus, the first muscles activated are usually from the thoracic cord, with slow upward and downward spread. Myoclonic jerks can sometimes arise from a peripheral nerve, plexus, or spinal root. Myoclonus can be classified into the following etiologic categories: physiologic myoclonus, essential myoclonus, epileptic myoclonus, and symptomatic myoclonus. Examples of physiologic myoclonus include sleep jerks and hiccough. Essential myoclonus may be familial or sporadic, is not associated with other neurologic abnormalities, and does not have a progressive course. Some patients with essential myoclonus have features of dystonia, and it is uncertain whether essential myoclonus and the entity known as myoclonic dystonia are the same entity. Epileptic myoclonus occurs in patients whose main complaint is epilepsy but who also have myoclonus. Symptomatic myoclonus is the largest etiologic group. In this category, myoclonus occurs as part of a more widespread encephalopathy, including storage diseases, spinocerebellar degenerations, dementias, infectious encephalopathies, metabolic encephalopathies, toxic encephalopathies, physical encephalopathies (e.g., posthypoxic and posttraumatic), and with focal brain damage. The infectious encephalopathy of Whipple disease features a facial myoclonus referred to as oculofacial-masticatory myorhythmia; other common features include a supranuclear vertical gaze palsy and cognitive changes. Among the toxic encephalopathies is the serotonin syndrome due to medications that produce excessive serotonergic stimulation; along with myoclonus there is diaphoresis, flushing, rigidity, hyperreflexia, shivering, confusion, agitation, restlessness, coma, and autonomic instability. Thus, myoclonus is classified by three different approaches ( Table 110.1). What was previously called “nocturnal myoclonus” is now referred to as periodic movements of sleep, which accompanies the restless-legs syndrome.

TABLE 110.1. CLASSIFICATION OF MYOCLONUS

An uncommon form of myoclonus is polyminimyoclonus, in which the jerks are of small amplitude, resembling irregular tremor that is continuous and generalized. The eyes are often involved with spontaneous, irregular, chaotic saccades. Because the dancing eyes are known as opsoclonus, the term opsoclonus-myoclonus syndrome is sometimes applied. First described as part of an encephalopathic picture in infants, particularly in association with a neuroblastoma, it also has been found in adults, usually as a paraneoplastic or postviral syndrome. The latter disorder is self-limiting after months or years. The paraneoplastic syndrome is associated with antineuronal antibodies and may remit on removal of the tumor. Exaggerated startle syndromes, related to the myoclonias and of brainstem origin, consist of a sudden jump to an unexpected auditory, tactile, or visual stimulus. Included are a blink, contraction of the face, flexion of the neck and trunk, and abduction and flexion of the arms. The motor reaction can be either a short or a prolonged complex motor act; falling can result. Known as hyperekplexia (MIM 244100), this disorder can result from a brainstem disorder or can be primary and inherited as an autosomal dominant trait with mutations on chromosome 5q coding the a 1 subunit of the inhibitory glycine receptor. When hyperekplexia appears in infancy, it is sometimes called the stiff-baby syndrome because prolonged tonic spasms occur when the infant is handled. Apnea can occur during these spasms; the dibenzodiazepine, clobazam, has been reported to be an effective treatment. Certain excessive startle syndromes may be culturally related and also can manifest echolalia and automatic obedience. These syndromes are known by colorful regional names, such as jumping Frenchmen of Maine (Quebec), myriachit (Siberia), latah (Indonesia, Malaysia), and ragin' cajun (Louisiana). Myoclonus and hyperekplexia can sometimes be controlled with the anticonvulsants clonazepam and valproic acid and with the serotonin precursor 5-hydroxytryptophan. Treatment of myoclonus usually requires polypharmacy. The most successful medications have been sodium valproate, clonazepam, primidone, and piracetam. SUGGESTED READINGS

Antel JP, Rasmussen T. Rasmussen's encephalitis and the new hat. Neurology 1996;46:9–11. Bodner RA, Lynch T, Lewis L, Kahn D. Serotonin syndrome. Neurology 1995;45:219–223. Brown P. Myoclonus: a practical guide to drug therapy. CNS Drugs 1995;3:22–29. Brown P, Rothwell JC, Thompson PD, et al. The hyperekplexias and their relationship to the normal startle reflex. Brain 1991;114:1903–1928. Caviness JN. Myoclonus. Mayo Clin Proc 1996;71:679–688. Caviness JN, Forsyth PA, Layton DD, McPhee TJ. The movement disorder of adult opsoclonus. Mov Disord 1995;10:22–27. Cockerell OC, Rothwell J, Thompson PD, Marsden CD, Shovron SD. Clinical and physiological features of epilepsia partialis continua: Cases ascertained in the UK. Brain 1996;119:393–407. Deuschl G, Toro C, Vallssole J, Zeffiro T, Zee DS, Hallett M. Symptomatic and essential palatal tremor. 1. Clinical, physiological and MRI analysis. Brain 1994;117:775–788. Fahn S, Marsden CD, Van Woert NH, eds. Myoclonus. Adv Neurol. New York: Raven Press, 1986. Fahn S, Sjaastad O. Hereditary essential myoclonus in a large Norwegian family. Mov Disord 1991; 6:237–247. Hammer MS, Larsen MB, Stack CV. Outcome of children with opsoclonus-myoclonus regardless of etiology. Pediatr Neurol 1995; 13:21–24. Ikeda A, Shibasaki H, Tashiro K, et al. Clinical trial of piracetam in patients with myoclonus: nationwide multiinstitution study in Japan. Mov Disord 1996;11:691–700. Koskiniemi M, Vanvleymen B, Hakamies L, Lamusuo S, Taalas J. Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo. J Neurol Neurosurg Psychiatry 1998;64:344–348. Lance JW, Adams RD. The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain 1963;86:111–136. Louis ED, Lynch T, Kaufmann P, Fahn S, Odel J. Diagnostic guidelines in central nervous system Whipple's disease. Ann Neurol 1996;40:561–568. Marsden CD, Hallett M, Fahn S. The nosology and pathophysiology of myoclonus. In: Marsden CD, Fahn S, eds. Movement disorders. London: Butterworths, 1982:196–248. Marsden CD, Harding AE, Obeso JA, Lu CS. Progressive myoclonic ataxia (the Ramsay Hunt syndrome). Arch Neurol 1990;47:1121–1125. Obeso JA, Artieda J, Burleigh A. Clinical aspects of negative myoclonus. Adv Neurol 1995;67:1–7. Quinn NP. Essential myoclonus and myoclonic dystonia. Mov Disord 1996;11:119–124. Rio J, Montalban J, Pujadas F, Alvarez-Sabin J, Rovira A, Codina A. Asterixis associated with anatomic cerebral lesions: a study of 45 cases. Acta Neurol Scand 1995;91:377–381. Scarcella A, Coppola G. Neonatal sporadic hyperekplexia: a rare and often unrecognized entity. Brain Dev 1997;19:226–228. Shiang R, Ryan SG, Zhu YZ, et al. Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat Genet 1993;5:351–358. Werhahn KJ, Brown P, Thompson PD, Marsden CD. The clinical features and prognosis of chronic posthypoxic myoclonus. Mov Disord 1997;12:216–220.

CHAPTER 111. GILLES DE LA TOURETTE SYNDROME MERRITT’S NEUROLOGY

CHAPTER 111. GILLES DE LA TOURETTE SYNDROME STANLEY FAHN Suggested Readings

The Gilles de la Tourette syndrome (MIM 137580), commonly shortened to Tourette syndrome, is defined as a neurobehavioral disorder consisting of both multiple motor and phonic tics that change in character over time, onset before 21 years of age, and symptoms that wax and wane but last more than 1 year. Many patients have a behavioral component of obsessive-compulsive or attention deficit disorder. Although the definition is a useful criterion for research on the disorder, it excludes chronic motor tics or an onset beyond the age of 21 years. It is likely that these situations represent milder expressions of Tourette syndrome. Tourette syndrome is the most common cause of tics; other causes include neuroacanthocytosis, encephalitis, neuroleptics, and head trauma. Tics range from intermittent simple brief jerks to a complex pattern of rapid, coordinated, involuntary movements, often preceded by an unpleasant sensation that is relieved by the movement. Although tics usually can be suppressed for short periods of time, the inner sensation builds up, consequently leading to a burst of tics when the patient stops suppressing them. Tics usually begin in the face (eye blinking, grimacing) and neck (head shaking). They may spread to involve the limbs and may be accompanied by sounds (sniffing, throat clearing, barking, words, or parts of words) and sometimes by foul utterances (coprolalia). Repeating sounds (echolalia) or movements (echopraxia) are sometimes seen. The speed of tics range from very fast (clonic tics) to sustained contractions (dystonic tics). Simple clonic tics resemble essential myoclonus, and the two conditions are difficult to distinguish. Dystonic tics need to be differentiated from primary torsion dystonia. Sydenham chorea is distinct in manifesting as a continuous restless type of movement pattern, and it is self-limited. Premonitory sensations, intermittency, and suppressibility help distinguish tics from most other movement disorders. On average, tics begin around age 5 years and increase in severity, reaching its most intense period around age 10. After the most severe period, there is usually a steady decline in tic severity. By age 18 years, nearly half of the patients are virtually free from tics. Tourette syndrome is frequently associated with compulsive ideation and hyperactive behavior. Neuroimaging has shown inconsistent asymmetries in the basal ganglia. Serum antibodies against the putamen have been found. The genetic inheritance pattern of Tourette syndrome is controversial, but complex segregation analysis suggests that susceptibility is conveyed by a major locus in combination with a multifactorial background. The analysis does not support other models of inheritance, including polygenic models, single major locus models, and mixed models with dominant and recessive major loci. Genetic linkage has not yet been discovered, though most of the genome has been searched. The prevalence in adolescents is about 5 per 10,000 in males and 3 per 10,000 in females. In patients who have come to necropsy, no specific morphologic changes in the brain have been noted. Dopamine receptors are not increased in the striatum, but hyperinnervation with dopamine terminals has been suggested by increased mazindol binding. When tics are mild and not socially disabling, no treatment is required. When more severe, motor and phonic tics can sometimes be reduced with clonidine or clonazepam. Dopamine antagonists and depletors are more effective but often have more adverse effects. The antagonists can cause the more serious complication of tardive dystonia and thus should be reserved as a last resort. Attention deficit and obsessive-compulsive disorders are usually a greater social problem than are the tics. SUGGESTED READINGS Chase TN, Friedhoff A, Cohen DJ, eds. Tourette's syndrome. Adv Neurol. New York: Raven Press, 1992. Comings DE, Himes JA, Comings BG. An epidemiologic study of Tourette's syndrome in a single school district. J Clin Psychiatry 1990;51:463–469. Fahn S. Motor and vocal tics. In: Kurlan R, ed. Handbook of Tourette's syndrome and related tic and behavioral disorders. New York: Marcel Dekker, 1993. Kurlan R, ed. Handbook of Tourette's syndrome and related tic and behavioral disorders. New York: Marcel Dekker, 1993. Leckman JF, Zhang HP, Vitale A, et al. Course of tic severity in Tourette syndrome: the first two decades. Pediatrics 1998;102:14–19. Singer HS, Giuliano JD, Hansen BH, et al. Antibodies against human putamen in children with Tourette syndrome. Neurology 1998;50:1618–1624. Singer HS, Hahn IH, Moran TH. Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette's syndrome. Ann Neurol 1991;30:558–562. Tourette Syndrome Classification Study Group. Definitions and classification of tic disorders. Arch Neurol 1993;50:1013–1016. Walkup JT, LaBuda MC, Singer HS, Brown J, Riddle MA, Hurko O. Family study and segregation analysis of Tourette syndrome: evidence for a mixed model of inheritance. Am J Hum Genet 1996;59:684–693.

CHAPTER 112. DYSTONIA MERRITT’S NEUROLOGY

CHAPTER 112. DYSTONIA STANLEY FAHN AND SUSAN B. BRESSMAN Classification of Torsion Dystonia Primary Torsion Dystonias Dystonia-Plus Syndromes Secondary Dystonia Heredodegenerative Dystonia Other Dyskinesia Syndromes With Dystonia Pseudodystonia Treatment Suggested Readings

After parkinsonism, dystonia is the movement disorder most commonly encountered in movement disorder clinics. The term dystonia was coined by Oppenheim in 1911 to indicate that the disorder he was describing manifested hypotonia at one occasion and tonic muscle spasms at another, usually but not exclusively elicited upon volitional movements. Although the term dystonia has undergone various definitions since 1911, today it is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Limb, axial, and cranial voluntary muscles can all be affected by dystonia. The involuntary movements are often exacerbated during voluntary movements, so-called action dystonia. If the dystonic contractions appear only with a specific action, it is referred to as task-specific dystonia (e.g., writer's cramp and musician's cramp). As the dystonic condition progresses, voluntary movements in parts of the body not affected with dystonia can induce dystonic movements of the involved body part, so-called overflow. Talking is the most common activity that causes overflow dystonia in other body parts. With still further worsening, the affected part can develop dystonic movements while at rest. Thus, dystonia at rest is usually more severe than pure action dystonia. Sustained abnormal postures of affected body parts may be the eventual outcome. Dystonic movements tend to increase with fatigue, stress, and emotional states; they tend to be suppressed with relaxation, hypnosis, and sleep. Dystonia often disappears during deep sleep, unless the movements are extremely severe. A characteristic and almost unique feature of dystonic movements is that they can be diminished by tactile or proprioceptive “sensory tricks” (geste antagoniste). For example, patients with cervical dystonia (torticollis) often place a hand on the chin or side of the face to reduce nuchal contractions, and orolingual dystonia is often helped by touching the lips or placing an object in the mouth. Lying down may reduce truncal dystonia; walking backward or running may reduce leg dystonia. Rapid muscle spasms that occur in a repetitive pattern may be present in torsion dystonia; when rhythmic, the term dystonic tremor is applied. Although rare, some children and adolescents with primary or secondary dystonia may experience a crisis, a sudden increase in the severity of dystonia, which has been called dystonic storm or status dystonicus. It can cause myoglobinuria, with a threat of death by renal failure. Placing the patient in an intensive care unit for barbiturate narcosis is usually necessary for relief.

CLASSIFICATION OF TORSION DYSTONIA To emphasize the twisting quality of the abnormal movements and postures, the term torsion is often placed in front of the word dystonia. Torsion dystonia is classified in three ways: age at onset, body distribution of abnormal movements, and etiology ( Table 112.1). Age at onset is the single most important factor related to prognosis of primary dystonia. As a general rule, the younger the age at onset, the more likely the dystonia will become severe and spread to multiple parts of the body. In contrast, the older the age at onset, the more likely dystonia will remain focal. Onset of dystonia in a leg is the second most important predictive factor for a more rapidly progressive course.

TABLE 112.1. CLASSIFICATIONS OF TORSION DYSTONIA

Because dystonia usually begins in a single body part and because dystonia either remains focal or spreads to other body parts, it is useful to classify dystonia according to anatomic distribution. Focal dystonia affects only a single area. Frequently seen types of focal dystonia tend to have specific labels: blepharospasm, torticollis, oromandibular dystonia, spastic dysphonia, writer's cramp, or occupational cramp. If dystonia spreads, it usually affects a contiguous body part. When dystonia affects two or more contiguous parts of the body, it is segmental dystonia. Generalized dystonia is a combination of leg involvement plus some other area. Multifocal dystonia fills a gap in the preceding designations, describing involvement of two or more noncontiguous parts. Dystonia affecting one half of the body is hemidystonia, which is usually symptomatic rather than primary. Adult-onset dystonia is much more often focal than generalized. The most common focal dystonia is cervical dystonia (torticollis), followed by dystonias of cranial muscles: blepharospasm, spasmodic dysphonia, or oromandibular dystonia. Less common is arm dystonia, such as writer's cramp. The most common segmental dystonia involves the cranial muscles (Meige syndrome) or cranial and neck muscles (cranial-cervical dystonia). The etiologic classification identifies four major categories: primary, dystonia-plus syndromes, secondary (environmental causes), and heredodegenerative diseases. Primary dystonia (familial or sporadic) is a pure dystonia (except that tremor may be present); primary excludes a symptomatic cause. Dystonia-plus syndromes are related to the primary dystonias in this classification scheme because neither type is neurodegenerative; instead they are neurochemical disorders. Dystonia-plus syndromes include symptoms and signs in addition to dystonia; for instance, dopa-responsive dystonia includes parkinsonism and myoclonus-dystonia includes myoclonus. Secondary dystonias are due to environmental insult. Heredodegenerative dystonias are neurodegenerative diseases usually inherited; these conditions usually have other neurologic features in addition to dystonia.

PRIMARY TORSION DYSTONIAS Primary torsion dystonia comprises familial and nonfamilial (sporadic) types. Neurologic abnormality is restricted to dystonic postures and movements except that there may be a tremor resembling essential tremor. Within the primary dystonias are several genetic disorders, some with genes already mapped (DYT1, DYT6, and DYT7). But most primary dystonias are sporadic and with an onset in adult years and a focal or segmental dystonia. Oppeneheim Dystonia The DYT1 gene has been cloned and causes the dystonia described by Oppenheim. The mean (± SD) age at onset of symptoms in Oppenheim dystonia is 12.5 ± 8.2 years. Onset is rare after age 29 years. In about 95% of patients, symptoms begin in an arm or leg, and the disorder spreads to the neck or larynx. This gene is responsible for most cases of early and limbonset primary torsion dystonia.

When Oppenheim dystonia begins in a leg, the likelihood of eventual progression to generalized dystonia is about 90%. With onset in an arm, it is about 50%. With leg involvement, action dystonia results in a peculiar twisting of the leg when the child walks forward, even though walking backward, running, or dancing may still be normal. Bizarre stepping or a bowing gait may be noted when the dystonic movements affect proximal muscles of the leg. Difficulty in placing the heel on the ground is evident when distal muscles are affected ( Fig. 112.1). As the disorder progresses, the movements may appear when the leg is at rest; the foot is often plantar flexed and turned inward, and the knee and hip often assume a flexed posture.

FIG. 112.1. Generalized dystonia with involvement of the legs, trunk, and arms. Patient is still able to walk.

With arm involvement, action dystonia may interfere with writing; the fingers curl, the wrist flexes and pronates, the triceps contracts, and the elbow elevates. Dystonic tremor of the arm is common, with features of both postural and action tremors. With progression, other activities of the arm are impaired; the arm often moves backward behind the body when the patient walks. Later, dystonia may be present when the arm is at rest. With onset in the arm, spread is usually to the other arm or sometimes to the neighboring segments of neck and trunk. As the dystonia becomes worse, the contractions become constant, so that instead of moving, the body part remains in a fixed twisted posture. Oppenheim dystonia also tends to spread to other parts of the body, particularly after onset in a leg, advancing from focal to segmental to generalized. The trunk may develop wiggling movements and fixed scoliosis, lordosis, and tortipelvis. The neck may become involved with torticollis, anterocollis, retrocollis, or head tilt and shift. Facial grimacing and difficulties in speech may occur but are much less common. Although muscle tone and power seem normal, the involuntary movements interfere and make voluntary activity extremely difficult. In general, mental activity is normal, and there are no alterations in tendon reflexes or sensation. The rate of progression of this type is extremely variable; in most cases, it is most severe within the first 5 to 10 years, after which there may be a quiescent static phase. The continuous spasms result in marked distortion of the body to a degree rarely seen in any other disease ( Fig. 112.2). With active treatment, it is now uncommon to encounter the severe deformities seen before the 1980s.

FIG. 112.2. An advanced state of generalized dystonia with fixed postures: torticollis, scoliosis, tortipelvis, and limb dystonia.

Oppenheim dystonia is an autosomal dominant disorder; the gene, DYT1, maps to chromosome 9q34.1. The penetrance rate of gene expression is between 30% and 40%. In all cases the only mutation is a deletion of one of a pair of GAG triplets in the ATP-binding protein, torsinA. TorsinA, previously unknown, is found in neurons in many parts of the brain; it is most abundantly expressed in the substantia nigra pars compacta, the hippocampus, and the cerebellum. There is moderate expression in striatal cholinergic neurons, which might explain some beneficial effect from anticholinergic agents. TorsinA is distantly related to the heat-shock protein family, which could explain why stress may induce the onset or worsening of Oppenheim dystonia. Oppenheim dystonia affects most ethnic groups but is particularly prevalent in the Ashkenazi Jewish population, in which the disease occurs in about 1 per 6,000. The origin of the mutation has been traced to the northern part of the historic Jewish Pale of settlement in Lithuania and Byelorussia about 350 years ago. Non-DYT1 Primary Dystonia The DYT1 gene has been excluded in many families with primary torsion dystonia. The phenotype differs in that many begin in the cranial-cervical region, and most are focal and segmental. There is some clinical phenotypic overlap between Oppenheim dystonia and DYT6 dystonia, which has been mapped to 8p21q22. DYT6 dystonia has been found in the Mennonite population. It is an autosomal dominant dystonia with onset in either children or adults, involving limbs, cervical, and cranial regions. Dysphonia and dysarthria are often the most disabling features. DYT7 dystonia is a predominantly cervical form in northwest Germany. It was originally mapped to chromosome 18p. Doubt has been raised about this locus in German and European populations. Some designations of DYT have been applied to other primary dystonias that have yet to be genetically mapped ( Table 112.2). The primary dystonias are DYT1, DYT2, DYT4, DYT6, and DYT7. DYT5, DYT11, and DYT12 are dystonia-plus disorders, and DYT3 is a heredodegenerative dystonia. DYT8, DYT9, and DYT10 are paroxysmal dyskinesias.

TABLE 112.2. GENE NOMENCLATURE FOR THE DYSTONIAS

Most primary dystonias are of adult onset and without a family history. Their precise prevalence is not known, but it is about 30 per 100,000 population in Rochester, Minnesota. These dystonias often remain in the site where the dystonia begins (i.e., a focal dystonia). Common sites are neck (cervical dystonia), face (blepharospasm), jaw (oromandibular dystonia), vocal cords (spastic dysphonia), and arm (writer's cramp). In some of these adult-onset cases, the disease spreads to neighboring segments. Focal dystonia is the most common form (50%) of all primary dystonias, with segmental dystonia next (one-third) and generalized dystonia least (one-sixth). Cervical dystonia, commonly known as spasmodic torticollis or wry neck, is the most common focal dystonia. It occurs at any age, usually beginning between ages 20 and 60. Any combination of neck muscles can be involved, especially the sternocleidomastoid, trapezius, splenius capitus, levator scapulae, and scalenus muscles. Sustained turning, tilting, flexing, or extending the neck or shifting the head laterally or anteriorly can result ( Fig. 112.3). The shoulder is usually elevated and anteriorly displaced on the side to which the chin turns. Some neck muscles contract in compensation for the movements of the primary agonists, sometimes making it difficult to decide which muscles to inject with botulinum toxin. Instead of sustained deviation of the head, some patients have jerking movements of the head. Neck pain occurs in about two-thirds of patients with cervical dystonia and usually responds successfully to injections of botulinum toxin at the site of the pain. A common sensory trick to relieve cervical dystonia is the placement of one hand on the back of the head or on the chin. About 10% of patients with cervical dystonia have a remission, usually within a year of onset; most remissions are followed by a relapse years later. Some patients with torticollis have a horizontal head tremor that may be impossible to distinguish from essential tremor. Other considerations in the differential diagnosis of torticollis are congenital contracture of the sternocleidomastoid muscle, which can be treated with surgical release. In young boys after a full meal, extreme head tilt may be caused by gastroesophageal reflux ( Sandifer syndrome) that can be treated by plication surgery. Other diagnostic considerations are trochlear nerve palsy; Arnold-Chiari malformation; malformations of the cervical spine, such as Klippel-Feil fusion or atlantoaxial subluxation; cervical infections; and spasms from cervical muscle shortening.

FIG. 112.3. Spasmodic torticollis with some dystonia of facial muscles (segmental dystonia).

Blepharospasm is caused by contraction of the orbicularis oculi muscles. It usually begins with increased frequency of blinking, followed by closure of the eyelids and then more firm and prolonged closure of the lids. Sometimes lid closure is forceful. Untreated blepharospasm usually causes functional blindness. Blinking and lid closure can be intermittent and are often temporarily suppressed by talking, humming, singing, or looking down. The condition is worsened by walking and by bright light. A common sensory trick that relieves contractions is placing of a finger just lateral to the orbit. Blepharospasm is usually accompanied by cocontraction of lower facial muscles, such as the platysma and risorius. This type of focal dystonia sometimes becomes segmental by spreading to other cranial targets, such as the jaw, tongue, vocal cords, or cervical muscles. The combination of blepharospasm with other cranial dystonias is called Meige syndrome. Blepharospasm occurs more often in women than in men, usually beginning after age 50, although younger people may be affected. Abnormalities of the blink reflex have been found with blepharospasm and with other cranial or cervical dystonias. The differential diagnosis of blepharospasm includes hemifacial spasm, which is unilateral. Rarely, hemifacial spasm is bilateral, but the contractions on the two sides of the face are not synchronous as they are in blepharospasm. Blinking tics can resemble blepharospasm, but tics almost always begin in childhood. SjĂśgren syndrome of dry eyes often causes the eyelids to close, but testing for tear production usually distinguishes this disorder. Injections of botulinum toxin are effective in more than 80% of patients with blepharospasm. Writer's cramp of adult onset usually remains limited to one limb, usually the dominant side. In about 15% of cases, it spreads to the other arm. When it affects only writing, the patient may learn to write with the nondominant hand. For bilateral involvement or for dystonia that affects other activities (buttoning, shaving, or playing a musical instrument), carefully placed injections of botulinum toxin may be effective. Dystonia of the vocal cords occurs in two forms. The more common type is spastic (spasmodic) dysphonia in which the vocalis muscles contract, bringing the vocal cords together and causing the voice to be restricted, strangled, and coarse, often broken up with pauses. Breathy (whispering) dysphonia is caused by contractions of the posterior cricoarytenoids (abductor muscles of the vocal cords), so that the patient cannot talk in a loud voice and tends to run out of air while trying to speak. Spastic dysphonia is often associated with tremor of the vocal cords. Essential tremor (with vocal cord tremor) is an important differential diagnosis; the presence of tremor in the hands or neck leads to such diagnosis. Injections of botulinum toxin can be dramatically effective for spastic dysphonia but are more uncertain for breathy dysphonia. For each type, a physician must be experienced with the procedure of injecting the correct muscle. Pathology and Pathophysiology of Primary Dystonia The pathology of the primary torsion dystonias is unknown. Gross examination of the brain and histologic studies by light microscopy do not reveal any consistent morphologic changes. These disorders are therefore considered neurochemical rather than neurodegenerative. Dystonic symptoms probably arise from dysfunction within the basal ganglia because, in those conditions with secondary and heredodegenerative dystonia, such as Wilson disease, encephalitis lethargica, and Hallervorden-Spatz disease, characteristic pathologic changes are found in this region. Furthermore, in traumatic hemidystonia, infarction of the contralateral caudate and putamen has been encountered. In support of a biochemical abnormality are the documented instances of dystonic reactions to pharmacologic agents, particularly those that affect striatal dopamine function, such as the dopamine receptor blocking agents and levodopa as used in treating Parkinson disease. The electromyogram in the dystonias shows cocontraction of agonist and antagonist muscles with prolonged bursts and overflow to extraneous muscles. Spinal and brainstem reflex abnormalities, including reduced reciprocal inhibition and protracted blink reflex recovery, indicate a reduced presynaptic inhibition of muscle afferent input to the inhibitory interneurons as a result of defective descending motor control. The sensorimotor cerebral cortex shows an increased region of activation related to the affected body part. Positron emission tomography studies found increased metabolic activity in the lentiform nuclei. In DYT1 dystonia, two patterns of abnormal metabolic activity have been found. In nonmanifesting carriers and in affected carriers who are asleep, there is hypermetabolism of the lentiform, cerebellum, and supplementary motor cortex. On the other hand, in DYT1 patients having active muscle contractions, metabolic activity is increased in the thalamus, cerebellum, and midbrain.

DYSTONIA-PLUS SYNDROMES This category includes nondegenerative disorders in which parkinsonism (dopa-responsive dystonia and rapid-onset dystonia-parkinsonism) or myoclonus (myoclonus-dystonia) coexists with the dystonia. Dopa-responsive Dystonia About 10% of patients with childhood-onset dystonia have the autosomal dominant disorder, dopa-responsive dystonia (DRD), sometimes called Segawa disease. Distinguishing DRD from primary torsion dystonia, usually Oppenheim dystonia, is important because DRD responds so well to treatment. It differs from other childhood dystonias by the presence of bradykinesia, cogwheel rigidity, and impaired postural reflexes; diurnal fluctuations with improvement after sleep and worsening as the day wears on; a peculiar “spastic� straight-legged gait, with a tendency to walk on the toes; hyperreflexia, particularly in the legs and sometimes with

Babinski signs; and a remarkable therapeutic response to low doses of levodopa, dopamine agonists, or anticholinergic drugs. DRD usually begins between ages 6 and 16 but can appear at any age. When it begins in infants, it resembles cerebral palsy. When it begins in adults, it usually manifests as pure parkinsonism, mimicking Parkinson disease, responding to levodopa, and with a generally benign course. DRD affects girls more often than boys (4:1 ratio), has a worldwide distribution, and is not known to have a higher prevalence in any specific ethnic group. Mutations of the gene for GTP cyclohydrolase I (GCHI) located at 14q22.1 are responsible. GCHI catalyzes the first step in the biosynthesis of tetrahydrobiopterin (BH4), the cofactor required for the enzymes tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase. These hydroxylase enzymes add an –OH group to the parent amino acid and are required for the synthesis of biogenic amines. The genetic label for DRD is DYT5. Pathologic investigations of DRD revealed no loss of neurons within the substantia nigra pars compacta, but the cells are immature with little neuromelanin. Neuromelanin synthesis requires dopamine (or other monoamines) as the initial precursor. Biochemically, there is marked reduction of dopamine concentration within the striatum in DRD. These pathologic and biochemical findings demonstrate that the disorder is a neurochemical disease rather than a neurodegenerative disease. Rare cases of DRD are found in an autosomal recessive disorder with mutations in the gene for tyrosine hydroxylase; the dystonia-parkinsonism begins in infancy or early childhood. Additionally, several autosomal recessive biopterin deficiency disorders show features of decreased norepinephrine and serotonin in addition to dystonia and parkinsonism. These clinical features include miosis, oculogyria, rigidity, hypokinesia, chorea, myoclonus, seizures, temperature disturbance, and hypersalivation; hyperphenylalaninemia is present, and the disorder may respond partially to levodopa. Another disorder of infants is the autosomal recessive deficiency of the enzyme aromatic L-amino acid decarboxylase, which catalyzes the transformation of levodopa to dopamine; levodopa is ineffective in this disorder, but patients respond to dopamine agonists coupled with a monoamine oxidase inhibitor. In the differential diagnosis of DRD is juvenile parkinsonism, a progressive nigral degenerative disorder, in which dystonia often precedes the parkinsonian features that become the major clinical feature. One distinguishing laboratory test is fluorodopa positron emission tomography, which is normal in DRD; in juvenile parkinsonism, there is marked reduction of fluorodopa uptake in the striatum. A phenylalanine loading test has also been proposed; in DRD, there is a slower conversion to tyrosine. Other differential features of DRD from juvenile parkinsonism and Oppenheim dystonia are listed in Table 112.3.

TABLE 112.3. DIFFERENTIAL FEATURES BETWEEN JUVENILE PARKINSON DISEASE (JPD), DOPA-RESPONSIVE DYSTONIA (DRD), AND PRIMARY TORSION DYSTONIA (PTD)

One may also suspect DRD if a young patient with dystonia responds dramatically to low doses of anticholinergic agents. But the most effective agent is levodopa. The suggested starting dose of carbidopa/levodopa for DRD is 12.5/50 mg two or three times a day, a dose low enough to avoid dyskinesias. The usual maintenance dose is 25/100 mg two or three times a day. Rapid-onset Dystonia-Parkinsonism Rapid-onset dystonia-parkinsonism is an autosomal dominant disease; the gene has been mapped to 19q. Affected individuals develop dystonia and parkinsonism between ages 14 and 45 years, reaching maximum involvement of dystonia with parkinsonism in hours or days. Some affected members of the family may have a more gradual progression for 6–18 months. The cerebrospinal fluid homovanillic acid concentration is low, and there are no imaging abnormalities. There is no effective treatment. Myoclonus-Dystonia Although lightning-like movements occasionally occur in Oppenheim dystonia, they are a prominent feature in a distinct autosomal dominant disorder known as myoclonus-dystonia. The myoclonic jerks respond to alcohol. Myoclonus-dystonia may not be an entity separate from hereditary essential myoclonus, a problem to be resolved by genetic studies. The onset is in childhood or adolescence. The myoclonus and dystonia are located predominantly in the arms and neck, and the symptoms tend to plateau after a period of progression.

SECONDARY DYSTONIA Secondary dystonia is defined as a dystonic disorder that develops mainly as the result of environmental factors that affect the brain. Spinal cord injury and peripheral injury are also recognized causes of dystonia. Examples include levodopa-induced dystonia in the treatment of parkinsonism; acute and tardive dystonia due to dopamine receptor blocking agents; and dystonias associated with cerebral palsy, cerebral hypoxia, cerebrovascular disease, cerebral infectious and postinfectious states, brain tumor, and toxicants such as manganese, cyanide, and 3-nitroproprionic acid. Other causes include psychogenic disorders, peripheral trauma followed by focal dystonia in the affected region, head injury, and delayed-onset dystonia after cerebral infarct or other cerebral insult. Prior history of one of these insults suggests the correct diagnosis, as does neuroimaging that shows a lesion in the basal ganglia or their connections. A more complete listing of secondary dystonias is presented in Table 112.4. A number of disorders in this group, such as the infectious and toxicant-induced neurodegenerations, are not limited to pure dystonia but show a mixture of other neurologic features, often the parkinsonian features bradykinesia and rigidity. Tardive dystonia, a persistent complication of agents that block dopamine receptors, is the most common form of secondary dystonia. Tardive dystonia is usually focal or segmental, affecting the cranial structures in adults; in children, however, it can be generalized, involving the trunk and limbs. It often is associated with features of tardive dyskinesia, especially oral-buccal-lingual movements (see Chapter 116). Clues suggesting a secondary dystonia are listed in Table 112.5.

TABLE 112.4. CAUSES OF SECONDARY DYSTONIA

TABLE 112.5. CLUES SUGGESTIVE OF SYMPTOMATIC DYSTONIA

Psychogenic dystonia can be considered within the secondary dystonia category. For many decades, Oppenheim dystonia was considered psychogenic because of the bizarre nature of the symptoms, exaggeration in periods of stress, variability, and suppression by sensory tricks. This misdiagnosis often led to a long delay in identification of the nature of the disorder and to prolonged periods of needless psychotherapy. Awareness of the capricious nature of the disorder and serial observation of patients can avoid this pitfall. On the other hand, psychogenic dystonia does occur but in less than 5% of patients who otherwise would be considered to have primary torsion dystonia. Clues suggestive of psychogenic dystonia are listed in Table 112.6.

TABLE 112.6. CLUES SUGGESTIVE OF PSYCHOGENIC DYSTONIA

HEREDODEGENERATIVE DYSTONIA This is a category where neurodegenerations produce dystonia as a prominent feature. Usually other neurologic features, especially parkinsonism, are also present and can even predominate. In some patients with these disorders, dystonia may fail to appear, and other neurologic manifestations may be the presenting feature, for example, chorea in Huntington disease, in which dystonia may be a late-stage feature. Tremor or juvenile parkinsonism may be the mode of onset of Wilson disease, and dystonia may fail to appear in such patients. Because many of these neurodegenerations are due to genetic abnormalities, the term heredodegenerative is applied to this category. However, some of the diseases listed here are of unknown etiology, and it is not clear what the role of genetics might be. For convenience, we place all the neurodegenerations in this category. These are listed in Table 112.7 in which heredodegenerative disorders are organized by the nature of their genetics whenever the genes are known, followed by other neurodegenerations in which the etiology remains unknown.

TABLE 112.7. HEREDODEGENERATIVE DISEASES (TYPICALLY NOT PURE DYSTONIA)

An X-linked recessive disorder causing dystonia and parkinsonism affects young adult Filipino men. The Filipino name for the condition is lubag. It has been designated as DYT3. It can begin with dystonia in the feet or cranial structures; lingual and oromandibular dystonia are common, sometimes with stridor. With progression, generalized dystonia often develops. Many patients develop parkinsonism; in some patients, the sole manifestation may be progressive parkinsonism. The abnormal gene has been localized to the centromeric region of the X chromosome. Pathologic study reveals a mosaic pattern of gliosis in the striatum. Patients respond only partially to levodopa, anticholinergics, baclofen, or clonazepam.

OTHER DYSKINESIA SYNDROMES WITH DYSTONIA Dystonia can appear in disorders not ordinarily considered to be a part of torsion dystonia ( Table 112.8). These include dystonic tics that are more conveniently classified with tic disorders (see Chapter 111), paroxysmal dyskinesias more conveniently classified with paroxysmal dyskinesias (see Chapter 9), and hypnogenic dystonia that can be either paroxysmal dyskinesias or seizures (see Chapter 9).

TABLE 112.8. OTHER MOVEMENT DISORDERS IN WHICH DYSTONIA MAY BE PRESENT

PSEUDODYSTONIA To complete the revised classification, Table 112.9 lists disorders that can mimic torsion dystonia but are not generally considered to be a true dystonia. These disorders typically manifest themselves as sustained muscle contractions or abnormal postures, which is why they are often mistaken for dystonia. But these contractions are secondary to either a peripheral or reflex mechanism or as a reaction to some other problem. For example, Sandifer syndrome is due to gastroesophageal reflux, with apparent reduction of the gastric contractions when the head is tilted to the side; Isaacs syndrome is due to continuous peripheral neural firing; orthopedic disease causes a number of postural changes; and seizures can result in sustained twisting postures.

TABLE 112.9. PSEUDODYSTONIAS (NOT CLASSIFIED AS DYSTONIA BUT CAN BE MISTAKEN FOR DYSTONIA BECAUSE OF SUSTAINED POSTURES)

TREATMENT After levodopa therapy has been tested to be certain that DRD has not been overlooked, the following drugs that have been reported to be effective in dystonia should be tried: high-dose anticholinergics (e.g., trihexyphenidyl), high-dose baclofen, benzodiazepines (clonazepam, diazepam), and antidopaminergics (reserpine, dopamine receptor blockers). Stereotaxic thalamotomy may be useful in unilateral dystonia, but bilateral thalamotomy carries about a 30% risk of dysarthria. Posteroventral pallidotomy has been shown to be effective for some patients with Oppenheim dystonia; its comparison with thalamotomy still needs to be accomplished. For focal dystonias, such as blepharospasm, torticollis, oromandibular dystonia, and spastic dysphonia, local injections of botulinum toxin are beneficial. This agent also can be used to treat generalized dystonia, with injections limited to the most severely affected focal site. This muscle-weakening agent can be effective for about 3 months before a repeat injection is needed. About 5% of patients develop antibodies to botulinum toxin, thus rendering that particular strain of toxin ineffective. Local surgery also can be used for focal dystonias. Selective denervation of the affected muscles by section of extradural fibers of the anterior cervical root or the spinal accessory nerve has been successful is some patients in otherwise intractable cervical dystonia. SUGGESTED READINGS Almasy L, Bressman SB, Raymond D, et al. Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families. Ann Neurol 1997;42:670–673. Augood SJ, Penney JB, Friberg IK, et al. Expression of the early-onset torsion dystonia gene (DYT1) in human brain. Ann Neurol 1998;43:669–673. Bara-Jimenez W, Catalan MJ, Hallett M, Gerloff C. Abnormal somatosensory homunculus in dystonia of the hand. Ann Neurol 1998;44:828–831. Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD. The pathophysiology of primary dystonia. Brain 1998;121:1195–1212. Bhatia KP, Quinn NP, Marsden CD. Clinical features and natural history of axial predominant adult onset primary dystonia. J Neurol Neurosurg Psychiatry 1997;63:788–791. Brashear A, de Leon D, Bressman SB, Thyagarajan D, Farlow MR, Dobyns WB. Rapid-onset dystonia-parkinsonism in a second family. Neurology 1997;48:1066–1069. Bressman SB, de Leon D, Brin MF, et al. Idiopathic torsion dystonia among Ashkenazi Jews: Evidence for autosomal dominant inheritance. Ann Neurol 1989;26:612–620. Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 1986;36:160–164. Dauer WT, Burke RE, Greene P, Fahn S. Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia. Brain 1998;121:547–560. Eidelberg D, Moeller JR, Antonini A, et al. Functional brain networks in DYT1 dystonia. Ann Neurol 1998;44:303–312. Fahn S. The varied clinical expressions of dystonia. Neurol Clin 1984;2:541–552. Fahn S, Bressman SB, Marsden CD. Classification of dystonia. Adv Neurol. 1998;78:1–10. Fahn S, Marsden CD, Calne DB, eds. Dystonia 2. Adv Neurol 1988;50. Fahn S, Marsden CD, DeLong MR, eds. Dystonia 3. Adv Neurol 1998;78. Ford B, Greene P, Louis ED, et al. Use of intrathecal baclofen in the treatment of patients with dystonia. Arch Neurol 1996;53:1241–1246. Greene P, Kang UJ, Fahn S. Spread of symptoms in idiopathic torsion dystonia. Mov Disord 1995;10:143–152. Hyland K, Fryburg JS, Wilson WG, et al. Oral phenylalanine loading in dopa-responsive dystonia: a possible diagnostic test. Neurology 1997;48:1290–1297. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 1994;8:236–242. Jankovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med 1991;324:1186–1194. Knappskog PM, Flatmark T, Mallet J, Ludecke B, Bartholome K. Recessively inherited L-dopa-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum Mol Genet 1995;4:1209–1212. Kupke KG, Graeber MB, Muller U. Dystonia-parkinsonism syndrome (XDP) locus—flanking markers in Xq12-q21.1. Am J Hum Genet 1992;50:808–815. Lang AE. Psychogenic dystonia: a review of 18 cases. Can J Neurol Sci 1995;22:136–143. Maller A, Hyland K, Milstien S, Biaggioni I, Butler IJ. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a second family. Manji H, Howard RS, Miller DH, et al. Status dystonicus: the syndrome and its management. Brain 1998;121:243–252. Marsden CD, Obeso JA, Zarranz JJ, Lang AE. The anatomical basis of symptomatic hemidystonia. Brain 1985;108:463–483. Nutt JG, Muenter MD, Aronson A, et al. Epidemiology of focal and generalized dystonia in Rochester, Minnesota. Mov Disord 1988;3:188–194.

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Nygaard TG, Trugman JM, de Yebenes JG, Fahn S. Dopa-responsive dystonia: the spectrum of clinical manifestations in a large North American family. Neurology 1990;40:66–69. Oppenheim H. Uber eine eigenartige Krampfkrankheit des kindlichen und jugendlichen Alters (Dysbasia lordotica progressiva, Dystonia musculorum deformans). Neurol Centrabl 1911;30:1090–1107. Ozelius LJ, Hewett JW, Page CE, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP binding protein. Nat Genet 1997;17:40–48. Quinn NP. Essential myoclonus and myoclonic dystonia. Mov Disord 1996;11:119–124. Rajput AH, Gibb WRG, Zhong XH, et al. DOPA-responsive dystonia: pathological and biochemical observations in a case. Ann Neurol 1994;35:396–402. Saint-Hilaire M-H, Burke RE, Bressman SB, et al. Delayed-onset dystonia due to perinatal or early childhood asphyxia. Neurology 1991;41:216–222. Sawle GV, Leenders KL, Brooks DJ, et al. Dopa-responsive dystonia: [F-18]dopa positron emission tomography. Ann Neurol 1991;30:24–30. Thony B, Blau N. Mutations in the GTP cyclohydrolase I and 6-pyruvoyltetrahydropterin synthase genes. Hum Mutat 1997;10:11–20. Zweig RM, Hedreen JC, Jankel WR, et al. Pathology in brainstem regions of individuals with primary dystonia. Neurology 1988;38:702–706.

CHAPTER 113. ESSENTIAL TREMOR MERRITT’S NEUROLOGY

CHAPTER 113. ESSENTIAL TREMOR ELAN D. LOUIS AND PAUL E. GREENE Treatment Differential Diagnosis Suggested Readings

Essential tremor, the most common adult-onset movement disorder, is characterized by an 8- to 12-Hz postural and kinetic tremor of the arms. Tremor may also involve the head, the voice, and rarely the legs. The tremor is present with sustained posture (arms extended in front of the body) or during movement (touching finger-to-nose, writing, drinking water). The tremor is often mildly asymmetric. It is rarely present at rest, in contrast to the tremor of Parkinson disease. The crude prevalence of essential tremor in different populations has been estimated to be between 0.4% and 3.9%; among those over the age of 65 years, the prevalence is higher. The disorder is partly genetic. There are large kindreds with an autosomal dominant form of essential tremor, and in a small number, linkage has been demonstrated to regions on chromosomes 2p and 3q. However, the existence of sporadic cases of essential tremor and the variability in age at onset in familial cases argues for the presence of nongenetic environmental causes in some cases. The extent to which essential tremor is a genetic disorder or a sporadic disorder is unknown. In different studies, 17% to 100% of cases report at least one affected relative. There have been few published autopsy studies, and there are no pathognomonic pathologic abnormalities. Several positron emission tomography studies have revealed metabolic abnormalities in the cerebellum. It is not known whether the disease is the result of a progressive loss of selected neuronal populations or a static insult. The onset occurs at any age, although incidence increases markedly with advancing age. Initially, the tremor may be mild, intermittent, and asymptomatic. In 90% to 99.5% of individuals with essential tremor, the tremor is mild and medical attention is never sought. The condition may remain static for years, even decades. However, patients often note a gradual increase in severity, confirming the finding in observational studies that older patients tend to have tremors of lower frequency and higher amplitude. The tremor may spread to involve the head in a rhythmic bobbing that may be either vertical or horizontal. It then may spread to the vocal cords or diaphragm, causing a characteristic vocal tremor. Many patients note that tremor is temporarily suppressed by drinking alcoholic beverages, but a rebound exacerbation sometimes follows.

TREATMENT The tremor may be severe enough to result in embarrassment and functional disability. In up to 15% of those attending clinics, the tremor leads to early retirement. Beta-blockers and primidone, alone or in combination, are the most effective pharmacologic therapies. Propranolol has been used in doses up to 240 mg daily; primidone may be effective in doses of 50 mg or less daily. Both drugs reduce the amplitude of tremor in some patients but do not abolish the tremor; benefit may disappear with time. Stereotactic thalamotomy can reduce essential tremor in the contralateral limbs, but the condition is rarely sufficiently disabling to warrant brain surgery. High-frequency thalamic stimulation has been effective in reducing tremor severity. Clonazepam, methazolamide, glutethimide, clozapine, and gabapentin have been reported to benefit some patients.

DIFFERENTIAL DIAGNOSIS Essential tremor is frequently misdiagnosed as parkinsonism, especially in the elderly. Differentiation may readily be made, however, by the absence of parkinsonian features, such as rest tremor, muscular rigidity, bradykinesia, or loss of postural control. Handwriting is large, irregular, and tremulous in striking contrast to the tremulous micrographia of parkinsonism. Head tremor rarely occurs in parkinsonism; instead, tremor affects the lips, tongue, and jaw. Patients with a long history of tremor of both hands occasionally develop typical signs and symptoms of Parkinson disease. It is not known whether this development is a coincidence of common conditions or whether patients with essential tremor are at increased risk of parkinsonism. Absence of dysdiadochokinesia, dysmetria, exaggeration of the tremor with intention, and other cerebellar signs distinguishes essential tremor from cerebellar “intention” tremor. Hyperthyroidism or the use of lithium or valproate are usually excluded by clinical history. The most difficult differential is between a mild case of essential tremor and enhanced physiologic tremor. Task-specific tremors, such as tremors restricted to the act of writing, or tremor associated with a task-specific dystonic posturing, such as writer's cramp, are diagnostic gray areas between essential tremor and primary torsion dystonia. SUGGESTED READINGS Bain PG, Findley LJ, Thompson PD, et al. A study of heredity of essential tremor. Brain 1994;117:805–824. Elble RJ. Central mechanisms of tremor. J Clin Neurophysiol 1996;13:133–144. Findley LJ. The pharmacology of essential tremor. In: Marsden CD, Fahn S, eds. Movement disorders II. London: Butterworths, 1987. Gulcher JR, Jonsson P, Kong A, et al. Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nat Genet 1997;17:84–87. Higgins JJ, Pho LT, Nee LE. A gene (ETM) for essential tremor maps to chromosome 2p22-p25. Mov Disord 1977;12:859–864. Jenkins IH, Bain PG, Colebatch JG, et al. A positron emission tomography study of essential tremor: evidence for overactivity of cerebellar connections. Ann Neurol 1993;34:82–90. Koller W, Pahwa R, Busenbark K, et al. High-frequency unilateral thalamic stimulation in the treatment of essential and Parkinsonian tremor. Ann Neurol 1997;42:292–299. Larsson T, Sjögren T. Essential tremor: a clinical and genetic population study. Acta Psychiatr Neurol Scand 1960:36[Suppl 144]:1–176. Louis ED, Ford B, Pullman S. Prevalence of asymptomatic tremor in relatives of patients with essential tremor. Arch Neurol 1997;54:197–200. Louis ED, Ottman R. How familial is familial tremor? Genetic epidemiology of essential tremor. Neurology 1996;46:1200–1205. Louis ED, Ottman R, Hauser WA. How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998;13:5–10. Louis ED, Wendt KJ, Pullman SL, Ford B. Is essential tremor symmetric? Observational data from a community-based study of essential tremor. Arch Neurol 1998;55:1553–1559. Rajput AH, Offord KP, Beard CM, Kurland LT. Essential tremor in Rochester, Minnesota: a 45-year study. J Neurol Neurosurg Psychiatry 1984;47:466–470. Rajput AH, Rozdilsky B, Ang L, Rajput A. Clinicopathological observations in essential tremor: report of six cases. Neurology 1991;41:1422–1424.

CHAPTER 114. PARKINSONISM MERRITT’S NEUROLOGY

CHAPTER 114. PARKINSONISM STANLEY FAHN AND SERGE PRZEDBORSKI Parkinson Disease (Primary Parkinsonism) Drug-Induced Parkinsonism Hemiparkinsonism-Hemiatrophy Syndrome Normal Pressure Hydrocephalus Postencephalitic Parkinsonism 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism Vascular Parkinsonism Cortical-Basal Ganglionic Degeneration Lytico-Bodig (Parkinson Dementia Amyotrophic Lateral Sclerosis Complex of Guam) Other Parkinson-Dementia Syndromes Multiple System Atrophy Treatment Stages of Parkinson Disease Complications of Long-Term Levodopa Therapy Mental and Behavioral Changes Course Suggested Readings

In 1817, James Parkinson described the major clinical features of what today is recognized as a symptom complex manifested by any combination of six cardinal features: tremor at rest, rigidity, bradykinesia-hypokinesia, flexed posture, loss of postural reflexes, and the freezing phenomenon. At least two of these features, with at least one being either tremor at rest or bradykinesia, must be present for a diagnosis of definite parkinsonism. The many causes of parkinsonism ( Table 114.1) are divided into four categories—idiopathic, symptomatic, Parkinson-plus syndromes, and various heredodegenerative diseases in which parkinsonism is a manifestation.

TABLE 114.1. CLASSIFICATION OF MAJOR PARKINSONIAN SYNDROMES

The core biochemical pathology in parkinsonism is decreased dopaminergic neurotransmission in the basal ganglia. In most of the diseases in Table 114.1, degeneration of the nigrostriatal dopamine system results in marked loss of striatal dopamine content. In some, degeneration of the striatum with loss of dopamine receptors is characteristic. Drug-induced parkinsonism is the result of blockade of dopamine receptors or depletion of dopamine storage. It is not known how hydrocephalus or abnormal calcium metabolism produces parkinsonism. Physiologically, the decreased dopaminergic activity in the striatum leads to disinhibition of the subthalamic nucleus and the medial globus pallidus, which is the predominant efferent nucleus in the basal ganglia. Understanding the biochemical pathology led to dopamine replacement therapy; understanding the physiologic change led to surgical interventions, such as pallidotomy, thalamotomy, and subthalmic nucleus stimulation. The clinical features of tremor, rigidity, and flexed posture are referred to as positive phenomena and are reviewed first; bradykinesia, loss of postural reflexes, and freezing are negative phenomena. In general, the negative phenomena are the more disabling. Rest tremor at a frequency of 4 to 5 Hz is present in the extremities, almost always distally; the classic “pill-rolling” tremor involves the thumb and forefinger. Rest tremor disappears with action but reemerges as the limbs maintain a posture. Rest tremor is also common in the lips, chin, and tongue. Rest tremor of the hands increases with walking and may be an early sign when others are not yet present. Stress worsens the tremor. Rigidity is an increase of muscle tone that is elicited when the examiner moves the patient's limbs, neck, or trunk. This increased resistance to passive movement is equal in all directions and usually is manifest by a ratchety “give” during the movement. This so-called cogwheeling is caused by the underlying tremor even in the absence of visible tremor. Cogwheeling also occurs in patients with essential tremor. Rigidity of the passive limb increases while another limb is engaged in voluntary active movement. The flexed posture commonly begins in the arms and spreads to involve the entire body ( Fig. 114.1). The head is bowed, the trunk is bent forward, the back is kyphotic, the arms are held in front of the body, and the elbows, hips, and knees are flexed. Deformities of the hands include ulnar deviation of the hands, flexion of the metacarpal-phalangeal joints, and extension of the interphalangeal joints (striatal hand). Inversion of the feet is apparent, and the big toes may be dorsiflexed (striatal toe). Lateral tilting of the trunk is common.

FIG. 114.1. Parkinson patient body posture. A: Front view. B: Side view.

Akinesia is a term used interchangeably with bradykinesia and hypokinesia. Bradykinesia (slowness of movement, difficulty initiating movement, and loss of automatic movement) and hypokinesia (reduction in amplitude of movement, particularly with repetitive movements, so-called decrementing) are the most common features of parkinsonism, although they may appear after the tremor. Bradykinesia has many facets, depending on the affected body parts. The face loses spontaneous expression (masked facies, hypomimia) with decreased frequency of blinking. Poverty of spontaneous movement is characterized by loss of gesturing and by the patient's tendency to sit motionless. Speech becomes soft (hypophonia), and the voice has a monotonous tone with a lack of inflection ( aprosody). Some patients do not enunciate clearly ( dysarthria) and do not separate syllables clearly, thus running the words together ( tachyphemia). Bradykinesia of the dominant hand results in small and slow handwriting (micrographia) and in difficulty shaving, brushing teeth, combing hair, buttoning, or applying makeup. Playing musical instruments is impaired. Walking is slow, with a shortened stride length and a tendency to shuffle; arm swing decreases and eventually is lost. Difficulty rising from a deep chair, getting out of automobiles, and turning in bed are symptoms of truncal bradykinesia. Drooling saliva results from failure to swallow spontaneously, a feature of

bradykinesia, and is not caused by excessive production of saliva. The patients can swallow properly when asked to do so, but only constant reminders allow them to keep swallowing. Similarly, arm swing can be normal if the patient voluntarily and, with effort, wishes to have the arms swing on walking. Pronounced bradykinesia prevents a patient with parkinsonism from driving an automobile; foot movement from the accelerator to the brake pedal is too slow. Bradykinesia is commonly misinterpreted by patients as weakness. Fatigue, a common complaint in parkinsonism, particularly in the mild stage of the disease before pronounced slowness appears, may be related to mild bradykinesia or rigidity. Subtle signs of bradykinesia can be detected even in the early stage of parkinsonism if one examines for slowness in shrugging the shoulders, lack of gesturing, decreased arm swing, and decrementing amplitude of rapid successive movements. With advancing bradykinesia, slowness and difficulty in the execution of activities of daily living increase. A meal normally consumed in 20 minutes may be only half eaten in an hour or more. Swallowing may become impaired with advancing disease, and choking and aspiration are concerns. Loss of postural reflexes leads to falling and eventually to inability to stand unassisted. Postural reflexes are tested by the pull-test, which is performed by the examiner, who stands behind the patient, gives a sudden firm pull on the shoulders, and checks for retropulsion. With advance warning, a normal person can recover within one step. The examiner should always be prepared to catch the patient when this test is conducted; otherwise, a person who has lost postural reflexes could fall. As postural reflexes are impaired, the patient collapses into the chair on attempting to sit down ( sitting en bloc). Walking is marked by festination, whereby the patient walks faster and faster, trying to move the feet forward to be under the flexed body's center of gravity and thus prevent falling. The freezing phenomenon (motor block) is transient inability to perform active movements. It most often affects the legs when walking but also can involve eyelid opening (known as apraxia of lid opening or levator inhibition), speaking (palilalia), and writing. Freezing occurs suddenly and is transient, lasting usually no more than several seconds with each occurrence. The feet seem as if “glued to the ground” and then suddenly become “unstuck,” allowing the patient to walk again. Freezing typically occurs when the patient begins to walk (“start-hesitation”), attempts to turn while walking, approaches a destination, such as a chair in which to sit (destination-hesitation), and is fearful about inability to deal with perceived barriers or time-restricted activities, such as entering revolving doors, elevator doors that may close, and crossing heavily trafficked streets (sudden transient freezing). Freezing is often overcome by visual clues, such as having the patient step over objects, and is much less frequent when the patient is going up steps than when walking on a level ground. The combination of freezing and loss of postural reflexes is particularly devastating. When the feet suddenly stop moving forward, the patient falls because the upper part of the body continues in motion as a result of the inability to recover an upright posture. Falling is responsible for the high incidence of hip fractures in parkinsonian patients. Likely related to the freezing phenomenon is the difficulty for parkinsonian patients to perform two motor acts simultaneously.

PARKINSON DISEASE (PRIMARY PARKINSONISM) Pathology The pathology of Parkinson disease (PD) is distinctive. Degeneration of the neuromelanin-containing neurons in the brainstem occurs, especially in the ventral tier of the pars compacta in the substantia nigra ( Fig. 114.2) and in the locus ceruleus; many of the surviving neurons contain eosinophilic cytoplasmic inclusions known as Lewy bodies, the pathologic hallmark of the disease. By the time symptoms appear, the substantia nigra already has lost about 60% of dopaminergic neurons and the dopamine content in the striatum is about 80% less than normal.

FIG. 114.2. Parkinson pathology. Depigmentation of substantia nigra of a Parkinson patient (left) in contrast to that of a normal patient (right).

Epidemiology PD makes up approximately 80% of cases of parkinsonism listed in Table 114.1. The age at onset assumes a bell-shaped curve with a mean of 55 years in both sexes and a wide range in age from 20 to 80. Onset at younger than 20 years is known as juvenile parkinsonism; when primary, it is usually familial and without Lewy bodies in the degenerating substantia nigra. Juvenile parkinsonism is not always primary and can be due to heredodegenerative diseases such as Huntington disease and Wilson disease. Onset of primary parkinsonism between 20 and 40 years is known as young-onset PD. PD is more common in men, with a male-to-female ratio of 3:2. The prevalence of PD is approximately 160 per 100,000, and the incidence is about 20 per 100,000/yr. Prevalence and incidence increase with age. At age 70, the prevalence is approximately 550 per 100,000, and the incidence is 120 per 100,000/yr. Symptoms and Signs The clinical motor features of PD are the six cardinal features described for parkinsonism in general. The onset is insidious; tremor is the symptom first recognized in 70% (Table 114.2). Symptoms often begin unilaterally, but as the disease progresses, it becomes bilateral. The disease can remain confined to one side, although steadily worsening for several years before the other side becomes involved. The disease progresses slowly, and if untreated, the patient eventually becomes wheelchair-bound and bedridden. Despite severe bradykinesia with marked immobility, patients with PD may rise suddenly and move normally for a short burst of motor activity, so-called kinesia paradoxica.

TABLE 114.2. INITIAL SYMPTOMS IN PARKINSON DISEASE

In addition to the motor signs that are used to define parkinsonism, most patients with PD have behavioral signs as well. Attention span is reduced, and there is visuospatial impairment. The personality changes; the patient slowly becomes more dependent, fearful, indecisive, and passive. The spouse gradually makes more of the decisions and becomes the dominant partner. The patient speaks less spontaneously. The patient eventually sits much of the day and is inactive unless encouraged to exercise. Passivity and lack of motivation are common and are expressed by the patient's aversion for visiting friends. Depression is frequent in

patients with PD, developing at a rate of about 2% per year. Cognitive decline is another common feature but is usually not the severe type of dementia seen in Alzheimer disease. Memory impairment is not a feature of PD; rather the patient is just slow in responding to questions, so-called bradyphrenia. The correct answer can be obtained if the patient is given enough time. Subtle signs of bradyphrenia, such as the inability to change mental set rapidly, may be present early in the disease. Fifteen percent to 20% of patients with PD have a more profound dementia, similar to that in Alzheimer disease. These patients are usually elderly and have developed concurrent Alzheimer disease or diffuse Lewy body disease, in which Lewy bodies are present in cortical neurons. These disorders are not always distinguishable, but Lewy body disease is often characterized by fluctuating hallucinations. Sensory symptoms are fairly common, but objective sensory impairment is not seen in PD. Symptoms of pain, burning, and tingling occur in the region of motor involvement. A patient may have dull pain in one shoulder as an early symptom of the disease, which often is misdiagnosed as arthritis or bursitis, and even before clearcut signs of bradykinesia appear in that same arm. Akathisia (inability to sit still, restlessness) and the restless legs syndrome occur in some patients with PD. In both syndromes, uncomfortable sensations disappear with movement, and sometimes the two conditions are difficult to distinguish. Akathisia is usually present most of the day; it may respond to levodopa but otherwise has not been treated successfully. The restless legs syndrome develops late in the day with crawling sensations in the legs and may be associated with periodic movements in sleep, thereby disturbing sleep. This problem can be treated successfully with opioids, such as propoxyphene, oxycodone, and codeine. Autonomic disturbances also are encountered. The skin is cooler, constipation is a major complaint, bladder emptying is inadequate, erection may be difficult to achieve, and blood pressure may be low. A major diagnostic consideration is the Shy-Drager syndrome, also called multiple system atrophy (MSA). Seborrhea and seborrheic dermatitis are common but can be controlled with good hygiene. Tendon reflexes are usually unimpaired in PD; an abnormal extensor plantar reflex suggests a Parkinson-plus syndrome. An uninhibited glabellar reflex ( Myerson sign), snout reflex, and palmomental reflexes are common, even early in the disease. Etiology, Pathogenesis, and Genetics The cause of PD is unknown. Research has concentrated on genetics, exogenous toxins, and endogenous toxins from cellular oxidative reactions. Based on twin studies, onset of PD before age 50 has a higher likelihood of a genetic etiology. Several genes have been identified, usually causing young-onset parkinsonism ( Table 114.3). The first (PD1) is due to mutations in the gene for the protein, alpha-synuclein, located on chromosome 4q21-q22. This protein is present in synapses and cell nuclei, but its function is unclear. The resulting parkinsonism transmits in an autosomal dominant pattern. It is rare, being seen only in a few families in Greece, Italy, and Germany. After the discovery of this genetic defect, however, alpha-synuclein was found to be present in Lewy bodies (even in patients with PD without this genetic mutation). It is believed that the abnormal protein aggregates and accumulates in cells, causing neuronal death.

TABLE 114.3. GENETIC FORMS OF PARKINSON DISEASE

The most commonly occurring gene defect causing PD is PD2 on chromosome 6q25-q27, coding for a previously unknown protein, named parkin. This protein is abundant in the substantia nigra and shares homology with ubiquitin and with other proteins involved in cell growth, differentiation, and development. Mutations in the parkin gene result in an autosomal recessive parkinsonism that is slowly progressive, with onset usually before the age of 40 years, and sleep benefit; rest tremor is not prominent. There is degeneration of substantia nigra neurons but no Lewy body inclusions. Some affected members of the so-called Iowa pedigree have essential tremor in addition to parkinsonism. Rare families with PD seem to exhibit a maternal mode of inheritance, suggesting a mitochondrial DNA defect. Dopa-responsive dystonia may present during adulthood as PD. It tends to be benign, responding to relatively low doses of levodopa and not progressing. This disorder is discussed in Chapter 112. The discovery that the chemical agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can cause parkinsonism raised the possibility that PD might be caused by an environmental toxin. No single environmental factor has emerged as essential, but growing up in a rural environment was disproportionately frequent in some studies. Because aging is associated with a loss of catecholamine-containing neurons and an increase in monoamine oxidase (types A and B) activity, an endogenous toxin hypothesis has emerged. Cellular oxidation reactions (such as enzymatic oxidation and autooxidation of dopamine and other monoamines) result in the formation of hydrogen peroxide and free radicals (oxyradicals), and if not removed properly, these agents can damage the monoamine neurons. Substantia nigra in patients with PD shows severe depletion of reduced glutathione, the major substrate required for the elimination of hydrogen peroxide. This change is also seen in brains with incidental Lewy bodies and therefore could be the earliest biochemical abnormality of PD. It is not known, however, if this change causes oxidative stress (increasing oxyradicals) or is the result of oxidative stress (because reduced glutathione is oxidized under conditions of oxidative stress). Iron in the substantia nigra may also play a critical role because it can catalyze the formation of the highly reactive hydroxyl radical from hydrogen peroxide. Postmortem biochemical observations showed that complex I activity of mitochondria is reduced in substantia nigra of patients with PD (MPP+ also affects complex I). This reduction could be the result of an exogenous toxin, oxidative stress, or a genetic defect stemming from the mitochondrial DNA. On the other hand, a primary defect of complex I would decrease the synthesis of ATP and also lead to the buildup of free electrons, thereby increasing oxyradicals and accentuating oxidative stress. Differential Diagnosis The diagnosis of PD is based on the clinical features of parkinsonism, insidious onset, slow progression, and the lack of other findings in the history, examination, or laboratory tests that would point to some other cause of parkinsonism. One of the most common disorders mistaken for PD is essential tremor (see Chapter 113), which is characterized by postural and kinetic tremor, not rest tremor. Several clinical clues suggest that a patient with parkinsonism has some form of the syndrome other than PD itself ( Table 114.4). In general, PD often appears with symptoms on only one side of the body, whereas patients with symptomatic parkinsonism or Parkinson-plus syndromes almost always have symmetric symptoms and signs (notable exceptions would be cortical-basal ganglionic degeneration and parkinsonism resulting from a focal brain injury, such as head trauma). Similarly, a rest tremor almost always indicates PD because it rarely is seen in symptomatic parkinsonism or Parkinson-plus syndromes, except in drug-induced and MPTP-induced parkinsonism, which do include rest tremor. The patient who does not have unilateral onset or rest tremor, however, still can have PD that begins symmetrically and without tremor. Perhaps the most important diagnostic aid is the response to levodopa. Patients with PD almost always have a satisfactory response to this drug. If a patient never responds to levodopa, the diagnosis of some other form of parkinsonism is likely. A response to levodopa, however, does not confirm the diagnosis of PD because many cases of symptomatic parkinsonism (e.g., MPTP, postencephalitic, reserpine-induced) and many forms of Parkinson-plus syndromes in their early stages (e.g., Shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy) also respond to levodopa. Table 114.4 provides a list of some helpful

clues.

TABLE 114.4. CLUES INDICATING THE LIKELY TYPE OF PARKINSONISM

DRUG-INDUCED PARKINSONISM Drugs that block striatal dopamine D2 receptors (e.g., phenothiazines and butyrophenones) or deplete striatal dopamine (e.g., reserpine, tetrabenazine) can induce a parkinsonian state (see also Chapter 116). This condition is reversible when the offending agent is withdrawn, but it may require several weeks. Parkinsonism that persists longer than 6 months is attributed to underlying PD that becomes evident during exposure to these antidopaminergic drugs. Anticholinergic drugs can ameliorate the parkinsonian signs and symptoms. The atypical neuroleptic clonazapine is the least likely antipsychotic agent to induce or worsen parkinsonism.

HEMIPARKINSONISM-HEMIATROPHY SYNDROME This relatively benign syndrome consists of hemiparkinsonism in association with ipsilateral body hemiatrophy or contralateral brain hemiatrophy. The parkinsonism usually begins in young adults and often remains as hemiparkinsonism, sometimes with hemidystonia. It tends to be nonprogressive or slowly progressive compared with PD. The disorder is thought to be the result of brain injury early in life, possibly even perinatally. It usually responds poorly to medications.

NORMAL PRESSURE HYDROCEPHALUS The gait disorder in normal pressure hydrocephalus (see Chapter 48) resembles that of parkinsonism, with shuffling short steps and loss of postural reflexes and sometimes freezing. Features of urinary incontinence and dementia occur later. Tremor is rare. The grossly enlarged ventricles lead to the correct diagnosis, with the symptoms improving on removal or shunting of cerebrospinal fluid. The gait disorder is in striking contrast to the lack of parkinsonism in the upper part of the body. The major differential diagnosis for lower body parkinsonism includes vascular parkinsonism and the idiopathic gait disorder of the elderly.

POSTENCEPHALITIC PARKINSONISM Although rarely encountered today, postencephalitic parkinsonism was common in the first half of this century. Parkinsonism was the most prominent sequela of the pandemics of encephalitis lethargica (von Economo encephalitis) that occurred between 1919 and 1926. Although the causative agent was never established, it affected mainly the midbrain, thus destroying the substantia nigra. The pathology is distinctive because of the presence of neurofibrillary tangles in the remaining nigral neurons. In addition to slowly progressive parkinsonism, with features similar to those of PD, oculogyric crises often occur in which the eyes deviate to a fixed position for minutes to hours. Dystonia, tics, behavioral disorders, and ocular palsies may be present. Patients with post-encephalitic parkinsonism are more sensitive to levodopa, with limited tolerance because of the development of dyskinesias, mania or hypersexuality at low dosages. Anticholinergics are tolerated well, however.

1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE-INDUCED PARKINSONISM Although rare, this disorder is important because this toxin selectively destroys the dopamine nigrostriatal neurons, and its mechanism has been investigated intensively for possible clues to the pathoetiology of PD. MPTP is a protoxin, being converted to MPP+ by the action of the enzyme monoamine oxidase type B. MPP+ is taken up selectively by dopamine neurons and terminals via the dopamine transporter system. MPP+ inhibits complex I in the mitochondria, depletes ATP, and increases the content of superoxide ion radicals. Superoxide in turn can react with nitric oxide to form the oxyradical peroxynitrite. MPTP-induced parkinsonism has occurred in drug abusers who used it intravenously and possibly also in some laboratory workers exposed to the toxin. The clinical syndrome is indistinguishable from PD and responds to levodopa. Positron emission tomography (PET) indicates that a subclinical exposure to MPTP results in a reduction of fluorodopa uptake in the striatum, thereby making the person liable to future development of parkinsonism.

VASCULAR PARKINSONISM Vascular parkinsonism resulting from lacunar disease is not common but can be diagnosed by neuroimaging with magnetic resonance imaging evidence of hyperintense T2-weighted signals compatible with small infarcts. Hypertension is usually required for the development of this disorder. The onset of symptoms, usually with a gait disorder, is insidious, and the course is progressive. A history of a major stroke preceding onset is rare, although a stepwise course is sometimes seen. Gait is profoundly affected (lower body parkinsonism), with freezing and loss of postural reflexes. Tremor is rare. Response to the typical antiparkinsonian agents is poor.

CORTICAL-BASAL GANGLIONIC DEGENERATION Initially reported as corticodentatonigral degeneration, this disorder is characterized pathologically by enlarged achromatic neurons in cortical areas (particularly parietal and frontal lobes) along with nigral and striatal neuronal degeneration. The onset is insidious and typically unilateral, with marked rigidity-dystonia on the involved arm. Cortical signs of apraxia, alien limb phenomena, cortical sensory loss, and cortical reflex myoclonus of that limb are also seen. Speech is hesitant, gait is poor, and occasionally action tremor is evident. The disease usually spreads slowly to involve both sides of the body, and supranuclear gaze difficulties often occur late. Medications have been ineffective.

LYTICO-BODIG (PARKINSON–DEMENTIA–AMYOTROPHIC LATERAL SCLEROSIS COMPLEX OF GUAM) A combination of parkinsonism, dementia, and motor neuron disease occurred among the Chamorro natives on Guam in the Western Pacific. The incidence has declined gradually. Epidemiologic evidence supports a probable environmental cause, with exposure occurring during adolescence or adulthood. One hypothesis is that environmental exposure to the neurotoxin found in the seed of the plant Cycas circinalis was responsible for the neuronal degeneration. Natives on Guam used this seed to make flour in World War II. But this hypothesis has been questioned. Besides parkinsonism, dementia, and motor neuron disease in various combinations, supranuclear gaze defects also appear. A characteristic pathologic finding is the presence of neurofibrillary tangles in the degenerating neurons, including the substantia nigra. Lewy bodies and senile plaques are absent.

OTHER PARKINSON-DEMENTIA SYNDROMES Although bradyphrenia is common in PD, dementia also occurs in 15% to 20% of patients. The incidence of dementia increases with age, and those with dementia have a higher mortality rate. The two most common pathologic substrates for dementia in parkinsonism are the changes typical of Alzheimer disease and the presence of Lewy bodies diffusely in the cerebral cortex. It is not known if the Alzheimer changes are coincidental because of the elderly population of affected individuals or whether Alzheimer and PD are somehow related. Similarly, it is not known whether the spread of Lewy bodies into the cortex is a feature of progression

of PD or a distinct entity. The presence of dementia limits the tolerance of antiparkinsonian agents because they tend to increase confusion and produce psychosis.

MULTIPLE SYSTEM ATROPHY MSA has been applied to a tetrad of four syndromes previously considered as distinct and separate entities: striatonigral degeneration, Shy-Drager syndrome, olivopontocerebellar atrophy, and parkinsonism-amyotrophy syndrome ( Table 114.5). The full pathologic spectrum consists of neuronal loss and gliosis in the neostriatum, substantia nigra, globus pallidus, cerebellum, inferior olives, basis pontine nuclei, intermediolateral horn cells, anterior horn cells, and corticospinal tracts. A common pathologic feature is the presence of widespread glial cytoplasmic inclusions, particularly in oligodendroglia. The presence of these argyophilic perinuclear structures, which are primarily composed of straight microtubules containing ubiquitin and tau protein, in this tetrad of syndromes supports the concept that these conditions are variations of the same disease process.

TABLE 114.5. DIFFERENT CLINICAL ENTITIES OF MULTIPLE SYSTEM ATROPHY

Patients with MSA have with parkinsonism one of the other clinical features listed in Table 114.5; each entity can be identified by its characteristic clinical feature. Corticospinal tract findings may be present as well. MSA may account for 10% of patients with parkinsonism. In striatonigral degeneration, nerve cell loss and gliosis are found predominantly in the substantia nigra and neostriatum. The symptoms are those of parkinsonism, without tremor. Also, the beneficial response to levodopa is slight because striatal neurons containing dopamine receptors are lost. Dystonic reactions commonly follow low-dosage levodopa therapy. Laryngeal stridor may be caused by paresis of one or both vocal cords. Occasionally, degeneration is seen in the cerebellum, but the presence of cerebellar symptoms classifies the disorder as olivopontocerebellar atrophy. In the Shy-Drager syndrome, the preganglionic sympathetic neurons in the intermediolateral horns are lost. In addition, other areas may be affected, particularly the substantia nigra (to produce parkinsonism), the cerebellum (to cause ataxia), and the striatum (to cause lack of response to levodopa). Less often, the anterior horn cells are involved (to cause amyotrophy). Because the postganglionic sympathetic neuron is intact in Shy-Drager syndrome, plasma norepinephrine is normal when the patient is supine but fails to rise when the patient stands. Orthostatic hypotension is a major disabling symptom, but other dysautonomic symptoms are also troublesome, including impotence and bladder and bowel dysfunction. Sometimes the striatum is spared, thus allowing a response to levodopa therapy. Levodopa, however, can exaggerate orthostatic hypotension. Measures to overcome this problem include wearing support hose, ingesting salt, and taking fludrocortisone or midodrine, but this approach can result in supine hypertension, which is partially offset if the patient sleeps at an incline instead of in a recumbent position. If the striatum becomes more involved, with presumed loss of dopamine receptors, the benefit of levodopa as an antibradykinetic drug diminishes. Many disorders make up the complex known as olivopontocerebellar atrophy. Familial olivopontocerebellar atrophy appears as a cerebellar syndrome, whereas sporadic olivopontocerebellar atrophy is characterized by a mixture of parkinsonism and cerebellar syndrome. In addition to degeneration of the olives, pons, and cerebellum, neuronal loss in the striatum and substantia nigra occurs. Some patients respond to levodopa therapy if the striatum is not severely degenerated. The least common part of the spectrum of MSA involves just the anterior horn cells (to cause amyotrophy) and the nigrostriatal complex (to cause parkinsonism). Only a few of these cases have been described. Helpful in diagnosing MSA is fluorodeoxyglucose PET showing hypometabolism in the striatum and the frontal lobes. Treatment of MSA, like other Parkinson-plus syndromes, requires testing levodopa to the maximum tolerated dose or up to 2 g/d (in the presence of carbidopa) to determine whether any therapeutic response can be obtained. In most situations, dopamine replacement therapy is of limited value. Anticholinergics may provide some mild benefit, however.

TREATMENT Treatment of parkinsonism in general is based on the treatment of PD, which is the focus of this section. At present, treatment is aimed at controlling symptoms because no drug or surgical approach unequivocally prevents progression of the disease. Treatment is individualized because each patient has a unique set of symptoms, signs, response to medications, and a host of social, occupational, and emotional needs that must be considered. The goal is to keep the patient functioning independently as long as possible. Practical guides are the symptoms and degree of functional impairment and the expected benefits and risks of therapeutic agents. Drug Therapy Although pharmacotherapy is the basis of treatment, physiotherapy is also important. It involves patients in their own care, promotes exercise, keeps muscles active, and preserves mobility. This approach is especially beneficial as parkinsonism advances because many patients tend to remain sitting and inactive. Psychiatric assistance may be required to deal with depression and the social and familial problems that may develop with this chronic disabling illness. Electroconvulsive therapy may have a role in patients with severe intractable depression. Table 114.6 lists the drugs useful in parkinsonism according to mechanisms of action. It also lists some of the surgical approaches available. Selection of the most suitable drugs for the individual patient and deciding when to use them in the course of the disease are challenges for the treating clinician. In many Parkinson-plus disorders, the response to treatment is not satisfactory, but the principles for treating PD are used in treating these disorders as well. Because PD is chronic and progressive, treatment is lifelong. Medications and their doses change with time as adverse effects and new symptoms are encountered. Tactical strategy is based on the severity of symptoms.

TABLE 114.6. THERAPEUTIC CHOICES FOR PARKINSON DISEASE

In Table 114.6, carbidopa is listed as the peripheral dopa decarboxylase inhibitor, but in many countries benserazide is also available. These agents potentiate the effects of levodopa, thus allowing about a fourfold reduction in dosage to obtain the same benefit. Moreover, by preventing the formation of peripheral dopamine, which can act at the area postrema (vomiting center), they block the development of nausea and vomiting. Domperidone is a dopamine receptor antagonist that does not enter the central nervous system, it is used to prevent nausea, not only from levodopa but also from dopamine agonists. Domperidone is not available in the United States. Of the listed dopamine agonists, only bromocriptine, pergolide, pramipexole and ropinirole are available in the United States; they are reviewed in a following section. Because it is water soluble, apomorphine is used as an injectable, in countries where available, as a rapidly acting dopaminergic to overcome “off� states. Cabergoline has the longest half-life. Catecholamine-O-methyl transferase inhibitors extend the elimination half-life of levodopa. Amantadine, selegiline, and the anticholinergics are reviewed in following sections. Because the anticholinergics can cause forgetfulness and even psychosis, they should be used cautiously in patients most susceptible (those older than 70 years). The antihistaminics, tricyclics, and cyclobenzaprine have milder anticholinergic properties that make them useful in PD, particularly in the older patient who should not take the stronger anticholinergics. Antidepressants are needed for treating depression. Because of its anticholinergic and soporific effects, amitriptyline can be useful for these properties as well as for its antidepressant effect. The serotonin uptake inhibitors are also effective in treating depression of PD but may aggravate parkinsonism if antiparkinsonian drugs are not given concurrently. Diazepam is usually well tolerated without worsening parkinsonism and can help to lessen tremor by reducing the reaction to stress that worsens tremor. Cisapride can help to overcome constipation, a common complaint in patients with PD or the Shy-Drager syndrome. Clozapine, a selective dopamine D4 receptor antagonist, can ameliorate levodopa-induced psychosis without worsening parkinsonism, but weekly monitoring of white blood cells is necessary to prevent irreversible agranulocytosis. The drug is discontinued if the white blood cell count declines. Quetiapine, a related drug, does not need hematologic monitoring and therefore can be tried first to overcome psychosis. Surgery The surgical approaches listed in Table 114.6 are not considered in the early stages of PD but are reserved for patients who have failed to respond satisfactorily to drugs. Thalamotomy and thalamic stimulation (target for both is the ventral intermediate nucleus) are best for contralateral intractable tremor. Tremor can be relieved in at least 70% of cases. Although a unilateral lesion carries a small risk, bilateral operations result in dysarthria in 15% to 20% of patients. Thalamic stimulation seems to be safer and can be equally effective against tremor, but it runs the risks associated with foreign bodies and thin electronic wires that can break. Pallidotomy (target is the posterolateral part of the globus pallidus interna) is most effective for treating contralateral dopa-induced dystonia and chorea but also has some benefit for bradykinesia and tremor. The target in the globus pallidus interna is believed to be the site of afferent excitatory glutamatergic fibers coming from the subthalamic nucleus, which is overactive in PD. Lesions of the subthalamic nucleus, although effective in relieving parkinsonism in animal models, are hazardous in humans because hemichorea or hemiballism may result. Instead, stimulation of the subthalamic nucleus is used and appears to be the most promising in reducing contralateral bradykinesia and tremor. Subthalamic nucleus stimulation in a patient appears to reduce symptoms of PD that respond to levodopa in that patient. It is not effective against symptoms that do not respond to levdodopa. This type of surgery often allows a marked reduction of levodopa dosage, thereby reducing dopa-induced dyskinesias and treating parkinsonian symptoms. Fetal dopaminergic tissue implants are being investigated. This surgical procedure may reduce bradykinesia and rigidity in younger patients but is less effective in those over age 60; it is not effective against tremor. Its long-term effect is not established, but in some patients it has replaced bradykinesia with persistent dyskinesia in the absence of levodopa. Until this problem can be solved, transplantation surgery is not a useful option. Levodopa is uniformly accepted as the most effective drug available for symptomatic relief of PD. If it were uniformly and persistently successful and also free of complications, new strategies for other treatment would not be needed. Unfortunately, 75% of patients have serious complications after 5 years of levodopa therapy (Table 114.7).

TABLE 114.7. FIVE MAJOR OUTCOMES AFTER MORE THAN 5 YR OF LEVODOPA THERAPY (N = 330 PATIENTS)

STAGES OF PARKINSON DISEASE Early Stage It is debated whether early use of levodopa is responsible for later response fluctuations and other complications ( Table 114.7). Authorities generally agree, however, that in the early stage of PD when symptoms are noticed but not troublesome, symptomatic treatment is not necessary. All symptomatic drugs can induce side effects, and if a patient is not troubled socially or occupationally by mild symptoms, drug therapy can be delayed until symptoms become more pronounced. The major decision is when to introduce levodopa, the most effective drug. All patients are likely to develop complications associated with long-term use. Younger patients, in particular, are more likely to show response fluctuations, so other antiparkinsonian drugs should be used first to delay the introduction of levodopa; when deemed necessary, levodopa should be administered at the lowest effective dose. This approach is known as the dopa-sparing strategy. On the other hand, clinicians who doubt that levodopa is responsible for these complications might choose to use levodopa first because the therapeutic response is greater. No controlled clinical trials have been carried out to determine the role played by long-term use and high dosage of levodopa, and opinions differ about retrospective studies. Selegiline delays the need for levodopa therapy by an average of 9 months. Although some protective effect from this monoamine oxidase type B inhibitor could have been a possible explanation, the 9-month delay can be explained entirely on its persistent mild symptomatic effect. Selegiline has few adverse effects when given without levodopa, but when given concurrently with levodopa, it can increase the dopaminergic effect, allows a lower dose of levodopa, and contributes to dopaminergic toxicity. Without proof that selegiline actually slows the progression of PD, no compelling reason exists for requiring its use for patients in the early stage of PD. It should be considered one of several symptomatic drugs that can be used in the early stage of the disease to delay the introduction of levodopa; the superiority of any of these drugs to the others is not known. The antioxidant tocopherol (vitamin E) was tested at a dose of 2,000 U/d in mild PD as part of a controlled clinical trial and had no effect in delaying the need for levodopa. Stage When Symptoms and Signs Require Symptomatic Treatment Eventually, PD progresses and symptomatic treatment must be used. The most common problems that clinicians consider important in deciding to use symptomatic agents are the following: threat to employment; threat to ability to handle domestic, financial, or social affairs; threat to handle activities of daily living; and appreciable

worsening of gait or balance. In clinical practice, a global judgment for initiating such therapy is made in discussions between the patient and the treating physician. The choice now is whether to introduce levodopa or some other antiparkinsonian drug, such as amantadine, an anticholinergic, or a dopamine agonist. Levodopa is superior in relieving symptoms. Patients and clinicians who prefer a dopa-sparing strategy, however, select other agents. Amantadine Amantadine is a mild indirect dopaminergic agent that acts by augmenting dopamine release for storage sites and possibly blocking reuptake of dopamine into the presynaptic terminals. It also has some anticholinergic and antiglutamatergic properties. In the early stages of PD, it is effective in about two-thirds of patients. A major advantage is that benefit, if it occurs, is seen in a couple of days. The effect can be substantial. Unfortunately, its benefit in more advanced PD is often short-lived, with patients reporting a fall-off effect after several months of treatment. After dopamine stores are depleted, the effect of amantadine is exhausted. A common adverse effect is livedo reticularis (a reddish mottling of skin) around the knees; other adverse effects are ankle edema and visual hallucinosis. Sometimes, when the drug is discontinued, a gradual worsening of parkinsonian signs may follow, thus indicating that the drug has been helpful. The usual dose is 100 mg two times per day, but sometimes a higher dose (up to 200 mg two times per day) may be required. Amantadine can be useful not only in the early phases of symptomatic therapy by forestalling use of levodopa or reducing the required dosage of levodopa but also in the advanced stages as an adjunctive drug to levodopa and the dopamine agonists. It can also reduce the severity of dopa-induced dyskinesias, probably by its antiglutamatergic mechanism of action. Anticholinergic (Antimuscarinic) Drugs As a general rule, anticholinergic agents are less effective antiparkinsonian agents than are the dopamine agonists. The anticholinergic drugs are estimated to improve parkinsonism by about 20%. Many clinicians find that when tremor is not relieved by an agonist or levodopa, addition of an anticholinergic drug can be effective. Because the anticholinergic agent sometimes can lessen tremor severity even without levodopa, many clinicians use such an agent as monotherapy for tremor. If not helpful, continual use of the drug can be beneficial while a dopamine agonist or levodopa is added. Later, if tremor is relieved by the dopaminergic agent, the anticholinergic drug may be discontinued. Trihexyphenidyl is a widely used anticholinergic agent. A common starting dose is 2 mg three times per day. It can be gradually increased to 20 mg or more per day. Adverse effects from anticholinergic drugs are common, particularly in the age range of most patients with PD. Adverse cerebral effects are predominantly forgetfulness and decreased short-term memory. Occasionally, hallucinations and psychosis occur, particularly in the elderly patient; these drugs should be avoided in patients older than 70 years. If tremor is not relieved by dopaminergic drugs and one wishes to add an anticholinergic agent to the therapy for an elderly patient, amitriptyline, diphenhydramine, orphenadrine, or cyclobenzaprine are sometimes beneficial, without the central side effects of more potent agents. Diphenhydramine and amitriptyline can cause drowsiness and can be used as a hypnotic. For tremor control, the dose is increased gradually to 50 mg three times per day. A similar dose schedule is useful for orphenadrine. Cyclobenzaprine can be increased gradually until 20 mg three times per day is reached. Peripheral side effects are common and are often the reason for discontinuing or limiting the dosage of anticholinergic drugs. These adverse effects, however, can usually be overcome by adding pilocarpine eye drops if blurred vision occurs or if glaucoma is present. Pyridostigmine, up to 60 mg three times per day, can help to overcome dry mouth and urinary difficulties. Dopamine Agonists Dopamine agonists can be used as conjunctive therapy with levodopa to potentiate an antiparkinsonian effect, to reduce the dosage needed for levodopa alone, and to overcome some of the adverse effects of long-term use of levodopa or as monotherapy in the early stage of the disease to delay introduction of levodopa. It is likely that early use of dopamine agonists, by delaying the introduction of levodopa, reduces the time to develop complications from chronic levodopa therapy. The agonists are less effective than levodopa as antiparkinsonian agents, and most patients require the addition of levodopa within a couple of years. Bromocriptine, pergolide, lisuride, and cabergoline are ergot derivatives. As such, they could induce red inflamed skin ( St. Anthony's fire), but this side effect is rare and is reversible on discontinuing the drug. Retroperitoneal fibrosis is a more serious adverse, but also rare, event. The nonergoline agonists, pramipexole and ropinirole, often are associated with drowsiness and ankle edema. Sleep attacks, including falling asleep when driving a vehicle, are infrequent problems with these two agents, but drivers need to be cautioned about such a serious possibility. All agonists tend to induce orthostatic hypotension, particularly when the drug is first introduced. Afterward, this complication is much less common. Therefore, the best starting regimen is a small dose at bedtime for the first 3 days (bromocriptine 1.25 mg, pergolide 0.05 mg, pramipexole 0.125 mg, ropinirole 0.25 mg) and then switch from bedtime to daytime regimens at this dose for the next few days. The daily dose can be increased gradually at weekly intervals to avoid adverse effects (bromocriptine 1.25 mg, pergolide 0.25 mg, pramipexole 0.25 mg, ropinirole 0.75 mg) until a benefit or a plateau dosage is reached (bromocriptine 5 mg three times per day, pergolide and pramipexole 0.5 mg three times per day, ropinirole 1 mg three times per day). If this plateau is not satisfactory, the dose either can be increased gradually until it is quadrupled or can be held constant while beginning carbidopa/levodopa. If the agonists alone still are not effective, carbidopa/levodopa is needed. Besides the adverse effects listed above, there are subtle differences among the dopamine agonists. Cabergoline has the longest pharmacologic half-life and theoretically could be taken in once-a-day dosing. Pergolide acts at both the D1 and D2 dopamine receptors ( Table 114.8). Bromocriptine is a partial D1 antagonist. All act at the D2 receptor, which may account for most, if not all, of their anti-PD activity. Pergolide, pramipexole, and ropinirole also act at the D3 dopamine receptor, but it is not clear what effect this has clinically. All three appear to be equally effective against PD; bromocriptine appears to have the weakest anti-PD effect. It also seems to be more likely to induce psychosis and confusion, whereas the other three agonists are more likely to induce dyskinesias. As a general rule, however, dopamine agonists are less likely than levodopa to induce dyskinesias, and they have a half-life longer than that of levodopa, thus making them useful to reduce the severity of “off� states.

TABLE 114.8. EFFECT ON RECEPTORS BY DOPAMINE AGONISTS

Levodopa Some clinicians prefer to begin therapy with carbidopa/levodopa for early symptomatic treatment and to add an agonist after a small dose has been reached (e.g., 25/100 mg three times per day). This approach is particularly useful if a patient already has some disability. The advantage of using levodopa at this stage in preference to a dopamine agonist is that a therapeutic response is virtually guaranteed. Nearly all patients with PD respond to levodopa and do so quickly. In contrast, only some benefit adequately from a dopamine agonist alone, and it may take months to discover this because of a slower buildup of dosage. Therefore, if a definite response is needed quickly (e.g., to remain at work or to be self-sufficient), levodopa is preferable. On the other hand, if there is no particular urgency for a rapid clinical response and if the patient has no cognitive problems and is younger than 70 years of age, then beginning with a dopamine agonist allows one to use

the dopa-sparing strategy. Stage When Symptoms and Signs Require Treatment with Levodopa When other antiparkinsonian medications are no longer bringing about a satisfactory response, levodopa is required to reduce the severity of parkinsonism. Levodopa is the most potent anti-PD drug. In treating patients with PD, the rule of thumb is to use the lowest dosage that can bring about adequate symptom reversal, not the highest dosage that the patient can tolerate. As previously mentioned, the longer the duration of levodopa therapy and the higher the dose, the greater the likelihood motor complications will occur. After 5 years of levodopa therapy, about 75% of patients with PD have some form of troublesome complication ( Table 114.7). Most clinicians prefer to use levodopa with a peripheral dopa decarboxylase inhibitor (e.g., carbidopa) to increase therapeutic potency and to avoid gastrointestinal adverse effects. Slow-release forms of carbidopa/levodopa (Sinemet CR) and benserazide/levodopa (Madopar HBS) provide a longer half-life and a lower peak plasma level of levodopa. In the early stage of levodopa therapy, when complications have not yet developed, use of slow-release carbidopa/levodopa has little proven advantage over use of the standard preparation; it does not delay motor fluctuations. However, it may be useful to start treatment with such a sustained release preparation in elderly patients to avoid too high a brain concentration of levodopa that might induce drowsiness. Once response fluctuations have developed, the slow-release preparation could reduce mild wearing off. Also, a bedtime dose often allows more mobility during the night. Disadvantages are a delay in the response with each dose and the possibility of an excessive response that can be prolonged, thereby resulting in sustained severe dyskinesias. For a quick response on awakening, patients often take the standard preparation as the first morning dose in addition to the slow-release form. Some patients need a combination of standard and sustained-release preparations of levodopa throughout the day to obtain a smoother response and minimize their motor complications. The slow-release tablets of carbidopa/levodopa are available in two strengths: scored (50/200 mg, which can be broken in half) and unscored (25/100 mg). Neither should be crushed because the matrix of the tablet that delays solubilization would no longer be effective. When added to a dopamine agonist, a dose of 25/100 mg three to four times per day often suffices. When used alone, a starting dose of 25/100 mg three times per day often is necessary and can be increased as needed to 50/200 mg three or four times per day. If greater relief is required, a dopamine agonist or standard carbidopa/levodopa should be added. It should be noted that because all of the slow-release formulation is not absorbed before the tablet reaches the large intestine, a patient needs to consume an approximately 1.4 times greater dose to reach the comparable effectiveness of a dose of standard carbidopa/levodopa. Inadequate Response to Levodopa Treatment As a general rule, the single most important piece of information to help the differential diagnosis of PD and other forms of parkinsonism is the response to levodopa. If the response is nil or minor, the disorder probably is not PD. An adequate response, however, does not ensure the diagnosis of PD. All presynaptic disorders (e.g., reserpine-induced, MPTP-induced, postencephalitic parkinsonism) respond to levodopa. Also, a response to levodopa occurs in the early stages of MSA (including Shy-Drager syndrome, olivopontocerebellar atrophy, and even striatonigral degeneration); only later, when striatal dopamine receptors are lost, is the response lost. Before concluding that levodopa is without effect on a given patient, an adequate dose must be tested. Not every symptom has to respond, but bradykinesia and rigidity respond best, whereas tremor can be resistant. Therefore, if rest tremor is the only symptom, lack of improvement does not exclude the diagnosis of PD. Tremor may never respond satisfactorily, even if adjunctive antiparkinsonian drugs are also used. Before concluding that carbidopa/levodopa is ineffective, a reasonable test dose of up to 2,000 mg levodopa/d should be given. If anorexia, nausea, or vomiting prevent attainment of a therapeutic dosage, the addition of extra carbidopa (additional 25 mg four times per day) or domperidone (10 to 20 mg before each levodopa dose) is usually effective in overcoming the adverse effect. If other adverse effects (drug-induced dystonia, psychosis, confusion, sleepiness, postural hypotension) prevent attainment of an effective dose, uncertainty about the diagnosis of PD will continue. In particular, dystonia induced by low doses of levodopa suggests a diagnosis of MSA. Similarly, drug-induced psychosis suggests diffuse Lewy body disease or accompanying Alzheimer disease. Using clozapine or quetiapine may suppress psychosis and allow the use of levodopa.

COMPLICATIONS OF LONG-TERM LEVODOPA THERAPY Response fluctuations, dyskinesias, and behavioral effects are the major problems encountered with long-term levodopa therapy ( Table 114.9 and Table 114.10).

TABLE 114.9. MAJOR FLUCTUATIONS AND DYSKINESIAS AS COMPLICATIONS OF LEVODOPA

TABLE 114.10. BEHAVIORAL ADVERSE EFFECTS WITH LEVODOPA

Fluctuations When levodopa therapy is initiated, the benefit from levodopa is usually sustained, with general improvement throughout the day and no dose-timing variations; this is the long-duration benefit. Skipping a dose is usually without loss of effect, and the response is evident on arising in the morning despite the lack of medication throughout the night. The pharmacokinetics of levodopa show a short initial distribution phase with a half-life of 5 to 10 minutes, a peak plasma concentration in about 30 minutes, and an elimination phase of about 90 minutes. Brain levels follow plasma levels. This long-duration benefit of levodopa is attributed to a combination of

prolonged storage of dopamine from exogenous levodopa in residual nigrostriatal nerve terminals and a prolonged postsynaptic effect on dopamine receptors. With chronic levodopa therapy, most patients, including all patients with onset before age 40, begin to experience fluctuations. At first, fluctuations take the form of wearing off (also known as end-of-dose deterioration), which is defined as a return of parkinsonian symptoms in less than 4 hours after the last dose. Gradually, the duration of benefit shortens further and the “off” state becomes more profound. Eventually, and possibly related to increasing frequency of dosing, these fluctuations become more abrupt in onset and random in timing; the condition is then the “on–off” effect and cannot be related to the timing of the levodopa intake. Motor “offs” are often accompanied by changes in mood (depression, dysphoria), anxiety, thought (more bradyphrenia), and sensory symptoms (pain). Loss of striatal storage sites of dopamine by itself is not the sole cause of this problem. Treatment with direct-acting agonists does not eliminate the fluctuations but does make the depths of the “off” state less severe. It seems that both the central effects on dopamine receptors and the peripheral pharmacokinetics of levodopa are involved. The dopamine receptor becomes more sensitive to levodopa in patients with fluctuations, thus affecting both the antiparkinsonian and the dyskinetic effects. Simultaneously, the duration of response is shorter. The brief peripheral half-life of levodopa, by itself, is not likely to be responsible for fluctuations. The half-life, present from the beginning of treatment, does not change. Also, no difference exists in the pharmacokinetics in patients with early disease who show a stable response and in those with advanced disease and fluctuations. One hypothesis is that intermittent (compared with continuous) administration of levodopa contributes to the development of motor complications. These peaks and valleys of brain dopamine levels are thought to alter the striatal dopaminoceptive medium spiny neurons, with a potentiation of glutamate receptors (of the N-methyl-D-aspartate subtype) on these GABAergic striatal efferents. This increased glutamatergic activity then produces the motor complications. Another potential mechanism is that dopamine can lead to the formation of free radicals by autoxidation or by enzymatic oxidation, and these oxyradicals could be the culprits attacking and altering the dopamine receptors. Once established, motor complications are seemingly irreversible. Substituting dopamine agonists for levodopa therapy or maintaining plasma concentrations at a constant therapeutic level by chronic infusion of levodopa diminishes the severity of the complications but does not eliminate them. In research centers, jejunal infusions of levodopa, subcutaneous infusions of apomorphine, and hourly oral administration of liquefied levodopa have been used. But these methods of treatment are often not practical. Selegiline is partially effective in treating mild wearing-off problems, probably by prolonging dopamine levels at the synapse. The addition of selegiline to patients taking levodopa, however, may lead to dopaminergic toxicity, including dyskinesias, confusion, and hallucinations. Another approach is to substitute the slow-release forms of carbidopa/levodopa (Sinemet CR) for the standard form. Again, this approach is effective mainly on wearing-off problems and not on complicated “on–off” fluctuations. Furthermore, the sustained-release formulation results in less predictable plasma levels of levodopa and often increases dyskinesias. Standard carbidopa/levodopa can be given alone by shortening the interval between doses. For the more severe state of “on–off” phenomenon, a more rapid and more predictable response sometimes can be achieved by dissolving the levodopa tablet in carbonated water or ascorbic acid solution because an acidic solvent is required to dissolve levodopa and to prevent autooxidation of the drug. Liquid levodopa enters the small intestine faster, is absorbed faster, and can be used to “fine-tune” dosing. Patients with fluctuations also usually have dose failures resulting from delayed entry of the tablet into the small intestine. Liquefying levodopa can help to resolve this problem. Direct-acting dopamine agonists, with a biologic half-life longer than that of levodopa, can be used in combination with standard or slow-release forms of levodopa. The agonists are useful for treating both wearing-off and “on–off” by reducing both the frequency and the depth of the “off” states. In yet another approach to treating “on–offs,” the patients inject themselves with apomorphine subcutaneously to quickly return the “on” state. The peripheral dopamine receptor antagonist domperidone is used to block nausea and vomiting. Catachol-O-methyl transferased inhibitors can extend the pharmokinetic half-life of levodopa, and thereby decrease the amount of “off” time. These drugs are added to levodopa therapy, but they can also increase dyskinesias, so the dose of levo-dopa may need to be reduced. Some patients report that high-protein meals tend to produce “off” states. Levodopa is absorbed from the small intestine by the transport system for large neutral amino acids and thus competes with these other amino acids for this transport. Patients with this problem may benefit from special diets that contain little protein for the first two meals of the day, followed by a high-protein meal at the end of the day when they can afford to be “off.” Dyskinesias Dyskinesias are commonly encountered with levodopa therapy but are often mild enough to be unnoticed by the patient. Severe forms, including chorea, ballism, dystonia, or combinations of these, can be disabling. The incidence and severity increase with duration and dosage of levodopa therapy, but they may appear early in patients with severe parkinsonism. Dyskinesias are divided into the following categories according to the timing of levodopa dosing: 1. Peak-dose dyskinesias appear at the height of antiparkinsonian benefit (20 minutes to 2 hours after a dose). 2. Diphasic dyskinesias, usually affecting the legs, appear at the beginning and end of the dosing interval. 3. “Off” dystonia, which can be painful sustained cramps, appear during “off” states and may be seen at first as early-morning dystonia presenting as foot cramps; these are relieved by the next dose of levodopa. Dyskinesias are usually seen in patients who have fluctuations, and some patients may move rapidly from severe dyskinesias to severe “offs”; this process is known as yo-yo–ing. These patients may have only a brief “on” state. More commonly, they have good “ons” for parts of the day but are intermittently disabled by dyskinesias or “offs.” These diurnal variations are major problems; patients with this combination have a narrow therapeutic window for levodopa. The mechanisms for dyskinesias and fluctuations are not thought to be identical or even linked. For example, sensitivity to dyskinesias is not altered by chronic infusion of levodopa, whereas fluctuations are suppressed. Because dopamine agonists are much less likely to cause dyskinesias (attributed to much less activation of the D1 receptor), increased sensitivity and response of the D1 receptor by dopamine derived from levodopa is thought to play a role in the production of dyskinesias. Treatment of peak-dose dyskinesias includes reducing the size of each dose of levodopa. If doing so results in more wearing off, the drug is given more frequently, a switch is made to the slow-release form, or a dopamine agonist or selegiline is added with the reduced dose of levodopa. Diphasic dyskinesias are more difficult to treat. Increasing the dosage of levodopa can eliminate this type of dyskinesia, but peak-dose dyskinesia usually ensues. A switch to a dopamine agonist as the major antiparkinsonian drug is more effective; low doses of levodopa are used as an adjunctive agent. The principle of treating “off dystonia” is to try to keep the patient “on” most of the time. Here again, using a dopamine agonist as the major antiparkinsonian drug, with low doses of levodopa as an adjunct, can often be effective. Freezing The freezing phenomenon is often listed as a type of fluctuation because of transient difficulty in initiating movement. But this phenomenon should be considered as distinct from the other types of fluctuations. “Off-freezing” must be distinguished from “on-freezing.” Off-freezing, best considered a feature of parkinsonism itself, was encountered before levodopa was discovered. The treatment goal of off-freezing is to keep the patient from getting “off.” On-freezing remains an enigma; it tends to be aggravated by increasing the dosage of levodopa or by adding direct-acting dopamine agonists or selegiline without reducing the dosage of levodopa. Rather, it is lessened by reducing the dosage of levodopa. Both on- and off-freezing seem to correlate with both the duration of illness and the duration of levodopa therapy. Patients with a combination of complicated fluctuations, dyskinesias, and off-freezing may respond to subthalamic nucleus stimulation.

MENTAL AND BEHAVIORAL CHANGES The adverse effects of confusion, agitation, hallucinosis, hallucinations, delusions, depression, and mania are probably related to activation of dopamine receptors in nonstriatal regions, particularly cortical and limbic structures. Elderly patients and those with diffuse Lewy body disease or concomitant Alzheimer disease are sensitive to small doses of levodopa. But all patients with PD, regardless of age, can develop psychosis if they take excessive amounts of levodopa to overcome “off” periods. Psychosis can often be treated without worsening parkinsonism by adding quetiapine or clozapine, antipsychotic agents that block the dopamine D4 and serotonin receptors. These drugs easily induce drowsiness, and they should be given at bedtime, starting with a dose of 12.5 mg. The dose can be gradually increased if necessary. If quetapine is not effective, use clozapine instead. Because clozapine induces agranulocytosis in 1% to 2% of patients, patients must have blood counts monitored weekly, and the drug must be discontinued if leukopenia develops. If clozapine is not tolerated, other drugs, including small doses of

olanzapine, molindone, pimozide, or other relatively weak antipsychotic drugs, can be used. If the antipsychotic drugs increase the parkinsonism, lowering the dosage of levodopa to avoid the psychosis is preferable to maintaining the antipsychotic agent at high dosage. Levodopa cannot be discontinued suddenly because the abrupt cessation may induce the neuroleptic malignant syndrome.

COURSE The degenerative forms of parkinsonism, including PD, worsen with time. Before the introduction of levodopa, PD caused severe disability or death in 25% of patients within 5 years of onset, in 65% in the next 5 years, and in 89% in those surviving 15 years. The mortality rate from PD was three times that of the general population matched for age, sex, and racial origin. Although no evidence indicates that levodopa alters the underlying pathologic process or stems the progressive nature of the disease, indications exist of a major impact on survival time and functional capacity. The mortality rate has dropped 50%, and longevity is extended by several years. The hemiparkinsonism-hemiatrophy syndrome progresses more slowly and may never cause the severe disability seen with PD. In these patients, fluorodeoxyglucose PET studies reveal hypometabolism in the contralateral striatum and frontal cerebral cortex. Another relatively benign form of parkinsonism is adult-onset dopa-responsive dystonia (see Chapter 112). In that disorder, features of PD appear, but the patients continue to respond to low-dosage levodopa treatment and never develop the complications encountered so frequently with PD. A debated point in the treatment of PD is the cause of declining efficacy from continuing treatment with levodopa seen in many patients ( Fig. 114.3). End-stage PD is denoted when the response to levodopa is inadequate to allow patient-assisted activities of daily living. Progression of the illness with further loss of dopamine storage sites in the presynaptic terminals cannot be the explanation for this outcome because loss of these structures in postencephalitic parkinsonism results in greater, not lower, sensitivity to levodopa. Perhaps as PD progresses it is associated with loss of striatal dopamine receptors and loss of the presynaptic dopaminergic neuron.

FIG. 114.3. Degree of improvement of Parkinson signs during each year of treatment with levodopa. Nonsurviving patients are compared with the total group treated.

SUGGESTED READINGS Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1436–1438. Chase TN. The significance of continuous dopaminergic stimulation in the treatment of Parkinson's disease. Drugs 1998;55:1–9. Dooneief G, Chen J, Mirabello E, et al. An estimate of the incidence of depression in idiopathic Parkinson's disease. Arch Neurol 1992;49:305–307. Dwork AJ, Balmaceda C, Fazzini EA, et al. Dominantly inherited, early-onset parkinsonism: neuropathology of a new form. Neurology 1993;43:69–74. Eidelberg D, Takikawa S, Moeller JR, et al. Striatal hypometabolism distinguishes striatonigral degeneration from Parkinson's disease. Ann Neurol 1993;33:518–527. Elble RJ, Hughes L, Higgins C. The syndrome of senile gait. J Neurol 1992;239:71–75. Fahn S. Adverse effects of levodopa. In: Olanow CW, Lieberman AN, eds. The scientific basis for the treatment of Parkinson's disease. Carnforth, England: Parthenon Publishing Group, 1992. Fahn S, Cohen G. The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. Ann Neurol 1992;32:804–812. FitzGerald PM, Jankovic J. Lower body parkinsonism: Evidence for vascular etiology. Mov Disord 1989;4:249–260. Friedman J, Lannon M, Comella C, et al. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N Engl J Med 1999;340:757–763. Friedman JH, Feinberg SS, Feldman RG. A neuroleptic malignant-like syndrome due to levodopa therapy withdrawal. JAMA 1985;254:2792–2795. Gibb WRG, Luthert PJ, Janota I, Lantos PL. Cortical Lewy body dementia: clinical features and classification. J Neurol Neurosurg Psychiatry 1989;52:185–192. Gibb WRG, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain 1989;112:1171–1192. Giladi N, Burke RE, Kostic V, et al. Hemiparkinsonism-hemiatrophy syndrome: clinical and neuroradiological features. Neurology 1990;40:1731–1734. Giladi N, McMahon D, Przedborski S, et al. Motor blocks in Parkinson's disease. Neurology 1992;42:333–339. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease—a clinicopathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–184. Jenner P, Schapira AHV, Marsden CD. New insights into the cause of Parkinson's disease. Neurology 1992;42:2241–2250. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392:605–608. Laitinen LV, Bergenheim AT, Hariz MI. Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J Neurosurg 1992;76:53–61. Limousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 1998;339:1105–1111. Mayeux R, Denaro J, Hemenegildo N, et al. A population-based investigation of Parkinson's disease with and without dementia: relationship to age and gender. Arch Neurol 1992;49:492–497. Metman LV, Deldotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease. Neurology 1998;50:1323–1326. Metman LV, Locatelli ER, Bravi D, Mouradian MM, Chase TN. Apomorphine responses in Parkinson's disease and the pathogenesis of motor complications. Neurology 1997;48:369–372. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045–2047. Przedborski S, Giladi N, Takikawa S, et al. The metabolic topography of the hemiparkinsonism-hemiatrophy syndrome. Neurology 1994;44:1622–1628. Przedborski S, Jackson-Lewis V. Mechanisms of MPTP toxicity. Mov Disord 1998;13[Suppl 1]:35–38. Quinn N. Multiple system atrophy—the nature of the beast. J Neurol Neurosurg Psychiatry 1989;[Suppl]:78–89. Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism—a prospective study. Can J Neurol Sci 1991;18:275–278.

Tanner CM, Goldman SM. Epidemiology of Parkinson's disease. Neuroepidemiology 1996;14:317–335. Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: An etiologic study. JAMA 1999;281:341–346. Wooten GF, Currie LJ, Bennett JP, Harrison MB, Trugman JM, Parker WD. Maternal inheritance in Parkinson's disease. Ann Neurol 1997;41:265–268.

CHAPTER 115. PROGRESSIVE SUPRANUCLEAR PALSY MERRITT’S NEUROLOGY

CHAPTER 115. PROGRESSIVE SUPRANUCLEAR PALSY PAUL E. GREENE Pathology Symptoms and Signs Laboratory Data Diagnosis Treatment Suggested Readings

Olszewski, Steele, and Richardson reviewed autopsies of patients who had a syndrome of pseudobulbar palsy, supranuclear ocular palsy (chiefly affecting vertical gaze), extrapyramidal rigidity, gait ataxia, and dementia. They found a consistent pattern of neuronal degeneration and neurofibrillary tangles, chiefly affecting the pons and midbrain. This condition became known as progressive supranuclear palsy (PSP), or Steele-Richardson-Olszewski syndrome.

PATHOLOGY Atrophy of the dorsal midbrain, globus pallidus, and subthalamic nucleus; depigmentation of the substantia nigra; and mild dilatation of the third and fourth ventricles and aqueduct are seen on gross visual inspection of the postmortem brain in typical PSP. Light microscopy shows neuronal loss with gliosis, numerous neurofibrillary tangles (NFTs), and neuropil threads in many subcortical structures, including the subthalamic nucleus, pallidum, substantia nigra, locus ceruleus, periaqueductal gray matter, superior colliculi, nucleus basalis, and vestibular, red, and oculomotor nuclei. Less severe neuronal loss, gliosis, and deposition of NFTs are usually found in the cerebral cortex, especially the prefrontal and precentral cortices. The NFTs are argyrophilic and appear as skeins of fine fibrils, globose in shape in the brainstem and coil-shaped in the cortex. Ultrastructurally, they are composed of short straight 12- to 15-nm tubules arranged in circling and interlacing bundles. They react with antisera to several antigens on neurofilaments and the neurotubule-associated protein tau; the pattern of immunoreactivity differs from that of NFTs in Alzheimer disease (AD). The histologic features in typical PSP are similar to those found in postencephalitic (von Economo) parkinsonism and Guamanian amyotrophic lateral sclerosis–Parkinson–dementia syndrome (Lytico-Bodig). New histologic techniques have demonstrated overlap in pathology between some cases of clinicaly diagnosed PSP and AD, corticobasal ganglionic degeneration, and Parkinson disease (PD). The significance of this overlap is not known.

SYMPTOMS AND SIGNS Patients with PSP have an akinetic rigid parkinson-like syndrome; rest tremor is uncommon. Balance difficulty and falling are early symptoms. Unlike PD, axial rigidity exceeds limb rigidity, and the posture may be erect. Patients have marked facial dystonia with deep nasolabial folds and furrowed brow, an appearance of surprise or concern (Fig. 115.1). When the patient walks, the neck may be extended; the arms are abducted at the shoulders and flexed at the elbows. Dysphagia and dysarthria are usually severe. The voice is slurred and hoarse, and some patients become anarthric as the disease progresses. “Freezing” may be prominent; transient arrest of motor activity interrupts walking, speaking, or other actions.

FIG. 115.1. A: Progressive supranuclear palsy. Oculocephalic maneuver demonstrates intact reflex downgaze in a patient unable to look down voluntarily.

The first visual symptoms are failure to maintain eye contact in social interactions and difficulty with tasks requiring downgaze, such as reading, eating, or descending stairs. The patients often complain of diplopia, blurred vision, or difficulty reading. Disturbances of eyelid motility are common, including blepharospasm and apraxia of eyelid opening or closing. The cognitive impairment of PSP has been considered the archetype of subcortical dementia. The striking features are severe bradyphrenia, impaired verbal fluency, and difficulty with sequential actions or shifting from one task to another. Cognitive tests that depend on visual performance are especially affected. Dementia is less severe than might be suggested by the dysarthria, bradyphrenia, poor eye contact, and loss of facial expression. Emotional incontinence is dominated by inappropriate weeping or, less frequently, laughing. The course is aggressive; at 3 to 4 years after onset, patients cannot walk without assistance, and a median of 5 years after onset they are confined to bed and chair. They succumb to infection (from aspiration or pressure ulcers) or the sequelae of falls. The course is one of inexorable deterioration, culminating in death in 6 to 10 years.

LABORATORY DATA Routine laboratory investigations are normal. The electroencephalogram may show some slowing and disorganization without localizing features. Atrophy of the pons, midbrain, and anterior temporal lobes may be noted on computed tomography or magnetic resonance imaging. Positron-emission tomography (PET) with [18F]fluoro-l-dopa shows equal loss of uptake in caudate and putamen; PET using [ 18F]fluorodeoxyglucose shows global reduction in metabolism, most severe in the frontal lobes. Neither of these PET findings is specific for PSP. Cerebrospinal fluid is unremarkable.

DIAGNOSIS Levodopa-unresponsive parkinsonism with abnormal gait, loss of postural reflexes, and supranuclear ophthalmoplegia suggest the diagnosis of PSP. Clinical criteria for possible, probable, and definite PSP have been proposed by the National Institute of Neurological Disorders and Stroke ( Table 115.1). These criteria are specific but will exclude some patients with PSP who are mild or have unusual clinical features. The chief differential diagnoses are PD, corticobasal ganglionic degeneration, cerebral multiinfarct disease, and diffuse Lewy body disease. Differentiation from olivopontocerebellar atrophy (OPCA) with ophthalmoplegia may also be difficult; but the ocular palsy in OPCA preferentially affects horizontal movements. In the absence of the characteristic ocular palsy, diagnosis is difficult.

TABLE 115.1. DIAGNOSTIC CRITERIA FOR PROGRESSIVE SUPRANUCLEAR PALSY (PSP)

Examination of ocular and eyelid motility is crucial to the clinical diagnosis of PSP. Eyelid opening and closing apraxias are far more common in PSP than in any other extrapyramidal disorder. Fixation instability with coarse square wave jerks and faulty suppression of the vestibuloocular reflex are helpful features. Hesitation on voluntary downgaze is one of the earliest signs. Loss of vertical opticokinetic nystagmus on downward movement of the target confirms that finding. The demonstration of greater impairment of voluntary than of pursuit movements and of preservation of reflex ocular movements supports the diagnosis. Similar abnormalities, however, are occasionally seen in corticobasal ganglionic degeneration, cerebral multiinfarct disease, and diffuse Lewy body disease.

TREATMENT The etiology of PSP is unknown, and there is no specific treatment. Levodopa/carbidopa and ther antiparkinson medications are usually ineffective, although they are rarely helpful in alleviating the parkinsonian features of rigidity and bradykinesia. When they are helpful, benefit is short-lived or limited by toxic psychic effects, which tend to become prominent when dementia develops. Tricyclic antidepressants may suppress inappropriate crying or laughing. Anticholinergic drugs administered in modest doses may be useful in controlling drooling. Apraxia of eyelid opening and painful neck or limb dystonia may improve with botulinum toxin injections. Some patients and families choose to use an enteric feeding tube when dysphagia becomes severe. SUGGESTED READINGS Brooks DJ. PET studies in progressive supranuclear palsy. In: Tolosa E, Duvoisin R, Cruz-Sánchez, eds. Progressive supranuclear palsy: diagnosis, pathology, and therapy. New York: Springer-Verlag/Wien, 1994:119–134. Chin SS, Goldman JE. Glial inclusions in CNS degenerative diseases. J Neuropathol Exp Neurol 1996;55:499–508. Golbe LI, Davis PH, Schoenberg BS, Duvoisin RC. Prevalence and natural history of progressive supranuclear palsy. Neurology 1988;38:1031–1034. Litvan I. Progressive supranuclear palsy revised. Acta Neurol Scand 1998;98:73–84. Litvan I, Agid Y, eds. Progressive supranuclear palsy: clinical and research approaches. New York: Oxford University Press, 1992. Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology 1996;47:1–9. Litvan I, Campbell G, Mangone CA, et al. Which clinical features differentiate progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) from related disorders? Brain 1997;120:65–74. Pierrot-Deseilligny C, Gaymard B, et al. Cerebral ocular motor signs. J Neurol 1997;244:65–70. Pillon B, Dubois B, Ploska A, et al. Severity and specificity of cognitive impairment in Alzheimer's, Huntington's, Parkinson's diseases and progressive supranuclear palsy. Neurology 1991;41:634–643. Riley DE, Fogt N, Leigh RJ. The syndrome of “pure akinesia” and its relationship to progressive supranuclear palsy. Neurology 1994;44:1025–1029. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy: a heterogenous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964;10:333–359. Tanner CM, Goetz CG, Klawans HL. Multiinfarct PSP. Neurology 1987;37:1819–1820. Tetrud JW, Golbe LI, Forno LS, et al. Autopsy-proven progressive supranuclear palsy in two siblings. Neurology 1996;46:931–934. Troost BT, Daroff RB. The ocular motor defects in progressive supranuclear palsy. Ann Neurol 1977;2:397–403.

CHAPTER 116. TARDIVE DYSKINESIA AND OTHER NEUROLEPTIC-INDUCED SYNDROMES MERRITT’S NEUROLOGY

CHAPTER 116. TARDIVE DYSKINESIA AND OTHER NEUROLEPTIC-INDUCED SYNDROMES STANLEY FAHN AND ROBERT E. BURKE Suggested Readings

The most widely used drugs that block dopamine D2 receptors are the antipsychotic agents, such as the phenothiazines and the butyrophenones; others include metoclopramide, flunarizine hydrochloride (Sibelium), and cinnarizine. These D2 receptor–blocking agents can cause the following various adverse neurologic effects: Acute dystonic reaction Oculogyric crisis Acute akathisia Drug-induced parkinsonism Neuroleptic malignant syndrome Withdrawal emergent syndrome Persistent dyskinesias (tardive dyskinesia syndromes) Classic orobuccolingual dyskinesia Tardive dystonia Tardive akathisia Tardive tics Tardive myoclonus Tardive tremor The “atypical” neuroleptic clozapine (Clozaril), a drug that predominantly blocks the D4 receptor, is free of these complications, except for acute akathisia. The related drug quetiapine appears to be similar in being relatively free from the above list of adverse effects. Other drugs, also commonly called “atypical” neuroleptics, such as olanzapine (Zyprexa) and risperidone (Risperdal) are more readily able to induce the above adverse effects. The dopamine-depleting drugs reserpine and tetrabenazine can induce acute akathisia and drug-induced parkinsonism but have never been convincingly implicated in causing the other complications listed, other than acute dystonic reactions from tetrabenazine. Acute dystonic reactions tend to occur within the first few days of exposure to the dopamine-receptor blocker and predominantly affect children and young adults, and males more than females. Severe twisting and uncomfortable postures of limbs, trunk, neck, tongue, and face are dramatic. Oculogyric crisis is a form of dystonia in which the eyes are deviated conjugately in a fixed posture for minutes or hours. Dystonic reactions are easily reversible with parenteral administration of antihistamines (e.g., diphenhydramine, 50 mg intravenously), anticholinergic drugs (e.g., benztropine mesylate [Cogentin], 2 mg intramuscularly), or diazepam (5 to 7.5 mg intramuscularly). Acute akathisia occurs within the first few months of drug use; it may appear as the dosage is being increased. Akathisia consists of a subjective sense of restlessness or aversion to being still. The motor features of restlessness include frequent and repetitive stereotyped movements, such as pacing, repeatedly caressing the scalp, or crossing and uncrossing the legs. It can occur in subjects of any age. The beta-adrenergic blocker propranolol may be helpful in doses of 20 to 80 mg per day. Anticholinergic agents occasionally help. Acute akathisia disappears on discontinuance of the offending drug. Drug-induced parkinsonism resembles idiopathic parkinsonism in manifesting all the cardinal signs of the syndrome. Levodopa is not effective in reversing this complication, probably because the dopamine receptors are blocked and occupied by the antipsychotic agent. Oral anticholinergic drugs and amantadine are effective. Upon withdrawal of the offending antipsychotic drug, the symptoms slowly disappear in weeks or months. The neuroleptic malignant syndrome is characterized by a triad of fever, signs of autonomic dysfunction (e.g., pallor, diaphoresis, blood pressure instability, tachycardia, pulmonary congestion, tachypnea), and a movement disorder (e.g., akinesia, rigidity, or dystonia). The level of consciousness may be depressed, eventually leading to stupor or coma; death may occur. Withdrawal of antipsychotic medication and supportive therapy, including intravenous hydration and cooling, are recommended. Although controlled trials have not been conducted, numerous reports suggest that dantrolene sodium (Dantrium), a muscle relaxant, or bromocriptine mesylate (Parlodel), a direct-acting dopamine agonist, may be beneficial. Carbamazepine (Tegretol) has also been found effective. In most patients, the antipsychotic medication can be restarted later without recurrence of the syndrome. The withdrawal emergent syndrome may be a variant of tardive dyskinesia. “Emergent” implies that the symptoms emerge after abrupt cessation of the chronic use of an antipsychotic drug. The syndrome is primarily one of children. The choreic movements resemble those of Sydenham chorea because the movements are flowing rather than repetitive, as occurs in classic tardive dyskinesia. The withdrawal emergent syndrome is self-limiting but may take weeks to resolve. Reintroducing the antipsychotic drug and then slowly tapering the dosage can eliminate the choreic movements. The persistent dyskinesia syndromes are the most feared complications of antipsychotic medications because the symptoms are long-lasting and often permanent. Classic tardive dyskinesia consists of repetitive (stereotypic) rapid movements. The lower part of the face is most often involved; this orobuccolingual dyskinesia resembles continual chewing movements, with the tongue intermittently darting out of the mouth (“fly-catcher” tongue). Movements of the trunk may cause a repetitive pattern of flexion and extension (body-rocking). The distal parts of the limbs may show incessant flexion-extension movements (“piano-playing” fingers and toes). The proximal muscles are usually spared, but respiratory dyskinesias are not uncommon. When the patient stands, there may be repetitive movements of the legs (“marching-in-place”). Occasionally, the gait is short-stepped, possibly because of an associated drug-induced parkinsonism. More often, the arms tend to swing more than normal, and the stride may be lengthened. The patient may not be aware of the dyskinesia. The prevalence of classic tardive dyskinesia increases with age; it is more severe among elderly women and more likely to occur with longer duration of exposure to antipsychotic drugs. The time of onset is difficult to discern because these drugs mask the movements. Reducing the dosage or discontinuing the offending drug can unmask the disorder, and reinstituting the drug can suppress the movements. Not all cases of oral dyskinesia are classic tardive dyskinesia. There are many other choreic and nonchoreic causes. Essential to the diagnosis of tardive dyskinesia is a history of exposure to dopamine D2 receptor–blocking drugs. For this diagnosis, the symptoms should have started while the patient was still taking the drug or less than 3 months after discontinuing the drug. If oral dyskinesia is induced by other types of drugs, it is not, by definition, tardive dyskinesia. The following list outlines the classification of movement disorders affecting the face: Chorea and stereotypes Encephalitis lethargica; postencephalitic Drug-induced Tardive dyskinesia (antipsychotics) Levodopa Anticholinergic drugs Phenytoin intoxication Antihistamines Tricyclic antidepressants Huntington disease Hepatocerebral degeneration Cerebellar and brainstem infarction Edentulous malocclusion Idiopathic Dystonia

Meige syndrome Complete: oromandibular dystonia plus blepharospasm Incomplete syndromes Mandibular dystonia Orofacial dystonia Lingual dystonia Pharyngeal dystonia Essential blepharospasm Bruxism As part of a segmental or generalized dystonic syndrome Myoclonus and tics Facial tics Facial myoclonus of central origin Facial nerve irritability Hemifacial spasm Myokymia Faulty regeneration; synkinesis Tremor Essential tremor of neck and jaw Parkinsonian tremor of jaw, tongue, and lips Idiopathic tremor of neck, jaw, tongue, or lips Cerebellar tremor of neck Huntington disease and oromandibular dystonia are the major differential diagnoses of the oral dyskinesias. Oromandibular dystonia is probably the most common form of spontaneous oral dyskinesia. Clinical features differentiating these disorders from classic tardive dyskinesia are presented in Table 116.1. Patients with Huntington disease are frequently treated with antipsychotic drugs; a resulting tardive dyskinesia may be superimposed on the chorea. The presence of akathisia or repetitive (stereotyped) involuntary movements suggests the additional diagnosis of tardive dyskinesia. Often, oromandibular dystonia takes the appearance of a repetitive opening and closing of the jaw as the patient attempts to overcome the muscle pulling. By asking the patient not to fight the involuntary movement but to let it “do what it wants to do,” one can usually discern whether the oral dystonia is of the jaw-closing or jaw-opening form.

TABLE 116.1. CLINICAL FEATURES OF CLASSIC TARDIVE DYSKINESIA (TD), OROMANDIBULAR DYSTONIA (OMD), AND HUNTINGTON DISEASE (HD)

Several important forms of tardive dyskinesia syndrome are now recognized. Unlike classic oral dyskinesia, these forms are frequently quite disabling. Tardive dystonia is a chronic dystonia resulting from exposure to dopamine D2 receptor blockers. Individuals of all ages are susceptible to tardive dystonia, and younger individuals are more likely to have a more severe generalized form. Tardive dystonia usually begins in the face or neck, and may remain confined to these regions or may spread to the arms and trunk. The legs are infrequently affected. Often, neck involvement consists of retrocollis, and the trunk arches backward. The arms are typically rotated internally, the elbows extended, and the wrists flexed. The differential diagnosis includes all the many causes of dystonia. Wilson disease, in particular, must be excluded specifically in any patient with psychiatric symptoms and dystonia. Tardive akathisia is another important disabling variant of tardive dyskinesia. It is a chronic akathisia consisting of a subjective aversion to being still. Motor signs of restlessness include frequent, repeated, stereotyped movements, such as marching in place, crossing and uncrossing the legs, and repetitively rubbing the face or hair with the hand. Patients may not use the word “restless” to describe their symptoms; instead they may use expressions such as “going to jump out of my skin” or “jittery” or “exploding inside.” Akathisia can appear as focal discomfort, such as pain, or as moaning sounds. It can be a distressing symptom. In contrast to acute akathisia, the delayed type tends to become worse when antipsychotic medication is withdrawn, similar to the worsening of classic tardive dyskinesia on discontinuance of these drugs. As with other types of tardive dyskinesia syndrome, tardive akathisia tends to persist. Usually, tardive akathisia is associated with classic oral dyskinesia. Classic tardive dyskinesia, tardive dystonia, and tardive akathisia may occur together. Less common variants of tardive dyskinesia include tardive tics, tardive myoclonus, and tardive tremor. Efforts should be made to avoid the tardive dyskinesia syndromes. Antipsychotic drugs should be given only when indicated, namely, to control psychosis or a few other conditions where no other effective agent has been helpful, as in some choreic disorders or tics. These drugs should not be used indiscriminately, and when they are used, the dosage and duration should be as low and as brief as possible. If the psychosis has been controlled, the physician should attempt to reduce the dosage and even try to eliminate the drug, if possible. Once a tardive dyskinesia syndrome has appeared, treatment depends on eliminating the causative agents, the dopamine D2 receptor–blocking drugs. Unfortunately, psychosis may no longer be under control if these drugs are withdrawn; if the medication is required, increasing the dosage or adding reserpine may suppress the dyskinesia and akathisia. If the antipsychotic drug can be tapered and discontinued safely, the dyskinesia and akathisia may slowly subside in months or years. If the dyskinetic or akathitic symptoms are too distressful, treatment with dopamine-depleting drugs, such as reserpine, may suppress them. The dosage of reserpine should be increased gradually to avoid the side effects of postural hypotension and depression. A dosage of 6 mg per day or more may be required. Addition of alpha-methyltyrosine may be necessary to relieve symptoms, but this combination is more likely to cause postural hypotension and parkinsonism. With time, these dopamine-depleting drugs may eventually be tapered and discontinued. Tardive dystonia may be treated by dopamine depletion, but unlike oral tardive dyskinesia and akathisia, it may be treated with anticholinergic drugs. Clozapine may be helpful in some patients with tardive dystonia. The pathogenesis of the tardive dyskinesia syndromes is unknown. No one hypothesis is able to explain the disorder, and more than one factor may be necessary. These factors include the development of dopamine-receptor supersensitivity, activation of dopamine D1 receptors, and loss of G-aminobutyric acid activity in the subthalamic nucleus. SUGGESTED READINGS Andersson U, Haggstrom JE, Levin ED, et al. Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia. Mov Disord 1989;4:37–46. Burke RE, Kang UK, Jankovic J, et al. Tardive akathisia: an analysis of clinical features and response to open therapeutic trials. Mov Disord 1989;4:157–175. Fahn S. A therapeutic approach to tardive dyskinesia. J Clin Psychiatry 1985;46:19–24. Ford B, Greene P, Fahn S. Oral and genital tardive pain syndromes. Neurology 1994;44:2115–2119. Friedman J, Feinberg SS, Feldman RG. A neuroleptic malignant-like syndrome due to l-dopa withdrawal. Ann Neurol 1984;16:126–127.

Henderson VW, Wooten GF. Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade? Neurology 1981;31:132–137. Kane JM, Woerner M, Borenstein M, et al. Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull 1986;22:254–258. Kang UJ, Burke RE, Fahn S. Natural history and treatment of tardive dystonia. Mov Disord 1986;1:193–208. Kiriakakis V, Bhatia KP, Quinn NP, Marsden CD. The natural history of tardive dystonia: a long-term follow-up study of 107 cases. Brain 1998;121:2053–2066. Paulsen JS, Caligiuri MP, Palmer B, McAdams LA, Jeste DV. Risk factors for orofacial and limb-truncal tardive dyskinesia in older patients: a prospective longitudinal study. 1996;123:307–314.

Psychopharmacology

Seeman P, Tallerico T. Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 1998;3:123–134. Smith JM, Baldessarini RJ. Changes in prevalence, severity and recovery in tardive dyskinesia with age. Arch Gen Psychiatry 1980;37:1368–1373. Thomas P, Maron M, Rascle C, Cottencin O, Vaiva G, Goudemand M. Carbamazepine in the treatment of neuroleptic malignant syndrome. Biol Psychiatry 1998;43:303–305. Van Harten PN, Kamphuis DJ, Matroos GE. Use of clozapine in tardive dystonia. Prog Neuropsychopharmacol Biol Psychiatry 1996;20:263–274.

CHAPTER 117. HEREDITARY AND ACQUIRED SPASTIC PARAPLEGIA MERRITT’S NEUROLOGY

XVI SPINAL CORD DISEASES CHAPTER 117. HEREDITARY AND ACQUIRED SPASTIC PARAPLEGIA LEWIS P. ROWLAND Hereditary Spastic Plaraplegia Tropical Myeloneuropathies Primary Lateral Sclerosis (pls) Suggested Readings

Several different diseases are evident solely or primarily by spastic gait disorder (spastic paraparesis), which may progress to spastic paralysis of the legs (paraplegia). Autopsy usually reveals degeneration of the corticospinal tracts with or without involvement of other motor, sensory, or cerebellar systems. Among both heritable and acquired diseases, there is heterogeneity of pathogenesis.

HEREDITARY SPASTIC PARAPLEGIA Harding (1993) divided hereditary spastic paraplegia (HSP) syndromes into pure and complicated types, depending on the clinical manifestations. The complications include epilepsy, dementia, parkinsonism, ataxia, amyotrophy, peripheral neuropathy, and blindness or deafness. One multisystem syndrome gained the acronym CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity, hydrocephalus). Even in pure HSP, sensory evoked responses may be abnormal, and the spinocerebellar tracts were affected at autopsy in Strumpell's original description in 1890. Genetics The syndrome is genetically heterogeneous; most families show autosomal-dominant inheritance, but some are autosomal-recessive and others are X-linked ( Table 117.1). Locus heterogeneity is evident because some X-linked forms map to chromosome Xq28, others to Xq22. Some autosomal-dominant families map to 14q, 15q, or 2p, and others are unlinked ( Table 117.2). Families mapped to 16q24.3 have homozygous mutations in the gene for paraplegin, a mitochondrial ATPase. Mutations have been found in the genes for prion protein, presenilin, or a triplet nucleotide expansion; anticipation has been found in some families. In one X-linked family, the mutation affected the gene for proteolipid protein, which is also involved in Pelizaeus-Merzbacher disease. Both pure and complicated HSP have been mapped to chromosome 2p, but the two syndromes seem mostly genetically separate. Not all familial forms are inherited because infection with human T-cell lymphotropic virus type I (HTLV-I) can affect more than one person in a family.

TABLE 117.1. CLASSIFICATION OF THE HEREDITARY SPASTIC PARAPLEGIAS

TABLE 117.2. FAMILIAL SPASTIC PARAPLEGIA

Clinical Manifestations The syndrome is also clinically heterogeneous. Some cases start early, others after age 35 years. Some are mild and some are severe. The complicated forms differ in the nature of the clinical associations. All are usually slowly progressive. The spastic gait disorder is one of coordination; there may be no weakness in manual muscle tests. Tendon reflexes are overactive, and Babinski signs and clonus are often evident. Sensation is usually normal on routine examination, but quantitative studies may show an abnormality. Sphincter symptoms may appear in late-onset forms. Variability of manifestations often occurs within the same family. Laboratory Data Laboratory studies, including magnetic resonance imaging (MRI) of the brain or spinal cord, are usually unrevealing; however, one family showed white matter lesions in the brain, and some show prominent thinning of the corpus callosum. Sensory evoked potentials may be abnormal even without clinically evident sensory loss. Magnetic stimulation usually shows an abnormality of central motor conduction; responses are either absent or delayed. The cerebrospinal fluid (CSF) is not diagnostic. Diagnosis and Treatment Diagnosis is usually evident from the clinical and family data. Sporadic cases could be the result of new mutations, but most prove to be multiple sclerosis, as reviewed later in the differential diagnosis of primary lateral sclerosis. Management is primarily symptomatic. Intrathecal administration of baclofen (Lioresal) seems to be gaining favor because gait may improve. Tizanidine (Zanaflex) is also reported to be beneficial but seems no better than oral administration of baclofen.

TROPICAL MYELONEUROPATHIES The term tropical myeloneuropathies refers to several syndromes encountered in equatorial countries around the world. The syndromes are manifestations of lesions in the spinal cord and peripheral nerves, separately or together. These disorders have been long-standing public health problems. Some have been traced to specific etiologies, including infection with HTLV-I, or the chronic ingestion of cassava beans or lathyrogenic agents. Other exogenous toxins may play a role. In the past and perhaps still today, similar syndromes have been ascribed to nutritional deprivation. Among the numerous names for these disorders are Strachan syndrome, Jamaican neuropathy, tropical spastic paraparesis (TSP), tropical ataxic neuropathy (TAN), konzo, and lathyrism. TSP has generated other acronyms: RAM (for retrovirus-associated myelopathy) and HAM (for HTLV-I-associated myelopathy). History, Clinical Manifestations, and Patholog Because the symptoms and signs of these disorders are similar and the modes of pathogenesis are only now being identified with precision, it seems reasonable to describe the several conditions together. Strachan Syndrome (Nutritional Neuropathy) Strachan (1897) is credited with the first description of these syndromes when he reported his observations of a disorder found on the Caribbean island of Jamaica. The symptoms included numbness and burning in the limbs, girdling pains, impairment of vision and hearing, muscle weakness and wasting, hyporeflexia, and sensory ataxia. Mucocutaneous lesions included angular stomatitis, glossitis, and scrotal dermatitis. Scott later described similar manifestations in Jamaican sugar-cane workers; identical cases were reported in World War II prisoner-of-war camps in the Middle East and Asia, in the malnourished populations of Africa, India, and Malaya, and among those besieged in Madrid in the Spanish Civil War. Most patients so afflicted with Strachan syndrome have a predominantly sensory neuropathy, presumably a consequence of nutritional depletion. Neuropathologic studies have demonstrated symmetric ascending (secondary) degeneration in the posterior columns, spinocerebellar tracts, optic nerves, and peripheral nerves. Jamaican Neuropathies: Tropical Ataxic Neuropathy and Tropical Spastic Paraparesis Montgomery and colleagues (1964) described another group of patients in Jamaica. The dominant signs were spasticity and other evidence of corticospinal tract disease, sometimes with the peripheral manifestations of Strachan syndrome. Two seemingly distinct varieties have been identified. Both are primarily diseases of adults. The ataxic form seems less common in Jamaica (but is more common in Nigeria). It evolves slowly and is generally less severe than the spastic type. Manifestations include sensory ataxia, numbness and burning sensations in the feet, deafness, visual impairment with optic atrophy and a central or paracentral scotoma, mild spasticity with Babinski signs, and wasting and weakness of the legs, sometimes with footdrop. Patients appear undernourished but without stigmata of nutritional disorder. TSP is the more common variety of Jamaican neuropathy. It is a subacute condition in which pyramidal tract signs predominate and are accompanied by impairment of posterior column sensibility, bladder dysfunction, and girdling lumbar pain ( Table 117.3). In both varieties, histamine-fast gastric achlorhydria and positive serologic tests for syphilis are frequent; in the more common subacute form, protein elevation and lymphocytic pleocytosis are found in the CSF. Myopathy, peripheral neuropathy, and leukoencephalopathy have been seen in some patients with HTLV-I infection. Antibodies to HTLV-I have been found in more than 80% of patients with TSP, and the virus has been isolated from CSF. The serologic abnormalities are similar in tropical countries throughout the world—Colombia, the Seychelles, Martinique, and the southernmost part of Japan around the city of Kagoshima.

TABLE 117.3. NEUROLOGIC SIGNS IN TROPICAL SPASTIC PARAPARESIS

Lathyrism The clinical manifestations of lathyrism are similar to those of TSP. It is mainly a disease of adults, and the manifestations are primarily those of pyramidal tract dysfunction. It is slowly progressive but may ultimately cause paraplegia. Descriptions of the disease extend back to ancient Hindu writings and to Hippocrates. Lathyrism was once probably prevalent in Europe, as well as tropical countries, but now seems restricted to India, Bangladesh, and Ethiopia. Etiology Malnutrition Nutritional deprivation has long been recognized as a cause of peripheral neuropathy, optic neuropathy, and myelopathy. Avitaminosis and lack of other dietary necessities may account for some of the original cases of TSP and TAN, but other causes are now likely. Persistent Viral Infection The evidence of widespread HTLV-I infection in patients with TSP has had a major impact. Theoretically, it again shows that chronic viral infection can cause chronic human disease. The pathogenesis has not been elucidated, but transmission has been linked to blood transfusion, venereal contacts, contaminated needles of intravenous drug users, and the milk of nursing mothers. People with serologic evidence of syphilis, yaws, or human immunodeficiency virus (HIV) infection have a higher frequency of antibodies to HTLV-I. The disease may occur in more than one person in a family and could be confused with hereditary spastic paraparesis. Other Toxins and Nutritional Deprivation No other toxins have been shown to be important in TSP or TAN. However, another myelopathy closely resembling TSP clinically was encountered in Japan until corrective measures were taken. That condition, called subacute myelopathy-neuropathy, was attributed to use of iodochlorhydroxyquinoline to treat traveler's diarrhea. The drug was withdrawn, and the syndrome seems to have disappeared. Vernant disease is seen in the French West Indies and is characterized by the triad of optic neuritis, cervical myelopathy, and hypothalamic-hypophyseal abnormalities. The cause is not known. In Cuba, an epidemic of optic neuritis has been ascribed to nutritional deficiency.

Prevention and Treatment These tropical diseases are widespread and have been called the “hidden endemias.” Prevention seems more likely to have an impact than treatment. Malnutrition ought to be preventable. Venereal transmission is amenable to control (though not easily). Exogenous toxins can be excluded from th0e environment. Blood intended for transfusion must be monitored for HTLV-I. Once neurologic damage exists, however, the task is more difficult. Prednisone therapy seems to be effective in TSP; however, it seems more likely to benefit motor function in Japan and Colombia and to help bladder symptoms in Jamaica. Antiviral drug therapy remains a goal. Even replacement therapy with vitamins may not restore function to normal. Rehabilitation and adaptation remain important.

PRIMARY LATERAL SCLEROSIS (PLS) In theory, primary lateral sclerosis (PLS) should be the pure upper motor neuron component of amyotrophic lateral sclerosis (ALS), just as progressive spinal muscular atrophy is the purely lower motor neuron version of that disease. That assumption has not been proved, however, and the condition is still a diagnosis of exclusion. Before the introduction of MRI, many clinicians eschewed the clinical diagnosis of PLS because some other condition often turned up at autopsy. Now, however, MRI plays a key role in the clinical diagnosis, which concerns the differential diagnosis of spastic paraparesis of middle life. Information about the prevalence of this condition is not available, but the syndrome accounts for less than 5% of all cases of motor neuron disease. Clinical Manifestations PLS commences after age 40 with a spastic gait disorder that is slowly progressive and becomes stable. In our experience, patients rarely lose the ability to walk with a cane or other assistance. No paresthesias or findings of sensory loss are evident on examination. Most patients with PLS have no sphincter symptoms. Laboratory Data MRI with or without gadolinium shows no consistent abnormality, but after age 40 years many asymptomatic people show white matter lesions in the brain; PLS patients are not more likely to show these changes. The CSF is usually normal, but the protein content may be increased, without a rise in gamma globulin content or oligoclonal bands. Although electromyography should not show signs of denervation, it sometimes does so without uniformly predicting the later appearance of lower motor neuron disease. Magnetic stimulation of the brain may show delayed conduction of the corticospinal tracts. Sensory evoked potentials should be normal. Diagnosis The clinical diagnosis is made only after other possible causes of adult-onset progressive spastic paraparesis have been excluded. This process can be done with a reasonable dependence on modern imaging and a few blood tests ( Table 117.4).

TABLE 117.4. DIFFERENTIAL DIAGNOSIS OF PRIMARY LATERAL SCLEROSIS

No reliable figures exist for the relative frequency of the different diseases that cause spastic paraparesis. Most observers agree, however, that the main cause is the chronic and progressive form of spinal multiple sclerosis (MS). That diagnosis can be excluded with more than 90% certainty if none of the characteristic abnormalities of MS show on all three modern tests: MRI with gadolinium to examine the brain and upper cervical cord, CSF examination including oligoclonal bands and gamma globulin, and evoked responses. Prominent bladder symptoms are more likely to be found in MS. In the process of evaluating for MS, MRI also excludes other possible causes, such as cervical spondylotic myelopathy, Chiari malformation or other hindbrain anomaly, arteriovenous malformation, or tumor at the foramen magnum. Exclusion of cervical spondylosis may be difficult because the MRI findings of that condition are so prevalent in asymptomatic people. MRI also evaluates the possibility of multiinfarct brain disease. Some authorities have placed reliance of MRI evidence of atrophy of the motor cortex or high signal in the corticospinal tract. However, we and others have found MR spectroscopy more reliable in identifying pathology of the upper motor neuron in both PLS and ALS. Since PLS is likely to be heterogeneous in pathology, some cases may involve subcortical structures primarily, and MR spectroscopy may therefore be normal. In theory, ALS sometimes should start first as a purely upper motor neuron disorder, but that seems truly exceptional. Clinical evidence of fasciculation implicates the lower motor neurons and, by definition, excludes PLS. However, PLS is truly a diagnosis of exclusion, and conversion to ALS has been reported after 20 years of PLS. Clinical signs of parkinsonism, cerebellar disorder, or orthostatic hypotension imply a multisystem central nervous system disease, such as the Machado-Joseph syndrome or multiple system atrophy (Shy-Drager syndrome). One patient with PLS proved to have Lewy body disease. Rare causes of paraparesis are HTLV-I infection, HIV myelopathy, or adrenoleukodystrophy, which can be detected by appropriate tests. In time, some of these adult-onset cases are likely to be sporadic examples of one of the hereditary spastic paraparesis syndromes, but that possibility awaits better delineation of the specific mutations so that they can be tested. The condition is age-related, with almost all cases starting after age 40 years, so similar findings in children are likely to be due to some other disease. SUGGESTED READINGS Hereditary Spastic Paraplegia Benson KF, Horwitz M, Wolff J, et al. CAG expansion in autosomal dominant familial spastic paraplegia: novel expansion in a subset of patients. Hum Mol Genet 1998;7:1179–1186. Bonneau D, Rozet JM, Bulteau C, et al. X-linked spastic paraplegia (SPG2): clinical heterogeneity at a single locus. J Med Genet 1993;30:381–384. Casari G, De Fusco M, Ciarmatori S, et al. Spastic parplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 1998;93:973–983. Claus D, Waddy HM, Harding AE, et al. Hereditary motor and sensory neuropathies and hereditary spastic paraplegia: a magnetic stimulation study. Ann Neurol 1990;28:43–49. Fink JK. Advances in hereditary spastic paraplegia. Curr Opin Neurol 1997;10:313–318. Fink JK, Heiman-Patterson T, Bird T, et al. Hereditary spastic paraplegia: advances in genetic research. Hereditary Spastic Paraplegia Working Group. Neurology 1996;46:1507–1514.

Gutmann DH, Fischbeck KH, Kamholz J. Complicated spastic paraparesis with cerebral white matter lesions. Am J Med Genet 1990;36:251–257. Harding AE. Hereditary spastic paraplegia. Semin Neurol 1993; 13:333–336. Hazan J, Lamy C, Melki J, et al. Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to 14q. Nat Genet 1993;5:163–167. Kitamoto T, Amano N, Terao Y, et al. A new inherited prion disease (PrP-P105L mutation) showing spastic paraparesis. Ann Neurol 1993; 34:808–813. Krabbe K, Nielsen JE, Fallentin E, Feneger K, Nerning M. MRI of autosomal dominant pure spastic paraplegia. Neuroradiology 1997;39:724–727. Meyer T, Munch C, Volkel H, Booms P, Ludolph AC. The EAAT2 (GLT-1) gene in motor neuron disease: absence of point mutations in ALS and a point mutation in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 1998;65:594–596. Polo JM, Calleja J, Combaros O, Berciano J. Hereditary “pure” spastic paraplegia: study of nine families. 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Lancet 1985;2:1211–1212. Cruickshank EK. Neuromuscular disease in relation to nutrition. Fed Proc 1961;20[Suppl 7]:345–360. Cuetter AC. Strachan's syndrome: a nutritional disorder of the nervous system. Proceedings of the weekly seminar in neurology. Edward Hines Jr. Veterans Administration Hospital, Hines, IL. 1968;18. Denny-Brown D. Neurological conditions resulting from prolonged and severe dietary restriction. Medicine 1947;26:41–113. Domingues RB, Muniz MR, Jorge ML, et al. Human T-cell lymphotropic virus type-1-associated myelopathy/tropical spastic paraparesis in Sao Paulo, Brazil: association with blood transfusion. Am J Trop Med Hyg 1997;57:56–59. Douen AG, Pringle CE, Guberman A. Human T-cell lymphotropic virus type 1 myositis, peripheral neuropathy, and cerebral white matter lesions in the absence of spastic paraparesis. Arch Neurol 1997;54:896–900. Fisher CM. Residual neuropathological changes in Canadians held prisoners of war by the Japanese. Can Service Med J 1955;11:157–199. Gessain A, Gout O. Chronic myelopathy associated with human T-lymphotropic virus type 1 (HTLV-1). Ann Intern Med 1992;117:933–946. Hollsberg P, Hafler DA. Pathogenesis of diseases induced by human lymphotropic virus type 1 infection. N Engl J Med 1993;328:123–138. Izumo S, Umehara F, Kashio N, Kubota R, Sato E, Osame M. Neuropathology of HTLV-1-associated myelopathy (HAM/TSP). Leukemia 1997;11[Suppl 3]:82–84. Janssen RS, Kaplan JE, Khabbaz RF, et al. HTLV-1-associated myelopathy/tropical spastic paraparesis in the United States. Neurology 1991;41:1355–1357. Kira J, Fujihara K, Itoyama Y, et al. Leucoencephalopathy in HTLV-1-associated myelopathy/tropical spastic paraparesis: MRI analysis and two-year follow-up study after corticosteroid therapy. J Neurol Sci 1991;106:41–49. Montgomery RD, Cruickshank EK, Robertson WB, McMenemey WH. Clinical and pathological observations on Jamaican neuropathy. Brain 1964;87:425–462. Osame M, Matsumoto M, Usuku K, et al. Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemia-like cells. Ann Neurol 1987;21:117–123. Osuntokun BO. An ataxic neuropathy in Nigeria: a clinical, biochemical and electrophysiological study. Brain 1965;91:215–248. Rodgers-Johnson PEB, Ono SG, Asher DM, Gibbs CJ. Tropical spastic paraparesis and HTLV-1 myelopathy: clinical features and pathogenesis. In: Waksman BH, ed. Immunologic mechanisms in neurologic and psychiatric disease. New York: Raven Press, 1990. Roman GC. Tropical myeloneuropathies revisited. Curr Opin Neurol 1998;11:539–544. Roman GC, Spencer PS, Schoenberg BS. Tropical myeloneuropathies: the hidden endemias. Neurology 1985;35:1158–1170. Roman GC, Vernant JC, Osame M, eds. HTLV-1 and the nervous system. New York: Alan R Liss, 1989. Rudge P, Ali A, Cruickshank JK. Multiple sclerosis, tropical spastic paraparesis, and HTLV-1 infection in Afro-Caribbean patients in the United Kingdom. J Neurol Neurosurg Psychiatry 1991;54:689–694. Salazar-Grueso EF, Holzer TJ, Gutierrez RA, et al. Familial spastic paraparesis syndrome associated with HTLV-1 infection. N Engl J Med 1990;108:732–737. Smith CR, Dickson D, Samkoff L. Recurrent encephalopathy and seizures in a U.S. native with HTLV-1 associated myelopathy/tropical spastic paraparesis: clinicopathologic study. Neurology 1992;42:658–661. Spencer PS, Schaumberg HH. Lathyrism: a neurotoxic disease. Neurobehav Toxicol Teratol 1983;5:625–629. Strachan H. On a form of multiple neuritis prevalent in the West Indies. Practitioner 1897;59:477. Tylleskar T, Howlett WP, Rwiza HT, et al. Konzo: a distinct disease entity with selective upper motor neuron damage. J Neurol Neurosurg Psychiatry 1993;56:638–643. Vernant JC, Cabre P, Smadjia D, et al. Recurrent optic neuromyelitis with endocrinopathies: a new syndrome. Neurology 1997;48:58–64. Vernant JC, Maurs L, Gesain A, et al. Endemic tropical spastic paraparesis associated with human T-lymphotropic virus type I: a clinical and seroepidemiological study of 25 cases. Ann Neurol 1987;21:123–131. Yoshioka A, Hirose G, Ueda Y, et al. Neuropathological studies of the spinal cord in early stage HTLV-1-associated myelopathy (HAM). J Neurol Neurosurg Psychiatry 1993;56:1004–1007. Primary Lateral Sclerosis Brown WF, Ebers GC, Hudson AJ, et al. Motor-evoked responses in primary lateral sclerosis. Muscle Nerve 1992;15:626–629. Forsyth PA, Dalmau J, Graus F, Cwik V, Rosenblum MK, Posner JB. Motor neuron syndromes in cancer patients. Ann Neurol 1997;41:722–730. Grignani G, Gobbi PG, Piccolo G, et al. Progressive necrotic myelopathy as a paraneoplastic syndrome: report of a case and some pathogenetic considerations. J Intern Med 1992;231:81–85. Hainfellner JA, Pliz P, Lassmann H, et al. Diffuse Lewy body disease as substrate of primary lateral sclerosis. 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Pringle CE, Hudson AJ, Munoz DG, et al. Primary lateral sclerosis: clinical features, neuropathology, and diagnostic criteria. Brain 1992;115:495–520. Rowland LP. Paraneoplastic primary lateral sclerosis and amyotrophic lateral sclerosis. Ann Neurol 1997;41:703–705. Rowland LP. Diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1998;160[Suppl 1];S6–S24. Rowland LP. Primary lateral sclerosis: disease, syndrome, both, or neither? J Neurol Sci 1999;170:1–4. Swash M, Desai J, Misra VP. What is primary lateral sclerosis? J Neurol Sci 1999;170:5–10. Younger DS, Chou S, Hays AP, et al. Primary lateral sclerosis: a clinical diagnosis reemerges. Neurology 1988;45:1304–1307. Baclofen Therapy Coffey RJ, Cahill D, Steers W, et al. Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study. McLean BN. Intrathecal baclofen in severe spasticity. Br J Hosp Med 1993;49:262–267.

J Neurosurg 1993;78:226–232.

CHAPTER 118. HEREDITARY AND ACQUIRED MOTOR NEURON DISEASES MERRITT’S NEUROLOGY

CHAPTER 118. HEREDITARY AND ACQUIRED MOTOR NEURON DISEASES LEWIS P. ROWLAND Definitions and Classifications Progressive Spinal Muscular Atrophies of Childhood Focal Muscular Atrophies of Childhood and Adolescence Motor Neuron Diseases of Adult Onset Suggested Readings

DEFINITIONS AND CLASSIFICATIONS Several different diseases are characterized by progressive degeneration and loss of motor neurons in the spinal cord with or without similar lesions in the motor nuclei of the brainstem or the motor cortex, and by replacement of the lost cells by gliosis. All these can be considered motor neuron diseases (plural). The term motor neuron disease (singular), however, is used to describe an adult disease, amyotrophic lateral sclerosis (ALS), in which upper motor neurons are affected, as well as lower motor neurons. (The terms motor neuron disease and ALS have become equivalent in the United States.) The term spinal muscular atrophy (SMA) refers to syndromes characterized solely by lower motor neuron signs. The official classification of the World Federation of Neurology lists numerous different forms of SMA in children. Some are differentiated by associated conditions, such as optic atrophy, deafness, or mental retardation. Childhood SMA is inherited and is not accompanied by upper motor neuron signs. In adults, some patients also show only lower motor neuron signs in life ( progressive spinal muscular atrophy [PSMA]). In two autopsy series, however, 17 of 25 patients with adult-onset PSMA showed degeneration of the corticospinal tracts ( Table 118.1). For that reason, adult-onset PSMA is considered a form of ALS. Almost all adult-onset cases are sporadic, not familial.

TABLE 118.1. AUTOPSY FINDINGS IN CLINICAL SYNDROMES OF MOTOR NEURON DISEASE: DEGENERATION OF PYRAMIDAL TRACTS

A motor neuropathy is also evident by lower motor neuron signs alone, with no sensory loss, and therefore resembles PSMA. The condition is considered a neuropathy rather than a disease of the perikaryon because nerve conduction measurements show evidence of diffuse demyelination, focal demyelination (conduction block), or axonal neuropathy (see Chapter 15). Rarely, the diagnosis of motor neuropathy might depend on histologic changes in nerve rather than on physiologic criteria.

PROGRESSIVE SPINAL MUSCULAR ATROPHIES OF CHILDHOOD Three major syndromes of SMA occur in children. They differ in age at onset and severity of symptoms. All are autosomal-recessive and map to the same locus, chromosome 5q11-q13. They are therefore regarded as examples of allelic heterogeneity;/ that is, mutations of the same gene. In theory, there ought to be some locus heterogeneity, with some families showing the same or similar phenotype but mapping to different chromosomes; in fact, however, families throughout the world map to the same locus. The gene is called survival motor neuron gene (SMN); a neighboring gene is the neuronal apoptosis inhibitory protein gene (NAIP). Both have two almost identical copies, one telomeric (SMNt) and one centromeric (SMNc). If there were a conversion from the telomeric to the centromeric, SMNt would seem to have been deleted, but there would be extra copies of SMNc, as is actually found in the less severe forms of the disease. In 98% of children with the severe infantile SMA type 1, there is a deletion of SMNt, and point mutations are found in the few who lack a deletion. The frequency of deletions of NAIP is lower, but it is also included in large deletions. Adjacent to NAIP is another gene, p44, which is sometimes deleted as well, but less often than SMN or NAIP. In general, the size of the deletion parallels clinical severity; the largest deletions may encompass all three genes. Direct deletion analysis has high sensitivity and specificity and can be used for diagnosis without muscle biopsy in suspected cases; it is also effective in antenatal diagnosis in an at-risk fetus. The SMN protein is depleted in the spinal cord of patients, but its normal role is not known, except that it is found in the cytoplasm and in nuclear structures called “gems,” where it is linked to ribonucleic acid–binding proteins and seems to be involved in the biogenesis of ribonucleoproteins. Another possibly important association of both SMN and NAIP is with Bcl-2, an antiapoptotic protein. How absence of SMN leads to the disease, however, still has to be elucidated. Infantile SMA type 1 (Werdnig-Hoffmann syndrome) (MIM 253300) is evident at birth or soon thereafter, always before age 6 months. Mothers may notice that intrauterine movements are decreased. In the neonatal period, nursing problems may occur, and limb movements are feeble and decreased; this is one of the most common forms of the floppy infant syndrome. Proximal muscles are affected before distal muscles, but ultimately complete flaccid quadriplegia results. The tongue is often seen to fasciculate, but twitching is only seen rarely in limb muscles, presumably because of the ample subcutaneous fat. Sooner or later, respiration is compromised, and paradoxical movements of the chest wall are seen; the sternum may be depressed with inspiration. Tendon reflexes are absent. The condition is devastating, and 85% of the children die before age 2 years. The others may survive but never walk; their condition may remain stable for many years. Some authorities believe the survivors form a special intermediate class, SMA type 2 (MIM 253550); this category also includes cases of onset from 6 months to 1 year. With the introduction of electromyography (EMG) after World War II, Kugelberg and Welander noted physiologic evidence of denervation in adolescents with proximal limb weakness. The essentials of that disorder were delineated in the title of their paper, “Juvenile spinal muscular atrophy simulating muscular dystrophy;” the condition described is now called the Kugelberg-Welander syndrome, or SMA type 3 (MIM 253400). Symptoms begin with a slowly progressive gait disorder in late childhood or adolescence. The onset is followed by symptoms of proximal arm weakness and wasting; tendon reflexes are lost. Unlike the Werdnig-Hoffmann syndrome, fasciculation of limb muscles, as well as of the tongue, may be visible. This condition is relatively benign; many patients continue to function socially with a normal life span. Others may be handicapped, but serious dysphagia or respiratory compromise is rare. Sensation is spared, and no other organ systems are affected. Laboratory Data Electrodiagnostic studies show evidence of denervation with normal nerve conductions. Muscle biopsy similarly shows evidence of denervation. The cerebrospinal fluid (CSF) shows no characteristic changes. Serum levels of sarcoplasmic enzymes, such as creatine kinase, may be increased; in the Kugelberg-Welander type, the increase may be 20 times normal, in the range of many myopathies. The electrocardiogram is normal. Diagnosis now depends on deoxyribonucleic acid (DNA) analysis. Muscle biopsy and even EMG are not necessary if a deletion or mutation of SMN is found.

Treatment There is no specific therapy. Treatment of survivors is analogous to that described for children with muscular dystrophy: rehabilitation measures, bracing, attention to scoliosis, and assistance in education and social adaptation. Some authorities believe that children with SMA are characteristically of high intelligence; education programs are important.

FOCAL MUSCULAR ATROPHIES OF CHILDHOOD AND ADOLESCENCE These syndromes do not map to 5q11 and differ in the focal distribution of symptoms and signs. Most are autosomal-recessive, but some families show dominant inheritance. Fazio-Londe Syndrome In contrast to the sparing of cranial nerve functions in most juvenile SMA, selective dysarthria and dysphagia in Fazio-Londe syndrome (MIM 211500) begin in late childhood or adolescence. Wasting of the tongue with visible fasciculation occurs. Symptoms may be restricted for years, but weakness of the arms and legs may occur later, and respiration may be affected. There have been few documented cases and fewer autopsy-proven cases. Scapuloperoneal and Facioscapulohumeral Forms Scapuloperoneal (MIM 271220, 181400) and facioscapulohumeral (FSH) (MIM 182970) forms of SMA have been reported. Some may actually have had FSH muscular dystrophy with ambiguous results on EMG and biopsy that led to incorrect classification as a neurogenic disorder. The distinction now depends on DNA analysis. Childhood Spinal Muscular Atrophy with Known Biochemical Abnormality Hexosaminidase deficiency (MIM 272800) may cause a syndrome of SMA starting in childhood or adolescence. The pattern of inheritance is autosomal recessive. Some patients also have upper motor neuron signs, as in ALS. Associated psychosis, dementia, or cerebellar signs may appear. Other rare biochemical abnormalities seen with SMA are lysosomal diseases, phenylketonuria, hydroxyisovaleric aciduria, mutations of mitochondrial DNA, perioxosomal disease, and ceroid lipofuscinosis. Diagnosis Most of the childhood SMAs can be identified by the history and clinical examination. They must be differentiated from muscular dystrophies by EMG, muscle biopsy, or DNA analysis; the family history aids in classification. Hexosaminidase deficiency is suspected in families of Ashkenazi-Jewish background, especially if there are known cases of Tay-Sachs disease in the family or if some family members are known to be carriers of the gene. Kennedy syndrome is recognized by onset after age 40 years, distribution of weakness, and gynecomastia.

MOTOR NEURON DISEASES OF ADULT ONSET X-linked Recessive Spinobulbar Muscular Atrophy (Kennedy Disease) Symptoms of X-linked recessive spinobulbar muscular atrophy (Kennedy disease) (MIM 313200) usually begin after age 40 years with dysarthria and dysphagia; limb weakness is delayed for years. The tongue fasciculates, and twitching of limb muscles is often visible. Limb weakness is usually more severe proximally. Tendon reflexes are lost, and upper motor neuron signs are never evident. Although the condition is purely motor in life, nerve conduction studies suggest a large-fiber sensory peripheral axonopathy; sensory evoked potentials may be abnormal and sensory tracts in the spinal cord may be affected at autopsy. Exceptional cases have shown upper motor neuron signs or dementia. Gynecomastia is present in most but not all patients; reproductive fitness is only slightly decreased. Diagnosis is aided by the characteristic distribution of signs, lack of upper motor neuron signs, slow progression, and a family history suggesting X-linkage. Nevertheless, 2% of patients diagnosed with ALS show the Kennedy mutation, so diagnosis is not always straightforward. The gene maps to Xq11-12, the site of the androgen receptor. The mutation is an expansion of a CAG repeat. At autopsy immunochemical studies show the presence of both normal and mutant gene products, including nuclear inclusions that contain androgen receptor. It is not known how these abnormalities cause the disease. There have been no reports of a neurologic disorder in people with the testicular feminizing syndrome, the major clinical manifestation of a mutation in the gene for the androgen receptor. This and other evidence suggest that, with the expanded polyglutamine repeat, the disease results from a toxic gain of function. Kennedy syndrome was one of the first to be associated with an expansion of a trinucleotide repeat and, as in others of this class, there is an inverse relationship between the number of repeats and the severity of the disorder. Amyotrophic Lateral Sclerosis Definition ALS is of unknown cause and pathogenesis, and is defined pathologically as one in which there is degeneration of both upper and lower motor neurons. Charcot made the early clinical and pathologic description, and the disease is named for him in Europe. In the United States, the disease is colloquially called “Lou Gehrig's disease” after a famous baseball player who had the disease. The SMA form is deduced from clinical observations, but few patients show only lower motor neuron changes at autopsy. In life, the disease is defined by finding evidence of both lower motor neuron disease (weakness, wasting, fasciculation) and upper motor neuron disease (hyperactive tendon reflexes, Hoffmann signs, Babinski signs, or clonus) in the same limbs. The accuracy of clinical diagnosis is assumed to be more than 95%, but that figure has not been formally tested. Nevertheless, the reliability of clinical diagnosis suffices to make the findings in the history and examination part of the definition. Problems in diagnosis are reviewed below. Epidemiology The disease is found worldwide in roughly the same prevalence (about 50 × 10 -6). In 1945, however, about 50 times that number were found on the island of Guam, where the findings of ALS were frequently associated with parkinsonism and dementia. With modernization of the island, the disease seems to have declined in frequency to levels found elsewhere. (Some authorities believe dementia has replaced ALS as the people now live longer, creating a different form of the same basic disease.) A few other areas of unexplained high incidence have surfaced. Apparent clusters in a building or a small community have not yet led to identification of an etiologic agent. Similarly, case–control studies have not identified consistent risk factors related to occupation, trauma, diet, or socioeconomic status. The disease is one of middle and late life. Only 10% of cases begin before age 40 years; 5% begin before age 30. An increase in age-adjusted incidence is seen in succeeding decades, except for a decrease after age 80. In most series, men are affected one to two times more often than women. There is no known ethnic predilection. About 5% of cases are familial in an autosomal dominant pattern (MIM 105400). About 20% of familial cases map to chromosome 21, where there are mutations in the gene for superoxide dismutase (SOD). The evidence suggests no deficiency in normal SOD; rather the mutant protein exerts a toxic effect on motor neurons. The essential elements of the disease have been reproduced in transgenic mice bearing the mutant protein, providing the first clue to the pathogenesis of motor neuron disease. The familial cases that do not map to this locus are taken as evidence of locus heterogeneity. The occurrence of dementia and parkinsonism seems to increase in first-degree relatives of patients with ALS, thus implying a possible common susceptibility to the neurodegenerative diseases of aging.

Pathogenesis The cause of sporadic ALS is not known. Because of the high incidence in Guam, environmental factors have been suspected, but none has emerged there or anywhere else. Lead and mercury intoxication may cause similar syndromes but are no longer seen in modern societies. Excitotoxic amino acids, especially glutamate, are now held suspect, but there is no indication how the condition might arise or why the same theory should be considered for Alzheimer disease or Parkinson disease. Some authorities believe that an autoimmune disorder is present in all patients; others think there is a higher than expected frequency of monoclonal gammopathy or lymphoproliferative disease, but, together, these abnormalities are found in less than 10%. Among the sporadic cases, fewer than 5% are new SOD mutations. Information from the transgenic mice has reinforced the theory that both sporadic and familial ALS result from excitotoxic effects. In sporadic ALS, evidence of glutamate toxicity is accumulating, and drugs with antiglutamate effects have been tested in humans and transgenic mice. The evidence is marginal but supports the excitotoxic theory. Whether there is a paraneoplastic form of ALS has long been debated. An increased frequency of malignancy has been difficult to prove in a case–control study of patients with ALS. Several reports, however, have described ALS syndromes that improved or disappeared when a lung or renal cancer was cured. In addition, the frequency of association of ALS and lymphoma seems to be disproportionate. The pathology of ALS implies selective vulnerability of motor neurons, which show several neuronal inclusions that include ubiquitinated skeins or Lewy-like formations and Bunina bodies. These structures are found in most patients with sporadic ALS. In familial forms, a different form is the “hyaline conglomerate”, which includes neurofilaments and does not contain ubiquitin. Determination of the nature of these structures could elucidate, which pathogenesis. Some authorities believe the cellular abnormalities identify a common basic mechanism for the syndromes of ALS, adult-onset SMA, primary lateral sclerosis (PLS), and ALS-dementia. The clinical syndrome of ALS can be induced by several known agents, including radiotherapy, lead poisoning, and lightning stroke. Less dramatic environmental effects could bring on more typical sporadic ALS in a person who is genetically susceptible. The search is on for susceptibility factors and environmental agents. Clinical Manifestations Weakness may commence in the legs, hands, proximal arms, or oropharynx (with slurred speech or dysarthria, or difficulty swallowing). Often, the hands are affected first, usually asymmetrically. Painless difficulty with buttons or turning a key is an ominous symptom in midlife. Gait is impaired because the muscles are weak, and footdrop is characteristic, although proximal muscles are sometimes affected first. Alternatively, a spastic gait disorder may ensue. Slowly, the weakness becomes more severe, and more areas of the body are affected, leading to an increasing state of dependency. Muscle cramps (attributed to the hypersensitivity of denervated muscle) and weight loss (resulting from the combination of muscle wasting and dysphagia) are characteristic symptoms. Respiration is usually affected late but, occasionally, may be an early or even the first manifestation; breathing is compromised by paresis of intercostal muscles and diaphragm, or the dysphagia may lead to aspiration and pneumonitis, which can be the terminal event. Sensation is not clinically affected; pain and paresthesia are impermissible with this diagnosis, unless there is a complicating disease (e.g., diabetic neuropathy) and bladder function is spared. The eye muscles are affected only exceptionally. Pain is not an early symptom but may occur later when limbs are immobile. Lower motor neuron signs must be evident if the diagnosis is to be considered valid. Fasciculation may be seen in the tongue, even without dysarthria. If there is weakness and wasting of limb muscle, fasciculation is almost always seen. Tendon reflexes may be increased or decreased; the combination of overactive reflexes with Hoffmann signs in arms with weak, wasted, and fasciculating muscles is virtually pathognomonic of ALS (except for the syndrome of motor neuropathy, which is discussed later). Unequivocal signs of upper motor neuron disorder are Babinski signs and clonus. If a spastic gait disorder is seen without lower motor neuron signs in the legs, weakness in the legs may not be found, but incoordination is evident by clumsiness and slowness in the performance of alternating movements. The cranial nerve motor nuclei are implicated by dysarthria, lingual wasting and fasciculation, and impaired movement of the uvula. Facial weakness and wasting can be discerned, especially in the mentalis muscle, but is usually not prominent. Dysarthria and dysphagia caused by upper motor neuron disease ( pseudobulbar palsy) is made evident by movements of the uvula that are more vigorous on reflex innervation than on volition; that is, the uvula does not move well (or at all) on phonation, but a vigorous response is seen in the pharyngeal or gag reflex. A common manifestation of pseudobulbar palsy is emotional lability with inappropriate laughing or, more often, crying that can be regarded erroneously as a reactive depression because of the diagnosis; it is better regarded as a release phenomenon of the complex reflexes involved in emotional expression. The course is relentless and progressive without remissions, relapses, or even stable plateaus. Death results from respiratory failure, aspiration pneumonitis, or pulmonary embolism after prolonged immobility. The mean duration of symptoms is about 4 years; 20% of patients live longer than 5 years. Once a tracheostomy has been placed, the patient may be kept alive for years, although totally paralyzed and unable to move anything other than the eyes; this condition can be a locked-in state. Exceptional patients die in the first year or live longer than 25 years. About 10% of patients have associated dementia. The most common pathology is that of frontotemporal dementia; some show changes of Alzheimer disease and some show nonspecific pathology. The chromosome 17–related dementia, a tauopathy, has included amyotrophy in a few cases. Clinical Classification In addition to the terms SMA and ALS, two other labels have been used. Progressive bulbar palsy implies prominent dysarthria and dysphagia. This term, however, is falling into disfavor because almost all patients with bulbar symptoms already have fasciculations in arms and legs or display upper motor neuron signs; that is, the signs are not restricted to the cranial nerves and the syndrome is clearly ALS. PLS refers to a syndrome of upper motor neuron disorder only in life. At autopsy, cases of this nature are found in 5% or fewer of patients, and it is difficult to prove that the condition is really a form of ALS rather than a separate disease. PLS is described in Chapter 117 in the differential diagnosis of spastic paraparesis. Pure SMA (lower motor neuron signs alone) also accounts for fewer than 5% of cases at autopsy. Laboratory Data There is no pathognomonic laboratory abnormality, but the clinical diagnosis should be confirmed by EMG evidence of active denervation in at least three limbs. Nerve conduction velocities should be normal or nearly so; conduction block is rare in patients with frank upper motor neuron signs. CSF protein content is increased above 50 mg/dL in about 30% of patients and above 75 mg/dL in about 10%; the higher values seem more likely to occur in the presence of monoclonal gammopathy or lymphoma. Gammopathy is found by sensitive methods, such as immunofixation electrophoresis, in 5% to 10% of patients. Bone marrow examination is reserved for patients with monoclonal gammopathy. Magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation are emerging as effective measures of upper motor neuron dysfunction in patients who have few or no clinical corticospinal signs. Antibodies to the neuronal ganglioside GM 1 are demonstrable in 10% or less. No evidence supports the notion that ALS may be a manifestation of Lyme disease. A few cases have been found in patients with serologic evidence of human immunodeficiency virus or human T-cell lymphotropic virus type I infection. Diagnosis In adults, the finding of widespread lower motor neuron signs is virtually diagnostic of motor neuron disease, especially if Babinski signs or clonus appear. Even if these definite upper motor neuron signs are lacking the diagnosis is similarly secure if inappropriately active tendon reflexes or Hoffmann signs are found in arms with weak, wasted, and twitching muscles. The accuracy of clinical diagnosis has not been formally determined but, from clinical experience, is probably better than 95%. Rarely, some other condition, such as polyglucosan body disease, turns up at autopsy in a patient with clinical signs of ALS. The combination of ALS and dementia has been associated with several different pathologic changes (including Pick disease, Lewy body disease, or nonspecific subcortical gliosis). Although clinical diagnosis can be considered reliable, several common diagnostic problems occur: 1. The most important disorder, because it is treatable, is multifocal motor neuropathy with conduction block (MMNCB), which is defined by finding conduction block in more than one nerve and not at sites of entrapment neuropathy. Strict criteria include more than 50% decline in amplitude between proximal and distal

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sites of stimulation with less than 50% increase in duration of the response. As described, MMNCB primarily affects the hands, is asymmetric, affects men much more often than women, and is “predominantly lower motor neuron.” None of these features, however, clearly distinguishes the disorder from ALS. MMNCB progresses more slowly than ALS, so that relatively little disability after 5 years of symptoms would favor the diagnosis; however, that criterion is not applicable if a patient is seen soon after onset. More of a problem is the fact that about 50% of patients with MMNCB have had active tendon jerks in limbs with clear lower motor neuron signs. Regardless of the clinical similarities to ALS, the finding of conduction block is an indication for immunosuppressive drug therapy or intravenous immunoglobulin therapy because many patients with MMNCB show a good response. In the few autopsies of patients with MMNCB, there has been loss of motor neurons, suggesting that both motor neuron and peripheral nerve are affected in some cases. Myasthenia gravis (MG) is a common cause of dysarthria and dysphagia in people who are in the age range of those afflicted with ALS. If there is concomitant ptosis or ophthalmoparesis, if diurnal fluctuation in severity is marked, or if remissions have occurred, MG is more likely. If the syndrome is compatible and if there is an unequivocal response to edrophonium chloride, high titer of antibodies to acetylcholine receptor, or evidence of thymoma on computed tomography, the diagnosis is MG. If fasciculations are evident and the patient is not taking pyridostigmine bromide, or if upper motor neuron signs appear, the syndrome cannot be caused by MG. The differential diagnosis of spastic paraplegia in middle life includes multiple sclerosis (MS), ALS, cervical spondylosis, tropical spastic paraplegia, vitamin B 12 deficiency, and adrenoleukodystrophy. The appropriate tests are described in Chapter 117. Because magnetic resonance imaging (MRI) evidence of spondylosis is so common in asymptomatic people, the findings can be seen coincidentally in patients with ALS. The differentiation of ALS from spondylotic myelopathy can therefore be vexing; the diagnosis of spondylotic myelopathy should be made cautiously if unequivocal lower motor neuron signs are found in the hands without sensory symptoms or signs. The presence of fasciculations in legs or tongue is incompatible with cervical spondylosis. In contrast, neck pain and persistent paresthesia with unequivocal sensory loss are incompatible with ALS, unless there is an additional condition. MRS and transcranial magnetic stimulation of the motor cortex may be helpful in identifying PLS. Pseudobulbar palsy is seen in ALS and MS and after bilateral strokes. MRI is especially useful in identifying the causes other than motor neuron disease. Clinically, lower motor neuron signs are found in all patients with ALS, and they are incompatible with MS or stroke. In a patient with ALS, the liability to weeping should not be construed as a reactive depression. In our center, we carry out tests for monoclonal gammopathy, conduction block, antibodies to GM 1 ganglioside and myelin-associated glycoprotein (MAG), and lymphoproliferative disease in all patients with ALS. ALS is differentiated from myopathies by finding fasciculations or upper motor neuron signs on examination. If these are lacking, the differential diagnosis depends on EMG evidence of denervation. The postpolio syndrome is important for theoretic reasons (because persistent infection by the virus might cause ALS) and for practical reasons (because survivors of acute poliomyelitis have feared that the virus might be revived and attack again). No evidence suggests that survivors of acute childhood polio are at increased risk of ALS. The postpolio syndrome takes three forms: loss of ability to compensate for residual paresis with increasing age; addition of arthritis or some other physical condition that impedes adaption and compensation; or, decades after the original paralysis, new weakness of muscles thought not to have been affected in the childhood attack. These developments are accompanied by evidence of chronic denervation on EMG, but conduction velocities are normal; the consensus is that this syndrome is a residual effect in previously paralyzed muscles and that it is not a new motor neuron disease. Progression is slow and is limited to previously paralyzed muscles. No upper motor neuron signs appear, and clinically evident fasciculations are exceptional. Monomelic muscular atrophy (Hirayama syndrome) affects young men, not women, at about age 20 years and is restricted to one limb, usually an arm and hand rather than a leg. Although the condition was first reported in Japan, it has been seen in other countries. Many of those affected seem to be athletes, but the syndrome is not overtly related to cervical trauma. The condition progresses slowly for 1 or 2 years and then seems to become arrested. The origin of this disorder is not known. The patient must be observed for some months to be certain that other signs of motor neuron disease do not appear. Reversible motor neuron disease is the hope of diagnosis, but cases of spontaneous recovery are so rare that it is difficult to mention the possibility to a patient with ALS. The reversible syndrome may be one of lower motor neurons alone or may include the full picture of ALS. Many patients are younger than 30, but some are older. The syndrome of benign fasciculation and cramps is virtually restricted to medical students, physicians, and other medical workers because they are the only people in society who know the malignant implications of fasciculating muscles. The syndrome can be called the Denny-Brown, Foley syndrome after the discoverers. The condition has been rediscovered several times and given other names. The origin is not known, but because neither weakness nor wasting occurs, it is not ALS. In theory, ALS should sometimes start with this syndrome. For reasons unknown, however, it almost never does; only one case has been reasonably documented.

Treatment Sadly, there is no effective drug therapy for ALS. Therapeutic trials have shown no benefit from immunosuppression, immunoenhancement, plasmapheresis, lymph node irradiation, glutamate antagonists, nerve growth factors, antiviral agents, and numerous other categories of drugs. Riluzole (Rilutek), a glutamate inhibitor, is the only drug approved by the U.S. Food and Drug Administration for the treatment of ALS. It is said to prolong life by 3 to 6 months but has no visible effect on function or quality of life. Treatment is therefore symptomatic, and emotional support is vitally important; management may be carried out most efficiently in an ALS center. Early in the course, patients should try to continue to perform routine activities as long as they can. There is difference of opinion about exercising weak muscles, but physical therapy can help maintain function as long as possible. Drooling of saliva (sialorrhea) may be helped by atropine sulfate, glycopyrrolate (Robinul), or amitriptyline. Dysphagia leads to percutaneous gastrostomy to maintain nutrition and to protect against aspiration. Antispastic agents have not been helpful in the spastic gait disorder, but intrathecal administration of baclofen (Lioresal) might be considered in a few patients. The major decision concerns the use of tracheostomy and chronic mechanical ventilation, which can be done at home. In making the decision, patients should be informed fully about the long-term consequences of life without movement; they must decide whether they want to be kept alive or made as comfortable as possible—two choices that are not identical. Palliative care is emerging as a major option (see Chapter 165). Immunosuppressive therapy, starting with intravenous immunoglobulin, is used for the few patients with lymphoproliferative disease, monoclonal gammopathy, conduction block, or high titers of antibodies to GM 1 or MAG. Chronic therapy with cyclophosphamide or fludarabine (Fludara) may follow. In familial ALS, the question of presymptomatic diagnosis raises other ethical questions. SUGGESTED READINGS Spinal Muscular Atrophy Biros I, Forrest S. Spinal muscular atrophy: untangling the knot? J Med Genet 1999;36:1–8. Brzustowicz LM, Lehner T, Castilla LH, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 1990;344:540–541. Crawford TO, Sladky JT, Hurko O, Besner-Johnson A, Kelley RJ. Abnormal fatty acid metabolism in childhood spinal muscular atrophy. Ann Neurol 1999;45:337–343. Dubowitz V. Chaos in classification of the spinal muscular atrophies of childhood. Neuromuscul Disord 1991;1:77–80. Gilliam TC, Brzustowicz LM, Castilla LH, et al. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature 1990;345:823–825. Lefebvre S, Burglen L, Frezal J, Munnich A, Melki J. The role of the SMN gene in proximal spinal muscular atrophy. Hum Mol Genet 1998;7:1531–1536. McShane MA, Boyd S, Harding B, et al. Progressive bulbar paralysis of childhood: a reappraisal of Fazio-Londe disease. Brain 1992;115:1889–1900. Melki J, LeFebvre S, Burglen L, et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science 1994;264:1474–1476. Moulard B, Salachas F, Chassande B, et al. Association between centromeric deletions of the SMN gene and sporadic adult-onset lower motor neuron disease. Ann Neurol 1998;43:640–644. Rowland LP. Molecular basis of genetic heterogeneity: role of the clinical neurologist. J Child Neurol 1998:13:122–132. Rubi-Gozalbo ME, Smeitink JAM, Ruitenbeck W, et al. Spinal muscular atrophy-like picture, cardiomyopathy, and cytochrome- c-oxidase deficiency. Neurology 1999:52:383–386. Stewart H, Wallace A, McGaughran J, Mountford R, Kingston H. Molecular diagnosis of spinal muscular atrophy. Arch Dis Child 1998;78:531–535.

Kennedy Disease Fischbeck KH. Kennedy disease. J Inherit Metab Dis 1997;20:152–158. Harding AE, Thomas PK, Baraister M, et al. X-linked bulbospinal neuronopathy: report of 10 cases. J Neurol Neurosurg Psychiatry 1982;45:1012–1019. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutation in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77–79. Li M, Miwa S, Kobayashi Y, et al. Nuclear inclusions of the androgren receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 1998;44:249–254. Merry DE, Kobayashi Y, Bailey CK, Taye AA, Fischbeck KH. Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum Mol Genet 1998;7:693–701. Paraboosingh JS, Figlwicz DA, Krizus A, et al. Spinobulbar muscular atrophy can mimic ALS: the importance of genetic testing in male patients with atypical ALS. Neurology 1997;49:568–572. Shaw PJ, Thagesen H, Tomkins J, et al. Kennedy's disease: unusual molecular pathologic and clinical features. Neurology 1998;51:252–255. Trojaborg W, Wulff CH. X-linked bulbospinal neuronopathy (Kennedy's syndrome): a neurophysiological study. Acta Neurol Scand 1994;89:214–219. Amyotrophic Lateral Sclerosis Armon C, Daube JR, Windebank AJ, Kurland LT. How frequently does classic amyotrophic lateral sclerosis develop in survivors of poliomyelitis? Neurology 1990;40:172–174. Belsh JM, Schiffman MG, eds. Amyotrophic lateral sclerosis. Armonk NY: Futura Publishing, 1996. Ben Hamida M, Hentati F, Hamida CB. Hereditary motor system disease (chronic juvenile amyotrophic lateral sclerosis). Brain 1990;113:347–363. Blexrud MD, Windebank AJ, Daube JR. Long-term follow-up of 121 patients with benign fasciculations. Ann Neurol 1993;34:622–625. Bonduelle M. Amyotrophic lateral sclerosis. In: Vinken PJ, Bruyn GW, de Jong JMBV, eds. System disorders and atrophies. Handbook of clinical neurology, vol 22. Amsterdam: North-Holland Publishing Co, 1975:281–338. Boothby J, DeJesus PV, Rowland LP. Reversible forms of motor neuron disease: lead “neuritis.” Arch Neurol 1974;31:18–23. Borchelt DR, Wong PC, Sisodia SS, Price DL. Transgenic mouse models of Alzheimer's disease and amyotrophic lateral sclerosis. Brain Pathol 1998;8:735–757. Bradley WG, Tobison SH, Tandan R, Besser D. Post-radiation motor neuron syndromes. Adv Neurol 1991;56:341–356. Brown RH Jr. Amyotrophic lateral sclerosis and the inherited motor neuron diseases. In Martin JB, ed. Scientific American molecular neurology. New York: Scientific American, 1998:223–238. Brownell B, Trevor-Hughes J. Central nervous system in motor neuron disease. J Neurol Neurosurg Psychiatry 1970;33:338–357. Bruyn GW. Progressive bulbar palsy in adults. In: Vinken PJ, Bruyn GW, Klawans HL, de Jong JMBV, eds Diseases of the motor system. Handbook of clinical neurology, vol 59. New York: Elsevier Science 1991:217–229. Chaudry V, Corse AM, Cornblath DR, et al. Multifocal motor neuropathy: response to human immune globulin. Ann Neurol 1993;33:237–242. Cornblath DR, Kuncl RW, Mellits D, et al. Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve 1992;15:1111–1115. Dalakas MC, Elder G, Hallet M, et al. A long-term follow-up study of patients with post-poliomyelitis neuromuscular symptoms. N Engl J Med 1986;314:959–963. DeCarolis P, Montagna P, Cipiuli M, et al. Isolated lower motor neuron involvement following radiotherapy. J Neurol Neurosurg Psychiatry 1986;48:718–719. Eisen A, Krieger S, eds. Amyotrophic lateral sclerosis: a synthesis of research and clinical practice. New York: Cambridge University Press, 1998. Ellis CM, Simmons A, Andrews C, Dawson JM, Williams SC, Leigh PN. A proton magnetic resonance spectroscopic study in ALS: correlation with clinical findings. Neurology 1998;51:1104–1109. Evans BK, Fagan C, Arnold T, et al. Paraneoplastic motor neuron disease and renal cell carcinoma. Neurology 1990;40:960–963. Forsyth PA, Dalmau J, Graus F, Cwik V, Rosenblum MK, Posner JB. Motor neuron syndromes in cancer patients. Ann Neurol 1997;41:722–730. Gordon PH, Rowland LP, Younger DS, et al. Lymphoproliferative disorders and motor neuron disease. Neurology 1997;48:1671–1678. Ince PG, Lowe J, Shaw PJ. Amyotrophic lateral sclerosis: current issues in the classification, pathogenesis, and molecular pathology. Neuropathol Appl Neurobiol 1998;24:104–117. Jubelt B. Motor neuron diseases and viruses: poliovirus, retroviruses, and lymphomas. Curr Opin Neurol Neurosurg 1992;5:655–658. Kaji R, Oka N, Tsuji T, et al. Pathological findings at the site of conduction block in multifocal motor neuropathy. Ann Neurol 1993;33:152–158. Kaji R, Shibasaki H, Kimura J. Multifocal demyelinating motor neuropathy: cranial nerve involvement and immunoglobulin therapy.

Neurology 1992;42:506–509.

Kuroda Y, Sugihara H. Autopsy report of HTLV-1-associated myelopathy presenting with ALS-like manifestations. J Neurol Sci 1991;106: 199–205. Kurtzke JF. Risk factors in amyotrophic lateral sclerosis. Adv Neurol 1991;56:245–270. Lange DJ, McDonald TD, Trojaborg W, Blake DM. Persistent and transient “conduction block” in motor neuron diseases. Muscle Nerve 1993;16:896–903. Lange DJ, Trojaborg W, Latov N, et al. Multifocal motor neuropathy with conduction block: is it a distinct clinical entity? Neurology 1992;42:497–505. Latov N. Antibodies to glycoconjugates in neurologic disease. Clin Aspect Autoimmun 1990;4:18–29. Lawyer T, Netsky MG. Amyotrophic lateral sclerosis: clinico-anatomic study of 53 cases. Arch Neurol Psychiatry 1953;69:171–192. Lin CL, Bristol LA, Jin L, et al. Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in ALS. Neuron 1998;20:589–602. Malapert D, Brugieres P, Degos JD. Motor neuron syndrome in the arms after radiation treatment. J Neurol Neurosurg Psychiatry 1991;54:1123–1124. Martyn CN. Poliovirus and motor neuron disease. J Neurol 1990;237:336–358. Matherson L, Barrau K, Blin O. Disease management: the example of amyotrophic lateral sclerosis. J Neurol 1998:245[Suppl 2]:S20–S28. Mitsumoto H, Chad DA, Piro EP, eds. Amyotrophic lateral sclerosis. Philadephia: FA Davis Co, 1998. Moss AH, Case P, Stocking CB, et al. Home ventilation for amyotrophic lateral sclerosis patients: outcomes, costs, and patient, family, and physician attitudes. Neurology 1993;43:438–443. Munsat TL. Post-polio syndrome. Boston: Butterworth-Heinemann, 1991. Norris F, Shepher R, Denys E, et al. Onset, natural history, and outcome in idiopathic adult motor neuron disease. J Neurol Sci 1993;118:48–55. Pestronk A, Cornblath DR, Ilyas AA, et al. A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol 1988;24:73–78. Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59–62.

Rosenfeld MR, Posner JB. Paraneoplastic motor neuron disease. Adv Neurol 1991;56:445–463. Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 1992;326:1464–1468. Rowland LP, ed. Amyotrophic lateral sclerosis and other motor neuron diseases. New York: Raven Press, 1991. Rowland LP. Ten central themes in a decade of ALS research. Adv Neurol 1991;56:3–23. Rowland LP. Surgical treatment of cervical spondylotic myelopathy: time for a controlled trial. Neurology 1992;42:5–13. Rowland LP. Diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1998;160[Suppl 1]:S6–S24. Santoro M, Thomas FP, Fink ME, et al. IgM deposits at nodes of Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal conduction block. Ann Neurol 1990;28:373–377. Serratrice G. Spinal monomelic amyotrophy. Adv Neurol 1991;56:169–173. Smith RG, Hamilton S, Hofmann F, et al. Serum antibodies to L-type calcium channels in patients with ALS. N Engl J Med 1992;327:1721–1728. Smith RG, Henry YK, Mattson MP, Appel SH. Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Ann Neurol 1998;44:696–699. Smith RG, Siklos L, Alexianu ME, et al. Autoimmunity and ALS. Neurology 1996[Suppl 2]:S40–S46. Tucker T, Layzer RB, Miller RG, Chad D. Subacute reversible motor neuron disease. Neurology 1991;41:1541–1544. Vinken PJ, Bruyn GW, Klawans HL, DeJong JMBV, eds. Diseases of the motor system. Handbook of clinical neurology, vol 59. New York: Elsevier Science, 1991.

CHAPTER 119. SYRINGOMYELIA MERRITT’S NEUROLOGY

CHAPTER 119. SYRINGOMYELIA ELLIOTT L. MANCALL AND PAUL C. MCCORMICK Clinical Manifestations Pathology and Pathogenesis Laboratory Data Differential Diagnosis Treatment Suggested Readings

Cavitation within the spinal cord was first described by Esteinne in 1546 in La dissection du corps humain. Ollivier D'Angers applied the term syringomyelia in 1827. This term connotes a chronic, progressive disorder that most often involves the spinal cord. The exact incidence of syringomyelia is not known, but it is rare. It occurs more frequently in men than in women. Familial cases have been described. The disease usually appears in the third or fourth decade of life, with a mean age at onset of about 30 years. It is rare in childhood or late-adult years. Syringomyelia usually progresses slowly; the course extends over many years. An acute course may be evident when the brainstem is affected ( syringobulbia). Syringomyelia rarely occurs de novo or in isolation, but usually arises as a result of an associated anomaly. Over two-thirds of cases of syringomyelia are associated with the Arnold-Chiari malformation. Less commonly, a variably sized syringomyelic cavity, or syrinx, may be found within or in proximity to an intramedullary tumor, generally a glioma. Syringomyelia may also be a late consequence of spinal cord trauma, arising ex vacuo after absorption of an intramedullary hematoma (hematomyelia). In about 5% of patients with spinal cord injury, the delayed onset of an ascending spinal cord syndrome is caused by an expanding syrinx. Cerebrospinal fluid (CSF) circulation may be impaired by dense arachnoiditis at the site of the trauma, thereby causing the delayed formation of a syrinx on an ischemic basis.

CLINICAL MANIFESTATIONS Symptoms depend primarily on the location of the lesion, Milhorat and his colleagues have isolated several individual cavitary patterns, each producing a more or less distinctive clinical appearance. The syrinx is most commonly encountered in the lower cervical region, particularly at the base of the posterior horn, extending into the central gray matter and anterior commissure. The cyst interrupts the decussating spinothalamic fibers that mediate pain and temperature sensibility, resulting in loss of these sensations; light touch, vibratory sense, and position sense are relatively preserved, at least early in the disease, by virtue of sparing of the posterior columns. This pattern of loss of cutaneous sensibility with preservation of posterior column sensory modalities is commonly referred to as dissociated sensory loss. Pain and temperature sensations are typically impaired in the arm on the involved side, sometimes in both arms or in a shawl-like distribution ( en cuirasse) across the shoulders and upper torso, front and back. When the cavity enlarges to involve the posterior columns, there is loss of position and vibratory sense in the feet, and astereognosis may be noted in the hands. Extension of the lesion into the anterior horns with loss of motor neurons causes amyotrophy that begins in the small muscles of the hands (brachial amyotrophy), ascends to the forearms, and ultimately affects the shoulder girdle. The hand may be strikingly atrophied, with the development of a claw-hand deformity (main en griffe). Weakness appears in the hands, forearms, and shoulder girdle, and fasciculations may be seen. Because the syrinx is asymmetrically placed early in its development, manifestations in the arms and hands tend to be similarly asymmetric. Muscle stretch reflexes in the arms are characteristically lost early. As the syrinx extends into the lateral columns, spasticity appears in the legs, with paraparesis, hyperreflexia, and extensor plantar responses. Impairment of bowel and bladder functions may be a late manifestation. A Horner syndrome may appear, reflecting damage to the sympathetic neurons in the intermediolateral cell column. Pain, generally deep and aching in quality, is sometimes experienced and may be severe. It involves the neck and shoulders or follows a radicular distribution in the arms or trunk. The syrinx sometimes ascends into the medulla. Syringobulbia is evidenced by dysphagia, pharyngeal and palatal weakness, asymmetric weakness and atrophy of the tongue, sensory loss involving primarily pain and temperature sense in the distribution of the trigeminal nerve, and nystagmus. Signs of cerebellar dysfunction may appear. Rarely, the syrinx extends even higher in the brainstem or into the centrum semiovale as a syringocephalus. Many other clinical abnormalities are evident. Scoliosis is characteristically seen, and neurogenic arthropathies ( Charcot joints) may affect the shoulder, elbow, or wrist. Acute painful enlargement of the shoulder may appear and is associated with destruction of the head of the humerus. Painless ulcers of the hands are frequent. The hands are occasionally the site of remarkable subcutaneous edema and hyperhidrosis ( main succulente), presumably caused by interruption of central autonomic pathways. A cyst sometimes develops in the lumbar cord either in association with or independent of a cervical syrinx. Lumbar syringomyelia is characterized by atrophy of proximal and distal leg muscles with dissociated sensory loss in lumbar and sacral dermatomes. Stretch reflexes are lost in the legs; impairment of sphincter function is common. The plantar responses are ordinarily flexor.

PATHOLOGY AND PATHOGENESIS As emphasized by Greenfield, syringomyelia may be defined as a tubular cavitation of the spinal cord, usually beginning within the cervical cord and generally extending over many segments. Syringomyelia should be regarded as distinct from simple cystic expansion of the central canal of the cord; the term hydromyelia is more appropriately applied to that condition. The syrinx may communicate with the central canal, and ependymal cells occasionally line the wall of the syrinx. The fluid within the cyst is similar to, if not identical with, CSF. The syrinx may be limited to the cervical cord or may extend the length of the cord; it tends to vary in transverse diameter from segment to segment, usually achieving maximal extent in the cervical and lumbosacral enlargements. Originally confined to the base of a posterior horn or to the anterior commissure, the cyst slowly enlarges to involve much of both gray and white matter; at times, only a narrow rim of cord parenchyma can be identified histologically. The cyst itself is surrounded by a dense glial fibril wall. Extension of the cavity into the medulla or, rarely, higher within the neuraxis may be noted. Developmental abnormalities in the cervical spine and at the base of the skull, such as platybasia, are common. Features of the Arnold-Chiari malformation, such as displacement of the cerebellar tonsils into the cervical canal, are often identified. Hydrocephalus is frequent, and cerebellar hypoplasia may be found. In a few patients, ependymoma or astrocytoma of the spinal cord is encountered, usually in juxtaposition with the syrinx itself. The pathogenesis of syringomyelia is uncertain. Following Gardner, it is widely held that most cases of syringomyelia are of a “communicating” variety. Dilatation of the central canal is attributed to CSF pulsations directed downward from the fourth ventricle because the foramina of exit are occluded by a developmental defect in the rhombic roof or other anomalies of the medullocervical junction. According to this hydrodynamic theory, obstruction or atresia of the normal outlets of the fourth ventricle is essential; in most cases, the ventricular obstruction is associated with features of the Arnold-Chiari malformation and, often, with hydrocephalus. As a modification of Gardner's theory, Boulay and associates emphasized systolic excursions of CSF in the basal cisterns in the formation of the cystic cavity. Alternatively, Williams proposed that the Arnold-Chiari malformation is an acquired anomaly that results from excessive molding of the head during difficult, usually high forceps, delivery. A ball-valve effect of the cerebellar tonsils in the foramen magnum could create a dissociation between cranial and spinal CSF pressures, particularly during Valsalva maneuvers, which in turn could lead to syrinx formation. Both the Gardner and Williams hypotheses are challenged by the evidence cited by Milhorat and associates to the effect that most syrinx cavities do not in fact communicate with the fourth ventricle; caudal flow of CSF from the fourth ventricle into the central canal cannot therefore be considered the explanation for the appearance of a syrinx with a lesion of the hindbrain. In the traditional nomenclature of Greenfield, distention of the central canal is therefore designated hydromyelia, with the term syringomyelia reserved for a noncommunicating cyst. From this perspective, and in keeping with the observations of Milhorat, the syringomyelic cavity cannot be considered part of the ventricular system in what is essentially a persistent embryonic configuration; rather it is an independent development. As already stressed, noncommunicating syrinx has been attributed to several factors, including extension of CSF under pressure along the Virchow-Robin spaces, cystic degeneration of an intramedullary glioma, and ischemia with cyst formation secondary to arachnoiditis caused by meningitis or subarachnoid hemorrhage with resultant insufficiency of blood flow in the anterior spinal artery. A syrinx may also develop after spinal cord trauma either soon after resorption of an intramedullary hematoma ( hematomyelia) or as a delayed

phenomenon after cord contusion or compression with microcystic cavitation. Birth trauma may be important in the development of syringomyelia. In the last analysis, the distinction between communicating and noncommunicating forms of syringomyelia may be artificial; the term syringohydromyelia has been suggested as a more inclusive term. Most instances of syringomyelia do seem to fall into the Gardner communicating variety, although the precise pathogenetic mechanisms remain incompletely understood. In some individuals, the original communication with the fourth ventricle may have been obliterated with time, resulting in the spurious appearance of a noncommunicating configuration.

LABORATORY DATA CSF ordinarily demonstrates few abnormalities. CSF pressure is sometimes elevated, and complete subarachnoid block may be noted. The cell count is only rarely more than 10/mm3. A mild elevation of CSF protein content occurs in 50% of patients; in presence of subarachnoid block, CSF protein may exceed 100 mg/dL. Magnetic resonance imaging (MRI) is the diagnostic procedure of choice for the diagnosis and evaluation of syringomyelia. Cystic enlargement of the spinal cord extends over several segments (Fig. 119.1). The signal intensity of the cyst is generally similar to that of CSF. The cyst margins are often irregular and may demonstrate periodic folds or septations that may result from turbulent flow within the cavity. If syringomyelia is identified on MRI, further evaluation should include MRI of the brain and craniovertebral junction to identify associated anomalies, such as hydrocephalus or an Arnold-Chiari malformation. If syringomyelia occurs without an Arnold-Chiari malformation or prior spinal cord injury, a complete spinal MRI with gadolinium is performed to rule out an intramedullary spinal cord tumor. Myelography and computed tomography (CT) are rarely used for the diagnosis or evaluation of syringomyelia. Plain films and CT may be useful in consideration of bony anomalies that commonly occur at the craniovertebral junction in patients with hindbrain abnormalities.

FIG. 119.1. Sagittal T1-weighted MRI shows a large syrinx. Note the associated Arnold-Chiari malformation with cerebellar tonsillar herniation below the foramen magnum. Decompression of the foramen magnum usually results in resolution of the syrinx.

DIFFERENTIAL DIAGNOSIS Amyotrophic lateral sclerosis (ALS) commonly causes weakness, atrophy, and reflex loss in the arms that is often asymmetric, with heightened reflexes and extensor-plantar responses in the legs. Sensory loss, however, does not occur in ALS. Multiple sclerosis (MS) may mimic syringomyelia. Early atrophy of hand muscles, however, does not occur in MS, and the lack of evidence of dissemination of lesions elsewhere argues against this diagnosis. MRI of brain and spinal cord separates MS and syringomyelia. Intrinsic tumors of the spinal cord may produce clinical signs similar to those of syringomyelia. Again, MRI generally distinguishes the two. MRI also differentiates syringomyelia from cervical spondylosis. Anomalies of the craniovertebral junction and cervical ribs may also cause symptoms reminiscent of syringomyelia; because both may be associated with true syringomyelia, identification of these abnormalities is not sufficient to exclude cavitation within the spinal cord.

TREATMENT The treatment of syringomyelia consists of either drainage of the syrinx cavity or correction of the abnormal dynamics that allowed the syrinx to develop. In tumor-associated syringomyelia, for example, removal of the mass nearly always results in resolution of the syrinx. Syringomyelia arising as a late consequence of spinal cord trauma usually requires direct drainage because the dense arachnoiditis at the level of the trauma generally cannot be corrected. Simple drainage can consist of either percutaneous needle aspiration or open syringotomy. These maneuvers provide temporary relief at best, and the cavity usually reexpands because of spontaneous closure of the syringotomy and persistence of the filling mechanism. Prolonged successful drainage usually requires the insertion through laminectomy of a small Silastic tube directly into the syrinx cavity. The other end of the catheter is placed in either the pleural or the peritoneal space, thereby allowing continuous drainage of the syrinx into a cavity of lower pressure. Management of syringomyelia that occurs in association with an Arnold-Chiari malformation is more complicated. Ventriculoperitoneal shunting is generally performed initially if significant hydrocephalus is present. In the absence of hydrocephalus or if the ventriculoperitoneal shunt fails to relieve symptoms, a posterior fossa decompression with or without simultaneous shunting of the syrinx can be performed. The posterior fossa decompression consists of a wide suboccipital craniectomy and cervical laminectomy with duraplasty to enlarge the foramen magnum effectively. Plugging of the obex with muscle or the placement of a Silastic stent into the fourth ventricle to improve the CSF outflow into the basal cisterns and subarachnoid space may also be performed, but each is controversial. In most patients, adequate posterior fossa decompression results in shrinkage or even resolution of the syrinx. In refractory cases, a direct syrinx shunt may be placed. SUGGESTED READINGS Barnett HJM, Foster JB, Hudgson P. Syringomyelia. Philadelphia: WB Saunders, 1973. Batzdorf U, Klekamp J, Johnson JP. A critical appraisal of syrinx cavity shunting procedures. J Neurosurg 1998;89:382–388. Berry RG, Chambers RA, Lublin FD. Syringoencephalomyelia (syringocephalus). J Neuropathol Exp Neurol 1981;40:633–644. Caplan LR, Norohna AB, Amico LL. Syringomyelia and arachnoiditis. J Neurol Neurosurg Psychiatry 1990;53:106–113. Del Bigio MR, Deck JHN, MacDonald JK. Syrinx extending from conus medullaris to basal ganglia: a clinical, radiological, and pathological correlation. Can J Neurol Sci 1993;20:240–246. Donauer E, Rascher K. Syringomyelia: a brief review of ontogenetic, experimental and clinical aspects. Neurosurg Rev 1993;16:7–13. Dyste GN, Menezes AH, VanGilder JC. Symptomatic Chiari malformations: an analysis of presentation, management, and long-term outcome. J Neurosurg 1989;71:159–168. Fischbein NJ, Dillon WP, Cobbs C, Weinstein PR. The “presyrinx state”: a reversible myelopathic condition that may precede syringomyelia. AJNR 1999;20:7–20. Gardner WH, McMurry FG. “Non-communicating” syringomyelia: a nonexistent entity. Surg Neurol 1976;6:251–256. Gardner WJ. Hydrodynamic mechanism of syringomyelia: its relationship to myelocele. J Neurol Neurosurg Psychiatry 1965;28:247–259. Goldstein JH, Kaptain GJ, Do HM, Cloft HJ, Jane JA Sr, Phillips CD. CT-guided percutaneous drainage of syringomyelia. J Comput Assist Tomogr 1998;22:984–988. Graham DI, Lantos PL, eds. Greenfields neuropathology, vol. 1, 6th ed. Edward Arnold, 1997:486–490. Haponik EF, Givens D, Angelo J. Syringobulbia-myelia with obstructive sleep apnea. Neurology 1983;33:1046–1049.

Hodge C, Jones M. Syringomyelia and spinal cord tumors. Curr Opin Neurol Neurosurg 1991;4:597–600. Igbal JB, Bradey N, Macfaul R, Cameron MM. Syringomyelia in children: six case reports and review of the literature. Br J Neurosurg 1992;6:13–20. Isu T, Susaki H, Takamura H, Kobayashi N. Foramen magnum decompression with removal of the outer layer of the dura as treatment for syringomyelia occurring with Chiari I malformation. Neurosurgery 1993;33:844–849. Jones J, Wolf S. Neuropathic shoulder arthropathy (Charcot joint) associated with syringomyelia. Neurology 1998;50:825–827. Keung YK, Cobos E, Whitehead RP, et al. Secondary syringomyelia due to intramedullary spinal cord metastasis: case report and review of literature. Am J Clin Oncol 1997;20:577–579. Mariani C, Cislaghi MG, Barbieri S, et al. The natural history and results of surgery in 50 cases of syringomyelia. J Neurol 1991;238:433–438. Milhorat, TH, Capocelli, AL, Anzil, AP, et al. Pathological basis of spinal cord cavitation in syringomyelia: analysis of 105 autopsy cases. J Neurosurg 1995;82;802–812. Milhorat TH, Johnson WD, Miller JI, et al. Surgical treatment of syringomyelia based on magnetic resonance imaging criteria. Neurosurgery 1992;31:231–244. Milhorat TH, Miller JI, Johnson WD, et al. Anatomical basis of syringomyelia occurring with hindbrain lesions. Neurosurgery 1993;32;748–754. Oldfield EH, Muraszko K, Shawker TH, Patronas NJ. Pathophysiology of syringomyelia associated with Chiari I malformation of the cerebellar tonsils: implications for diagnosis and treatment. J Neurosurg 1994;80:3–15. Pillay PK, Awad IA, Hahn JF. Gardner's hydrodynamic theory of syringomyelia revisited. Cleve Clin J Med 1992;59:373–380. Poser CM. The relationship between syringomyelia and neoplasm. Springfield, IL: Charles C Thomas, 1956. Sackellares JC, Swift TR. Shoulder enlargement as the presenting sign in syringomyelia. JAMA 1976;236:2878–2879. Schurch B, Wichmann W, Rossier AB. Post-traumatic syringomyelia (cystic myelopathy): a prospective study of 449 patients with spinal cord injury. J Neurol Neurosurg Psychiatry 1996;60:61–67. Vassilouthis J, Papandreou A, Anagnostaras S, Pappas J. Thecoperitoneal shunt for syringomyelia: report of three cases. Neurosurgery 1993;33:324–327. Williams B. On the pathogenesis of syringomyelia: a review. J R Soc Med 1980;73:798–806. Williams B. Post-traumatic syringomyelia, an update. Paraplegia 1990;28:296–313. Williams B. Syringomyelia. Neurosurg Clin N Am 1990;1:653–685.

CHAPTER 120. MYASTHENIA GRAVIS MERRITT’S NEUROLOGY

SECTION XVII. DISORDERS OF THE NEUROMUSCULAR JUNCTION CHAPTER 120. MYASTHENIA GRAVIS AUDREY S. PENN AND LEWIS P. ROWLAND Etiology and Pathogenesis Special Forms of Myasthenia Gravis Pathology Incidence Symptoms Signs Laboratory Data Diagnosis Differential Diagnosis Treatment Suggested Readings

Myasthenia gravis (MG) is caused by a defect of neuromuscular transmission due to an antibody-mediated attack on nicotinic acetylcholine receptors (AchR) at neuromuscular junctions. It is characterized by fluctuating weakness that is improved by inhibitors of cholinesterase.

ETIOLOGY AND PATHOGENESIS The pathogenesis of MG is related to the destructive effects of autoantibodies to AChR, as indicated by several lines of evidence: 1. In several species of animals, experimental immunization with AChR purified from the electric organ of the torpedo, an electric fish, induced high titers of antibody to the receptor. Overt evidence of weakness varies but may be uncovered by small doses of curare. Many animals also showed the essential electrophysiologic and pathologic features of human MG. This was first found in rabbits by Patrick and Lindstrom (1973). 2. Serum antibodies that react with human AChR are found in humans with MG. 3. Toyka and colleagues (1975) found that the electrophysiologic features of MG were reproduced by passive transfer of human immunoglobulin (Ig) G to mice. By analogy, human transient neonatal MG could then be explained by transplacental transfer of maternal antibody. 4. Pinching found that plasmapheresis reduced plasma levels of anti-AChR and ameliorated MG symptoms and signs. The polyclonal IgG antibodies to AChR are produced by plasma cells in peripheral lymphoid organs, bone marrow, and thymus. These cells are derived from B cells that have been activated by antigen-specific T-helper (CD4+) cells. The T-cells have also been activated, in this case by binding to AChR antigenic peptide sequences (epitopes) that rest within the histocompatibility antigens on the surface of antigen-presenting cells. The AChR antibodies react with multiple determinants, and enough antibody circulates to saturate up to 80% of all AChR sites on muscle. A small percentage of the anti-AChR molecules interfere directly with the binding of ACh, but the major damage to endplates seems to result from actual loss of receptors due to complement-mediated lysis of the membrane and to acceleration of normal degradative processes (internalization, endocytosis, lysosomal hydrolysis) with inadequate replacement by new synthesis. As a consequence of the loss of AChR and the erosion and simplification of the endplates, the amplitude of miniature endplate potentials is about 20% of normal, and patients are abnormally sensitive to the competitive antagonist curare. The characteristic decremental response to repetitive stimulation of the motor nerve reflects failure of endplate potentials to reach threshold so that progressively fewer fibers respond to arrival of a nerve impulse. How the autoimmune disorder starts is not known. In human disease, in contrast to experimental MG in animals, the thymus gland is almost always abnormal; there are often multiple lymphoid follicles with germinal centers (“hyperplasia of the thymus”), and in about 15% of patients, there is an encapsulated benign tumor, a thymoma. These abnormalities are impressive because the normal thymus is responsible for the maturation of T-cells that mediate immune protection without promoting autoimmune responses. AChR antibodies are synthesized by B cells in cultures of hyperplastic thymus gland. The hyperplastic glands contain all the elements needed for antibody production: class II HLA-positive antigen-presenting cells, T-helper cells, B cells, and AChR antigen; that is, messenger ribonucleic acid for subunits of AChR has been detected in thymus, and “myoid cells” are found in both normal and hyperplastic thymus. The myoid cells bear surface AChR and contain other muscle proteins. When human myasthenic thymus was transplanted into severely congenitally immunodeficient mice, the animals produced antibodies to AChR that bound to their own motor endplates, even though weakness was not evident. Excessive and inappropriately prolonged synthesis of thymic hormones that normally promote differentiation of T-helper cells may contribute to the autoimmune response. Still another possible initiating factor is immunogenic alteration of the antigen, AChR, at endplates, because penicillamine therapy in patients with rheumatoid arthritis may initiate a syndrome that is indistinguishable from MG except that it subsides when administration of the drug is stopped. There are few familial cases of the disease, but disproportionate frequency of some HLA haplotypes (B8, DR3, DQB1) in MG patients suggests that genetic predisposition may be important. Other autoimmune diseases also seem to occur with disproportionate frequency in patients with MG, especially hyperthyroidism and other thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, and pemphigus. Most AChR antibodies are directed against antigenic determinants other than the ACh binding site. Nevertheless, the summed effects of the polyclonal anti-AChR antibodies with differing modes of action result in destruction of the receptors. Physiologic studies indicate impaired postsynaptic responsiveness to ACh, which accounts for the physiologic abnormalities, clinical symptoms, and beneficial effects of drugs that inhibit acetylcholinesterase.

SPECIAL FORMS OF MYASTHENIA GRAVIS Juvenile and Adult Forms Typical MG may begin at any age, but it is most common in the second to fourth decades. It is less frequent before age 10 or after age 65 years. Circulating AChR antibodies are demonstrated in 85% to 90% of patients with generalized MG and 50% to 60% of those with restricted ocular myasthenia. Patients without antibodies do not differ clinically or in response to immunotherapy; this seronegative MG may be more common in patients who are symptomatic before puberty. These are the typical forms of MG; other forms are rare. Neonatal Myasthenia About 12% of infants born to myasthenic mothers have a syndrome characterized by impaired sucking, weak cry, limp limbs, and, exceptionally, respiratory insufficiency. Symptoms begin in the first 48 hours and may last several days or weeks, after which the children are normal. The mothers are usually symptomatic but may be in complete remission; in either case, AChR antibodies are demonstrable in both mother and child. Symptoms disappear as the antibody titer in the infant declines. Severe respiratory insufficiency may be treated by exchange transfusion, but the natural history of the disorder is progressive improvement and total disappearance of all symptoms within days or weeks. Respiratory support and nutrition are the key elements of treatment. Rare instances of arthrogryposis multiplex congenita have been attributed to transplacental transfer of antibodies that inhibit fetal AChR. Congenital Myasthenia Children with congenital MG, although rarely encountered, show several characteristics. The mothers are asymptomatic and do not have circulating anti-AChR in the blood. Usually, no problem occurs in the neonatal period; instead, ophthalmoplegia is the dominant sign in infancy. Limb weakness may be evident. The condition is often familial. Antibodies to AChR are not found, but there are decremental responses to repetitive stimulation. Ultrastructural and biochemical examination of motor endplates, microelectrode analysis, and identification of mutations have delineated a series of disorders that include both presynaptic and postynaptic proteins.

Disorders of the ion channel formed by the AChR molecule include the slow-channel syndrome, in which the response to ACh is enhanced because the opening episodes of the channel are abnormally prolonged. Forearm extensors tend to be selectively weak. More than 11 different mutations have been identified in different AChR subunits. Quinidine shortens the prolonged openings and gives therapeutic benefit. A fast-channel syndrome, with impaired response to ACh has been reported in rare patients with mutations of the epsilon subunit. Another mutation in the same subunit leads to abnormal kinetics of AChR activation so that the channel opens more slowly and closes more rapidly than normal. The 24 known mutations in the epsilon subunit are inherited recessively and result in severe lack of AChR in the endplates. One syndrome results from mutations in the collagen tail subunit of the enzyme, creating deficiency of acetylcholinesterase. These landmark observations were made at the Mayo Clinic by Andrew G. Engel and his colleagues. Anticholinesterase drugs may help in some of these disorders, but parents should be warned that sudden apneic spells may be induced by mild infections. Drug-induced Myasthenia The best example of this condition occurs in patients treated with penicillamine for rheumatoid arthritis, scleroderma, or hepatolenticular degeneration (Wilson disease). The clinical manifestations and AChR antibody titers are similar to those of typical adult MG, but both disappear when drug administration is discontinued. Cases attributed to trimethadione (Tridione) have been less thoroughly studied.

PATHOLOGY The overt pathology of MG is found primarily in the thymus gland. About 70% of thymus glands from adult patients with MG are not involuted and weigh more than normal. The glands show lymphoid hyperplasia: In normal individuals, germinal centers are numerous in lymph nodes and spleen but are sparse in the thymus. Immunocytochemical methods indicate that these thymic germinal centers contain B cells, plasma cells, HLA class II DR-positive T cells, and interdigitating cells. Another 10% of myasthenic thymus glands contain thymomas of the lymphoepithelial type. The lymphoid cells in these tumors are T cells; the neoplastic elements are epithelial cells. Benign thymomas may nearly replace the gland, with only residual glandular material at the edges, or they may rest within a large hyperplastic gland. Thymomas tend to occur in older patients, but in Castleman's series, 15% were found in patients between ages 20 and 29 years. They may invade contiguous pleura, pericardium, or blood vessels, or seed onto more distant thoracic structures, including the diaphragm; however, they almost never spread to other organs. In older patients without thymoma, thymus gland appears involuted, often showing hyperplastic foci within fatty tissue on microscopic examination of multiple samples. In about 50% of cases, muscles contain lymphorrhages, which are focal clusters of lymphocytes near small necrotic foci without perivascular predilection. In a few cases, especially in patients with thymoma, there is diffuse muscle fiber necrosis with infiltration of inflammatory cells; similar lesions are rarely encountered in the myocardium. Lymphorrhages are not seen near damaged neuromuscular junctions (although inflammatory cells may be seen in necrotic endplates in rat experimental autoimmune MG), but morphometric studies have shown loss of synaptic folds and widened clefts. Some nerve terminals are smaller than normal, and multiple small terminals are applied to the elongated, simplified postsynaptic membrane; others are absent. Other endplates appear normal. On residual synaptic folds, immunocytochemical methods show Y-shaped antibody-like structures, IgG, complement components 2 and 9, and complement membrane attack complex.

INCIDENCE MG is a common disease. An apparent increase in the incidence of the disease in recent years is probably due to improved diagnosis. According to Phillips and Torner (1996), the prevalence rate is 14 per 100,000 (or about 17,000 cases) in the United States. Before age 40 years, the disease is three times more common in women, but at older ages both sexes are equally affected. Familial cases are rare; single members of pairs of fraternal twins and several sets of identical twins have been affected. Young women with MG tend to have HLA-B8, -DR3, and -DQB1* 0102 haplotypes; in young Japanese women HLA-A12 is prominent. These observations imply the presence of a linked immune response gene that encodes a protein involved in the autoimmune response. First-degree relatives show an unusual incidence of other autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, thyroid disease) and HLA-B8 haplotype.

SYMPTOMS The symptoms of MG have three general characteristics that, together, provide a diagnostic combination. Formal diagnosis depends on demonstration of the response to cholinergic drugs, electrophysiologic evidence of abnormal neuromuscular transmission, and demonstration of circulating antibodies to AChR. The fluctuating nature of myasthenic weakness is unlike any other disease. The weakness varies in the course of a single day, sometimes within minutes, and it varies from day to day or over longer periods. Major prolonged variations are termed remissions or exacerbations; when an exacerbation involves respiratory muscles to the point of inadequate ventilation, it is called a crisis. Variations sometimes seem related to exercise; this and the nature of the physiologic abnormality have long been termed “excessive fatigability,” but there are practical reasons to deemphasize fatigability as a central characteristic of MG. Patients with the disease almost never complain of fatigue or symptoms that might be construed as fatigue except when there is incipient respiratory muscle weakness. Myasthenic symptoms are always due to weakness and not to rapid tiring. In contrast, patients who complain of fatigue, if they are not anemic or harboring a malignant tumor, almost always have emotional problems, usually depression. The second characteristic of MG is the distribution of weakness. Ocular muscles are affected first in about 40% of patients and are ultimately involved in about 85%. Ptosis and diplopia are the symptoms that result. Other common symptoms affect facial or oropharyngeal muscles, resulting in dysarthria, dysphagia, and limitation of facial movements. Together, oropharyngeal and ocular weakness causes symptoms in virtually all patients with acquired MG. Limb and neck weakness is also common, but in conjunction with cranial weakness. Almost never are limbs affected alone. Crisis seems most likely to occur in patients with oropharyngeal or respiratory muscle weakness. It seems to be provoked by respiratory infection in many patients or by surgical procedures, including thymectomy, although it may occur with no apparent provocation. Both emotional stress and systemic illness may aggravate myasthenic weakness for reasons that are not clear; in patients with oropharyngeal weakness, aspiration of secretions may occlude lung passages to cause rather abrupt onset of respiratory difficulty. Major surgery may be followed by respiratory weakness without aspiration, however, so this cannot be the entire explanation. “Spontaneous” crisis seems to be less common now than it once was. The third characteristic of myasthenic weakness is the clinical response to cholinergic drugs. This occurs so uniformly that it has become part of the definition, but it may be difficult to demonstrate in some patients, especially those with purely ocular myasthenia. Aside from the fluctuating nature of the weakness, MG is not a steadily progressive disease. The general nature of the disease, however, is usually established within weeks or months after the first symptoms. If myasthenia is restricted to ocular muscles for 2 years, certainly if it is restricted after 3 years, it is likely to remain restricted, and only in rare cases does it then become generalized. (Solely ocular myasthenia differs serologically from generalized MG because AChR antibodies are found in lower frequency [50%] and in low titer.) Spontaneous remissions are also more likely to occur in the first 2 years. Before the advent of intensive care units and the introduction of positive pressure respirators in the 1960s, crisis was a life-threatening event, and the mortality of the disease was about 25%. With improved respiratory care, however, patients rarely die of MG, except when cardiac, renal, or other disease complicates the picture.

SIGNS The vital signs and general physical examination are usually within normal limits, unless the patient is in crisis. The findings on neurologic examination depend on the distribution of weakness. Weakness of the facial and levator palpebrae muscles produces a characteristic expressionless facies with drooping eyelids. Weakness of the ocular muscles may cause paralysis or weakness of isolated muscles, paralysis of conjugate gaze, complete ophthalmoplegia in one or both eyes, or a pattern resembling internuclear ophthalmoplegia. Weakness of oropharyngeal or limb muscles, when present, can be shown by appropriate tests. Respiratory muscle weakness can be detected by pulmonary function tests, which should not be limited to measurement of vital capacity but should also include inspiratory and expiratory pressures, the measurements of which may be abnormal even before overt symptoms exist. Muscular wasting of variable degree is found in about 10% of patients, but is not focal and is usually encountered only in patients with malnutrition due to severe dysphagia. Fasciculations do not occur, unless the patient has received

excessive amounts of cholinergic drugs. Sensation is normal and the reflexes are preserved, even in muscles that are weak.

LABORATORY DATA Routine examinations of blood, urine, and cerebrospinal fluid are normal. The characteristic electrodiagnostic abnormality is progressive decrement in the amplitude of muscle action potentials evoked by repetitive nerve stimulation at 3 or 5 Hz. In generalized MG, the decremental response can be demonstrated in about 90% of patients, if at least 3 nerve–muscle systems are used (median-thenar, ulnar-hypothenar, accessory-trapezius). In microelectrode study of intercostal muscle, the amplitude of miniature endplate potentials is reduced to about 20% of normal. This is caused by a decrease in the number of AChR available to agonists applied by microiontophoresis. In single-fiber electromyography (EMG), a small electrode measures the interval between evoked potentials of the muscle fibers in the same motor unit. This interval normally varies, a phenomenon called jitter, and the normal temporal limits of jitter have been defined. In MG, the jitter is increased, and an impulse may not appear at the expected time; this is called blocking, and the number of blockings is increased in myasthenic muscle. All these electrophysiologic abnormalities are characteristic of MG, but blocking and jitter are also seen in disorders of ACh release. The standard EMG is usually normal, occasionally shows a myopathic pattern, and almost never shows signs of denervation unless some other condition supervenes. Similarly, nerve conduction velocities are normal. Antibodies to AChR are found in 85% to 90% of patients of all ages with generalized MG if human muscle is used as the test antigen. There have been no false-positive results except for rare patients with Lambert-Eaton syndrome or thymoma without clinical or provocable MG, or in remission; these may be considered unusual forms of MG. Antibodies may not be detected in patients with strictly ocular disease, in some patients in remission (or after thymectomy), or even in some patients with severe symptoms. The titer does not match the severity of symptoms; patients in complete clinical remission may have high titers. Antibodies to myofibrillar proteins (titin, myosin, actin, actomyosin) are found in 85% of patients with thymoma and may be the first evidence of thymoma in some cases. The different forms of congenital MG can be identified only in a few special centers that are prepared to perform microelectrode and ultrastructural analyses of intercostal muscle biopsies for miniature endplate potentials, AChR numbers, and determination of bound antibodies. It seems likely that deoxyribonucleic acid analysis may soon suffice for diagnosis. Other serologic abnormalities are encountered with varying frequency, but in several studies, antinuclear factor, rheumatoid factor, and thyroid antibodies were encountered more often than in control populations. Laboratory (and clinical) evidence of hyperthyroidism occurs at some time in about 5% of patients with MG. Radiographs of the chest (including 10-degree oblique films) provide evidence of thymoma in about 15% of patients, especially in those older than 40 years. Computed tomography (CT) of the mediastinum demonstrates all but microscopic thymomas. Magnetic resonance imaging does not appear to be any more useful than CT.

DIAGNOSIS The diagnosis of MG can be made without difficulty in most patients from the characteristic history and physical examination. The dramatic improvement that follows the injection of neostigmine bromide (Prostigmin) or edrophonium chloride makes the administration of these drugs essential. Return of strength in weak muscles occurs uniformly after the injection of neostigmine or edrophonium ( Fig. 120.1); if no such response occurs, the diagnosis of MG can be doubted. Demonstration of the pharmacologic response is sometimes difficult; however, if the clinical features are suggestive, the test should be repeated, perhaps with a different dosage or rate of administration. Withholding anticholinesterase medication overnight may be helpful. False-positive responses to edrophonium are exceptional but have been recorded with structural lesions, such as a brainstem tumor. (MG can also coexist with other diseases, such as Graves ophthalmopathy or the Lambert-Eaton syndrome.)

FIG. 120.1. Myasthenia gravis. A: Severe ptosis of the lids. B: Same patient 1 minute after intravenous injection of edrophonium (10 mg). (From Rowland et al., 1961; with permission.)

The diagnosis of MG is buttressed by the finding of high titers of antibodies to AChR, but a normal titer does not exclude the diagnosis. Somnier found that the test had a specificity of more than 99.9%; sensitivity was 88% because of the negative tests. Responses to repetitive stimulation and single-fiber EMG also help. If a thymoma is present, the diagnosis of MG (rather than some other neuromuscular disease) is likely. In the past, clinicians used the increased sensitivity to curare as a test to prove that a syndrome simulating MG was actually psychasthenia or something else; however, the test was inconvenient and, if done without proper precautions, was even hazardous. Since the advent of the antibody test, the curare test has virtually disappeared. In the neostigmine test, 1.5 to 2 mg of the drug and atropine sulfate, 0.4 mg, are given intramuscularly. Objective improvement in muscular power is recorded at 20-minute intervals up to 2 hours. Edrophonium is given intravenously in a dose of 1 to 10 mg. The initial dose is up to 2 mg followed in 15 seconds by an additional 3 mg and in another 15 seconds by 5 mg to a maximum of 10 mg. Improvement is observed within 30 seconds and lasts a few minutes. Because of the immediate and dramatic nature of the response, edrophonium is preferred for evaluation of ocular and other cranial muscle weakness, and neostigmine is generally reserved for evaluation of limb or respiratory weakness, which may require more time. Placebo injections are sometimes useful in evaluating limb weakness, but placebos are not necessary in evaluating cranial muscle weakness because that abnormality cannot be simulated. For all practical purposes, a positive response is diagnostic of MG.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes all diseases that are accompanied by weakness of oropharyngeal or limb muscles, such as the muscular dystrophies, amyotrophic lateral sclerosis, progressive bulbar palsy, ophthalmoplegias of other causes, and the asthenia of psychoneurosis or hyperthyroidism. There is usually no difficulty in differentiating these conditions from MG by the findings on physical and neurologic examination and by the failure of symptoms in these conditions to improve after parenteral injection of neostigmine or edrophonium. Occasionally, blepharospasm is thought to mimic ocular myasthenia, but the forceful eye closure in that condition involves both the upper and lower lids; the narrowed palpebral fissure and signs of active muscle activity are distinctive. The only other conditions in which clinical improvement has been documented after use of edrophonium are other disorders of neuromuscular transmission: botulinum intoxication, snake bite, organophosphate intoxication, or unusual disorders that include features of both MG and the Lambert-Eaton syndrome. Denervating disorders, such as motor neuron disease or peripheral neuropathy, do not show a reproducible or unequivocal clinical response to edrophonium or neostigmine. The response should be unequivocal and reproducible. If a structural lesion of the third cranial nerve seems to respond, the result should be photographed (and even published).

TREATMENT Clinicians must choose the sequence and combination of five different kinds of therapy: Anticholinesterase drug therapy and plasmapheresis are symptomatic

treatments, whereas thymectomy, steroids, and other immunosuppressive drugs may alter the course of the disease. It is generally agreed that anticholinesterase drug therapy should be given as soon as the diagnosis is made. Of the three available drugs—neostigmine, pyridostigmine bromide, and ambenonium (Mytelase)—pyridostigmine is the most popular but has not been formally assessed in controlled comparison with the other drugs. The muscarinic side effects of abdominal cramps and diarrhea are the same for all three drugs but are least severe with pyridostigmine; none has more side effects than another. The usual starting dose of pyridostigmine is 60 mg given orally every 4 hours while the patient is awake. Depending on clinical response, the dosage may be increased, but incremental benefit is not to be expected in amounts greater than 120 mg every 2 hours. If patients have difficulty eating, doses can be taken about 30 minutes before a meal. If patients have special difficulty on waking in the morning, a prolonged-release 180-mg tablet of pyridostigmine (Mestinon Timespans) can be taken at bedtime. Muscarinic symptoms can be ameliorated by preparations containing atropine (0.4 mg) with each dose of pyridostigmine. Excessive doses of atropine can cause psychosis, but the amounts taken in this regimen have not had this effect. Other drugs may be taken if diarrhea is prominent. There is no evidence that any one of the three drugs is more effective than the others in individual patients, and there is no evidence that combinations of two drugs are better than any one drug alone. Although cholinergic drug therapy sometimes gives impressive results, there are serious limitations. In ocular myasthenia, ptosis may be helped, but some diplopia almost always persists. In generalized MG, patients may improve remarkably, but some symptoms usually remain. Cholinergic drugs do not return function to normal, and the risk of crisis persists because the disease is not cured. Therefore, usually, one of the other treatments is used promptly to treat generalized MG. Thymectomy was originally reserved for patients with serious disability because the operation had a high mortality. With advances in surgery and anesthesia, however, the operative mortality is now negligible in major centers. About 80% of patients without thymoma become asymptomatic or go into complete remission after thymectomy; although there has been no controlled trial of thymectomy, these results seem to diverge from the natural history of the untreated disease. Thus, thymectomy is now recommended for most patients with generalized MG. Decisions made for children or patients older than 65 must be individualized. Although it is safe, thymectomy is a major operation and is not usually recommended for patients with ocular myasthenia unless there is a thymoma. The beneficial effects of thymectomy are usually delayed for months or years. It is never an emergency measure, and other forms of therapy are usually needed in the interim. Prednisone therapy is used by some authorities to prepare patients for thymectomy, but that function is also served by plasmapheresis or by intravenous immunoglobulin (IVIG) therapy. Exchanges of about 5% of calculated blood volume may be given several times before the day of surgery to be certain that the patient is functioning as well as possible, and to ameliorate or avoid a postoperative respiratory crisis. Plasmapheresis is also used for other exacerbations; the resulting improvement, seen in most patients, may be slight or dramatic and may last only a few days or several months. Plasmapheresis is safe but expensive and is not convenient for many patients. IVIG therapy is usually given in five daily doses to a total of 2 g/kg body weight. Side effects include headache, aseptic meningitis, and a flulike syndrome that can be alarming but subsides in 1 or 2 days. Thromboembolic events, including stroke, have occurred but are not clearly related to the treatment, which is generally regarded as safe, less cumbersome than plasmapheresis, and less dependent on technical staff who may not be available on weekends. Both treatments are also available for management of exacerbations. If a patient is still seriously disabled after thymectomy, most clinicians use prednisone, 60 to 100 mg every other day, to achieve a response within a few days or weeks. An equally satisfactory response can be seen with a lower dosage, but it takes longer; for instance, if the dose is 25 to 40 mg, benefit may be seen in 2 to 3 months. Once improvement is achieved, the dosage should be reduced gradually to 20 to 35 mg every other day. This has become a popular form of treatment for disabled patients, but there has been no controlled trial. If the patient does not improve in about 6 months, treatment with azathioprine (Imuran) or cyclophosphamide would be considered, in doses up to 2.5 mg/kg daily for an adult. The dosage should be increased gradually and may have to be taken with food to avert nausea. Whether steroids and immunosuppressive drugs have additive effects is uncertain, and the relative risks are difficult to assess. The numerous side effects of prednisone must be weighed against the possibilities of marrow suppression, susceptibility to infection, or delayed malignancy in patients who are taking immunosuppressive drugs. Prednisone, 20 to 35 mg on alternate days, is also recommended by some clinicians for ocular myasthenia, weighing risks against potential benefit. For some patients in sensitive occupations, the risks of prednisone therapy may be necessary (e.g., actors, police officers, roofers or others who work on heights, or those who require stereoscopic vision). Ocular myasthenia is not a threat to life; however, pyridostigmine may alleviate ptosis. An eye patch can end diplopia, and prisms help some patients with stable horizontal diplopia. Thymectomy has become so safe that it might be considered for ocular myasthenia that is truly disabling. Patients with thymoma are likely to have more severe MG and are less likely to improve after thymectomy; nevertheless, many of these patients also improve if the surrounding thymus gland is excised in addition to the tumor. Myasthenic crisis is defined as the need for assisted ventilation, a condition that arises in about 10% of myasthenic patients. It is more likely to occur in patients with dysarthria, dysphagia, and documented respiratory muscle weakness, presumably because they are liable to aspirate oral secretions, but crisis may also occur in other patients after respiratory infection or major surgery (including thymectomy). The principles of treatment are those of respiratory failure in general. Cholinergic drug therapy is usually discontinued once an endotracheal tube has been placed and positive pressure respiration started; this practice avoids questions about the proper dosage or cholinergic stimulation of pulmonary secretions. Crisis is viewed as a temporary exacerbation that subsides in a few days or weeks. The therapeutic goal is to maintain vital functions and to avoid or treat infection until the patient spontaneously recovers from the crisis. Cholinergic drug therapy need not be restarted unless fever and other signs of infection have subsided, there are no pulmonary complications, and the patient is breathing without assistance. To determine whether plasma exchange or IVIG therapy actually shortens the duration of crisis would require a controlled trial, but that has not been done. Even so, pulmonary intensive care is now so effective that crisis is almost never fatal and many patients go into a remission after recovery from crisis. Because of advances in therapy, MG is still serious, but not so grave. SUGGESTED READINGS Battocchi AP, Majolini L, Evoli A, Lino MM, Minisci C, Tonali P. Course and treatment of myasthenia gravis during preganancy. Neurology 1999;52:447–452. Bever CT Jr, Chang HW, Penn AS, et al. Penicillamine-induced myasthenia gravis: effects of penicillamine on acetylcholine receptor.

Neurology 1982;32:1077–1082.

Borodic G. Myasthenic crisis after botulinum toxin [Letter]. Lancet 1998;352:1832. Bufler J, Pitz R, Czep M, Wick M, Franke C. Purified IgG from seropositive and seronegative patients with myasthenia gravis reversibly blocks currents through nicotinic acetylcholine receptor channels. Ann Neurol 1998;43:458–464. Castleman B. The pathology of the thymus gland in myasthenia gravis. Ann NY Acad Sci 1966;135:496–505. Christensen PB, Jensen TS, Tsiropoulos I, et al. Mortality and survival in myasthenia gravis: a Danish population based study. J Neurol Neurosurg Psychiatry 1998;64:78–83. Donaldson JO, Penn AS, Lisak RP, et al. Antiacetylcholine receptor antibody in neonatal myasthenia gravis. Am J Dis Child 1981;135:222–226. Eaton LM, Lambert EH. Electromyography and electric stimulation of nerves in diseases of motor unit: observations in myasthenic syndrome associated with malignant tumors. JAMA 1957;163:1117–1120. Engel AG, ed. Myasthenia gravis and myasthenic disorders. New York: Oxford University Press, 1999. Engel AG, Ohno K, Sine SM. Congenital myasthenic syndromes: recent advances. Arch Neurol 1999;56:163–171. Engel AG, Ohno K, Wang HL, Milone M, Sine SM. Molecular basis of congenital myasthenic syndrome: mutations in the acetylcholine receptor. Neuroscientist 1998;4:185–194. Erb W. Zur Causistik der bulbären Lächmungen: über einem neuen, wahrscheinlich bulbären Symptomencomplex. Arch Psychiatr Nervenkr 1879;336–350. Gajdos P, Chervet S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol 1997;41:789–796.

Goldflam S. über einen scheinbar heilbaren bulbärparalytischen Symptomencomplex mit Beteiligungen der Extremitäten. Dtsch Z Nervenheilk 1893;4:312–352. Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol 1998;43:480–484. Jaretzki A III, Penn AS, Younger DS, et al. “Maximal” thymectomy for myasthenia gravis: results. J Thorac Cardiovasc Surg 1988;95:747–757. Jolly F. über Myasthenia Gravis pseudoparalytica. Berl Klin Wochenschr 1895;1:1–7. Katz JS, Wolfe GI, Bryan WW, Tintner R, Barohn RJ. Acetylcholine receptor antibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1998;50:470–475. Lindberg C, Andersen O, Lefvert AK. Treatment of myasthenia gravis with methylprednisolone pulse: a double-blind study. Acta Neruol Scand 1998;97:370–373. Lindner A, Schalke B, Toyka KV. Outcome in juvenile onset myasthenia gravis: a retrospective study with long-term follow-up of 79 patients. J Neurol 1997;244:515–520. Lindstrom J, Seybold M, Lennon VA, et al. Antibody to acetylcholine receptor in myasthenia gravis: prevalence, clinical correlates, and diagnostic value. Neurology 1976;26:1054–1059. Lisak RP, ed. Handbook of myasthenia gravis. New York: Marcel Dekker, 1994. Lisak RP, Barchi RL. Myasthenia gravis. Philadelphia: WB Saunders, 1982. Miller RG, Filler-Katz A, Kiprov D, Roan R. Repeat thymectomy in chronic refractory myasthenia gravis. Neurology 1991;41:923–924. Morel E, Eynard B, Vernet B, et al. Neonatal myasthenia gravis: clinical and immunologic appraisal in 30 cases. Neurology 1988;38:138–142. Randomised clinical trial comparing prednisone and azathioprine in myasthenia gravis: results of the second interim analysis. Myasthenia Gravis Clinical Study Group. J Neurol Neurosurg Psychiatry 1993;56:1157–1163. Odel JG, Winterkorn JMS, Behrens MM. The sleep test for myasthenia gravis. J Clin Neuroophthal 1991;11:288–292. Oosterhuis HGJH. The natural course of myasthenia gravis: a long-term follow-up study. J Neurol Neurosurg Psychiatry 1989;52:1121–1127. Palace J, Newsom-Davis J, Lecky B, and the Myasthenia Gravis Study Group. A randomized double-blind trial of pednisolone alone or with azathioprine in myasthenia gravis. Neurology 1998;50:1778–1783. Pascuzzi RM. Iatrogenic disorders of the neuromuscular junction. In Biller J, ed. Iatrogenic neurology. Boston: Butterworth-Heinemann, 1998:283–304. Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor. Science 1973;180:871–872. Penn AS, Richman DP, Ruff RL, Lennon VA, eds. Myasthenia gravis and related disorders: experimental and clinical aspects. Conference proceedings, Washington, DC, April 12–15, 1992. Ann N Y Acad Sci 1993;681:1–622. Phillips LH 2nd, Torner JC. Epidemiologic evidence for a changing natural history of myasthenia gravis. Neurology 1996;47:1233–1238. Pinching AJ, Peters DK. Remission of myasthenia gravis following plasma exchange. Lancet 1976;2:1373–1376. Qureshi AJ, Choudry MA, Akbar MS, et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology 1999;52:629–632. Robertson NP, Deans J, Compston DAS. Myasthenia gravis: a population-based epidemiological study in Cambridgeshire, England. J Neurol Neurosurg Psychiatry 1998;65:492–496. Rowland LP. Controversies about the treatment of myasthenia gravis. J Neurol Neurosurg Psychiatry 1980;43:644–659. Rowland LP, Hoefer PFR, Aranow H Jr. Myasthenic syndromes. Res Publ Assoc Res Nerv Ment Dis 1961;38:548–600. Rowland LP, Hoefer PFA, Aranow H Jr, Merritt HH. Fatalities in myasthenia gravis: a review of 39 cases with 26 autopsies. Neurology 1956;6:307–326. Soliven B, Lange DJ, Penn AS, et al. Seronegative myasthenia gravis. Neurology 1988;38:514–517. Somnier FE. Clinical implementation of anti-acetylcholine receptor antibodies. J Neurol Neurosurg Psychiatry 1993;56:496–504. Steinman L, Mantegazza R. Prospects for specific immunotherapy in myasthenia gravis. FASEB J 1990;4:2726–2731. Thomas CE, Mayer SA, Gungor Y, et al. Myasthenic crisis: clinical features, mortality, complications, and risk factors for intubation. Neurology 1997;48:1253–1260. Toyka KV, Drachman DB, Pestronk A, Kao I. Myasthenia gravis: passive transfer from man to mouse. Science 1975;190:397–399. Vincent A, Jacobson L, Plested P, et al. Antibodies affecting ion channel function in acquired neuromyotonia, in seropositive and seronegative myasthenia gravis, and in antibody-mediated arthrogryposis multiplex congenita. Ann N Y Acad Sci 1998;841:482–496. Wang ZU, Karachunski PI, Howard JF, Conti-Fine B. Myasthenia in SCID mice grafted with myasthenic patient lymphocytes: role of CD4 and CD8 cells. Neurology 1999;52:484–497. Wittbrodt ET. Drugs and myasthenia gravis: an update. Arch Intern Med 1997;157:399–408.

CHAPTER 121. LAMBERT-EATON SYNDROME MERRITT’S NEUROLOGY

CHAPTER 121. LAMBERT-EATON SYNDROME AUDREY S. PENN Suggested Readings

The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of peripheral cholinergic synapses. Antibodies are directed against voltage-gated calcium channels in peripheral nerve terminals. A disease of adults, LEMS is found in 60% of patients with small-cell carcinoma of the lung. The neurologic symptoms almost always precede those of the tumor; the interval may be as long as 5 years. Other tumors have also been implicated, but about 33% of cases are not associated with tumor. Cell lines derived from the lung cancer show reactive antigens in the calcium channel proteins; the antibodies presumably arise in reaction to the tumor. If tumor cells are grown in the presence of immunoglobulin (Ig) G from a patient with LEMS, the number of functional channels declines. Similar antigens are found in calcium channel proteins from neuroendocrine tumors. The cultured carcinoma cells also bear receptors for dihydropyridines. The abnormality of neurotransmission is attributed to inadequate release of acetylcholine (ACh) from nerve terminals at both nicotinic and muscarinic sites and is related to abnormal voltage-dependent calcium channels. When IgG from affected patients is injected into mice, the number ACh quanta released by nerve stimulation is reduced, and there is disarray of the active zone particles that is detected by freeze-fracture ultrastructural analysis. Purified calcium channel proteins can be directly radiolabeled. An alternative label can be generated by the use of a specific ligand, omega-conotoxin, which is prepared from a marine snail and has been used to identify P/Q-type calcium channels in extracts of small-cell carcinoma, neuroblastoma, and other neuroendocrine cell lines. A diagnostic test for the autoantibodies is based on radiolabeled preparations, but it is not fully specific. In the series of Motomura and associates (1997), 92% of 72 patients had a positive reaction. There have been a few positive tests in paraneoplastic cerebellar disorders. Some patients have both LEMS and a cerebellar syndrome. LEMS may be suspected in patients with symptoms of proximal limb weakness who have lost knee and ankle jerks and complain of dry mouth or myalgia. Other, less common autonomic symptoms include impotence, constipation, and hypohidrosis. LEMS differs clinically from myasthenia gravis (MG) because diplopia, dysarthria, dysphagia, and dyspnea are lacking. Autonomic symptoms are more common in LEMS than in MG. The disease is defined, and the diagnosis made, by the characteristic incremental response to repetitive nerve stimulation, a pattern that is the opposite of MG. The first evoked potential has an abnormally low amplitude, which decreases even further at low rates of stimulation. At rates greater than 10 Hz, however, there is a marked increase in the amplitude of evoked response (2 to 20 times the original value). This incremental response results from facilitation of release of transmitter at high rates of stimulation; at low rates the number of quanta released per impulse (quantal content) is inadequate to produce endplate potentials that achieve threshold. Similar abnormalities are found in preparations exposed to botulinum toxin or to a milieu low in calcium or high in magnesium. Some patients with LEMS have ptosis with antibodies to ACh receptor. This “combined” syndrome may be an example of multiple autoimmune diseases in the same individual. Treatment is directed to the concomitant tumor. The neuromuscular disorder is treated with drugs that facilitate release of ACh. A combination of pyridostigmine bromide and 3,4-diaminopyridine improves strength, but other aminopyridines may be hazardous. Other drugs that facilitate release of ACh have had adverse effects. Guanidine hydrochloride (20 to 30 mg/kg per day) may depress bone marrow or cause severe tremor and cerebellar syndrome. 4-Aminopyridine causes convulsions. Plasmapheresis is often helpful, but the effects are transient. Cytotoxic drugs should be used cautiously because a risk of malignancy is already present, even in patients who do not seem to have one already. Intravenous immunoglobulin therapy is another alternative. SUGGESTED READINGS Fetell MR, Shin HS, Penn AS, Lovelace RE, Rowland LP. Combined Eaton-Lambert syndrome and myasthenia gravis. Neurology 1978;28:398. Johnson I, Lang B, Leys K, Newsom-Davis J. Heterogeneity of calcium channel autoantibodies detected using a small cell lung cancer line derived from a Lambert-Eaton myasthenic syndrome patient. Neurology 1994;44:334–338. Katz JS, Wolfe GI, Bryan WW, Tintner R, Barohn RJ. Acetylcholine receptor antibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1998;50:470–475. Lambert EH, Rooke ED, Eaton LM, Hodgson CH. Myasthenic syndrome occasionally associated with bronchial neoplasm: neurophysiologic studies. In: Viets HR, ed. Myasthenia gravis. Springfield, IL: Charles C Thomas, 1961:362–410. Lang B, Newsom-Davis J, Wray D, et al. Autoimmune etiology for myasthenic (Eaton-Lambert) syndrome. Lancet 1981;2:224–226. Lennon VA, Kryzer TJ, Griesmann GE, et al. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 1995;332:1467–1474. Leys K, Lang B, Johnston I, Newsom-Davis J. Calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Ann Neurol 1991;29:307–314. Lund H, Nilsson O, Rosen I. Treatment of Lambert-Eaton syndrome: 3,4-diaminopyridine and pyridostigmine. Neurology 1984;34:1324–1330. Mason WP, Graus F, Lang B, et al. Small-cell lung cancer, paraneoplastic cerebellar degeneration, and the Lambert-Eaton myasthenic syndrome. Brain 1997;120:1279–1300. McEvoy K, Windebank AJ, Daube JR, Low PA. 3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med 1989;321:1567–1571. Motomura M, Lang B, Johnston I, Palace J, Vincent A, Newsom-Davis J. Incidence of serum anti-P/O-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. J Neurol Sci 1997;147:35–42. Newsom-Davis J. Antibody-mediated channelopathies at the neuromuscular junction. Neuroscientist 1997;3:337–346. Newsom-Davis J. A treatment algorithm for Lambert-Eaton myasthenic syndrome. Ann N Y Acad Sci 1998;841:817–822. Newsom-Davis J, Leys K, Vincent A, et al. Immunological evidence for the co-existence of the Lambert-Eaton myasthenic syndrome and myasthenia gravis in two patients. J Neurol Neurosurg Psychiatry 1991;54:452–453. Oh SJ, Kim DS, Head TC, Claussen GC. Low-dose guanidine and pyridostigmine: relatively safe and effective long-term symptomatic therapy in Lambert-Eaton myasthenic syndrome. Muscle Nerve 1997;20:1146–1152. O'Neill JH, Murray NMF, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome: a review of 50 cases. Brain 1988;111:577–596. Penn AS, Richman DP, Ruff RL, Lennon VA, eds. Myasthenia gravis and related disorders: experimental and clinical aspects. Conference proceedings, Washington, DC, April 12–15, 1992. Ann N Y Acad Sci 1993;681:1–622. Raymond C, Walker D, Bichet D, et al. Antibodies against the beta subunit of voltage-dependent calcium channels in Lambert-Eaton myasthenic syndrome. Neuroscience 1999;90:269–277. Roberts A, Perera S, Lang B, et al. Paraneoplastic myasthenic syndrome IgG inhibits

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Ca2+ flux in a small cell carcinoma line. Nature 1985;2:737–739.

Verschuuren JJ, Dalmau J, Tunkel R, et al. Antibodies against the calcium channel beta subunit in Lambert-Eaton myasthenic syndrome. Neurology 1998;50:475–479. Vincent A. Antibodies to ion channels in paraneoplastic disorders. Brain Pathol 1999;9:285–291. Waterman SA, Lang B, Newsom-Davis J. Effect of Lambert-Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse. Ann Neurol 1997;42:147–156.

CHAPTER 122. BOTULISM AND ANTIBIOTIC-INDUCED NEUROMUSCULAR DISORDERS MERRITT’S NEUROLOGY

CHAPTER 122. BOTULISM AND ANTIBIOTIC-INDUCED NEUROMUSCULAR DISORDERS AUDREY S. PENN Botulism Antibiotic-Induced Neuromuscular Blockade Suggested Readings

BOTULISM Botulism is a disease in which nearly total paralysis of nicotinic and muscarinic cholinergic transmission is caused by botulinum toxin acting on presynaptic mechanisms for release of acetylcholine (ACh) in response to nerve stimulation. The toxin is produced by spores of Clostridium botulinum, which may contaminate foods grown in soil (types A, B, F, and G) or fish (type E). Intoxication results if contaminated food is inadequately cooked and the spores are not destroyed, or if fish are not eviscerated before drying or salt curing. Toxin can be produced in anaerobic wounds that have been contaminated by organisms and spores. Ingestion or inhalation of spores by infants may cause botulism when toxin type A is then produced in the gastrointestinal tract during periods of constipation. An analogous syndrome may occur in adults with persistent growth of C. botulinum in the intestine after surgery, from gastric achlorhydria, or from antibiotic therapy. The toxin causes destruction of the terminal twigs of cholinergic nerve endings, which require several months to regenerate and remodel after a single exposure. Electrophysiologic evidence of severely disturbed neuromuscular transmission includes an abnormally small single-muscle action potential evoked in response to a supramaximal nerve stimulus. When the synapse is driven by repetitive stimulation at high rates (20 to 50 Hz), the evoked response is potentiated up to 400%. In affected infants, muscle action potentials are unusually brief, of low amplitude, and overly abundant. This is presumably related to involvement of terminal nerve twigs in endings of many motor units. In patients who have been treated for blepharospasm or other movement disorders by intramuscular injections of botulinum toxin, single-fiber electromyography shows increased jitter in muscles remote from those injected, and the jitter is maximally increased at low firing rates. These abnormalities are not symptomatic but imply an effect of circulating toxin. C. botulinum toxin may be the “most poisonous poison” (the lethal dose for a mouse is 10 -12 g/kg body weight). If the patient survives and reaches a hospital, symptoms include dry, sore mouth and throat, blurred vision, diplopia, nausea, and vomiting. Signs include hypohidrosis, total external ophthalmoplegia, and symmetric descending facial, oropharyngeal, limb, and respiratory paralysis. Pupillary paralysis, however, is not invariable. Not all patients are equally affected, suggesting variable toxin intake or variable individual responses. When cases occur in clusters, the diagnosis is usually suspected immediately. Isolated cases in children and adolescents may be thought to be Guillain-Barré syndrome, myasthenia gravis, or even diphtheria. Ptosis has responded to intravenous edrophonium chloride in a few patients, but response to anticholinesterase drugs is neither sufficiently extensive nor sufficiently prolonged to be therapeutic. Infants with botulism are usually younger than 6 months. They show generalized weakness, decreased or absent sucking and gag reflex, facial diplegia, lethargy, ptosis, and ophthalmoparesis. Diagnosis is made by the following characteristics: clustering of cases, symmetry of signs, dry mouth or absence of secretion, pupillary paralysis, and the characteristic incremental response to repetitive nerve stimulation. The Centers for Disease Control and Prevention (CDC) (with a dedicated emergency 24-hour telephone number) or appropriate state laboratories should be notified so that the toxin can be identified in refrigerated samples of serum, stool, or residual food samples. In suspected infantile botulism, feces should be evaluated for the presence of C. botulinum, as well as toxin. Patients should be treated in intensive care facilities for respiratory care. Specific therapy includes antitoxin (a horse serum product that may cause serum sickness or anaphylaxis) available from the CDC, and guanidine hydrochloride, which promotes release of transmitter from residual spared nerve endings but may depress bone marrow.

ANTIBIOTIC-INDUCED NEUROMUSCULAR BLOCKADE Aminoglycoside antibiotics (neomycin sulfate, streptomycin sulfate, and kanamycin sulfate [Kantrex]) and polypeptide antibiotics (colistin sulfate [Coly-Mycin S] and polymyxin B sulfate) may cause symptomatic block in neuromuscular transmission in patients without any known neuromuscular disease. Antibiotics occasionally aggravate myasthenia gravis. The problem surfaces when blood levels are excessively high, which usually occurs in patients with renal insufficiency, but levels may be within the therapeutic range. Studies of bath-applied streptomycin in nerve–muscle preparations disclosed inadequate release of ACh; the effect was antagonized by an excess of calcium ion. In addition, the sensitivity of the postjunctional membrane to ACh was reduced. Different compounds differed in relative effects on preand postsynaptic events. Neomycin and colistin produced the most severe derangements. The effects of kanamycin, gentamicin sulfate, streptomycin, tobramycin sulfate (Nebcin), and amikacin sulfate (Amikin) were moderate; tetracycline, erythromycin, vancomycin hydrochloride, penicillin G, and clindamycin (Cleocin) had negligible effects. Patients who fail to regain normal ventilatory effort after anesthesia or who show delayed depression of respiration after extubation and are receiving one of the more potent agents should receive ventilatory support until the agent can be discontinued or another antibiotic substituted. SUGGESTED READINGS Arnon SS, Midura TF, Clay SH, et al. Infant botulism: epidemiological, clinical and laboratory aspects. JAMA 1977;237:1946–1951. Barrett DH. Endemic blood-borne botulism: clinical experience, 1973–1986 at Alaska Native Medical Center. Alaska Med 1991;33:101–108. Cherington M. Clinical spectrum of botulism. Muscle Nerve 1998;21:701–710. Davis LE, Johnson JK, Bicknell JM, Levy H, McEvoy KM. Human type A botulism and treatment with 3,4-diaminopyridine. Electromyogr Clin Neurophysiol 1992;32:379–383. DeJesus PV, Slater R, Spitz LK, Penn AS. Neuromuscular physiology of wound botulism. Arch Neurol 1973;29:425–431. Griffin PM, Hathaway CL, Rosenbaum RB, Sokolow R. Endogenous antibody production to botulinum toxin in an adult with intestinal colonization botulism and underlying Crohn's disease. J Infect Dis 1997;175:633–637. MacDonald KL, Rutherford GW, Friedman SM, et al. Botulism and botulism-like illness in chronic drug abusers. Ann Intern Med 1985;102:616–618. Maselli RA, Ellis W, Mandler RN, et al. Cluster of wound botulism in California: clinical, electrophysiological, and pathologic study. Muscle Nerve 1997;20:1284–1295. Montecucco C, Schiavo G, Tugnoli V, de Grandis D. Botulism neurotoxins: mechanism of action and therapeutic applications. Mol Med Today 1996;2:418–424. Pickett J, Berg B, Chaplin E, Brunstelter-Shafer M. Syndrome of botulism in infancy: clinical and electrophysiologic study. N Engl J Med 1976;295:770–772. Sanders DB. Clinical neurophysiology of disorders of the neuromuscular junction. J Clin Neurophysiol 1993;10:167–180. Terranova W, Palumbo JN, Breman JG. Ocular findings in botulism type B. JAMA 1979;241:475–477. Woodrull BA, Griffin PM, McCroskey LM, et al. Clinical and laboratory comparison of botulism from toxin types A, B, and E in the United States, 1975–1988.

J Infect Dis 1992;166:1281–1286.

CHAPTER 123. ACUTE QUADRIPLEGIC MYOPATHY MERRITT’S NEUROLOGY

CHAPTER 123. ACUTE QUADRIPLEGIC MYOPATHY MICHIO HIRANO Suggested Readings

In 1977, MacFarlane and Rosenthal described an acute myopathy after high-dose steroid therapy. Since then, more than 200 cases of this acute quadriparesis in critically ill patients have been reported ( Table 123.1). The majority of these patients were given corticosteroids, nondepolarizing neuromuscular blocking agents, or both; however, the acute myopathy developed in at least two individuals who received neither agent. Most commonly, patients were being treated for status asthmaticus, after organ transplantation, and after trauma. The others had diverse disorders but rarely neuromuscular diseases.

TABLE 123.1. CLINICAL AND LABORATORY FEATURES OF 33 REPORTED CASES OF ACUTE QUADRIPLEGIC MYOPATHY

Severe quadriplegia and muscle atrophy commence 4 days to 2 weeks after initiation of intensive care therapy. The weakness may be primarily distal or proximal but is usually diffuse; tendon reflexes are lost in many patients. Ophthalmoparesis and facial muscle weakness are sometimes present. Persistent respiratory muscle weakness makes weaning patients from ventilators difficult. Improvement is evident in 1 month to 5 years in most individuals who survive their critical illness. Laboratory studies have shown normal or elevated serum creatine kinase levels. Nerve conduction and electromyographic studies have given normal, myogenic, or neurogenic results; however, muscle biopsies demonstrated predominantly myopathy. In some patients, direct muscle stimulation has shown a loss of excitability, which, in a rodent model, has been attributed to reductions of voltage-gated sodium channel. Enhanced expression of calcium-activated proteases (calpains) have been observed and postulated to play a pathogenic role. Three distinct histologic features have been described in skeletal muscle biopsies; the abnormalities may be present in isolation or in variable combinations. Muscle fiber atrophy, often more prominent in type 2 fibers, is routinely seen. In patients with markedly elevated creatine kinase levels, necrosis of muscle fibers has been observed. The most striking feature revealed by electron microscopy is loss of thick (myosin) filaments. The loss of myosin has been corroborated by antimyosin-antibody stains. Thus, acute myopathy must be distinguished from the persistent weakness that may follow administration of nondepolarizing blocking agents to a person with impaired hepatic metabolism, reduced renal excretion, or both. Critical-illness polyneuropathy, an axonal neuropathy in the setting of sepsis, multiorgan failure, or both, is an alternative cause of weakness in intensive care unit patients and may coexist with acute quadriplegic myopathy. In addition, an idiopathic poliomyelitis-like neurogenic disease, Hopkins syndrome, has been reported in children after exacerbation of bronchial asthma. Nerve or muscle histology reports in Hopkins syndrome do not appear to have determined whether that syndrome and acute quadriplegic myopathy are the same or different. SUGGESTED READINGS Danon MJ, Carpenter S. Myopathy with thick filament (myosin) loss following prolonged paralysis with vecuronium during steroid treatment. Muscle Nerve 1991;14:1131–1139. Hirano M, Ott BR, Raps EC, et al. Acute quadriplegic myopathy: a complication of treatment with steroids, nondepolarizing blocking agents, or both. Neurology 1992;42:2082–2087. Lacomis D, Petrella JT, Giuliani MJ. Causes of neuromuscular weakness in the intensive care unit: a study of ninety-two patients. Muscle Nerve 1997;1998:610–617. MacFarlane IA, Rosenthal FD. Severe myopathy after status asthamaticus [Letter]. Lancet 1977;2:615. Rich MM, Pinter MJ, Kraner SD, Barchi RL. Loss of electrical excitability in an animal model of acute quadriplegic myopathy. Ann Neurol 1998;43:171–179. Rich MM, Teener JW, Raps EC, et al. Muscle is electrically inexcitable in acute quadriplegic myopathy. Neurology 1996;46:731–736. Segredo V, Caldwell JE, Matthay MA, et al. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 1992;327:524–527. Shahar EM, Hwang PA, Niesen CE, Murphy EG. Poliomyelitis-like paralysis during recovery from acute bronchial asthma: possible etiology and risk factors. Pediatrics 1991;88:276–279. Sher JH, Shafiq SA, Schutta HS. Acute myopathy with selective lysis of myosin filaments. Neurology 1991;41:921–923. Showalter CJ, Engel AG. Acute quadriplegic myopathy: analysis of myosin isoforms and evidence for calpain-mediated proteolysis. Muscle Nerve 1997;20:316–322.

CHAPTER 124. IDENTIFYING DISORDERS OF THE MOTOR UNIT MERRITT’S NEUROLOGY

SECTION XVIII. MYOPATHIES CHAPTER 124. IDENTIFYING DISORDERS OF THE MOTOR UNIT LEWIS P. ROWLAND Laboratory Data Definitions Suggested Readings

Muscle weakness may result from lesions of the corticospinal tract or the motor unit. Central disorders are accompanied by the distinctive and recognizable signs of upper motor neuron dysfunction. However, lesions of the motor unit (which includes the anterior horn cell, peripheral motor nerve, and muscle) are all manifested by flaccid weakness, wasting, and depression of tendon reflexes. Because the abnormalities are so similar, there may be problems identifying disorders that affect one or another of the structures of the motor unit. As a result, there has been controversy about the classification of individual cases, as well as about some of the criteria used to distinguish the disorders. Nevertheless, for many reasons, it is still convenient to separate diseases of the motor unit according to the signs, symptoms, and laboratory data, as indicated in Table 124.1. It is necessary to oversimplify to prepare such a table; there are probably exceptions to each of the statements made in the table, and individual cases may be impossible to define because of ambiguities or incongruities in clinical or laboratory data. However, there is usually a satisfactory consistency between the different sets of findings. Some syndromes can be recognized clinically without recourse to laboratory tests, including typical cases of Duchenne dystrophy, Werdnig-Hoffmann disease, peripheral neuropathies, myotonic dystrophy, myotonia congenita, periodic paralysis, dermatomyositis, myasthenia gravis, and the myoglobinurias, to name a few. Controversies are mostly limited to syndromes of proximal limb weakness without clear signs of motor neuron disease (fasciculation) or peripheral neuropathy (sensory loss and high cerebrospinal fluid protein content).

TABLE 124.1. IDENTIFICATION OF DISORDERS OF THE MOTOR UNIT

LABORATORY DATA The essential laboratory tests have been described in detail in other chapters: electrodiagnosis in Chapter 14, electromyography (EMG) and nerve conduction velocity in Chapter 15, and biopsy of muscle and nerve in Chapter 18. EMG is essential in identifying neurogenic or myopathic disorders. Measurement of nerve conduction velocities helps distinguish axonal and demyelinating sensorimotor peripheral neuropathy; slow conduction implies demyelination. In motor neuron diseases, conduction is typically normal or only slightly delayed. However, conduction velocity is also normal in axonal forms of peripheral neuropathy. Therefore, slow conduction indicates the presence of a peripheral neuropathy, but normal values can be seen in either an axonal peripheral neuropathy or a motor neuron disease (spinal muscular atrophy). Muscle Biopsy Muscle biopsy helps distinguish neurogenic and myopathic disorders. Evidence of degeneration and regeneration involves fibers in a random pattern in a myopathy. Some fibers are unusually large, and fiber splitting may be evident. In chronic diseases, there is usually little or no inflammatory cellular response; however, infiltration by white blood cells may be prominent in dermatomyositis and polymyositis. In the dystrophies, there may be infiltration by fat and connective tissue, especially as the disease advances. In denervated muscle, the major fiber change is simple atrophy, and groups of small fibers are typically seen adjacent to groups of fibers of normal size. In histochemical stains, fibers of different types are normally intermixed in a random checkerboard pattern, but in denervated muscle, fibers of the same staining type are grouped, presumably because of reinnervation of adjacent fibers by one motor neuron. In denervated muscle, angular fibers may be the earliest sign. In other conditions, histochemical stains may give evidence of storage products, such as glycogen or fat, or may indicate structurally specific abnormalities, such as nemaline rods, central cores, or other unusual structures. Serum Enzymes Serum enzyme determination is another important diagnostic aid. Creatine kinase (CK) is the most commonly used enzyme for diagnostic purposes; it is present in high concentration in muscle and is not significantly present in liver, lung, or erythrocytes. To this extent, it is specific, and high serum content of CK usually indicates disease of the heart or skeletal muscle. The highest values are seen in Duchenne dystrophy, dermatomyositis, polymyositis, and attacks of myoglobinuria. In these conditions, other sarcoplasmic enzymes are also found in the serum, including aspartate transaminase (SGOT), alanine transaminase (SGPT), and lactate dehydrogenase. CK may also be increased in neurogenic diseases, especially Werdnig-Hoffmann disease, Kugelberg-Welander syndrome, and amyotrophic lateral sclerosis, although not to the same extent as in the myopathies named. For instance, with the normal maximum value for CK at 50 U/L, values of about 3,000 U/L are common in Duchenne dystrophy or dermatomyositis, and may reach 50,000 U/L in myoglobinuria. In the denervating diseases, CK values greater than 500 U/L would be unusual but do occur. In some individuals, CK may be inexplicably increased with no other evidence of any muscle disease. Cardiologists have used isoenzyme analysis of CK to help differentiate between skeletal muscle and heart as the source of the increased serum activity. However, in the differential diagnosis of muscle disease, isoenzyme study has not been helpful, and the appearance of the “cardiac” isoenzyme of CK does not necessarily implicate the heart when there is limb weakness.

DEFINITIONS It is useful to define some terms. Atrophy is used in three ways: to denote wasting of muscle in any condition, to denote small muscle fibers under the light microscope, and to name some diseases. By historical accident, all the diseases in which the word atrophy has been used in the name proved to be neurogenic (e.g., peroneal muscular atrophy or spinal muscular atrophy). Therefore, it seems prudent to use the word wasting in clinical description of limb muscles, unless it is known that the disorder is neurogenic. Myopathies are conditions in which the symptoms are due to dysfunction of muscle and in which there is no evidence of causal emotional disorder or of denervation on clinical grounds or in laboratory tests. The symptoms of myopathies are almost always due to weakness, but other symptoms include impaired relaxation (myotonia), cramps or contracture (McArdle disease), or myoglobinuria. Dystrophies are myopathies with five special characteristics: (1) they are inherited; (2) all symptoms are due to weakness; (3) the weakness is progressive; (4) symptoms result from dysfunction in voluntary muscles; and (5) there are no histologic abnormalities in muscle other than degeneration and regeneration, or the reaction to those changes in muscle fibers (infiltration by fat and connective tissue). There is no storage of abnormal metabolic products. Some heritable myopathies are not called dystrophies because weakness is not the dominant symptom (e.g., familial myoglobinurias) or the syndrome is not usually progressive (e.g., periodic paralysis or static, presumably congenital myopathies), and other

names are assigned. SUGGESTED READINGS Brooke MM. A clinician's view of neuromuscular disease, 2nd ed. Baltimore: Williams & Wilkins, 1986. Engel AG, Franzini-Armstrong C, eds. Myology, 2nd ed. New York: McGraw-Hill, 1994. Walton JN, ed. Disorders of voluntary muscle, 6th ed. Edinburgh: Churchill Livingstone, 1994.

CHAPTER 125. PROGRESSIVE MUSCULAR DYSTROPHIES MERRITT’S NEUROLOGY

CHAPTER 125. PROGRESSIVE MUSCULAR DYSTROPHIES LEWIS P. ROWLAND Classification Laboratory Diagnosis X-Linked Muscular Dystrophies Emery-Dreifuss Muscular Dystrophy Facioscapulohumeral Muscular Dystrophy Myotonic Muscular Dystrophy Limb-Girdle Muscular Dystrophy Congenital Muscular Dystrophies Distal Myopathies (Distal Muscular Dystrophies) Suggested Readings

A muscular dystrophy has five essential characteristics: 1. It is a myopathy, as defined by clinical, histologic, and electromyographic (EMG) criteria. No signs of denervation or sensory loss are apparent unless there is a concomitant and separate disease. 2. All symptoms are effects of limb or cranial muscle weakness. (The heart and visceral muscles may also be involved.) 3. Symptoms become progressively worse. 4. Histologic changes imply degeneration and regeneration of muscle, but no abnormal storage of a metabolic product is evident. 5. The condition is recognized as heritable, even if there are no other cases in a particular family. Although not part of the definition, there are two further characteristics that we hope will be reversed in the future: 1. It is not understood why muscles are weak in any of these conditions, even when the affected gene product is known. 2. As a result, there is no effective therapy for any of the dystrophies, and gene therapy has not yet been successful. Therefore, prevention is often the best help that can be offered. The acceleration of research progress may change this state of affairs. The definition requires some qualifications. For instance, some familial myopathies are manifest by symptoms other than limb weakness, but those conditions are not called dystrophies. Familial recurrent myoglobinuria, for example, is considered a metabolic myopathy. The several forms of familial periodic paralysis do not qualify as dystrophies, even if there is progressive limb weakness, because the attacks are the dominant manifestation in most patients. Syndromes with myotonia include that word in the name of the disease (e.g., myotonia congenita), but the condition is called muscular dystrophy only when there is limb weakness. In addition, a static condition is not called a dystrophy; instead, for instance, a disease of that type is a congenital myopathy. This distinction has some exceptions: A slowly progressive dystrophy may seem static, and some congenital myopathies slowly become more severe. Another exception is the term congenital muscular dystrophy, which may be severe and static from birth.

CLASSIFICATION The modern classification of mnuscular dystrophies commenced three decades ago and has not required much revision. It has served both biochemical and molecular genetics and has not been replaced, except for the gradual erosion of the category called limb-girdle muscular dystrophy (LGMD). This classification of muscular dystrophies, developed by John Walton and his associates, is based on clinical and genetic patterns, starting with three main types: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic muscular dystrophy. Each type differs from the others in age at onset, distribution of weakness, rate of progression, presence or absence of calf hypertrophy or high serum levels of sarcoplasmic enzymes, such as creatine kinase (CK), and pattern of inheritance ( Table 125.1).

TABLE 125.1. FEATURES OF THE MOST COMMON MUSCULAR DYSTROPHIES

Early investigators recognized that these three types did not include all muscular dystrophies, so they included a fourth type, LGMD. That class has been depleted, however, with the recognition of metabolic myopathies, mitochondrial myopathies, structurally specific congenital myopathies, and manifesting carriers of X-linked dystrophies. Progress has also been made in identifying polymyositis and distal myopathies. LGMD is still a diagnosis of exclusion, but classification may soon depend on deoxyribonucleic acid (DNA) analysis to demonstrate how many forms there actually are.

LABORATORY DIAGNOSIS It has become conventional to perform EMG and muscle biopsy for each new patient in a family. The availability of DNA analysis in white blood cells, however, often obviates biopsy. DNA studies are needed for the diagnosis of Duchenne, Becker, facioscapulohumeral, scapuloperoneal, myotonic, and LGMDs. If no defining mutation is found in a limb-girdle syndrome, it may be useful to carry out histochemical and electrophoretic studies of dystrophin. If unusual features are encountered in the biopsy, a regional research center can be consulted. Muscle biopsy is needed to characterize most congenital and metabolic myopathies. Serum CK determination and electrocardiogram (ECG) should be included for all patients with any kind of myopathy.

X-LINKED MUSCULAR DYSTROPHIES Definitions Duchenne and Becker dystrophies (MIM 310200) are defined by the features listed in Table 125.1. The conditions, however, can also be defined in molecular terms. The two diseases are the result of mutations in the gene for dystrophin at Xp21. Although other diseases that map to Xp21 may differ from Duchenne or Becker dystrophies, neither disease can be diagnosed if no abnormality of the gene or gene product is found. In that sense, they are dystrophinopathies. Nondystrophin diseases that map to the same position can be called Xp21 myopathies. Prevalence and Incidence

The incidence of Duchenne dystrophy is about 1 in 3,500 male births. There is no geographic or ethnic variation in this figure. Approximately one-third of the cases are caused by new mutations; the others are more clearly familial. Because the life span of patients with Duchenne dystrophy is shortened, the prevalence is less—about 1 in 18,000 males. Becker dystrophy is much less common, with a frequency of about 1 in 20,000. Duchenne and Becker Muscular Dystrophies Duchenne Muscular Dystrophy Duchenne dystrophy is inherited as an X-linked recessive trait. Girls and women who carry the gene are carriers; some are manifesting carriers with limb weakness, calf hypertrophy, or high serum CK levels. The condition may become evident at birth if serum enzymes are measured, for example, for an incidental respiratory infection. Authorities often state that symptoms do not begin until age 3 to 5 years, but that view may be a measure of the crudeness of muscle evaluation in infants. Walking may be delayed, and the boys probably never run normally; there is much commotion, but little forward progression because they cannot raise their knees properly. Soon, toe-walking and waddling gait are evident. Then, the condition progresses to overt difficulty in walking, climbing stairs, and rising from chairs. An exaggerated lordosis is assumed to maintain balance (Fig. 125.1). The boys tend to fall easily if jostled, and then they have difficulty rising from the ground. In doing so, they use a characteristic maneuver called the Gowers sign (Fig. 125.2): They roll over to kneel, push down on the ground with extended forearms to raise the rump and straighten the legs, then move the hands to the knees and push up from there. The process has been called “climbing up himself.” It is also seen in other conditions that include proximal limb and trunk weakness, such as spinal muscular atrophy. At this stage, the knee jerks may be lost, whereas ankle jerks are still present; this discrepancy is a measure of the proximal accentuation of weakness.

FIG. 125.1. Progressive muscular dystrophy. Lumbar lordosis. (Courtesy Dr. P.I. Yakovlev.)

FIG. 125.2. Gowers sign in a patient with Duchenne or Becker MD. Postures assumed in attempting to rise from the supine position.

As the disease progresses, the arms and hands are affected. Slight facial weakness may be seen, but speech, swallowing, and ocular movements are spared. Iliotibial contractures limit hip flexion; heel cord contractures are partly responsible for toe-walking. At ages 9 to 12 years, the boys no longer walk; they use a wheelchair. Now, scoliosis may become serious; contractures at elbows and knees contribute to disability. By about age 20, respiration is compromised, and mechanical ventilation is needed. The heart is usually spared clinically, but congestive heart failure (CHF) may result from cardiomyopathy. The ECG is abnormal in most patients, with increased RS amplitude in lead V 1 and deep, narrow Q waves in left precordial leads. Signs of CHF may supervene in a few cases. The gastrointestinal system is usually spared, but acute gastric dilatation is an uncommon complication. Mental retardation seems to affect about one-third of boys with Duchenne dystrophy. However, there is no adequate control group to account for the impact on test results of the progressive social and educational isolation of the disease; in no other childhood disease does a child start out almost normal and then gradually face total disability and death. There is neither a characteristic brain pathology nor any correlation of intelligence with changes in dystrophin or the affected gene. Becker Muscular Dystrophy This condition resembles Duchenne dystrophy in essential characteristics: It is X-linked, calf hypertrophy is present, weakness is greatest proximally, and serum CK levels are high. EMG and muscle histology are the same. The two differences are age at onset (usually after age 12) and rate of progression (still walking after age 20, often later). Diagnosis The clinical diagnosis of Duchenne dystrophy is usually evident from clinical features. In sporadic and atypical cases, spinal muscular atrophy might be mistaken for Duchenne dystrophy. Clinical fasciculation and EMG evidence of denervation, however, identify the neurogenic disorder; in a few cases, dystrophin analysis has made the correct diagnosis. High values for CK are sometimes encountered in automated chemistry analysis and have mistakenly led to the diagnosis of Duchenne dystrophy. However, values typical of Duchenne or Becker dystrophy are usually at least 20 times normal, and few other conditions attain these levels, not even interictal phosphorylase deficiency or acid maltase deficiency, which typically show high levels. Increased serum levels of CK are seen in Xp21 gene carriers, in some patients with spinal muscular atrophy, and, for unknown reasons, in some otherwise normal people ( idiopathic hyperCKemia). High values are seen in men with the nonvacuolar form of distal myopathy. When a child with an incidental infection has routine blood tests, increased serum enzyme values may lead to a diagnosis of hepatitis; serum CK should then be assayed, and if it is elevated, a myopathy should be suspected, not a liver disease. Molecular Genetics The same gene is involved in both Duchenne and Becker dystrophies; they are allelic diseases. The gene was mapped, before the gene product was known, by a

process called positional cloning. The gene product was inferred from DNA sequencing, and then it was identified as dystrophin, a cytoskeletal protein located at the plasma membrane. The brain and other organs contain slightly different isoforms. In muscle, dystrophin is associated with membrane glycoproteins that link it to laminin on the external surface of the muscle fiber ( Fig. 125.3). The protein may therefore play an essential role in maintaining the integrity of muscle fiber. If dystrophin is absent, as in Duchenne dystrophy, or abnormal, as in Becker dystrophy, the sarcolemma becomes unstable in contraction and relaxation, and the damage results in excessive influx of calcium, thereby leading to muscle cell necrosis. If the glycoproteins are abnormal or missing, the same problems arise, as in some LGMDs (described later).

FIG. 125.3. Components of the dystrophin-glycoprotein complex are indicated by open ellipsis (light red shading); proteins known to be associated with the complex are in darker red shading. The complex is thought to play a role in stabilizing the sarcolemma and in protecting against stress on the surface membranes from muscle contraction. (From Lim and Campbell, 1998; with permission.)

These findings have been put to practical use in the diagnosis of Duchenne and Becker dystrophies and in providing genetic counseling. DNA analysis demonstrates a deletion or a duplication at Xp21 in 60% to 70% of patients with Duchenne or Becker dystrophy. Point mutations account for the remainder but have been difficult to identify. The presence of a deletion in a patient with compatible clinical findings is diagnostic. Carriers can be similarly identified, and the test can be used for antenatal diagnosis ( Fig. 125.4).

FIG. 125.4. Prenatal diagnosis in Duchenne MD. A: Autoradiograph of Southern blot of 1% agarose gel with DNA samples from each individual digested with the restriction enzyme Xmnl and probed with pERT87-15. The affected male is deleted (no signal). His sister who was pregnant has a deleted X and an X chromosome with the 1.6/1.2 allele. Her husband's X chromosome contains the 2.8 allele. The fetus contains the husband's X and the deleted X. B: Diagram of the four possible outcomes of the prenatal diagnosis. The fetus is a carrier female. (Courtesy A.D. Roses.)

If there is no deletion, the diagnosis can be made by dystrophin studies, which require a muscle biopsy and are therefore not suitable for prenatal diagnosis. There are two types of studies: immunocytochemical and electrophoresis with immunochemical identification of the protein (Western blot). In Duchenne dystrophy, dystrophin is not evident by either method. In Becker dystrophy, the cytochemical method shows an interrupted pattern of staining in the surface membrane, and the Western blot shows two abnormalities: decreased abundance of dystrophin and an abnormal protein size, usually smaller than normal but sometimes larger than normal (if there is an insertion or duplication in the gene). In carriers, there is a mosaic pattern in the biopsy; some fibers contain dystrophin and others show none at all. A relationship between the site of the deletion and the clinical syndrome is seen in analysis of Becker dystrophy. The gene contains 79 exons. More severe types tend to be related to deletions in either the C-terminal or the N-terminal regions. Milder Becker syndromes are associated with deletions in the central part of the rod domain. In most typical Becker cases, the deletion involves exon 45. A hot spot for Duchenne mutations is located in the first 20 exons. However, it is not known why the lack of dystrophin results in the clinical syndrome or in high serum CK values, or why an abnormal amount or structure of dystrophin leads to the Becker type. In an animal model, an X-linked disease of the mdx mouse, dystrophin is also totally absent and serum CK levels are high, but weakness is not evident and histologic changes are mild. Treatment There is no specific drug therapy for these diseases. Prednisone therapy was better than placebo in controlled trials, but the side effects of chronic administration limit the practical usage of steroids. Oral administration of creatine is said to increase strength in several neuromuscular disorders, without mention of effects on daily function. Attempts to replace the missing gene by implantation of healthy myoblasts have been limited by inefficiency of the process; the transplanted myoblasts produce normal dystrophin, but only about 1% of the fibers are replaced. Management is therefore directed to bracing and surgical correction of spine and limb deformities to maintain ambulation as long as possible. Bracing may prevent scoliosis in wheelchair-bound patients. The children and their families need social support to aid financially, educationally, and emotionally. Genetic counseling is crucial. Heart transplantation has been used for the cardiomyopathy seen occasionally in Becker patients. Children with Duchenne dystrophy, unlike other dystrophies, are at risk of myoglobinuria after general anesthesia. The syndrome resembles malignant hyperthermia and should be treated accordingly when it occurs. Other Xp21 Myopathies Dystrophinopathies A myopathy may appear when a deletion in a neighboring gene extends into the dystrophin gene. The resulting syndrome may be dominated by congenital adrenal insufficiency or glycerol kinase deficiency, but there is also a myopathy that may be mild or severe. In addition, syndromes are customarily called Becker variants if the dystrophin abnormalities are compatible with that disease. This nomenclature may be confusing, however, because the original definition of Becker dystrophy was based on clinical criteria, and these syndromes are clinically different. Among them are myopathies that affect girls or women (not only manifesting carriers but girls with Turner syndrome or balanced translocations that involve Xp21), syndromes of atypical distribution of weakness (e.g., distal myopathy or quadriceps myopathy), and syndromes that lack weakness but are manifested by some other symptoms (e.g., recurrent myoglobinuria or X-linked cramps). The appearance of any of these disorders warrants appropriate study of dystrophin.

Nondystrophin-related Xp21 Myopathies One of the mysteries of molecular genetics is Mcleod syndrome, a disorder first discovered in blood banks because the donors lacked a red cell antigen, the Kell antigen. These people were soon found to have abnormally shaped red blood cells (acanthocytes), and serum CK values were often 29 times normal or even higher. In addition, there was sometimes limb weakness, and the condition was linked to Xp21. Therefore, this condition, too, was expected to be a dystrophinopathy. In fact, however, dystrophin is normal. How the myopathy arises is not known.

EMERY-DREIFUSS MUSCULAR DYSTROPHY Emery-Dreifuss muscular dystrophy (EDMD) (MIM 310300) meets the criteria previously listed for a muscular dystrophy. It is characterized clinically by several unusual manifestations: 1. The distribution of weakness is unusual, with a humeroperoneal emphasis; that is, the biceps and triceps are affected rather than shoulder girdle muscles, and distal muscles are affected in the legs 2. Contractures are disproportionately severe and are experienced before much weakness is noted; the contractures affect the elbows, knees, ankles, fingers, and spine. A rigid spine develops, and neck flexion is limited. 3. Heart block is common and often leads to placement of a pacemaker. The myopathy may be mild or severe. The gene for EDMD maps to the long arm of the X chromosome, at Xq28, and more than 60 mutations have been found. The affected gene product, emerin, is localized to the nuclear membrane in muscle and other tissues. In patients, immunochemical methods show that emerin is absent not only in muscle nuclei but also in circulating white blood cells and skin. As a result, skin biopsy or leukocyte studies could be used diagnostically instead of muscle biopsy. The simplest alternative is to take a swab of the inner cheek and study exfoliated mucosal cells. DNA or gene product analysis is now needed for precise diagnosis because of clinical diagnostic problems and because cardiac surveillance is crucial. EDMD must be distinguished from other conditions. First, some patients meet the clinical criteria for EDMD, but the pattern of inheritance is autosomal dominant or recessive, not X-linked. These variants have not yet been mapped but do not involve the expression of emerin. Second, the rigid spine syndrome includes vertebral and limb contractures, but not cardiopathy, muscle wasting, or X-linked inheritance. Because the cardiac abnormality may not be evident in childhood, some patients with a rigid spine might be expected to have EDMD. In one study, DNA analysis showed this in one of seven rigid-spine patients. Third, Bethlem myopathy (MIM 158810) includes contractures and myopathy, but not cardiopathy. Fourth, other myopathies include cardiomyopathy with CHF rather than solely anomalies of rhythm. Management is symptomatic.

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY Definition Facioscapulohumeral muscular dystrophy (FSHMD) (MIM 158900) is defined by clinical and genetic features that differ from those of the Duchenne form in all particulars. It is inherited in autosomal-dominant fashion. The name reflects the characteristic distribution of the weakness; the face is probably always affected. Progression is slow; it may even be asymptomatic. Onset is usually in adolescence, but the disease is occasionally detected in children. Serum enzyme levels are normal or near-normal. Molecular Genetics The autosomal-dominant disease shows almost complete penetrance. It maps to chromosome 4q35-qter; the gene product has not been identified. Most apparently sporadic cases prove to have the same mutation; many are new mutations. Diagnosis by deletion analysis is defining, but about 10% of clinically diagnosed cases are not linked, which implies locus heterogeneity. The deletions at 4q35 do not seem to interrupt any identifiable gene. Instead, they move the telomere closer to the centromere, and this position-effect variegation presumably and indirectly affects some neighboring gene. Clinical Manifestations In full-blown FSHMD, the following features are characteristic: 1. Facial weakness is evident not only in limited movements of the lips but also in the appearance of the slightly everted lips and wide eyes. Patients state that they have never been able to whistle or blow up a balloon. Some are said to sleep with eyes open. 2. Scapular winging is prominent. This feature can be seen with the arms dependent. The traditional test is to ask the patient to push against a wall at shoulder level, exaggerating the winging. The winging also becomes more evident when the patient tries to elevate the arms laterally; in addition to exaggeration of winging, there is limitation, and the patient often cannot raise the arms to shoulder level, even though no deltoid weakness is noted on manual testing. The limitation is the inadequate fixation of the scapula. Considerable disability may result from this problem, even though limb weakness may not be detectable. 3. The shoulder girdle has a characteristic appearance. Viewed from the front, the clavicles seem to sag and the tips of the scapulae project above the supraclavicular fossa; this abnormality becomes more marked when the subject tries to raise the arms laterally to shoulder level. Smallness of the pectorals affects the anterior axillary fold, which is ordinarily diagonal but assumes a vertical position in FSHMD. 4. Weakness of the legs may affect proximal muscles or, more often, the anterior tibials and peroneals. In family studies, asymptomatic individuals can be identified by mild versions of these signs. We once concluded that mild facial weakness was the most reliable sign, but that impression was not put to a test by DNA diagnosis. Within a single family, the condition may vary from this mild state to disability. Progression is slow, however, and the condition may not shorten longevity. Few patients are so severely affected that they must use a wheelchair. Associated Disorders The childhood form seems to include an unusual frequency of deafness, oropharyngeal symptoms, and, possibly, mental retardation, as well as facial diplegia. Tortuous retinal vessels and Coats disease (exudative telangiectasia of the retina) have also been reported in children with FSHMD but do not seem to be consistent findings. How these disorders relate to the genetic abnormality remains to be elucidated. Laboratory Studies EMG and muscle biopsy, by definition, should show a myopathic pattern. The histologic changes are mild. Occasional diagnostic problems are reviewed later. Serum enzyme values are usually normal or trivially elevated. The ECG is normal or shows the common changes with age and atherosclerosis. Presymptomatic diagnosis is possible in families with more than one affected member, but this procedure should be done only with appropriate counseling. Apparently sporadic cases often prove to be new mutations by DNA analysis. FSHMD is now defined by identification of deletions at 4q35. Diagnosis Three persistent diagnostic problems have been discussed in the literature ( Table 125.2). One comprises reports of a spinal muscular atrophy of FSH distribution; this diagnosis depends entirely on the interpretation of muscle biopsy and EMG. In our experience, however, FSH manifestations, without exception, have been associated with myopathic changes in these studies (i.e., the clinical diagnosis is FSHMD).

TABLE 125.2. SYNDROMES RESEMBLING FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

The second problem is the tendency to see inflammatory cells in the muscle biopsy, which has led to the belief that there may be an FSH form of polymyositis. Immunosuppressive therapy has always failed in these patients, however. The significance of the inflammatory cells is not known. The third problem is evident in reports of an autosomal dominant scapuloperoneal myopathy or atrophy, thereby implying that this condition differs from FSHMD. The difference depends on the difficult determination of whether the face is affected. Both scapuloperoneal syndromes have been linked, providing new criteria for diagnosis and seemingly confirming the existence of both myopathic and neurogenic syndromes that map to different chromosomes. Additionally, EDMD has sometimes been confused with FSHMD, but the characteristic clinical features of that syndrome differ in essentials from FSH. Another diagnostic problem is created by a mitochondrial myopathy with FSH distribution and cardiomyopathy. This disorder may be the most important reason to perform a muscle biopsy in the propositus of newly identified families or sporadic cases. Infantile onset of FSHMD is rare, but facial weakness may be severe enough to simulate the Mรถbius syndrome of congenital facial diplegia. Management Treatment is symptomatic. Some authorities have suggested that wiring the scapulae to the chest wall makes the arms more useful, but there has been too little experience to recommend such extensive surgery. In an open trial, albuterol, a beta-2-adrenergic agonist, improved muscle strength; a blinded trial was planned.

MYOTONIC MUSCULAR DYSTROPHY Definition Myotonic dystrophy (MIM 160900) is an autosomal-dominant, multisystem disease that includes a dystrophy of unique distribution, myotonia, cardiopathy, ocular cataracts, and endocrinopathy. The diverse manifestations are called pleiotropic. Epidemiology Myotonic dystrophy is compatible with long life, and the penetrance of the gene is almost 100%. Because of these characteristics, myotonic dystrophy is a disease of high prevalence, about 5 per 100,000 throughout the world, with no specific geographic or ethnic variation. It is probably the most common form of muscular dystrophy. The incidence is about 13.5 per 100,000 live births. Clinical Manifestations Like many other autosomal-dominant diseases, there is great variation in the age at onset and severity of the different manifestations of myotonic dystrophy. Some affected people are asymptomatic but show signs of the disease on examination. The myopathy is distinctive in distribution ( Fig. 125.5). Unlike any of the other major forms of muscular dystrophy, it affects cranial muscles in addition to those of the face. There is ptosis; in some patients, eye movements are impaired. Dysarthria and dysphagia may be problems. The temporalis muscles are small. The overall appearance is distinctive, with a long lean face and ptosis. In men, frontal baldness contributes to the impression. (To this day, insensitive clinicians perpetuate unkind words to describe this facial appearance.) The sternomastoid muscles are characteristically small and weak in manual tests. The limb myopathy is most pronounced distally and affects the hands and feet equally. This dystrophy is one of the few neuromuscular disorders in which weakness of the finger flexors is prominent. Distal leg weakness may cause a footdrop or steppage gait. Most patients are generally thin, and focal wasting is not prominent. The tendon jerks are lost in proportion to the weakness. Muscles of respiration may be affected even before there is much limb weakness; this symptom may be manifested as hypersomnia. Sensitivity to general anesthesia may be increased, with prolonged hypoventilation in the postoperative period. Myotonic dystrophy, however, is not a muscle disease likely to cause alveolar hypoventilation. The rate of progression is slow and longevity may not be affected, but variation is evident; some people are almost asymptomatic, and some become disabled.

FIG. 125.5. Myotonic dystrophy. Atrophy of facial, temporal, neck, and hand muscles.

Myotonia has a dual definition. First, clinically, it is a phenomenon of impaired relaxation. Second, the EMG shows a pattern of waxing and waning of high-frequency discharge that continues after relaxation begins, thus prolonging and impeding the effort. EMG activity is essential to the definition because there are other forms of impaired relaxation (see Chapter 129). Myotonia is most evident in the hands. Symptomatically, it may impair skilled movements or may embarrass the patient by complicating the attempt to shake hands or turn a doorknob because it is difficult to let go. As a sign on examination, the slow relaxation can be elicited by tapping the thenar eminence or, in the forearm, the bellies of the extensors of the fingers. Eliciting percussion myotonia in other limb muscles may be difficult for reasons unknown, but lingual myotonia may be present. The activity can also be evoked by asking the patient to grasp forcefully and then relax, which a normal person can do rapidly. In a patient with myotonia, however, the grasp is followed by slow relaxation. The abnormal activity arises in the muscle because the response to percussion persists in curarized muscle of these patients; that is, the activity persists after neuromuscular transmission has been blocked. Cataracts are almost universal but take years to appear. Early findings include characteristic iridescent opacities and posterior opacities. Before DNA analysis

became available, the finding of cataracts on slit-lamp examination was the most sensitive way to determine which members of a family were affected; cataracts were sometimes the only manifestation of the disease. Endocrinopathy is most readily seen in men. Frontal baldness is almost universal, and testicular atrophy is common; fertility is little diminished, however, so that the disease continues to be propagated in the family. Menstrual irregularities and ovarian failure are not nearly so frequent, and fertility is little decreased in women. Diabetes mellitus is more common than in the general population, but otherwise no specific endocrine abnormalities are encountered. The cardiac disorder is manifested mostly by abnormalities in the ECG. Conduction abnormalities (with first-degree heart block or bundle branch block) and sometimes abnormal rhythms are seen, but they are rarely symptomatic and pacemakers are rarely needed. CHF and syncope or sudden death may be no more common in affected individuals than in age-matched cohorts of normal people, but this risk has not been assessed by a case–control study. Gastrointestinal disorders are not common, but pseudoobstruction or megacolon can be dramatic. There may be a tendency to constipation, but in general the autonomic nervous system is not affected. Cerebral symptoms are not common, but many clinicians are impressed by the personalities of some patients with myotonic dystrophy, who may seem cantankerous and ornery. Many patients, however, have normal social adjustment. Laboratory Studies EMG shows evidence of myopathy and the characteristic waxing and waning after-discharge of myotonia. The muscle biopsy shows mild and nonspecific changes. Serum CK level may be normal or slightly increased, but never to the extent seen in Duchenne dystrophy or polymyositis. The ECG and ocular findings were previously described. No consistent changes appear on brain imaging. DNA analysis is now obligatory for precise diagnosis but may raise sensitive questions in a family, and some individuals at risk may not wish to be tested. Molecular Genetics and Pathophysiology The gene for myotonic dystrophy maps to 19q13.2. The mutation is an expansion of a CTG triplet repeat within the dystrophia myotonica protein kinase (DMPK) gene. Unaffected people have 5 to 40 CTG repeats; affected individuals have more than 100. It is uncertain how the mutation exerts its effects, partly because the mutation is outside the open reading frame of the gene. Several proposals of pathogenesis have not been proved. The expansion may alter the DNA in chromatin. It may affect ribonucleic acid metabolism of DMPK or neighboring genes. It may affect the DMPK protein itself, but there seems to be no consistent deficiency of this protein. Whatever the fundamental fault, it is uncertain how this change could cause the pleiotropic disorder, with manifestations in so many different organs. The characteristic myotonia is an abnormality of the muscle surface membrane, but the molecular basis is not clear. The gene was one of the first to demonstrate expansion, a phenomenon that allows direct DNA diagnosis. There is a correlation between the number of repeats and the severity of symptoms, with instability between generations as the explanation for anticipation (earlier age at onset in succeeding generations) and potentiation (more severe disease in the next generation). This increase is attributed to an increase in the number of trinucleotide repeats in germ cells. The most extreme example is congenital myotonic dystrophy, which affects children of either sex who are born to a woman with the usual adult form of the disease, which is often so mild that the woman may be asymptomatic but shows signs of the condition; the mother is almost always the affected parent. Children with the congenital disease have difficulty in the newborn period, develop slowly, are often mentally retarded, and show developmental anomalies of the face and jaws, as well as severe limb weakness and clubfeet (Table 125.3).

TABLE 125.3. MANIFESTATIONS OF CONGENITAL MYOTONIC DYSTROPHY (54 CASES REPORTED AFTER 1977)

Diagnosis Typical myotonic dystrophy is so characteristic that diagnosis is often evident at a glance and is confirmed by finding small sternomastoids, distal myopathy, and myotonia of grasp and percussion. Diagnostic problems may arise if a man is not bald or if the facial appearance is not typical. Footdrop may be the first symptom of myotonic dystrophy and might be confused with Charcot-Marie-Tooth neuropathy, but the EMG shows a myopathic pattern, as well as myotonia. Noting an autosomal-dominant pattern in other members of the family helps make the diagnosis. Congenital myotonic dystrophy can be mistaken for other causes of mental retardation of chromosome abnormalities. As DNA analysis is perfected, it will be used increasingly to resolve diagnostic problems, including the identification of presymptomatic individuals in a family. A syndrome called proximal myotonic myopathy (PROMM) is similar to myotonic dystrophy in many respects, including autosomal-dominant myopathy, myotonia, cataracts, and weakness of the sternomastoids. It differs in the distribution of limb weakness, because myotonic dystrophy is primarily a distal myopathy, and in other, less conspicuous ways. For instance, myotonia is more difficult to elicit, symptoms are less severe, and there may be calf hypertrophy. Most important, the syndrome does not map to chromosome 19. A similar syndrome was called “myotonic muscular dystrophy type 2” and mapped to chromosome 3q; soon afterward PROMM mapped to the same position. Myotonia is found in several other conditions that are described in other chapters: hyperkalemic periodic paralysis and paramyotonia congenita (see Chapter 126), and myotonia congenita and the Schwartz-Jampel syndrome (see Chapter 127). “Pseudomyotonia,” or impaired relaxation without the typical EMG pattern, is seen in Isaacs syndrome or neuromyotonia (see Chapter 129). Myotonic-like patterns are seen in the EMG of patients with acid maltase deficiency, but clinical myotonia is not seen in that syndrome. None of these other myotonic syndromes is accompanied by the characteristic myopathy of myotonic dystrophy; none of them causes diagnostic confusion. Management and Genetic Counseling Myotonia can be ameliorated with quinine, phenytoin sodium (Dilantin), or other anticonvulsant drugs. However, myotonia is only rarely a bothersome symptom; it is the weakness that is disabling, and little can be done about that. Rehabilitation measures are helpful in keeping the muscles functioning as best they can and in assisting the patient in the activities of daily living. Orthoses help the footdrop. The ocular and cardiac symptoms are treated as they would be in any patient. An ECG should be recorded annually for adults, and slit-lamp examination is also carried out periodically. The families are educated about the nature of the disease, inheritance, and the availability of DNA diagnosis for adults and for prenatal testing.

LIMB-GIRDLE MUSCULAR DYSTROPHY History and Definition LGMD (MIM 253600; 159000; 253700) is a category of muscular dystrophy that was conceived as a diagnosis of exclusion to include syndromes not meeting the

diagnostic criteria for Duchenne, FSH, or myotonic dystrophy. As a result, autosomal-dominant and recessive forms were described, as well as familial disorders of proximal or distal limb weakness. These disorders were long assumed to be heterogeneous, awaiting separation on the basis of pathogenesis, and that has been forthcoming. Metabolic myopathies have been separated, especially acid maltase and debrancher enzyme deficiencies; other limb-girdle syndromes proved to be Becker dystrophy, mitochondrial myopathies, polymyositis, inclusion body myositis, or other diseases ( Table 125.4). With the advance of molecular genetics, dystrophin-normal myopathies were mapped, and gene products were identified as a new class of mostly cytoskeletal proteins. Immunochemical identification of these proteins and DNA analysis now play a major role in both diagnosis and definition.

TABLE 125.4. CONDITIONS SIMULATING LIMB-GIRDLE MUSCULAR DYSTROPHY

LGMD can be defined as follows: It comprises a heterogeneous group of muscular dystrophies that are predomiantly proximal in limb distribution. They are distinguished by patterns of inheritance, site of mutation, and nature of the affected protein. In all of them, dystrophin is present, and there is no mutation at Xp21. Childhood forms are related to mutations in genes for cytoskeletal proteins. In cases of adolescent or adult onset, LGMD is still a diagnosis of exclusion and is likely to be heterogeneous in etiology. Clinical Manifestations Onset may be in childhood, adolescence, or adulthood, and inheritance may be autosomal dominant or recessive. The disorder may be more severe in some families than in others. The legs are usually affected first, with difficulty climbing stairs and rising from chairs. A waddling gait then develops. Later, raising the arms becomes difficult, and winging of the scapula may be seen. Knee jerks tend to be lost before ankle jerks. Cranial muscles are usually spared. Progression is slow. EMG and muscle biopsy, by definition, show myopathic changes. Serum CK is elevated, usually less so than in Duchenne dystrophy but in the same range. Diagnosis now depends on DNA analysis. In one late-onset disorder, quadriceps myopathy, symptoms are focal, as the name implies; it may be inherited as an autosomal-dominant trait. Polymyositis may be similarly restricted, and some quadriceps syndromes seem to be neurogenic. In rare cases, dystrophin is lacking. There are still some limb-girdle disorders that have not been mapped. Distal and congenital myopathies are described in later sections. Molecular Genetics The discovery of the affected gene product in Duchenne MD was rapidly followed by remarkable advances in the cell biology of muscle and, simultaneously, in the analysis of LGMDs. These diseases resemble the Duchenne form clinically but differ because dystrophin is normal and inheritance is autosomal dominant or recessive rather than X-linked. Starting with these diseases, Kevin Campbell and colleagues discovered new proteins by mapping the genes responsible for dystrophin-normal dystrophies and then identifying the affected gene products. The dystrophin-associated glycoproteins include some that are extracellular (merosin, formerly called laminin, and dystroglycans), some that are located on the cytoplasmic side of the muscle plasma membrane (dystrophin, syntrophin, and utrophin), and some that span the surface membrane (sarcoglycans). They function as a group to anchor intracellular cytoskeletal components (including actin and dystrophin) to extracellular proteins supporting the surface membrane as the muscle contracts and relaxes (see Fig. 125.3). The importance of sarcoglycans and dystroglycans is emphasized by the limb-girdle diseases that result when these glycoproteins are genetically absent. In these conditions, one of the sarcoglycans is missing ( Table 125.5). All but one of these newly recognized disease-associated proteins is part of the muscle cytoskeleton; the exception is calpain, a muscle-specific calcium-activated protease. However, some families show no linkage to these loci, and identified mutations account for only about 10% of all myopathies with normal dystrophin. As a group, these LGMDs exemplify locus heterogeneity, whereby different mutant gene products are encoded on different chromosomes but give rise to clinically similar syndromes. The sarcoglycanopathies teach us that dystrophin is needed to anchor the sarcoglycans, but the glycoproteins are important themselves and seem to function as a complex. If a key sarcoglycan is missing, dystrophin does not function properly. Further, mutation of one sarcoglycan leads to secondary loss of the other components of the complex. The nonmapped conditions indicate that still other mechanisms need to be identified. For instance, merosin deficiency is the cause of 50% of all cases of congenital muscular dystrophy but is also found in some limb-girdle syndromes starting after age 20 years.

TABLE 125.5. LIMB-GIRDLE MUSCULAR DYSTROPHIES

CONGENITAL MUSCULAR DYSTROPHIES These are the only conditions called “dystrophy� that are not clearly progressive. Instead, the appellation was taken from histologic changes in muscle. Limb weakness and floppiness are evident at bith. One type has been mapped to 6q2; the affected protein is laminin a2 (merosin); it is called merosin-deficient cogenital dystrophy. The histology is that of a dystrophy, but inflammatory cells may be prominent. This form accounts for almost 50% of all congenital dystrophy cases. Disability may be mild or severe. Contractures and respiratory problems are common; CK values may be high in early stages. Mental development is normal. Merosin-positive cases are unmapped, and the disease is milder on all scores. In Fukuyama congenital muscular dystrophy (MIM 253800), severe neuromuscular symptoms are apparent at birth, with difficulty swallowing and feeble limb movements, but little change later. Additionally, congenital abnormalities of the brain, especially microcephaly and hydrocephalus, are manifested by seizures and mental retardation. The children never walk, and severe disability leads to inanition and

death by age 10. Fukuyama congenital dystrophy is autosomal-recessive and maps to 9q31; the gene product is not yet known. In the Walker-Warburg syndrome (MIM 236670), the myopathy and cerebral abnormalities are similar, but ocular malformations characteristically include cataracts and retinal dysplasia. Lissencephaly (agyria) is a prominent cerebral anomaly. Another congenital disorder is the muscle-eye-brain syndrome or Santavuori disease. In addition to severe limb weakness, mental retardation, malformations of the brain, retinal dysplasia and optic atrophy are all seen. Except for merosin, the gene products are not known in congenital dystrophies, but consanguinity in many families suggests recessive inheritance. The Fukuyama syndrome seems especially prevalent in Japan but has been seen in Europe and the United States. In sporadic cases, dystrophin analysis is needed to be certain that an unusual congenital myopathy is not a variant of Duchenne dystrophy.

DISTAL MYOPATHIES (DISTAL MUSCULAR DYSTROPHIES) Distal myopathies (distal muscular dystrophies) (MIM 160500) are defined by clinical manifestations in the feet and hands before proximal limb muscles are affected. As heritable diseases with features of myopathy and slow progression, they are properly considered muscular dystrophies The distinction from heritable neuropathies depends on the sparing of sensation, as well as histologic and electrodiagnostic features of myopathy. Most distal myopathies have been assigned to different map positions, confirming the clinical differences in patterns of inheritance, onset in leg or hands, predominant leg weakness in anterior or posterior compartments, presence or absence of vacuoles, and rise in serum CK ( Table 125.6).

TABLE 125.6. DISTAL MYOPATHIES

The most common form is Welander distal myopathy, which was first described in Sweden; inheritance is autosomal-dominant. Symptoms begin in adolescence or adult years and progress slowly. The legs are affected before the hands. Histologic changes are mild, but filamentous inclusions may resemble those seen in oculopharyngeal dystrophy or inclusion body myositis. Serum CK is only slightly elevated. In the autosomal-recessive Nonaka variant, a vacuolar myopathy is seen, the gastrocnemius muscles are spared, and serum enzyme values are only slightly increased. Nonaka distal myopathy and hereditary inclusion body myopathy share clinical and morphologic similarities; both conditions map to 9p1-q1. Miyoshi distal myopathy is also autosomal recessive but differs from Nonaka in that the histologic changes are nonspecific (without vacuoles), the gastrocnemius muscles are affected first, and serum CK values are as high as those in Duchenne dystrophy; hyperCKemia may be noted before there is any symptomatic weakness. The Miyoshi variety and LGMD type 2B (proximal limb weakness) both map to 2p17. The gene product has been named dysferlin. Some Miyoshi families do not link to this position, which implies locus heterogeneity. Another form of distal myopathy is accompanied by vocal cord and pharyngeal weakness. Still more variants are likely to be identified. SUGGESTED READINGS General Emery AEH, ed. Neuromuscular disorders: clinical and molecular genetics. New York: John Wiley and Sons, 1998. Griggs RC, Mendell JR, Miller RG. Evaluation and treatment of myopathies. Philadelphia: FA Davis Co, 1995. Karpati G, Carpenter S. Skeletal muscle pathology in neuromuscular diseases. In: Vinken PJ, Bruyn GW, Klawans HL, Rowland LP, DiMauro S, eds. Myopathies. Handbook of clinical neurology, rev ser, vol 62(18). New York: Elsevier Science, 1992:1–48. Kissel T, Hendell J, eds. Muscular dystrophies. Semin Neurol 1999;19:1–100. Tarnopolsky M, Martin J. Creatine monohydrate increases strength in patients with neuromuscular disease. Neurology 1999;52:854–857. Vinken PJ, Bruyn GW, Klawans HL Rowland LP, DiMauro S, eds. Myopathies. Handbook of clinical neurology, rev ser, vol 62(18). New York: Elsevier Science, 1992. Walton JN, ed. Diseases of voluntary muscle, 5th ed. London: Churchill Livingstone, 1994. Walton JN, Nattrass FJ. On the classification, natural history and treatment of the myopathies. Brain 1954;77:170–231. Duchenne and Becker Dystrophies and Other X-linked Diseases Ades LC, Gedeon AK, Wilson MJ, et al. Barth syndrome: clinical features and confirmation of gene localization to distal Xq28. Am J Med Genet 1993;45:327–334. Anderson MS, Kunkel LM. The molecular and biochemical basis of Duchenne muscular dystrophy. Trends Biochem Sci 1993;17:289–292. Barth PG, Van Wijngaarden GK, Bethlem J. X-linked myotubular myopathy with fatal neonatal asphyxia. Neurology 1975;25:531–536. Becker PE, Kiener F. Eine neue X-chromosomale Muskeldystrophie. Arch Psychiatr Z Neurol 1955;193:427–448. Bush A, Dubowitz V. Fatal rhabdomyolysis complicating general anesthesia in a child with Becker dystrophy. Neuromuscul Disord 1991;1:201–204. Bushby KMD. Genetic and clinical correlations of Xp21 muscular dystrophy. J Inherit Metab Dis 1992;15:551–564. Bushby KMD, Gardner-Medwin S. The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. I. Natural history. J Neurol 1993;240:98–104. Bushby KMD, Gardner-Medwin S, Nicholson LVB, et al. The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. II. Correlation of phenotype with genetic and protein abnormalities. J Neurol 1993;240:105–112. Bushby KM, Hill A, Steele JG. Failure of early diagnosis in symptomatic Duchenne muscular dystrophy. Lancet 1999;353:557–558. Case records of the Massachusetts General Hospital. Case 22-1998. Becker's muscular dystrophy involving skeletal muscle and myocardium. N Engl J Med 1998:339:182–190. Dubrovsky AL, Angelini C, Bonifati DM, Pegoraro E, Mesa L. Steroids in muscular dystrophy: where do we stand? Neuromuscul Disord 1998;8:380–384. Hoffman EP. Genotype/phenotype correlations in Duchenne/Becker dystrophy. In: Partridge T, ed. Molecular and cell biology of muscular dystrophy. London: Chapman & Hall, 1993. Hoffman EP, Arahata K, Minetti C, et al. Dystrophinopathy in isolated cases of myopathy in females. Neurology 1992;42:957–975.

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Jerusalem F, Sieb JP. The limb-girdle syndromes. In: Vinken PJ, Bruyn GW, Klawans HL, Rowland LP, DiMauro S, eds. Myopathies. Handbook of clinical neurology, rev ser, vol 62(18). New York: Elsevier Science, 1992:179–195. Lim LE, Campbell KP. The sarcoglycan complex in limb-girdle muscular dystrophy. Curr Opin Neurol 1998;11:443–452. Matsumara K, Campbell KP. Deficiency of dystrophin-associated proteins: a common mechanism leading to muscle cell necrosis in severe childhood muscular dystrophies. Neuromuscul Disord 1993;3:109–118. Smith FJD, Eady RAJ, Leigh IM, et al. Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nat Genet 1996;13:450–457. Speer MC, Tandan R, Rao PN, et al. Evidence for locus heterogeneity in the Bethlem myopathy and linkage to 2q37. Hum Mol Genet 1996;5:1043–1046. Distal Muscular Dystrophies Barohn RJ, Amato AA, Griggs RC. Overview of distal myopathies: from the clinical to the molecular. Neuromuscul Disord 1998;8:309–316. Feit H, Silergleit A, Schneider LB, et al. Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5p31. Am J Hum Genet 1998;63:1732–1742. Galassi G, Rowland LP, Hays AP, et al. High serum levels of creatine kinase: asymptomatic prelude to distal myopathy. Muscle Nerve 1987;10:346–350. Ikeuchi T, Asaka T, Saito M, et al. Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9. Ann Neurol 1997;41:432–437. Linssen WHJP, de Visser M, Notermans NC, et al. Genetic heterogeneity in Miyoshi-type distal muscular dystrophy. Neuromuscul Disord 1998;8:317–329. Liu J, Aoki M, Illa I, et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb-girdle muscular dystrophy. Nat Genet 1998;20:31–36. Miyoshi K, Iwasa M, Kawai H, et al. Autosomal recessive distal muscular dystrophy: a new variety of distal muscular dystrophy predominantly seen in Japan. Brain 1986;109:31–54. Somer H, Paetau A, Udd B. Distal myopathies. In: Emery AEH, ed. Neuromuscular disorders: clinical and molecular genetics. New York: John Wiley and Sons, 1998:181–202. Sunohara N, Nonaka I, Kamei N, Satoyaoshi E. Distal myopathy with rimmed vacuole formation. Brain 1989;112:65–83. Udd B. Limb-girdle type muscular dystrophy in a large family with distal myopathy: homozygous manifestation or a dominant gene? J Med Genet 1992;29:383–389. Udd B, Rapola J, Nkelainen P, et al. Nonvacuolar myopathy in a large family with both late adult-onset distal myopathy and severe proximal dystrophy. J Neurol Sci 1992;112:214–231. Weiler T, Greenberg CR, Nylen E, et al. Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype. Am J Hum Genet 1996;59:872–878. Congenital Muscular Dystrophies Beggs AH, Neumann PE, Arahata K, et al. Possible influences on the expression of X-chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy. Proc Natl Acad Sci U S A 1992;89:623–627. Cohn RD, Herrmann R, Sorokin L, Wewer UM, Voit T. Laminin a2 chain-deficient congenital muscular dystrophy: variable epitope expression in severe and mild cases. Neurology 1998;51:94–101. Fukuyama U, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type: clinical, genetic and pathologic considerations. Brain Dev 1981;3:1–10. Matsumara K, Nonaka I, Campbell KP. Abnormal expression of dystrophin-associated protein in Fukuyama-type congenital muscular dystrophy. Lancet 1993;341:521–522. Pegotato E, Mancias P, Swerdlow SH, et al. Congenital muscular dystrophy wtih primary lamnin a2 (merosin) deficiency presenting as inflammatory myopathy. Ann Neurol 1996;40:782–791. Pegotato E, Marks H, Garcia CA, et al. Laminin a2 muscular dystrophy: genotype/phenotype studies of 22 patients. Neurology 1998;51:101–110. Shewell MI, Rosenblatt B, Silver K. Inflammatory myopathy and Walker-Warburg syndrome: etiologic implications. Can J Neurol Sci 1993;20:227–229. Tomé FMS, Guicheney P, Fardeau M. Congenital muscular dystrophies. In: Emery AEH, ed. Neuromuscular disorders: clinical and molecular genetics. New York: John Wiley and Sons, 1998:21–58.

CHAPTER 126. FAMILIAL PERIODIC PARALYSIS MERRITT’S NEUROLOGY

CHAPTER 126. FAMILIAL PERIODIC PARALYSIS LEWIS P. ROWLAND Hypokalemic Periodic Paralysis Hyperkalemic Periodic Paralysis Suggested Readings

Familial periodic paralysis comprises diseases characterized by episodic bouts of limb weakness. On clinical grounds, there are three main types: hypokalemic periodic paralysis (HoPP) (MIM 170400), hyperkalemic (HyPP) (MIM 170500), and periodic paralysis with cardiac arrhythmia (MIM 170390). HyPP maps to 17q13, the locus of the gene for the alpha subunit of the sodium channel. HoPP maps to the gene for the dihydropyridine-sensitive L-type calcium channel of muscle, which is localized at 1q31. A third type, with cardiac arrhythmia, maps to neither site. Locus heterogeneity validates the clinical classification, although many investigators now lump the conditions as “channelopathies,” including paramyotonia congenita and other “nondystrophic myotonias.” Attacks are similar in all three conditions but differ somewhat in severity and duration ( Table 126.1). The two main types were first separated by the level of serum potassium during a spontaneous or induced attack. Provocative tests can be performed by intravenous administration of glucose and insulin to drive the potassium level down or by administration of potassium salts to increase the serum level.

TABLE 126.1. CLINICAL FEATURES OF LOW- AND HIGH-SERUM POTASSIUM PERIODIC PARALYSIS AND PARAMYOTONIA

The greatest uncertainty concerns paramyotonia congenita, which most investigators consider a separate syndrome that is manifested only by myotonia, with no attacks of paralysis. Some authorities believe that there are disease-specific mutations within the sodium channel gene. The word paramyotonia is used because the condition is thought to differ from ordinary myotonia in two ways: Paramyotonia is brought on by cold (but so are other forms of myotonia), and it is “paradoxic” in that it becomes more severe with exercise, whereas the myotonia of other diseases is ameliorated by exercise. In families with HyPP, however, many individuals have myotonia, and in presumed families of paramyotonia congenita, some individuals have attacks of paralysis (including the original families described by Eulenberg in Germany and Rich in the United States). Some people with paramyotonia congenita are susceptible to attacks induced by administration of potassium. The diseases are allelic, mapping to the same gene. Similarly, the same gene accounts for paramyotonic variants, such as myotonia fluctuans, acetazolamide-responsive myotonia, and painful myotonia. The third type of familial periodic paralysis, now called Andersen syndrome, was first thought to be normokalemic, then hyperkalemic. In fact, spontaneous attacks have been associated with high, low, or normal potassium levels. Nevertheless, patients are sensitive to administered potassium, which always provoked an attack before the provocative test was deemed dangerous. The hazard is feared because affected children are likely to have cardiac arrhythmias that lead to the need for a pacemaker. The syndrome was named after Andersen because she described a dysmorphic boy; since then dysmorphism has become one of five criteria for diagnosis; the others are periodic paralysis, potassium sensitivity, myotonia (usually mild), and cardiac arrhythmia. The dysrhythmia may be preceded by an asymptomatic prolonged QT interval on the ECG. The disease does not link to sodium or calcium channel genes or to the gene for the cardiac potassium channel that is responsible for most long QT syndromes. Vacuoles are found in the muscles in the early stages of both HoPP and HyPP. These vacuoles seem to arise both from the terminal cisterns of the sarcoplasmic reticulum and from proliferation of the T tubules. In the later stage, there may be degeneration of the muscle fibers, possibly related to persistent weakness in the intervals between attacks.

HYPOKALEMIC PERIODIC PARALYSIS In HoPP, the potassium content decreases in a spontaneous attack to values of 3.0 mEq/L or lower. Attacks may be induced by the injection of insulin, epinephrine, fluorohydrocortisone, or glucose, or they may follow ingestion of a meal high in carbohydrates. The potassium content of the urine is also decreased in an attack. It is not clear why potassium shifts into muscle to cause the attack. Incidence The disease is rare. There are no large series reported in the literature, and only one or two new patients are seen each year in any of the large neurologic centers in the United States. Males are affected two to three times as frequently as females. The first attack usually occurs at about the time of puberty, but it may occur as early as age 4 years or be delayed until the sixth decade. Symptoms and Signs An attack usually begins after a period of rest. It commonly develops during the night or is present on waking in the morning. The extent of the paralysis varies from slight weakness of the legs to complete paralysis of all the muscles of the trunk and limbs. The oropharyngeal and respiratory muscles are usually spared, even in severe attacks. There may be retention of urine and feces during a severe attack. The duration of an individual attack varies from a few hours to 24 or 48 hours. According to some patients, strength improves if they move around and keep active (“walk it off”). The interval between attacks may be as long as 1 year, or one or more attacks of weakness may occur daily. Weakness is especially likely to be present in the morning after ingestion of a high-carbohydrate meal before retiring on the previous night. Rarely, the disease may occur in association with peroneal muscular atrophies. In the interval between attacks, patients are usually strong, and the potassium content of the serum is normal. In some patients, mild proximal limb weakness persists. In a mild attack, tendon reflexes and electrical reactions of the muscles are diminished in proportion to the degree of weakness. In severe attacks, tendon and cutaneous reflexes are absent and the muscles do not respond to electrical stimulation. Cutaneous sensation is not disturbed. Course Familial HoPP is not accompanied by any impairment of general health. As a rule, the frequency of the paralytic attacks decreases with the passage of years, and they may cease altogether after age 40 or 50. Fatalities are rare, but death may occur from respiratory paralysis. The fixed myopathy, usually mild, may be severe and disabling.

Diagnosis The diagnosis can usually be made without difficulty on the basis of the familial occurrence of transient attacks of weakness. The diagnosis is usually confirmed by finding low potassium and high sodium content in the serum during an attack, or by inducing an attack with an intravenous infusion of glucose (100 g) and regular insulin (20 U). Now, the provocative test can be avoided by DNA testing. However, if a patient is in the hospital during a spontaneous attack, it is important to determine which type of periodic paralysis is to be treated. In sporadic cases, the first attack must be differentiated from other causes of hypokalemia ( Table 126.2). Persistent hypokalemia from any cause may manifest as an acute attack of paralysis or persistent limb weakness with high levels of serum creatine kinase. Sometimes, there are attacks of myoglobinuria.

TABLE 126.2. POTASSIUM AND PARALYSIS: NONINHERITED FORMS

Repeated attacks of HoPP, identical clinically to the familial form, occur in patients with hyperthyroidism. Japanese and Chinese people seem to be especially susceptible to this disorder. The paralytic attacks cease when the thyroid disorder has been successfully treated. Treatment Acute attacks, spontaneous or induced, may be safely and rapidly terminated by ingestion of 20 to 100 mEq of potassium salts. Intravenous administration of potassium is usually avoided because of the hazard of inducing hyperkalemia. The basis of prophylactic therapy is oral administration of the carbonic anhydrase inhibitor acetazolamide (Diamox), 250 to 1,000 mg daily. This regimen prevents attacks in about 90% of patients with HoPP and also improves the interictal weakness attributed to the vacuolar myopathy. The mechanism of action of acetazolamide is uncertain; the beneficial effect may be related to the mild metabolic acidosis it induces. For those not helped by acetazolamide, other effective agents include triamterene (Dyrenium) or spironolactone (Aldactone), which promote retention of potassium. Another carbonic anhydrase inhibitor of value is dichlorphenamide (Daranide). Dietary controls are usually not accepted by patients and are not effective. Treatment of other forms of HoPP depends on the nature of the underlying renal disease, diarrhea, drug ingestion, or thyrotoxicosis. Patients with thyrotoxic periodic paralysis are susceptible to spontaneous or induced attacks during the period of hyperthyroidism. When the patients become euthyroid, spontaneous attacks cease and they are no longer sensitive to infusion of glucose and insulin. Glucose and insulin are useful in the interim between treatment of hyperthyroidism by drugs or radioiodine, before the euthyroid state returns. Repeated attacks can be prevented by either acetazolamide or propranolol.

HYPERKALEMIC PERIODIC PARALYSIS In 1951, Frank Tyler recognized a form of familial periodic paralysis in which attacks were not accompanied by a decrease in the serum potassium content. In 1957, Gamstorp and colleagues drew attention to several other features of these cases that separated them from the usual cases of periodic paralysis. The disease is transmitted by an autosomal-dominant gene with almost complete penetrance. In addition to the absence of hypokalemia in the attacks, the syndrome is characterized by an early age of onset (usually before age 10). The attacks tend to occur in the daytime and are likely to be shorter and less severe than those in HoPP. Myotonia is usually demonstrable by EMG, but abnormalities of muscular relaxation are rarely symptomatic. Myotonic lid lag ( Fig. 126.1) and lingual myotonia may be the sole clinical evidence of the trait. Serum potassium content and urinary excretion of potassium may be increased during an attack, possibly the result of leakage of potassium from muscle. The attacks tend to be precipitated by hunger, rest, or cold or by administration of potassium chloride.

FIG. 126.1. Paramyotonia congenita. Myotonia of muscles of the upper eyelids on looking downward. (Courtesy of Dr. Robert Layzer.)

Attacks may be terminated by administration of calcium gluconate, glucose, and insulin. Acetazolamide, 250 mg to 1 g orally daily, has been effective in reducing the number of attacks or in abolishing them altogether. Other diuretics that promote urinary excretion of potassium are also effective. If acetazolamide therapy fails, thiazides or fludrocortisone acetate (Florinef Acetate) may be beneficial. In addition, beta-adrenergic drugs may be effective prophylactic agents. Epinephrine, Salbutamal, and metaproterenol have been used. They presumably act by increasing the activity of Na+,K+-ATPase. Pathophysiology The pathophysiology of the HyPP has been analyzed by the team of Rudel, Ricker, and Lehmann-Horn (1993); their findings led to the suspicion that a sodium channel protein would be a good candidate gene. First, using microelectrode studies of intercostal muscle, they confirmed that muscle isolated from patients with HyPP is partially depolarized at rest. The abnormal depolarization was blocked by tetrodotoxin, which specifically affects the alpha subunit of the sodium channel. Patch clamp experiments showed faulty inactivation, leading to the conclusion that excessive sodium influx was accompanied by excessive efflux of potassium, thereby raising levels in extracellular fluids. They found that muscle from patients with more paramyotonia than sensitivity to potassium was more sensitive to cold. In contrast, the calcium channel gene for HoPP was found not by physiology but by a genome-wide search. The pathophysiology of HoPP is not clear but may include an indirect effect on a sarcolemmal ATP-sensitive potassium channel.

The challenge now is to determine just how the single amino acid substitutions result in the altered function. Because periodic paralysis and potassium sensitivity are seen in families with paramyotonia, it is important to determine whether disease-specific mutations exist. Alternatively, as in myotonic muscular dystrophy and other autosomal-dominant diseases, there could be pleiotropic expression of the mutation, which is expressed by four abnormalities: paralytic attacks, myotonia, potassium sensitivity, and cold sensitivity. In the same family, one or more of these manifestations may be dominant in different individuals. SUGGESTED READINGS Hypokalemic Periodic Paralysis Comi G, Testa D, Cornelio F, et al. Potassium depletion myopathy: a clinical and morphological study of six cases. Muscle Nerve 1985;8:17–21. Conway MJ, Seibel JA, Eaton RP. Thyrotoxicosis and periodic paralysis: improvement with beta blockade. Ann Intern Med 1974;81:332–336. Engel AG, Lambert EH, Rosevear JW, Tauxe WN. Clinical and electromyographic studies in a patient with primary hypokalemic periodic paralysis. Am J Med 1965;38:626–640. Fontain B, Trofatter J, Rouleau GA, et al. Different gene loci for hyperkalemic and hypokalemic periodic paralysis. Neuromuscul Disord 1991;1:235–238. Griggs RC, Engel WK, Resnik JS. Acetazolamide treatment of hypokalemic periodic paralysis: prevention of attacks and improvement of persistent weakness. Ann Intern Med 1970;73:39–48. Holtzapple GE. Periodic paralysis. JAMA 1905;45:1224–1231. Johnsen T. Familial periodic paralysis with hypokalemia. Dan Med Bull 1981;28:1–27. Knochel JP. Neuromuscular manifestations of electrolyte disorders. Am J Med 1982;72:525–535. Layzer RB, Goldfield E. Periodic paralysis caused by abuse of thyroid hormone. Neurology 1974;24:949–952. Links TP, Zwarts MJ, Oosterhuis HJGH. Improvement of muscle strength in familial hypokalemic periodic paralysis with acetazolamide. J Neurol Neurosurg Psychiatry 1988;51:1142–1145. Martin AR, Levinson SR. Contribution of the Na,K pump to membrane potential in familial periodic paralysis. Muscle Nerve 1985;8:359–362. Marx A, Ruppersberg JP, Pietrzyk C, Rudel R. Thyrotoxic periodic paralysis and the sodium-potassium pump. Muscle Nerve 1989;12:810–815. Minaker KL, Menelly GS, Flier JS, Rowe JW. Insulin-mediated hypokalemia and paralysis in familial hypokalemic periodic paralysis. Am J Med 1988;84:1001–1006. Morrill JA, Brown RH Jr, Cannon SC. Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by hypokalemic periodic paralysis mutation R528H. J Neurosci 1998;18:10320–10334. Roadma JS, Reidenberg MM. Symptomatic hypokalemia resulting from surreptitious diuretic ingestion. JAMA 1981;246:1687–1689. Vern BA, Danon MJ, Hanlon K. Hypokalemic periodic paralysis with unusual responses to acetazolamide and sympathomimetics. J Neurol Sci 1987;81:159–172. Vroom FQ, Jarrell MA, Maren TH. Acetazolamide treatment of hypokalemic periodic paralysis: probable mechanisms of action. Arch Neurol 1975;32:385–392. Yazaki K, Kuribayashi T, Yamamura Y, et al. Hypokalemic myopathy associated with 17a-hydroxylase deficiency: a case report. Neurology 1982;32:94–97. Hyperkalemic Periodic Paralysis Barchi RL. Phenotype and genotype in the myotonic disorders. Muscle Nerve 1998;21:1119–1120. Bendheim PE, Reale EO, Berg BO. Beta-adrenergic treatment of hyperkalemic periodic paralysis. Neurology 1985;35:746–749. Benstead TJ, Camfield PR, Ding DB. Treatment of paramyotonia congenita with acetazolamide. Can J Neurol Sci 1987;14:156–158. Borg K, Hovmoller M, Larsson L, Edstrom L. Paramyotonia congenita (Eulenberg): clinical, neurophysiological and muscle biopsy observations in a Swedish family. Acta Neurol Scand 1993;87:37–42. Bradley WG. Adynamia episodica hereditaria: clinical, pathological, and electrophysiological studies in an affected family. Brain 1969;92:345–378. Christopher GA, Johnson JP, Palevsky PM, Greenberg A. Hyperkalemia in hospitalized patients. Arch Intern Med 1998;158:917–924. De Silva S, Kuncl RW, Griffin JW, et al. Paramyotonia congenita or hyperkalemic periodic paralysis? Clinical and electrophysiological features of each entity in one family. 1990;13:21–26.

Muscle Nerve

Eulenberg A. Über einer familiäre, durch 6 Generationen verfolgbare Form congenitaler Paramyotonie. Neurol Centralbl 1886;5:265–272. Evers S, Engelien A, Karsch V, Hund M. Secondary hyperkalemic paralysis. J Neurol Neurosurg Psychiatry 1998;64:249–252. Gamstorp I. Adynamia episodica hereditaria. Acta Pediatr (Uppsala) 1956;45(Suppl 108):1–126. Hanna MF, Stewart J, Schapira AH, Wood NW, Morgan-Hughes JA, Murray NM. Salbutamol treatment in a patient with hyperkalaemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A). J Neurol Neurosurg Psychiatry 1998;65:248–250. Heine R, Pika U, Lehmann-Horn F. A novel SCN4A mutation causing myotonia aggravated by cold and potassium. Hum Mol Genet 1991;2:1349–1353. Hoffman EH, Wang J. Duchenne-Becker muscular dystrophy and the nondystrophic myotonias. Arch Neurol 1993;50:1227–1237. Layzer RB, Lovelace RE, Rowland LP. Hyperkalemic periodic paralysis. Arch Neurol 1967;16:455–472. Lisak RP, Lebeau J, Tucker SH, Rowland LP. Hyperkalemic periodic paralysis and cardiac arrhythmia. Neurology 1972;22:810–815. Magee KR. A study of paramyotonia congenita. Arch Neurol 1963;8:461–470. McArdle B. Adynamia episodica hereditaria and its treatment. Brain 1962;85:121–148. McClatchey AI, Trofatter J, McKenna-Yasek D, et al. Dinucleotide repeat polymorphisms at the SCN4A locus suggest allelic heterogeneity of hyperkalemic periodic paralysis and paramyotonia congenita. Am J Hum Genet 1992;50:896–901. Moxley RT, Ricker KM, Kingston WJ, Bohlen R. Potassium uptake in muscle during paramyotonic weakness. Neurology 1989;39:952–955. Ponce SP, Jennings AE, Madias NE, Harrington JT. Drug-induced hyperkalemia. Medicine 1985;64:357–370. Ptacek LJ, Johnson KJ, Griggs RC. Genetics and physiology of the myotonic muscle disorders. N Engl J Med 1993;328:482–489. Ptacek LJ, Timmer JS, Agnew WS, et al. Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium channel locus. Am J Hum Genet 1991;49:851–854. Rich EC. A unique form of motor paralysis due to cold. Med News 1894;65:210–213. Ricker K, Bohlen R, Rohkamm R. Different effectiveness of tocainide and hydrochlorothiazide in paramyotonia congenita with hyperkalemic episodic paralysis. Neurology 1983;33:1615–1618. Riggs JE, Griggs RC, Moxley RT. Acetazolamide-induced weakness in paramyotonia congenita. Ann Intern Med 1977;86:169–173. Rudel R, Ricker K, Lehmann-Horn F. Genotype-phenotype correlations in human skeletal muscle sodium channel diseases. Arch Neurol 1993;50:1241–1248.

Sansone V, Griggs RC, Meola G, et al. Andersen's syndrome: a distinct periodic paralysis. Ann Neurol 1997;42:305–312. Streib EW. Hypokalemic paralysis in two patients with paramyotonia congenita and known hyperkalemic/exercise-induced weakness. Muscle Nerve 1989;12:936–937. Tricarico D, Servidei S, Tonali P, Jurkat-Rott K, Camerino DC. Impairment of skeletal muscle adenosine triphosphate-sensitive K+ channels in patients with hypokalemic periodic paralysis. Invest 1999;103:675–682.

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CHAPTER 127. CONGENITAL DISORDERS OF MUSCLE MERRITT’S NEUROLOGY

CHAPTER 127. CONGENITAL DISORDERS OF MUSCLE LEWIS P. ROWLAND Myotonia Congenita Chondrodystrophic Myotonia (Schwartz-Jampel Syndrome) Congenital Myopathies Suggested Readings

Several different categories of muscle disease are evident from birth; most of them are familial in mendelian patterns of inheritance, but some are characteristically sporadic. The cause of such cases is uncertain. Terminology is currently unsatisfactory because there is no clear distinction between congenital muscular dystrophies (see Chapter 125) and the congenital myopathies. The diseases in either group may be evident at birth or become evident because motor milestones are delayed, and then remain static or be steadily progressive. The conditions called congenital myopathies here are mostly static or only slowly progressive. One group is characterized by a disorder of contractility with little or no weakness (myotonia congenita); another combines myotonia with severe dysmorphic features (Schwartz-Jampel syndrome). Others are defined by structurally specific histologic characteristics (congenital myopathies).

MYOTONIA CONGENITA Myotonia congenita (MIM 160800), often called Thomsen disease, was described by a Danish physician in 1876. He had a close view of the condition, which affected his own family in an autosomal-dominant pattern. Symptoms are caused only by myotonia or the consequences thereof. The disease differs from myotonic muscular dystrophy in that there is no muscle weakness or wasting and no systemic disorder is present (i.e., no cataracts, electrocardiogram abnormalities, or endocrinopathy). The myotonia tends to be more severe than that in myotonic MD, where myotonia is rarely sufficiently bothersome to warrant symptomatic treatment. In myotonia congenita, however, the myotonia may be a functional handicap and more often leads to treatment. Presumably as a consequence of involuntary isometric contraction, the muscles tend to hypertrophy and give the person an athletic appearance. The myotonia is also more widespread, and in addition to the characteristic difficulty in relaxing the grip, the myotonia may affect the orbicularis oculi (difficulty opening the eyes after a forceful closure), leg muscles (difficulty in starting to walk or run), or even muscles of the pharynx (difficulty in swallowing). Respiration is spared. The myotonia is painless. Patients usually adapt well to the condition and live a normal life span. The myotonia shows the usual physiologic characteristics of other forms of myotonia, including myotonic dystrophy and hyperkalemic periodic paralysis (HyPP). A repetitive discharge of muscle fiber potentials occurs after a forceful contraction, and the myotonia originates in the muscle surface membrane, as demonstrated by experiments in which percussion myotonia could still be evoked after the muscle had been isolated from the central and peripheral nervous systems by curarization. Characteristically, the myotonia is worse on the initiation of exercise and is ameliorated by gradually increasing the vigor of movements by “warming up.” Physiologic studies in a herd of myotonic goats implied an abnormality of the chloride channel (in contrast to the dysfunctional sodium channel in HyPP). As a result, chloride conductance is decreased. The chloride channel was then found to be affected in symptomatic humans, and the gene for both channel and disease was mapped to chromosome 7q35. In almost all cases, inheritance is autosomal-dominant, but a recessive pattern (MIM 255700) has been identified in a few families in which mild weakness improves with exercise. Remarkably, both autosomal dominant and recessive forms seem to be linked to the same chloride channel gene, CLCN1; the gene product is ClC-1. Other variants, such as painful myotonia or fluctuating myotonia, have been described clinically, but the relationship of these conditions to myotonia congenita awaits clarification by genetic studies. In contrast to the chloride channel myotonias, the sodium channel diseases are often associated with periodic paralysis and are grouped as nondystrophic myotonias (see Chapter 126). Myotonia congenita can be relieved by phenytoin sodium (Dilantin), 300 to 400 mg daily for serum level of 10 to 20 mg/mL, or quinine sulfate, 200 to 1,200 mg daily. Acetazolamide (Diamox) is sometimes effective. Hexiletine, an antiarrhythmic agent, is also helpful. Procainamide hydrochloride ameliorates myotonia but may induce systemic lupus erythematosus and is therefore avoided. The mode of action of these drugs is not clear, except that they seem to stabilize muscle membranes.

CHONDRODYSTROPHIC MYOTONIA (SCHWARTZ-JAMPEL SYNDROME) Chondrodystrophic myotonia (Schwartz-Jampel syndrome) is an autosomal-recessive syndrome that is recognizable at birth because of the facial abnormalities: narrow palpebral fissures (blepharophimosis), pinched nose, and micrognathia. Other skeletal anomalies include short neck, flexion contractures of the limbs, and kyphosis. Limb muscles are clinically stiff and often hypertrophied. On EMG, the myotonia is often continuous, with little waxing and waning. Like other forms of myotonia, the chondrodystrophic form persists after curarization. The myotonia can be treated, but the skeletal abnormalities are more disabling. The condition must be differentiated from Isaacs syndrome (see Chapter 129). Three forms of Schwartz-Jampel syndrome are recognized. The most common is autosomal-recessive and has been mapped to chromosome 1p34-p36.1; symptoms begin in late infancy or childhood. A second, more severe type is the neonatal variety, which may be fatal and does not map to chromosome 1. The third type is autosomal-dominant and unmapped.

CONGENITAL MYOPATHIES In the 1960s, the application of histochemical stains to muscle biopsy specimens led to the recognition of unusual structures in children with mild myopathies. The myopathies are determined by changes in the EMG and muscle biopsy, with only slight increase in serum creatine kinase. The syndromes are not usually evident in the first 2 years of life, except for delayed walking. The persistent and relatively static weakness, however, suggests that the myopathy is congenital. Sometimes, however, symptoms do appear in the neonatal period, especially difficulty in sucking. They may cause the floppy infant syndrome (see Chapter 75). Conversely, there are later-onset forms, including some that appear first in adults. Whatever the clinical course, the disorders are named after the dominant structural abnormality (Table 127.1).

TABLE 127.1. CONGENITAL MUSCULAR DYSTROPHIES AND CONGENITAL MYOPATHIES

In central core disease (MIM 117000), an amorphous area in the center of the fiber stains blue with the Gomori trichrome stain and contrasts with the red-staining peripheral fibrils. The cores are devoid of enzymatic activity histochemically, and under the electron microscope, the area lacks mitochondria. In nemaline disease (from the Greek word for thread) (MIM 161800), small rods near the sarcolemma stain bright red with the trichrome stain and seem to originate from Z-band material.

In myotubular or centronuclear myopathy (MIM 310400), the nuclei are situated centrally instead of in the normal sarcolemmal position, and are surrounded by a pale halo. Cytoplasmic body myopathy is characterized by accumulations of desmin, and some authorities suggest a category of desmin-related myopathies. Fiber-type disproportion, fingerprint bodies, tubular aggregates, and numerous other anomalies have been seen in different families, and variants of the original anomalies include minicores and multicores. For most of these myopathies, the origin of the structure is not known. In some nonspecific congenital myopathies, myopathic changes are found with no specific structure. A few clinical clues might predict findings on muscle biopsy. In some patients, the usual static or slow progression of the disease with normal life expectancy gives way to more serious weakness or even premature death. Skeletal abnormalities are seen in centronuclear or nemaline myopathies or with fiber-type disproportion; a long, lean face, prognathism, kyphoscoliosis, pedal deformities, and congenital dislocation of the hip are characteristic. Centronuclear myopathy seems to be associated more often than the other congenital disorders with progressive ophthalmoplegia. Nemaline myopathy may be the most common of the group to cause respiratory problems in infancy and throughout life. Arthrogryposis congenita multiplex is the name given to a condition characterized by flexion contracture of the limbs; as determined by EMG and muscle biopsy, the syndrome is sometimes neurogenic and sometimes a congenital myopathy of the nonspecific type. In the Prader-Willi syndrome (MIM 176270), the findings include hypotonia, neonatal dysphagia, tented upper lip, depressed myotatic reflexes, and cryptorchidism; these manifestations are prominent in infancy, but there is no permanent weakness. The syndrome is later recognized by mental retardation, obesity, short stature, skeletal anomalies, and childhood diabetes. Progress is being made in the molecular genetics of these disorders. The following have been mapped: myotubular myopathy, Xq28; central core disease, 19q13.1; and nemaline myopathy, 1q21-q23 and 2q22. The Prader-Willi syndrome has been linked to deletions at 15q11-q13 and is a disease in which imprinting is involved; the autosomal-dominant condition results if the paternal chromosome is affected. If the maternal chromosome is affected, a different clinical disorder called the Angelman syndrome (MIM 234400) results; it is also manifested by mental retardation, but the other Prader-Willi manifestations are lacking. Instead, characteristics are microcephaly, lack of speech, and inappropriate laughter, leading to the appellation of the “happy puppet syndrome.” Although chromosome map positions have been established, only four gene products have been identified. In X-linked myotubular myopathy, the MTM1 gene encodes myotubularin, which is a protein tyrosine phosphatase. The gene product for autosomal recessive, chromosome-1q21-linked nemaline disease is slow tropomyosin. The affected protein in autosomal dominant nemaline disease is alpha-tropomyosin in some families, but others lack this mutation. The fourth known gene product is that of central core disease, which maps to the ryanodine receptor at 19q13.1. This is also the map position noted for malignant hyperthermia (MIM 145600). Patients with central core disease are at increased risk for malignant hyperthermia, and the two conditions may be found in different people in the same family. The diagnosis of these conditions rests on the muscle pathology. Other congenital syndromes include myasthenia gravis, congenital myotonic dystrophy, and spinal muscular atrophy. In addition, the typical morphologic structures are sometimes found in adult-onset myopathies or other conditions. For instance, a late-onset nemaline disease can cause a severe myopathy after age 50 years. Treatment of the congenital myopathies is symptomatic. SUGGESTED READINGS Myotonia Congenita Becker PE. Myotonia congenita and syndromes associated with myotonia: clinical-genetic studies of the nondystrophic myotonias . Stuttgart: Thieme, 1977. Deymeer F, Cakirkaya S, Serdaroglu P, et al. Transient weakness and compound muscle action potential decrement in recessive myotonia congenita. Muscle Nerve 1998;21:1334–1337. Koch MC, Steinmeyer K, Lorenz C, et al. Skeletal muscle chloride channel in dominant and recessive human myotonia. Science 1992;257:797–800. Kubisch C, Schmidt-Rose T, Fontaine B, Bretag AH, Jentsch TJ. ClC-1 chloride channel mutations in myotonia congenita: variable penetrance of mutations shifting the voltage dependence. Hum Mol Genet 1998;7:1753–1760. Plassart-Schliess E, Garvais A, Eymard B, et al. Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with various modes of inheritance including incomplete dominance and penetrance. Neurology 1998;50:1176–1179. Trudell RG, Kaiser KK, Griggs RC. Acetazolamide-responsive myotonia congenita. Neurology 1987;37:488–491. Wagner S, Deymeer F, Kurz LL, et al. The dominant chloride channel mutant G200R causing fluctuating myotonia: clinical findings, electrophysiology, and channel pathology. Muscle Nerve 1998;21:1122–1128. Chondrodystrophic Myotonia (Schwartz-Jampel Syndrome) Brown KA, Al-Gazali LI, Moynihan M, Lench NJ, Markham AF, Mueller RF. Genetic heterogeneity in Schwartz-Jampel syndrome: two families with neonatal Schwartz-Jampel syndrome do not map to chromosome 1p34-p36.1. J Med Genet 1997;34:685–687. Farrell SA, Davidson RG, Thorp P. Neonatal manifestations of Schwartz-Jampel syndrome. Am J Med Genet 1987;27:799–805. Nicole S, Ben Hamida C, Beighton P, et al. Localization of the Schwartz-Jampel syndrome locus to chromosome 1p34-36.1 by homozygosity mapping. Hum Mol Genet 1995;4:1633–1636. Schwartz O, Jampel RS. Congenital blepharophimosis associated with a unique generalized myopathy. Arch Ophthalmol 1962;68:52–57. Spaans F, Theunissn P, Reekerss AD, et al. Schwartz-Jampel syndrome. I. Clinical, electromyographic, and histologic studies. Muscle Nerve 1990;13:516–527. Taylor RG, Layzer RB, Davis HS, Fowler WM. Continuous muscle fiber activity in the Schwartz-Jampel syndrome. Electroencepahlogr Clin Neurophysiol 1972;33:497–502. Congenital Myopathies Baeta AM, Figarella-Branger D, Bille-Ture F, Lepidi H, Pellissier JF. Familial desmin myopathies and cytoplasmic body myopathies. Acta Neuropathol 1996;92:499–510. De Angelis MS, Palmucci L, Leone M, Doriguzzi C. Centronucleolar myopathy: clinical, morphological, and genetics characters: a review of 288 cases. J Neurol Sci 1991;103:2–9. Glenn CC, Nicholls RD, Robinson WP, et al. Modification of 15q11-q13 DNA methylation imprints in unique Angelman and Prader-Willi patients. Hum Mol Genet 1993;2:1377–1382. Goebel HH, Anderson JR. Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies). 56th European Neuromuscular Centre (ENMC) sponsored international workshop, December 12–14, 1997, Naarden, The Netherlands. Neuromuscul Disord 1999;9:50–57. Goebel HH, Lenard HG. Congenital myopathies. In: Vinken PJ, Bruyn GW, Klawans HL, Rowland LP, DiMauro S, eds. Myopathies. Handbook of clinical neurology, rev ser, vol 62(18). New York: Elsevier Science, 1992:331–368. Gordon N. Arthrogryposis multplex congenita. Brain Dev 1998;20:507–511. Griggs RC, Mendell JR, Miller RG. Evaluation and treatment of myopathies. Philadelphia: FA Davis Co, 1995. Gyure KA, Prayson RA, Estes ML. Adult-onset nemaline myopathy: case report and review of the literature. Arch Pathol Lab Med 1997;121:1210–1213. Howard RS, Wiles CM, Hirsch NP, Spencer GT. Respiratory involvement in primary muscle disorders: assessment and management. Q J Med 1993;86:175–189. Laing NG, Wilton SD, Akkari PA, et al. A mutation of the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nat Genet 1995;9:75–79. Erratum: Nat Genet 1995;10:249. Romero NB, Nivoche Y, Lunardi J, et al. Malignant hyperthermia and central core disease: analysis of two families with heterogeneous clinical expression. Neuromuscul Disord 1993;3:547–551. Shuaib A, Martin JME, Mitchell LB, Brownell AKW. Multicore myopathy: not always a benign entity. Can J Neurol Sci 1988;15:10–14.

Shuaib A, Paasuke RT, Brownell AKW. Central core disease: clinical features in 13 patients. Medicine 1987;66:389–396. Shy GM, Engel WK, Somers JE, Wanko T. Nemaline myopathy: a new congenital myopathy. Brain 1963;86:793–810. Spargo E, Doshi B, Whitwell HL. Fatal myopathy with cytoplasmic inclusions. Neuropathol Appl Neurobiol 1988;14:516. Spiro AJ, Shy GM, Gonatas NK. Myotubular myopathy. Arch Neurol 1966;14:1–14. Tanner SM, Schneider V, Thomas NST. Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated X-linked myotubular myopathy patients. Neuromuscul Disord 1999;9:41–49. Tein I, Haslam RHA, Rhead WJ, Bennett MJ, Becker LE , Vockley J. Short-chain acyl-coA dehydrogenase deficiency: a cause of ophthalmoplegia and multicore myopathy. Neurology 1999;52:366–372. Tome FMS, Guicheney P, Fardeau M. Congenital muscular dystrophies. In Emery AEH, ed. Neuromuscular disorders: clinical and molecular genetics. New York: John Wiley and Sons, 1998:21–58. Vajsar J, Becker LE, Freedom RM, Murphy EG. Familial desminopathy: myopathy with accumulation of desmin-type intermediate filaments. J Neurol Neurosurg Psychiatry 1993;56:644–648. Wallgren-Petterson C. Genetics of the nemaline myopathies and the myotubular myopathies. Neuromuscul Disord 1998;8:401–404.

CHAPTER 128. MYOGLOBINURIA MERRITT’S NEUROLOGY

CHAPTER 128. MYOGLOBINURIA LEWIS P. ROWLAND Suggested Readings

When necrosis of muscle is acute, myoglobin escapes into the blood and then into the urine. In the past, the term myoglobinuria was reserved for grossly pigmented urine, but modern techniques can detect amounts of this protein so minute that discoloration may not be evident. (Determination of serum myoglobin content by radioimmunoassay has the same diagnostic significance as measurement of serum creatine kinase [CK] activity.) The clinically important syndromes, however, are associated with gross pigmenturia. Sometimes, the disorder can be recognized without direct demonstration of myoglobin in the urine, for instance, in cases of acute renal failure with very high levels of serum CK activity. Inexplicably, rhabdomyolysis has become the official (Index Medicus) term for these syndromes, although it is really a synonym for myoglobinuria. No classification of the myoglobinurias is completely satisfactory, but Table 128.1 lists the most important causes. Many cases of inherited recurrent myoglobinuria are due to unidentified abnormalities. In six forms, however, the genetic defect has been recognized: lack of phosphorylase (McArdle), phosphofructokinase (Tarui), carnitine palmityltransferase (CPT) (DiMauro-Bank), phosphoglyceraldehyde kinase (DiMauro), phosphoglycerate mutase (DiMauro), and lactate dehydrogenase (Kanno). CPT is important in lipid metabolism; the others are involved in glycogenolysis or glycolysis, and are reviewed in Chapter 84. In all these conditions, there is a disorder in the metabolism of a fuel necessary for muscular work; in all six, exercise is limited by painful cramps after exertion, and myoglobinuria occurs after especially strenuous activity. There may be a subtle difference in the kinds of activity that provoke attacks, which are more prolonged in CPT deficiency than in the glycogen disorders. The glycogen disorders can be identified by a simple clinical test: A cramp is induced by ischemic exercise of forearm muscles for less than 1 minute, and venous lactate fails to rise as it does in normal individuals or those with CPT deficiency. Specific diagnosis requires histochemical or biochemical analysis of muscle homogenates. Five of the conditions are inherited in autosomal-recessive pattern; phosphoglycerate kinase deficiency is X-linked.

TABLE 128.1. CLASSIFICATION OF HUMAN MYOGLOBINURIA

The relative frequency of the causes of recurrent myoglobinuria differed in two studies. In the United States, samples were sent to an active referral laboratory, and almost 50% had an identifiable cause; phosphorylase, phosphorylase kinase, phosphofructokinase, CPT, and myoadenylate deaminase deficiencies accounted for almost all in the report of Tonin and colleagues (1990). In Finland, however, only 23% of 22 patients with recurrent myoglobinuria had an identifiable cause, and none had CPT deficiency or myoadenylate deaminase deficiency. Lofberg and associates (1998) gave two explanations of recurrent myoglobinuria without an enzyme defect: disappearance of some genes from the genetically isolated population in Finland and an increase in recreational distance running or body building. Another important form of inherited myoglobinuria occurs in malignant hyperthermia (MIM 180901, 145600), which is attributed to succinylcholine, halothane, or both together. The characteristic syndrome includes widespread muscular rigidity, a rapid rise in body temperature, myoglobinuria, arrhythmia, and metabolic acidosis. In some cases, muscular rigidity is lacking. The pathogenesis is uncertain, but the offending drugs may interact with a defective protein in the muscle sarcoplasmic reticulum that fails to bind calcium. The muscle, flooded with calcium, shortens to create the stiff muscles and attendant muscle necrosis. The syndrome is often familial in an autosomal dominant pattern, but many cases are sporadic. In some families, the gene mapped to chromosome 19q12-13.2, the site of the gene for the ryanodine receptor, which is the calcium release channel and also the locus for central core disease, a congenital myopathy that seems to increase the risk of malignant hyperthermia. A similar syndrome in pigs maps to the same gene product. However, there is evidence of locus heterogeneity because only 50% of all families map to that locus. Another calcium-binding protein of the sarcoplasmic reticulum is the dihydropyridine receptor, but the disease does not map to the locus for that candidate gene product. Yet another sign of heterogeneity is the occurrence of the syndrome in children with Duchenne muscular dystrophy or myotonia congenita. A closely related disorder is the neuroleptic malignant syndrome, which is similar in clinical manifestations, although the offending drugs are different and the disorder has not yet appeared in a family with malignant hyperthermia. Most attacks of acquired myoglobinuria occur in nonathletic individuals who are subjected to extremely vigorous exercise, a hazard faced primarily by military recruits. These individuals are otherwise normal. Even trained runners may experience myoglobinuria in marathon races. If muscle is compressed, as occurs in the crush syndrome of individuals pinned by fallen timber after bombing raids, or after prolonged coma in one position, myoglobinuria may ensue. Ischemia after occlusion of large arteries may also lead to necrosis of large amounts of muscle. Depression of muscle metabolism, especially after drug ingestion, may also be responsible in some cases. Hypokalemia from any cause may predispose to myoglobinuria, but especially after chronic licorice ingestion or abuse of thiazide diuretics. Alcoholics seem especially prone to acute attacks of myoglobinuria, which may punctuate or initiate a syndrome of chronic limb weakness (alcoholic myopathy). In children, as in adults, the attacks may be precipitated by exercise (often with an identifiable enzymatic defect); in contrast to adults, however, myoglobinuria in children seems more often associated with a nonspecific viral infection and fever. Whatever the cause, the clinical syndrome is similar: widespread myalgia, weakness, malaise, renal pain, and fever. Pigmenturia usually ceases within a few days, but the weakness may persist for weeks, and high concentrations of serum enzymes may not return to normal for even longer. The main hazard of the syndrome is heme-induced nephropathy with anuria, azotemia, and hyperkalemia. Hypercalcemia occurs in a few patients after anuria. Occasionally, respiratory muscles are symptomatically weakened. Treatment of an acute episode of myoglobinuria is directed primarily toward the kidneys. Promotion of diuresis with mannitol seems desirable whenever there is oliguria. Dialysis and measures to combat hyperkalemia may be necessary. In recurrent cases due to defects of glycolytic enzymes or to unknown cause, various therapeutic regimens have been tried, but patients usually learn the limits of exercise tolerance. The treatment of malignant hyperthermia is unsatisfactory because the rigidity is not abolished by curare. Intravenous infusions of dantrolene sodium (Dantrium) are given because this drug inhibits the release of calcium from the sarcoplasmic reticulum, relaxing the hypercontracted muscle. The average dose in successfully treated patients is 2.5 mg/kg body weight. Once a person has been identified with malignant hyperthermia, the clinician must determine whether other family members are at risk. With the mapping of the gene to chromosome 19, it was hoped that a DNA test would be available. Locus heterogeneity, however, means that other, still unidentified genes are sometimes responsible. An alternative test to identify susceptibility is the caffeine contracture test, during which bundles of fibers from a muscle biopsy are exposed to the drug and tension is measured. Individuals are deemed susceptible if the response is significantly greater than normal. Unfortunately, the test is not completely reliable. Nevertheless, the condition is now so well known to anesthesiologists that offending volatile and neuromuscular blocking agents are avoided in people who may be at risk, and the frequency of attacks has fallen.

For the malignant neuropletptic syndrome, bromocriptine mesylate (Parlodel) and carbamazepine (Tegretol) have reportedly been beneficial (see Chapter 116). SUGGESTED READINGS Ball SP, Johnson KJ. The genetics of malignant hyperthermia. J Med Genet 1993;30:89–93. Bank WJ, DiMauro S, Bonilla E, et al. A disorder of lipid metabolism and myoglobinuria: absence of carnitine palmityl transferase. N Engl J Med 1975;292:443–449. Bristow MF, Kohen D. How “malignant” is the neuroleptic malignant syndrome? BMJ 1993;307:1223–1224. Britt BA, Kalow W. Malignant hyperthermia: a statistical review. Can Anaesth Soc J 1970;17:293–315. Corpier CL, Jones PH, Suki WN, et al. Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant patients. JAMA 1988;260:239–241. Denborough M. Malignant hypethermia. Lancet 1998;352:1131–1136. DiMauro S, Dalakas M, Miranda AF. Phosphoglycerate kinase deficiency: another cause of recurrent myoglobinuria. Ann Neurol 1983;13:11–19. DiMauro S, DiMauro PMM. Muscle carnitine palmityl transferase deficiency and myoglobinuria. Science 1973;182:929–931. Duthie DJR. Heat-related illness. Lancet 1998;352:1329–1330. Ebadi M, Pfeiffer RF, Murrin LC. Pathogenesis and treatment of neuroleptic malignant syndrome. Gen Pharmacol 1990;21:367–386. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine 1982;61:141–152. Hogan K. The anesthetic myopathies and malignant hyperthermias. Curr Opin Neurol 1998;11:469–476. Knochel JP. Rhabdomyolysis and myoglobinuria. Annu Rev Med 1982;33:435–443. Kolb ME, Horne ML, Matz R. Dantrolene in human malignant hyperthermia: a multicenter study. Anaesthesiology 1982;56:254–262. Lofberg M, Jankala H, Paetau A, Harkonen M, Somer H. Metabolic causes of recurrent rhabdomyolysis. Acta Neurol Scand 1998;98:268–275. Manning BM, Quane KA, Ording H, et al. Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. Am J Hum Genet 1998;62:599–609. Melamed I, Romen Y, Keren G, et al. March myoglobinuria: a hazard to renal function. Arch Intern Med 1982;142:1277–1279. Nelson TE, Butler IJ. Malignant hyperthermia: skeletal muscle defects predisposing to labile Ca 2+ regulation? J Child Neurol 1992;7:329–331. Penn AS, Rowland LP, Fraser DW. Drugs, coma, and myoglobinuria. Arch Neurol 1972;26:336–343. Perkoff GT. Alcoholic myopathy. Annu Rev Med 1971;22:125–132. Quane KA, Healy JMS, Keating KE, et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet 1993;5:51–55. Romero NB, Nivoche Y, Lunardi J, et al. Malignant hyperthermia and central core disease: analysis of two families with heterogeneous clinical expression. Neuromuscul Disord 1993;3:547–551. Rowland LP. Myoglobinuria. Can J Neurol Sci 1984;11:1–13. Tein I, DiMauro S, Rowland LP. Myoglobinuria. In: Vinken PJ, Bruyn GW, Klawans HL, Rowland LP, DiMauro S, eds. Myopathies. Handbook of clinical neurology, rev ser, vol 62(18). New York: Elsevier Science, 1992:479–526. Tonin P, Lewis P, Servidei S, DiMauro S. Metabolic causes of myoglobinuria. Ann Neurol 1990;27:181–185. Ueda M, Hamamoto M, Nagayama H, et al. Susceptibility to neuroleptic malignant syndrome in Parkinson's disease. Neurology 1999;52:777–781. Wedel DJ. Malignant hyperthermia and neuromuscular disease. Neuromuscul Disord 1993;3:157–164. Yaqub B, Al Deeb S. Heat strokes: aetiopathogenesis, neurological characteristics, treatment and outcome. J Neurol Sci 1998;156:144–151.

CHAPTER 129. MUSCLE CRAMPS AND STIFFNESS MERRITT’S NEUROLOGY

CHAPTER 129. MUSCLE CRAMPS AND STIFFNESS ROBERT B. LAYZER AND LEWIS P. ROWLAND Ordinary Muscle Cramps Neuromyotonia (Isaacs Syndrome) Tetany Stiff-Man Syndrome (Moersch-Woltman Syndrome) Suggested Readings

The term muscle stiffness implies a state of continuous muscle contraction at rest; cramps or spasms are transient, involuntary contractions of a muscle or group of muscles. Table 129.1 lists some of the many disorders that cause muscle stiffness or cramps.

TABLE 129.1. MOTOR UNIT DISORDERS CAUSING CRAMPS AND STIFFNESS

ORDINARY MUSCLE CRAMPS The common muscle cramp is a sudden, forceful, often painful muscle contraction that lasts from a few seconds to several minutes. Cramps are provoked by a trivial movement or by contracting a shortened muscle. They may occur during vigorous exercise but are more likely to occur after exercise ceases. Unusually frequent cramps tend to accompany pregnancy, hypothyroidism, uremia, profuse sweating or diarrhea, hemodialysis, and lower motor neuron disorders, especially anterior horn cell diseases. Benign fasciculations or myokymia may be associated with frequent muscle cramps in apparently healthy people. Nocturnal cramps typically cause forceful flexion of the ankle and toes, but cramps can affect almost any voluntary muscle. A cramp often starts with fasciculations, after which the muscle becomes intermittently hard and knotlike as the involuntary contraction waxes and wanes, passing from one part of the muscle to another. Electromyography (EMG) shows brief, periodic bursts of motor unit potentials discharging at a frequency of 200 to 300 Hz, appearing irregularly and intermingling with similar discharges from adjacent motor units. Several foci within the same muscle may discharge independently. This electrical activity clearly arises within the lower motor neuron; whether it occurs in the soma, in the peripheral nerve, or in the intramuscular nerve terminals is still debated. The chemical mechanisms are not understood. Stretching the affected muscle usually terminates a cramp. Information about prophylactic therapy is largely anecdotal, and no single agent appears to be uniformly effective. For nocturnal leg cramps, a bedtime dose of quinine, phenytoin sodium (Dilantin), carbamazepine (Tegretol), or diazepam may be used. The beneficial effects of quinine have been demonstrated by controlled trials. Serious adverse effects are uncommon; tinnitus is relieved by interrupting treatment. The conventional dosage is 300 or 600 mg at bedtime. Frequent daytime cramps sometimes respond to maintenance therapy with carbamazepine or phenytoin. Most people have cramps at some time, but a few people have inordinately frequent cramps, often accompanied by fasciculations. The syndrome of benign fasciculation with cramps is disproportionately more frequent among physicians and other medical workers because they are more likely to know the ominous implications of fasciculations for the diagnosis of motor neuron disease. In fact, however, motor neuron disease almost never starts with fasciculations alone. If neither weakness nor wasting exists, motor neuron disease is essentially excluded. The syndrome of benign fasciculation has been reported many times with variations on the name. Because the syndrome and the physiologic analysis were completely described by Denny-Brown and Foley, a reasonable eponym is the Denny-Brown, Foley syndrome. True cramps must be distinguished from cramplike muscle pain unaccompanied by spasm. The cramps of McArdle disease occur only during intense or ischemic exercise. Because no electrical activity is evident in the EMG during the painful shortening of muscle affected by McArdle disease, the term contracture is used. The origin of the contracture is not known; depletion of adenosine triphosphate has long been suspected (because of the block of glycogen metabolism) but has not been proved, even by magnetic resonance spectroscopy. Mild dystrophinopathies, with little or no clinical weakness, may be manifested by exertional muscle pain and even myoglobinuria. These symptoms have been referred to as muscle cramps, but actual muscle spasm has not been described in such cases; the pain may simply be a measure of muscle injury. Myalgia and cramps are believed to be especially common in myoadenylate deaminase deficiency (MIM 102770), but that state is common in asymptomatic people (found in 1% to 3% of all muscle biopsies). Therefore, the association is difficult to confirm. Moreover, in affected families, a poor correlation exists between the muscle enzyme deficiency and clinical symptoms. An autosomal-dominant cramp syndrome is seen without known biochemical abnormality (MIM 158400).

NEUROMYOTONIA (ISAACS SYNDROME) Isaacs first described this disorder as a state of “continuous muscle fiber activity.” The invariable clinical manifestation is myokymia (clinically visible and continuous muscle twitching that may be difficult to distinguish from vigorous fasciculation). The word has two meanings, one clinical and the other electromyographic. Physiologically, spontaneous activity is seen at rest in the form of fasciculations, doublets, and multiplets that may lead to prolonged trains of discharges at a rate up to 60 Hz. In Isaacs syndrome, both the clinical and the EMG features are present, but myokymia may be found in the EMG of some individuals without any clinically visible twitching. Neuromyotonic discharges start and stop abruptly, and the discharge rate of 150 to 300 Hz is higher than that in myokymia. As a result of the continuous activity, a second characteristic of the syndrome is the finding of abnormal postures of the limbs, which may be persistent or intermittent and are identical to carpal or pedal spasm. A third characteristic is pseudomyotonia, which resembles the difficulty in relaxing in true myotonia; here, however, the characteristic EMG pattern—waxing and waning of myotonic bursts—is not seen. Instead, continuous motor unit activity interferes with relaxation. In addition, there is no percussion myotonia. The fourth characteristic is liability to cramps. Hyperhidrosis, or increased sweating, is variable. The syndrome affects children, adolescents, or young adults and begins insidiously, progressing slowly for months or a few years. Slow movement, clawing of the fingers, and toe-walking are later joined by stiffness of proximal and axial muscles; occasionally, oropharyngeal or respiratory muscles are affected. The stiffness and myokymia are seen at rest and persist in sleep. Voluntary contraction may induce a spasm that persists during attempted relaxation. The EMG recorded from stiff muscles reveals prolonged, irregular discharges of action potentials that vary in amplitude and configuration; some of them resemble fibrillations. Voluntary effort triggers more intense discharges that persist during relaxation, accounting for the myotonia-like after-contraction. The condition is often attributed to a peripheral neuropathy because acral sensory loss is noted in some patients, nerve conduction may be slow, or abnormality may appear on sural nerve

biopsy. Perhaps, most important, the EMG activity may persist after nerve block by injection of local anesthetic but is abolished by botulinum toxin, implying that the activity arises distal to the nerve block and proximal to the neuromuscular junction; the generator must be in the nerve terminals. In an analysis of 28 reported cases, however, only four patients had definite evidence of peripheral neuropathy ( Table 129.2), and some of the features suggested a disorder of the nerve cell itself.

TABLE 129.2. MANIFESTATIONS OF ISAACS SYNDROME IN 28 PATIENTS

Sometimes, neuromyotonia is seen in association with a tumor; that is, it may be a paraneoplastic syndrome. Several patients have had thymoma with or without myasthenia gravis. Newsom-Davis, Vincent, and their associates have demonstrated antibodies to neural potassium channels in most patients. Treatment with carbamazepine or phenytoin usually controls the symptoms and signs. Plasmapheresis and intravenous immunoglobulin therapy have been effective in some patients.

TETANY Tetany is a clinical syndrome characterized by convulsions, paresthesia, prolonged spasms of limb muscles, or laryngospasm; it is accompanied by signs of hyperexcitability of peripheral nerves. It occurs in patients with hypocalcemia, hypomagnesemia, or alkalosis; it occasionally represents a primary neural abnormality. Hyperventilation may unmask latent hypocalcemic tetany, but respiratory alkalosis itself only rarely causes outright tetany. Intense circumoral and digital paresthesia generally precedes the typical carpopedal spasms, which consist of adduction and extension of the fingers, flexion of the metacarpophalangeal joints, and equinovarus postures of the feet. In severe cases, the spasms spread to the proximal and axial muscles, eventually causing opisthotonus. In all forms of tetany, the nerves are hyperexcitable, as manifested by the reactions to ischemia (Trousseau sign) and percussion (Chvostek sign). The spasms are due to spontaneous firing of peripheral nerves, starting in the proximal portions of the longest nerves. EMG shows individual motor units discharging independently at a rate of 5 to 25 Hz; each discharge consists of a group of two or more identical potentials. The treatment of tetany consists of correcting the underlying metabolic disorder. In hypomagnesemia, tetany does not respond to correction of the accompanying hypocalcemia unless the magnesium deficit is also corrected.

STIFF-MAN SYNDROME (MOERSCH-WOLTMAN SYNDROME) The catchy name for this syndrome was coined by two senior clinicians at the Mayo Clinic in 1956. The name has been perpetuated since, but the titles have sometimes been awkward (e.g., stiff-man syndrome in a woman, stiff-man syndrome in a boy, stiff-baby syndrome, or stiff-person syndrome). We now strive for gender-neutral language; the masculine version is especially inappropriate for a syndrome that occurs equally often in women and men. The eponym seems apropos. Clinical Manifestations The Moersch-Woltman syndrome is defined clinically, with progressive muscular rigidity and painful spasms that resemble a chronic form of tetanus. The symptoms develop over several months or years and may either increase slowly or become stable. Aching discomfort and stiffness tend to predominate in the axial and proximal limb muscles, causing awkwardness of gait and slowness of movement. Trismus does not occur, but facial and oropharyngeal muscles may be affected. The stiffness diminishes during sleep and under general anesthesia. Later, painful reflex spasms occur in response to movement, sensory stimulation, or emotion. The spasms may lead to joint deformities and are powerful enough to rupture muscles, rip surgical sutures, or fracture bones. Passive muscle stretch provokes an exaggerated reflex contraction that lasts several seconds. Whether any of the findings in Table 129.3 must be present to make the diagnosis is not clear. For instance, the response to diazepam may not be complete, or the spinal deformity may not be present. And some investigators have noted that findings on examination and EMG activity are compatible with those of voluntary behavior. A psychogenic cause has been mentioned, however, only to be derided because the tin-soldier appearance of the patient is so dramatic and because the spasms may cause physical injury.

TABLE 129.3. DEFINING CHARACTERISTICS OF THE MOERSCH-WOLTMAN SYNDROME

Laboratory Data EMG recordings from stiff muscles show a continuous discharge of motor unit potentials resembling normal voluntary contraction. As in tetanus, the activity is not inhibited by voluntary contraction of the antagonist muscles; however, a normal silent period is present during the stretch reflex, indicating that there is no impairment of recurrent spinal inhibition. The rigidity is abolished by spinal anesthesia, by peripheral nerve block, or by selective block of gamma motor nerve fibers. Some authors have postulated that both alpha and gamma motor neurons are rendered hyperactive by excitatory influences descending from the brainstem. The electroencephalogram is normal. Routine cerebrospinal fluid (CSF) analysis is also normal, but immunoglobulin (Ig) G concentration may be increased and oligoclonal IgG bands may be present. Administration of diazepam is the most effective symptomatic treatment; high doses may be required. Additional benefit can be obtained in some cases from administration of baclofen, phenytoin, clonidine hydrochloride (Catapres), or tizanidine (Zanaflex). Intrathecal baclofen (Lioresal) has been used. The long-term prognosis is still uncertain.

The pathogenesis may involve autoimmunity. Antibodies to glutamate decarboxylase have been found in both serum and CSF in this syndrome and in diabetes mellitus; the frequency of the association of the two diseases seems to be inordinately high. Plasmapheresis may be beneficial. Other autoimmune diseases may be present, and the Moersch-Woltman syndrome is sometimes paraneoplastic. Differential Diagnosis Evidence of corticospinal tract disease or abnormality of the CSF implies an anatomic disorder of the central nervous system (CNS), but in postmortem examination of typical cases, no CNS histopathology is revealed. Patients with similar physical findings may show CSF pleocytosis or Babinski signs. In autopsies of those patients, however, inflammation has been sufficient to warrant the term encephalomyelitis. Stiffness of the arms in some patients with cervical lesions is attributed to spontaneous activity of alpha motor neurons isolated from synaptic influences. That combination is best regarded as stiff encephalomyelitis, because the pathogenesis ought to differ in the two categories with or without clear evidence of CNS disease. However, antibodies to glutamate decarboxylase have also been found in patients with myelitis. A related disorder has been called the stiff limb syndrome. The main distinction between Moersch-Woltman and Isaacs syndromes is the distribution of the symptoms, which affect the distal arms and legs in Isaacs and the trunk in Moersch-Woltman. Myokymia is seen only in Isaacs. Many of the features of Isaacs syndrome are similar to those of tetany, as are the painful tonic spasms of multiple sclerosis (MS). MS, however, is identified by other signs of disseminated CNS lesions. These tonic spasms, like other paroxysmal symptoms in MS, are thought to originate as ectopic activity in demyelinated CNS nerve tracts. They usually last less than 1 minute but occur many times a day. The attacks usually respond promptly to treatment with carbamazepine or phenytoin. The startle reactions of Moersch-Woltman syndrome are similar to those in the autosomal-dominant condition hyperekplexia or startle disease (MIM 149400). Hyperekplexia, however, lacks axial rigidity and has been mapped to a subunit of an inhibitory glycine receptor on chromosome 5. It is relieved by the t-aminobutyric acid agonist clonidine. The Moersch-Woltman syndrome itself is rarely autosomal-dominant (MIM 184850). The fixed postures of the limbs in Isaacs syndrome can be simulated by the Schwartz-Jampel syndrome (SJS) (see Chapter 127). However, SJS is characterized by a unique facial appearance (blepharophimosis), short stature, and bony abnormalities. In SJS, the more frequent EMG pattern is that of myotonia, but there may be continuous motor activity with both myokymic and neuromyotonic discharges. SUGGESTED READINGS Cramps and Related Disorders Blexrud MD, Windebank AJ, Daube JR. Long-term follow-up of 121 patients with benign fasciculations. Ann Neurol 1993;34:622–625. Connolly PS, Shirley EA, Wasson JH, Nierenberg DW. Treatment of nocturnal leg cramps: crossover trial of quinine versus vitamin E. Arch Intern Med 1992;152:1877–1880. Dressler D, Thompson PD, Gledhill RF, Marsden CD. The syndrome of painful legs and moving toes. Mov Disord 1994;9:13–21. Man-Son Hing M, Wells G, Lau A. Quinine for nocturnal leg cramps: a meta-analysis including unpublished data. J Gen Intern Med 1998;13:600–606. Pagni CA, Canavero D. Pain, muscle spasms, and twitching fingers following brachial plexus avulsion: three cases relieved by dorsal root entry zone coagulation. J Neurol 1993;240:468–470. Rose MR, Ball JA, Thompson PD. Magnetic resonance imaging in tonic spasms of multiple sclerosis. J Neurol 1993;241:115–117. Rowland LP. Cramps, spasms, and muscle stiffness. Rev Neurol (Paris) 1985;4:261–273. Rowland LP, Trojaborg W, Haller RG. Muscle contracture: physiology and clinical classification. In: Serratrice G, ed. Muscle contracture. In press. Neuromyotonia Deymeer F, Oge AE, Serdaroglu P, Yaaziei J, Ozdemir C, Basio A. The use of botulinum toxin in localizing neuromyotonia to the terminal branches of the peripheral nerve. 1998;21:643–646.

Muscle Nerve

Hart HC, Waters C, Vincent A, et al. Autoantibodies detected to K+ channels are implicated in neuromyotonia. Ann Neurol 1997;41:238–246. Heidereich F, Vincent A. Antibodies to ion-channel proteins in thymoma with myasthenia, neuromyotonia, and peripheral neuropathy. Neurology 1998;50:1483–1485. Jamieson PW, Katirj MB. Idiopathic generalized myokymia. Muscle Nerve 1994;17:42–51. Layzer RB. Neuromyotonia: a new autoimmune disease. Ann Neurol 1995;38:701–702. Newsom-Davis J, Mills KR. Immunological associations of acquired neuromyotonia (Isaacs' syndrome). Brain 1993;116:453–469. Taylor RG, Layzer RB, Davis HS, Fowler WM. Continuous muscle fiber activity in the Schwartz-Jampel syndrome. Electroencephalogr Clin Neurophysiol 1972;33:497–509. Torbensen T, Stalberg E, Brautaset NJ. Generator sites for spontaneous activity in neuromyotonia: an EMG study. Electroencephalogr Clin Neurophysiol 1996;101:69–78. Van Dijk JG, Lammers GJ, Wintzen AR, Molenaar PC. Repetitive CMAPs: mechanisms of neural and synaptic genesis. Muscle Nerve 1996;19:1127–1133. Wakayama Y, Ohbu S, Machida H. Myasthenia gravis, muscle twitch, hyperhidrosis and limb pain associated with thymoma: proposal of possible new myasthenic syndrome. Tohoku J Exp Med 1991;164:285–291. Stiff-man Syndrome (Moersch-Woltman Syndrome) Barker RA, Revesz T, Thom M, Marsden CD, Brown P. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1998;65:633–640. Floeter MK, Valla-Sole J, Toro C, Jacobowitz D, Hallett M. Physiologic studies of spinal inhibitory circuits in patients with stiff-person syndrome. Neurology 1998;51:85–93. Grimaldi LME, Martino G, Braghi S, et al. Heterogeneity of autoantibodies in stiff-man syndrome. Ann Neurol 1993;34:57–64. Kissel JT, Elble RJ. Stiff-person syndrome: stiff opposition to a simple explanation. Neurology 1998;51:11–14. Layzer RB. Stiff-man syndrome—an autoimmune disease? N Engl J Med 1988;53:695–696. Layzer RB. Motor unit hyperactivity states. In: Engel AG, Franzini-Armstrong C, eds. Myology, 2nd ed. London: Churchill Livingstone, 1994. Lorish TR, Thorsteinsson G, Howard FH Jr. Stiff-man syndrome updated. Mayo Clin Proc 1989;64:629–636. McEvoy KM. Stiff-man syndrome. Mayo Clin Proc 1991;66:303–304. Meinck HM, Ricker K, Hulser PJ, et al. Stiff man syndrome: clinical and laboratory findings in 8 patients. J Neurol 1993;241:157–166. Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (stiff-man syndrome): report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin 1956;31:421–427. Penn RD, Mangieri EA. Stiff-man syndrome treated with intrathecal baclofen. Neurology 1993;43:2412. Piccolo G, Martino G, Moglia A, et al. Autoimmune myasthenia gravis with thymoma following spontaneous remission of stiff-man syndrome. Ital J Neurol Sci 1990;11:177–180. Rosin L, De Camilli P, Butler M, et al. Stiff-man syndrome in a woman with breast cancer: an uncommon central nervous system paraneoplastic syndrome. Neurology 1998;50:94–98. Schmierer K, Valueza JM, Bender A, et al. Stiff-man syndrome with spinal MRI findings, amphiphysin autoantibodies, and immunosuppressive treatment. Neurology 1998;51:250–252.

Solimena M, De Camilli P. Autoimmunity to glutamic acid decarboxylase (GAD) in stiff-man syndrome and insulin-dependent diabetes mellitus. Trends Neurosci 1991;14:452–457. Solimena M, Folli F, Aparisi R, et al. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff man syndrome. N Engl J Med 1990;322:1555–1560. Thompson PD. Stiff muscles. J Neurol Neurosurg Psychiatry 1993;56:121–124.

CHAPTER 130. DERMATOMYOSITIS MERRITT’S NEUROLOGY

CHAPTER 130. DERMATOMYOSITIS LEWIS P. ROWLAND Pathology and Pathogenesis Incidence Symptoms and Signs Diagnosis Prognosis Treatment Suggested Readings

Dermatomyositis, a disease of unknown etiology, is characterized by inflammatory changes in skin and muscle.

PATHOLOGY AND PATHOGENESIS Dermatomyositis is thought to be an autoimmune disease, but there has been no consistent evidence of either antibodies or lymphocytes directed against specific muscle antigens. However, there has been growing agreement among muscle histologists that dermatomyositis is humorally mediated, characterized by more B cells than T cells in the muscle infiltrates, as well as a vasculopathy with deposits of immunoglobulins in intramuscular blood vessels. This contrasts with the predominance of T cells in polymyositis, which is attributed to a disorder of lymphocyte regulation. Some authorities believe that the pathogenesis of the disease differs in adults and children. The acute changes of both skin and muscle are marked by signs of degeneration, regeneration, edema, and infiltration by lymphocytes. The inflammatory cells are found around small vessels or in the perimysium rather than within the muscle fiber itself. In muscle biopsies, however, lymphocytic infiltration may be lacking in 25% of patients; this probably depends on the time of sampling, as well as on the distribution and severity of the process. The lymphocytes are predominantly B cells, with some CD4 (T-helper) cells. Capillaries often show endothelial hyperplasia; deposits of immunoglobulin (Ig) G, IgM, and complement (the membrane attack complex) may be found within and occluding these vessels. Evidence of muscle degeneration and regeneration is multifocal and may be most marked at the periphery of muscle bundles (perifascicular atrophy), where the capillaries are occluded. Increasingly, investigators have come to believe that the primary attack is on blood vessels. A similar myopathy without skin lesions can be induced in animals by immunization with muscle extracts. Viruslike particles have been seen in some cases, but no virus has been cultured from muscle.

INCIDENCE Dermatomyositis is rare. Together with polymyositis, the incidence has been estimated to be about seven cases each year for a population of 1 million. That figure may be too low; in our 1,200-bed hospital, we see five new cases of dermatomyositis and 15 to 20 cases of polymyositis each year. Dermatomyositis occurs in all decades of life, with peaks of incidence before puberty and at about age 40 years. In young adults, women are more likely to be affected. Familial cases are rare. It is generally believed that about 10% of cases starting after age 40 are associated with malignant neoplasms, most often carcinoma of lung or breast. Typical findings, including the rash, have also been seen in patients with agammaglobulinemia, graft-versus-host disease, toxoplasmosis, hypothyroidism, sarcoidosis, ipecac abuse, hepatitis B virus infection, penicillamine reactions, or vaccine reactions. Cases have even been ascribed to azathioprine (Imuran).

SYMPTOMS AND SIGNS The first manifestations usually involve both skin and muscle at about the same time. The rash may precede weakness by several weeks, but weakness alone is almost never the first symptom. Sometimes, the rash is so typical that the diagnosis can be made even without evidence of myopathy (“amyopathic dermatomyositis”), and sometimes weakness is not evident but there is electromyographic (EMG), biopsy, or serum creatine kinase (CK) evidence of myopathy. The rash may be confined to the face in a butterfly distribution around the nose and cheeks, but the edema and erythema are especially likely to affect the eyelids, periungual skin, and extensor surfaces of the knuckles, elbows, and knees. The upper chest is another common site. The initial redness may be replaced later by brownish pigmentation. The Gottron sign is denoted by red-purple scaly macules on the extensor surfaces of finger joints. Fibrosis of subcutaneous tissue and thickening of the skin may lead to the appearance of scleroderma. Later, especially in children, calcinosis may involve subcutaneous tissues and fascial planes within muscle. The calcium deposits may extrude through the skin. Affected muscles may ache and are often tender. Weakness of proximal limb muscles causes difficulty in lifting, raising the arms overhead, rising from low seats, climbing stairs, or even walking on level ground. The interval from onset of weakness to most severe disability is measured in weeks. Cranial muscles are spared, except that difficulty in swallowing is noted by about one-third of patients. Some patients have difficulty in holding the head up because neck muscles are weak. Sensation is preserved, tendon reflexes may or may not be lost, and there is no fasciculation. Systemic symptoms are uncommon. Fever and malaise may characterize the acute stage in a minority of patients. Pulmonary fibrosis has been encountered, and rarely there are cardiac symptoms. Arthralgia may be prominent, but deforming arthritis and renal failure have never been documented. In about 10% of patients, the cutaneous manifestations have features of both scleroderma and dermatomyositis, warranting the name sclerodermatomyositis. These cases have sometimes been designated as mixed connective tissue disease, with a high incidence of antibody to extractable nuclear antigen; however, it now seems unlikely that the mixed syndrome is unique in any way.

DIAGNOSIS The characteristic rash and myopathy usually make the diagnosis clear at a glance. Problems may arise if the rash is inconspicuous; in those cases the differential diagnosis is that of polymyositis (see Chapter 131). Other collagen-vascular diseases may cause both rash and myopathy at the same time, but systemic lupus erythematosus is likely to affect kidneys, synovia, and the CNS in patterns that are never seen in dermatomyositis. Similarly, there has never been a documented case of typical rheumatoid arthritis with typical dermatomyositis. The diagnosis of dermatomyositis is therefore clinical, based on the rash and myopathy. There is no pathognomonic laboratory test. Except for the presence of lymphocytes and perifascicular atrophy in the muscle biopsy and increased serum CK (and other sarcoplasmic enzymes), there are no characteristic laboratory abnormalities. The EMG shows myopathic abnormalities and, often, evidence of increased irritability of muscle. Computed tomography (CT) and magnetic resonance imaging (MRI) of muscle have not been widely adopted but are useful in evaluating pulmonary fibrosis. Nonspecific serologic abnormalities include rheumatoid factor and several different kinds of antinuclear antibodies, none consistently present in patients with dermatomyositis. For instance, anti-Jo antibodies (against histidyl transfer RNA synthetase) are present in about 50% of patients with pulmonary fibrosis, but only 20% of all patients with inflammatory myopathy. Once the diagnosis is made, many clinicians set off on a search for occult neoplasm. In preimaging days, Callen (1982) showed that in most cases a tumor was already evident or that there was an abnormality in some simple routine test (blood count, erythrocyte sedimentation rate, test for heme pigment in stool, chest film) or in findings on physical examination including pelvis and rectum. However, investigations have not yet evaluated the impact of CT or MRI of the chest, abdomen, and pelvis on the discovery of tumors in patients with dermatomyositis. Sometimes, no matter how exhaustive the search, the tumor is not discovered until an autopsy is performed.

PROGNOSIS

The natural history of dermatomyositis is now unknown because patients are automatically treated with steroids. The disease may become inactive after 5 to 10 years. Although the mortality rate 50 years ago was given as 33% to 50%, it is not appropriate to use those ancient figures for current comparison; antibiotics and respirators affect outcome as much as any presumably specific immunotherapy. Even so, in reviews published after 1982, mortality rates were 23% to 44%. Because few fatalities have occurred in children, many of the deaths are caused by the associated malignancy. Other causes of death are myocarditis, pulmonary fibrosis, or steroid-induced complications. The myopathy may also be severe. In an analysis of survivors of childhood dermatomyositis, 83% were capable of self-care, almost all were working, and 50% were married; 33% had persistent rash or weakness, and a similar number had calcinosis.

TREATMENT The standard therapy for dermatomyositis is administration of prednisone. The recommended dose for adults is at least 60 mg daily; higher dosages are often given for severe cases. For children, the recommended dose is higher: 2 mg/kg body weight. The basic dosage is continued for at least 1 month, perhaps longer. If the patient has improved by then, the dosage can be reduced slowly. If there has been no improvement, choices include prolonging the trial of prednisone in the same or a higher dosage with or without the addition of an immunosuppressive drug chosen according to local usage. In the past decade, improvement was reported in 80% of all steroid-treated patients in one series, but only 50% or fewer patients benefited in other studies. Apparent response to treatment of individual patients with apparent relapses on withdrawal of medication has been reported anecdotally many times. In one retrospective analysis, favorable outcome of childhood dermatomyositis seemed to be linked to early treatment (less than 4 months after onset) and use of high doses of prednisone. Dubowitz (1984), however, reported just the reverse: better outcome and fewer steroid complications with low doses of prednisone (1 mg/kg body weight). The value of steroid treatment is still unproved, however, because there has never been a prospectively controlled study. In one retrospective analysis, untreated patients were seen many years before treated patients. In another study, there was no difference in outcome of patients treated with prednisone alone or with both prednisone and azathioprine. Moreover, it is not clear whether immunosuppressive drugs are more or less dangerous than steroids, and there is no evidence that any single immunosuppressive drug is superior to others. Azathioprine, methotrexate, cyclophosphamide, and cyclosporine have all been championed. Plasmapheresis was of no value in a controlled trial, but intravenous immunoglobulin (IVIG) therapy was uniformly beneficial in eight patients with steroid-resistant dermatomyositis, in contrast to no improvement in seven blinded, control patients who were given placebo. IVIG therapy may therefore be the procedure of choice for acute therapy of seriously ill patients. Some long-term immunosuppressive therapy, however, would have to be added. IVIG therapy is also useful in adults or children who do not respond to other agents. Some clinicians worry that exercising a weak muscle may be harmful, but formal tests in dermatomyositis and polymyositis have shown benefit. SUGGESTED READINGS Akira M, Hara H, Sakatani M. Interstitial lung disease in association with polymyositis-dermatomyositis: long-term follow-up CT evaluation in seven patients. Radiology 1999;210:333–338. Amato AA, Barohn RJ. Idiopathic inflammatory myopathies. Neurol Clin 1997;15:615–648. Andrews A, Hickling P, Hutton C. Familial dermatomyositis. Br J Rheumatol 1998;37:231–232. Banker BQ, Victor M. Dermatomyositis (systemic angiopathy) in childhood. Medicine 1966;45:261–289. Bohan A, Peter JB, Bowman RL, Pearson CM. A computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine 1977;56:255–286. Bowyer SL, Blane CE, Sullivan DB, Cassidy JT. Childhood dermatomyositis: factors predicting functional outcome and development of dystrophic calcification. J Pediatr 1983;103:882–888. Callen JP. The value of malignancy evaluation in patients with dermatomyositis. J Am Acad Dermatol 1982;6:253–259. Chalmers A, Sayson R, Walters K. Juvenile dermatomyositis: medical, social and economic status in adulthood. Can Med Assoc J 1982;126:31–33. Chou SM, Mike T. Ultrastructural abnormalities and perifascicular atrophy in childhood dermatomyositis. Arch Pathol Lab Med 1981;105:76–85. Dalakas MC. Molecular immunology and genetics of inflammatory muscle diseases. Arch Neurol 1998;55:1509–1512. Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993–2000. Dubowitz V. Prognostic factors in dermatomyositis [Letter]. J Pediatr 1984;105:336–337. Esmie-Smith AM, Engel AG. Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol 1990;27:343–356. Euwer RL, Sontheimer RD. Amyopathic dermatomyositis (dermatomyositis sine myositis): six new cases. J Am Acad Dermatol 1991;24:959–966. Fujino H, Kobayashi T, Goto I, Onitsuka H. MRI of muscle in patients with polymyositis and dermatomyositis. Muscle Nerve 1991;14:716–720. Heffner RR. Inflammatory myopathies: a review. J Neuropathol Exp Neurol 1993;52:339–350. Hochberg MC. Mortality from polymyositis and dermatomyositis in the United States, 1968–1978. Arthritis Rheum 1983;26:1465–1472. Hochberg MC, Feldman D, Stevens MB. Adult-onset polymyositis/dermatomyositis: an analysis of clinical and laboratory features and survival of 76 patients. Semin Arthritis Rheum 1986;15:168–178. Kissel JT, Halterman RK, Rammohan KW, Mendell JR. The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis. Arch Neurol 1991;48:26–30. Mantegazza R, Bernasconi P, Confalonieri P, Cornelio F. Inflammatory myopathies and systemic disorders: a review of immunopathogenetic mechanisms and clinical features. J Neurol 1997;244:277–287. Mastaglia FL, Phillips BA, Zilko PJ. Immunoglobulin therapy in inflammatory myopathies. J Neurol Neuosurg Psychiatry 1998;65:107–110. Maugars YM, Berthelot JMM, Aabbas AA, et al. Long-term prognosis of 69 patients with dermatomyositis or polymyositis. Clin Exp Rheumatol 1996;14:263–274. Medsger TA Jr, Oddis CV. Classification and diagnostic criteria for polymyositis and dermatomyositis [Editorial]. J Rheumatol 1995;22:581–585. Mease PJ, Ochs HD, Wedgwood RJ. Successful treatment of echovirus meningoencephalitis and myositis-fasciitis with intravenous immune globulin therapy in a patient with X-linked agammaglobulinemia. N Engl J Med 1981;304:1278–1281. Nimmelstein SH, Brody S, McShane D, Holman HR. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine 1980;59:239–248. Ollivier I, Wolkenstein P, Gheradi R, et al. Dermatomyositis-like graft-versus-host disease. Br J Dermatol 1998;138:358–359. Pachman LM, Hayford JR, Chung A, et al. Juvenile dermatomyositis at diagnosis: clinical characteristics of 79 children. J Rheumatol 1998;25:1198–1204. Rowland LP, Clark C, Olarte MR. Therapy for dermatomyositis and polymyositis. Adv Neurol 1977;17:63–97. Sansome A, Dubowitz V. Intravenous immunoglobulin in juvenile dermatomyositis: four-year review of nine cases. Arch Dis Child 1995;72:25–28. Sigurgeirsson B, Lindelof B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis or polymyositis: a population-based study. N Engl J Med 1992;326:363–367. Tanimoto K, Nakano K, Kano, S et al. Classification criteria for polymyositis and dermatomyositis. J Rheumatol 1995;22:668–674.

Wiesinger GF, Quittan M, Graninger M, et al. Benefit of 6 months' long-term physical training in polymyositis/dermatomyositis patients. Br J Rheumatol 1998;37:1338–1342.

CHAPTER 131. POLYMYOSITIS, INCLUSION BODY MYOSITIS, AND RELATED MYOPATHIES MERRITT’S NEUROLOGY

CHAPTER 131. POLYMYOSITIS, INCLUSION BODY MYOSITIS, AND RELATED MYOPATHIES LEWIS P. ROWLAND Definition Of Polymyositis Clinical Manifestations Laboratory Data Pathogenesis Diagnosis Relation Of Polymyositis To Dermatomyositis Relation Of Polymyositis To Inclusion Body Myositis Relation Of Polymyositis To Eosinophilic Myositis Myopathy In Acquired Immunodeficiency Syndrome Relation of Polymyositis to Polymyalgia Rheumatica Therapy Suggested Readings

DEFINITION OF POLYMYOSITIS Polymyositis is a disorder of skeletal muscle of diverse causes characterized by acute or subacute onset, possible intervals of improvement of symptoms, and typically infiltration of muscle by lymphocytes. It is one of the three major categories of inflammatory myopathy; each differs from the others clinically and in muscle pathology. The other two conditions are dermatomyositis and inclusion body myositis (IBM). This definition is insufficiently precise, however, because there is no pathognomonic clinical syndrome, laboratory test, or combination of the two. The problem arises because lymphocytic infiltration of muscle may be lacking in an individual case or the typical pattern may not be seen; also, lymphocytic infiltration may be seen in other conditions. Additionally, polymyositis may occur alone or as part of a systemic disease, especially a collagen-vascular disease.

CLINICAL MANIFESTATIONS The symptoms are those of a myopathy that primarily affects proximal limb muscles: difficulty climbing stairs or rising from low seats, lifting packages or dishes, or working with the arms overhead. Weakness of neck muscles may result in difficulty holding the head erect. Distal muscles are usually affected later, so difficulty using the hands is not encountered at first. Eyelids and ocular movements are spared; the only cranial symptom is dysphagia, usually without dysarthria. Respiration is only rarely affected. Symptoms of systemic disease, malaise, or even weight loss are not evident. In many cases, arthralgia is symptomatic without objective change in the joints. Raynaud symptoms may be prominent, but by definition, there is no rash of dermatomyositis. No visceral lesions appear, other than interstitial lung disease and pulmonary fibrosis in some patients. Myocarditis may also occur. The syndrome is usually subacute in onset, reaching a nadir in months rather than weeks or years, but both acute and chronic forms are seen. Symptoms may persist for years and then the condition seems to become quiescent.

LABORATORY DATA The findings are those of a myopathy, with characteristic electromyographic (EMG) findings of small-amplitude short-duration potentials and full recruitment. Signs of muscle “irritability” may be noted, with fibrillations and positive waves but no fasciculations. Nerve conduction studies give normal values. Serum levels of creatine kinase (CK) and other sarcoplasmic enzymes are usually increased to values 10 times normal or even more. Serum enzyme levels may be normal, however, probably depending on the stage of the disease. A definite diagnosis requires characteristic changes in the muscle biopsy, especially infiltration around healthy muscle fibers by cells that have the immunocytochemical characteristics of CD8+ T lymphocytes. Signs of muscle necrosis and regeneration are apparent, but the pattern differs from that of dermatomyositis because neither vascular lesions nor perifascicular atrophy are seen. The pattern differs from IBM because vacuoles or the defining inclusions are not evident.

PATHOGENESIS Polymyositis is considered an autoimmune disease of disordered cellular immunity (in contrast to the presumed humoral abnormalities of dermatomyositis). The nature of the antigen is not known, however, and the nature of the immunologic aberration is not known. The association with collagen-vascular disease increases the likelihood of autoimmune disorder, as does the association of polymyositis with other autoimmune diseases, including Crohn disease, biliary cirrhosis, sarcoidosis, myasthenia gravis with thymoma and candidiasis, or graft versus host disease. Human immunodeficiency virus and human T-cell lymphotropic virus type I are viral diseases associated with polymyositis; it is not known whether polymyositis is a viral infection of muscle or an autoimmune reaction. In contrast to dermatomyositis, myopathy without rash is uncommon in patients with concomitant malignant neoplasms. Fibers adjacent to the T cells express the class 1 major histocompatibility complex, an antigen that is lacking in normal fibers and is a recognition factor for the activation of T cells. Circulating T cells may be cytotoxic to cultures of the patient's cultured myotubes. In the past decade, interest has been directed to antibodies to cytoplasmic ribonucleoproteins. Because they are not disease specific, however, they neither help to explain pathogenesis nor provide a major diagnostic tool. Anti-Jo antibodies are found in about half of all patients with both polymyositis and pulmonary fibrosis.

DIAGNOSIS In the past, polymyositis was regarded as dermatomyositis without a rash. The histologic differences are now recognized, but the clinical problem remains: How can we identify the qualities of polymyositis that are similar to those of dermatomyositis while distinguishing polymyositis from other myopathies with which it might be confused, such as muscular dystrophies, metabolic myopathies, or disorders of the neuromuscular junction? The following criteria are suggested: 1. There is no family history of similar disease and onset is usually after age 35. No familial limb-girdle dystrophy starts so late. Cases of younger onset are few, unless there is some associated collagen-vascular or other systemic disease. If there is no family history, it may be necessary to test for sarcoglycanopathies. 2. Progression from onset to peak weakness is measured in weeks or months, not years as in the muscular dystrophies. 3. Symptoms may improve spontaneously or concomitantly with the administration of drugs, unlike any muscular dystrophy. 4. In addition to proximal limb weakness, there may be dysphagia or weakness of neck flexors, but other cranial muscles are not affected. (If eyelids or ocular muscles were involved, it would be difficult or impossible to distinguish the disorder from myasthenia gravis.) 5. Arthralgia, myalgia, and Raynaud symptoms help to make the diagnosis, but lack of these symptoms does not exclude the diagnosis. 6. Muscle biopsy usually shows the abnormalities described above, especially early in the course. As in patients with dermatomyositis, however, lymphocytic infiltration may be lacking in muscle biopsies in polymyositis. Typical histologic changes help to make the diagnosis; lack of these changes does not exclude the diagnosis because the changes may be focal in the muscle or transient and not present in the muscle at the site and time of the biopsy. In histochemical stains, there must be no evidence of excess lipid or glycogen storage and there should be no signs of denervation. 7. In addition to conventional EMG signs of myopathy, increased irritability of muscle may be evident. The problem of diagnosis is exemplified by a patient with limb weakness at age 40 when EMG and muscle biopsy indicate that the disorder is a myopathy. Search must then be made for known causes of myopathy (Table 131.1). If none is found, the diagnosis of exclusion is idiopathic polymyositis.

TABLE 131.1. DIFFERENTIAL DIAGNOSIS OF POLYMYOSITIS

It seems unlikely that this residual group is all due to one disease because there is clinical heterogeneity, such as differences in rapidity of progression, distribution of weakness, or severity of disorder. In addition, if there are so many known causes of similar syndromes, it is likely that still more remain to be identified. A restricted concept of idiopathic polymyositis will emerge only when more is known about the disordered immunology of dermatomyositis itself. If there is no family history of similar disease and, especially if there are no inflammatory cells in the muscle biopsy, a form of limb-girdle muscular dystrophy must be considered. Sometimes polymyositis is the suspected diagnosis, but muscle biopsy shows glycogen or lipid accumulation or mitochondrial disease.

RELATION OF POLYMYOSITIS TO DERMATOMYOSITIS These conditions are usually considered together because of the similarities in course and muscle disease. There are, however, important differences, as follows: 1. Dermatomyositis is a homogeneous condition, only rarely associated with a known cause other than carcinoma. Polymyositis is associated with some other systemic disease in about half the cases. 2. Polymyositis is often a manifestation of a specific collagen-vascular disease, such as systemic lupus erythematosus, systemic sclerosis, or different forms of vasculitis. Dermatomyositis, however, is rarely if ever associated with evidence of collagen-vascular disease other than scleroderma. When polymyositis occurs in a patient with lupus erythematosus, for instance, it can be regarded as a manifestation of lupus, not a combination of two different disorders (or an “overlap syndrome”). 3. Dermatomyositis occurs at all ages, including childhood. Polymyositis is rare before puberty. 4. As assessed by inability to walk, the myopathy of dermatomyositis is severe more often than the myopathy of polymyositis. 5. Dermatomyositis is far more likely to be associated with malignant neoplasm than is myopathy without rash.

RELATION OF POLYMYOSITIS TO INCLUSION BODY MYOSITIS The attempt to link polymyositis to a viral infection led Chou (1986) to find tubular filaments in nuclear and cytoplasmic vacuoles in some patients with other pathologic features of polymyositis. Yunis and Samaha coined the name in 1971. These histologic findings were then related to a characteristic clinical syndrome ( Table 131.2).

TABLE 131.2. DEFINITION OF INCLUSION BODY MYOSITIS IN ANALYSIS OF 48 PATIENTS

Polymyositis and IBM are similar in that they are inflammatory myopathies, lack a rash, and rarely affect children. IBM is slower in progression. Dysphagia is common in both. Neither IBM nor polymyositis, in contrast to dermatomyositis, is often a paraneoplastic disorder. The two conditions differ clinically and histologically. Clinically, IBM affects proximal limb muscles but, in contrast to polymyositis, is much more likely to affect distal muscles of the legs, and IBM is one of the few myopathies that causes weakness of the long finger flexors, an early symptom and sign in most IBM patients. IBM characteristically affects men after age 50; polymyositis affects younger adults as well and women more often than men. IBM more often shows mixed neurogenic and myopathic features in conventional EMG. In contrast to polymyositis, IBM is less often seen with collagen-vascular or other autoimmune disorders. Serum CK values are normal or only slightly increased in IBM. A major distinction is the failure of IBM to respond to steroid therapy. IBM and polymyositis differ pathologically because IBM is characterized by rimmed vacuoles, with the defining cellular inclusions and vacuoles. The pathogenesis of IBM is not known. Originally, IBM was thought to be a variant of polymyositis because, in addition to the inclusions, muscle is often infiltrated by lymphocytes in distribution, number, and T-cell characteristics similar to those of polymyositis. However, the vacuoles give immunochemical stains for proteins seen in the brain of patients with Alzheimer disease (beta-amyloid precursor protein and others), which leads some investigators to regard IBM as a “degenerative disease” rather than an autoimmune disorder. Yet another peculiar facet of IBM is the presence of ragged fibers and cytochrome c oxidase negative fibers, findings that imply abnormalities of mitochondria, which prove to be multiple deletions of mitochondrial DNA. How this arises or what it means in the pathogenesis of the disorder is still uncertain. IBM may be familial with little inflammation and vacuolar histologic characteristics similar to those of autosomal dominant Welander distal muscular dystrophy or oculopharyngeal muscular dystrophy; these syndromes differ clinically, but the similarities may cause problems in classification.

RELATION OF POLYMYOSITIS TO EOSINOPHILIC MYOSITIS Rarely, a myopathy is associated with infiltration of muscle by eosinophils in addition to or instead of lymphocytes. One is the eosinophilic myositis of trichinosis or other parasitic infestation. Another form was seen in an epidemic in Spain of the toxic oil syndrome that was attributed to ingestion of denatured rapeseed oil. In addition to rash, fever, adenopathy, and other symptoms, some patients had prominent myalgia, but serum CK values were normal. In 1989, an epidemic in the United States of similar symptoms was finally attributed to ingestion of a contaminated preparation of L-tryptophan as a sedative. As many as 10,000 cases of that eosinophilia-myalgia syndrome may have occurred. Arthralgia, limb swelling, and evidence of myopathy or sensorimotor peripheral neuropathy were prominent. Muscle biopsy showed fascitis, perimyositis, and inflammatory microangiopathy. Eosinophilic myositis was found in some cases. The neuropathy had physiologic features of axonal damage in most patients, but some had conduction block.

MYOPATHY IN ACQUIRED IMMUNODEFICIENCY SYNDROME Myopathy may appear in patients with AIDS. Intense debate has ensued about the pathogenesis of the disorder. Some believe it is an autoimmune polymyositis or the result of viral invasion of muscle. Others believe it is virtually restricted to those taking zidovudine; in those cases most show ragged-red fibers, and depletion of mitochondrial DNA has been documented. DNA levels return to normal when the drug therapy is interrupted.

RELATION OF POLYMYOSITIS TO POLYMYALGIA RHEUMATICA In polymyalgia rheumatica, no symptomatic weakness or elevation of serum CK levels occurs. If overt weakness or high CK levels were evident, the syndrome would be impossible to distinguish from polymyositis. Polymyalgia can be defined as a syndrome in which a person older than age 65 has joint pains, myalgia, malaise, and a high erythrocyte sedimentation rate as described in Chapter 155.

THERAPY Polymyositis itself is treated with steroids and immunosuppressive drugs, as described for dermatomyositis in Chapter 130. The advantages and risks must be balanced against the patient's disability. In controlled trials, plasmapheresis and leukapheresis had no effect, but intravenous immunoglobulin therapy has been beneficial, at least temporarily. IBM characteristically does not respond to steroid therapy; this feature has led to the diagnosis of IBM in patients originally thought to have polymyositis. IBM does not respond to plasmapheresis but benefit was found in a few patients participating in a trial of intravenous immunoglobulin. Favorable results have been few. The eosinophilia-myalgia syndrome has not responded to conventional immunosuppression, steroids, or plasmapheresis. SUGGESTED READINGS Polymyositis (also refer to Suggested Readings in Chapter 130) 1Amato AA, Barohn RJ. Idiopathic inflammatory myopathies. Neurol Clin 1997;15:615–648. Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. V. T8+ cytotoxic and suppressor cells. Ann Neurol 1988;23:493–499. Bautista J, Gil-Necija E, Castilla J, et al. Dialysis myopathy: 13 cases. Acta Neuropathol (Berl) 1983;61:71–75. Benbassat J, Gefel D, Larholt K, et al. Prognostic factors in polymyositis. A computer-assisted analysis of 92 cases. Arthritis Rheum 1985;28:249–255. Cohen O, Steiner I, Argov Z, et al. Mitochondrial myopathy with atypical subacute presentation. J Neurol Neurosurg Psychiatry 1998;410–411. Crennan JM, Van Scoy RE, McKenna CH, Smith TF. Echovirus polymyositis in patients with hypogammaglobulinemia: failure of high-dose intravenous gamma globulin therapy. Am J Med 1986;81:35–42. Cumming WJK, Weiser R, Teoh R, et al. Localized nodular myositis: a clinical and pathological variant of polymyositis. Q J Med 1977;184:531–546. Dalakas MC. Inflammatory myopathies. Handb Clin Neurol 1992;18:369–390. Dewberry RG, Schneider BF, Cale WF, Phillips LH II. Sarcoid myopathy presenting with diaphragm weakness. Muscle Nerve 1993;16:832–835. Gheradi RK, Coquet M, Cherin P, et al. Macrophagic myofasciitis: an emerging entity. Lancet 1998;352:347–352. Hart FD. Polymyalgia rheumatica. Correct diagnosis and treatment. Drugs 1987;33:280–287. Hopkinson ND, Shawe DJ, Gumpel JM. Polymyositis, not polymyalgia rheumatica. Ann Rheum Dis 1991;50:321–322. Kaufman LD, Kephart GM, Seidman RJ, et al. The spectrum of eosinophilic myositis. Arthritis Rheum 1993;36:1014–1024. Lampe J, Kitzler H, Walter MC, Lochmuller H, Reichmann H. Methionine homozygosity at prion gene codon 129 may predispose to sporadic inclusion-body myositis. Lancet 1999;353:465–466. Lange DJ. Neuromuscular diseases associated with HIV infection. Muscle Nerve 1994;7:16–30. Layzer RB. The hypereosinophilic syndromes. In: Serratrice G, Pellissier J, Desnuelle C, Pouget J, eds. Myelopathies, neuropathies et myopathies: acquisitions recentes (advances in neuromuscular diseases). Paris: Expansion Scientifique Francaise, 1989. Layzer RB, Shearn MA, Satya-Murti S. Eosinophilic polymyositis. Ann Neurol 1977;1:65–71. Miller FW. Myositis-specific autoantibodies. Touchstones for understanding inflammatory myopathies. JAMA 1993;270:1846–1849. Moskovic E, Fisher C, Wetbury G, Parsons C. Focal myositis: a benign inflammatory pseudotumor: CT appearance. Br J Radiol 1991;64:489–493. Navarro C, Bragado FG, Lima J, Fernandez JM. Muscle biopsy findings in systemic capillary leak syndrome. Hum Pathol 1990;21:297–301. Persellin ST. Polymyositis associated with jejunoileal bypass. J Rheumatol 1983;10:637–639. Phillips BA, Zilko P, Garlepp MJ, Mastaglia FL. Frequency of relapses in patients with polymyositis and dermatomyositis. Muscle Nerve 1998;21:1668–1672. Pickering MC, Walport MJ. Eosinophilic myopathic syndromes. Curr Opin Rheumatol 1998;10:504–510. Ringel SP, Thorne EG, Phanuphak P, et al. Immune complex vasculitis, polymyositis, and hyperglobulinemic purpura. Neurology 1979;29:682–689. Rowland LP, Clark C, Olarte M. Therapy for dermatomyositis and polymyositis. In: Griggs RC, Moxley RT, eds. Treatment of neuromuscular disease. New York: Raven Press, 1977. Spuler S, Emslie-Smith A, Emgel AG. Amyloid myopathy: an underdiagnosed entity. Ann Neurol 1998;43:719–728. Symmans WA, Beresford CH, Bruton D, et al. Cyclic eosinophilic myositis and hyperimmunoglobulin-E. Ann Intern Med 1986;104:26–32. Tsokos GC, Moutsopoulos M, Steinberg AD. Muscle involvement in systemic lupus erythematosus. JAMA 1981;246:766–768. Vaish AK, Mehrotra S, Kushwaha MRS. Proximal muscle weakness due to amyloid deposition. J Neurol Neurosurg Psychiatry 1998;409–410. Drug-induced Myopathies Arnaudo E, Dalakas M, Shanske S, et al. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 1991;337:508–510. Batchelor TT, Taylor LP, Thaler HT et al. Steroid myopathy in cancer patients. Neurology 1997;48:1234–1238. Choucair AK, Ziter FA. Pentazocine abuse masquerading as familial myopathy. Neurology 1984;34:524–527. Doyle DR, McCurley TL, Sergent JS. Fatal polymyositis in D-penicillamine-induced nephropathy and polymyositis. N Engl J Med 1983;308:142–145. Giordano N, Senesesi M, Mattii G, et al. Polymyositis associated with simvastatin. Lancet 1997;349:1600–1601.

Haller RG, Knochel JP. Skeletal muscle disease in alcoholism. Med Clin North Am 1984;68:91–103. Kalkner KM, Ronnblom L, Karlsson Parra AK, et al. Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon. Q J Med 1998;91:393–399. Mastaglia FL. Adverse effects of drugs on muscle. Drugs 1982;24:304–321. Ojeda VJ. Necrotizing myopathy associated with steroid therapy. Report of two cases. Pathology 1982;14:435–438. Schultz CE, Kincaid JC. Drug-induced myopathies. In: Biller J, ed. Iatrogenic neurology. Boston: Butterworth-Heinemann, 1998:305–318. Simpson DM, Citak KA, Godfrey E, et al. Myopathies associated with HIV and zidovudine. Can their effects be distinguished? Neurology 1993;43:971–976. Simpson DM, Slasor P, Dafni U, et al. Analysis of myopathy in a placebo-controlled zidovudine trial. Muscle Nerve 1997;20:382–385. Takahasi K, Ogita T, Okudaira H, et al. Penicillamine-induced polymyositis in patients with rheumatoid arthritis. Arthritis Rheum 1986;29:560–564. Inclusion Body Myositis Amato AA, Gronseth GS, Jackson CE, et al. Inclusion body myositis: clinical and pathological boundaries. Ann Neurol 1996;40:581–586. Askanas V. New developments in hereditary inclusion body myositis. Ann Neurol 1997;41:421–422. Askanas V, Serratrice G, Engel WK, eds. Inclusion-body myositis. Cambridge: Cambridge University Press, 1998. Barohn RJ. The therapeutic dilemma of inclusion body myositis. Neurology 1997;48:567–568. Brannagan TH, Hays AP, Lange DJ, Trojaborg W. The role of quantitative electromyography in inclusion body myositis. J Neurol Neurosurg Psychiatry 1997;63:776–779. Chou SM. Inclusion body myositis: a chronic persistent mumps myositis? Hum Pathol 1986;17:765–777. Garlepp MJ, Mastaglia F. Inclusion body myositis. J Neurol Neurosurg Psychiatry 1996;60:251–255. Griggs RC, Askansas V, DiMauro S, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705–713. Lindberg C, Borg K, Edstrom L, et al. Inclusion body myositis and Welander distal myopathy: a clinical, neurophysiological, and morphological comparison. J Neurol Sci 1991;103:76–81. Lotz BP, Engel AG, Nishino H, et al. Inclusion body myositis. Observations in 40 patients. Brain 1989;112:727–747. Moslemi A-R, Lindberg C, Oldfors A. Analysis of multiple mitochondrial DNA deletions in inclusion body myositis. Hum Mutat 1997;10: 381–386. Sadeh M, Gadoth N, Hadar H, Ben-David E. Vacuolar myopathy sparing the quadriceps. Brain 1993;116:217–232. Sivakumar K, Dalakas MC. Inclusion body myositis and myopathies. Curr Opin Neurol 1997;10:413–420.

CHAPTER 132. MYOSITIS OSSIFICANS MERRITT’S NEUROLOGY

CHAPTER 132. MYOSITIS OSSIFICANS LEWIS P. ROWLAND Suggested Readings

The identifying characteristic of myositis ossificans (MIM 135100), a rare disorder, is the deposition of true bone in subcutaneous tissue and along fascial planes in muscle. McKusick (1974) believed that the primary disorder is in connective tissue and preferred the term fibrodysplasia ossificans rather than its traditional name, which implies a disease of muscle. Nevertheless, in some cases myopathic changes occur in muscle biopsy or electromyogram, and occasionally serum creatine kinase levels are increased. Symptoms usually start in the first or second year of life. Transient and localized swellings of the neck and trunk are the first abnormality. Later, minor bruises are followed by deposition of solid material beneath the skin and within muscles. Plates and bars of material may be seen and felt in the limbs ( Fig. 132.1), paraspinal tissues, and abdominal wall. These concretions are readily visible on radiographic examination, magnetic resonance imaging, or computed tomography; when they cross joints, a deforming ankylosis results. The cranial muscles are spared, but the remainder of the body may be encased in bone. The extent of disability depends on the extent of ossification, which varies considerably. No abnormality of calcium metabolism has been detected.

FIG. 132.1. Ossification of muscle biopsy scar in boy with myositis ossificans. The outer border of marks indicates extent of spontaneous ossification.

Almost all cases are sporadic, but it is suspected that the disease is inherited because minor skeletal abnormalities occur in almost all patients, and these abnormalities seem to be transmitted in the family in an autosomal dominant pattern. The most common deformity is a short great toe ( microdactyly) and curved fingers (clinodactyly), and other digital variations are also seen. Most cases are attributed to new mutations because reproductive fitness is much reduced. The gene locus has not been mapped yet. Restricted ossification at the site of single severe injury may also occur in otherwise normal adults with no apparent genetic risk. Treatment is symptomatic. Excision of ectopic bone is fruitless because local recurrence is invariable and disability may become worse. Surgery sometimes helps to refix a joint in a functionally better position. Treatment with diphosphonates inhibits calcification of new ectopic matrix but does not block production of the fibrous material and may have adverse effects on normal skeleton. SUGGESTED READINGS Amendola MA. Myositis ossificans circumscripta: computed tomography diagnosis. Radiology 1983;149:775–779. Cohen RB, Hahn CV, Tabas JA, et al. The natural history of heterotopic ossification in patients with fibrodysplasia ossificans progressiva: 44 patients. J Bone Joint Surg [Am] 1993;75:215–219. Connor JM. Fibrodysplasia ossificans progressiva. In: Royce PM, ed. Connective tissue and its heritable disorders. New York: Wiley Press, 1993. Connor JM, Skirton H, Lunt PW. A three-generation family with fibrodysplasia ossificans progressiva. J Med Genet 1993;30:687–689. Debene-Bruyerre C, Chikhami L, Lockhart R, et al. Myositis ossificans progressiva: five generations where the disease was exclusively limited to the maxillofacial region. Int J Oral Maxillofac Surg 1998;27:299–302. DeSmet AA, Norris AA, Fisher DR. MRI of myositis ossificans: 7 cases. Skel Radiol 1992;21:503–507. Kaplan FS, Tabas JA, Gauman FH, et al. The histopathology of fibrodysplasia ossificans progressiva. J Bone Joint Surg [Am] 1993;75:220–230. McKusick VA. Heritable diseases of connective tissue, 4th ed. St Louis: CV Mosby, 1972. Smith R. ENMC-sponsored international workshop: fibrodysplasia (myositis) ossificans progressiva (FOP). Neuromusc Disord 1997:7:407–410.

CHAPTER 133 MULTIPLE SCLEROSIS MERRITT’S NEUROLOGY

SECTION XIX. DEMYELINATING DISEASES CHAPTER 133. MULTIPLE SCLEROSIS JAMES R. MILLER Definition Incidence and Epidemiology Etiology and Pathogenesis Pathology Symptoms and Signs Mode of Onset Laboratory Data Diagnosis Differential Diagnosis Course and Prognosis Variants of Multiple Sclerosis Management Suggested Readings

DEFINITION Multiple sclerosis (MS) is a chronic disease that begins most commonly in young adults and is characterized pathologically by multiple areas of central nervous system (CNS) white matter inflammation, demyelination, and glial scarring (sclerosis). The lesions are therefore multiple in space. The clinical course varies from a benign, largely symptom-free disease to one that is rapidly progressive and disabling. Most patients begin with relapsing and remitting symptoms. At first, recovery from relapses is almost complete, but then neurologic disabilities accrue gradually. The lesions are therefore multiple in time and space. The cause is elusive, although autoimmune mechanisms, possibly triggered by environmental factors in genetically susceptible individuals, are thought to be important.

INCIDENCE AND EPIDEMIOLOGY Age at onset follows a unimodal distribution with a peak between ages 20 and 30 years; symptoms rarely begin before age 10 or after age 60. In a series of 660 patients, Bauer and Hanefeld (1993) found that almost 70% of patients had symptoms at ages 21 to 40, 12.4% at ages 16 to 20, and 12.8% at 41 to 50. The youngest patient had symptoms at age 3 and the oldest at 67 years. Younger and older cases have been reported. In women, the incidence of MS is 1.4 to 3.1 times higher than in men. Among patients with later onset, the sex ratio tends to be equal. The geographic distribution is uneven. In general, the disease increases in frequency with latitude in both the northern and southern hemispheres, although the rates tend to decrease above 65 degrees north or south. Because of differences in methods of case finding and the need to rely on subjective clinical criteria in identifying cases of MS in large populations, the absolute numbers in any given area are uncertain. The distribution of MS is best considered in terms of zones. High prevalence areas are those with cases equal to or more than 30 per 100,000 population, medium prevalence areas have rates between 5 and 30 per 100,000, and low prevalence areas have rates less than 5 per 100,000. Most of northern Europe, northern United States, southern Canada, and southern Australia and New Zealand are areas of high prevalence. Southern Europe, southern United States, Asia Minor, the Middle East, India, parts of northern Africa, and South Africa have medium prevalence rates. Low prevalence areas are Japan, China, and Latin and South America. MS is virtually unknown among native Inuit in Alaska and among the indigenous people of equatorial Africa. Although latitude may be an independent variable affecting MS prevalence rates, racial differences may explain some of the geographic distribution. This is illustrated by comparing the prevalence rate for MS in Britain (85 per 100,000) and Japan (1.4 per 100,000), although both countries lie at the same latitude. When racial differences are correlated with prevalence rates for MS worldwide, white populations are at greatest risk and both Asian and black populations have a low risk. Studies of migrant populations provide evidence of environmental changes on the risk of MS while keeping genetic factors constant. Children born in Israel of immigrants from Asian and North African countries showed relatively higher incidence rates, like those of European immigrants, rather than the low rates characteristic of their parents. This finding implies that an environmental factor is critically important in pathogenesis. Similar differences were noted among the native-born South African whites, who had a relatively low incidence, as opposed to the high incidence among immigrants from Great Britain. Refinement of these studies suggested that age at time of immigration played an important role; an immigrant leaving the country of origin before age 15 years had nearly the same risk of acquiring MS as that of the native-born Israeli or South African. Individuals migrating after age 15 have the risk of the country of origin. These studies were confirmed by studies of people migrating from the Indian subcontinent or the West Indies to Great Britain. The data suggest that an infectious agent of long latency is acquired at the time of puberty. Reports of epidemics of MS provide further evidence of an environmental factor. The most impressive epidemic occurred in the Faroe Islands where cases appeared shortly after the islands were occupied by British troops in World War II. Similar epidemics of cases have been seen in Iceland, in the Orkney and Shetland Islands, and in Sardinia. Rigorous epidemiologic scrutiny failed to prove, however, that these cases were true point-source epidemics. Therefore, other plausible explanations cannot be excluded. MS is reported to occur more frequently in higher socioeconomic classes and in urban areas, but these assertions are unproved.

ETIOLOGY AND PATHOGENESIS The cause of MS is unknown. Genetic susceptibility, autoimmune mechanisms, and viral infections may play a pathogenic role in the demyelination. Genetic Susceptibility Compelling data indicate that susceptibility to MS is inherited. The epidemiologic studies just summarized reveal a racial susceptibility to the development of MS. Whites appear most susceptible. Within this group are regional trends; the highest rates are associated with areas in which Nordic invasions took place. Alternatively, genetic resistance to MS in Asians and descendants of black Africans helps to explain racial variations in prevalence rates of MS. Because racial prevalence of MS changes with migration, however, definite conclusions of genetic predisposition cannot be drawn. Studies of families and twins provide more support for genetic susceptibility. In high-prevalence regions, the lifetime risk of developing MS is about 0.00125% in the general population. Siblings of MS patients have a risk of about 2.6%, parents a risk of about 1.8%, and children a risk of about 1.5%. First-, second-, and third-degree relatives also have a higher risk. Overall, about 15% of patients with MS have an affected relative. Data from twin studies indicate a concordance rate of about 25% in monozygotic twins and of only 2.4% for same-sex dizygotic twins. These studies suggest a substantial genetic component. Rather than a single dominant gene, however, multiple genes probably confer susceptibility. Pedigree data from families with more than one affected member are consistent with the hypothesis that multiple unlinked genes predispose to MS. The major histocompatibility complex (MHC) on chromosome 6 has been identified as one genetic determinant for MS. The MHC encodes the genes for the histocompatibility antigens (the human leukocyte antigen [HLA] system) involved in antigen presentation to T cells. Of the three classes of HLA genes, the strongest association is with

the class II alleles, particularly the DR and DQ regions. In whites, the class II haplotype DR15, DQ6, Dw2 is associated with increased risk of MS. Delineation of this haplotype in patients with MS and in normal people, however, revealed no significant differences; genetic susceptibility to MS may therefore reside in functional aspects of these genes. The roles of other genes in MS, including the T-cell receptor (TCR) andimmunoglobulin heavy chain genes, are reviewed later in the chapter. Immunology Substantial evidence from peripheral blood abnormalities, cerebrospinal fluid (CSF) findings, and CNS pathology in MS and animal models of demyelination suggests that autoimmune mechanisms are involved. In the peripheral blood, several nonspecific changes are seen, particularly in secondary progressive MS. These changes are similar to those encountered in other autoimmune diseases, such as systemic lupus erythematosus (SLE). The activity of suppressor CD8+ T cells is reduced, as is the autologous mixed lymphocyte reaction, which seems to be an indicator of autoreactive cell suppression. In MS, as in SLE, there are fewer CD4+CD45RA+ suppressor-inducer T cells in the peripheral blood. An increase in activated T cells in MS is unlikely because cell surface molecules associated with T-cell activation are not abundant and lymphokine levels are normal. CSF pleocytosis is common, particularly in the acute phases of MS. T cells that are helper-inducers (CD4+CDw29+ cells) constitute most of these cells and are found in higher ratios in CSF than in the peripheral circulation. By contrast, the number of CD4+CD45RA T cells, which induce suppressor cells, is decreased. Although some T lymphocytes in the CSF of patients with MS are activated, the antigenic stimulus is unclear. T-cell reactivity is found against several epitopes of myelin basic protein (MBP) and proteolipid protein. Analysis of the TCR gene, which is unique for each T-cell clone, suggests that the immune response is polyclonal and likely to have multiple antigenic specificities. Sequencing the variable regions of these cells reveals a high degree of somatic hypermutation, as is seen in chronic stimulation in vivo. Antibody-secreting B cells are also activated in MS. The amount of IgG in the CSF and the rate of IgG synthesis are increased. Because only a few clones of CSF cells are activated, the response is oligoclonal. This seems to be a restricted response to stimulation within the neuraxis because similar oligoclonal IgGs are not found at all or are found in lower concentration in the serum than in CSF. Oligoclonal IgG is found in other inflammatory or infectious conditions, such as viral encephalitis or CNS syphilis. In these situations, however, the oligoclonal IgGs are antibodies directed against the agents of the infecting agent. In MS, an antigen for most of the oligoclonal IgG has not been identified. Therefore, the CSF IgG may be a secondary effect, possibly a result of the decrease in CD4+CD45RA+ suppressor-inducer cells, which allows a few clones of antibody-producing cells to escape suppression. Perivascular lymphocyte and macrophage infiltration is characteristic of the CNS immunopathology. The predominant lymphocytes in MS lesions are helper-inducer cells (CD4+CDw29+). Interleukin-2 receptors are demonstrable on many of the T cells, thereby indicating that these cells are secreting cytokines and are immunologically activated. Also, astrocytes, which normally do not express MHC molecules, express class II molecules in active lesions. This pattern suggests that astrocytes are involved in antigen presentation to T cells. In more chronic lesions, g/d T cells are present around the edges of the plaque. Oligoclonal IgG is also present in MS plaques. Overall, the types of immunologically active cells and IgGs in the CNS lesions are similar to those found in CSF. The cytokines produced by activated T cells and macrophages may play a role in some of the tissue damage. The cytokine called tissue necrosis factor is toxic to oligodendroglial cells and myelin and can be found in MS plaques. Further, CSF levels of tissue necrosis factor may correlate with MS disease activity. Further evidence that MS may have an immunologic basis comes from the animal model experimental allergic encephalomyelitis (EAE), which is induced in genetically susceptible animals by immunization with normal CNS tissue and an adjuvant. The chronic relapsing-remitting form of EAE is pathologically similar to that of MS. EAE can also be induced by immunization with MBP or immunodominant peptide regions of MBP, thus suggesting that MBP is the putative antigen in EAE. T cells reactive against MBP and proteolipid protein mediate the CNS inflammation, as shown by “adoptive transfer�: Sensitized T cells from an animal with EAE can transfer disease to a healthy syngeneic recipient. The T-cell response in EAE seems to be genetically restricted to a few families on the TCR gene, however, and removal or suppression of these T-cell lines leads to immunity from EAE. This response contrasts with the findings in human MS where the TCR gene response is more heterogeneous. Although current understanding of MS pathogenesis derives mainly from consideration of the EAE and chronic EAE models, many features of the human disease are not understood or explained by this animal model. We do not know the precipitant antigens or even if the immune process is the primary force. There are differences in the pathology of the experimental and clinical disorders, the relative roles of cytokine activation, and antibody-mediated immunity; macrophage activity may differ. Healthy skepticism is warranted in considering theories of pathogenesis. Viruses Epidemiologic data imply a role for environmental exposure. Viral encephalitis in children may be followed by demyelination. In animals, the most widely studied model of viral-induced demyelinating disease is created by the Theiler virus, a murine picornavirus. Infection with some Theiler strains results in an infection of oligodendrocytes with multifocal perivascular lymphocytic infiltration and demyelination. Genetic factors influence susceptibility to development of demyelination and clinical disease; this susceptibility is linked to the immune response generated in the animals against viral determinants. Therefore, in MS, demyelination could be precipitated by a viral infection. Measles, rubella, mumps, coronavirus, parainfluenza, herpes simplex, Epstein-Barr, vaccinia, and human T-cell lymphotropic virus type I viruses all have been reported to be present in patients with MS. None of these agents, however, has been detected reproducibly. Human herpesvirus-6 has been implicated in MS disease activity; it is a ubiquitous agent that causes roseola subitum in children. Over 90% of adults have antibodies to the agent, and infection, mostly asymptomatic, probably occurs in early childhood. Human herpesvirus-6 then persists in a latent state in neural tissue. Results have not been uniform, but some investigators found an increased incidence of viral activity in areas around acute MS plaques. Activity of the virus may precipitate a flareup of symptoms. Studies are in progresss to determine if prophylactic treatment with an antiviral agent could reduce the frequency of episodes in MS. Perhaps no single virus is the trigger for demyelination in all patients with MS. Instead, several different viruses may be involved. Other Factors Other mechanisms have been suggested as precipitating the onset of MS or relapses. Physical trauma has been invoked as precipitating or aggravating the disease. In a population-based cohort study, however, Siva et al. (1993) found no association between MS and head injuries in 819 patients. Other studies also failed to show any causal correlation between trauma and MS. The effect of pregnancy is difficult to evaluate because MS is most common in women of childbearing age. If the pregnancy year is considered, however, exacerbations seem to cluster in the postpartum period rather than during pregnancy. Whether this clustering is related to hormonal changes or other factors is unclear. In any event, no convincing evidence has revealed that MS is worsened by pregnancy. Therefore, interruption of pregnancy in women with MS is not indicated on this basis alone. Vaccination is also cited frequently as a precipitating event, although the evidence is anecdotal. One study with influenza vaccine found no relationship. In the absence of definitive studies, patients with MS should be advised against routine casual vaccination, especially if previous exacerbations have been preceded by vaccination. However, medically indicated inoculations should not be withheld. Surgery, anesthesia, and lumbar punctures also have been invoked in MS, but controlled studies failed to show any relationship.

PATHOLOGY The gross appearance of the external surface of the brain is usually normal. Frequently in long-standing cases there is evidence of atrophy and widening of cerebral sulci with enlargement of the lateral and third ventricles. Brain sections reveal numerous small irregular grayish areas in older lesions and pink areas in acute lesions in the cerebral hemispheres, particularly in the white matter and in periventricular regions ( Fig. 133.1). The white matter that forms the superior lateral angle of the body of the lateral ventricles is frequently and characteristically affected. Similar areas of discoloration are also found in the brainstem and cerebellum. These are the plaques of MS.

FIG. 133.1. Gross appearance, coronal section, occipital lobe. Note extensive periventricular lesions. Several small lesions are scattered elsewhere in the white matter. (Courtesy of Dr. Daniel Perl.)

The external appearance of the spinal cord is usually normal. In a few cases, the cord is slightly shrunken and the pia arachnoid may be thickened. The cord occasionally may be swollen over several segments if death follows soon after the onset of an acute lesion of the cord. Plaques similar to those seen in the cerebrum are seen occasionally on the external surface of the cord, but they are recognized most easily on cross-section. The optic nerves may be shrunken, but the external appearance of the other cranial nerves is usually normal. Myelin sheath stains of CNS sections show areas of demyelination in the regions that were visibly discolored in the unstained specimen. In addition, many more plaques are apparent. These plaques are sharply circumscribed and are diffusely scattered throughout all parts of the brain and spinal cord ( Fig. 133.2). The lesions in the brain tend to be grouped around the lateral and third ventricles. Lesions in the cerebral hemispheres vary from the size of a pinhead to large areas that encompass the major portion of one lobe of the hemisphere. Small lesions may be found in the gray matter and in the zone between the gray and white matter. Plaques of varying size may be found in the optic nerves, chiasm, or tracts ( Fig. 133.3). Lesions in the corpus callosum are not uncommon (Fig. 133.4). The lesions in the brainstem are usually numerous (Fig. 133.5), and sections from this area when stained by the Weigert method have a characteristic “Holstein cow� appearance (Fig. 133.6).

FIG. 133.2. A: Normal contrast-enhanced computed tomography. B: The axial T2-weighted magnetic resonance image in the same patient during the same period shows multiple white matter lesions, the largest designated by arrows.

FIG. 133.3. Multiple sclerosis. Demyelinization of optic nerves and chiasm. (Courtesy of Dr. Abner Wolf.)

FIG. 133.4. Myelin sheath stain of right cerebral hemisphere in multiple sclerosis (celloidin). Note lesions in corpus callosum and superior lateral angle of the ventricle and several plaques in the subcortical white matter. (Courtesy of Dr. Charles Poser.)

FIG. 133.5. Multiple sclerosis. Myelin sheath stain. Lesions in pons, middle cerebellum peduncle, and cerebellar white matter, typically near the dentate nuclei. (Courtesy of Dr. Charles Poser.)

FIG. 133.6. Myelin sheath stain of brainstem in multiple sclerosis. Note sharp demarcation of lesions.

In sections of the spinal cord, the areas of demyelination vary from small lesions involving a portion of the posterior or lateral funiculi to almost complete loss of myelin in an entire cross-section of the cord ( Fig. 133.7 and Fig. 133.8).

FIG. 133.7. Myelin sheath stain: tenth thoracic segment of spinal cord. Almost complete demyelination of the entire section. The gray matter is severely involved, and cystic degeneration causes obliteration of normal architecture.

FIG. 133.8. Multiple sclerosis. A: Almost complete loss of myelin in transverse section of cord. B: Symmetric lesions in the posterior and lateral funiculi simulating distribution of lesions in combined system disease. (From Merritt HH, Mettler FA, Putnam TJ. Fundamentals of clinical neurology. Philadelphia: Blakiston, 1947.)

Lesions are usually characterized by sharp delimitation from the surrounding normal tissue. Within the lesion is variable destruction of the myelin and to a lesser degree damage to the neurons, proliferation of the glial cells, changes in the blood vessels, and relatively good preservation of the ground structure. Only rarely is the damage severe enough to affect the ground substance and produce a cyst ( Fig. 133.6). Most myelin sheaths within a lesion are destroyed, and many of those that remain show swelling and fragmentation. The degree of damage to the neurons varies. In the more severe lesions, axons may be entirely destroyed, but more commonly only a few are severely injured and the remainder appear normal or show only minor changes. However, loss of axons is found in even the earliest MS plaques. Secondary degeneration of long tracts occurs when the axons have been significantly destroyed. Recently, it has been appreciated that axonal loss and resulting brain atrophy are probably more closely correlated with irreversible clinical dysfunction than the number or size of plaques. When the lesion involves gray matter, nerve cells are less affected than is myelin, but some cells may be destroyed and show degenerative changes. In the early or acute lesion there is marked hypercellularity, with macrophage infiltration and astrocytosis accompanied by perivenous inflammation with lymphocytes and plasma cells. Myelin sheaths disintegrate, and chemical breakdown of myelin occurs. It is not yet established whether the cellular response leads to, or occurs as a result of, the myelin breakdown. These acute lesions may remain active for several months with continued macrophage and astrocytic hyperactivity and breakdown of myelin. Phagocytic cells are laden with lipid degradation products of myelin. In these active but nonacute plaques, the inflammatory cell response is minimal centrally. At the edges, however, myelin disintegration is still active, and numbers of macrophages, lymphocytes, and plasma cells are increased. With time, the plaques become inactive. Demyelination is prominent, almost total oligodendrocyte cell loss occurs, and gliosis is extensive. Inactive lesions are hypocellular and devoid of myelin breakdown products. Remyelination in MS plaques, particularly after the early acute phase, is thought to result from the differentiation of a precursor cell that is common to type II astrocytes and oligodendrocytes. This remyelination, however, is usually aberrant and incomplete. Uniform areas of incomplete myelination (“shadow plaques�) are evident in some chronic lesions; it is not known whether these regions result from partial demyelination or incomplete remyelination. Electron microscopy reveals different aspects of myelin disorder in MS, including widening of the outer myelin lamellae, splitting and vacuolation of myelin sheaths, vesicular dissolution of myelin, myelin sheath fragmentation, ball and ovoid formation, filamentous accumulations in sheath, thin myelin sheaths, and macrophage-associated pinocytosis and actual peeling of layers of myelin by the processes of these microglial cells. The peripheral nerves are usually normal. Subtle changes, however, in sural nerve biopsies include endothelial pinocytosis, expansion of the endoneurial space, mononuclear cell infiltration, or demyelination. In addition, hypertrophic neuropathy and chronic inflammatory demyelinating polyneuropathy have been reported in

patients with MS. Biochemical analysis of MS lesions reveals a decrease in both the protein and the lipid components of normal myelin. Thus, by immunocytochemistry, a decrease in staining for the MBP and myelin-associated glycoprotein and a decrease in cholesterol, glycolipids, phosphoglycerides, and sphingomyelins result. Because of phagocytosis and lysosomal activation, myelin breakdown products, including polypeptides, glycerol, fatty acids, and triglycerides, are abundant, particularly in active lesions. Based largely on immunohistologic analysis of cell types in lesions, some investigators believe that there are variants in the pathology of MS and that individual patients tend to have one type of pathology. For example, lesions may vary in the prominence of T cells or macrophages and may vary in the extent of demyelination. This has led to the suggestion that MS may not be a single disease but rather a group of disorders all characterized by the final common pathway of inflammatory mediated demyelination. Others have found too much pathologic overlap in a single patient to warrant the view that these variants imply different forms of MS.

SYMPTOMS AND SIGNS MS is characterized by dissemination of lesions in time and space. Exacerbations and remissions occur frequently. In addition, signs and symptoms usually indicate more than one lesion. Clinical manifestations may be transient and some may seem bizarre. The patient may experience unusual sensations that are difficult to describe and impossible to verify objectively. The symptoms and signs (Table 133.1 and Table 133.2) are diverse and seem to include all the symptoms that can result from injury to any part of the neuraxis from the spinal cord to the cerebral cortex. The chief characteristics are multiplicity and tendency to vary in nature and severity with time. Complete remission of the first symptoms frequently occurs, but with subsequent attacks, remissions tend not to occur or are incomplete. The clinical course extends for one or many decades in most cases, but a rare few are fatal within a few months of onset.

TABLE 133.1. COMMON SYMPTOMS AND SIGNS IN CHRONIC MULTIPLE SCLEROSIS

TABLE 133.2. SYMPTOMS AND SIGNS SEEN INFREQUENTLY IN MULTIPLE SCLEROSIS

The clinical manifestations depend on the particular areas of the CNS involved. Although no “classic” form of MS exists, for unknown reasons the disease frequently involves some areas and systems more than others. The optic chiasm, brainstem, cerebellum, and spinal cord, especially the lateral and posterior columns, are commonly involved (Table 133.1). Because of these predilections, some clinicians have classified MS into spinal, brainstem, cerebellar, and cerebral forms. These “forms” are often combined, and such classification is of no clinical value. In fact, the combination of anatomically unrelated symptoms and signs forms the basis for the clinical diagnosis of MS. Visual symptoms include diplopia, blurred vision, diminution or loss of visual acuity on one or both sides, and visual field defects ranging from a unilateral scotoma or field contraction (Fig. 133.9) to homonymous hemianopsia. These symptoms characteristically begin over hours or days. Patients may also complain of a curious and quite distinctive problem in recognizing objects or faces, often stated as “blurry vision.” This symptom is caused by optic nerve lesions that result in loss of contrasts of shade and colors. In early or mild optic or retrobulbar neuritis, color vision may be decreased, whereas black and white vision remains normal. Rarely, when color vision is affected in both eyes, either transient or permanent color blindness, almost always of the red-green type, may result. Examination of the visual fields with a red or green test object may uncover a central scotoma or field contraction that is not apparent with the usual white test object. Optic neuritis must be differentiated from papilledema because the fundoscopic appearance of both may be similar if the plaque is near the nerve head. Optic neuritis, however, is characterized by early impairment of visual acuity, which is a late manifestation of papilledema. A central or cecocentral scotoma is the most characteristic field loss. Retrobulbar neuritis, a common manifestation of MS, may not be associated with any fundoscopic abnormality but is revealed only by loss of visual acuity.

FIG. 133.9. Cecocentral scotoma in patient with acute right optic neuropathy: multiple sclerosis of 3 years' duration.

Diplopia may be caused by lesions in the medial longitudinal fasciculus that produce internuclear ophthalmoplegia. In young adults, internuclear ophthalmoplegia is uncommon in any other condition and is therefore an important sign in the diagnosis of MS. It is characterized by paresis of one medial rectus with failure of the eye to

adduct on the side of the lesion and by nystagmus and weakness of the lateral rectus on the other side. This impairment of gaze may be present on attempts to look to one or both sides. In uncomplicated lesions of the medial longitudinal fasciculus, action of the medial rectus is preserved in reflex convergence, thus implying a supranuclear lesion. Mild diplopia may be reported as blurred vision. The true nature of the complaint is discovered only if the patient shuts one eye and vision improves. The sudden onset of optic neuritis, without any other CNS signs or symptoms, is often interpreted as the first symptom of MS. Optic neuritis may also result, however, from a postinfectious or postvaccinal reaction or other conditions. The frequency by which MS follows a single isolated episode of optic neuritis is difficult to determine; published figures range from 15% to 85%. This spread is probably the result of differences of follow-up periods or of diagnostic and assessment measures. A critical review of published figures suggests that 35% to 40% of patients with optic neuritis ultimately develop MS. The most common pupillary abnormalities are irregularities in the outline of the pupil, partial constriction, and partial loss of the light reflex. Involvement of the descending root of the fifth cranial nerve occurs in some patients. Pain sensation in the face may be impaired and the corneal reflex may be diminished or lost. Paroxysmal pain indistinguishable from cryptogenic trigeminal neuralgia may occur. This symptom often responds to carbamazepine. MS should be considered whenever a young adult develops trigeminal neuralgia. Weakness of the facial muscles of the lower half of one side of the face is common, but complete peripheral facial palsy is rare. On the other hand, hemifacial spasm (consisting of spasmodic contractions of facial muscles) is a rare but characteristic paroxysmal disorder of MS. True vertigo, which often lasts several days and may be severe, is seen with new lesions of the floor of the fourth ventricle but is seldom a chronic symptom. Dysarthria and, rarely, dysphagia are seen in advanced MS because of cerebellar lesions or bilateral demyelination of corticobulbar tracts that cause pseudobulbar palsy, which is also characterized by emotional lability and forced laughing or crying without the accompanying affect. Limb weakness is the most common sign, almost always present in advanced cases. Monoparesis, hemiparesis, or tetraparesis may be present; an asymmetric paraparesis is most common. Fatigability out of proportion to demonstrable muscular weakness is common. Direct testing of muscle strength alone often does not correlate with the degree of difficulty in walking. Concomitant spasticity and ataxia augment the gait disturbance. Gait ataxia is caused by a combination of lesions in the cerebellar pathways and loss of proprioception resulting from lesions in the posterior columns of the spinal cord. In some patients, particularly those with late onset, the disease may appear as a slowly progressive spastic paraparesis, with no abnormality except corticospinal signs (spasticity, hyperreflexia, bilateral Babinski signs) and slight impairment of proprioceptive sensation. The cerebellum and its connections with the brainstem are usually involved, thereby causing dysarthria, gait ataxia, tremor, and incoordination of the trunk or limbs. Tremor of the head and body is occasionally almost continuous when the patient is awake. The characteristic scanning speech of MS is a result of cerebellar incoordination of the palatal and labial muscles combined with dysarthria of corticobulbar origin. (The so-called Charcot triad of dysarthria, tremor, and ataxic gait is a combination of cerebellar symptoms.) Urinary symptoms are also common, including incontinence and frequency or urgency of urination, and must be differentiated from manifestations of urinary tract infections or local conditions. Fecal incontinence or urgency is less common than urinary disturbances, but constipation is not unusual, especially in established cases. Loss of libido and erectile impotence are common problems in men. Almost invariably these are associated sphincter disturbances or corticospinal tract dysfunction, but psychologic problems may compound the problem. Sexual dysfunction in women is also frequent. Lack of lubrication and failure to reach orgasm are the major problems, but sensory dysesthesias are also significant. Paresthesias and sensory impairment are common. When they are symptoms of an acute relapse, they tend to resolve completely in 6 to 8 weeks. In advanced disease, vibratory perception is commonly affected. Frequently, patients feel tingling or numbness in the limbs, trunk, or face. The Lhermitte symptom is a sensation of “electricity” down the back after passive or active flexion of the neck. It indicates a lesion of the posterior columns in the cervical spinal cord and may be seen in other diseases. The Lhermitte symptom is rarely elicited by flexion of the trunk. Pain is increasingly recognized as a frequent and disabling symptom. Pain may be associated with the Lhermitte phenomenon, trigeminal neuralgia, or retrobulbar neuritis. Other types of pain include painful flexor-extensor spasms; painful tonic spasms of the limbs (which can be evoked by hyperventilation); local pain such as constricting pain around a limb, burning pain, or pseudoradicular pain; foreign body sensation; headache; pain with pressure sores; pain caused by joint contractures and osteoporosis; pseudorheumatic pain with myalgia and arthralgia; or neuralgic pain shooting down the legs or around the abdomen, as in tabetic pain. Psychiatric mood disorder symptoms are frequent. Depression is common. Whether it is directly related to MS lesions or a psychologic response to the disease is unclear. Both mechanisms are likely. Euphoria was once considered characteristic of MS patients. Even when this symptom exists, it appears more likely to be a frontal lobe dysinhibition syndrome, and underlying depression is often found. Some have found hypomanic behavior or bipolar disorders to be more common than expected by chance. This does not appear to be part of the disease, because the lifestyle is apparent long before neurologic symptoms occur. A genetic linkage has been suggested, but significant epidemiologic data have not been obtained. Some have commented upon a tendency of patients to exaggerate and extend symptoms that have an obvious anatomic basis. Thus, diplopia may be transformed into triplopia, quadriplopia, or monocular double vision. However, because even the most obvious sensory symptoms often lack distinct correlates in the neurologic examination, it is dangerous to assume that unexplained sensory phenomenon are “psychogenic.” Cognitive, judgment, and memory disorders are important features in MS and may be more important than physical disorders in causing disability. These changes may range from the very obvious to subtle; even sophisticated psychometric studies may not detect early changes. Remedial training for memory problems may be helpful. Awareness of these potential difficulties may help relatives, friends, and patients cope with otherwise difficult behavior. Aphasic disorders are occasionally the major feature of an exacerbation. Fatigue is another common symptom. It may appear as persistent fatigue, easy fatigability related to physical activity, or fatigue related to minor degrees of mental exertion. It is often the prodromal symptom of an exacerbation. Fatigue is not related to age because it is noted with the same frequency by patients under 30 or over 50. Also, fatigue is not related to the amount of physical disability because it is noted in more than 50% of patients with early MS. It is important to analyze the symptom; depression or lack of sleep due to nocturia may play a role. The fatigue of MS may respond to brief naps. As may be seen from Table 133.1, most symptoms described occur in more than 50% of patients with MS at some time. The clinical features of MS, however, are protean; almost any part of the CNS may be affected (Table 133.2). One of the characteristics of MS symptoms is evanescence. Diplopia may last only a few seconds. Paresthesias may last for seconds or hours; diminution of visual acuity may be equally short-lived. Transient loss of color vision may presage the onset of optic neuritis. Because of the transient and bizarre nature of these symptoms, they are frequently deemed hysterical before clearer manifestations arise. There may also be paroxysmal limb spasms, incoordination syndromes, or neuralgias. Trigeminal neuralgia in young people is most clearly associated with MS, but similar pains in other distributions may occur. Both the paroxysmal movements and neuralgias often respond to carbamazepine. Other transient disorders may be precipitated by exercise, exposure to heat, or other stimuli. Transient dysesthesias, visual blurring or diplopia, or weakness after hot showers or exercise may occur. These episodes appear to represent derangements of the neurologic signal through previous damaged pathways and not an increase in the inflammatory process. They invariably disappear soon after the provoking activity is stopped. Remissions are also characteristic, but clinicians have difficulty agreeing on the nature or duration of some remissions. If a remission is defined only by the complete or almost complete disappearance of a major symptom, such as loss of vision, marked weakness of a limb, or diplopia, clinical remissions occur in about 70% of all patients early in the course of the disease.

MODE OF ONSET The onset is usually acute or subacute within days and is only rarely apoplectic. There is no characteristic mode of onset, but some symptoms and signs are more common (Table 133.3). Monosymptomatic onset is most common, but when onset is polysymptomatic, the clinical features often help to establish the diagnosis.

Frequently, however, the past history reveals remote or recent episodes of other manifestations that had been ignored or not considered significant by the patient or physician. Dismissal is particularly true of transient paresthesias, mild urinary disturbances, or mild ocular manifestations, such as blurred vision or transient diminution of monocular visual acuity.

TABLE 133.3. COMMON SYMPTOMS AND SIGNS AT THE ONSET OF DISEASE IN PATIENTS WITH CLINICALLY DEFINITE MULTIPLE SCLEROSIS

LABORATORY DATA There is no pathognomonic test for MS, but magnetic resonance imaging (MRI), CSF examination, and evoked potential studies are of greatest diagnostic value (Table 133.4).

TABLE 133.4. LABORATORY FINDINGS IN MULTIPLE SCLEROSIS (MS)

The most valuable laboratory aid is MRI, which shows multiple white matter lesions in 90% of patients ( Fig. 133.10) and is the imaging procedure of choice in the diagnosis of MS. T2-weighted imaging has been the standard for demonstrating areas of involvement. Subsequently, proton density images and the fluid-attenuated inversion recovery technique have enhanced the ability to detect lesions, particularly in periventricular distribution. The distribution and morphology of plaques on T2-weighted MRI may be strongly suggestive of MS (Fig. 133.11) but occasionally it is difficult to distinguish from other lesions, particularly vascular disease. The MS plaques are found in the white matter in a periventricular distribution; the posterior poles of the lateral ventricles and the area of the centrum semiovale are most frequently involved. Corpus callosum lesions are characteristic and are brought out best with saggital proton density or fluid-attenuated inversion recovery. The most common appearance is of homogeneously hyperintense lesions; less commonly, ring or cystic lesions may occur. T1-imaging is not sensitive, but hypodense areas (“black holes�) may be observed; these may be superimposed on active lesions or with frank tissue necrosis and glial scarring. Gadolinium enhancement is useful in defining areas of active inflammation. Triple-dose gadolinium is more sensitive than the standard dose, and delay in scanning after injection also enhances detection of inflammation. Because nonspecific white matter abnormalities are commonly seen, particularly in patients older than 50 years, a careful approach is still advisable when interpreting MRI studies despite the improvement in techniques ( Table 133.4). Correlation of the MRI and the clinical history is of paramount importance.

FIG. 133.10. A: Proton-density axial magnetic resonance image shows multiple hyperintense lesions within the periventricular white matter and corona radiata that are suggestive of demyelinating plaques. B: T1-weighted axial magnetic resonance image after gadolinium enhancement shows that some of these lesions exhibit contrast enhancement. (Precontrast T1-weighted images showed no hyperintense lesions.) Contrast enhancement of demyelinating plaques suggests active demyelination, and acute exacerbation of multiple sclerosis was evident clinically in this patient. (Courtesy of Dr. S. Chan.)

FIG. 133.11. A and B: Proton-density and T2-weighted axial magnetic resonance images demonstrate multiple periventricular hyperintense lesions, many of which abut the ependymal lining of the lateral ventricles. C: T2-weighted axial magnetic resonance image shows single hyperintense lesion within inferior left pons. D: T2-weighted sagittal magnetic resonance image shows two hyperintense lesions within cervical cord. This distribution of lesions is highly suggestive of multiple sclerosis. (Courtesy of Dr. S. Chan and Dr. A. G. Khandji.)

Although MRI has been most useful diagnostically, correlation with clinical findings and disability has been disappointing. First, MRI abnormality is only an indirect measure of the actual lesions, and histologic damage may be far less than the size on the scan. This amplification factor is useful diagnostically but reduces the correlation with function. Also, much of observed motor dysfunction is based on spinal cord lesions, which are difficult to image and are unobserved if only the brain is imaged. Volumetric MRI studies demonstrate cerebral atrophy even early in MS when obvious lesions are relatively sparse. This atrophy reflects axonal and neuronal loss and correlates better with disability than other scanning techniques, particularly with cognitive and memory dysfunction. Unfortunately, these techniques are largely clinically unavailable. MR spectroscopy is useful for analyzing the parenchyma involved in MS lesions. Changes in tissue components may antedate by 1 week even the earliest observable MRI finding of gadolinium enhancement. Some have speculated that this may indicate the inflammatory process is only secondary to some other neuropil involvement. Further studies are required to resolve the issue. Examination of the CSF frequently provides supportive information for the diagnosis ( Table 133.4). The characteristic changes in CSF gamma globulins (IgG) are the most useful findings. The presence of oligoclonal IgG bands by electrophoretic analysis of CSF is the most frequent abnormality. A few antibody-producing plasma cell clones are thought to proliferate within the neuraxis in MS. The IgG production of these clones stands out in the electrophoretic analysis of the CSF as distinct oligoclonal bands (OCBs). This pattern is not seen in normal people, in whom the CSF IgGs are passively derived from the serum and appear as diffuse broad bands in electrophoretic gels. For OCBs to be diagnostically useful, two or more bands must be seen, and these bands should be either absent from the serum or present in lower concentrations than in CSF, implying primary intrathecal synthesis of the IgG. More than 90% of patients with clinically definite MS have CSF OCBs, but they are also detected in patients with other CNS inflammatory or infectious diseases. The other conditions, however, often reveal serum bands of at least equal intensity, thus indicating the systemic nature of the illness. For reasons unknown, OCBs are found in about 5% of patients with other (noninflammatory) neurologic problems. The first abnormality of CSF IgG reported in MS was a relative increase in concentration of IgG compared with CSF total protein. This increase is found in only 70% of patients with clinically definite MS. Refinements of technique now compare the concentration of CSF IgG to serum IgG and take into account the relative concentrations of serum and CSF albumin, thereby increasing the sensitivity. By accounting for the relative albumin concentrations, the method can be used when the CSF total protein content is elevated, indicating breakdown of the blood–brain barrier and passive diffusion of antibody into the CSF from the serum. Formulas have been derived to estimate intrathecal IgG synthetic rate, which is elevated in MS. The sensitivity of these measurements now approaches the frequency of detection of CSF OCBs by electrophoresis. The recording of cortical-evoked responses from visual, auditory, and somatosensory stimulation is also of great value in demonstrating clinically unsuspected lesions (Table 133.4). Visual-evoked responses to both flash and pattern reversal stimuli demonstrate abnormalities in many patients without symptoms or signs of visual impairment. Somatosensory-evoked potentials may help but are usually normal unless there are distinct clinical symptoms or findings. Brainstem auditory-evoked responses are even less sensitive in detecting abnormalities in asymptomatic patients but may be useful in confirming abnormalities in patients with brainstem symptoms or signs. These procedures are simple, noninvasive, harmless, and may be useful in providing evidence of anatomic abnormalities when clinical data are not clear. Magnetically evoked motor potentials detect lesions of the motor pathways from the cortex to spinal cord. This technique is not yet widely available.

DIAGNOSIS Because no specific test for MS is available, the diagnosis rests on the multiple signs and symptoms with characteristic remissions and exacerbations ( Table 133.5). The diagnosis can rarely be made with assurance at the time of the first attack. The diagnosis of MS is based on the ability to demonstrate, on the basis of the history, neurologic examination, and laboratory tests, the existence of lesions involving different parts of the CNS. The history should bring out mild and transient past events, and the examination should be detailed (e.g., testing for monocular color vision).

TABLE 133.5. CRITERIA FOR CLINICAL DIAGNOSIS OF MULTIPLE SCLEROSIS (MS)

The advent of technologically based laboratory tests ( Table 133.4) has added a new dimension to the documentation of multiple lesions. Even in patients who have had a single attack of optic neuritis or transverse myelitis, these tests may indicate more than one lesion, thereby changing the diagnosis from “probable” to laboratory-supported “definite” MS. At present, the following guidelines combine the clinical criteria of 1976 ( Table 133.5) and those of 1983 (Table 133.6) with a few modifications:

TABLE 133.6. CRITERIA FOR THE DIAGNOSIS OF MULTIPLE SCLEROSIS

1. Clinically definite MS requires either evidence from both history and neurologic examination of more than one lesion or evidence from history of two episodes, signs of one lesion on examination, and evidence from evoked responses or MRI of other lesions. 2. Laboratory-supported definite MS requires evidence of two lesions in either history or examination. If only one lesion is evident in either of those categories, at least one more lesion must be evident in evoked response or MRI. In addition, CSF IgG content and pattern should be abnormal. 3. In clinically probable MS, either history or examination, but not both, provides evidence of more than one lesion. If only one lesion is evident by history and only one by neurologic examination, evoked potentials or MRI may provide evidence of one or more lesions in addition. In this category, CSF IgG studies are normal. In practice, these criteria are overly conservative because the diagnosis can certainly be made in patients even if symptoms begin after age 50. Finally, when the

diagnosis of MS cannot be made with certainty, the clinician should reevaluate the patient rather than make a hasty diagnostic decision. In some cases, however, MS may remain asymptomatic, and a firm diagnosis may be made only at autopsy.

DIFFERENTIAL DIAGNOSIS In young adults with characteristic manifestations ( Table 133.3) and laboratory abnormalities (Table 133.4), the diagnosis is easily made. Although the complete list of diagnostic possibilities may seem endless, only a few disorders have similar clinical or laboratory features that lead to diagnostic difficulties ( Table 133.7).

TABLE 133.7. DIFFERENTIAL DIAGNOSIS OF MULTIPLE SCLEROSIS

It is difficult, if not impossible, to differentiate between the first attack of MS and acute disseminated encephalomyelitis (ADEM). ADEM follows infection or vaccination and occurs most commonly in children. A clear distinction between the two conditions may not be possible because about 25% of patients diagnosed as having ADEM later develop MS. Furthermore, the pathologic lesions of MS and ADEM are difficult to distinguish. In endemic areas, Lyme disease is an important consideration because chronic CNS infection with Borrelia burgdorferi can cause spastic paraparesis, cerebellar signs, and cranial nerve palsies. The MRI and CSF abnormalities of MS can also be seen in Lyme disease, so the diagnosis of Lyme disease must rest on a history of characteristic acute symptoms and rash of Lyme disease, with demonstration of antibodies to Borrelia antigens in high titer and in both CSF and serum. Because other infections may mimic MS, serologic tests for human immunodeficiency virus, human T-cell lymphotropic virus type I, and syphilis are required. Progressive multifocal leukoencephalopathy should be considered in immunosuppressed individuals. Several autoimmune diseases have CNS manifestations and particularly MRI changes that can resemble MS. SLE, polyarteritis nodosa, Sjögren syndrome, Behçet disease, and sarcoidosis are the most notable. The non-CNS features of these diseases usually distinguish them from MS, but if diagnostic difficulties are encountered, specific serum antibody tests, such as anti-DNA antibodies in SLE, or a biopsy of an appropriate site, such as in sarcoidosis, are sufficient to clinch the diagnosis. Paraneoplastic syndromes with cerebellar signs may cause diagnostic problems, particularly in older patients. Serum antibodies to Purkinje cells are useful in making the diagnosis. Subacute combined degeneration should be excluded in all cases of spinal MS by measuring serum vitamin B 12 levels. Similarly, women with progressive spastic paraparesis should have a test for the plasma content of very-long-chain fatty acids to exclude the heterozygous carrier state of adrenomyeloneuropathy. Subacute myelooptic neuritis is an adverse reaction to chlorhydroxyquinoline; relapses of sensory symptoms, limb weakness, and optic neuritis may occur. Subacute myelooptic neuritis is restricted almost exclusively to Japanese people, and no further cases should be seen because the drug has been withdrawn. Hereditary spinocerebellar ataxia syndromes can cause diagnostic dilemmas. If the syndrome is Friedreich ataxia, differentiation is easily made on clinical grounds, but if only cerebellar and pyramidal signs develop, diagnosis may be difficult. The most vexing problem is to separate slowly progressive spastic paraparesis of MS from hereditary spastic paraplegia or primary lateral sclerosis, especially if CSF studies and MRI are normal. Vascular disease, arteriovenous malformations, tumors of brain or spinal cord, and arachnoid cysts can have relapsing-remitting signs. MRI is usually defining. The effects of an Arnold-Chiari malformation can simulate MS clinically, but MRI findings are usually diagnostic. Cervical spondylotic myelopathy may simulate spinal MS; MRI of the brain and CSF changes may indicate MS. Common neurologic conditions, including cerebrovascular disease or cervical spondylosis, may be found in a patient who also has MS. Determination of whether new symptoms are caused by relapse of MS or by the coexisting condition may be challenging. History, examination, and MRI are of greatest use in determining the cause.

COURSE AND PROGNOSIS The clinical course of MS varies. Exceptional cases are clinically silent for a lifetime; the typical pathologic findings are discovered only at autopsy. At the other extreme, some cases are so rapidly progressive or malignant that only a few months elapse between onset and death. Clinical observation of the course of MS led to the description of “types.” Relapsing-remitting MS is one type. This pattern is usually present at the outset and is characterized by exacerbations followed by a variable extent of improvement, ranging from complete resolution of neurologic deficit to symptomatic residual dysfunction. About 10% of patients have relatively few attacks throughout their life and accrue minimal disability. This is referred to as benign MS. Relapsing-remitting MS frequently (approximately 85% of the time) evolves into a situation in which the course progresses slowly in between or in lieu of discrete attacks. This is referred to as secondary-progressive MS. Subsets have also been described. These descriptions have limitations because a relapsing-remitting course may occur for several years followed by a chronic-progressive illness. Also, no universal agreement has been reached about the definition of relapse or remission. Determining if a patient is having a relapse may be difficult, especially in mild cases, and the assessment is often made in retrospect. There is no discernible difference in MRI activity between relapsing-remitting and secondary-progressive MS, and the change of course does not indicate a change in the inflammatory process. This is supported by newer information that the b-interferons appear to be beneficial in the treatment of both these phases of MS. Primary-progressive MS has some different characteristics from the other types of MS and is discussed more fully below as a variant. The diagnostic use of evoked potentials, CSF OCBs, and MRI has changed concepts about the course of MS. People once thought to have a mild neurologic disorder of undetermined cause are now included as having probable or definite MS, altering the incidence and prevalence data of clinical subtypes. The question most frequently asked by patients is that of prognosis. Unfortunately, no reliable prognostic indicators are available, and the generalizations that follow may not be applicable in individual cases. The characteristics of a good prognosis in order of usefulness are minimal disability 5 years after onset, complete and rapid remission of initial symptoms, age 35 years or less at onset, only one symptom in the first year, acute onset of first symptoms, and brief duration of the most recent exacerbation. In general, onset with sensory symptoms or mild optic neuritis is also associated with a good prognosis. Poor prognostic indicators include polysymptomatic onset, cerebellar signs of ataxia or tremor, vertigo, or corticospinal tract signs. Disability and work capacity are important concerns in any chronic disease with onset from 15 to 55 years ( Table 133.8). Overall, MS has only a modest effect on life

expectancy, but disability is a major issue. After 10 years, 70% of MS patients are not working full-time because of cognitive and memory disorders, spastic paraparesis, poor coordination, and sphincter dysfunction.

TABLE 133.8. WORKING CAPACITY AND SURVIVAL IN 800 PATIENTS WITH MULTIPLE SCLEROSIS

Death from MS itself is rare. Bronchopneumonia after aspiration or respiratory insufficiency is the most common cause of death. Other causes include cardiac failure, malignancies (as would be expected in older patients regardless of MS), septicemia (decubitus ulcers, urinary infections), and suicide. In the last few decades, average survival has increased from 25 years to 35 years after onset, probably as a result of better management of infection and decubitus ulcers.

VARIANTS OF MULTIPLE SCLEROSIS Several variants of MS are recognized. The typical form of relapsing-remitting disease, which often evolves into more progressive disease, is called the Charcot variant. Primary-progressive MS differs from the more common form because it is progressive from the outset and distinct exacerbations do not occur. It accounts for about 10% of MS cases and is more common in older men. Brain MRI lesions tend to be sparse or absent, and this seems to be mainly a spinal cord syndrome. Not infrequently, optic neuropathy is present as demonstrated by visual evoked responses (VERs). The pathology tends to show a less exuberant immune inflammatory component than in more typical disease. OCBs are, however, found in the CSF in over 50% of patients. The course is more relentless than that of typical MS. A more rapidly progressive disease with severe disability and frequently death in the first year is the Marburg variant. The pathology usually shows more exuberant inflammation and axonal loss than in the Charcot variant. Some patients have a fulminant myelitis with optic neuritis, which is frequently bilateral; this combination is called the Devic syndrome. Some consider it a separate disease because of the severely necrotic lesions and a relative paucity of immune active cells. However, many cases with typical pathology of Devic syndrome have had a previous course consistent with the Charcot variant and many cases have lesions that elsewhere are indistinguishable from classic MS. Schilder disease appears to be fulminant MS in children. The pathology is similar to that of MS, but confluent lesions involving both hemispheres are typical. The concentric sclerosis of Balo also occurs primarily in children. The course is similar to typical MS but the pathology is strikingly different and characterized by concentric rings of inflammation and demyelination. It is not known how this pattern comes about. Although these variants are unusual, without clear knowledge of etiology and pathogenesis it is impossible to state authoritatively whether they are separate diseases or forms of MS. Finally, some paroxysmal inflammatory CNS disorders in adults are equivocally related to MS. Cases of recurrent optic neuritis without any evidence of other neuraxis involvement are well known. Similarly, recurrent episodes of myelitis may occur without other CNS lesions. The CSF may be inflammatory, but OCBs are often absent. ADEM may be clinically indistinguishable from an attack of MS. Lesions tend to be more inflammatory and less demyelinating than MS plaques. ADEM is characteristically a monophasic illness and may be more of a cognate for EAE than MS. Recurrences have been reported, but unless there is a distinct immune stimulant, it is hard to understand why these cases should not be classified as MS.

MANAGEMENT MS presents a major challenge for the physician. The fact that no known cure exists is often interpreted as meaning that no treatment is effective. This error leads to neglect of symptoms and complications that are amenable to prevention and treatment. The skepticism and pessimism pervasive among physicians are based in large part on the long list of ineffective therapeutic regimens that have been tried. Although no cure is in sight, the results of controlled therapeutic trials with b-interferons suggest that the natural history of MS can be favorably altered. Before making specific recommendations about treatment, some general guidelines are appropriate: 1. The patient and family should be informed of the diagnosis by specific name when it is firmly established, so they can begin to accept the diagnosis and can avail themselves of all accessible services. 2. The disease should be explained in understandable terms, with a realistic but best possible prognosis. 3. At first, the patient should be reevaluated at short intervals for counseling and support and then at regular intervals to monitor possible complications and to evaluate progress. 4. The patient should be given realistic information about the goals of therapy and should participate in decisions (e.g., adjustment of antispastic medication). 5. Patients with MS have complex problems, and many benefit from care at MS centers, where a team approach provides comprehensive service. 6. The patient should be informed about local and national MS societies that provide educational material, support groups, and other services. Therapeutic regimens are either disease specific (immunosuppressive or immunomodulatory) or symptomatic. If the symptoms of an acute attack are severe enough to warrant treatment, methylprednisolone is given in a dose of 1 g by intravenous infusion daily for 7 to 10 days. This is followed by oral prednisone in a tapering schedule. A typical tapering regimen follows: prednisone 80 mg daily for 4 days; followed by 60, 40, 20, 10, and 5 mg each for 4 days; and then four doses of 5 mg on alternate days. Tapering schedules are arbitrary and are often empiric or based on speculative theoretic considerations. They may be considerably longer or shorter than the one described. Alternatively, corticotropin may be given, but it has lost favor because it seems to give less rapid improvement. In controlled trials, steroid therapy hastens recovery from acute attacks, but it is not clear whether it affects the eventual outcome. Both CSF pleocytosis and MRI findings are reduced in patients who receive intravenous high-dose steroid therapy. A shorter (3-day) high-dose intravenous methylprednisolone treatment was compared with oral steroids and placebo over a 2-year period in patients with a first episode of optic neuritis alone. The effect on speeding up recovery without influencing eventual outcome was confirmed. Retrospective data analysis suggested that the development of MS was delayed in the intravenous methylprednisolone group. The 3-day course of intravenous high-dose cortico-steroids is a matter of convenience and has never been demonstrated to be as effective as longer courses. In the short term, adverse effects of corticosteroids are usually minimal or transitory. Psychologic agitation is perhaps most common and should be treated if it occurs. Avascular necrosis of joints is rare but can occur regardless of the steroid dose. Patients who have frequent relapses and are treated repeatedly with steroids, however, are at risk of serious adverse effects. To minimize these effects, the steroid dosage is tapered and calcium carbonate supplements (650 mg two times per day) are given to forestall osteoporosis. Chronic oral steroid use has no merit, either daily or on alternate days, because this treatment does not alter the course of the disease.

In 1993, the first practical treatments for use in early MS that affected the course of the disease became available in the United States and subsequently in other countries. Two classes of medications are now in use. b-Interferon is available in two preparations with a third expected soon. The first released was b-interferon-1b (Betaseron), a form chemically modified from naturally occurring human b-interferon. This medication is given on alternate days subcutaneously in a dose of 0.250 mg. b-Interferon-1a (Avonex) is chemically unaltered and is given intramuscularly once week in a dose of 30 µg. Rebif is also classified as a b-interferon-1a but is not yet commercially available. In initial trials it was given three times weekly in doses of 22 or 44 µg subcutaneously. In placebo-controlled studies, all three forms of b-interferon have given remarkably similar results. They all seem to reduce the frequency of attacks in the relapsing-remitting phase by about 30%. The severity of attacks also seems to be reduced. Favorable effects on MRI changes have also been noted. Most important, a favorable effect on the development of disability is now being established for these medications. Studies in progressive disease are also being concluded; one published study of Betaseron confirms its usefulness in retarding progression. Similar results can be anticipated for the other b-interferons. The b-interferons are well tolerated. Early in treatment a “flulike” syndrome may follow each injection but rarely lasts longer than 24 hours. It may include myalgia, arthralgia, headache, and fever, which dissipate in about a month. Taking the medication in the evening and with acetaminophen or a nonsteroidal anti-inflammatory drug often ameliorates the syndrome. Low doses of corticosteroids at the outset of treatment have also been advocated. Rarely, these symptoms persist and force discontinuation of treatment. Some patients find that their function decreases the day after an injection, and this may also necessitate discontinuation. Hepatic abnormalities and bone marrow depression may occur but rarely necessitate discontinuation. Periodic blood studies are advisable in the first 2 years of administration. Although there is no known danger to the fetus, manufacturers have indicated pregnancy (including the period of conception and breastfeeding) as a contraindication to the use of the b-interferons. Depression is commonly thought to be caused by the b-interferons, but there is no scientific support for this contention, based solely on anecdote. All these medications can be self-administered, if neurologic function permits. Neutralizing antibodies against b-interferon may appear and render treatment ineffective. Development of antibodies seems to be more frequent with Betaseron (approximately 25%), intermediate with Rebif, and least frequent with Avonex (5% to 10%). The subcutaneous route for injection may be a factor in antibody development. If antibodies interfere, medication should probably be stopped and alternative treatment considered. There is now debate about the optimum route of administration and dosage, the intensity of which is matched only by the lack of directly comparable information. Unfortunately, the information is unlikely to be forthcoming, because it would require a direct comparison of the medications, and the expense of such a study would be staggering. The other disease-specific therapy currently available is glatiramer acetate (Copaxone or copolymer I), a mixture of polymers of four amino acids. One of the sequences is a nonencephalitogenic peptide fragment of MBP. It has been demonstrated to have effects similar to the b-interferons on exacerbation frequency and attack severity. However, effects on MRI lesions or development of disability are less well established. Some consider this to be the drug of choice in early mild cases, as suggested by controlled studies. Its effect on progressive problems is currently being studied. Glatiramer acetate is given subcutaneously on a daily basis. It is not associated with systemic symptoms or abnormalities; some patients report chest pressure similar to angina, but there is no evidence of cardiac ischemia. The injections can be associated with intense but brief pain. When disease-specific treatment first became available, fewer patients accepted treatment then was anticipated. The reasons were diverse but included reluctance to take injections and disappointment because of the partial effect. As evidence accrued of a favorable effect on progression, the importance of early treatment became more apparent. The current recommendation of the National Multiple Sclerosis Society is that all patients with clinically definite exacerbating disease should be taking medication. In view of the information supporting the use of b-interferon in progressive illness, many experts are treating MS patients as well. A study of Avonex is designed to determine the benefit of taking b-interferon before a second attack occurs. Severe and frequent relapses or rapidly progressive MS pose a difficult therapeutic problem. This may occur at the outset of the disease or later even with treatment with one of the prophylactic agents. Typically, these patients have no response to high-dose intravenous steroids or, more frequently, have a modest initial response and minimal responses with subsequent cycles of therapy. If a b-interferon is being administered, it is appropriate to determine the neutralizing antibody level. Alternative treatments that may be used are mainly the immunosupressants. Cyclophosphamide is used in monthly pulse doses of 800 to 1,000 mg/m 4 helper cells, and some consider this a theoretic advantage. Azathioprine taken orally in a dose of 1 to 2 mg/kg body weight merits mention. As with all other such agents, its use is limited by toxicity, and reliable controlled studies are wanting. Mitoxantrone has been widely used in Europe. Methotrexate taken in doses similar to those used in rheumatoid arthritis (7.5 to 15 mg orally once a week) is modestly effective in progressive disease. It should be considered in situations when prophylactic agents or more intensive chemotherapy is not indicated. In a disease that cannot be prevented or cured, symptomatic therapy is important to minimize functional impairment and discomfort. Spasticity with stiffness, painful flexor or extensor spasms, and clonus are major causes of disability. If untreated, contractures may develop and increase disability. Baclofen is the most commonly used drug at a dose of 40 to 80 mg/day in divided doses. If tolerated, higher doses may be used in severe cases. Diazepam or dantrolene may be added or substituted if necessary. Tizanidine in doses up to 24 mg daily may also be considered. It supposedly does not cause as much weakness as the other antispasticity agents but sedation is a major problem with tizanidine, and very slow titration is required. For localized adductor spasms, injections of botulinum toxin may be useful. However, the large muscle groups involved required large doses of medication and antibody production rapidly develops. In resistant cases, baclofen may be administered intrathecally with an indwelling catheter and implantation of a reservoir pump. Only patients who have a beneficial effect with an intrathecal test bolus dose of 50 to 100 µg baclofen should have the pump implanted. Adverse effects are not common but include meningitis and seizures. Cracks in the tubing may develop and should be considered if effect is rapidly lost. In addition to relief of spasticity, bladder symptoms frequently improve. The dosage of all antispastic agents must be monitored and titrated with the clinical response; flaccidity and unmasked weakness changes in mentation may result in functional deterioration. Bladder management is important to prevent debilitating and life-threatening infections or stone formation and to allow maximum functional independence. The basic problem may be failure to retain urine, excessive urinary retention, or a combination of the two. In all these problems, the symptoms of urgency, frequency, and incontinence are similar. The most important measures are postvoiding residuals, urine cultures, and, occasionally, urodynamic studies or renal ultrasound studies. The atonic bladder with a residual volume over 100 mL is best managed by a program of clean intermittent self-catheterization. Cholinergic drugs, such as bethanechol, carbachol, and pyridostigmine, are marginally and transiently effective in aiding bladder emptying. For acute urinary retention during a relapse of MS, phenoxybenzamine is the drug of choice because it induces relaxation of the bladder neck. Patients with bladder atony are susceptible to urinary infections. Some authorities routinely use urine acidifiers, such as vitamin C, and urinary antiseptics, such as methenamine mandelate, for all such patients. Detrusor muscle hyperexcitability that causes the spastic bladder is the most common cause of urinary urgency and incontinence in patients with MS. Oxybutinin is the most effective agent in relieving symptoms, but other anticholinergic medications include propantheline, hycosamine, and imipramine. Tolterodine (Detrol), a long-acting anticholinergic, has been released and decreases the frequency of dosing. A sustained-release form of oxybutinin is currently under study. The synthetic antidiuretic hormone (vasopressin), desmopressin acetate, has been used with success as an intranasal spray, particularly for patients with nocturia. The usual dose is 10 to 40 µg at night. Serum osmolality and electrolytes should be measured weekly for the first month and then monthly as a precaution in these patients. Some patients find a morning-after rebound effect that is unacceptable. In patients with long-standing bladder disease, indwelling catheters may have to be used even though the risk of infection increases. Disposable catheters, periodic irrigation, weekly catheter renewal, and urine acidifiers minimize infections. Bladder augmentation with a section of bowel has been helpful when bladder size has diminished because of spasticity. A continent port may be placed on the abdominal wall to facilitate catheterization in appropriate situations. In late stages, suprapubic cystostomy or urinary diversion procedures may be appropriate. In all patients with urinary symptoms, a urine culture should be obtained because treatment of infection alone may suffice to relieve new symptoms. Cerebellar symptoms are generally resistant to therapy. An occasional patient with disabling intention tremor may respond to propranolol or clonazepam. Cryothalamotomy may be effective but is reserved for severe cases. Painful radiculopathy or neuralgia and painful parasthesias may respond to carbamazepine or, if not tolerated, to phenytoin or amitriptyline. Less specific pain syndromes may respond to nonsteroidal anti-inflammatory agents. Fatigue may respond to amantadine or pemoline and to a change in work schedule. Methylphenidate is also used to control fatigue. Depression may contribute to fatigue and usually responds to selective serotonin reuptake inhibitor antidepressants. Whether these drugs affect fatigue independent of depression is conjectural.

Constipation responds best to changes in diet, bulk-providing substances, and stool softeners. Laxatives are reserved for resistant cases. Bowel incontinence is less common and is generally unresponsive to medication. Regularization of bowel habits seems the most useful approach. Anticholinergic drugs may be useful adjuncts. Sexual dysfunction should be treated with counseling for both partners, but treatments exist to alleviate the problems. In the past, erectile dysfunction had been treated with papaverine injections, alprostadil intracavernosal injections, or intraurethral suppositories or less effectively with vacuum devices designed to increase penile blood flow. Although often successful, few patients continue to use these treatments. However, sildenafil citrate (Viagra) is successful in treating erectile dysfunction in MS patients. Ease of use makes it likely to be of continuing benefit. In women, lubricating agents may help. The usefulness of sildenafil in restoring orgasmic capability and lubrication is currently being studied in women with MS. When paraparesis is severe, skin care is essential to prevent decubitus ulcers. Physical therapy and nursing care with adequate nutrition and hydration are valuable in preventing painful disabling complications, such as decubitus ulcers, renal and bladder calculi, contractures, and intercurrent infections. When these complications occur, aggressive attempts to relieve them often give gratifying results. Diet therapy and vitamin supplements are frequently advocated, but no special supplementation or elimination diet has proved to be more beneficial than a well-balanced diet that maintains correct body weight and provides sufficient roughage for bowel management. Other therapies, such as hyperbaric oxygen, plasmapheresis, intravenous immunoglobulin, neurostimulation, cobra or bee sting venom, and acupuncture, are unproven, and any response to these treatments is usually a result of coincidental spontaneous remission so often seen early in the disease. Physical therapy should be applied judiciously with the goals of maintaining mobility in ambulatory patients or avoiding contractures in bedridden patients. Excessive active exercise may exhaust the patient, and the increase in body temperature may cause transient symptoms. Swimming in cool water is the best active physical therapy. Occupational therapy is important to assist patients in activities of daily living. MS is one of the few diseases for which a cure is unavailable, yet a comprehensive therapeutic regimen supervised by an experienced and sympathetic physician can give rewarding results. SUGGESTED READINGS Ablashi D, Lapps W, Kaplan M, Whitman J, Richert J, Pearson G. 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Lancet

Filippi M, Iannucci G, Tortorella C, et al. Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI. Neurology 1999;52:588–594. Filippi M, Rocca MA, Martino G, Horsfield MA, Comi G. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann Neurol 1998;43:809–814. Filippi M, Silver N, Yousry T, Miller D. Newer magnetic resonance techniques and disease activity in multiple sclerosis: new concepts and new concerns. Multiple Sclerosis 1998;4:469–470. Garell PC, Menezes AH, Baumbach G, et al. Presentation, management and follow-up of Schilder's disease. Pediatr Neurosurg 1998;29:86–91. Haegert DG, Francis GS. HLA-DQ polymorphisms do not explain HLA class II associations with multiple sclerosis in two Canadian patient groups. Neurology 1993;43:1207–1210. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655–661. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial [see comments]. Neurology 1995;45:1277–1285. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285–294. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group [see comments]. Neurology 1995;45:1268–1276. Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998;50:701–708. Kermode AG, Thompson AJ, Tofts P, et al. Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain 1990;113[Pt 5]:1477–1489. Kim MO, Lee SA, Choi CG, Huh JR, Lee MC. Balo's concentric sclerosis: a clinical case study of brain MRI, biopsy, and proton magnetic resonance spectroscopic findings. J Neurol Neurosurg Psychiatry 1997;62:655–658. Kupersmith MJ, Kaufmann D, Paty DW, et al. Megadose corticosteroids in multiple sclerosis. Neurology 1994;44:1–4. Leuzzi V, Lyon G, Cilio MR, et al. Childhood demyelinating diseases with a prolonged remitting course and their relation to Schilder's disease: report of two cases. J Neurol Neurosurg Psychiatry 1999;66:407–408. Lucchinetti CF, Bruck W, Rodriguez M, Lassmann H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol 1996;6:259–274. Lucchinetti CF, Brueck W, Rodriguez M, Lassmann H. Multiple sclerosis: lessons from neuropathology. Semin Neurol 1998;18:337–349.

Mandler RN, Davis LE, Jeffery DR, Kornfeld M. Devic's neuromyelitis optica: a clinicopathological study of 8 patients. Ann Neurol 1993;34:162–168. Mathews WB, Compston A, Allen IV, Martyn CN, eds. McAlpine's multiple sclerosis. Edinburgh: Churchill-Livingstone, 1991. Metz L. Multiple sclerosis: symptomatic therapies. Semin Neurol 1998;18:389–395. Miller DH. Multiple sclerosis: use of MRI in evaluating new therapies. Semin Neurol 1998;18:317–325. Miller JR, Burke AM, Bever CT. Occurrence of oligoclonal bands in multiple sclerosis and other CNS diseases. Ann Neurol 1983;13:53–56. Molyneux PD, Filippi M, Barkhof F, et al. Correlations between monthly enhanced MRI lesion rate and changes in T2 lesion volume in multiple sclerosis. Ann Neurol 1998;43:332–339. Murray T. Amantadine therapy of fatigue in multiple sclerosis. Can J Neurol Sci 1985;12:251–254. Myhr KM, Riise T, Green Lilleas FE, et al. Interferon-alpha2a reduces MRI disease activity in relapsing-remitting multiple sclerosis. Norwegian Study Group on Interferon-alpha in Multiple Sclerosis. Neurology 1999;52:1049–1056. Nelson RF. Ethical issues in multiple sclerosis. Semin Neurol 1997;17:227–234. Noseworthy JH. Multiple sclerosis clinical trials: old and new challenges. Semin Neurol 1998;18:377–388. Paty D, Ebers G, eds. Multiple sclerosis. Philadelphia: FA Davis, 1998. Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group [see comments]. Neurology 1993;43:662–667. Phadke J, Best P. Atypical and clinically silent multiple sclerosis: a report of 12 cases discovered unexpectedly at necropsy. J Neurol Neurosurg Psychiatry 1983;46:414–420. Poser CM. Serial magnetization transfer imaging to characterize the early evolution of new MS lesions [letter]. Neurology 1999;52:1717. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–231. PRISMS (Prevention of Relapses and Diability by Interferon b-1a Subcutaneouly in Multiple Sclerosis) Study Group. Randomized double-blind placebo-controlled study of interferon b-1a in relapsing/remitting multiple sclerosis. Lancet 1998;352:1498–1504. Ravborg M, Liguori R, Christiansen P, et al. The diagnostic reliability of magnetically evoked motor potentials in multiple sclerosis. Neurology 1992;42:1296–1301. Rice GP, Paszner B, Oger J, Lesaux J, Paty D, Ebers G. The evolution of neutralizing antibodies in multiple sclerosis patients treated with interferon beta-1b. Neurology 1999;52:1277–1279. Rudick RA, Goodkin DE, Jacobs LD, et al. Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 1997;49:358–363. Rudick RA, Simonian NA, Alam JA, et al. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG) [see comments]. Neurology 1998;50:1266–1272. Sadovnick AD, Ebers GC, Wilson RW, Paty DW. Life expectancy in patients attending multiple sclerosis. Neurology 1992;42:991–994. Sibley WA. Therapeutic claims in multiple sclerosis. New York: Demos, 1992. Siva A, Radhaskrishnan K, Kurland LT, et al. Trauma and multiple sclerosis: a population based cohort study from Olstead County, Minnesota. Neurology 1993;43:1878–1881. Sorensen TL, Ransohoff RM. Etiology and pathogenesis of multiple sclerosis. Semin Neurol 1998;18:287–294. Staugaitis S, Roberts JK, Sacco RL, Miller JR, Dwork AJ. Devic type multiple sclerosis in an 81 year old woman. J Neurol Neurosurg Psychiatry 1998;64:417–418. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278–285. Weiner HL, Mackin GA, Orav EJ, et al. Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology 1993;43:910–918. Weinshenker BG. The natural history of multiple sclerosis. Neurol Clin 1995;13:119–146. Weinshenker BG. The natural history of multiple sclerosis: update 1998. Semin Neurol 1998;18:301–307. Weinshenker BG, Issa M, Baskerville J. Long-term and short-term outcome of multiple sclerosis: a 3-year follow- up study. Arch Neurol 1996;53:353–358.

CHAPTER 134. MARCHIAFAVA-BIGNAMI DISASE MERRITT’S NEUROLOGY

CHAPTER 134. MARCHIAFAVA-BIGNAMI DISASE JAMES R. MILLER Etiology Pathology Incidence Symptoms and Signs Diagnosis Course Treatment Suggested Readings

Primary degeneration of the corpus callosum is clinically characterized by altered mental status, seizures, and multifocal neurologic signs. Demyelination of the corpus callosum without inflammation is the primary pathologic feature, but other areas of the central nervous system may be involved. The disease was first described by Marchiafava and Bignami in 1903.

ETIOLOGY The cause is not known. The disease was first noted in middle-aged and elderly Italian men who consumed red wine. It has been described worldwide, however, and is not confined only to drinkers of red wine. In some cases, alcohol consumption was not a factor. Nutritional deficiencies also have been implicated. The syndrome is rare, however, even in severe malnutrition. Toxic factors have been suggested, but no agent has been implicated.

PATHOLOGY The sine qua non is necrosis of the medial zone of the corpus callosum. The dorsal and ventral rims are spared. The necrosis varies from softening and discoloration (Fig. 134.1) to cavitation and cyst formation. Usually, all stages of degeneration are found. In most cases, the rostral position of the corpus callosum is affected first. The lesions arise as small symmetric foci that extend and become confluent. Although medial necrosis of the corpus callosum is the principal finding, there also may be degeneration of the anterior commissure ( Fig. 134.2), the posterior commissure, centrum semiovale, subcortical white matter, long association bundles, and middle cerebellar peduncles. All these lesions have a constant bilateral symmetry. Usually spared are the internal capsule, corona radiata, and subgyral arcuate fibers. The gray matter is not grossly affected.

FIG. 134.1. Marchiafava-Bignami disease. Acute necrosis of corpus callosum and neighboring white matter of the frontal lobes. (From Merritt HH, Weisman AD. J Neuropathol Exp Neurol 1945;4:155–163.)

FIG. 134.2. Marchiafava-Bignami disease. Medial necrosis of the corpus callosum and anterior commissure with sparing of the margins. (Courtesy of Dr. P.I. Yakovlev.)

Few diseases have such a well-defined pathologic picture. The corpus callosum may be infarcted as a result of occlusion of the anterior cerebral artery, but the symmetry of the lesions, sparing of the gray matter, and occurrence of similar lesions in the anterior commissure, long association bundles, and cerebellar peduncles are found only in Marchiafava-Bignami disease. The microscopic alterations are the result of a sharply defined necrotic process with loss of myelin but relative preservation of axis cylinders in the periphery of the lesions. There is usually no evidence of inflammation aside from a few perivascular lymphocytes. In most cases, fat-filled phagocytes are common. Gliosis is usually not well advanced. Capillary endothelial proliferation may be present in the affected area, but no thrombi are seen. The disease has been reported with central pontine myelinolysis or Wernicke encephalopathy in alcoholics and in nonalcoholic persons, thus suggesting a possible common pathogenesis.

INCIDENCE More than 100 cases have been reported, but the disease is probably more common. Before the advent of modern imaging, however, the diagnosis was rarely made before death because the symptoms and findings are nonspecific. Genetic predisposition has been suspected because of the frequent reports in Italian men. The onset is usually in middle age or late life.

SYMPTOMS AND SIGNS The onset is usually insidious, and the first symptoms are so nonspecific that an accurate estimate of the exact time of onset is difficult. There is a mixture of focal and diffuse signs of cerebral disease, especially dementia. In addition to memory loss and confusion, manic, paranoid, or delusional states may occur. Depression and

extreme apathy are typical.

DIAGNOSIS Marchiafava-Bignami disease may be suspected when insidiously developing dementia, multifocal neurologic signs, and seizures occur in elderly, particularly alcoholic, men. Computed tomography and especially magnetic resonance imaging have enhanced the ability to diagnose the disease before death. Either form of imaging can show the typical callosal lesions and symmetric demyelinating lesions in other areas. Brain single-photon emission computed tomographies may also prove useful in analysis of cases.

COURSE The disease is usually slowly progressive and results in death within 3 to 6 years. There is a rare acute fever lasting days or weeks. In an occasional patient there is a temporary remission. Some reports of reversibility exist, but the diagnosis has only been by imaging studies.

TREATMENT There is no known therapy. SUGGESTED READINGS Baron R, Heuser K, Marioth G. Marchiafava-Bignami disease with recovery diagnosed by CT and MRI: demyelination affects several CNS structures. J Neurol 1989;236:364–366. Berek K, Wagner M, Chemelli AP, Aichner F, Benke T. Hemispheric disconnection in Marchiafava-Bignami disease: clinical, neuropsychological and MRI findings.

J Neurol Sci 1994;123:2–5.

Chang KH, Cha SH, Han MH, et al. Marchiafava-Bignami disease: serial changes in corpus callosum on MRI. Neuroradiology 1992;34:480–482. Gass A, Birtsch G, Olster M, Schwartz A, Hennerici MG. Marchiafava-Bignami disease: reversibility of neuroimaging abnormality. J Comput Assist Tomogr 1998;22:503–504. Georgy BA, Hesselink JR, Jernigan TL. MR imaging of the corpus callosum. AJR 1993;160:949–955. Ghatak N, Hadfield N, Rosenblum W. Association of central pontine myelinolysis and Marchiafava-Bignami disease. Neurology 1978;28:1295–1298. Humbert T, De Guilhermier P, Maktouf C, Grasset G, Lopez FM, Chabrand P. Marchiafava-Bignami disease. A case studied by structural and functional brain imaging. Eur Arch Psychiatry Clin Neurosci 1992;242:69–71. Ironside R, Bosanquet FD, McMenemey WH. Central demyelination of the corpus callosum (Marchiafava-Bignami disease). Brain 1961;84:212–230. Marchiafava E, Bignami A. Sopra un'alterazione del corpo calloso osservata in soggetti alcoolisti. Riv Patol Nerve 1903;8:544–549. Yamashita K, Kobayashi S, Yamaguchi S, Koide H, Nishi K. Reversible corpus callosum lesions in a patient with Marchiafava-Bignami disease: serial changes on MRI. Eur Neurol 1997;37:192–193.

CHAPTER 135. CENTRAL PONTINE MYELINOLYSIS MERRITT’S NEUROLOGY

CHAPTER 135. CENTRAL PONTINE MYELINOLYSIS GARY L. BERNARDINI AND ELLIOTT L. MANCALL Suggested Readings

In 1959, Adams, Victor, and Mancall described a distinctive, previously unrecognized disease characterized primarily by the symmetric destruction of myelin sheaths in the basis pontis. They called it central pontine myelinolysis and numerous reports followed. The general term myelinolysis may be more appropriate because the condition affects extrapontine brain areas as well. Most patients who develop pontine myelinolysis have had documented hyponatremia, and serum sodium levels were corrected rapidly to normal or supranormal levels. Chronic alcoholism and undernutrition are frequently associated with this condition. Pontine myelinolysis has been seen, however, in hyponatremic nonalcoholic patients, including some with dehydration resulting from vomiting, diarrhea, or diuretic therapy; with postoperative overhydration; or with compulsive water drinking. Severe malnutrition, including that resulting from extensive burn injuries, may be a predisposing condition. The main underlying factor to the development of pontine myelinolysis in these cases seems to be too rapid the correction of serum sodium levels. Correction after hypernatremia rather than hyponatremia has also been encountered. The condition has been described with increasing frequency in patients undergoing orthotopic liver transplantation. Pontine myelinolysis is found in 0.28% to 9.8% of these cases. The clinical manifestations vary from asymptomatic to comatose, although there may be signs of a generalized encephalopathy associated with low levels of serum sodium. Neurologic signs and symptoms of myelinolysis usually appear within 2 to 3 days after rapid correction of sodium levels. Findings include dysarthria or mutism, behavioral abnormalities, ophthalmoparesis, bulbar and pseudobulbar palsy, hyperreflexia, quadriplegia, seizures, and coma. Typically, a rapidly progressive corticobulbar and corticospinal syndrome may be noted in a debilitated patient, often during an acute illness with associated electrolyte imbalance. Although the patients are mute, coma is unusual. The patients may be “locked-in”; communication by eye blinking can sometimes be established. The course is rapid, and death generally ensues within days or weeks of the onset of symptoms. Extrapontine myelinolysis is seen in about 10% of all cases of pontine myelinolysis. Clinically, extrapontine myelinolysis can present with ataxia, irregular behavior, visual field deficits, or movement disorders such as Parkinson disease or parkinsonism, choreoathetosis, or dystonia. The movement disorders can appear with or without radiographic evidence of extrapontine myelinolysis. Bilateral symmetric involvement outside the pons may affect the cerebellum, putamen, thalamus, corpus callosum, subcortical white matter, claustrum, caudate, hypothalamus, lateral geniculate bodies, amygdala, subthalamic nuclei, substantia nigra, or medial lemnisci. Although most cases have been diagnosed only at autopsy, the syndrome can be diagnosed in life. The clinical diagnosis is supported by radiologic studies. Computed tomography may be normal, especially early in the course, but computed tomography abnormalities include symmetric areas of hypodensity in the basis pontis and extrapontine regions without associated mass effect. Magnetic resonance imaging is more sensitive in diagnosing the condition; lesions appear hyperintense on T2-weighted images and hypointense on T1-weighted images but typically do not enhance ( Fig. 135.1). The lesions may take 2 weeks to appear on magnetic resonance imaging. Brainstem auditory-evoked responses may demonstrate prolonged III-V and I-V latencies consistent with bilateral pontine lesions. An electroencephalogram may show slowing and low voltage. Cerebrospinal fluid levels of protein and myelin basic protein may be elevated.

FIG. 135.1. A: T1-weighted sagittal magnetic resonance (MR) image in a 21-year-old alcoholic woman after rapid correction of severe hyponatremia, showing a hypointense area in the basis pons consistent with the lesion of pontine myelinolysis. B: T2-weighted axial MR image in the same patient demonstrating the characteristic centrally located hyperintense areas consistent with demyelination within the pons. (Courtesy of Dr. L. A. Heier.)

The principal pathologic change is demyelination; within affected areas, nerve cells and axon sheaths are spared, blood vessels are unaffected, and there is no inflammation. In animal studies, the initial event after administration of hypertonic saline in hypotonic rats seems to be opening of the blood–brain barrier, followed sequentially by swelling of the inner loop of the myelin sheath, oligodendrocyte degeneration, and release of macrophage-derived factors leading to the eventual breakdown of myelin. Histologically, the lesion begins in the median raphe and may involve all or part of the base of the pons ( Fig. 135.2). The lesion may spread into the pontine tegmentum or superiorly into the mesencephalon or involve bilateral extrapontine areas with or without concurrent basis pontis lesions. Microscopically, the lesions resemble those of Marchiafava-Bignami disease.

FIG. 135.2. Central pontine myelinolysis. Histologic section through rostral pons showing characteristic lesion. (Courtesy of Dr. J. Kepes.)

The cause of pontine myelinolysis is uncertain. In those with hyponatremia that has been rapidly corrected to normal or supranormal levels, it is not clear whether the low sodium, the rate of correction, or the absolute change in the serum sodium content is the causative factor. Symptoms are, however, more likely to develop with rapid correction of chronic (more than 48 hours) rather than acute hyponatremia. In experimental animals, pontine myelinolysis develops in hyponatremic rats, rabbits, or dogs treated rapidly with hypernatremic saline. Animals left with untreated hyponatremia did not develop neuropathologic changes. Therefore, attention has focused on the rate of correction of the hyponatremia rather than on the hyponatremia itself as the mechanism of injury. Prevention of myelinolysis includes judicious correction of hyponatremia with normal saline and free water restriction, discontinuation of diuretic therapy, and correction of associated metabolic abnormalities and medical complications. Hyponatremic patients who are asymptomatic may not require saline infusion; those with

agitated confusion, seizures, or coma should be treated with normal saline until the symptoms improve. Based on clinical data and animal studies, there is a low incidence of myelinolysis if the increase in serum sodium is less than or equal to 12 mmol/L in 24 hours. Late appearance of tremor and dystonia or cognitive and behavioral changes have been reported in survivors. Full recovery has also been seen. SUGGESTED READINGS Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients. Arch Neurol Psychiatry 1959;81:154–172. Ayus JC, Krothpalli RK, Arieff AI. Treatment of symptomatic hyponatremia and its relation to brain damage. N Engl J Med 1987;317:1190–1195. Brunner JE, Redmond JM, Haggar AM, et al. Central pontine myelinolysis and pontine lesions after rapid correction of hyponatremia: a prospective magnetic resonance imaging study. Ann Neurol 1990;27:61–66. Donahue SP, Kardon RH, Thompson HS. Hourglass-shaped visual fields as a sign of bilateral lateral geniculate myelinolysis. Am J Ophthalmol 1995;119:378–380. Hadfield MG, Kubal WS. Extrapontine myelinolysis of the basal ganglia without central pontine myelinolysis. Clin Neuropathol 1996;15:96–100. Harris CP, Townsend JJ, Baringer JR. Symptomatic hyponatremia: can myelinolysis be prevented by treatment? J Neurol Neurosurg Psychiatry 1993;56:626–632. Kandt RS, Heldrich FJ, Moser HW. Recovery from probable central pontine myelinolysis associated with Addison's disease. Arch Neurol 1983;40:118–119. Kleinschmidt-Demasters BK, Norenberg MD. Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis. Science 1981;211:1068–1071. Laureno R, Karp BI. Myelinolysis after correction of hyponatremia. Ann Intern Med 1997;126:57–62. Morlan L, Rodriguez E, Gonzales J, et al. Central pontine myelinolysis following correction of hyponatremia: MRI diagnosis. Eur Neurol 1990;30:149–152. Norenberg MD, Leslie KO, Robertson AS. Association between rise in serum sodium and central pontine myelinolysis. Ann Neurol 1982;11:128–135. Rojiani AM, Cho ES, Sharer L, et al. Electrolyte-induced demyelination in rats. 2. Ultrastructural evolution. Acta Neuropathol 1994;88:293–299. Salerno SM, Kurlan R, Joy SE, et al. Dystonia in central pontine myelinolysis without evidence of extrapontine myelinolysis. J Neurol Neurosurg Psychiatry 1993;56:1221–1223. Schrier RW. Treatment of hyponatremia. N Engl J Med 1985;312:1121–1122. Thompson DS, Hutton JT, Stears JC, et al. Computerized tomography in the diagnosis of central and extrapontine myelinolysis. Arch Neurol 1981;38:243–246. Wright DG, Laureno R, Victor M. Pontine and extrapontine myelinolysis. Brain 1979;102:361–385.

CHAPTER 136. NEUROGENIC ORTHOSTATIC HYPOTENSION AND AUTONOMIC FAILURE MERRITT’S NEUROLOGY

SECTION XX. AUTONOMIC DISORDERS CHAPTER 136. NEUROGENIC ORTHOSTATIC HYPOTENSION AND AUTONOMIC FAILURE LOUIS H. WEIMER Multiple System Atrophy Pure Autonomic Failure Suggested Readings

MULTIPLE SYSTEM ATROPHY In 1960, Shy and Drager described two patients with generalized autonomic failure and additional findings in other central and peripheral systems. This combination differed from the pure autonomic failure (PAF) described in 1925 by Bradbury and Eggleston. Currently, the Shy-Drager syndrome with initial or predominate autonomic failure is considered a manifestation of multiple system atrophy (MSA). Distinguishing this form of MSA from PAF or idiopathic Parkinson disease (PD) is still clinically challenging. Clinical Manifestations Autonomic failure is the hallmark of Shy-Drager syndrome, but demonstrable evidence of autonomic dysfunction is eventually found in 97% of patients clinically diagnosed with any form of MSA (see Chapter 114). Orthostatic hypotension (OH) or syncope is often the first recognized and most disabling symptom. However, other autonomic symptoms often predate OH, including impotence or ejaculatory dysfunction, decreased sweating, and urinary and less commonly fecal incontinence. Postprandial hypotension starting 10 to 15 minutes after a meal can be disabling. Parkinsonism is common with rigidity and bradykinesia more prominent than rest tremor but may be mild or not evident for several years after the onset of autonomic failure. Parkinsonian symptoms usually respond poorly to levodopa therapy, yet some have initial symptomatic relief. Levodopa therapy may also exacerbate or unmask underlying OH. Cerebellar and corticospinal tract signs provide evidence of multisystem involvement. Less commonly, fasciculations and amyotrophy are evident, as in one of the two original cases. Rarely, peripheral neuropathy or signs of a mild frontal lobe dementia are seen. Inspiratory stridor is a frequent feature with laryngeal muscle denervation. A variety of sleep disturbances and altered respiratory patterns are common and include apnea producing hypoxemia and paroxysmal sleep movements. Laboratory Data An autonomic screening battery (Table 136.1) in addition to bedside tests can aid in establishing the diagnosis, especially before the development of OH. Formal testing is also beneficial in MSA and in other cases of dysautonomia to characterize the individual autonomic problems, monitor progression, and assess treatment effects. To enhance reliability, before testing patients should be free of autonomically active medications such as caffeine or nicotine, recovered from any acute illness, and in a relaxed euvolemic state.

TABLE 136.1. TESTS OF AUTONOMIC FUNCTION

The degenerative process in MSA has a special predilection for Onuf nucleus, spinal somatic motor neurons that serve voluntary urinary and anal sphincter function. Concentric needle electromyography of striated sphincters may show chronic partial denervation, an important diagnostic sign in all forms of MSA, not simply Shy-Drager syndrome. Paradoxically, these sphincter muscles are spared in amyotrophic lateral sclerosis. Formal sleep studies may document dangerous nocturnal apneic episodes or other alterations of sleep or respiratory patterns. MSA patients have normal or mildly reduced supine resting levels of norepinephrine that fail to show a normal increase on head-up tilt. PAF patients have low resting norepinephrine levels, which also fail to elevate with tilt. Pathology Demonstration of argyrophilic glial cytoplasmic inclusions in oligodendroglia (GCIs) has enhanced and refined the pathologic diagnosis of MSA over earlier assessments based on patterns of neuronal loss and gliosis. However, the inclusions are occasionally seen in other disorders. GCIs are prominent in vital sites of autonomic control such as the intermediolateral column of the spinal cord, dorsal vagal nucleus, solitary tract and nucleus, pontobulbar reticular formation, and medullary tegmentum. GCIs correlate better with clinical findings than do areas of neuronal loss. Diagnosis Classification of MSA cases remains inexact before autopsy. The main difficulty is separating cases with initial autonomic failure from the rare PAF cases and, more problematically, from idiopathic PD with autonomic features. Severe autonomic failure is rare in typical PD. However, autonomic symptoms and lesser degrees of autonomic dysfunction are relatively common. When more marked autonomic failure occurs in PD, it tends to be later in the disease and in elderly patients. MagalhĂŁes et al. (1995) retrospectively reviewed autonomic symptoms in 135 autopsy-proven cases of PD and MSA. One-third of the 33 MSA cases were misdiagnosed as PD before autopsy. Autonomic symptoms at onset, stridor, and cerebellar signs were rare in PD patients in this series. The degree of clonidine-induced growth hormone release has been proposed as an alternate test to separate MSA from PD. Course and Prognosis Prognosis studies have divided MSA into parkinsonian (striatonigral degeneration) and cerebellar (sporadic OPCA) forms, without separate data on patients with autonomic onset. In general, however, the prognosis is worse than for either PAF or PD with autonomic features or MSA without autonomic onset.

PURE AUTONOMIC FAILURE Isolated PAF without involving other systems is rare but well described (idiopathic OH, Bradbury-Eggleston syndrome). Widespread autonomic failure is present with prominent and often disabling OH. However, approximately 10% develop into MSA within 3 to 5 years. In contrast to MSA and idiopathic chronic pandysautonomia, severe cholinergic impairment and gastrointestinal symptoms other than constipation are less apparent. Supine norepinephrine levels are reduced, and the response to norepinephrine infusion is excessive because of denervation supersensitivity. Histopathology is predominantly that of degeneration of postganglionic sympathetic

neurons. Some loss of sympathetic neurons in the intermediolateral spinal cell column has been noted. Lewy bodies staining for ubiquitin may be seen in sympathetic ganglia. Other Causes of Autonomic Failure A multitude of peripheral neuropathies show some degree of impairment in autonomic function on formal testing, especially in distal vasomotor and sudomotor function. However, only some lead to frank clinically important autonomic failure with prominent OH. Particularly noteworthy causes include diabetes, amyloidosis, paraneoplastic, selected hereditary neuropathies, and dopamine b-hydoxylase deficiency ( Table 136.2). Other disorders that disrupt central or peripheral autonomic pathways may also lead to OH (Table 136.2) or less marked dysautonomia, especially lesions in the region of the third ventricle, posterior fossa, spinal cord, autonomic ganglia, and small diameter nerve fibers. In addition, processes may be pathway specific such as predominantly cholinergic, regional, or organ specific.

TABLE 136.2. SELECTED DISORDERS OF AUTONOMIC FUNCTION

Treatment Therapy of autonomic failure is aimed at symptomatic relief and improved quality of life. Treatment of OH, generally the most disabling symptom, depends on the underlying mechanism. Asymptomatic hypotension on standing usually does not require treatment. Cerebral perfusion typically does not drop significantly until the systolic pressure is reduced below 80 mm Hg due to compensatory effects of cerebrovascular autoregulation. Simple maneuvers are tried initially and may be sufficient. Measures include maintaining the head and trunk at about 15 to 20 degrees higher than the legs in bed, which promotes the release of renin and stimulates baroreceptors. This can be achieved with a hospital bed with head elevation or by placing blocks under the head of an ordinary bed. Counterpressure support garments that provide abdominal and lower limb compression (such as Jobst half-body leotard) can reduce venous pooling, but patients often find these garments too uncomfortable and cumbersome to put on, especially if they are hampered by other neurologic impairment. Physical countermaneuvers such as squatting and leg crossing may provide some benefit. Particular care after situations that predictably lower blood pressure is prudent, including meals, vigorous exercise, hot temperature, and motionless standing. No single drug is ideal for the treatment of neurogenic OH. Common useful therapies include supplemental sodium chloride (2 to 4 g/day) to increase plasma volume and, if necessary, fludrocortisone, starting at 0.1 mg/day to increase salt and water retention. The patient must be watched carefully to avoid excessive water retention, rising blood pressure, or heart failure. Oral sympathomimetics, such as ephedrine, phenylephrine, and tyramine, are usually of limited benefit; however, midodrine (a selective alpha-1 agonist now approved in the United States) is of proven benefit in OH. Anemia is a common exacerbating condition with autonomic failure. Epoetin alpha (Epogen) increases hematocrit, reduces symptoms, and elevates systolic pressure an average of 10 to 15 mm Hg. Other drugs of potential but less consistent benefit include indomethacin, somatostatin analogues, caffeine, ergot alkaloids, nocturnal desmopressin, and 3,4-dihydroxyphenylserine, which is specifically indicated in the rare but distinctive hereditary dopamine b-hydoxylase deficiency. Concomitant treatment of urinary dysfunction, gastric and intestinal dysmotility, impotence, and secretomotor dysfunction is often necessary. In MSA, inspiratory stridor may necessitate tracheostomy, and nocturnal positive pressure ventilation may be needed for sleep apnea. SUGGESTED READINGS Appenzeller O, Goss JE. Autonomic deficits in Parkinson's syndrome. Arch Neurol 1971;24:50–57. Assessment: clinical autonomic testing report of the therapeutics and technology assessment subcommittee of the American Association of Neurology. Neurology 1996;46:873–880. Biaggioni I, Robertson D, Frantz S, Krantz S, Jones M, Haile V. The anemia of primary autonomic failure and its reversal with recombinant erythropoietin. Ann Intern Med 1994;121:181–186. Bradbury S, Eggleston C. Postural hypotension: a report of three cases. Am Heart J 1925;1:73–86. Cohen J, Low P, Fealey R, Sheps S, Jiang N-S. Somatic and autonomic function in progressive autonomic failure and multiple system atrophy. Ann Neurol 1987;22:692–699. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology 1996;46:1470. Hague K, Lento P, Morgello S, Caro S, Kaufmann H. The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature. Acta Neuropathol (Berl) 1997;94:192–196. Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: A double-blind, placebo-controlled study with Midodrine. JAMA 1993;95:38–48. Kanda T, Tomimitsu H, Yokota T, Ohkoshi N, Hayashi M, Mizusawa H. Unmyelinated nerve fibers in sural nerve in pure autonomic failure. Ann Neurol 1998;43:267–271. Kimber JR, Watson L, Mathias CJ. Distinction of idiopathic Parkinson's disease form multiple-system atrophy by stimulation of growth-hormone release with clonidine. Lancet 1997;349:1877–1881. Kontos HA, Richardson DW, Norvell JE. Mechanisms of circulatory dysfunction in orthostatic hypotension. Trans Am Clin Climatol Assoc 1976;87:26–33. Low PA, Bannister R. Multiple system atrophy and pure autonomic failure. In: Low PA, ed. Clinical autonomic disorders, 2nd ed. Philadelphia: Lippincott-Raven, 1997:555–575. Magalhães M, Wenning GK, Daniel SE, Quinn NP. Autonomic dysfunction in pathologically confirmed multiple system atrophy and idiopathic Parkinson's disease—a retrospective comparison. Acta Neurol Scand 1995;91:98–102. Mannen T, Iwata M, Toyokura Y, Nagashima K. The Onuf's nucleus and the external anal sphincter muscles in amyotrophic lateral sclerosis and Shy-Drager syndrome. Acta Neuropathol 1982;58:255–260. Martignoni E, Pacchetti C, Godi L, Micieli G, Nappi G. Autonomic disorders in Parkinson's disease. J Neurol Transm 1995;45[Suppl]:11–19. Mathias CJ. Desmopressin reduces nocturnal polyuria, reverses overnight weight loss and improves morning postural hypotension in autonomic failure. Br Med J 1986;293:353–354. Mathias CJ. Orthostatic hypotension: causes, mechanisms, and influencing factors. Neurology 1995;45[Suppl 5]:S6–S11. McLeod JD, Tuck RR. Disorders of the autonomic nervous system. Part I. Pathophysiology and clinical features. Ann Neurol 1987;21:419–430. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusion in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 1989;94:79–100. Papp MI, Lantos PL. The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 1994;117:235–243. Ravits J, Hallett M, Nilsson J, Polinsky R, Dambrosia J. Electrophysiological tests of autonomic function in patients with idiopathic autonomic failure syndromes.

Muscle Nerve 1996;19:758–763.

Robertson D, Davis RL. Recent advances in the treatment of orthostatic hypotension. Neurology 1995;45[Suppl 5]:S26–S32. Sandroni P, Ahlskog JE, Fealey RD, Low PA. Autonomic involvement in extrapyramidal and cerebellar disorders. Clin Auton Res 1991;1:147–155. Schatz IJ. Farewell to the “Shy-Drager” syndrome. Ann Intern Med 1996;125:74–75. Shy GM, Drager GA. A neurological syndrome associated with orthostatic hypotension: a clinical-pathologic study. Arch Neurol 1960;2:511–527. Sung JH, Mastri AR, Segal E. Pathology of Shy-Drager syndrome. J Neuropathol Exp Neurol 1979;38:353–368. Thomas JE, Schirger A. Idiopathic orthostatic hypotension: a study of its natural history in 57 neurologically affected patients. Arch Neurol 1970;22:289–293.

CHAPTER 137. ACUTE AUTONOMIC NEUROPATHY MERRITT’S NEUROLOGY

CHAPTER 137. ACUTE AUTONOMIC NEUROPATHY LOUIS H. WEIMER Suggested Readings

Acute autonomic neuropathy (AAN) is rare, but there have been numerous reports since the initial description by Young et al. in 1975. Autonomic manifestations include orthostatic hypotension, nausea and vomiting, constipation or diarrhea, bladder atony, impotence, anhidrosis, impaired lacrimation and salivation, and pupillary abnormalities. Gastroparesis may be prominent. In pure dysautonomia, there is no somatic disturbance, but minor sensory findings are not uncommon, and in severe cases cutaneous sensation may be markedly impaired. Motor involvement is less common. Roughly one-fourth of cases have a purely cholinergic form, without orthostatic hypotension (OH), and rarely findings are restricted to gastrointestinal dysmotility. Although OH is the hallmark of the dysautonomia, exaggerated orthostatic tachycardia may be evident without change in blood pressure. This has led to the proposal that a syndrome of orthostatic intolerance without OH (postural orthostatic tachycardia syndrome) may be an attenuated form of AAN. This assertion is supported by abnormalities of sudomotor and other autonomic systems in roughly one-half of cases and an antecedent viral infection at the same percentage, as seen in AAN. Symptoms include postural dizziness, palpitations, and presyncope despite minimal changes in blood pressure. Possible etiologies are multiple, including distal loss of vasomotor control with excessive venous pooling, volume depletion, and altered cerebrovascular autoregulation. In pure dysautonomia, electromyography, nerve conduction velocities, sural nerve biopsy, and cerebrospinal fluid are normal. In complicated cases, these studies may yield abnormalities blurring the distinction from Guillain-Barré syndrome. Additionally, autonomic involvement is common in typical Guillain-Barré syndrome and may be a prominent cause of morbidity and mortality. Functional tests in AAN usually reveal widespread abnormalities of autonomic function ( Table 136.1). The etiology of AAN is unknown, but many cases are presumed to be immune mediated and follow diverse viral infections. Sural nerve biopsies show epineural mononuclear cell infiltrates. Symptoms may evolve for several weeks, plateau for many weeks, and then slowly improve. The differential diagnosis includes other subacute neuropathies, such as paraneoplastic panautonomic neuropathy, Guillain-Barré syndrome, botulism, porphyria, and some drug or other toxic neuropathies. Treatment is symptomatic based on the involved systems. Control of OH is typically most important. Anecdotal reports suggest that intravenous immune globulin therapy may be effective. Recovery is slow and often incomplete. SUGGESTED READINGS Bennett JL, Mahalingam R, Wellish MC, et al. Epstein-Barr virus associated with acute autonomic neuropathy. Ann Neurol 1996;40:453–455. Fagius J, Westerburg CE, Olsson Y. Acute pandysautonomia and severe sensory deficit with poor recovery. A clinical, neurophysiological and pathological case study. J Neurol Neurosurg Psychiatry 1983;46:725–733. Hart RG, Kanter MC. Acute autonomic neuropathy: two cases and clinical review. Arch Intern Med 1990;150:2373–2376. Heafield MTE, Gammage MD, Nightingale S, Williams AC. Idiopathic dysautonomia treated with intravenous gammaglobulin. Lancet 1996;347:28–29. Laiwah ACY, MacPhee GJA, Boyle MR, Goldberg A. Autonomic neuropathy in acute intermittent porphyria. J Neurol Neurosurg Psychiatry 1985;48:1025–1030. Low PA, Dyck PJ, Lambert EH, et al. Acute panautonomic neuropathy. Ann Neurol 1983;13:412–417. McLeod JG, Tuck RR. Disorders of the autonomic nervous system. Ann Neurol 1987;21:419–430, 519–529. Neville BG, Sladen OF. Acute autonomic neuropathy following primary herpes simplex infection. J Neurol Neurosurg Psychiatry 1984;47:648–650. Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome. An attenuated form of acute pandysautonomia? Neurology 1993;43:132–137. Suarez GA, Fealey RD, Camilleri M, Low PA. Idiopathic autonomic neuropathy: clinical, neurophysiologic and follow-up studies on 27 patients. Neurology 1994;44:1675–1682. Young RR, Asbury AK, Corbett JL, Adams RD. Pure pandysautonomia with recovery. Brain 1975;98:613–636.

CHAPTER 138. FAMILIAL DYSAUTONOMIA MERRITT’S NEUROLOGY

CHAPTER 138. FAMILIAL DYSAUTONOMIA ALAN M. ARON Overview Clinical Presentation Diagnosis Biochemical and Pathologic Data Pathophysiology Prognosis Treatment Suggested Readings

OVERVIEW Familial dysautonomia was described by Riley et al. in 1949. The autonomic symptoms are prominent, but the condition also affects other parts of the nervous system and general somatic growth. It is a rare autosomal recessive disease; more than 500 cases have been reported. Virtually all patients are of Eastern European (Ashkenazi) Jewish descent where the carrier rate is 1 in 30. The causative gene has been mapped to chromosome 9q31-q33. There results a sensory and autonomic neuropathy whose biochemical and genetic defects are yet to be defined. Linkage analyses using closely related markers have permitted reliable prenatal diagnosis in families with a previously affected child. The condition can be diagnosed in the perinatal period. Clinical manifestations tend to increase with age. Biochemical alterations point to decreased synthesis of noradrenaline. Hypersensitivity to sympathomimetic drugs suggests a denervation type of supersensitivity. The exact pathophysiology has yet to be elucidated.

CLINICAL PRESENTATION The dysautonomic infant frequently shows low birth weight and breech presentation. Neurologic abnormalities detected in the neonatal period include decreased muscle tone, diminished or absent deep tendon reflexes, absent corneal responses, poor Moro response, and weak cry and suck. The tongue tip lacks fungiform papillae and appears smooth. Uncoordinated swallowing with resultant regurgitation may cause aspiration and pneumonia. Some infants require tube feeding, gastrostomy, and fundoplication because of gastroesophageal reflux. Absence of overflow tears, which may be normal for the first 3 months, persists thereafter and becomes a consistent feature. Corneal ulceration can occur. During the first 3 years of life, affected children show delayed physical and developmental milestones, episodic vomiting, excessive sweating, excessive drooling, blotchy erythema, and breathholding spells. Dysautonomic crises occur after age 3, with irritability, self-mutilation, negativistic behavior, diaphoresis, tachycardia, hypertension, and thermal instability. The most outstanding symptom is episodic vomiting, which may be cyclic and require hospitalization for stabilization with parenteral hydration. The school-aged dysautonomic child tends to have short stature, awkward gait, and nasal speech. School performance may be poor. As a group, patients score in the average range on intelligence tests but they are frequently 20 or more points below unaffected siblings. Scoliosis is frequent and can begin in childhood and progress rapidly during preadolescence. Some poorly developed patients show delayed puberty. Vomiting and vasomotor crises tend to decrease during adolescence when more frequent symptoms center on decreased exercise tolerance, poor general coordination, emotional difficulties, and postural hypotension. Vasovagal responses may occur after micturition or during laryngeal intubation for anesthesia. Up to one-third of patients have seizures during early life. These are usually associated with fever, breathholding spells, or hypoxia. Less than 10% of patients have subsequent long-standing seizure disorders. Patients show abnormal responses to altered atmospheric air. Hypercapnia and hypoxia do not produce expected increases in ventilatory effort. Drownings have occurred, presumably because air hunger did not develop when submerged. Coma has occurred in patients at high altitudes.

DIAGNOSIS The diagnosis should be made on the constellation of clinical symptoms and genetic background. The most distinctive sign is the absence or paucity of overflow tearing. Low doses of methacholine may restore transient tearing. Other cardinal clinical features include hyporeflexia, absent corneal responses, and the absence of the fungiform tongue papillae. This is associated with impaired taste sensation. There is relative indifference to pain, poor temperature control, and postural hypotension. Intradermal histamine phosphate in a dosage of 1:1,000 (0.03 to 0.05 mL) normally produces pain and erythema. Within minutes, a central wheal forms and is surrounded by an axon flare that is a zone of erythema measuring 2 to 6 cm in diameter. The flare lasts for several minutes. In dysautonomic patients, pain is greatly reduced and there is no axon flare. In infants, a saline solution of 1:10,000 histamine should be used. The methacholine test involves installation of one drop of 2.5% methacholine into the eye. (One drop of dilute pilocarpine [0.0625%] is equivalent to 2.5% methacholine.) The other eye serves as control. The pupils are compared at 5-minute intervals for 20 minutes. The normal pupil remains unchanged; the dysautonomic pupil develops miosis. The pupillary responses to light and accommodation in familial dysautonomia appear normal. The combination of axon flare response to intradermal histamine, miosis with methacholine or pilocarpine, and absent glossal fungiform pupillae are diagnostic. Frequently, there is an elevated urinary homovanillic acid–vanilylmandelic acid ratio. This assay is not required for diagnosis.

BIOCHEMICAL AND PATHOLOGIC DATA The neuronal abnormality is probably present at birth, but subsequent degenerative changes seem to occur. The primary metabolic defect is unknown. Fibroblast study has shown normal mitochondrial DNA and respiratory chain activity. Mitochondrial dysfunctions due to glycosphingolipid accumulation, changes in mitochondrial DNA, or mutation of chromosome 9 genetic material in mitochrondial factions have not been demonstrated. Serum levels of both norepinephrine and dopamine are markedly elevated during dysautonomic crises. Vomiting coincides with high dopamine levels; hypertension correlates with increased norepinephrine levels. Pathologic data reveal hypoplastic cervical sympathetic ganglia with diminished volume and neuronal counts. Sympathetic preganglionic spinal cord neurons seem to be reduced in number. Patients are deficient in type C fibers. The parasympathetic sphenopalatine ganglia have shown the most depleted neuronal populations with only minimal reductions in the ciliary ganglia. The lingual submucosal neurons and sensory axons are reduced. Tastebuds are scant; circumvallate papillae are hypoplastic.

PATHOPHYSIOLOGY Gastroesophageal dysfunction, manifest by prolonged esophageal transit time, gastroesophageal reflux, and delayed gastric emptying, has been demonstrated by scintigraphic analysis, cine radiography, PH monitoring, and endoscopy. There is severe oropharyngeal incoordination. Cardiovascular instability is a prominent manifestation. Prolonged QT intervals greater than 440 mse without shortening during exercise demonstrate a defect in autonomic regulation of cardiac conduction. Renal insufficiency, common in adult patients, can be assessed by noninvasive Doppler techniques to detect changes in renal blood flow. Sympathetic denervation may increase the responsiveness to regulators of cardiovascular integrity such as atrial natriuretic peptide. Medication can also influence circulating atrial natriuretic peptide and cathecol amines. Excessive drooling and swallowing difficulties are common and can be attributable to salivary gland denervation hypersensitivity. Hypersalivation may account for the

low caries rate and increased plaque formation. Postural hypotension can be explained by peripheral sympathetic denervation. Skin blotching and hypertension are attributed to denervation supersensitivity at the sympathetic effector sites. Lack of overflow tears correlates with the diminution of neurons in the sphenopalatine ganglia. Other symptoms can be explained as manifestations of a diffuse sensory deficit and autonomic insufficiency with hypersensitivity to acetylcholine and possibly to catecholamines. In addition, there may be decreased or dysfunctional adrenoceptors and decreased denervation.

PROGNOSIS Long-term survival has been documented. Surviving patients include women whose pregnancies terminated in the birth of normal infants. Infant and childhood fatalities may be due to aspiration pneumonia, gastric hemorrhage, or dehydration. A second cluster of fatalities between the ages of 14 and 24 showed pulmonary complications, sleep deaths, and cardiopulmonary arrests. The oldest patients are now in their fifth decade.

TREATMENT Laparoscopic surgery for performing a modified Nissen fundoplication and gastrostomy has modified gastroesophageal reflux and the resultant pulmonary complications associated with aspiration. The use of epidural anesthesia has been advocated for surgical procedures such as Nissen fundoplication and cesarean section. This is to avoid intubation and the sometimes fatal complications of general anesthesia. Midodrine, a peripheral a-adrenergic agonist, may be useful in the management of orthostatic hypotension in a dose of 0.25 mg/kg/day. Symptomatic treatment is indicated for dysautonomic crises with parenteral fluids, diazepam, sedation, and antiemetic therapy. SUGGESTED READINGS Alvarez E, Ferrer T, Perez-Conde C, et al. Evaluation of congenital dysautonomia other than Riley-Day syndrome. Neuropediatrics 1996;27:26–31. Axelrod FB. Familial dysautonomia: a 47-year perspective. How technology confirms clinical acumen. J Pediatr 1998;132[3 Pt 2]:S2–S5. Axelrod FB, Goldstein DS, Holmes C, et al. Genotype and phenotype in familial dysautonomia. Adv Pharmacol 1998;42:925–928. Axelrod FB, Krey L, Glickstein JS, et al. Atrial natriuretic peptide response to postural change and medication in familial dysautonomia. Clin Auton Res 1994;4:311–318. Axelrod FB, Porges RF, Seir ME. Neonatal recognition of familial dysautonomia. J Pediatr 1987;110:969–948. Blumenfeld A, Slaugenhaupt SA, Axelrod FB. Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis.

Nat Genet 1993;4:160–164.

Eng-CM, Slaugenhaupt SA, Blumenfeld A, et al. Prenatal diagnosis of familial dysautonomia by analysis of linked CA-repeat polymorphisms on chromosome 9q31-q33. Am J Med Genet 1995;59:349–355. Glickstein JS, Schwartzman D, Friedman D, et al. Abnormalities of the corrected QT interval in familial dysautonomia: an indicator of autonomic dysfunction.

J Pediatr 1993;122:925–928.

Korczyn AD, Rubenstein AE, Yahr MD, Axelrod FB. The pupil in familial dysautonomia. Neurology 1981;31:628–629. Pearson J, Pytel B. Quantitative studies of sympathetic ganglia and spinal cord intermediolateral gray columns in familial dysautonomia. J Neurol Sci 1978;39:47–59. Pearson J, Pytel B. Quantitative studies of ciliary and sphenopalatine ganglia in familial dysautonomia. J Neurol Sci 1978;39:123–130. Riley CM, Day RL, Greely DM, Langford NS. Central autonomic dysfunction with defective lacrimation. I. Report of five cases. Pediatrics 1949;3:468–478. Smith AA, Dancis J. Responses to intradermal histamine in familial dysautonomia—a diagnostic test. J Pediatr 1963;63:889–894. Strasberg P, Bridge P, Merante F, Yeger H, Pereira J. Normal mitochondrial DNA and respiratory chain activity in familial dysautonomia fibroblasts. Biochem Mol Med 1996;59:20–27. Szald A, Udassin R, Maayan C, et al. Laparoscopic modified Nissen fundoplication in children with familial dysautonomia. J Pediatr Surg 1996;31:1560–1562. Udassin R, Seror D, Vinograd I, et al. Nissen fundoplication in the treatment of children with familial dysautonomia. Am J Surg 1992;164:332–336. Weiser M, Helz MJ, Bronfin L, Axelrod FB. Assessing microcirculation in familial dysautonomia by laser Doppler flowmeter. Clin Auton Res 1998;8:13–23.

CHAPTER 139. MIGRAINE AND OTHER HEADACHES MERRITT’S NEUROLOGY

SECTION XXI.PAROXYSMAL DISORDERS CHAPTER 139. MIGRAINE AND OTHER HEADACHES NEIL H. RASKIN Migraine Cluster Headache Cough Headache Coital Headache Postconcussion Headaches Giant Cell Arteritis Lumbar Puncture Headache Brain Tumor Headache Suggested Readings

When headache is chronic, recurrent, and unattended by signs of disease, the physician confronts a challenging but ultimately gratifying problem. Previously, head pain was thought to originate from either contracted scalp and neck muscles or vascular dilatation. Neither of these mechanisms achieved scientific support; central mechanisms of head pain are of current interest. In migraine, the neurologic symptoms are attributed to neuronal dysfunction similar to that of spreading depression; a phase of vasoconstriction and vasodilatation also undoubtedly occurs, as does a final phase that results in the secretion of vasoactive peptides. Most recurring headaches are probably caused by impaired central inhibitory mechanisms at varying loci within the brain.

MIGRAINE The term migraine derives from Galen's usage of hemicrania to describe a periodic disorder that comprises paroxysmal and blinding hemicranial pain, vomiting, photophobia, recurrence at regular intervals, and relief by darkness and sleep. Hemicrania was later corrupted into low Latin as hemigranea and migranea; eventually the French translation, migraine, gained acceptance in the 18th century and has prevailed ever since. This designation is misleading, however, because head pain is lateralized in less than 60% of those affected. Furthermore, undue emphasis on the dramatic features of migraine has often led to the illogical conclusion that a periodic headache lacking such characteristics is not migrainous in mechanism. Severe headache attacks, regardless of causation, are more likely to be throbbing and associated with vomiting and scalp tenderness. Milder headaches tend to be nondescript—tight bandlike discomfort often involving the entire head, the profile of “tension headache.” These differing clinical patterns of headaches that are not caused by an intracranial structural anomaly or systemic disease are probably different points on a continuum rather than disparate clinical entities. Whether a common mechanism underlies the different headaches remains to be determined. A working descriptive definition follows. Migraine is a benign recurring headache, recurring neurologic dysfunction, or both; it is usually attended by pain-free interludes and is almost always provoked by stereotyped stimuli. It is far more common in women; those affected have a hereditary predisposition toward attacks; and the cranial circulatory phenomena that attend attacks seem to be due to a primary brainstem disorder. Clinical Subtypes The designation classic migraine (migraine with aura) denotes the syndrome of headache associated with characteristic premonitory sensory, motor, or visual symptoms; common migraine (migraine without aura) denotes the syndrome in which no focal neurologic symptoms precede the headache. Focal symptoms, however, occur in only a small proportion of attacks and are more common during headache attacks than as prodromal symptoms. Focal neurologic symptoms without headache or vomiting are called migraine equivalents or accompaniments and seem to be more common in patients between the ages of 40 and 70 years. The term complicated migraine is generally used to describe migraine with dramatic focal neurologic features, thus overlapping with classic migraine; it has also been used to connote a persisting neurologic disorder after a migraine attack. Common Migraine Benign periodic headache lasting several hours and often attributed to tension by its sufferers is the most liberal way of describing common migraine. The fallacy intrinsic to most of the traditionally acceptable definitions is that they define severe attacks but do not include patients with more modest degrees of head pain; thus, unilateral pain, attendant nausea or vomiting, positive family history, responsiveness to ergotamine, and scalp tenderness in varying combinations have been alleged to establish a diagnosis of migraine. Each of these occurs in 60% to 80% of patients as dependent variables, however, and the validity of using these clinical features to diagnose migraine has never been established. Common migraine is the most frequent type of headache and includes the now anachronistic concept of periodic “tension headache.” Classic Migraine The most common premonitory symptoms are visual, arising from dysfunction of occipital lobe neurons. Scotomas or hallucinations occur in about one-third of migraineurs and usually appear in the central portion of the visual fields. A highly characteristic syndrome occurs in about 10% of patients; it usually begins as a small paracentral scotoma that slowly expands into a C shape. Luminous angles appear at the enlarging outer edge and become colored as the scintillating scotoma expands and moves toward the periphery of the involved half of the visual field. It eventually disappears over the horizon of peripheral vision; the entire process consumes 20 to 25 minutes. This phenomenon never occurs during the headache phase of an attack and is pathognomonic of migraine; it has never been described with a cerebral structural anomaly. It is commonly called a “fortification spectrum” because the serrated edges of the hallucinated C seemed to Dr. Hubert Airy to resemble a “fortified town with bastions all round it”; “spectrum” is used in the sense of an apparition or specter. Basilar Migraine Symptoms implying altered brainstem function include vertigo, dysarthria, and diplopia; they occur as the only neurologic symptoms of migraine in about 25% of patients. Bickerstaff called attention to a stereotyped sequence of dramatic neurologic events, often comprising total blindness and sensorial clouding; this is most commonly seen in adolescent women but also occurs in others. The episodes begin with total blindness accompanied or followed by admixtures of vertigo, ataxia, dysarthria, tinnitus, and distal and perioral paresthesia. In about 25% of patients, a confusional state supervenes. The symptoms usually persist for about 30 minutes and are usually followed by a throbbing occipital headache. The basilar migraine syndrome also occurs in children or adults over age 50. Sensorial alterations, including confusional states that may be mistaken for psychotic reactions, may last as long as 5 days. Carotidynia The carotidynia syndrome, sometimes called “lower-half headache” or “facial migraine,” is more prominent among older patients, with peak incidence at ages 30 to 69. Pain is usually located at the jaw or neck and is sometimes periorbital or maxillary. It is often continuous, deep, dull, and aching and becomes pounding or throbbing episodically. Sharp ice pick–like jabs are commonly superimposed. Attacks occur one to several times a week, each lasting minutes to hours. Tenderness and prominent pulsations of the cervical carotid artery and swelling of soft tissues over the carotid are usually present homolateral to the pain; many patients report throbbing ipsilateral headache concurrent with carotidynia and interictally. Dental trauma is a common precipitant of this syndrome. Carotid artery involvement in the more traditional forms of migraine is also common; more than 50% of patients with frequent migraine attacks show carotid tenderness at several points homolateral to the cranial side involved in most of their attacks. Hemiplegic Migraine Hemiparesis occasionally occurs during the prodromal phase of migraine; like the fortification spectrum, it often resolves in 20 to 30 minutes, and contralateral head pain then commences. The affected side may vary from attack to attack. A more profound form appears as hemiplegia, often affecting the same side, that persists for days to weeks after headache subsides. A clear autosomal dominant pattern of attacks may appear within a family. The gene for familial hemiplegic migraine maps to

chromosome 19 in half the families; a mutation in a P/Q-type calcium channel (1-subunit gene has been identified. Dysarthria and aphasia occur in more than 50% of patients; hemihypesthesia attends hemiparesis in nearly every case. There may be cerebrospinal fluid (CSF) pleocytosis as high as 350 cells/mm 3 or transient CSF protein elevations to 200 mg/dL. Ophthalmoplegic Migraine Rarely, patients report infrequent attacks of periorbital pain accompanied by vomiting for 1 to 4 days. As the pain subsides, ipsilateral ptosis appears, and within hours, a complete third nerve palsy occurs, often including pupillary dilatation. The ophthalmoplegia may persist for several days to as long as 2 months. After many attacks, some ophthalmoparesis may remain. This syndrome usually begins in childhood, whereas the Tolosa Hunt syndrome, another painful ophthalmoplegia, is a condition of adults. Pathogenesis Modern orientations toward migraine began with Liveing's 1873 publication, A Contribution to the Pathology of Nerve Storms, the first major treatise devoted to the subject of migraine. He believed that the analogy of migraine to epilepsy was obvious and that the clinically apparent circulatory phenomena of migrainous attacks were caused by cerebral discharges or nerve storms. In the 1930s, attention was focused on the vascular features of migraine by Graham and Wolff, who found that the administration of ergotamine reduced the amplitude of temporal artery pulsations in patients and that this effect was often, but not consistently, associated with a decrease in head pain. Therefore, many authorities believed for many years that the headache phase of migrainous attacks was caused by extracranial vasodilatation and that neurologic symptoms were produced by intracranial vasoconstriction, the “vascular” hypothesis of migraine. A barrage of publications by Wolff and coworkers supported the hypothesis, and observations made during the 1940s nonresonant with their hypothesis were ignored. In 1941, K. S. Lashley, a neuropsychologist, was among the first to chart his own migrainous fortification spectrum. He estimated that the evolution of his own scotoma proceeded across the occipital cortex at a rate of 3 mm/min. He speculated that a wave front of intense excitation was followed by a wave of complete inhibition of activity across the visual cortex. Uncannily, in 1944, the phenomenon of “spreading depression” was described in the cerebral cortex of laboratory animals by the Brazilian physiologist Leão. A slowly moving (2 to 3 mm/min) potassium-liberating depression of cortical activity is preceded by a wave front of increased metabolic activity. Spreading depression can be produced by a variety of experimental stimuli, including hypoxia, mechanical trauma, and the topical application of potassium. These observations, striking in retrospect, could not be incorporated into the vascular model of migraine. Cerebral blood flow studies, however, have rendered untenable a primary vascular mechanism and support the possibility that spreading depression, or more likely a neuronal phenomenon with similar characteristics, is important in the pathogenesis of migraine. The mechanism of migraine can be partitioned into three phases. The first is brainstem generation; the second may be considered “vasomotor activation” in which arteries within and outside the brain may contract or dilate. In the third phase, cells of the trigeminal nucleus caudalis become active and release vasoactive neuropeptides at terminations of the trigeminal nerve on blood vessels, possibly explaining the soft tissue swelling and tenderness of blood vessels during migraine attacks. Activation of any of the three phases is sufficient for headache production; one phase may dominate in an individual's migrainous syndrome. For example, the fortification spectrum is probably entirely neurogenic, requiring only the first phase. During attacks of classic migraine, studies of regional cerebral blood flow have shown a modest cortical hypoperfusion that begins in visual cortex and spreads forward at a rate of 2 to 3 mm/min. The decrease in blood flow averages 25% to 30% (too little to explain symptoms) and progresses anteriorly in a wavelike fashion that is independent of the topography of cerebral arteries. The wave of hypoperfusion persists for 4 to 6 hours, follows the convolutions of the cortex, and does not cross the central or lateral sulcus but progresses to the frontal lobe via the insula. Subcortical perfusion is normal. Contralateral neurologic symptoms appear during the period of temporoparietal hypoperfusion; at times, hypoperfusion persists in these regions after symptoms cease. More often, frontal spread continues as the headache phase begins. A few patients with classic migraine show no abnormalities of blood flow; rarely, focal ischemia is sufficient to cause symptoms. Focal ischemia, however, does not appear necessary for focal symptoms to occur. In attacks of common migraine, no abnormalities of blood flow have been seen. The changes in cerebral blood flow are attributed to alterations of cerebral neuronal function. The cortical events require a “generator,” which has been identified within the brainstem. Pharmacologic data converge on serotonin receptors. About 35 years ago, methysergide was found to antagonize peripheral actions of serotonin (5-hydroxytryptamine) and was introduced as the first drug capable of preventing migraine attacks by stabilizing the basic fault. Platelet levels of serotonin fall at the onset of headache, and migrainous episodes can be triggered by drugs that release serotonin. These changes in circulating levels proved to be pharmacologically trivial, however, and interest in the role of serotonin declined, only to be revived by the introduction of sumatriptan, which is remarkably effective for migraine attacks. Sumatriptan is a designer drug synthesized to activate selectively a particular subpopulation of serotonin receptors. The main families of serotonin receptors are types 1, 2, 3, and 4; within each family are receptor subtypes. Sumatriptan interacts as an agonist with 1A receptors and especially with 1D and 1B receptors. By contrast, dihydroergotamine, another drug effective in aborting migraine attacks, is most potent as an agonist of 1A receptors but is an order of magnitude less potent at 1D and 1B receptors. After systemic administration, dihydroergotamine in the brain is found in highest concentrations in the midbrain dorsal raphe. The dorsal raphe contains the highest concentration of serotonin receptors in the brain and could be the generator of migraine and the main site of drug action. Raphe receptors are mainly of 1A, but 1D receptors are also present. Electrical stimulation near dorsal raphe neurons can result in migrainelike headaches. Projections from the dorsal raphe terminate on cerebral arteries and alter cerebral blood flow. The dorsal raphe also projects to visual processing neurons in the lateral geniculate body, superior colliculus, retina, and visual cortex. These projections could provide the anatomic and physiologic bases for the circulatory and visual characteristics of migraine. The dorsal raphe cells stop firing during deep sleep, and sleep ameliorates migraine; antimigraine drugs also stop the firing of the dorsal raphe cells through a direct or indirect agonist effect ( Fig. 139.1). The shutdown of an inhibitory system may enhance or stabilize neurotransmission.

FIG. 139.1. The actions of the antimigraine drugs at brainstem and forebrain synapses. The solid arrows indicate agonist properties; the segmented arrows indicate inhibitory properties. (From Raskin NH. Headache, 2nd ed. New York: Churchill Livingstone, 1988.)

Migraine may therefore be considered a hereditary perturbation of central inhibitory mechanisms. Similar perturbations may underlie many types of head pain; “ordinary” periodic headaches may be the “noise” of the normally functioning system. Treatment Nonpharmacologic treatments have been advocated, but rigorously controlled trials have shown no benefit without concomitant drug treatment. The mainstay of therapy is the judicious use of one or more of the many drugs that are relatively specific for migraine.

Acute Treatment In general, an adequate dose of whichever agent is chosen should be used at the onset of an attack. If additional medication is requested in 30 to 60 minutes because symptoms have returned or have not abated, the initial dosage should be increased for subsequent attacks. Drug absorption is impaired during attacks because of reduced gastrointestinal motility. Absorption may be delayed in the absence of nausea, and the delay is related to the severity of the attack but not to the duration. Therefore, when oral agents fail, the major considerations revolve about rectal administration of ergotamine, subcutaneous sumatriptan, parenteral dihydroergotamine, and intravenous chlorpromazine or prochlorperazine. For patients with a prolonged buildup of headache, oral agents may suffice. When aspirin and acetaminophen fail, the addition of butalbital and caffeine to these analgesics is highly effective; ibuprofen (600 to 800 mg) and naproxen (375 to 750 mg) are often useful. One or two capsules of isometheptene compound are effective for mild to moderate “stress headaches.” When these measures fail, more aggressive therapy is considered. A subnauseating dose of ergotamine, if possible, should be determined for the individual patient; a dose that provokes nausea—probably a centrally mediated effect—is too high for therapy and may intensify head pain. The average oral dose of ergotamine is 3 mg (three 1-mg ergotamine-caffeine tablets); the average dose of the 2-mg suppository is one-half (1 mg). Many patients use one-fourth of a suppository (0.5 mg) with an optimal result. Sumatriptan may be given as an oral 50-mg dose, a 20-mg intranasal dose, or a 6-mg subcutaneous dose; the recurrence rate is high because of the short half-life of this drug (2 hours), and a second dose may be necessary. Rizatriptan and zolmitriptan have similar success rates, and peak blood levels are achieved more quickly. Naratriptan has the best side-effect profile of this group of drugs and the lowest recurrence rate; it is less effective than the other “triptans.” Dihydroergotamine is available as a parenteral preparation and as a nasal spray. Peak plasma levels of dihydroergotamine are achieved 45 to 60 minutes after nasal administration, 45 minutes after subcutaneous administration, 30 minutes after intramuscular administration, and 3 minutes after intravenous administration. If an attack has not already peaked, subcutaneous or intramuscular administration of 1 mg suffices for about 90% of patients. A common intravenous protocol is the mixture of prochlorperazine 5 mg and dihydroergotamine 0.5 mg given over 2 minutes (they are miscible). When a patient's headache profile transforms into a chronic daily headache syndrome, opiate-type analgesics should be restricted to 2 days out of 7. The mainstay of therapy for these patients is daily amitriptyline (30 to 100 mg) or nortriptyline (40 to 120 mg). For recalcitrant individuals, valproate (500 to 2,000 mg) or phenelzine (45 to 90 mg) may be necessary. Drugs that have antidepressant effects act independent of such effects in migraine. Prophylaxis Several drugs can stabilize migraine and prevent attacks; for this purpose, the drugs must be taken daily ( Table 139.1). When to implement this approach depends on the frequency of attacks and how effective the acute treatment is. At least two or three attacks a month could signal this approach. Usually a lag of about 2 weeks must pass before an effect is seen; this may be the time needed to downregulate serotonin receptors. The major drugs and their daily dose are propranolol (60 to 240 mg), amitriptyline (30 to 100 mg), valproate (500 to 2,000 mg), verapamil (120 to 480 mg), phenelzine (45 to 90 mg), and methysergide (4 to 12 mg).

TABLE 139.1. DRUG STABILIZATION OF MIGRAINE

Phenelzine and methysergide are usually reserved for more recalcitrant headaches because of serious adverse effects. Because phenelzine is a monoamine oxidase inhibitor, concomitant use of tyramine-containing foods, decongestants, or meperidine is contraindicated. Methysergide may cause retroperitoneal or cardiac valvular fibrosis when it is used for more than 8 months; thus, monitoring is requisite for patients using this drug. Imaging of the pelvis and abdomen and cardiac auscultation should be carried out at least yearly. The risk of the fibrotic complications is about 1 in 1,500 and is likely to reverse after the drug is stopped. The probability of success with any one of the antimigraine drugs is about 60% to 75%. If one drug is assessed each month, the likelihood is high that stabilization will be achieved within a few months. Most patients are managed successfully with propranolol or amitriptyline; for more urgent resolution, valproate, methysergide, or phenelzine can be implemented. Once effective, the drug is continued for about 6 months, and the dose is then tapered slowly to assess continued need. Many patients can discontinue medication and experience fewer and less severe attacks for a long time, thus suggesting that the drugs may alter the natural history of migraine.

CLUSTER HEADACHE Recognition of this disorder has been retarded by confusing names, including Raeder syndrome, histamine cephalalgia, and sphenopalatine neuralgia. Cluster headache is firmly established as a distinct syndrome that is likely to respond to treatment. The episodic type, the most common, is characterized by one to three short-lived attacks of periorbital pain each day for 4 to 8 weeks, followed by a pain-free interval for a mean of 1 year. The chronic form may begin de novo or may appear several years after an episodic pattern has been established. The attacks are similar, but there are no sustained periods of remission. Either type may transform into the other. Men are affected more often than women in a proportion of about 8:1. Hereditary factors are usually absent. The prevalence is 69 cases per 100,000 people. Although most patients begin experiencing headache between the ages of 20 and 50 years, the syndrome may begin as early as the first decade and as late as the eighth decade. The cluster syndrome differs from migraine genetically, biochemically, and clinically. Propranolol and amitriptyline are largely ineffective in cluster headache. However, lithium is beneficial for the cluster syndrome and ineffective in migraine. Nevertheless, the two disorders may blend into one in occasional patients, suggesting that the mechanisms include some features in common. Clinical Features Periorbital or, less commonly, temporal pain begins without warning and reaches a crescendo within 5 minutes. It is often excruciating in intensity and is deep, nonfluctuating, and explosive in quality; only rarely is it pulsatile. Pain is strictly unilateral and usually affects the same side in subsequent months. Attacks last from 30 minutes to 2 hours; the associated symptoms of homolateral lacrimation, reddening of the eye, nasal stuffiness, lid ptosis, and nausea often appear. Alcohol provokes attacks in about 70% of patients but has no effect when the bout remits; this on–off vulnerability to alcohol is pathognomonic of cluster headache. Only rarely do foods or emotional factors activate the mechanism, in contradistinction to migraine. Periodicity of attacks is evident in at least 85% of patients. At least one of the daily attacks of pain recurs at about the same hour each day for the duration of a bout. This clock mechanism is set for nocturnal hours in about 50% of patients; in these circumstances, the pain usually wakens patients within 2 hours of falling asleep.

Pathogenesis No consistent changes in cerebral blood flow attend attacks of pain. Perhaps the strongest evidence pointing to a central mechanism is the “periodicity”; reinforcing this conclusion are the bilateral autonomic symptoms that accompany the pain and are more severe on the painful side. The hypothalamus may be the site of activation. The posterior hypothalamus contains cells that regulate autonomic functions, and the anterior hypothalamus contains cells (the suprachiasmatic nuclei) that serve as the principal circadian pacemaker in mammals. Activation of both is necessary to explain the symptoms of cluster headache. The pacemaker is modulated serotonergically through projections of the dorsal raphe. Therefore, both migraine and cluster headache may result from abnormal serotonergic neurotransmission, albeit at different loci. Treatment The most satisfactory treatment is the administration of drugs to prevent cluster attacks until the bout is over. The major prophylactic drugs are prednisone, lithium, methysergide, ergotamine, and verapamil. Lithium (600 to 900 mg daily) appears to be particularly effective for the chronic form. A 10-day course of prednisone, beginning at 60 mg daily for 7 days and rapidly tapering, seems to curtail the bout for many patients. Ergotamine is most effective when given 1 or 2 hours before an expected attack; for patients with a single nocturnal episode, 1 mg ergotamine in suppository formulation taken at bedtime may be all that is necessary. Patients must be educated regarding the early symptoms of ergotism (limb claudication) when ergotamine is used daily; a weekly limit of 14 mg should be followed. For the attacks themselves, oxygen inhalation (9 L/min given with a loose mask) is effective; 15 minutes of inhalation of 100% oxygen is often necessary. The self-administration of intranasal lidocaine, either 4% topical or 2% viscous, to the most caudal aspect of the inferior nasal turbinate can deliver a sphenopalatine ganglion block that is often remarkably effective for the termination of an attack. Sumatriptan, 6 mg subcutaneously, usually shortens an attack to 10 to 15 minutes.

COUGH HEADACHE A male-dominated (4:1) syndrome, cough headache is characterized by transient severe head pain upon coughing, bending, lifting, sneezing, or stooping. Head pain persists for seconds to a few minutes. Many patients date the origin of the syndrome to a lower respiratory infection accompanied by severe coughing or to strenuous weight-lifting programs. Headache is usually diffuse but is lateralized in about one-third of patients. The incidence of serious intracranial structural anomalies causing this condition is about 25%; the Arnold-Chiari malformation is a common cause. Magnetic resonance imaging is indicated for these patients. The benign disorder may persist for a few years; it is inexplicably and remarkably ameliorated by indomethacin at doses of 50 to 200 mg daily. A large-volume (40 mL) lumbar puncture dramatically terminates the syndrome for 50% of patients so treated. Many patients with migraine note that attacks of headache may be provoked by sustained physical exertion, such as during the third mile of a 5-mile run. Such headaches build up over hours and thus are distinctly different from the cough headache syndrome. The term “effort migraine” has been used for this syndrome to avoid the ambiguous term “exertional headache.”

COITAL HEADACHE In another male-dominated (4:1) syndrome, headaches occur during coitus, usually close to orgasm. They are abrupt in onset and subside in a few minutes if coitus is interrupted. These headaches are nearly always benign and usually occur sporadically; if coital headaches persist for hours or are accompanied by vomiting, subarachnoid hemorrhage must be evaluated by computed tomography or CSF examination. An unruptured aneurysm may result in a headache during coitus and can be indistinguishable from benign coital headache; therefore, angiography should be considered for the first attack of coital headache. If attacks occur frequently and are brief, however, the disorder is benign.

POSTCONCUSSION HEADACHES After a seemingly trivial head injury and particularly after a rear-end motor vehicle collision, many people report admixtures of headache, vertigo, and impaired memory and concentration for months or years after the injury. This syndrome is usually not associated with an anatomic lesion of the brain and may occur whether or not the person was rendered unconscious by head trauma. In general, this headache is “neurobiologic” rather than “psychologic.” The syndrome usually persists long after the settlement of a lawsuit. Some evidence suggests that concussion perturbs neurotransmission within the brain and that restoration of this condition is typically delayed. Understanding this common problem is contingent upon clarification of the biology of cerebral concussion. Treatment is symptomatic, including repeated encouragement that the syndrome eventually remits.

GIANT CELL ARTERITIS This is a common disorder in elderly patients; the average annual incidence is 77 per 100,000 people aged 50 and older. Women account for 65% of cases, and the average age at onset is 70 years, with a range of 50 to 85 years. The inflammatory process may result in blindness in 50% of patients if corticosteroid treatment is not instituted; indeed, the ischemic optic neuropathy of giant cell arteritis is the major cause of rapidly developing bilateral blindness after age 60 years. The most common initial symptoms are headache, polymyalgia rheumatica, jaw claudication, fever, and weight loss (see Chapter 155). Headache is the dominant symptom and usually appears with malaise and muscle aches. Head pain may be unilateral or bilateral and is located temporally in 50% of patients but may involve any and all aspects of the cranium. Pain usually appears gradually over a few hours before peak intensity is reached; occasionally, it is explosive in onset. The quality of pain is only seldom throbbing; it is almost invariably described as dull and boring with superimposed episodic ice pick–like lancinating pains similar to the sharp pains that appear in migraine. Most patients can recognize that the origin of their head pain is superficial, and external to the skull, rather than deep within the cranium (the site of pain in migraine). Scalp tenderness is present, often to a marked degree; brushing the hair or resting the head on a pillow may be impossible because of pain. Headache is usually worse at night and is often aggravated by exposure to cold. Reddened tender nodules or red streaking of the skin overlying the temporal arteries is found in highest frequency in patients with headache, as is tenderness of the temporal or, less commonly, the occipital arteries. Temporal artery biopsy may be followed by cessation of headache. The erythrocyte sedimentation rate is often but not always elevated; a normal erythrocyte sedimentation rate does not exclude giant cell arteritis. After the temporal artery biopsy, prednisone is given at 80 mg daily for the first 4 to 6 weeks, when clinical suspicion is high. Because patients with migraine also report amelioration of headaches with prednisone therapy, therapeutic responses are not diagnostic. Contrary to widespread notions, the prevalence of migraine among the elderly population is substantial, considerably higher than that of giant cell arteritis.

LUMBAR PUNCTURE HEADACHE Headache after lumbar puncture usually begins within 48 hours but may be delayed for up to 12 days. The mean incidence is about 30%. Head pain is dramatically positional; it begins when the patient sits or stands upright and subsides on reclining or with abdominal compression. The longer the patient is upright, the longer the latency before head pain subsides. It is worsened by head shaking or jugular vein compression. The pain is usually a dull ache but may be throbbing; the location is occipitofrontal. Nausea and stiff neck often accompany headache, and some patients report blurred vision, photophobia, tinnitus, and vertigo. The symptoms resolve over a few days but may persist for weeks or months. Loss of CSF volume decreases the supportive cushion of the brain; when the patient is erect, vascular dilatation probably results and tension is placed on anchoring intracranial structures, including the pain-sensitive dural sinuses. There is often intracranial hypotension, but the full-blown syndrome may occur with normal CSF pressure. Treatment is remarkably effective. Intravenous caffeine sodium benzoate given over a few minutes as a 500-mg dose promptly terminates headache in 75% of patients; a second dose 1 hour later brings the total success rate to 85%. An epidural blood patch accomplished by injection of 15 mL of the patient's blood rarely fails for those who do not respond to caffeine. The mechanism for these treatment effects is not clear because the blood patch has an immediate effect; thus, the sealing of a dural hole with blood clot is an unlikely mechanism of action.

BRAIN TUMOR HEADACHE About 30% of patients with brain tumors consider headache their chief complaint. The head pain syndrome is nondescript; a deep dull aching quality of moderate intensity occurs intermittently, is worsened by exertion or change in position, and is associated with nausea and vomiting. This pattern of symptoms results from migraine far more often than from brain tumor. Headache disturbs sleep in about 10% of patients. Vomiting that precedes the appearance of headache by weeks is highly characteristic of posterior fossa brain tumors. SUGGESTED READINGS Cutrer FM, Sorensen AG, Weisskoff RM, et al. Perfusion-weighted imaging defects during spontaneous migrainous aura. Ann Neurol 1998;43:25–37. Ferrari MD. Migraine. Lancet 1998;351:1043–1051. Goadsby PJ. A triptan too far? J Neurol Neurosurg Psychiatry 1998;64:143–147. Goadsby PJ, Gundlach AL. Localization of 3H-dihydroergotamine binding sites in the cat central nervous system: relevance to migraine. Ann Neurol 1991;29:91–94. Grimson BS, Thompson HS. Raeder's syndrome. A clinical review. Surg Ophthalmol 1980;24:199–210. Hoskin KL, Kaube H, Goadsby PJ. Sumatriptan can inhibit trigeminal afferents by an exclusively neural mechanism. Brain 1996;119:1419–1428. Lance JW, Goadsby PJ. Mechanism and management of headache, 6th ed. London: Butterworth Scientific, 1998. Nyholt DR, Lea RA, Goadsby PJ, et al. Familial typical migraine. Neurology 1998;50:1428–1432. Olesen J. Cerebral and extracranial circulatory disturbances in migraine: pathophysiological implications. Cerebrovasc Brain Metab Rev 1991;3:1–28. Raps EC, Rogers JD, Galetta SL, et al. The clinical spectrum of unruptured intracranial aneurysms. Arch Neurol 1993;30:265–268. Raskin NH. Lumbar puncture headache: a review. Headache 1990;30:197–200. Raskin NH. Short-lived head pains. Neurol Clin 1997;15:143–152. Schraeder PL, Burns RA. Hemiplegic migraine associated with an aseptic meningeal reaction. Arch Neurol 1980;37:377–379. Silberstein SD. The pharmacology of ergotamine and dihydroergotamine. Headache 1997;37[Suppl]:S15–S25. Symonds C. Cough headache. Brain 1956;79:557–568. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995;1:658–660.

CHAPTER 140. EPILEPSY MERRITT’S NEUROLOGY

CHAPTER 140. EPILEPSY TIMOTHY A. PEDLEY, CARL W. BAZIL AND MARTHA J. MORRELL Classification of Seizures and Epilepsy Selected Generalized Epilepsy Syndromes Selected Localization-Related Epilepsy Syndromes Epidemiology Initial Diagnostic Evaluation Long-Term Monitoring Medical Treatment Reproductive Health Issues Gene Defects in Epilepsy Psychosocial and Psychiatric Issues Suggested Readings

An epileptic seizure is the result of a temporary physiologic dysfunction of the brain caused by a self-limited, abnormal, hypersynchronous electrical discharge of cortical neurons. There are many different kinds of seizures, each with characteristic behavioral changes and electrophysiologic disturbances that can usually be detected in scalp electroencephalographic (EEG) recordings. The particular manifestations of any single seizure depend on several factors: whether most or only a part of the cerebral cortex is involved at the beginning, the functions of the cortical areas where the seizure originates, the subsequent pattern of spread of the electrical ictal discharge within the brain, and the extent to which subcortical and brainstem structures are engaged. A seizure is a transient epileptic event, a symptom of disturbed brain function. Although seizures are the cardinal manifestation of epilepsy, not all seizures imply epilepsy. For example, seizures may be self-limited in that they occur only during the course of an acute medical or neurologic illness; they do not persist after the underlying disorder has resolved. Some people, for no discoverable reason, have a single unprovoked seizure. These kinds of seizures are not epilepsy. Epilepsy is a chronic disorder, or group of chronic disorders, in which the indispensable feature is recurrence of seizures that are typically unprovoked and usually unpredictable. About 40 million people are affected worldwide. Each distinct form of epilepsy has its own natural history and response to treatment. This diversity presumably reflects the fact that epilepsy can arise from a variety of underlying conditions and pathophysiologic mechanisms, although most cases are classified as “idiopathic” or “cryptogenic.”

CLASSIFICATION OF SEIZURES AND EPILEPSY Accurate classification of seizures and epilepsy is essential for understanding epileptic phenomena, developing a rational plan of investigation, making decisions about when and for how long to treat, choosing the appropriate antiepileptic drug, and conducting scientific investigations that require delineation of clinical and EEG phenotypes. Classification of Seizures The classification used today is the 1981 Classification of Epileptic Seizures developed by the International League Against Epilepsy (ILAE) ( Table 140.1). This system classifies seizures by clinical symptoms supplemented by EEG data.

TABLE 140.1. ILAE CLASSIFICATION OF EPILEPTIC SEIZURES

Inherent in the classification are two important physiologic principles. First, seizures are fundamentally of two types: those with onset limited to a part of one cerebral hemisphere partial or focal seizures) and those that seem to involve the brain diffusely from the beginning ( generalized seizures). Second, seizures are dynamic and evolving; clinical expression is determined as much by the sequence of spread of electrical discharge within the brain as by the area where the ictal discharge originates. Variations in the seizure pattern exhibited by an individual imply variability in the extent and pattern of spread of the electrical discharge. Both generalized and partial seizures are further divided into subtypes. For partial seizures, the most important subdivision is based on consciousness, which is preserved in simple partial seizures or lost in complex partial seizures. Simple partial seizures may evolve into complex partial seizures, and either simple or complex partial seizures may evolve into secondarily generalized seizures. In adults, most generalized seizures have a focal onset whether or not this is apparent clinically. For generalized seizures, subdivisions are based mainly on the presence or absence and character of ictal motor manifestations. The initial events of a seizure, described by either the patient or an observer, are usually the most reliable clinical indication to determine whether a seizure begins focally or is generalized from the moment of onset. Sometimes, however, a focal signature is lacking for several possible reasons: 1. The patient may be amnesic after the seizure, with no memory of early events. 2. Consciousness may be impaired so quickly or the seizure generalized so rapidly that early distinguishing features are blurred or lost. 3. The seizure may originate in a brain region that is not associated with an obvious behavioral function; thus, the seizure becomes clinically evident only when the discharge spreads beyond the ictal onset zone or becomes generalized. Partial Seizures Simple partial seizures result when the ictal discharge occurs in a limited and often circumscribed area of cortex, the epileptogenic focus. Almost any symptom or phenomenon can be the subjective (“aura”) or observable manifestation of a simple partial seizure, varying from elementary motor (“jacksonian seizures,” adversive seizures) and unilateral sensory disturbance to complex emotional, psychoillusory, hallucinatory, or dysmnesic phenomena. Especially common auras include an epigastric rising sensation, fear, a feeling of unreality or detachment, deja vu and jamais vu experiences, and olfactory hallucinations. Patients can interact normally with the environment during simple partial seizures except for limitations imposed by the seizure on specific localized brain functions. Complex partial seizures, on the other hand, are defined by impaired consciousness and imply bilateral spread of the seizure discharge, at least to basal forebrain and limbic areas. In addition to loss of consciousness, patients with complex partial seizures usually exhibit automatisms, such as lip-smacking, repeated swallowing, clumsy perseveration of an ongoing motor task, or some other complex motor activity that is undirected and inappropriate. Postictally, patients are confused and disoriented for several minutes, and determining the transition from ictal to postictal state may be difficult without simultaneous EEG recording. Of complex partial

seizures, 70% to 80% arise from the temporal lobe; foci in the frontal and occipital lobes account for most of the remainder. Generalized Seizures Generalized tonic-clonic (grand mal) seizures are characterized by abrupt loss of consciousness with bilateral tonic extension of the trunk and limbs ( tonic phase), often accompanied by a loud vocalization as air is forcedly expelled across contracted vocal cords ( epileptic cry), followed by synchronous muscle jerking (clonic phase). In some patients, a few clonic jerks precede the tonic-clonic sequence; in others, only a tonic or clonic phase is apparent. Postictally, patients are briefly unarousable and then lethargic and confused, often preferring to sleep. Many patients report inconsistent nonspecific premonitory symptoms ( epileptic prodrome) for minutes to a few hours before a generalized tonic-clonic seizure. Common symptoms include ill-defined anxiety, irritability, decreased concentration, and headache or other uncomfortable feelings. Absence (petit mal) seizures are momentary lapses in awareness that are accompanied by motionless staring and arrest of any ongoing activity. Absence seizures begin and end abruptly; they occur without warning or postictal period. Mild myoclonic jerks of the eyelid or facial muscles, variable loss of muscle tone, and automatisms may accompany longer attacks. When the beginning and end of the seizure are less distinct, or if tonic and autonomic components are included, the term atypical absence seizure is used. Atypical absences are seen most often in retarded children with epilepsy or in epileptic encephalopathies, such as the Lennox-Gastaut syndrome (defined later). Myoclonic seizures are characterized by rapid brief muscle jerks that can occur bilaterally, synchronously or asynchronously, or unilaterally. Myoclonic jerks range from isolated small movements of face, arm, or leg muscles to massive bilateral spasms simultaneously affecting the head, limbs, and trunk. Atonic (astatic) seizures, also called drop attacks, are characterized by sudden loss of muscle tone, which may be fragmentary (e.g., head drop) or generalized, resulting in a fall. When atonic seizures are preceded by a brief myoclonic seizure or tonic spasm, an acceleratory force is added to the fall, thereby contributing to the high rate of self-injury with this type of seizure. Classification of Epilepsy (Epileptic Syndromes) Attempting to classify the kind of epilepsy a patient has is often more important than describing seizures, because the formulation includes other relevant clinical data of which the seizures are only a part. The other data include historical information (e.g., a personal history of brain injury or family history of first-degree relatives with seizures); findings on neurologic examination; and results of EEG, brain imaging, and biochemical studies. The ILAE classification separates major groups of epilepsy first on the basis of whether seizures are partial ( localization-related epilepsies) or generalized (generalized epilepsies) and second by cause (idiopathic, symptomatic, or cryptogenic epilepsy). Subtypes of epilepsy are grouped according to the patient's age and, in the case of localization-related epilepsies, by the anatomic location of the presumed ictal onset zone. Classification of the epilepsies has been less successful and more controversial than the classification of seizure types. A basic problem is that the classification scheme is empiric, with clinical and EEG data emphasized over anatomic, pathologic, or specific etiologic information. This classification is useful for some reasonably well-defined syndromes, such as infantile spasms or benign partial childhood epilepsy with central-midtemporal spikes, especially because of the prognostic and treatment implications of these disorders. On the other hand, few epilepsies imply a specific disease or defect. A further drawback to the ILAE classification is that the same epileptic syndrome (e.g., infantile spasms or Lennox-Gastaut syndrome) may be produced by a specific disease (e.g., tuberous sclerosis), considered “cryptogenic” on the basis of nonspecific imaging abnormalities, or categorized as “idiopathic.” Another biologic incongruity is the excessive detail in which some syndromes are identified, with specific entities culled from what are more likely simply different biologic expressions of the same abnormality (e.g., childhood and juvenile forms of absence epilepsy). With these reservations, there is little question that defining common epilepsy syndromes has practical value. Table 140.2 gives a modified version of the ILAE classification, which continues to evolve.

TABLE 140.2. MODIFIED CLASSIFICATION OF EPILEPTIC SYNDROMES

SELECTED GENERALIZED EPILEPSY SYNDROMES Infantile Spasms (West Syndrome) The term infantile spasms denotes a unique age-specific form of generalized epilepsy that may be either idiopathic or symptomatic. When all clinical data are considered, including results of imaging studies, only about 15% of patients are now classified as idiopathic. Symptomatic cases result from diverse conditions, including cerebral dysgenesis, tuberous sclerosis, phenylketonuria, intrauterine infections, or hypoxic-ischemic injury. Seizures are characterized by sudden flexor or extensor spasms that involve the head, trunk, and limbs simultaneously. The attacks usually begin before 6 months of age. The EEG is grossly abnormal, showing chaotic high-voltage slow activity with multifocal spikes, a pattern termed hypsarrhythmia. The treatment of choice is corticotropin or prednisone; spasms are notoriously refractory to conventional antiepileptic drugs. Vigabatrin, an antiepileptic drug that is not approved for use in the United States but is widely available elsewhere, is an exception. Several small series indicate that vigabatrin is an effective alternative to corticotropin in selected cases. Although corticotropin therapy usually controls spasms and reverses the EEG abnormalities, it has little effect on long-term prognosis. Only about 5% to 10% of children with infantile spasms have normal or near-normal intelligence, and more than 66% have severe disabilities. Childhood Absence (Petit Mal) Epilepsy This disorder begins most often between the ages of 4 and 12 years and is characterized predominantly by recurrent absence seizures, which, if untreated, can occur literally hundreds of times each day. EEG activity during an absence attack is characterized by stereotyped, bilateral, 3-Hz spike-wave discharges. Generalized tonic-clonic seizures also occur in 30% to 50% of cases. Most children are normal, both neurologically and intellectually. Ethosuximide and valproate are equally effective in treating absence seizures, but valproate or lamotrigine are preferable if generalized tonic-clonic seizures coexist. Topiramate may also be effective in generalized-onset seizures. Lennox-Gastaut Syndrome This term is applied to a heterogeneous group of childhood epileptic encephalopathies that are characterized by mental retardation, uncontrolled seizures, and a distinctive EEG pattern. The syndrome is not a pathologic entity, because clinical and EEG manifestations result from brain malformations, perinatal asphyxia, severe

head injury, central nervous system infection, or, rarely, a progressive degenerative or metabolic syndrome. A presumptive cause can be identified in 65% to 70% of affected children. Seizures usually begin before age 4 years, and about 25% of children have a history of infantile spasms. No treatment is consistently effective, and 80% of children continue to have seizures as adults. Best results are generally obtained with broad-spectrum antiepileptic drugs, such as valproate, lamotrigine, or topiramate. Despite the higher incidence of severe side effects, felbamate is often effective when these other agents do not result in optimal seizure control. Refractory cases may be considered for corpus callosotomy. Juvenile Myoclonic Epilepsy This subtype of idiopathic generalized epilepsy most often begins in otherwise healthy individuals between the ages of 8 and 20 years. The fully developed syndrome comprises morning myoclonic jerks, generalized tonic-clonic seizures that occur just after waking, normal intelligence, a family history of similar seizures, and an EEG that shows generalized spikes, 4- to 6-Hz spike waves, and multiple spike (“polyspike”) discharges. The myoclonic jerks vary in intensity from bilateral massive spasms and falls to minor isolated muscle jerks that many patients consider nothing more than “morning clumsiness.” Valproate is the treatment of choice and controls seizures and myoclonus in more than 80% of cases. Lamotrigine or acetazolamide are alternatives, although lamotrigine can exacerbate myoclonus in some patients. Some linkage studies have identified a marker for juvenile myoclonic epilepsy on the short arm of chromosome 6; the gene product is not known.

SELECTED LOCALIZATION-RELATED EPILEPSY SYNDROMES Benign Focal Epilepsy of Childhood Several “benign” focal epilepsies occur in children, of which the most common is the syndrome associated with central-midtemporal spikes on EEG. This form of idiopathic focal epilepsy, also known as benign rolandic epilepsy, accounts for about 15% of all pediatric seizure disorders. Onset is between 4 and 13 years; children are otherwise normal. Most children have attacks mainly or exclusively at night. Sleep promotes secondary generalization, so that parents report only generalized tonic-clonic seizures; any focal manifestations go unobserved. In contrast, seizures that occur during the day are clearly focal with twitching of one side of the face; speech arrest; drooling from a corner of the mouth; and paresthesias of the tongue, lips, inner cheeks, and face. Seizures may progress to include clonic jerking or tonic posturing of the arm and leg on one side. Consciousness is usually preserved. The interictal EEG abnormality is distinctive and shows stereotyped di- or triphasic sharp waves over the central-midtemporal (rolandic) regions. Discharges may be unilateral or bilateral. They increase in abundance during sleep and, when unilateral, switch from side to side on successive EEGs. In about 30% of cases, generalized spike-wave activity also occurs. The EEG pattern is inherited as an autosomal dominant trait with age-dependent penetrance. The inheritance pattern of the seizures, although clearly familial, is probably multifactorial and less well understood. More than half the children who show the characteristic EEG abnormality never have clinical attacks. Linkage has recently been reported in some families to chromosome 15q14. The prognosis is uniformly good. Seizures disappear by mid to late adolescence in all cases. Seizures in many children appear to be self-limited, and more physicians now defer treatment until after the second or third attack, a policy with which we agree. Because seizures are easily controlled and self-limited, drugs with the fewest adverse effects, such as carbamazepine or gabapentin, should be used. Low doses, often producing subtherapeutic blood concentrations, are generally effective. Temporal Lobe Epilepsy This is the most common epilepsy syndrome of adults. In most cases, the epileptogenic region involves mesial temporal lobe structures, especially the hippocampus, amygdala, and parahippocampal gyrus. Seizures usually begin in late childhood or adolescence, and a history of febrile seizures is common. Virtually all patients have complex partial seizures, some of which secondarily generalize. Auras are frequent; visceral sensations are particularly common. Other typical behavioral features include a motionless stare, loss of awareness that may be gradual, and oral-alimentary automatisms, such as lip-smacking. A variable but often prolonged period of postictal confusion is the rule. Interictal EEGs show focal temporal slowing and epileptiform sharp waves or spikes over the anterior temporal region. Antiepileptic drugs are usually successful in suppressing secondarily generalized seizures, but 50% or more of patients continue to have partial attacks. When seizures persist, anterior temporal lobe resection is the treatment of choice. In appropriately selected patients, complete seizure control is achieved in more than 80% of cases. Frontal Lobe Epilepsy The particular pattern of the many types of frontal lobe seizures depends on the specific location where the seizure discharge originates and on the pathways subsequently involved in propagation. Despite this variability, the following features, when taken together, suggest frontal lobe epilepsy: 1. Brief seizures that begin and end abruptly with little, if any, postictal period; 2. A tendency for seizures to cluster and to occur at night; 3. Prominent, but often bizarre, motor manifestations, such as asynchronous thrashing or flailing of arms and legs, pedaling leg movements, pelvic thrusting, and loud, sometimes obscene, vocalizations, all of which may suggest psychogenic seizures; 4. Minimal abnormality on scalp EEG recordings; 5. A history of status epilepticus. Posttraumatic Seizures Seizures occur within 1 year in about 7% of civilian and in about 34% of military head injuries. The differences relate mainly to the much higher proportion of penetrating wounds in military cases. The risk of developing posttraumatic epilepsy is directly related to the severity of the injury and also correlates with the total volume of brain lost as measured by computed tomography (CT). Depressed skull fractures may or may not be a risk; the rate of posttraumatic epilepsy was 17% in one series but not increased above control levels in another. Head injuries are classified as severe if they result in brain contusion, intracerebral or intracranial hematoma, unconsciousness, or amnesia for more than 24 hours or in persistent neurologic abnormalities, such as aphasia, hemiparesis, or dementia. Mild head injury (brief loss of consciousness, no skull fracture, no focal neurologic signs, no contusion or hematoma) do not increase the risk of seizures significantly above general population rates. Nearly 60% of those who have seizures have the first attack in the first year after the injury. In the Vietnam Head Injury Study, however, more than 15% of patients did not have epilepsy until 5 or more years later. Posttraumatic seizures are classified as early (within the first 1 to 2 weeks after injury) or late. Only recurrent late seizures (those that occur after the patient has recovered from the acute effects of the injury) should be considered posttraumatic epilepsy. Early seizures, however, even if isolated, increase the chance of developing posttraumatic epilepsy. About 70% of patients have partial or secondarily generalized seizures. Impact seizures occur at the time of or immediately after the injury. These attacks are attributed to an acute reaction of the brain to trauma and do not increase the risk of later epilepsy. Overt seizures should be treated according to principles reviewed later in this chapter. The most controversial issue concerns the prophylactic use of antiepileptic drugs to retard or abort the development of subsequent seizures. Based on the data of Temkin et al. (1990), we recommend treating patients with severe head trauma, as just defined, with phenytoin for the first week after injury to minimize complications from seizures occurring during acute management. Phenytoin, or fosphenytoin, should be given intravenously in a loading dose of about 20 mg/kg; subsequent doses should be adjusted to maintain blood levels of 15 to 20 µg/mL. If seizures have not occurred, we do not continue phenytoin beyond the initial 1 to 2 weeks, because evidence does not show that longer treatment prevents the development of later seizures or of posttraumatic epilepsy. Recent data have also shown that valproate is less effective than phenytoin in suppressing acute seizures and also ineffective in preventing the development of posttraumatic seizures. Epilepsia Partialis Continua Epilepsia partialis continua (EPC) refers to unremitting motor seizures involving part or all of one side of the body. They typically consist of repeated clonic or myoclonic jerks that may remain focal or regional or may march from one muscle group to another, with the extent of motor involvement waxing and waning in endless variation. In adults, EPC occurs in diverse settings, such as with subacute or chronic inflammatory diseases of the brain (Kozhevnikov Russian spring-summer

encephalitis; Behçet disease) or with acute strokes, metastases, and metabolic encephalopathies, especially hyperosmolar nonketotic hyperglycemia. The most distinctive form of EPC, known as the Rasmussen syndrome, occurs in children; it usually begins before the age of 10 years. The underlying disorder is chronic focal encephalitis, although an infectious agent has not been identified consistently. About two-thirds of patients report an infectious or inflammatory illness 1 to 6 months before onset of EPC. Generalized tonic-clonic seizures are often the first sign and appear before the EPC establishes itself. About 20% of cases begin with an episode of convulsive status epilepticus. Slow neurologic deterioration inevitably follows, with development of hemiparesis, mental impairment, and, usually, hemianopia. If the dominant hemisphere is affected, aphasia occurs. EEGs are always abnormal, but findings are not specific, and they frequently do not correlate with clinical manifestations. Magnetic resonance imaging (MRI) may be normal early but later show unilateral cortical atrophy and signal changes consistent with gliosis. Antiepileptic drugs are usually ineffective, as are corticosteroids and antiviral agents. When seizures have not spontaneously remitted by the time hemipleiga and aphasia are complete, functional hemispherectomy can control seizures and leads to substantial improvement in many patients. Whether hemispherectomy should be performed before the maximal motor or language deficit has developed is controversial.

EPIDEMIOLOGY In the United States, about 6.5 persons per 1,000 population are affected with recurrent unprovoked seizures, so-called active epilepsy. Based on 1990 census figures, age-adjusted annual incidence rates for epilepsy range from 31 to 57 per 100,000 in the United States ( Fig. 140.1). Incidence rates are highest among young children and the elderly; epilepsy affects males 1.1 to 1.5 times more often than females.

FIG. 140.1. Age-specific incidence of epilepsy in Rochester, Minnesota, 1935–1984. (From Hauser et al. [1993].)

Complex partial seizures are the most common seizure type among newly diagnosed cases, but age-related variability occurs in the proportions of different seizure types (Fig. 140.2). The cause of epilepsy also varies somewhat with age. Despite advances in diagnostic capabilities, however, the “unknown” etiologic category remains larger than any other for all age groups ( Fig. 140.3). Cerebrovascular disease, associated developmental neurologic disorders (e.g., cerebral palsy and mental retardation), and head trauma are the other most commonly identified causes.

FIG. 140.2. Proportion of seizure types in newly diagnosed cases of epilepsy in Rochester, Minnesota, 1935–1984. (From Hauser et al. [1993].)

FIG. 140.3. Etiology of epilepsy in all cases of newly diagnosed seizures in Rochester, Minnesota, 1935–1984 (From Hauser et al. [1993].)

Although defined genetic disorders account for only about 1% of epilepsy cases, heritable factors are important. Monozygotic twins have a much higher concordance rate for epilepsy than do dizygotic twins. By age 25, nearly 9% of children of mothers with epilepsy and 2.4% of children of affected fathers develop epilepsy. The reason for an increased risk of seizures in children of women with epilepsy is not known. Some forms of epilepsy are more heritable than others. For example, children of parents with absence seizures have a higher risk of developing epilepsy (9%) than do offspring of parents with other types of generalized seizures or partial seizures (5%). As a general rule, though, even offspring born to a “high-risk” parent have a 90% or greater chance of being unaffected by epilepsy. Many persons who experience a first unprovoked seizure never have a second. By definition, these people do not have epilepsy and generally do not require long-term drug treatment. Unfortunately, our ability to identify such individuals with accuracy is incomplete. Treatment decisions must be based on epidemiologic and individual considerations. Some seizure types, such as absence and myoclonic, are virtually always recurrent by the time the patient is seen by a physician. On the other hand, patients with convulsive seizures may seek medical attention after a first occurrence because of the dramatic nature of the attack. Prospective studies of recurrence after a first seizure indicate a 2-year recurrence risk of about 40%, which is similar in children and adults. The risk is lowest in people with an idiopathic generalized first seizure and normal EEG (about 24%), higher with idiopathic generalized seizures and an abnormal EEG (about 48%), and highest with symptomatic (i.e., known preceding brain injury or neurologic syndrome) seizures and an abnormal EEG (about 65%). Epileptiform, but not nonepileptiform, EEG abnormalities impart a greater risk for recurrence. If the first seizure is a partial seizure, the relative risk of recurrence is also increased. The risk for further recurrence after a second unprovoked seizure is greater than 80%; a second unprovoked seizure is, therefore, a reliable marker of epilepsy.

About 4% of persons living to age 74 have at least one unprovoked seizure. When provoked seizures (i.e., febrile seizures or those related to an acute illness) are included, the likelihood of experiencing a seizure by age 74 increases to at least 9%. The risk of developing epilepsy is about 3% by age 74. Of persons with epilepsy, 60% to 70% achieve remission of seizures with antiepileptic drug therapy. Factors that favor remission include an idiopathic (or cryptogenic) form of epilepsy, normal findings on neurologic examination, and onset in early to middle childhood (except neonatal seizures). Unfavorable prognostic factors include partial seizures, an abnormal EEG, and associated mental retardation or cerebral palsy ( Table 140.3).

TABLE 140.3. PREDICTORS OF INTRACTABILITY

Mortality is increased in persons with epilepsy, but the risk is incurred mainly by symptomatic cases in which higher death rates are related primarily to the underlying disease rather than to epilepsy. Accidental deaths, especially drowning, are more common, however, in all patients with epilepsy. Sudden unexplained death is nearly 25 times more common in patients with epilepsy than in the general population; estimates of incidence rates range from 1 in 500 to 1 in 2,000 per year. Severe epilepsy and uncontrolled generalized convulsions are risk factors.

INITIAL DIAGNOSTIC EVALUATION The diagnostic evaluation has three objectives: to determine if the patient has epilepsy; to classify the type of epilepsy and identify an epilepsy syndrome, if possible; and to define the specific underlying cause. Accurate diagnosis leads directly to proper treatment and formulation of a rational plan of management. The differential diagnosis is considered in Chapter 3. Because epilepsy comprises a group of conditions and is not a single homogeneous disorder, and because seizures may be symptoms of both diverse brain disorders and an otherwise normal brain, it is neither possible nor desirable to develop inflexible guidelines for what constitutes a “standard” or “minimal” diagnostic evaluation. The clinical data from the history and physical examination should allow a reasonable determination of probable diagnosis, seizure and epilepsy classification, and likelihood of underlying brain disorder. Based on these considerations, diagnostic testing should be undertaken selectively. History and Examination A complete history is the cornerstone for establishing a diagnosis of epilepsy. An adequate history should provide a clear picture of the clinical features of the seizures and the sequence in which manifestations evolve; the course of the epileptic disorder; seizure precipitants, such as alcohol or sleep deprivation; risk factors for seizures, such as abnormal gestation, febrile seizures, family history of epilepsy, head injury, encephalitis or meningitis, and stroke; and response to previous treatment. In children, developmental history is important. In describing the epileptic seizure, care should be taken to elicit a detailed description of any aura. The aura was once considered to be the “warning” of an impending attack, but it is actually a simple partial seizure made apparent by subjective feelings or experiential phenomena observable only by the patient. Auras precede many complex partial or generalized seizures and are experienced by 50% to 60% of adults with epilepsy. Auras confirm the suspicion that the seizure begins locally within the brain; they may also provide direct clues about the location or laterality of the focus. Information about later events in the seizure usually are obtained from an observer because of the patient's impaired awareness or frank loss of consciousness or because of postictal amnesia even though responses to questions during the seizure indicate preserved responsiveness. The nature of repetitive automatic or purposeless movements (automatisms), sustained postures, presence of myoclonus, and the duration of the seizure help to delineate specific seizure types or epileptic syndromes. Nonspecific postictal findings of lethargy and confusion must be distinguished from focal neurologic abnormalities, such as hemiparesis or aphasia, that point to the hemisphere of seizure onset. Information about risk factors (Table 140.4) may suggest a particular cause and assist in prognosis. Discussion with parents may be necessary, because children or adults may be uninformed about, or may not recall, early childhood events, such as perinatal encephalopathy, febrile seizures, brain infections, head injuries, or intermittent absence seizures. Age at seizure onset and course of the seizure disorder should be clarified, because these features differ in the various epilepsy syndromes.

TABLE 140.4. RISK FACTORS FOR EPILEPSY

Findings on neurologic examination are usually normal in patients with epilepsy but occasionally may provide etiologic clues. Focal signs indicate an underlying cerebral lesion. Asymmetry of the hand or face may indicate localized or hemispheric cerebral atrophy contralateral to the smaller side. Phakomatoses are commonly associated with seizures and may be suggested by cafe-au-lait spots, facial angioma, conjunctival telangiectasia, hypopigmented macules, fibroangiomatous nevi, or lumbosacral shagreen patches. Electroencephalography Because epilepsy is fundamentally a physiologic disturbance of brain function, the EEG is the most important laboratory test in evaluating patients with seizures. The

EEG helps both to establish the diagnosis of epilepsy and to characterize specific epileptic syndromes. EEG findings may also help in management and in prognosis. Epileptiform discharges (spikes and sharp waves) are highly correlated with seizure susceptibility and can be recorded on the first EEG in about 50% of patients. Similar findings are recorded in only 1% to 2% of normal adults and in a somewhat higher percentage of normal children. When multiple EEGs are obtained, epileptiform abnormalities eventually appear in 60% to 90% of adults with epilepsy, but the yield of positive studies does not increase substantially after three or four tests. It is important to remember, therefore, that 10% to 40% of patients with epilepsy do not show epileptiform abnormalities on routine EEG; a normal or nonspecifically abnormal EEG never excludes the diagnosis. Sleep, hyperventilation, photic stimulation, and special electrode placements are routinely used to increase the probability of recording epileptiform abnormalities. Different and distinctive patterns of epileptiform discharge occur in specific epilepsy syndromes as summarized in Chapter 14. Brain Imaging MRI should be performed in all patients over age 18 years and in children with abnormal development, abnormal findings on physical examination, or seizure types that are likely to be manifestations of symptomatic epilepsy. CT will often miss common epileptogenic lesions such as hippocampal sclerosis, cortical dysplasia, and cavernous malformations. Because CT is very sensitive for detecting brain calcifications, a noncontrast CT (in addition to MRI) may be helpful in patients at risk for neurocysticercosis. Routine imaging is not necessary for children with idiopathic epilepsy, including the benign focal epilepsy syndromes (see later section). Brain MRI, although more costly, is more sensitive than CT in detecting potentially epileptogenic lesions, such as cortical dysplasia, hamartomas, differentiated glial tumors, and cavernous malformations. Both axial and coronal planes should be imaged with both T1 and T2 sequences. Gadolinium injection does not increase the sensitivity for detecting cerebral lesions but may assist in differentiating possible causes. Imaging in the coronal plane perpendicular to the long axis of the hippocampus and other variations in technique have improved the detection of hippocampal atrophy and gliosis, findings that are highly correlated with mesial temporal sclerosis ( Fig. 140.4) and an epileptogenic temporal lobe. An even more sensitive measure of hippocampal atrophy is MRI measurement of the volume of the hippocampus. Hippocampal volume measurements in an individual patient then can be compared with those of normal control subjects.

FIG. 140.4. Mesial temporal sclerosis. A and B: Short-tau inversion recovery (STIR) coronal magnetic resonance images through the temporal lobes show increased signal and decreased size of right hippocampus as compared with left. These findings are characteristic of mesial temporal sclerosis. Note incidental focal dilatation of left choroid fissure, which represents a choroid fissure cyst, and is a normal variant. (Courtesy of Dr. S. Chan, Columbia University College of Physicians and Surgeons, New York, NY.)

Other Laboratory Tests Routine blood tests are rarely diagnostically useful in healthy children or adults. They are necessary in newborns and in older patients with acute or chronic systemic disease to detect abnormal electrolyte, glucose, calcium, or magnesium values or impaired liver or kidney function that may contribute to seizure occurrence. In most patients, serum electrolytes, liver function tests, and a complete blood count are useful mainly as baseline studies before initiating antiepileptic drug treatment. Any suspicion of meningitis or encephalitis mandates lumbar puncture. Urine or blood toxicologic screens should be considered when otherwise unexplained new-onset generalized seizures occur.

LONG-TERM MONITORING The most direct and convincing evidence of an epileptic basis for a patient's episodic symptoms is the recording of an electrographic seizure discharge during a typical behavioral attack. This recording is especially necessary if the history is ambiguous, EEGs are repeatedly normal or nonspecifically abnormal, and reasonable treatment has failed. Because most patients have seizures infrequently, routine EEG rarely records an attack. Long-term monitoring permits EEG recording for a longer time, thus increasing the likelihood of recording seizures or interictal epileptiform discharges. Two methods of long-term monitoring are now widely available: simultaneous closed-circuit television and EEG (CCTV/EEG) monitoring and ambulatory EEG. Both have greatly improved diagnostic accuracy and the reliability of seizure classification and both provide continuous recordings through one or more complete waking-sleep cycles and capture ictal episodes. Each has additional specific advantages and disadvantages. The method used depends on the question posed by a particular patient. Long-term monitoring using CCTV/EEG, usually in a specially designed hospital unit, is the procedure of choice to document psychogenic seizures and other nonepileptic paroxysmal events. It can also establish electrical-clinical correlations and localize epileptogenic foci for resective surgery. The emphasis in monitoring units is usually on behavioral events, not interictal EEG activity. The availability of full-time technical or nursing staff ensures high-quality recordings and permits examination of patients during clinical events. Antiepileptic drugs can be discontinued safely to facilitate seizure occurrence. Computerized detection programs are used to screen EEG continuously for epileptiform abnormalities and subclinical seizures. The other method of long-term monitoring is designed for outpatient use in the patient's home, school, or work environment. Ambulatory EEG is often especially helpful in pediatrics, because children are often more comfortable in their familiar and unrestricted home environment. The major limitations of ambulatory monitoring are the limited coverage of cortical areas, variable technical quality resulting from lack of expert supervision, frequent distortion of EEG data by environmental contaminants, and the absence of video documentation of behavioral changes. Ambulatory monitoring is most useful in documenting interictal epileptiform activity when routine EEGs have been repeatedly negative or in recording ictal discharges during typical behavioral events. At present, however, ambulatory EEG is not a substitute for CCTV/EEG monitoring, especially when psychogenic seizures are an issue or when patients are being evaluated for epilepsy surgery.

MEDICAL TREATMENT Therapy of epilepsy has three goals: to eliminate seizures or reduce their frequency to the maximum extent possible, to avoid the side effects associated with long-term treatment, and to assist the patient in maintaining or restoring normal psychosocial and vocational adjustment. No medical treatment now available can induce a permanent remission (“cure�) or prevent development of epilepsy by altering the process of epileptogenesis. The decision to institute antiepileptic drug therapy should be based on a thoughtful and informed analysis of the issues involved. Isolated infrequent seizures, whether convulsive or not, probably pose little medical risk to otherwise healthy persons. However, even relatively minor seizures, especially those associated with loss or alteration of alertness, have many psychosocial, vocational, and safety ramifications. Finally, the probability of seizure recurrence varies substantially among patients, depending on the type of epilepsy and any associated neurologic or medical problems. Drug treatment, on the other hand, carries a risk of adverse effects, which

approaches 30% after initial treatment. Treatment of children raises additional issues, especially the unknown effects of long-term antiepileptic drug use on brain development, learning, and behavior. These considerations mean that although drug treatment is indicated and beneficial for most patients with epilepsy, certain circumstances call for antiepileptic drugs to be deferred or used for only a limited time. As a rule of thumb, antiepileptic drugs should be prescribed when the potential benefits of treatment clearly outweigh possible adverse effects of therapy. Acute Symptomatic Seizures These seizures are caused by, or associated with, an acute medical or neurologic illness. A childhood febrile seizure is the most common example of an acute symptomatic seizure, but other frequently encountered causes include metabolic or toxic encephalopathies and acute brain infections. To the extent that these conditions resolve without permanent brain damage, seizures are usually self-limited. The primary therapeutic concern in such patients should be identification and treatment of the underlying disorder. If antiepileptic drugs are needed to suppress seizures acutely, they generally do not need to be continued after the patient recovers. The Single Seizure About 25% of patients with unprovoked seizures come to a physician after a single attack, nearly always a generalized tonic-clonic seizure. Most of these people have no risk factors for epilepsy, have normal findings on neurologic examination, and show a normal first EEG. Only about 25% of these patients later develop epilepsy. For this group, the need for treatment is questionable. For many years, no convincing data indicated any beneficial effect of treatment on preventing recurrence. In 1993, a large multicenter randomized study from Italy convincingly demonstrated that antiepileptic drugs reduce the risk of relapse after the first unprovoked convulsive seizure. Among nearly 400 children and adults, treatment within 7 days of a first seizure was followed by a recurrence rate of 25% at 2 years. In contrast, untreated patients had a recurrence rate of 51%. When patients with previous “uncertain spells� were excluded from the analysis, treatment benefit was still evident, but the magnitude of the effect was reduced to a recurrence rate of 30% in the treated group and 42% in untreated patients. Although treatment of first seizures reduces the relapse rate even in low-risk patients, there is no evidence that such treatment alters the prognosis of epilepsy. Thus, treatment should not be automatic, and the decision to treat should be made only in consultation with the patient or parents after weighing the unique circumstances posed by that individual. In most patients with idiopathic epilepsy, deferring treatment until a second seizure occurs is a reasonable and often preferable decision. Benign Epilepsy Syndromes Several electroclinical syndromes begin in childhood and are associated with normal development, normal findings on neurologic examination, and normal brain imaging studies. They have a uniformly good prognosis for complete remission in mid to late adolescence without long-term behavioral or cognitive problems. The most common and best characterized of these syndromes is benign partial epilepsy of childhood with central-midtemporal sharp waves (rolandic epilepsy). Most seizures occur at night as secondarily generalized convulsions. Focal seizures occur during the day and are characterized by twitching of one side of the face, anarthria, salivation, and paresthesias of the face and inner mouth followed variably by hemiclonic movements or hemitonic posturing. Other benign syndromes include benign partial epilepsy with occipital spike waves and benign epilepsy with affective symptoms. Because of the good prognosis, the sole goal of treatment in such cases is to prevent recurrence. Because many children, especially those who are older, tend to have only a few seizures, treatment is not always necessary. Antiepileptic drugs are usually reserved for children whose seizures are frequent or relatively severe or whose parents, or the children themselves, are distressed at the prospect of future episodes. With these considerations in mind, only about half the children with benign partial epilepsy require treatment. Antiepileptic Drugs Selection of Antiepileptic Drugs Two nationwide collaborative Veterans Administration Cooperative Studies (1985 and 1992) compared the effectiveness of antiepileptic drugs. In the 1985 study, carbamazepine, phenytoin, primidone, and phenobarbital were equally effective in controlling complex partial and secondarily generalized seizures. In the 1992 study, carbamazepine was slightly more effective than valproate in treating complex partial seizures, but both drugs were of equal efficacy in controlling secondarily generalized seizures. These studies also demonstrated that despite their relatively uniform ability to suppress seizures, the drugs had different risks of adverse effects. Considering both efficacy and tolerability, carbamazepine and phenytoin are drugs of first choice for patients with partial and secondarily generalized seizures. For patients who have predominantly secondarily generalized seizures, valproate is also effective. No clinical trials have addressed the relative efficacy of antiepileptic drugs against different symptomatic localization- related epilepsies. There are also few data about the effectiveness of newer antiepileptic drugs (those approved since 1993) compared with older agents or each other. Preliminary studies from Europe indicate that lamotrigine is comparable in effectiveness with phenytoin and carbamazepine and that gabapentin shows similar efficacy to carbamazepine for treatment of new-onset partial seizures. Drugs are therefore chosen based on the patient's predominant seizure type. In general, valproate is the drug of choice for generalized-onset seizures and can be used advantageously as monotherapy when several generalized seizure types coexist (Table 140.5). Lamotrigine and probably topiramate are alternatives if valproate is ineffective or not tolerated. Phenytoin and carbamazepine are also effective against generalized tonic-clonic seizures, but the response is less predictable than that with valproate. Carbamazepine, phenytoin, gabapentin, and sometimes lamotrigine can aggravate myoclonic seizures; all of these except lamotrigine also sometimes exacerbate absence seizures. Tiagabine can aggravate or induce absence seizures. Ethosuximide is as effective as valproate in controlling absence seizures and has fewer side effects. Ethosuximide is ineffective against tonic-clonic seizures, however, so its main use is as an alternative to valproate in patients who only have absence seizures.

TABLE 140.5. DRUGS USED IN TREATING DIFFERENT TYPES OF SEIZURES

Adverse Effects of Antiepileptic Drugs All antiepileptic drugs have undesirable effects in some patients. Although interindividual variation occurs, most adverse drug effects are mild and dose related. Many are common to virtually all antiepileptic drugs, especially when treatment is started. These include sedation, mental dulling, impaired memory and concentration, mood changes, gastrointestinal upset, and dizziness. Other adverse effects are relatively specific for individual agents.

Dose-related Side Effects These typically appear when a drug is first given or when the dosage is increased. They usually, but not always, correlate with blood concentrations of the parent drug or major metabolites (Table 140.6). Dose-related side effects are always reversible on lowering the dosage or discontinuing the drug. Adverse effects frequently determine the limits of treatment with a particular drug and have a major influence on compliance with the prescribed regimen. Because dose-related side effects are broadly predictable, they are often the major differentiating feature in choosing among otherwise equally effective therapies.

TABLE 140.6. TOXICITY OF ANTIEPILEPTIC DRUGS

Idiosyncratic Side Effects Idiosyncratic reactions account for most serious and virtually all life-threatening adverse reactions to antiepileptic drugs. All antiepileptic drugs can cause similar serious side effects (Table 140.6), but with the exception of rash, these are fortunately rare. For example, the risk of carbamazepine-induced agranulocytosis or aplastic anemia is about 2 per 575,000; with felbamate, the risk of aplastic anemia may be as high as 1 per 5,000. Idiosyncratic reactions are not dose related; rather they arise either from an immune-mediated reaction to the drug or from poorly defined individual factors, largely genetic, that convey an unusual sensitivity to the drug. An example of the genetic mechanism is valproate-induced fatal hepatotoxicity. Valproate, like most antiepileptic drugs, is metabolized in the liver, but several biochemical pathways are available to the drug. Clinical and experimental data indicate that one of these pathways results in a hepatotoxic compound that may accumulate and lead to microvesicular steatosis with necrosis. The extent to which this pathway is involved in biotransformation is age dependent and promoted by concurrent use of other drugs that are eliminated in the liver. Thus, most patients who have had fatal hepatotoxicity were younger than 2 years of age and treated with polytherapy (Table 140.7). In addition, most had severe epilepsy associated with mental retardation, developmental delay, or congenital brain anomalies. No hepatic deaths have occurred in persons older than 10 years of age treated with valproate alone.

TABLE 140.7. EFFECT OF AGE AND TREATMENT ON RISK OF DEVELOPING FATAL VALPROATE HEPATOTOXICITY

No laboratory test, certainly not untargeted routine blood monitoring, identifies individuals specifically at risk for valproate hepatotoxicity or any other drug-related idiosyncratic reaction. Clinical data, however, permit identification of groups of patients at increased risk for serious adverse drug reactions, including patients with known or suspected metabolic or biochemical disorders, a history of previous drug reactions, and medical illnesses affecting hematopoesis or liver and kidney function. Antiepileptic Drug Pharmacology Table 140.8 provides summary information about dose requirements, pharmacokinetic properties, and therapeutic concentration ranges for the major antiepileptic drugs available in the United States. Of patients with epilepsy, 60% to 70% achieve satisfactory control of seizures with currently available antiepileptic drugs, but fewer than 50% of adults achieve complete control without drug side effects. Many patients continue to have frequent seizures despite optimal medical therapy.

TABLE 140.8. ANTIEPILEPTIC DRUGS: DOSAGE AND PHARMACOKINETIC DATA

Therapy should start with a single antiepileptic drug chosen according to the type of seizure or epilepsy syndrome and then be modified, as necessary, by considerations of side effects, required dosing schedule, and cost. Phenytoin, phenobarbital, and gabapentin can be loaded acutely. In most cases, however, antiepileptic drugs should be started in low dosages to minimize acute toxicity and then increased according to the patient's tolerance and the drug's pharmacokinetics. The initial target dose should produce a serum concentration in the low-to-mid therapeutic range. Further increases can then be titrated according to the patient's clinical progress, which is measured mainly by seizure frequency and the occurrence of drug side effects. A drug should not be judged a failure unless seizures remain uncontrolled at the maximal tolerated dosage, regardless of the blood level. Dosage changes generally should not be made until the effects of the drug have been observed at steady-state concentrations (a time about equal to five drug

half-lives). If the first drug is ineffective, an appropriate alternative should be gradually substituted ( Table 140.5). Combination treatment using two drugs should be attempted only when monotherapy with primary antiepileptic drugs fails. Combination therapy is sometimes effective, but the price of improved seizure control is often additional drug toxicity. Sometimes combination therapy with relatively nonsedating drugs (e.g., carbamazepine, lamotrigine, gabapentin, or valproate) is preferable to high-dose monotherapy with a sedating drug (e.g., phenobarbital or primidone). When used together, carbamazepine and lamotrigine result in a pharmacodynamic interaction that often produces neurotoxicity at dosages that are usually well tolerated when either drug is used alone. Dosing intervals should usually be less than one-third to one-half the drug's half-life to minimize fluctuations between peak and trough blood concentrations. Large fluctuations can result in drug-induced side effects at peak levels and in breakthrough seizures at trough concentrations. Sometimes, however, a drug has a relatively long pharmacodynamic half-life, so that twice a day dosing is reasonable even if the pharmacokinetic half-life is short. This is typically the case with valproate, tiagabine, and, possibly, gabapentin. Therapeutic drug monitoring has improved the care of patients with epilepsy, but published “therapeutic ranges” are only guidelines. Most patients who achieve drug concentrations within a standard therapeutic range usually achieve adequate seizure control with minimal side effects, but notable exceptions occur. Some patients develop unacceptable side effects at “subtherapeutic” concentrations; others benefit from “toxic” concentrations without adverse effects. Determining serum drug concentrations when seizure control has been achieved or when side effects appear can assist in future management decisions. Drug levels are also useful in documenting compliance and in assessing the magnitude and significance of known or suspected drug interactions. Therapeutic drug monitoring is an essential guide to treating neonates, infants, young children, elderly persons, and patients with diseases (e.g., liver or kidney failure) or physiologic conditions (e.g., pregnancy) that alter drug pharmacokinetics. Although the total blood concentrations that are routinely reported are satisfactory for most indications, unbound (“free”) concentrations are useful when protein binding is altered, as in renal failure, pregnancy, extensive third-degree burns, and combination therapy using two or more drugs that are highly bound to serum proteins (e.g. phenytoin, valproate, tiagabine). Specific Drugs Phenytoin is unique among antiepileptic drugs because it exhibits nonlinear elimination at therapeutically useful serum concentrations. That is, hepatic enzyme systems metabolizing phenytoin become increasingly saturated at plasma concentrations greater than 10 to 12 µg/mL and metabolic rate approaches a constant value at high concentrations. With increasing doses, phenytoin plasma concentrations rise exponentially ( Fig. 140.5), so that steady-state concentration at one dose cannot be used to predict directly the steady-state concentration at a higher dose. Clinically, this requires cautious titration within the therapeutic range, using dose increments of 30 mg to avoid toxic effects.

FIG. 140.5. Phenytoin dose-concentration curves from three representative adult patients. Note the markedly nonlinear relationship in the 200- to 400-mg dose range. Careful dose titration is necessary in this portion of the curve to avoid neurotoxicity. Km, Michaelis-Menten constant; Vmax, maximum elimination rate.

Carbamazepine induces activation of the enzymes that metabolize it. The process, termed autoinduction, is time dependent. When carbamazepine is first introduced, the half-life approximates 30 hours. With increasing hepatic clearance in the first 3 to 4 weeks of therapy, however, the half-life shortens to 11 to 20 hours. As a result, the starting dose should be low, the dosage should be increased gradually, and dosing should be frequent (three or four times daily). Recently introduced extended-release formulations now permit twice a day administration. The principal metabolite is carbamazepine-10,11-epoxide, which is pharmacologically active. Under certain circumstances (e.g., when coadministered with valproate or felbamate), the epoxide metabolite accumulates selectively, thereby producing neurotoxic effects even though the plasma concentration of the parent drug is in the therapeutic range or low. Valproate is highly bound to plasma proteins, but the binding is concentration dependent and nonlinear. The unbound fraction increases at plasma concentrations greater than 75 µg/mL because protein binding sites become saturated. For example, doubling the plasma concentration from 75 to 150 µg/mL can result in a more than sixfold rise in concentration of free drug (from 6.5 to 45 µg/mL). Therefore, as the dose of valproate is increased, side effects may worsen rapidly because of the increasing proportion of unbound drug. Furthermore, adverse effects may vary in the course of a single day or from day to day, because concentrations of unbound drug fluctuate despite seemingly small changes in total blood levels. Additionally, circulating fatty acids displace valproate from protein binding sites. If fatty acid levels are high, the amount of unbound valproate increases. Lamotrigine and felbamate prolong valproates half-life; reduced dosage is typically necessary when these drugs are added. Gabapentin requires an intestinal amino acid transport system for absorption. Because the transporter is saturable, the percentage of drug that is absorbed after an oral dose decreases with increasing dosage. More frequent dosing schedules using smaller amounts may therefore be necessary to increase blood levels. When dosages above 3,600 mg/day are used, blood levels can be helpful in demonstrating that an increase in dosage is reflected in an increased serum concentration. Gabapentin does not interact to any clinically significant degree with any other drugs, which makes it especially useful when antiepileptic drug polytherapy is necessary and in patients with medical illnesses that also require drug treatment. It is not metabolized in the liver, but as it is excreted unchanged by the kidneys, dose adjustment is required in patients with renal failure. Lamotrigine is very sensitive to coadministration of other antiepileptic drugs. Enzyme-inducing agents, such as phenytoin and carbamazepine, decrease lamotrigine's half-life from 24 to 16 hours (or less). In contrast, enzyme inhibition by valproate increases lamotrigine's half-life to 60 hours. Therefore, lamotrigine dosing depends very much on whether it is used as monotherapy or in combination with other antiepileptic drugs. Lamotrigine has little or no effect on other classes of drugs. Rash occurs in about 10% of patients; it is more common in children and rarely leads to Stevens-Johnson syndrome. The incidence of rash can be minimized by slow titration schedules. Topiramate is also affected by coadministered antiepileptic drugs. Carbamazepine, phenytoin, and phenobarbital shorten topiramates half-life, but valproate has little effect. Topiramate does not affect most other drugs, although phenytoin blood levels may increase by 25%. Adverse cognitive effects frequently limit dosage, especially word-finding difficulties and memory impairment. These are usually dose dependent and can be minimized with slow titration schedules. Doses above 400 mg/day do not usually lead to better seizure control but are associated with an increasing incidence of side effects. Tiagabine is highly bound to serum proteins and will therefore displace other drugs (e.g., phenytoin, valproate) that are also protein bound. Other drugs do not affect tiagabine's metabolism significantly. Gastrointestinal side effects usually limit the rate at which the dosage may be increased. Felbamate has a much higher risk of serious adverse reactions, including aplastic anemia and hepatic failure, than other antiepileptic drugs. For this reason, its use is currently restricted to patients who are refractory to other agents and in whom the risk of continued seizures outweighs the risk of side effects. Use of felbamate is also limited by other common but less serious adverse effects, including anorexia, weight loss, insomnia, and nausea, and by numerous complex drug interactions. Nonetheless, felbamate remains useful in cases of severe epilepsy such as Lennox-Gastaut syndrome. Gender-based differences in antiepileptic drug pharmacokinetics, sex steroid hormones, and reproductive life events raise special issues for women with epilepsy. The management of pregnancy in the woman with epilepsy is discussed in detail in Chapter 156. This section focuses on the effects of reproductive hormones on

seizures and on the effects of seizures and antiepileptic drugs on reproductive health. Although the prevalence of epilepsy is not higher in women, epilepsy in women may be specially affected by changes in reproductive steroids. Estrogen is a proconvulsant drug in animal models of epilepsy, whereas progesterone and its metabolites have anticonvulsant effects. Ovarian steroid hormones act at the neuronal membrane and on the genome to produce immediate and long-lasting effects on excitability. Estrogen reduces GABA-mediated inhibition, whereas progesterone enhances GABA effects. Estrogen also potentiates the action of excitatory neurotransmitters in some brain regions and increases the number of excitatory synapses. These dynamic and significant changes in neuronal excitability are observed with changes in estrogen and progesterone concentrations similar to those observed in the human menstrual cycle. Approximately one-third of women with epilepsy report patterns of seizure occurrence that relate to phases of the menstrual cycle ( catamenial seizures). Women with catamenial seizures indicate that seizures are more frequent, or more severe, just before menstruation and during the time of menstrual flow. In some women, seizures also increase at ovulation. These are times in the menstrual cycle when estrogen levels are relatively high and progesterone concentration is relatively low. Several small clinical trials have described benefit from chronic progesterone therapy in women with catamenial seizure patterns. Changes in seizures related to puberty and menopause are not well understood. The pharmacokinetics of some antiepileptic drugs can complicate epilepsy management in women. Antiepileptic drugs that induce activity of the cytochrome P450 enzyme system (carbamazepine, phenytoin, phenobarbital, primidone, and, to a lesser extent, topiramate) interfere with the effectiveness of estrogen-based hormonal contraception. In women taking these drugs, the metabolism and binding of contraceptive steroids is enhanced, thus reducing the biologically active fraction of steroid hormone. The failure rate of oral contraceptive pills exceeds 6% per year in women taking enzyme-inducing antiepileptic drugs, in contrast to a failure rate of less that 1% per year in medication-compliant women without epilepsy. Women motivated to avoid pregnancy should consider using a contraceptive preparation containing 50 µg or more of an estrogenic compound or using an additional barrier method of contraception. Alternatively, they should discuss with their physician the possibility of selecting an antiepileptic drug that does not alter steroid metabolism or binding. Reproductive health may be compromised in both women and men with epilepsy. Fertility rates for men and women with epilepsy are one-third to two-thirds those of men and women without epilepsy. Lower birth rates cannot be explained on the basis of lower marriage rates, because marriage rates for women with epilepsy are now similar to those of nonepileptic women. Reduced fertility appears to be the direct result of a disturbance in reproductive physiology. Men and women with epilepsy show a higher than expected frequency of reproductive endocrine disturbances. These include abnormalities both in the cyclic release and concentration of pituitary luteinizing hormone and prolactin and in the concentration of gonadal steroid hormones. Some of these abnormalities are likely to be a consequence of seizure activity. Seizures involving mesial temporal lobe structures are associated with an immediate and significant (three- to fivefold) increase in pituitary prolactin levels. Similar disturbances have been reported with pituitary luteinizing hormone. Changes in these pituitary hormones may be one mechanism for the increased likelihood of anovulatory menstrual cycles and abnormalities in length of the menstrual cycle that are seen in about one-third of women with epilepsy. Antiepileptic drugs can also alter concentrations of gonadal steroids by affecting steroid hormone metabolism and binding. Antiepileptic drugs that increase steroid metabolism and binding reduce steroid hormone feedback at the hypothalamus and pituitary. Antiepileptic drugs that inhibit steroid metabolism (e.g., valproate) increase concentrations of steroid hormones, particularly androgens. Polycystic ovaries are more common in women with epilepsy: Multiple ovarian cysts are detected in 25% to 40% of women with epilepsy. The basis of this association is not known but may be related to antiepileptic drugs (especially valproate) or to seizures. In nonepileptic women, polycystic ovaries are associated with infertility, carbohydrate intolerance (insulin resistance), dyslipidemia, and elevated lifetime risk for endometrial carcinoma and other gynecologic malignancies. The long-term consequences of polycystic ovaries in women with epilepsy are unknown. Sexual dysfunction affects about one-third of men and women with epilepsy. Men report low sexual desire, difficulty achieving or maintaining an erection, or delayed ejaculation. Women with epilepsy can experience painful intercourse because of vaginismus and lack of lubrication. Although there are certainly psychosocial reasons for sexual dysfunction in some people with epilepsy, physiologic causes are demonstrable in others. Physiologic causes of sexual dysfunction include disruption of brain regions controlling sexual behavior by epileptogenic discharges, abnormalities of pituitary and gonadal hormones, and side effects of antiepileptic drugs. Women with epilepsy who have difficulty conceiving, irregular or abnormal menstrual cycles, midcycle menstrual bleeding, sexual dysfunction, obesity, or hirsutism should undergo a reproductive endocrine evaluation. This includes pituitary luteinizing hormone and prolactin levels, estrogen, testosterone and progesterone levels, and ovarian ultrasound examination. Men with sexual dysfunction or difficulty conceiving should also have an endocrine evaluation and semen analysis. All the reproductive disorders seen in people with epilepsy are potentially treatable. Discontinuing Antiepileptic Drugs Epidemiologic studies indicate that 60% to 70% of patients with epilepsy become free of seizures for at least 5 years within 10 years of diagnosis. Similarly, prospective clinical trials of treated patients whose seizures were in remission for 2 years or more showed that a nearly identical percentage of patients remained seizure free after drug withdrawal. These studies also identified predictors that permit patients to be classified as being at low or high risk for seizure relapse after drug therapy ends. The risk of relapse was high if patients required more than one antiepileptic drug to control seizures, if seizure control was difficult to establish, if the patient had a history of generalized tonic-clonic seizures, and if the EEG was significantly abnormal when drug withdrawal was considered. Continued freedom from seizures is favored by longer seizure-free intervals (up to 4 years) before drug withdrawal is attempted, few seizures before remission, monotherapy, normal EEG and examination, and no difficulty establishing seizure control. All benign epilepsy syndromes of childhood carry an excellent prognosis for permanent drug-free remission. In contrast, juvenile myoclonic epilepsy has a high rate of relapse when drugs are discontinued, even in patients who have been seizure free for years. The prognosis for most other epilepsy syndromes is largely unknown. Discontinuing antiepileptic drug therapy in appropriate patients is reasonable when they have been seizure free for at least 2 years. The most powerful argument for stopping antiepileptic drugs is concern about long-term systemic and neurologic toxicity, which may be insidious and not apparent for many years after a drug has been introduced. On the other hand, however, is the concern of the patient or family about seizure recurrence. Even a single seizure can have disastrous psychosocial and vocational consequences, particularly in adults. Therefore, the decision to withdraw drugs must be weighed carefully in the light of individual circumstances. If a decision is made to discontinue antiepileptic drugs, we favor slow withdrawal, over 3 to 6 months, but this recommendation is controversial because few studies have been conducted of different withdrawal rates. SURGICAL TREATMENT Surgery should be considered when seizures are uncontrolled by optimal medical management and when they disrupt the quality of life. Quantifying these issues, however, has defied strict definition, perhaps deservedly, because intractability is clearly more than continued seizures. Only patients know how their lives differ from what they would like them to be; the concept of disability includes both physical and psychologic components. Some patients with refractory seizures suffer little disability; others, for whatever reason, find their lives severely compromised by infrequent attacks. Still others have had their seizures completely cured by surgery but are still disabled and incapable of functioning productively. The determination of which patients are “medically refractory” and which are “satisfactorily controlled” can always be argued in the abstract. Fortunately, there is usually general agreement in practice about which patients should be referred for surgical evaluation. Few patients benefit from further attempts at medical treatment if seizures have not been controlled after two trials of high-dose monotherapy using two appropriate drugs and one trial of combination therapy. These therapeutic efforts can be accomplished within 1 to 2 years; the detrimental effects of continued seizures or drug toxicity warrant referral to a specialized center after that time. There are few blanket contraindications to epilepsy surgery today, although patients with severe concurrent medical illness and progressive neurologic syndromes are usually excluded. Some centers prefer not to operate on patients with psychosis or other serious psychiatric disorder, those older than 50, and those with an IQ of less than 70. Patients in these categories, however, must be considered individually. Many patients who undergo corpus callosum section for atonic seizures associated with Lennox-Gastaut syndrome have an IQ under 70. Although surgery for epilepsy is increasingly performed in children, functional resections in infancy remain controversial for several reasons: the uncertain natural history of seizures in many of these patients; the unknown effects of surgery on the immature brain; and the lack of data about long-term neurologic, behavioral, and psychologic outcomes.

Because of technical advances in imaging and electrophysiologic monitoring, epilepsy surgery is no longer automatically contraindicated in patients with multifocal interictal epileptiform abnormalities or even foci near language or other eloquent cortical areas. Resective Procedures Focal brain resection is the most common type of epilepsy surgery. Resection is appropriate if seizures begin in an identifiable and restricted cortical area, if the surgical excision will encompass all or most of the epileptogenic tissue, and if the resection will not impair neurologic function. These criteria are met most often by patients with temporal lobe epilepsy, but extratemporal resections are increasingly common. Anterior Temporal Lobe Resection This resective procedure is the most common, but the operation varies in what is considered “standard,� especially with regard to how much lateral neocortical and mesial limbic structures are removed. At our institution, most patients with unilateral temporal foci undergo Spencer's (1991) anteromedial temporal lobe resection, which includes removal of the anterior middle and inferior temporal gyri, parahippocampal gyrus, 3.5 to 4 cm of hippocampus, and a variable amount of amygdala. For nondominant foci, this approach is slightly modified to include the anterior superior temporal gyrus as well. Patients with medial temporal lobe epilepsy associated with hippocampal sclerosis are ideal candidates for anterior temporal lobe resection, because over 80% will become seizure free with the remainder having substantial improvement. Lesionectomy Well-circumscribed epileptogenic structural lesions (cavernous malformations, hamartomas, gangliogliomas, and other encapsulated tumors) can be removed by stereotactic microsurgery. The extent to which tissue margins surrounding the lesion are included in the resection depends on how the margins are defined (radiologic, visual, electrophysiologic, or histologic inspection) and the surgeon's preference. Seizures are controlled by this method in 50% to 60% of patients. A lesion involving the cerebral cortex should always be considered the source of a patient's seizures unless compelling EEG evidence suggests otherwise. Nonlesional Cortical Resections When a lesion cannot be visualized by MRI, it is difficult to demonstrate a restricted ictal onset zone outside the anterior temporal lobe. This situation almost always requires placement of intracranial electrodes to map the extent of epileptogenic tissue and to determine its relation to functional brain areas. Outcome after nonlesional cortical resections is not as good as with anterior temporal lobectomy or lesionectomy, mainly because the boundaries of epileptogenic cortical areas often cannot be delineated precisely, and removal of all the epileptogenic tissue often is not possible. Corpus Callosotomy Section of the corpus callosum disconnects the two hemispheres and is indicated for treatment of patients with uncontrolled atonic or tonic seizures in the absence of an identifiable focus suitable for resection. Most patients referred for corpus callosotomy have severe and frequent seizures of multiple types, usually with mental retardation and a severely abnormal EEG (the Lennox-Gastaut syndrome). Unlike resective surgery, corpus callosotomy is palliative, not curative. Nonetheless, it can be strikingly effective for generalized seizures, with 80% of patients experiencing complete or nearly complete cessation of atonic, tonic, and tonic-clonic attacks. This outcome is often remarkably beneficial because it eliminates falls and the associated self-injury. The effect on partial seizures, however, is inconsistent and unpredictable. Complex partial seizures are reduced or eliminated in about half the patients, but simple or complex partial seizures are exacerbated in about 25%. Therefore, refractory partial seizures alone are not an indication for corpus callosotomy. Similarly, absence, atypical absence, and myoclonic seizures either do not benefit or show an inconsistent response. Hemispherectomy Removal or disconnection of large cortical areas from one side of the brain is indicated when the epileptogenic lesion involves most or all of one hemisphere. Because hemispherectomy guarantees permanent hemiplegia, hemisensory loss, and usually hemianopia, it can be considered only in children with a unilateral structural lesion that has already resulted in those abnormalities and who have refractory unilateral seizures. Examples of conditions suitable for hemispherectomy include infantile hemiplegia syndromes, Sturge-Weber disease, Rasmussen syndrome, and severe unilateral developmental anomalies, such as hemimegalencephaly. In appropriate patients, the results are dramatic. Seizures cease, behavior improves, and development accelerates ( Table 140.9).

TABLE 140.9. OUTCOME AFTER EPILEPSY SURGICAL PROCEDURES

Preoperative Evaluation The objective in evaluating patients for focal resection is to demonstrate that all seizures originate in a limited cortical area that can be removed safely. This determination requires more extensive evaluation than is necessary in the routine management of patients with epilepsy. The different tests used provide complementary information about normal and epileptic brain functions. CCTV/EEG monitoring is necessary to record a representative sample of the patient's typical seizures to confirm the diagnosis and classification and also to localize the cortical area involved in ictal onset. Volumetric or other special MRI techniques may demonstrate unilateral hippocampal atrophy or other anatomic abnormalities that may be epileptogenic. Positron emission tomography and ictal single-photon emission CT are useful to demonstrate focal abnormalities in glucose metabolism or cerebral blood flow that correspond to the epileptogenic brain region. Neuropsychologic testing is useful in demonstrating focal cognitive dysfunction, especially language and memory. Intracarotid injection of amobarbital (the Wada test) to determine hemispheric dominance for language and memory competence is generally considered necessary before temporal lobectomy, but the implications of a failed test are uncertain. Intracranial electrodes are necessary if noninvasive methods do not unequivocally localize the epileptogenic area or if different noninvasive tests give conflicting results. Intracranial electrode placement is also necessary when vital brain functions (language, motor cortex) must be mapped in relation to the planned resection. Vagal Nerve Stimulation Vagal nerve stimulation is a novel nonpharmacologic treatment for medically refractory partial seizures. Like corpus callosotomy, vagal nerve stimulation is a palliative procedure, because very few patients become seizure free. Vagal nerve stimulation is delivered via a stimulating lead attached to the left vagus nerve. The stimulus

generator is implanted in the upper left chest. The device is usually programmed to give a 30-second electrical pulse every 5 minutes, although stimulus parameters can be adjusted to the requirements of an individual patient. In patients with aura, a magnetic wand can be used to deliver vagal nerve stimulation on demand, which may abort seizure progression. About 30% to 35% of patients have at least a 50% reduction in seizure frequency, which compares favorably with the efficacy of new antiepileptic drugs. Chronic adverse effects include hoarseness and difficulty swallowing, both of which increase at the time of stimulation.

REPRODUCTIVE HEALTH ISSUES Status Epilepticus Convulsive status epilepticus is a medical emergency, and failure to treat the condition in a timely and appropriate manner can result in serious systemic and neurologic morbidity. At least 65,000 cases of status epilepticus occur each year in the United States. It is diagnosed if seizures last longer than 10 minutes or if two or more seizures occur in close succession without recovery of consciousness. Status epilepticus may be either convulsive or nonconvulsive. The most life-threatening pattern, and that requiring the most urgent treatment, is convulsive status epilepticus, which, like seizures and epileptic syndromes, may be a manifestation either of idiopathic (i.e., nonfocal) epilepsy or secondary to spread from a localized epileptogenic brain region. Nonconvulsive status epilepticus occurs as a kind of twilight confusional state and is caused by either continuing generalized absence seizures or complex partial seizures. Status epilepticus is most frequent in infants and young children and in elderly persons, but it occurs at all ages. More than 50% of those affected do not have a history of epilepsy. In about 10% of patients with epilepsy, status epilepticus is the first manifestation, and about 15% of patients with epilepsy have had one or more episodes of status at some time. In two-thirds of cases of status epilepticus, an acute cause or precipitating factor, such as systemic metabolic derangement, alcohol or other drug abuse, hypoxia, head trauma, infection, or a cerebral lesion, such as a stroke or tumor, can be identified. Therefore, part of the emergency evaluation of patients in status is determining the probable cause ( Table 140.10).

TABLE 140.10. CAUSES OF STATUS EPILEPTICUS

Convulsive Status Epilepticus Convulsive status epilepticus generates metabolic and physiologic stresses that contribute to permanent brain damage, including hyperthermia, hypoxia, lactic acidosis, hypoglycemia, and hypotension. Plasma catecholamine levels are acutely elevated during the attack and may trigger fatal cardiac arrhythmias. Death usually results from the underlying condition rather than from the status epilepticus itself. Nonetheless, death from status epilepticus per se occurs in 2% to 3% of children and in 7% to 10% of adults. The goals of treatment are to eliminate all seizure activity and to identify and treat any underlying medical or neurologic disorder. Initial management is that of any comatose patient: to ensure airway and oxygenation, to access circulation and maintain blood pressure, and to monitor cardiac function ( Table 140.11). Blood should be obtained for antiepileptic drug levels, blood count, and routine chemistries. Brain imaging should be done in all adult patients with status epilepticus and in all children with nonfebrile status epilepticus. Patients should be in stable condition, and CT is usually sufficient to exclude an acute brain lesion. MRI should be obtained later if the CT was normal. Lumbar puncture should be performed in any febrile patient, even if signs of meningitis are not present. If brain infection is strongly suspected, the need for lumbar puncture is urgent, and the procedure should be carried out immediately. If signs of increased intracranial pressure are apparent or if a mass lesion is suspected, antibiotics should be given immediately and a CT obtained first.

TABLE 140.11. PROTOCOL AND TIMETABLE FOR TREATING STATUS EPILEPTICUS IN ADULTS AT THE NEUROLOGICAL INSTITUTE OF NEW YORK COLUMBIA-PRESBYTERIAN MEDICAL CENTER

If the history is at all uncertain, glucose should be given, preceded by thiamine in adults. Although several antiepileptic drug regimens are effective for treating status epilepticus, we begin with lorazepam, 0.1 mg/kg, or diazepam, 0.2 mg/kg, followed immediately by phenytoin (or fosphenytoin), 20 mg/kg. If there is no response, additional phenytoin (or fosphenytoin), 5 mg/kg, should be administered. If status persists, the patient should be intubated and anesthetized with pentobarbital or midazolam with EEG monitoring to ensure complete suppression of all electrical ictal activity. Fosphenytoin is a phosphate ester prodrug of phenytoin. Unlike intravenous phenytoin, fosphenytoin is compatible with all intravenous solutions in common use. Because it is much less alkaline, it causes only minimal local irritation and can be infused at much faster rates than phenytoin. After entering the blood, fosphenytoin is converted rapidly to phenytoin by phosphatases in the liver and red blood cells. Fosphenytoins pharmacologic properties are identical to those of phenytoin and is dosed in phenytoin equivalents. Unique side effects are paresthesias in the low back and groin, probably due to the phosphate load. After the patient has been stabilized and seizures controlled, a rigorous search for an underlying condition should be instituted. Nonconvulsive Status Epilepticus

This condition is difficult to diagnose clinically and is frequently unrecognized. Patients are most often middle-aged or elderly and usually have no past history of seizures. Onset is generally abrupt, and all patients show altered mentation and behavioral changes that typically last for days to weeks. Patients in nonconvulsive status are characteristically alert (although dull), and the absence of stupor or coma contributes to misdiagnosis. A psychiatric diagnosis is often the first consideration if the condition presents as bizarre behavior and change in affect, often with hallucinations, paranoia, or catatonia. When memory loss, disorientation, and mood changes predominate, diagnostic possibilities include dementia, stroke, or metabolic/toxic encephalopathy. Once the suspicion of nonconvulsive status epilepticus has been raised, diagnosis depends on demonstrating ictal patterns in the EEG while the patient is symptomatic. Most patients show continuous or nearly continuous 1- to 2.5-Hz generalized spike-wave (“atypical spike-wave�) activity. In these cases, status epilepticus is presumed to be a manifestation of generalized-onset epilepsy akin to absence status epilepticus in children. Occasionally, the EEG ictal activity is localized, usually to the frontal or temporal lobes, thus indicating that in these patients the nonconvulsive status is a form of continuous partial seizure activity. Diagnosis of nonconvulsive status epilepticus is confirmed by the response to intravenous diazepam (5 to 10 mg) or lorazepam (1 to 2 mg): Epileptiform EEG abnormalities disappear, and the patient's mental state reverts to normal. Long-term seizure control is achieved using valproate, phenytoin, or carbamazepine. Laboratory studies are usually normal, but occasionally they identify a cause for the nonconvulsive status epilepticus, such as nonketotic hyperglycemia, electrolyte imbalance, drug toxicity (e.g., lithium), or a focal cerebral lesion (e.g., frontal lobe infarction).

GENE DEFECTS IN EPILEPSY Genetic factors have been implicated strongly in several epilepsy syndromes, and twin studies have confirmed important genetic determinants in both localization-related and generalized types of seizure disorders. Hereditary aspects are easiest to discern in childhood absence epilepsy, juvenile myoclonic epilepsy, benign rolandic epilepsy, and idiopathic grand mal seizures. However, genetic epidemiologic studies have demonstrated clearly that complex polygenic susceptibilities exist in both the idiopathic and symptomatic epilepsies. Thus, a major challenge facing investigators today is to clarify how different genes alter an individual's susceptibility to seizures and epilepsy in the presence of acquired brain pathology or as a reaction to acute or subacute cerebral dysfunction. This is no easy task, however, because the number of genes that encode molecules that regulate cortical excitability directly through membrane and synaptic functions and the second messenger cascades that indirectly regulate membrane proteins involved in signal transduction is very large. These considerations imply a continuum between idiopathic and symptomatic epilepsies, with the development of epilepsy deriving from the complex interrelation of genetic factors and brain pathology. In any given patient, therefore, the relative contribution of genetic or acquired pathologic factors determines whether the epilepsy presents clinically as an idiopathic disorder or a symptomatic one. Linkage studies have identified specific gene loci for several human epilepsies ( Table 140.12). Genes have been identified for three autosomal recessive progressive myoclonic epilepsies (Unverricht-Lundborg disease, Lafora disease, and the form of neuronal ceroid lipofuchsinosis known as Batten's disease), an autosomal dominant idiopathic generalized epilepsy (benign familial neonatal seizures), an autosomal dominant form of febrile seizures, and one type of idiopathic partial epilepsy (autosomal dominant nocturnal frontal lobe epilepsy). The defective gene in Unverricht-Lundborg disease encodes cystatin B, a ubiquitous inhibitor of cysteine protease, a lysosomal enzyme that cannot, at the present time, be related easily to any known epileptogenic mechanism, although programmed neuronal cell death may be involved. An abnormal potassium-channel gene results in the syndrome of benign familial neonatal seizures, and an abnormal sodium channel gene leads to an autosomal dominant form of febrile seizures. Some, but not all, families with autosomal dominant frontal lobe epilepsy have an abnormality in the gene for the a 4-subunit of the neuronal nicotinic acetylcholine receptor. A point mutation in mitochondrial DNA results in myoclonic epilepsy with ragged red fibers (MERRF).

TABLE 140.12. HUMAN EPILEPSY GENES AND GENE DEFECTS

PSYCHOSOCIAL AND PSYCHIATRIC ISSUES The impact of epilepsy on the quality of life is usually greater than the limitations imposed by the seizures alone. The diagnosis of epilepsy frequently carries other consequences that can greatly alter the lives of many patients. For adults, the most important problems are discrimination at work and driving restrictions, which lead to loss of mobility and independence. Children and adults alike may be shunned by uninformed friends. Patients must learn to avoid situations that precipitate seizures, and a change in lifestyle may be necessary. Common factors that increase the likelihood of seizure occurrence include sleep deprivation, alcohol (and other drugs), and emotional stress ( Table 140.13). Compliance with antiepileptic drug treatment is often an issue, especially with adolescents. Psychiatric symptoms, especially depression, may complicate management.

TABLE 140.13. FACTORS THAT LOWER THE SEIZURE THRESHOLD

Some restrictions are medically appropriate, at least for limited times. For example, when seizures impair consciousness or judgment, driving and certain kinds of employment (working at exposed heights or with power equipment) and a few other activities (swimming alone) should be interdicted. On the other hand, legal prohibitions on driving vary in different states in the United States and in different countries and are often not medically justified. Employers frequently have unrealistic fears about the physical effects of a seizure, the potential for liability, and the impact on insurance costs. In fact, the Americans with Disabilities Act prohibits denying employment to persons with disability if the disability does not prevent them from meeting job requirements. Children have special problems because their seizures affect the entire family. Parents may, with the best of intentions, handicap the child by being overly restrictive.

The necessary and special attention received by the “sick” child may encourage passive manipulative behavior and overdependence while unintentionally exacerbating normal sibling rivalries. The physician must be sensitive to these important quality of life concerns, even when they are not raised spontaneously by the patient or family. In fact, psychosocial issues often become the major focus of follow-up visits after the diagnosis has been made, the initial evaluation completed, and treatment started. We cannot emphasize too much the physician's responsibility to educate society to counter misperceptions and prejudices and to separate myth from medical fact. The Epilepsy Foundation (Landover, Maryland; 1-800-EFA-1000; www.efa.org) and its nationwide system of affiliates have a wealth of materials about epilepsy suitable for patient, family, and public education. Compliance The most common cause of breakthrough seizures is noncompliance with the prescribed therapeutic regimen. Only about 70% of patients take antiepileptic medications as prescribed. For phenytoin or carbamazepine, noncompliance can be inferred when sequential blood levels vary by more than 20%, assuming similarly timed samples and unchanged dosage. Persistently low antiepileptic drug levels in the face of increasing dosage also generally imply poor compliance. Caution is warranted with phenytoin, however, because as many as 20% of patients have low levels as a result of poor absorption or rapid metabolism. Noncompliance is especially common in adolescents and elderly persons, when seizures are infrequent or not perceived as disabling, when antiepileptic drugs must be taken several times each day, and when toxic effects persist. Compliance can be improved by patient education, by simplifying drug regimens, and by tailoring dosing schedules to the patient's daily routines. Pill box devices that alert the patient to scheduled doses can be useful. Depression and Psychosis In referral centers, depression and suicide are more common in patients with epilepsy than in patients with other neurologic disorders or in disease-free control subjects. Whether this predilection is true for the epilepsy population at large is not known because few community-based population studies have been conducted. Depression in epilepsy may be influenced by several factors: the type or severity of the seizures, the location of the epileptogenic focus, associated neurologic or medical conditions, the antiepileptic drugs used, and by the personal stigma and limitations that accompany the diagnosis. Curiously, depression sometimes follows successful epilepsy surgery. Treatment of depression begins with optimal treatment of the seizure disorder. Barbiturate and succinimide drugs may adversely affect mood, inducing symptoms that mimic endogenous depression. Although tricyclic antidepressants reduce the seizure threshold in experimental models of epilepsy, this is not a practical concern because they only rarely trigger seizures or increase seizure frequency in humans. Monoamine oxidase inhibitors neither induce seizures nor increase seizure frequency. Modern electroconvulsive therapy does not worsen epilepsy. We have used both sertraline and fluoxetine without exacerbating seizures. The relation between psychosis and epilepsy is controversial. No convincing evidence shows that interictal psychosis is a manifestation of epilepsy, but some demographic features are overrepresented in patients with epilepsy. Phenothiazines, butyrophenones, and clozapine lower seizure threshold in experimental animals and occasionally seem to induce seizures in nonepileptic patients. Most occurrences have been associated with high drug doses or a rapid increase in dose. With the possible exception of clozapine, however, little evidence supports the notion that reasonable and conservative use of antipsychotic medications increases seizure frequency in patients with epilepsy. Interictal aggressive behavior is not more common in people with epilepsy. Directed aggression during seizures occurs in less than 0.02% of patients with severe epilepsy; it is almost certainly less common in the general epilepsy population. Undirected pushing or resistance occasionally occurs postictally when attempts are made to restrain confused patients. Postictal psychosis is a limited period of psychosis that follows a flurry of seizures, usually after an interval of appropriate behavior. This uncommon condition does not lead to chronic psychosis. SUGGESTED READINGS American EEG Society. Guidelines for long-term neurodiagnostic monitoring in epilepsy. J Clin Neurophysiol 1994;11:88–110. Annegers JF, Hauser WA, Coan SP, Rocca WA. A population-based study of seizures after traumatic brain injuries. N Engl J Med 1998;338:20–24. Bazil CW, Pedley TA. Advances in the medical treatment of epilepsy. Annu Rev Med 1998;49:135–162. Berg AT, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. Neurology 1991;41:965–972. Berkovic SF, Scheffer IE. Epilepsies with single gene inheritance. Brain Dev 1997;19:13–18. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996;334:168–175. Cascino GD, Jack CR, Parisi JE, et al. Magnetic resonance imaging-based volume studies in temporal lobe epilepsy: pathological correlations. Ann Neurol 1991;30:31–36. Cendes F, Cramanos Z, Andermann F, Dubeau F, Arnold DL. Proton magnetic resonance spectroscopic imaging and magnetic resonance imaging volumetry in the lateralization of temporal lobe epilepsy: a series of 100 patients. Ann Neurol 1997;42:737–746. Delgado-Escueta AV, Mattson RH, King L, et al. The nature of aggression during epileptic seizures. N Engl J Med 1981;305:711–716. DeLorenzo RJ, Pellock JM, Towne AR, Boggs JG. Epidemiology of status epilepticus. J Clin Neurophysiol 1995;12:316–325. Devinsky O. A guide to understanding and living with epilepsy. Philadelphia: FA Davis, 1994. Dodson WE, DeLorenzo RJ, Pedley TA, et al. Treatment of convulsive status epilepticus: recommendations of the Epilepsy Foundation of America's working group on status epilepticus. JAMA 1993;270:854–859. Dreifuss FE, Rosman NP, Clloyd JC, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med 1998;338:1869–1875. Dreifuss FE, Santilli N, Langer DH, et al. Valproic acid hepatic fatalities: a retrospective review. Neurology 1987;37:379–385. Engel J Jr, ed. Surgical treatment of the epilepsies, 2nd ed. New York: Raven Press, 1993. Engel J Jr, Pedley TA, eds. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven, 1998. First Seizure Trial Group. Randomized clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic-clonic seizure. Hauser WA. Status epilepticus: epidemiologic considerations. Neurology 1990;40[Suppl 2]:9–13. auser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 1993;34:453–468. Hauser WA, Hesdorffer DC. Epilepsy: frequency, causes and consequences. New York: Demos, 1990. Hauser WA, Rich SS, Annegers, JF, Anderson VE. Seizure recurrence after a 1st unprovoked seizure: an extended follow-up. Neurology 1990;40:1163–1170. Hauser WA, Rich SS, Lee JR-J, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 1998;338:429–434. Herman ST, Pedley TA. New options for the treatment of epilepsy. JAMA 1998;280:693–694.

Neurology 1993;43:478–483.

Jackson GD, Berkovic SF, Tress BM, et al. Hippocampal sclerosis can be reliably detected by magnetic resonance imaging. Neurology 1990;40:1869–1875. Krauss GL, Johnson MA, Miller NR. Vigabatrin-associated retinal cone system dysfunction. Electroretinogram and ophthalmologic findings. Neurology 1998;50:614–618. Kuzniecky R, Hugg JW, Hetherington H, et al. Relative utility of

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H spectroscopic imaging and hippocampal volumetry in the lateralization of mesial temporal lobe epilepsy. Neurology 1998;51:66–71.

Langendorf F, Pedley TA. Post-traumatic seizures. In: Engel J Jr, Pedley TA, eds. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven, 1998:2469–2474. Lee SI. Non-convulsive status epilepticus. Ictal confusion in later life. Arch Neurol 1985;42:778–781. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970–976. Mattson RH, Cramer JA, Collins JF. Comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. N Engl J Med 1992;327:765–771. Mattson RH, Cramer JA, Collins JF, et al. A comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313:145–151. McNamara JO. Emerging insights into the genesis of epilepsy. Nature 1999;399 (Suppl):A15–A22. Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 1991;337:1175–1180. Morrell MJ. Hormones, reproductive health, and epilepsy. In: Wyllie E, ed. The treatment of epilepsy: principles and practice, 2nd ed. Baltimore: Williams & Wilkins, 1996:179–187. Morrell MJ. Sexuality in epilepsy. In: Engel J Jr, Pedley TA, eds. Epilepsy: a comprehensive textbook. New York: Lippincott-Raven, 1998:2021–2026. Musicco M, Beghi E, Solari A, et al. Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. Neurology 1997;49:991–998. Pellock JM, Willmore LJ. A rational guide to routine blood monitoring in patients receiving antiepileptic drugs. Neurology 1991;41:961–964. Prasad AN, Prasad C, Stafstrom CE, Recent advances in the genetics of epilepsy: Insights from human and animal studies. Epilepsia 1999;40: 1329–1352. Salazar AM, Jabbari B, Vance SC, et al. Epilepsy after penetrating head injury. I. Clinical correlates: a report of the Vietnam Head Injury Study. Neurology 1985;35:1406–1414. Sillanpaa M, Jalava M, Kaleva O, Shinnar S. Long-term prognosis of seizures with onset in childhood. N Engl J Med 1998;338:1715– 1722. Spencer DD. Anteromedial temporal lobectomy: directing the surgical approach to the pathologic substrate. In: Spencer SS, Spencer DD, eds. Surgery for epilepsy. Boston: Blackwell Scientific, 1991. Sperling MR, Feldman H, Kirman J, et al. Seizure control and mortality in epilepsy. Ann Neurol 1999;46:45–50. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, double blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990;323:497–502. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 1998;339:792–798. Walczak TS, Radtke RA, McNamara JO, et al. Anterior temporal lobectomy for complex partial seizures: evaluation, results, and long-term follow-up of 100 cases.

Neurology 1990;40:413–418.

Zahn CA, Morrell MJ, Collins SD, et al. Management issues for women with epilepsy: a review of the literature. American Academy of Neurology Practice Guidelines. Neurology 1998;51:949–956.

CHAPTER 141. FEBRILE SEIZURES MERRITT’S NEUROLOGY

CHAPTER 141. FEBRILE SEIZURES DOUGLAS R. NORDLI JR. AND TIMOTHY A. PEDLEY Clinical Manifestations Diagnosis Prognosis and Treatment Suggested Readings

Febrile seizures are generalized convulsions that occur during a febrile illness that does not involve the brain. They represent acute symptomatic or reactive seizures, and even when recurrent they do not warrant the designation of epilepsy. Most febrile seizures occur in children between the ages of 6 months and 4 years; they are occasionally seen in children as old as 6 or 7 years. Febrile seizures are the most frequent cause of a convulsion in a child: Between 3%; and 5%; of all children in the United States and Europe and 6%; to 9%; of children in Japan have at least one febrile seizure before age 5 years. Hauser (1994) estimated 100,000 cases of febrile seizures in the United States in 1990. Genetic factors are important; overall, siblings and offspring of affected probands have a two- to threefold increased risk of seizures with fever. Recent linkage studies in a few large families indicate that febrile seizure susceptibility genes are located on portions of chromosomes 8 and 19 (see Chapter 140). The role of such genes in sporadic febrile seizures remains to be determined.

CLINICAL MANIFESTATIONS Febrile seizures appear typically early in the febrile illness, while the temperature is rapidly rising. In many children, the seizure is the first indication of illness. Although generalized convulsions are the rule, focal features or a Todd's paresis are seen in about 10%; of patients. Febrile seizures are subdivided operationally into simple and complex types. Simple (also called benign) febrile seizures are brief isolated occurrences that lack focal manifestations. Complex febrile seizures are frequently focal, last longer than 15 minutes, and tend to occur repeatedly within 24 hours.

DIAGNOSIS Diagnosis is made by excluding other possible causes of the convulsion, such as meningitis, metabolic abnormalities, or structural brain lesions. Depending on the manifestations and the clinician's experience, laboratory tests are not always necessary. Usually, a clinically identifiable infection, such as otitis media, roseola infantum, pharyngitis, or gastroenteritis, is present. Fever after immunization may also trigger a febrile seizure. Any suspicion of meningitis, however, mandates lumbar puncture. The typical indicators of meningeal irritation, such as nuchal rigidity and the Brudzinki sign, are not reliable in young infants. If the seizure has focal features or if the examination elicits focal neurologic abnormalities, brain imaging is necessary. Electroencephalography is not a useful test because it does not provide information regarding either risk of recurrence of febrile seizures or later development of epilepsy.

PROGNOSIS AND TREATMENT About one-third of children with febrile seizures have more than one attack. Recurrence is highest in infants whose first febrile seizure occurred before the age of 1 year and in children with a family history of febrile seizures. When the first seizure is a typical simple febrile seizure, only 1%; of patients have prolonged convulsions later. The risk of developing epilepsy is increased in children with febrile seizures, but the magnitude of the risk depends on several factors. In children with simple febrile seizures, the risk of later epilepsy is 2%; to 3%;. The incidence of epilepsy increases to about 10%; to 13%; in children who have had complex febrile seizures, who have a family history of afebrile seizures, or who were neurologically abnormal before the first febrile seizure. Young children who have unprovoked seizures after a febrile convulsion are at much greater risk of further seizures with subsequent febrile illnesses. Neither simple nor complex febrile seizures are associated with, nor do they lead to, mental retardation, low global IQ, poor school achievement, or behavioral problems. Some differences have been reported, however. Children with febrile seizures in the first year of life are more likely to require special schooling than those who have them later. In children with prolonged febrile convulsions, nonverbal intelligence measures may be slightly lower compared with children with simple febrile seizures. Mortality is not increased in children with febrile seizures who are neurologically normal. Because most children with febrile seizures have no long-term consequences, most clinicians now avoid chronic prophylactic treatment with antiepileptic drugs, even after two or three isolated convulsions. Although both phenobarbital and valproate are effective in reducing recurrence, evidence does not show that treatment alters the risk of later epilepsy. In addition, adverse drug effects occur in as many as 40%; of infants and children treated with phenobarbital, and valproate carries a risk of idiosyncratic fatal hepatotoxicity and pancreatitis. Phenytoin is ineffective. If treatment is considered at all, it should be reserved for children with complex febrile seizures who are neurologically abnormal or who have a strong family history of afebrile seizures. A reasonable alternative to chronic drug therapy is intermittent treatment using rectal diazepam. Several studies have shown that rectal administration of diazepam during febrile illnesses is safe and as effective as phenobarbital in reducing seizure recurrence. A rectal formulation of diazepam (Diastat) is now available in the United States, although the U.S. Food and Drug Administration has not yet approved it for use in prolonged febrile seizures. Watching their child have a convulsion is one of the most frightening experiences that parents can have. The physician therefore must provide reassurance to dispel any myths the family may have, emphasizing in particular that febrile seizures are neither life-threatening nor damaging to the brain. SUGGESTED READINGS American Academy of Pediatrics. Provisional Committee on Quality Improvement, Subcommittee on Febrile Seizures. Practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure. Pediatrics 1996;97:769–772. Berg AT, Darefsky AS, Holford TR, Shinnar S. Seizures with fever after unprovoked seizures: an analysis in children followed from the time of a first febrile seizure.

Epilepsia 1998;39:77–80.

Berg AT, Shinnar S, Darefsky AS, et al. Predictors of recurrent febrile seizures. A prospective cohort study. Arch Pediatr Adolesc Med 1997;151:371–378. Berg AT, Shinnar S, Shapiro ED, et al. Risk factors for a first febrile seizure: a matched case-control study. Epilepsia 1995;36:334–341. Johnson EW, Dubovsky J, Rich SS, et al. Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest. 1998;7:63–67.

Hum Mol Genet

Kolfen W, Pehle K, Konig S. Is the long-term outcome of children following febrile convulsions favorable? Dev Med Child Neurol 1998;40:667–671. Kugler SL, Johnson WG. Genetics of the febrile seizure susceptibility trait. Brain Dev 1998;20:265–274. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics 1978;61:720–727. Pfeiffer A, Thompson J, Charlier C, et al. A locus for febrile seizures (FEB 3) maps to chromosome 2q23-24. Ann Neurol 1999;46:671–678. Rosman NP, Colton T, Labazzo RNC, et al. A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 1993;329:79–84. Tarkka R, Rantala H, Huhari M, Pokka T. Risk of recurrence and outcome after the first febrile seizure. Pediatr Neurol 1998;18:218–220.

Verity CM, Greenwood R, Golding J. Long-term intellectual and behavioral outcomes of children with febrile convulsions. N Engl J Med 1998;338:1723–1728. Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na +-channel beta 1 subunit gene SCNIB. Nature Genetics 1998;19:366–370.

CHAPTER 142. NEONATAL SEIZURES MERRITT’S NEUROLOGY

CHAPTER 142. NEONATAL SEIZURES DOUGLAS R. NORDLI JR. AND TIMOTHY A. PEDLEY Classification Etiology Evaluation Treatment Prognosis Suggested Readings

Seizures are the most common sign of neurologic dysfunction in the neonate. They occur in 0.5% of all newborns, more often in preterm babies, and frequently signify injury to the developing brain. They are thus an urgent clinical problem that requires prompt diagnosis and treatment.

CLASSIFICATION The clinical semiology and electroencephalographic (EEG) features of neonatal seizures have been recognized for years to differ substantially from those of older children and adults. Therefore, the classification schemes used for seizures in older patients are inappropriate for newborns. Neonatal seizures are almost always identified by clinical observation, and traditionally, clinical features have been used for classification. Analysis of simultaneous closed-circuit television and EEG recordings has revealed that not all clinical seizure behaviors are accompanied by an EEG seizure discharge. Also, not all EEG ictal patterns produce clinical behavioral changes. The current classification proposed by Volpe (1989) recognizes four general patterns of clinical behavior and describes each by the presence or absence of a consistent EEG discharge (Table 142.1). Focal clonic, focal tonic, and some myoclonic seizures are accompanied by characteristic EEG discharges. In contrast, generalized tonic seizures, most motor automatisms (mouthing, pedaling, stepping, rotary arm movements), and some myoclonic seizures have inconsistent or no reliable EEG changes. Autonomic phenomena are common, especially in term newborns, but they almost always accompany other behavioral manifestations. In preterm infants, however, isolated autonomic phenomena may be the only evidence of seizure activity. Apnea is rarely the sole manifestation of an ictal event. A complete generalized tonic-clonic sequence does not occur in newborns.

TABLE 142.1. CLASSIFICATION OF NEONATAL SEIZURES

ETIOLOGY Although the incidence of neonatal seizures has not changed much in several decades, the frequency of different causes has been modified considerably. Former frequent causes of seizures in the newborn, such as hypocalcemia and obstetric injury, are rare today. Now, hypoxic-ischemic encephalopathy is the major cause (Table 142.2). Infants at highest risk for developing seizures second to asphyxia have low 5-minute Apgar scores, require intubation in the delivery room, and have severe acidemia. Other important causes of neonatal seizures include intraventricular and intracerebral hemorrhage, intrauterine or postnatal infection, cerebral malformations, and metabolic disorders, including hypoglycemia, hypocalcemia, hypomagnesemia, and inborn errors of metabolism (nonketotic hyperglycinemia, urea cycle defects). In many babies, multiple factors coexist (e.g., hypoxia and intraventricular hemorrhage), and concurrent metabolic abnormalities, especially hypoglycemia and hypocalcemia, occur frequently. A potassium channel gene defect has been identified as the cause of benign familial neonatal convulsions.

TABLE 142.2. CAUSES OF NEONATAL SEIZURES

EVALUATION As in older patients with seizures, the history is the most important component of the neurologic assessment, including the family history and details of the infant's gestation and delivery. With patience, seizures often can be observed directly. If not, the nursery attendant is a reliable source of information. Examination should assess the overall well-being of the child, the infant's resting posture and quality of spontaneous movements, and whether any abnormal postures or movements can be elicited by stimulation or positioning. The infant's head circumference should be determined, and note should be made of any congenital anomalies, signs of a neurocutaneous disorder, or organomegaly. Laboratory tests, including lumbar puncture and blood cultures, must be obtained rapidly to identify treatable metabolic abnormalities, sepsis, and meningitis. Ultrasound, head computed tomography, or brain magnetic resonance imaging assess possible hydrocephalus, intracranial hemorrhage, or major anomalies. Magnetic resonance imaging is usually necessary to detect more subtle developmental abnormalities, such as partial lissencephaly, polymicrogyria, or cortical dysplasia. Properly performed, magnetic resonance imaging demonstrates brain abnormalities in two-thirds of newborns with seizures, and diffuse brain lesions, irrespective of etiology, are associated with a high mortality rate. EEG provides important information about the physiologic state of the brain and may be diagnostic if a seizure is recorded.

The timing of the first seizure helps to distinguish diagnostic possibilities. Seizures resulting from severe brain malformations, intracerebral hemorrhage, and hypoxic-ischemic injury occur within 24 to 48 hours. Seizures caused by infection and inborn errors of metabolism typically begin toward the end of the first week of life or later. Seizures related to passive drug withdrawal usually occur within the first 3 days (e.g., alcohol, short-acting barbiturates) but may not appear for 2 to 3 weeks (e.g., methadone). Seizures resulting from sepsis occur at any time. Seizures must be distinguished from other paroxysmal phenomena in the newborn, including jitteriness, benign sleep myoclonus, dyskinesias (common with severe bronchopulmonary dysplasia), and the movements of rapid eye movement sleep. Brief generalized tonic postures occur with poor cerebral perfusion or with resolving encephalopathies; they do not signify convulsions. Epileptic (associated with an EEG ictal discharge) must be separated from nonepileptic seizures because of the therapeutic implications. Seizures without EEG changes are probably caused by subcortical or brainstem release phenomena rather than by cortical events and therefore result from different pathophysiologic mechanisms.

TREATMENT Treatment should be based on assumed physiologic mechanism. Epileptic seizures should be treated with antiepileptic drugs. Antiepileptic drugs are probably ineffective, however, in seizures that are not associated with an EEG discharge, and drugs may worsen already depressed forebrain function. It must be recognized, however, that some clinical and experimental evidence suggests that deep subcortical or brainstem structures may give rise to seizures in newborns without an EEG correlate. More controversial is the end point of therapy. Antiepileptic drug treatment often suppresses clinical manifestations whereas electrical seizure activity persists. Although experimental evidence indicates that prolonged electrical seizures can injure the brain, there is uncertainty and debate about the extent to which EEG ictal discharges contribute, by themselves, and in the absence of hypoxia and ischemia, to permanent neurologic sequelae. We recommend using antiepileptic drugs to the point that clinical seizure activity is eliminated or a high therapeutic blood level is achieved without compromising respiratory or circulatory function. We do not attempt to suppress EEG seizure activity that continues after clinical seizures end, mainly because the drug dosages necessary to achieve this end usually lead to obtundation, ventilatory failure, or cardiac depression. More data are needed about the possible long-term deleterious effects of subclinical electrical seizure discharges. Phenobarbital is the most frequently used antiepileptic drug in newborns. The infant should be given 20 mg/kg intravenously over 15 to 20 minutes. If seizures persist, then additional 5-mg/kg increments of phenobarbital can be given every 20 minutes up to a total loading dose of 40 mg/kg. The maintenance dose for phenobarbital is between 3 to 6 mg/kg/day. Therapeutic levels are 15 to 35 µg/mL; levels higher than 40 µg/mL produce lethargy. Phenytoin is an alternative drug when phenobarbital fails. It is given intravenously over about 20 minutes in a loading dose of 20 mg/kg. Some clinicians advise dividing the loading dose into two 10-mg/kg increments to minimize cardiac toxicity. Maintenance doses are 3 to 4 mg/kg/day. Fosphenytoin, the water-soluble phosphorylated version of phenytoin, has been administered safely to small groups of neonates as young as 26 weeks conceptional age. Midazolam, 0.1 to 0.4 mg/kg/hr administered by continuous intravenous infusion, may be useful in suppressing seizures refractory to phenobarbital and phenytoin. Hypoglycemia should be treated using a 10% glucose solution infused in a dosage of 2 ml/kg. When to stop antiepileptic drugs is a matter of judgment. If the infant is normal and the EEG is normal or near normal, we generally discontinue antiepileptic drug therapy before the child is discharged from the hospital. In other cases, we wait 1 to 3 months after the last seizure.

PROGNOSIS The long-term prognosis relates not to the seizures but to the underlying cause. Perinatal asphyxia, severe intracranial hemorrhage, and cerebral malformations all have a high correlation with permanent brain damage. Therefore, prognosis is guarded for most newborns with seizures; 33% to 50% have neurologic sequelae. Recurrent seizures from the first day of life that interfere with respiration and feeding schedules also carry a poor prognosis. Serial EEG studies assist in identifying term infants at high risk for abnormal neurologic outcome. Several EEG patterns (suppression-burst background activity, unreactive low-voltage recording, continuous multifocal ictal events) reliably predict a fatal outcome or disabling brain damage more than 90% of the time. EEG is less useful in predicting which infants will continue to have seizures beyond the neonatal period. About 15% to 30% of infants with neonatal seizures develop epilepsy. SUGGESTED READINGS Bye AM, Cunningham CA, Chee KY, Flanagan D. Outcome of neonates with electrographically identified seizures, or at risk of seizures. Pediatr Neurol 1997;16:225–231. Clancy RR, Legido A, Lewis D. Occult neonatal seizures. Epilepsia 1988;29:256–261. Hall RT, Hall FK Daily DK. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr 1998;132:345–348. Holmes GL, Gairsa JL, Chevassus-Au-Louis N, Ben-Ari Y. Consequences of neonatal seizures in the rat: morphological and behavioral effects. Ann Neurol 1998;44:845–857. Lanska MJ, Lanska DJ. Neonatal seizures in the United States: results of the National Hospital Discharge Survey, 1980–1991. Neuroepidemiology 1996;15:117–125. Leth H, Toft PB, Herning M, et al. Neonatal seizures associated with cerebral lesions shown by magnetic resonance imaging. Arch Dis Child Fetal Neonat Med 1997;77:F105–F110. Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987;37:1837–1844. Ortibus EL, Sum JM, Hahn JS. Predictive value of EEG for outcome and epilepsy following neonatal seizures. Electroencephalogr Clin Neurophysiol 1996;98:175–185. Perlman JM, Risser R. Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers? Pediatrics 1996;97:456–462. Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 1999;134:71–75. Sher MS. Seizures in the newborn infant. Diagnosis, treatment, and outcome. Clin Perinatol 1997;24:735–772. Sher MS, Aso K, Beggarly ME, et al. Electrographic seizures in preterm and full-term neonates: Clinical correlates, associated brain lesions, and risk of neurologic sequelae. Pediatrics 1993;91:128–134. Sheth RD, Buckley DJ, Gutierrez AR, et al. Midazolam in the treatment of refractory neonatal seizures. Clin Neuropharmacol 1996;19:156–170. Strober JB, Bienkowski RS, Maytal J. The incidence of acute and remote seizures in children with intraventricular hemorrhage. Clin Pediatr 1997;36:643–647. Volpe JJ. Neonatal seizures: current concepts and revised classification. Pediatrics 1989;84:422–428.

CHAPTER 143. TRANSIENT GLOBAL AMNESIA MERRITT’S NEUROLOGY

CHAPTER 143. TRANSIENT GLOBAL AMNESIA JOHN C.M. BRUST Suggested Readings

Transient global amnesia (TGA) is characterized by sudden inability to form new memory traces ( anterograde amnesia) in addition to retrograde memory loss for events of the preceding days, weeks, or even years. During attacks, which affect both verbal and nonverbal memory, there is often bewilderment or anxiety and a tendency to repeat one or several questions (e.g., “Where am I?”). Physical and neurologic examinations, including mental status, are otherwise normal. Immediate registration of events (e.g., serial digits) is intact, and self-identification is preserved. Attacks last minutes or hours, rarely longer than a day, with gradual recovery. Retrograde amnesia clears in a forward fashion, often with permanent loss for events occurring within minutes or a few hours of the attack; there is also permanent amnesia for events during the attack itself. TGA sometimes seems to be precipitated by physical or emotional stress, such as sexual intercourse, driving an automobile, or swimming in cold water. Because amnesia can accompany a variety of neurologic disturbances, such as head trauma, intoxication, partial complex seizures, or dissociative states, criteria for diagnosing TGA should include observation of the attack by others. Patients are usually middle-aged or elderly and otherwise healthy. Recurrent attacks occur in less than 25% of cases, and fewer than 3% have more than three attacks. Intervals between attacks range from 1 month to 19 years. Permanent memory loss is rare, although subtle defects have been reported after only one attack. The cause of TGA is uncertain. Case–control series and anecdotal reports variably implicate stroke, seizures, or migraine. In a large series of patients with TGA, the cause was epileptic in 7%. Attacks in this group were nearly always less than 1 hour in duration and tended to occur on awakening; two-thirds had additional seizure types, usually simple or complex partial seizures. Sleep, but not interictal, electroencephalograms revealed temporal lobe epileptiform discharges. Major risk factors for stroke (hypertension, diabetes mellitus, tobacco, ischemic heart disease, atrial fibrillation, and past stroke or transient ischemic attack) are no more common among patients with TGA than in age-matched controls, and TGA is not a risk factor for stroke. On the other hand, attacks have been associated with cerebral angiography (especially vertebral), polycythemia, cardiac valvular disease, and patent foramen ovale. Patients with amnestic stroke due to documented posterior cerebral artery occlusion do not report previous TGA; their neurologic signs include more than simple amnesia (e.g., visual impairment), and they do not exhibit repetitive queries. Reduced blood flow to the thalamus or temporal lobes has been documented during attacks of TGA but could be secondary to neuronal dysfunction rather than its cause. Epidemiologic studies confirm an association of TGA with migraine, even though in the great majority of patients migraine attacks are recurrent, whereas attacks of TGA are not. Sometimes, both amnestic and migrainous attacks (including visual symptoms and vomiting) have occurred simultaneously or followed one another. Spreading depression of Leao (possibly the pathophysiologic basis of cerebral symptoms in migraine) could, by affecting the hippocampus, explain some cases of TGA, as well. Diffusion-weighted magnetic resonance imaging during or soon after an attack of TGA in several patients revealed signal abnormalities in one or both temporal lobes that were more suggestive of spreading depression than primary ischemia. Thus, even when strict diagnostic criteria are applied, TGA probably has diverse origins. In patients in whom epilepsy and migraine can be excluded and who have risk factors for cerebrovascular disease, antiplatelet drugs may be considered, but the benign natural history makes it difficult to evaluate any preventive treatment. SUGGESTED READINGS Caplan LB. Transient global amnesia. In: Vinken PJ, Bruyn GW, Klawans HL, Frederiks JAM, eds. Clinical neuropsychology. Handbook of clinical neurology, rev ser, vol 45(1). Amsterdam: Elsevier Science, 1985:205–218. Fisher CM, Adams RD. Transient global amnesia syndrome. Acta Neurol Scand 1964;40[Suppl 9]:7–82. Hodges JR, Warlow CP. The aetiology of transient global amnesia: a case-control study of 114 cases with prospective follow-up. Brain 1990;113:639–658. Inzitari D, Pantoni L, Lamassa M, et al. Emotional arousal and phobia in transient global amnesia. Arch Neurol 1997;54:866–873. Melo TP, Ferro JM, Ferro H. Transient global amnesia: a case-control study. Brain 1992;115:261–270. Olesen J, Jorgensen MB. Leao's spreading depression in the hippocampus explains transient global amnesia: A hypothesis. Acta Neurol Scand 1986;73:219–220. Strupp M, Brüning R, Wu RH, et al. Diffusion-weighted MRI in transient global amnesia: elevated signal intensity in the left mesial temporal lobe in 7 of 10 patients.

Ann Neurol 1998;43:164–170.

Zeman AZJ, Boniface SJ, Hodges JR. Transient epileptic amnesia: a description of the clinical and neuropsychological features in 10 cases and a review of the literature. J Neurol Neurosurg Psychiatry, 1998;64:435–443. Zorzon M, Antonutti L, Masè G, et al. Transient global amnesia and transient ischemic attack: natural history, vascular risk factors, and associated conditions. Stroke 1995;26:1536–1542.

CHAPTER 144. MENIERE SYNDROME MERRITT’S NEUROLOGY

CHAPTER 144. MENIERE SYNDROME JACK J. WAZEN Signs and Symptoms Diagnosis Etiology and Pathogenesis Treatment Suggested Readings

First described in 1861 by the French physician Prosper Meniere, this syndrome affects people of all ages, especially those in middle age or older. It is characterized by a recurrent and episodic triad of spinning vertigo, hearing loss, and tinnitus.

SIGNS AND SYMPTOMS Patients with Meniere syndrome are usually asymptomatic between attacks. The acute episode may be preceded by warning symptoms of pressure sensation or fullness in one ear, which feels “blocked.” Hearing then drops, accompanied by a loud roaring tinnitus. Vertigo soon follows and lasts from a few minutes to many hours, rarely lasting as long as 24 hours. The interval between the onset of symptoms and the peak of vertigo varies from a few minutes to a full day or so. Depending on the severity of the vertigo, patients may experience nausea, vomiting, or diarrhea. Pallor and cold sweat are common. Early in the disease, once the spell is over, the ear clears, hearing returns to normal, and the tinnitus may subside. The patient may feel weak and unsteady for 1 or 2 days following a severe attack. A dull unilateral headache may accompany the sensation of blockage and fullness in the ear. Recurrence of the attacks is a cardinal feature. The attacks are of unpredictable frequency. At first, patients may have one attack per year. Then attacks may occur more frequently, once a week or even daily. The more frequent the spells, the more disabled the patient becomes; anxiety and panic reactions are generated by the fear that vertigo may occur at any moment. The hearing loss is usually most severe in the low frequencies. At first, it fluctuates. With progression of the disease, hearing loss becomes permanent, and the high frequencies are affected, resulting in a flat sensorineural hearing loss. Despite the progressive hearing loss, patients often complain of noise intolerance, which is attributed to recruitment in the cochlea. Recruitment is an abnormally rapid increase in the sense of loudness as sound intensity increases. The comfortable range of hearing becomes narrow, and patients become intolerant of sounds barely above their hearing threshold. Recruitment makes it difficult but still feasible to fit a patient with a hearing aid. Examination of a patient during a vertigo attack invariably reveals a rotatory-horizontal nystagmus beating toward the affected ear. This nystagmus of peripheral labyrinthine origin is reduced or abolished by visual fixation. A patient with Meniere syndrome does not necessarily experience all features of the syndrome with each attack, especially in the initial stages of the disease. Recurrent, fluctuating hearing loss may occur without vertigo, or recurrent vertigo may occur without hearing loss. Depending on the major symptom, the disorder may be considered primarily cochlear or vestibular. Eventually, however, the full complement of symptoms ensues. A few patients with Meniere syndrome experience drop attacks or tumarcin crisis. The vertigo is so sudden in onset and so intense that patients find themselves on the floor as if pushed by an invisible force, even from a sitting position, with no loss of consciousness or other neurologic symptoms. Symptoms in the contralateral ear occur in 20% to 30% of patients. The risk of bilateral disease depends on the cause of the syndrome (see below).

DIAGNOSIS The diagnosis is usually evident from the history. Audiologic tests confirm the low-frequency sensorineural hearing loss. Repeated audiograms reveal the fluctuating nature of the loss. Electronystagmography reveals a vestibular disorder in the affected ear. Other vestibular tests, such as rotational chair testing or dynamic platform posturography, are also diagnostic of a peripheral vestibular disorder, but they do not lateralize the lesion. The auditory brainstem response is consistent with a cochlear lesion. Computed tomography and magnetic resonance imaging are usually normal.

ETIOLOGY AND PATHOGENESIS Extensive research into the cause of this symptom complex has led to the present understanding that Meniere syndrome is not the result of any particular cause but is the reaction of the inner ear to different offending agents that cause disruption of endolymphatic homeostasis. Recognized causes include congenital inner ear deformities, labyrinthitis, physical trauma to the head and ear, acoustic trauma, congenital or acquired syphilis, allergic disorders, autoimmune disorders, and vascular disorders, including diabetes and hypertension. Most cases, however, are idiopathic. These idiopathic cases are labeled as Meniere disease. Postmortem histopathologic studies of temporal bones from patients with the syndrome revealed endolymphatic hydrops, which describes dilatation and ballooning of the endolymphatic compartment in the scala media of the cochlea, as well as of the saccule, utricle, and the semicircular canals. These findings suggest that the condition is caused by oversecretion or malabsorption of the endolymph. Disorders of endolymph malabsorption through the endolymphatic duct and sac are now believed to cause the dilatation. Some investigators noted that ruptures in the Reisner membrane, with sudden decompression and mixing of perilymph with endolymph, could result in loss of endocochlear potentials or hair cell injury. The membrane ruptures, however, may be caused by fixing artifacts. Current research centers on the functions of the endolymphatic sac, including its fluid absorption and immunologic properties.

TREATMENT Medical Management Treatment is directed to reducing the impact of the acute attack and the frequency of spells. Controlled trials of the efficacy of any treatment of an acute attack have been difficult to complete because of the unpredictable and variable nature of the syndrome. As a result, many drugs, such as meclizine hydrochloride (Antivert), diazepam, promethazine hydrochloride, and prochlorperazine, are used as labyrinthine sedatives. Similarly, no regimen has proved effective in reducing the frequency of attacks. Some authorities advocate a strict low-salt diet and diuretics to reduce the endolymphatic hydrops. Patients are advised to discontinue the use of caffeine, tobacco, and alcohol. Vasodilator therapy with histamine and nicotinic acid offers inconsistent results. Patients whose syndrome is allergic or has immunologic factors may respond well to a course of steroids. Patients are also encouraged to address anxiety, depression, and other psychologic symptoms that result from fear of attacks. Surgical Treatment About 20% of patients fail to respond to medical management and become candidates for surgery to relieve disabling vertigo. Patients who have lost hearing respond well to a labyrinthectomy, which is the complete removal of the vestibular end-organ. For patients who still have serviceable hearing, vestibular neurectomy is the procedure of choice, offering a 90% to 95% success rate in vertigo control while preserving hearing. Endolymphatic sac surgery with decompression and shunting of the endolymph into the mastoid cavity is still performed despite controversies about long-term effectiveness. Chemical Labyrinthectomy Nonsurgical candidates and patients who refuse surgery but yet fail to respond to medical treatments may benefit from the intratympanic injection of gentamicin sulfate, an aminoglycoside known for its ototoxicity. Gentamicin has a greater affinity for vestibular hair cells and thus causes a significant loss of vestibular function before attacking the cochlear hair cells. Given in the appropriate dose and with close supervision, intratympanic gentamicin is absorbed through the round window

membrane, creating a chemical labyrinthectomy with hearing preservation. Bilateral Meniere Disease Patients with active bilateral Meniere disease are treated with systemic injections of streptomycin sulfate. As an ototoxic agent, streptomycin has a stronger affinity for vestibular hair cells than for cochlear hair cells. Given in daily 1-g injections with close monitoring of vestibular function, treatment is interrupted after the first signs of vestibular ototoxicity and before the onset of hearing loss. Reduction in the vestibular hair cell population decreases the severity of the vertigo. Total bilateral ablation of vestibular hair cells leads to oscillopsia and permanent ataxia and therefore should be avoided. SUGGESTED READINGS Arenberg IK. Endolymphatic hypertension and hydrops in Meniere's disease: current perspectives. Am J Otol 1982;4:52s–65. Baloh RW. Dizziness, hearing loss, and tinnitus: essentials of neurology. Philadelphia: FA Davis Co, 1984. Blakeley BW. Clinical forum: a review of intratympanic therapy. Am J Otol 1997;18:520–526. Brackman DE. Neurological surgery of the ear and skull base. New York: Raven Press, 1982. Brookes GB. The pharmacological treatment of Meniere's disease. Clin Otolaryngol 1996;21:3–11. Brookes GB, Hodge RA, Booth JB, Morrison AW. The immediate effects of acetazolamide in Meniere's disease. J Laryngol Otol 1982;96:57–72. Dandy WE. Treatment of Meniere's disease by section of only the vestibular portion of the acoustic nerve. Bull Johns Hopkins Hosp 1933;53:52–55. Hallpike CS, Cairns H. Observations on the pathology of Meniere's syndrome. J Laryngol 1938;53:625–654. Meniere P. Sur une forme particulière de surditè grave dependant d'une lesion de l'oreille interne. Gaz Med Paris 1861;16:29. Pulec JL. Meniere's disease: etiology, natural history, and results of treatment. Otolaryngol Clin North Am 1973;6:25–39. Stahle J, Wilbrand HF, Rask-Andersen H. Temporal bone characteristics in Meniere's disease. Ann N Y Acad Sci 1981;374:794–807. Tomiyama S, Harris JP. The endolymphatic sac: its importance in inner ear immune responses. Laryngoscope 1986;96:685–691. Wazen JJ, Foyt D, Huang CC. Quantitative immunochemical studies of the endolymphatic sac in Meniere's disease. In: Barbara M, Filipo R, eds. Meniere's disease: pathogenesis, pathophysiology, diagnosis and treatment. proceedings of the third international symposium. Amsterdam: Kugler, 1994. Wazen JJ, Spitzer J, Kasper C, Anderson B. Long-term hearing results following vestibular surgery in Meniere's disease. Laryngoscope 1998;108:1470–1473.

CHAPTER 145. SLEEP DISORDERS MERRITT’S NEUROLOGY

CHAPTER 145. SLEEP DISORDERS JUNE M. FRY Sleep Physiology Diagnostic Procedures Specific Disorders of Sleep Suggested Readings

The clinical application of scientific knowledge of sleep physiology and biologic rhythms led to the development of standards for normal sleep and arousal, diagnostic tests, and a classification of sleep disorders ( Table 145.1). This classification is based on clinical signs, symptoms, age at onset, and natural history. Clinical polysomnography is an important diagnostic tool that provides objective confirmation of the clinical syndromes.

TABLE 145.1. INTERNATIONAL CLASSIFICATION OF SLEEP DISORDERS

SLEEP PHYSIOLOGY Sleep is an active and complex state comprising four stages of non–rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. Wakefulness and sleep stages are characterized by physiologic measures that are assessed by polysomnography. Standardized sleep scoring is based on the electroencephalogram (EEG), the electrooculogram (EOG; a measurement of eye movements), and the electromyogram (EMG) of the mentalis muscle (chin EMG). Stage 1 sleep is characterized by a low-voltage, mixed-frequency EEG and slow, rolling eye movements. Reactivity to outside stimuli is decreased, and mentation may occur but is no longer reality-oriented. Stage 2 consists of a moderate low-voltage background EEG with sleep spindles (bursts of 12- to 14-Hz activity lasting 0.5 to 2 seconds) and K-complexes (brief high-voltage discharges with an initial negative deflection followed by a positive component). Heart and respiratory rates are regular and slightly slower. Stage 3 sleep consists of high-amplitude theta (5 to 7 Hz) and delta (1 to 3 Hz) frequencies, as well as interspersed K-complexes and sleep spindles. Stage 4 sleep is similar to stage 3, except that high-voltage delta waves make up at least 50% of the EEG and sleep spindles are few or absent. Stages 3 and 4 are often combined and referred to as delta sleep, slow-wave sleep, or deep sleep. During this deeper sleep, heart and respiratory rates are slowed and regular. During NREM sleep, the tonic chin EMG is of moderately high amplitude but less than that of quiet wakefulness. The EEG pattern during REM sleep consists of low-voltage, mixed-frequency activity and is similar to that of stage 1 sleep. Moderately high-amplitude, 3- to 5-Hz triangular waveforms called saw-tooth waves are intermittently present and are unique to REM sleep. Intermittent bursts of rapid conjugate eye movements occur. Tonic chin EMG activity is absent or markedly reduced, and phasic muscle discharges occur in irregular bursts. The decreased EMG activity is a reflection of muscle paralysis resulting from active inhibition of muscle activity during REM sleep. During REM sleep, heart and respiratory rates are increased and irregular, and vivid dreaming occurs. NREM sleep alternates with REM sleep at intervals of 85 to 100 minutes. The normal healthy adult typically falls asleep within 10 minutes and goes through the sequence of stages 1 through 4 followed by the reverse (stages 4, 3, and 2). Afterward, the first REM sleep period occurs. This normal sleep pattern consists of three to five such cycles. Typically, stages 3 and 4 are more prominent during the first half of the sleep period, and the REM sleep episodes increase in duration and intensity of REM activity during the second half of the sleep period.

DIAGNOSTIC PROCEDURES Clinical polysomnography, the simultaneous recording of sleep and multiple physiologic variables, provides objective documentation of sleep disorders. An all-night polysomnogram consists of continuous EEG, EOG, mentalis EMG, surface EMG of the anterior tibialis muscles for detection of leg movements in sleep, electrocardiogram, and measurement of nasal and oral airflow, respiratory effort, and oxygen saturation. Polysomnographic tracings are analyzed in detail to determine a patient's sleep pattern and the presence and severity of a sleep disorder. Patients with excessive daytime sleepiness are also evaluated by the multiple sleep latency test (MSLT), a series of four or five nap opportunities with sleep recordings at 2-hour intervals throughout the day. The nap is terminated 15 minutes after sleep onset. If no sleep occurs, each recording session is terminated after 20 minutes. The sleep latency (time it takes to fall asleep) is determined for each nap and provides an objective measure of daytime sleepiness. Patients with pathologic daytime sleepiness generally fall asleep in less than 5 minutes on all naps. Normally alert individuals take more than 10 minutes to fall asleep or often remain awake. The MSLT is also used to determine the presence of sleep-onset REM periods found in narcolepsy, and REM sleep rebound.

SPECIFIC DISORDERS OF SLEEP Only selected disorders are described, primarily the most common and those of particular interest to neurologists. Disorders with a Complaint of Insomnia Transient insomnia lasts less than 3 weeks, is usually situational, and is caused by emotions such as excitement, sorrow, or anxiety resulting from a specific situation, or by a schedule change, such as jet lag or a work-shift change. A short course (2 weeks or less) of a hypnotic may be indicated for treatment of transient situational insomnia. Benzodiazepines became the drugs of choice soon after becoming available in the 1960s. New hypnotics, the imidazopyridines, have favorable properties and are useful for sleep-onset difficulties, but because of very short half-lives, they are less useful for middle-of-the-night or early-morning awakenings. Persistent or chronic insomnia has many underlying causes. When the cause is a psychiatric disorder, pain, gastroesophageal reflux, or drug or alcohol abuse, the underlying cause should be treated. Long-term use of hypnotic drugs is one cause of persistent insomnia. A common dyssomnia is psychophysiologic insomnia. This disorder usually follows a situational insomnia and results from somatized anxiety that is manifested as restlessness, apprehension, ruminative thoughts, and hypervigilance, all of which interfere with sleep. These factors, combined with negative conditioning, lead to a vicious cycle: The more the patient tries to sleep, the less successful the attempts become. The most effective treatment for this disorder is behavioral therapy consisting of relaxation therapy, stimulus control, good sleep hygiene ( Table 145.2), and sleep restriction.

TABLE 145.2. PRINCIPLES OF SLEEP HYGIENE

Alveolar hypoventilation syndrome, a cause of sleep disruption, is associated with major changes in respiratory function during sleep, including central sleep apnea and hypopnea associated with recurrent hypoxemia, hypercapnia, and a decreased tidal and minute volume. REM sleep is the time of greatest abnormality with the longest apneic episodes and the greatest fall in oxygen saturation. This syndrome may be idiopathic or associated with other disorders; these include chronic residual poliomyelitis, muscle diseases (e.g., myotonic dystrophy, anterior horn cell disease), involvement of thoracic cage bellows action or diaphragmatic muscle weakness, cervical spinal cordotomy, brainstem lesions of structures that control ventilation, dysautonomia syndromes, and massive obesity. Restless Legs Syndrome and Periodic Limb Movement Disorder In the restless legs syndrome (RLS), the patient feels an irresistible urge to move the legs, especially when sitting or lying down. There is a discomfort deep inside the leg, most commonly between the knee and ankle, that makes the patient move the legs or walk about vigorously. The symptoms interfere with and delay sleep onset, may recur during the night, and cause an insomnia complaint. Periodic limb movements in sleep (PLMS) are found in most patients with RLS who are studied with polysomnography. PLMS are stereotyped periodic movements of one or both legs and feet during sleep. The movements, which occur primarily in NREM sleep, consist of dorsiflexion of the foot, extension of the big toe, and often flexion of the leg at the knee and hip. This triple flexion movement has a mean duration of 1.5 to 2.5 seconds. Similar movements can occur in the upper extremities but are much less common. Limb movements may be accompanied by an arousal or awakening. These movements are remarkably periodic, with 20- to 40-second intervals, and may continue for minutes to hours. In contrast to most movement disorders, which are inhibited by sleep (e.g., cerebellar and extrapyramidal tremors, chorea, dystonia, hemiballism), PLMS are initiated by sleep or drowsiness. They are different from hypnic jerks (sleep starts), which are nonperiodic, isolated myoclonic movements that occur at sleep onset and simultaneously involve the muscles of the trunk and extremities. Hypnic jerks are considered normal. Patients with periodic limb movement disorder (PLMD) complain of chronically disturbed sleep or daytime sleepiness. The severity of symptoms appears to be related to the frequency of limb movements and associated arousals and awakenings. RLS, PLMD, or both occur in association with other sleep disorders, including sleep apnea, narcolepsy-cataplexy, and drug dependency. They may develop in patients being treated with antidepressants and during withdrawal from drugs (e.g., barbiturates, benzodiazepines), and in patients with chronic uremia, anemia, and iron deficiency. For many years, the treatment of choice for PLMD and RLS has been clonazepam (Klonopin), 0.5 to 3.0 mg in the evening, at bedtime, or both. Other benzodiazepines have also proved beneficial. Temazepam (Restoril) is often preferred for its intermediate half-life. Levodopa plus benzerazide or carbidopa is effective, but patients often experience increased or rebound daytime symptoms, when treated only at night. Dopaminergic agonists now appear to be the drugs of choice. Pergolide mesylate (Permax) and bromocriptine mesylate (Parlodel) have been used most commonly, and the doses required are very much smaller than those used for Parkinson disease. Pergolide is generally effective with doses of 0.15 to 0.50 mg daily. Opiates are also useful, especially in severe cases. Disorders of Excessive Somnolence The clinical neurologist is asked to evaluate symptoms of excessive daytime sleepiness more than any other major category of sleep complaint. Therefore, a patient's complaint and symptoms must be well-defined to provide the physician with a rational basis for a diagnostic and treatment decision. The major symptoms include sleepiness and napping during a time of day when the patient wishes to be awake. The complaint has often been present for months or years and includes an increased amount of unavoidable napping, apparent increase in total sleep during the 24-hour day, or difficulty in achieving full alertness after awakening in the morning. These symptoms should not be confused with complaints of tiredness or lack of energy, motivation, or drive, which may reflect dysphoric symptoms such as those that might accompany depression. Excessive sleepiness is caused by an insufficient quantity of sleep or poor sleep quality resulting from a sleep disorder, other disturbance, or both. Excessive sleepiness leads to impaired performance and diminished intellectual capacity, and is often a major factor or direct cause of accidents and catastrophes. Several common disorders must be considered in patients with a complaint of excessive daytime sleepiness ( Table 145.3). Obstructive sleep apnea (OSA) syndrome and narcolepsy account for most patients with a complaint of daytime sleepiness evaluated in sleep disorders centers.

TABLE 145.3. DIFFERENTIAL DIAGNOSIS FOR EXCESSIVE DAYTIME SLEEPINESS

Obstructive Sleep Apnea Syndrome A patient with OSA syndrome often falls asleep at inappropriate or dangerous times (e.g., while eating, driving a car, waiting for a red light) and has pervasive sleepiness throughout the day that seriously interferes with work, as well as leisure time. Almost all patients have loud snoring. The snoring pattern is recurrent, with pauses between snores of 20 to 50 seconds. Each cycle comprises a series of three to six loud snores and gasps followed by a relatively silent period. During the nonsnoring period, the patient makes ineffective respiratory efforts because of an obstructed upper airway. In addition to loud cyclic snoring, sleep is restless, with frequent brief arousals and unusual sleeping postures. The patient may talk during sleep, have nocturnal enuresis, fall out of bed, and wake in the morning with a generalized severe headache and a feeling of having had an unrefreshing night. In adults, OSA syndrome occurs predominantly between the fourth and sixth decades and is about 2.5 times more common in men. The prevalence of OSA syndrome increases with age and is higher in individuals with habitual snoring and obesity. Numerous congenital and acquired abnormalities of the upper airway are associated

with OSA. These include micrognathia, deviated nasal septum, narrow nasal passages from a previous fracture, enlarged adenoids or tonsils, palatopharyngeal abnormalities (e.g., Pierre-Robin syndrome, post-cleft-palate repair, Treacher Collins syndrome), enlarged tongue in acromegaly, hypothyroidism with myxedema of the upper-airway soft tissues, and temporomandibular joint abnormalities. In addition to daytime hypersomnia and nighttime sleep disturbances, many patients with OSA syndrome have systemic hypertension, primarily diastolic, and a wide variety of cardiac arrhythmias during sleep. Recognized systemic complications of OSA syndrome are pulmonary hypertension, cardiac enlargement, myocardial infarction, stroke, elevated hematocrit, and an increased risk of sudden death during sleep. Sleep apnea also occurs in infants and children. In infants, it has been associated with the “acute life-threatening event,� as well as familial, congenital, and acquired dysautonomia syndromes and craniofacial disorders. The peak incidence in children is around age 4 years and is often associated with adenotonsillar hypertrophy. Central sleep apnea syndrome is characterized by intermittent cessation or decreases in respiratory effort with associated decreases in oxygen saturation during sleep. It causes complaints of frequent awakenings and restless unrefreshing sleep and is much less common than OSA syndrome. An all-night polysomnographic recording is used to diagnose OSA and to quantify the frequency, severity, and type of respiratory disturbance. An apnea is defined as the cessation of airflow for 10 seconds or longer. A central apnea is the absence of respiratory effort. An obstructive apnea is the absence of airflow despite the presence of respiratory effort. A mixed apnea consists of an initial central component followed by obstruction. A hypopnea is a reduction in airflow for at least 10 seconds and may be central or obstructive. These respiratory events are accompanied by oxygen desaturation and usually by arousals. During recurrent apnea episodes in severe cases, oxygen saturation often falls to less than 50% and bradycardia (less than 60 beats per minute [beats/min]) alternates with tachycardia (greater than 110 beats/min) for each snoring cycle. Stages 3 and 4 sleep are diminished or absent, and there are many stage changes and arousals. The duration of apneic episodes and the degree of oxygen desaturation usually increase in REM sleep. Nasal continuous positive airway pressure (CPAP) is the most common and effective treatment for moderate and severe OSA syndrome. Air pressure is generated by a small blower, delivered via tubing to a nasal mask, and controlled by a pressure valve. Each patient must have a treatment trial during polysomnography to determine the pressure required to alleviate airway obstruction during sleep. If successful and well tolerated, a commercially available nasal CPAP unit is prescribed for home use. Prior to nasal CPAP, tracheostomy was the only reliably effective treatment and is still indicated for severe OSA if CPAP is not tolerated. In some patients, especially children and young adults, the removal of enlarged tonsils and adenoids relieves the obstruction. The surgical procedure, uvulopalatopharyngoplasty, has been an inconsistently beneficial treatment, and selection criteria are not well established. Hyoidplasty and mandibular advancement have successfully treated patients with structural abnormalities causing hypopharyngeal obstruction. Other treatments for less severe cases have been sustained weight loss in obese patients and use during sleep of a dental appliance that advances the lower jaw. Narcolepsy Narcolepsy (MIM 161400) is an incurable lifelong neurologic disorder. The classic narcolepsy tetrad consists of (1) excessive daytime sleepiness, (2) cataplexy, (3) sleep paralysis, and (4) hypnagogic hallucinations. Narcolepsy is not rare. Estimates of prevalence range between 2 and 10 per 10,000 individuals in North America and Europe. It is about five times more prevalent in Japan, and the incidence is only 1 per 500,000 in Israel. The onset of narcolepsy typically occurs between ages 15 and 30 years, although cases have been reported with onset as early as age 5 years and as late as 63 years. Men and women are equally affected. Daytime sleepiness is usually the first symptom to appear. Recognition that the patient has a medical disorder often takes years. Excessive daytime sleepiness is always present and is usually the most prominent symptom. Patients often complain of fatigue and impaired performance. Irresistible sleep occurs more frequently throughout the day if the patient is inactive, but also occurs at inappropriate times, such as during a conversation, eating, driving, or a monotonous or repetitious activity. These spontaneous naps are usually brief and somewhat refreshing. Patients with narcolepsy generally do not sleep more, but need to sleep more frequently. They have difficulty in sustaining wakefulness. More than 50% of narcoleptic patients have automatic behavior that they describe as memory lapses or blackouts. These episodes are caused by microsleeps that intrude into wakefulness. Patients are capable of carrying out semipurposeful activity associated with amnesia; thus, they can neither monitor the activity nor remember it later. Common examples include getting lost while driving, typing or writing gibberish, misplacing things, or walking into objects. Automatic behavior also occurs in other disorders of excessive sleepiness. Other complaints, such as poor memory and visual disturbances, appear to be related to excessive daytime sleepiness. The symptom of excessive daytime sleepiness is disabling and often leads to personal, social, and economic problems. In a patient with excessive daytime sleepiness, the presence of cataplexy is pathognomonic of narcolepsy. Cataplexy consists of a brief episode of paralysis or weakness of voluntary muscles without change in consciousness, and is precipitated by strong but normal emotions. The onset of cataplexy usually follows excessive daytime sleepiness by months or years. It only rarely appears before the sleepiness. The severity of cataplexy is variable. Some patients may have as few as two or three episodes in a lifetime, whereas others may have several episodes every day. A full range of severity exists between these extremes. The most common precipitant is laughter. Other strong emotions include anger, surprise, fear, and anticipation. Cataplexy may be partial and affect only certain muscles; common examples include dysarthria, drooping of the head, and slight buckling of the knees. Severe global attacks affect all skeletal muscles, except muscles of respiration, and cause collapse. Most episodes last only seconds, but severe attacks can last minutes. REM sleep mechanisms are involved in the pathophysiology of narcolepsy. Manifestations or fragments of REM sleep appear during waking hours and at sleep onset. Cataplexy is the appearance of the paralysis of REM sleep during wakefulness. REM sleep in a narcoleptic patient often begins within 10 minutes of sleep onset instead of after 85 to 100 minutes, as in the normal individual. This abnormal timing of REM sleep is called a sleep-onset REM period, which may include sleep paralysis, hypnagogic hallucinations, or both. Sleep paralysis is a global paralysis of voluntary muscles that occurs at the entry into or emergence from sleep. This muscle weakness is thought to result from the same motor inhibition that occurs during cataplexy in the narcoleptic individual and in REM sleep in everyone. Sleep paralysis without narcolepsy can occur in an isolated form in otherwise healthy individuals or in a familial form genetically transmitted. Isolated sleep paralysis most frequently occurs upon awakening. Familial sleep paralysis and sleep paralysis associated with narcolepsy occur more often at sleep onset. In isolated cases, sleep paralysis may occur only when precipitated by predisposing factors, such as irregular sleep habits, sleep deprivation, work shift, jet lag, and psychologic stress. Although the familial form and that associated with narcolepsy are more chronic, the frequency of episodes can be increased by the same factors. Hypnagogic hallucinations are vivid dreamlike images that the narcoleptic person experiences during sleep onset and offset. They are simple or bizarre visual hallucinations that can have auditory and tactile components. The patient is usually aware of the surroundings and has difficulty in discerning the hallucinations from reality; these hallucinations are often frightening. Hypnagogic hallucinations are most likely the result of dissociated central nervous system (CNS) processes involved in dreaming during REM sleep. They can be precipitated by sleep deprivation in normal individuals. Narcolepsy symptoms produce major social, familial, educational, and economic consequences for both patients and their family. Patients often do not achieve their intellectual potential and suffer frequent failures of occupation, education, and marriage. Family members, friends, and even patients often interpret the symptoms as indicating laziness, lack of ambition, delayed maturation, or psychologic defects. Because these symptoms begin during the crucial period of maturation from puberty to adulthood, misinterpretation and lack of a diagnosis can greatly affect a patient's personality and feelings of self-esteem. Genetic research shows the existence of a susceptibility gene in the region of the major histocompatibility complex located on the short arm of chromosome 6. Genetic family studies suggest that this gene is not sufficient and that an additional gene or genes may be needed for disease expression. The identification of several pairs of monozygotic twins discordant for narcolepsy indicates a role for environmental factors in the development of narcolepsy. Several clinical reports have described structural disease in the upper brainstem–hypothalamus area with narcoleptic symptoms and cataplectic-like behavior. This has been produced in cats after microinjection of cholinergic drugs in the pontine reticular formation; however, no pathology has been reported thus far in humans or animal models of narcolepsy-cataplexy. The current treatment for the sleepiness of narcolepsy is the use of adrenergic stimulant drugs: pemoline (Cylert), methylphenidate hydrochloride (Ritalin HCl), and amphetamines. Modafinil, a new wakefuless-promoting agent that is chemically and pharmacologically distinct from the above stimulants, has been shown to be

effective in reducing daytime sleepiness in patients with narcolepsy. Use of stimulant drugs should be carefully monitored; patients and physicians should cooperate in adjusting the amount and timing of doses to meet functional daytime needs and scheduling of patients' activities. Cataplexy, when present to a significant degree, is usually well controlled with the tricyclic compounds imipramine hydrochloride (e.g., imipramine, 10 to 25 mg, two or three times daily), protriptyline hydrochloride (Vivactil), or clomipramine; however, impotence can be an undesirable side effect in men. Selective serotonin reuptake inhibitors such as paroxetine hydrochloride (Paxil) and fluoxetine hydrochloride (Prozac) are also effective. These medications are thought to effectively treat cataplexy because they suppress REM sleep. An important adjunctive treatment for narcolepsy is the rational scheduling of daytime naps and the maintenance of proper sleep hygiene. The physician's role in providing the patient with a clear understanding of the nature of the symptoms and with emotional support in coping with the many adaptive difficulties cannot be overemphasized. Recurrent hypersomnia (Kleine-Levin syndrome) consists of recurrent episodes of hypersomnia and binge eating lasting up to several weeks, with an interval of 2 to 12 months between episodes. Neurobehavioral and psychologic changes, such as disorientation, forgetfulness, depression, depersonalization, hallucinations, irritability, aggression, and sexual hyperactivity, often accompany the episodes of hypersomnia. Onset is typically in early adolescent boys, but rarely in girls and adults. Episodes decrease in frequency and severity with age and are rarely present after the fourth decade. A definitive treatment for Kleine-Levin syndrome is not known, but there are reports of limited success with amphetamines and methylphenidate. Because of similarities between Kleine-Levin syndrome and bipolar depression, lithium has been used. Other Conditions Associated with Excessive Daytime Somnolence Various neurologic and medical conditions are associated with excessive daytime sleepiness; these include endocrine and metabolic disorders, liver failure, uremia, chronic pulmonary disease (with hypercapnia), hypothyroidism (severe with myxedema), incipient coma with diabetes mellitus, and severe hypoglycemia. Neurologic disorders, such as tumors in the area of the third ventricle (e.g., glioma, craniopharyngioma, dysgerminoma, pinealoma, pituitary adenoma), obstructive hydrocephalus, increased intracranial pressure, viral encephalitis, and other infections of the brain and surrounding membranes, can cause increased daytime somnolence. The postconcussion syndrome may also be associated with increased sleepiness. However, complaints of tiredness, fatigue, difficulty in concentrating, and memory impairment are usually more prominent symptoms. Disorders of the Sleep–Wake Schedule The study of human chronobiology has been important for the understanding of clinical disorders of the daily sleep–wake cycle. Many functions, including body temperature, plasma and urine hormones, renal functions, psychologic performance measures, and internal sleep-stage organization, all participate in this circadian rhythm. Evidence for the importance of these cyclic physiologic systems in sleep disturbances comes from studies of acute phase shifts, such as those that occur after transmeridian air flights or in shift work. The daily sleep period is disturbed after acute shifts in such a way that intrusive awakenings take place, sleep length is shortened, and REM phase advances relative to sleep onset. Adaptation is slower after an eastward flight or a phase advance in the laboratory than after a phase delay (westward flight). Disorders of the circadian sleep–wake cycle are divided into two major categories, transient and persistent. The transient disorders include the temporary sleep disturbance following an acute work-shift change and a rapid time-zone change (jet lag). Both sleep deprivation and the circadian phase shift produce symptoms including frequent arousals, especially at the end of sleep episodes, and excessive sleepiness. Affected individuals are fatigued, sleepy, and intermittently inattentive when they should be awake, and have partial insomnia during the daily time for sleep. A wide range of important occupations is involved in these acute phase-shift syndromes (e.g., doctors, nurses, police, firemen, airline pilots, air-traffic controllers, diplomats, international business executives, radar operators, postal workers, long-distance truck drivers, and others). Persistent sleep–wake cycle disorders are divided into several major clinical categories. Persons who frequently change their sleep–wake schedule (e.g., shift workers) have a mixed pattern of excessive sleepiness alternating with arousal at inappropriate times of the day. Sleep is typically shortened and disrupted. Waking is associated with a decrease in performance and vigilance. The physician caring for such patients should be aware that the syndrome often disrupts social and family life and becomes intolerable. The delayed-sleep-phase syndrome is a specific chronobiologic sleep disorder characterized by a chronic inability to sleep at the desired time to meet required work or study schedules. Patients are typically unable to fall asleep until some time between 2 and 6 a.m. On weekends and vacation days, they sleep until late morning or early afternoon and feel refreshed, but have great difficulty awakening at the required 7 or 8 a.m. for work or school. These patients have a normal sleep length and internal organization of sleep when clock time of sleep onset and sleep offset coincides with the circadian timing that controls daily sleep. When sleep onset is attempted at earlier times, there is usually a long latency to sleep onset. Successful treatment has been a phase shift of the time of the daily sleep episode by progressive phase delay of the sleep time. By delaying the time of going to sleep and awakening by 2 or 3 hours each day (i.e., a 26- or 27-hour sleep–wake cycle), the patient's sleep timing can be successfully reset to the preferred clock time. Alternatively, treatment with bright light, which phase-shifts the circadian rhythm of core body temperature, has proved helpful in achieving and maintaining a desired schedule. The advanced-sleep-phase syndrome is rare and is more likely to occur in elderly persons. Typical sleep onset is between 6 and 8 p.m., with wake times between 1 and 3 a.m. despite efforts to delay sleep time. The patient with the non-24-hour sleep–wake disorder is completely out of touch with the 24-hour cycle of the rest of society. These rare individuals maintain a 25- to 27-hour biologic day despite all attempts to entrain themselves to a 24-hour cycle. A personality disorder or blindness may predispose to this condition. An irregular sleep–wake pattern consists of considerable irregularity without an identifiable persistent sleep–wake rhythm. There are frequent daytime naps at irregular times and a disturbed nocturnal sleep pattern. Most patients with this syndrome have congenital, developmental, or degenerative brain dysfunction, although it does occur rarely in cognitively intact outpatients. Treatment is difficult but should include regularly scheduled activities and time in bed based on sleep hygiene principles. Parasomnias Parasomnias are disorders of arousal, partial arousal, and sleep-stage transition characterized by undesirable behaviors during sleep that are manifestations of CNS activation. Autonomic nervous system changes and skeletal muscle activity are prominent features. The arousal disorders include the classic disorders of sleepwalking and sleep terrors, as well as the more recently designated disorder confusional arousals. These behaviors typically emerge from slow-wave sleep during the first third of the night. Confusion during and following arousal and amnesia for the episodes are features common to the three disorders. Sleepwalking consists of complex behaviors, including automatic and semipurposeful motor acts, such as sitting up in bed, walking, opening and closing doors, opening a window, climbing stairs, dressing, and even preparing food. A subgroup of patients, usually young adult men, perform acts that are destructive or harmful to themselves, such as breaking furniture, throwing objects, and climbing out or walking through a window. A small nightly dose of a benzodiazepine, such as diazepam or temazepam, is useful, especially when violent behavior is present. A sleep terror is typically initiated with a sudden, loud, high-pitched scream and sitting up in bed. The patient appears agitated and frightened. Major autonomic changes occur, including rapid pulse and respiration, sweating, and pupillary dilation. Arousal disorders are common in children and generally benign, and decrease in frequency and severity or resolve with increasing age. These disorders, however, must be distinguished from recurrent nocturnal seizure disorders, such as partial complex seizures. Polysomnography with additional EEG channels and videotape of the behaviors is extremely useful for differentiating arousal disorders from sleep-related epilepsy. REM sleep behavior disorder (RBD), a parasomnia occurring during REM sleep, is characterized by intermittent loss of REM sleep atonia accompanied by motor activity consistent with dream enactment. RBD appears to be uncommon, but the true incidence is unknown. It is more common in older men and often associated with degenerative neurologic disorders, especially Parkinson disease or cerebrovascular disease. Injury to self or bed partner is a significant complication. The diagnosis is usually suggested by history and confirmed by polysomnography. Recordings show persistent muscle tone and complex behaviors during REM sleep. Most patients respond to treatment with a small dose (0.5 to 2 mg) of clonazepam at bedtime. However, daytime carry-over effects causing drowsiness and cognitive dysfunction

must be carefully monitored in elderly patients. Sleep Disorders Associated with Neurologic Disorders Degenerative neurologic disorders, including dementia and Parkinson disease, have associated sleep disturbances. Sleep may be abnormal because of involvement of brain structures that control and regulate sleep and wakefulness or because of abnormal movements or behaviors that occur during sleep. Fatal familial insomnia is a rare prion disease (see elsewhere in this volume). SUGGESTED READINGS Aharon-Peretz J, Masiah A, Pillar T, et al. Sleep-wake cycles in multi-infarct dementia and dementia of the Alzheimer type. Neurology 1991;41:1616–1619. American Sleep Disorders Association. The international classification of sleep disorders: diagnostic and coding manual, rev ed. Rochester, MN: American Sleep Disorders Association, 1997. Billiard M. Idiopathic hypersomnia. Neurol Clin 1996;14:573–582. Bresnitz EA, Goldberg R, Kosinski RM. Epidemiology of obstructive sleep apnea. Epidemiol Rev 1994;16:210–227. Chesson AL, Ferber RA, Fry JM, et al. The indications for polysomnography and related procedures. Sleep 1997;20:423–487. Coleman R, Pollak CP, Weitzman ED. Periodic movements in sleep (nocturnal myoclonus): relation to sleep disorders. Ann Neurol 1980;8:416–421. Consensus conference. Drugs and insomnia: the use of medications to promote sleep. JAMA 1984;251:2410–2414. Critchley M. Periodic hypersomnia and megaphagia in adolescent males. Brain 1962;85:627–656. Dement WC, Mitler MM, Rogh T, et al. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986;9:519–524. Earley CJ, Allen RP. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic limb movements in sleep in a consecutive series of patients. Sleep 1996;19:801–810. Feber R. Childhood sleep disorders. Neurol Clin 1996;14:493–511. Fry JM. Restless legs syndrome and periodic leg movements in sleep exacerbated or caused by minimal iron deficiency. Neurology 1986;36[Suppl 1]:276. Fry JM, ed. Current issues in the diagnosis of and management of narcolepsy. Neurology 1998;50:[Suppl 1]. Guilleminault C, ed. Sleeping and waking disorders: indications and techniques. Menlo Park, CA: Addison-Wesley, 1981. Hla KM, Young TB, Bidwell T, Palta M, Skatrud JB, Dempsey J. Sleep apnea and hypertension: a population study. Ann Intern Med 1994;120:382–388. Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. Philadelphia: WB Saunders, 1994. Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986;315:997–1003. Mahowald MW, Schenck CH. NREM sleep parasomnias. Neurol Clin 1996;14:675–696. Martin TJ, Sanders MH. Chronic alveolar hypoventilation: a review for the clinician. Sleep 1995;18:617–634. Obermeyer WH, Benca RM. Effects of drugs on sleep. Neurol Clin 1996;14:827–840. Orlosky MJ. The Kleine-Levine syndrome: a review. Psychosomatics 1982;23:609–621. Parish JM, Shepard JW. Cardiovascular effects of sleep disorders. Chest 1990;97:1220–1226. Prinz PN. Sleep and sleep disorders in older adults. J Clin Neurophysiol 1995;12:139–145. Prinzmetal M, Bloomberg W. The use of benzedrine for the treatment of narcolepsy. JAMA 1935;105:2051. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol 1998;43:88–97. Richardson GS, Malin HV. Circadian rhythm sleep disorders: pathophysiology and treatment. J Clin Neurophysiol 1996;13:17–31. Rosenthal NE, Joseph-Vanderpool JR, Levendosky AA, et al. Phase-shifting effect of bright morning light as treatment for delayed sleep-phase syndrome. Sleep 1990;13:354–361. Schenck CH, Mahowald MW. REM sleep parasomnias. Neurol Clin 1996;14:697–720. Schenck CH, Bundlie SR, Patterson AL, Mahowald MW. Rapid eye movement sleep behavior disorders: a treatable parasomnia affecting older males. JAMA 1987;257:1786–1789. Schmidt-Nowara W, Lowe A, Wiegand L, et al. Oral applications for the treatment of snoring and obstructive sleep apnea: a review. Sleep 1995;18:501–510. Silber MH, Shepard JW, Wisbey JA. Pergolide in the management of restless legs syndrome: an extended study. Sleep 1997;20:878–882. Spielman AJ, Nunes J, Glovinsky PB. Insomnia. Neurol Clin 1996;14:513–543. Spielman AJ, Saskin P, Thorpy MJ. Treatment of chronic insomnia by restriction of time in bed. Sleep 1987;10:45–56. Srollo PJ, Rogers RM. Obstructive sleep apnea. N Engl J Med 1996;334:99–104. Sullivan CE, Berthon-Jones M, Issa FG, et al. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1981;1:862–865. Trenkwalder C, Walters AS, Hening W. Periodic limb movements and restless legs syndrome. Neurol Clin 1996;14:629–650. Weitzman ED, Czeisler CA, Coleman RM, et al. Delayed sleep phase syndrome: a chronobiological disorder with sleep-onset insomnia. Arch Gen Psychiatry 1981;38:737–746. Weitzman ED, Czeisler CA, Zimmerman JC, Moore-Ede M. Biological rhythms in man: relationship of a sleep-wake, cortisol, growth hormone and temperature during temporal isolation. In: Martin JB, Reichlin S, Bick K, eds. Neurosecretion and brain peptides. New York: Raven Press, 1981:475–499.

CHAPTER 146. ENDOCRINE DISEASES MERRITT’S NEUROLOGY

SECTION XXII. SYSTEMIC DISEASES AND GENERAL MEDICINE CHAPTER 146. ENDOCRINE DISEASES GARY M. ABRAMS AND EARL A. ZIMMERMAN Pituitary Thyroid Parathyroid Pancreas Adrenal Gonads Suggested Readings

Endocrine secretions have a profound influence on the metabolism of the nervous system. Disturbances of consciousness and cognition, along with other neurologic symptoms, may occur with endocrine diseases. This chapter considers the common structural and secretory endocrine disorders that may cause important neurologic symptoms.

PITUITARY Hypopituitarism Hypofunction of the pituitary may follow damage to the gland by tumors, inflammatory processes, vascular lesions, or trauma. The location of the lesion may be the pituitary itself, the stalk that connects it with the hypothalamus, or the hypothalamus. Destruction of the hypophyseal portal system in the stalk or the median eminence above by a tumor, such as a craniopharyngioma, or sarcoidosis deprives the anterior pituitary of hypothalamic regulatory hormones. In hypothalamic disease, as in pituitary disease, peripheral blood levels of all the anterior pituitary hormones may be reduced except for prolactin (PRL), which is normally under inhibitory control by hypothalamic dopamine. Diabetes insipidus (DI; see later), which may result from disruption of neurosecretory pathways terminating in the posterior pituitary, is also a feature of some structural diseases causing hypopituitarism. Additionally, neurologic manifestations of hypopituitarism are due to “neighborhood effects” resulting from the contiguous location of the pituitary to the visual pathways and cranial nerves controlling ocular motility. Secretory and nonsecretory pituitary tumors are the most common causes of neurologic symptoms of hypopituitarism. The size of the lesion usually determines the extent of neurologic symptoms and the degree of hypopituitarism. Headache and visual loss are common when tumors are large and extend into the suprasellar region in the vicinity of the optic chiasm. Lateral extension of masses may produce syndromes involving structures in the cavernous sinus. Growth of tumors superiorly may compress the hypothalamus and obstruct the cerebrospinal fluid (CSF) pathways to cause hydrocephalus. Vascular lesions of the pituitary may cause dramatic and life-threatening onset of hypopituitarism. In pituitary apoplexy, sudden hemorrhage into a pituitary tumor may cause headache, meningismus, visual loss, oculomotor abnormalities, and alteration in the level of consciousness. Hypopituitarism, including acute adrenal insufficiency, may result from a combination of vascular necrosis and compression by the enlarging pituitary mass. Neurosurgical decompression can improve neurologic and endocrine function. Sheehan syndrome or postpartum necrosis of the pituitary may also cause actue hypopituitarism and local neurologic symptoms. Hypotension or shock from obstetric hemorrhage or infection causes occlusive spasm of pituitary arteries with anoxic-ischemic necrosis of a pituitary gland that has hypertrophied under estrogen stimulation from pregnancy. Acutely, there may be a shocklike syndrome with obtundation, hypotension, tachycardia, and hypoglycemia. Acute and chronic Sheehan syndromes are both characterized by syndromes of anterior pituitary insufficiency, particularly amenorrhea and failure to lactate. Rarely, DI occurs. A neurologic disorder might be suspected if patients complain of lightheadedness or diminished libido. In adults, hypopituitarism is often recognized first by impaired secretion of gonadotropins with irregular menstrual periods or amenorrhea in women or loss of libido, potency, or fertility in men. The skin is often thin, smooth, and dry; the peculiar pallor (alabaster skin) and inability to tan have been related to loss of melanotropic (melanocyte-stimulating hormone) or adrenocorticotropic (ACTH) hormones. Axillary and pubic hair may be sparse, with relatively infrequent facial shaving. Depending on the severity of the decrease of production of ACTH and thyroid-stimulating hormone (TSH), patients may note lethargy, weakness, fatigability, cold intolerance, and constipation. There may be an acute adrenal crisis with nausea, vomiting, hypoglycemia, hypotension, and circulatory collapse, particularly in response to stress. Hypothalamic hypopituitarism may additionally be accompanied by hyperprolactinemia with galactorrhea. Evaluation of patients with pituitary insufficiency caused by an intrasellar or hypothalamic lesion depends on measurement of pituitary hormone levels in the peripheral blood, coupled with functional assessment of the target organs. The basic endocrine evaluation includes thyroid functions (triiodothyronine [T 3], thyroxine [T 4], and TSH), PRL determination, and assessment of adrenal reserve, such as ACTH stimulation for cortisol responsiveness. Pituitary hormone levels must be interpreted in the context of clinical findings. For example, normal gonadotropin levels (follicle-stimulating hormone, luteinizing hormone) may indicate pituitary insufficiency after menopause, when elevated levels would be expected. Elevated levels of gonadotropin or TSH suggest primary gonadal or thyroid failure but, rarely, may be secreted by pituitary tumors. Dynamic tests of pituitary reserve or stimulation tests with synthetic hypothalamic releasing factors are sometimes needed to detect mild hypopituitarism or to distinguish between pituitary and hypothalamic causes of hypopituitarism. Pituitary Tumors Most pituitary tumors are associated with oversecretion of one or more anterior pituitary hormones or their subunits. These tumors produce symptoms related to the metabolic or trophic effect of the secreted hormone. Symptoms may be associated with variable degrees of hypopituitarism, depending on the extent of destruction caused by the tumor. Microadenomas (less than 10 mm) typically cause only symptoms referable to the secreted hormone; macroadenomas (greater than 10 mm) more often cause neural or pituitary dysfunction. Fewer than 10% of microadenomas that secrete PRL show progressive enlargement. The PRL-secreting adenoma, or prolactinoma, is the most common secretory adenoma of the pituitary. It is the most common cause of clinically manifest hyperprolactinemia. In women, there is often a microadenoma with amenorrhea and galactorrhea. In men, the endocrine effects of hyperprolactinemia include impotence, infertility, or, rarely, galactorrhea. In men, prolactinoma is more commonly associated with mass effects of the macroadenoma: headaches, visual-field deficits, and ocular motility problems. The causes of hyperprolactinemia are listed in Table 146.1. In prolactinoma, serum PRL levels may be less than 200 ng/mL and must be distinguished from other causes of hyperprolactinemia. Values above 200 ng/mL, however, are nearly always associated with a prolactinoma. There is a rough positive correlation between the PRL level and the size of the tumor. Several random PRL levels of more than 200 ng/mL establish the diagnosis of prolactinoma; more modest elevations may be caused by drugs, hypothalamic disorders, or hypothyroidism (see Table 146.1). In primary hypothyroidism, thyrotropin-releasing hormone (TRH) secretion is presumably enhanced in response to the low circulating levels of thyroid hormone; TRH is a potent stimulus for PRL release. The pituitary may be enlarged ( Fig. 146.1).

TABLE 146.1. CAUSES OF ELEVATED PROLACTIN LEVELS

FIG. 146.1. Pituitary enlargement in association with primary hypothyroidism is shown on MRI.

Computed tomography (CT) or magnetic resonance imaging (MRI) establishes the diagnosis of sellar or parasellar mass lesions. Prolactinoma does not have specific imaging characteristics; the diagnosis is established by correlation with clinical and laboratory findings. Important diagnostic considerations include carotid aneurysm, inflammatory (e.g., lymphocytic hypophysitis) and hormonal causes of pituitary enlargement (e.g., primary hypothyroidism), and craniopharyngioma. Treatment of hyperprolactinemia is accomplished with dopaminergic agonists, such as bromocriptine mesylate (Parlodel), which usually reduce serum PRL levels to normal, but treatment of the primary pathology (e.g., thyroid failure) may be more appropriate. Return of PRL levels to normal is usually associated with restoration of gonadal function and cessation of galactorrhea. In patients with a prolactinoma, bromocriptine therapy is often accompanied by reduction of tumor size, resolution of neurologic symptoms, and reversal of pituitary insufficiency. Long-term therapy is required because the tumor recurs if bromocriptine is withdrawn. Both microadenomas and macroadenomas can be removed by transsphenoidal adenomectomy. “Cure� rates are correlated with tumor size and PRL level, but surgery is most effective for rapid decompression of the optic nerves or chiasm. Surgical cures have been associated with tumor recurrence rates of 20% to 50% after 5 years. Radiotherapy alone or in combination with surgery or pharmacotherapy is also a therapeutic option. Infertility in women as a result of hyperprolactinemia from a pituitary tumor can be successfully treated with bromocriptine. If pregnancy results, bromocriptine therapy is discontinued, although there has been no evidence of teratogenesis. Estrogen stimulation of prolactinoma during pregnancy causes tumor enlargement, but clinically significant enlargement occurs in only 10% to 15% of macroadenomas. Bromocriptine therapy may be reintroduced with successful control of symptoms; in unusual cases, transsphenoidal surgery can be used. Excessive Growth Hormone and Acromegaly Growth hormone (GH)-secreting pituitary tumors are the most common cause of acromegaly (Fig. 146.2,Fig. 146.3 and Fig. 146.4). When fully developed, acromegaly is easily recognized by excessive skeletal and soft tissue growth. Facial features are coarse, with a large bulbous nose, prominent supraorbital ridges, a protruding mandible, separated teeth, and thick lips. Hands and feet are enlarged, and sweating is frequently increased. These changes are usually slowly progressive. Patients complain of headaches, fatigue, muscular pain, visual disturbances, and impairment of gonadal function. Paresthesia, sometimes with a typical carpal tunnel syndrome, may be present. Generalized arthritis and diabetes mellitus (DM) are frequent components; mortality is increased with acromegaly. In young patients before epiphyseal closure, excessive secretion of GH results in gigantism.

FIG. 146.2. Tufting of the terminal phalanges in acromegaly. (Courtesy of Dr. Juan Taveras.)

FIG. 146.3. Pituitary tumor with ballooning of the sella turcica, prognathism, and enlargement of the skull bones. (Courtesy of Dr. Juan Taveras.)

FIG. 146.4. Prognathism and enlargement of nose in acromegaly secondary to pituitary adenoma. (Courtesy of Dr. E. Herz.)

The neuroendocrine regulation of GH secretion is complex. The major releasing factor is GH-releasing hormone; the major inhibitory agent is somatostatin. GH has a predominantly nocturnal pattern of secretion and is influenced by age and sleep. The diagnosis of acromegaly is most easily established by demonstrating sustained elevation of GH that cannot be suppressed by physiologic stimuli, such as glucose. Paradoxic elevation of GH may occur with glucose or TRH, suggesting hypothalamic dysfunction. Many actions of GH are mediated by insulin-like growth factor I (formerly somatomedin C), and these levels may be elevated with acromegaly. MRI is sensitive in localizing even small GH-secreting adenomas, and surgical removal is the treatment of choice. Cure rate is highest for microadenomas. Surgical decompression and radiation therapy may be the best alternative for larger tumors. Bromocriptine therapy has been useful in some patients. The long-acting somatostatin analog octreotide acetate (Sandostatin) offers specific adjunctive therapy for control of GH secretion. Excessive Adrenocorticotropic Hormone Cushing disease results from hypersecretion of ACTH by a pituitary tumor. Such tumors are usually small and often difficult to detect. Cushing disease may be difficult to distinguish from other causes of hyperadrenalism, such as adrenal adenoma or ectopic ACTH production by neoplasms. The symptoms of Cushing disease include plethoric facies, centripetal obesity, hypertension, DM, amenorrhea, hirsutism, acne, and osteoporosis. Mental status changes or myopathy may be prominent. The differential diagnosis of Cushing syndrome can be challenging. Elevated urinary free cortisol levels and suppressibility of cortisol secretion by dexamethasone are the key tests for establishing the diagnosis of pituitary-dependent Cushing syndrome. Direct assay of plasma ACTH may be helpful; high levels are seen with ectopic ACTH production. The ACTH response to corticotropin-releasing factor may distinguish Cushing disease from other causes of hypercortisolism. Selective sampling of ACTH levels from the petrosal sinuses may help localize an adenoma within the pituitary. MRI with gadolinium is the most sensitive procedure for detecting these tumors. Transsphenoidal adenomectomy is the treatment of choice. In patients treated by bilateral adrenalectomy, an aggressive ACTH-secreting pituitary tumor may develop to cause the hyperpigmentation of Nelson syndrome. The hypothalamus may play a role in the pathogenesis of both Cushing disease and Nelson syndrome. Ketoconazole (Nizoral), an inhibitor of adrenal steroidogenesis, may inhibit the adverse effects of hypercortisolism. The empty sella syndrome rarely poses difficulty in the diagnosis of pituitary tumors. The syndrome develops with herniation of the subarachnoid space through the diaphragma sellae either idiopathically or following destruction or surgical removal of the pituitary gland. Remodeling and enlargement of the bony sella turcica may occur, and the sella may appear enlarged on skull x-ray film. CT or MRI usually clarifies the diagnosis. Pituitary dysfunction is uncommon and, if present, suggests that the apparently empty sella is accompanied by a pituitary tumor. The clinical accompaniments of the empty sella syndrome—obese women with headache—are similar to those of pseudotumor cerebri; chronically increased CSF pressure may precipitate the development of an empty sella. Diabetes Insipidus DI is characterized by excessive excretion of urine and an abnormally large fluid intake caused by impaired production of antidiuretic hormone (arginine vasopressin) in the posterior pituitary. There are two general groups of patients. In primary DI, there is no known lesion in the pituitary or hypothalamus; secondary DI is associated with lesions in the hypothalamus either in the supraoptic and paraventricular nuclei or in their tracts in the medial eminence or upper pituitary stalk. Among the lesions are tumors (e.g., pituitary adenoma, craniopharyngioma, meningioma), aneurysms, xanthomatosis (Schßller-Christian disease), sarcoidosis, trauma, infections, and vascular disease. Primary DI is rare. Heredity is a factor in some patients. Many different mutations have been found in familial autosomal-dominant DI. Autopsy studies of a few cases revealed loss of neurons in the supraoptic and paraventricular nuclei. Secondary or symptomatic DI is more frequent but still uncommon. It may follow head injury and is present in many patients with xanthomatosis and in some patients with tumors or other lesions in the hypothalamic region. The syndrome is evidence of hypothalamic disease. Unless complicated by other symptoms associated with the lesion, the symptoms of DI are limited to polyuria and polydipsia. Eight to 20 L or even more of urine are passed in 24 hours, and there is a comparably high level of water intake. The frequent voiding and excessive water intake may interfere with normal activities and disturb sleep. Usually, however, general health is maintained if this is an isolated deficiency of the hypothalamus. The symptoms and signs in patients with tumors or other lesions in the hypothalamic region are those usually associated with these conditions (see Chapter 58). The laboratory findings are normal, except for a low specific gravity of the urine (1.001 to 1.005) and increased serum osmolality in many patients. The diagnosis is made, based on polyuria and polydipsia. It is distinguished from DM by the glycosuria and high specific gravity of the urine in DM. A large amount of urine may be passed by patients with chronic nephritis but not the large volumes (more than 3 L per day) found in DI; the presence of albumin and casts in the urine and other findings should prevent any confusion in recognizing nephritis. Psychogenic polydipsia must be considered (see below). A rare cause of DI is failure of the kidneys to respond to vasopressin, a hereditary defect in infant boys. Absence of vasopressin is difficult to determine in blood by radioimmunoassay. Therefore, the diagnosis is made by clinical tests that include antidiuretic responses to exogenous vasopressin and dehydration. Administration of five pressor units of aqueous vasopressin rapidly results in a marked decrease in urinary output and an increase in osmolality (specific gravity greater than 1.011) in a patient with DI; there is no response in nephrogenic disease. Psychogenic polydipsia, however, may also show a limited response. In contrast to DI, however, there is a normal response to dehydration in psychogenic polydipsia, although the time required for an increase in urinary concentration may be 12 to 18 hours. Normal subjects dehydrated for 6 to 8 hours reduce urinary volume and concentrate urinary osmolality to roughly twice that of plasma (specific gravity greater than 1.015). Patients with severe DI do not respond and should be observed closely, with care taken to prevent loss of more than 3% of body weight during the test; otherwise, patients may become severely dehydrated. A useful clinical test, devised by Moses and Miller, that combines dehydration with the response to exogenous vasopressin distinguishes these disorders and also partial DI. The diagnosis of DI carries with it the necessity of determining the cause. This means a thorough neurologic examination with particular attention to visual acuity and visual fields. MRI is essential. In DI, the normally bright spot outlining the posterior pituitary gland on MRI may be absent or displaced more proximally in the hypothalamic infundibular stalk (ectopic) ( Fig. 146.5). MRI may also show craniopharyngioma, hamartoma, dysgerminoma, or histiocytosis X.

FIG. 146.5. Hypothalamic hypopituitarism. On MRI, the bright-spot (arrow) appearance of the posterior pituitary gland is missing from its normal location in the sella turcica. Instead, it is located in the lower hypothalamus and upper pituitary stalk in this child with congenital GH and TSH deficiency. Damage to the stalk interrupts the hypophyseal portal system and vasopressin fibers. These fibers regenerate, forming a new, usually smaller, posterior pituitary in this location (ectopic). Such patients may recover from or have partial DI. More proximal lesions in the hypothalamic nuclei and tracts to the vasopressin system do not regenerate. Interruption of the releasing-factor pathways and the portal system results in anterior pituitary deficiencies. (From Zimmerman, 1998; with permission.)

Primary DI may persist for years. DI caused by known lesions in the hypothalamus may also be permanent, but complete remission with reversal of symptoms is not infrequent. Treatment of DI associated with tumors or other remediable hypothalamic lesions is that appropriate to the lesion (surgical removal or radiation therapy). Symptomatic therapy of the DI, if it persists in these cases and in syndromes of unknown cause, is directed toward suppression of diuresis. No effort is made to limit fluid intake. Aqueous vasopressin (Pitressin) can be administered subcutaneously in five pressor-unit doses one to four times daily; it may also be sprayed transnasally in the form of lysine vasopressin or placed high in the nasopharynx on cotton pledgets. Vasopressin tannate in oil injected intramuscularly is slowly absorbed and may be effective for several days. The drug of choice is now the synthetic analog of vasopressin, 1-deamino-8-D-arginine vasopressin (DDAVP). DDAVP has no smooth muscle effects and has no pressor or cardiac complications. It also avoids the nasal irritation associated with administration of lysine vasopressin nasal spray. It is given by nasal instillation or spray and provides good control for about 8 hours. An oral form is also now available; the usual dose is 300 to 600 µg per day in divided doses. Partial DI may require no therapy or may be ameliorated by oral administration of clofibrate or chlorpropamide. Chlorpropamide occasionally causes hypoglycemia and, rarely, water intoxication. Excessive Secretion of Antidiuretic Hormone Inappropriate secretion of antidiuretic hormone may occur with injury to the hypothalamohypophyseal system by head injury, infections, tumors, and other causes. It has been reported in association with lung carcinoma and, occasionally, with other tumors that elaborate vasopressin. It may also be associated with lung diseases that may overstimulate afferent pathways to the hypothalamus or with drugs that cause excess secretion of vasopressin, such as carbamazepine (Tegretol). Other drugs associated with the syndrome include vasopressin and its oxytocin analog, nonsteroidal antiinflammatory medications, antipsychotics, thiazides, and selective serotonin-reuptake inhibitors. Hyponatremia and natriuresis in patients with intracranial disease may also be due to “cerebral salt wasting,” which is now recognized as different from inappropriate secretion of antidiuretic hormones, as it is associated with the loss of salt and hypovolemia and responds to their replacement. The salient features of the syndrome are hyponatremia and hypotonicity of body fluids, excessive urinary excretion of sodium despite hyponatremia, normal renal and adrenal function, absence of edema, hypotension, azotemia or dehydration, and improvement of the electrolyte disturbance and clinical symptoms on restriction of fluid intake. Evidence of cerebral dysfunction includes headache, confusion, somnolence, coma, seizures, transient focal neurologic signs, and an abnormal electroencephalogram (EEG). Mild forms clear with simple fluid restriction. Severe cases with seizures or coma are treated with furosemide (Lasix) diuresis and electrolyte replacement (3% sodium chloride). Caution should be used in rapid correction of hyponatremia to avoid central pontine demyelination. Intravenous urea and normal saline have also been used for rapid correction. In the near future, vasopressin antagonists may be useful in diagnosing and treating this condition.

THYROID Hypothyroidism Thyroid hormone is important in early growth and development, and the neurologic consequences of hypothyroidism depend on the age of the patient when the deficiency begins. Severe thyroid deficiency in utero or early life results in delayed physical and mental development or cretinism. Soon after birth, subcutaneous tissue thickens, the infant's cry becomes hoarse, the tongue enlarges, and the infant has widely spaced eyes, a potbelly, and an umbilical hernia. Anomalies of the cardiac and gastrointestinal system commonly accompany congenital hypothyroidism. If treatment is not prompt, dwarfism and mental deficiency result. Despite early treatment, mild hearing and vestibular dysfunction may persist. Juvenile myxedema is similar to cretinism, with variations that depend on age at onset of thyroid deficiency. The severity of physical and mental retardation is usually less than in infantile myxedema. Precocious puberty also occurs in juvenile hypothyroidism. Enlargement of the sella turcica has been seen in juvenile myxedema and other forms of long-standing hypothyroidism, which can be associated with hyperprolactinemia. Adult myxedema is characterized by lethargy; weakness; slowness of speech; nonpitting edema of the subcutaneous tissues; coarse, pale skin; dry, brittle hair; thick lips; macroglossia; and increased sensitivity to cold environmental temperatures. The neurologic complications of hypothyroidism include headache, disorders of the cranial and peripheral nerves, sensorimotor abnormalities, and changes in cognition and level of consciousness. Cranial nerve abnormalities, other than visual and acoustic nerve problems, are unusual. Decreased vision and hearing loss may occur, and vertigo and tinnitus may be present. Visual and auditory evoked potentials have been reported to be abnormal and respond to treatment. The cause of headache is uncertain. Pseudotumor cerebri has been reported in hypothyroidism in children receiving thyroid replacement therapy. Encephalopathy has recently been associated with euthyroid patients with Hashimoto thyroiditis. Two types of presentations have been noted: a strokelike pattern with mild cognitive impairment and a diffuse progressive type with seizures, psychotic episodes, and dementia. Some patients responded to steroids. A mild polyneuritis is a rare complication characterized mainly by paresthesia in the hands and feet. Entrapment neuropathy of the median nerve (carpal tunnel syndrome) is attributed to the accumulation of acid mucopolysaccharides in the nerve and surrounding tissues. Neuromuscular findings include slowing of voluntary movements and slow relaxation of tendon reflexes, particularly the ankle jerks. Electrically silent mounding of muscles on direct percussion is called myoidema. There may be myopathic weakness. Enlargement of muscles is the Hoffmann syndrome. Neuromuscular symptoms improve with thyroid replacement. In hypothyroid infants, a remarkable generalized enlargement or hypertrophy of muscles constitutes the Kocher-Debré-Sémélaigne syndrome, creating an “infant Hercules” (Fig. 146.6); the muscles decrease in size with replacement therapy.

FIG. 146.6. Enlargement of muscles in Kocher-Debré-Sémélaigne syndrome. (Courtesy of Dr. Arnold Gold.)

Cerebellar syndromes may occur in adults, manifestly ataxic gait. In children, cell loss has been detected in the vermis. Mental status changes may be prominent, with decreased attentiveness, poor concentration, lethargy, and dementia. Psychiatric symptoms—delirium, depression, or frank psychosis (myxedema madness)—may appear, depending on the severity and duration of thyroid deficiency. Myxedema coma may be accompanied by hypothermia, hypotension, and respiratory and metabolic disturbances, and, if untreated, has a high mortality rate. Severe hypothyroidism or myxedema is primarily associated with thyroid failure as opposed to hypothalamic–pituitary disease. The characteristic findings are low circulating T 4 and T3, elevated TSH, and low radioiodine uptake by the thyroid. The CSF protein content increases; values greater than 100 mg/mL are not exceptional. EEG abnormalities include slowing and generalized decrease in amplitude. The treatment of hypothyroidism depends on the severity of the deficiency. Myxedema coma should be treated rapidly with intravenous administration of levothyroxine. In other patients, gradually increasing doses of oral levothyroxine are recommended. Angina pectoris or heart failure can be precipitated by too rapid replacement in adults. In secondary hypothyroidism, thyroid replacement should not be started without concomitant corticosteroid replacement. Prophylactic treatment of cretinism is important in goiter districts, where iodine should be given to all pregnant women. Hyperthyroidism Hyperthyroidism or thyrotoxicosis is associated with an increased metabolic rate, abnormal cardiovascular and autonomic functions, tremor, and myopathy. It may present as atrial fibrillation in older adults. Mental disturbances range from mild irritability to psychosis. When hyperthyroidism is associated with diffuse goiter, ophthalmopathy, and dermopathy, it is termed Graves disease, which is an autoimmune disorder. Immunologic mechanisms probably play an important role in the thyroid, eye, and skin manifestations. Hyperthyroidism may be subtle in older patients, with apathy, myopathy, and cardiovascular disease as the most prominent symptoms. Ocular symptoms are common in thyrotoxicosis. These may be present as infrequent blinking, lid lag, or weakness of convergence and are distinct from the infiltrative ophthalmopathy associated with thyroid disease known as Graves ophthalmopathy. The relationship of the eye disorder to thyroid status is unclear; it may appear in hyperthyroid patients, in euthyroid patients after thyroidectomy, or in euthyroid patients with no history of hyperthyroidism. The pathologic changes are confined to the orbit. There is an increase in the orbital contents with edema, hypertrophy, infiltration, and fibrosis of the extraocular muscles (Fig. 146.7). Onset of symptoms is gradual; exophthalmos is often accompanied by diplopia secondary to paresis of one or more ocular muscles. Both eyes may be simultaneously involved, or the exophthalmos in one eye may precede the other by several months. With advance of the exophthalmos, paresis of the extrinsic muscles of the eye increases until, finally, the eyeball is almost totally fixed. Papilledema sometimes occurs, and ulcerations of the cornea may develop secondary to failure of the lid to protect the eye. The paralysis may involve all of the eye muscles concerned with the movement of the eyes in a particular plane. The symptoms progress rapidly for a few months and may lead to complete ophthalmoplegia. Occasionally, spontaneous improvement occurs; as a rule, the symptoms persist unchanged throughout a patient's life, unless relieved by therapy.

FIG. 146.7. Graves disease. Coronal T1-weighted (A) and axial T2-weighted fat-suppressed (B) MR images of the orbits show bilateral proptosis with enlargement of the medial rectus muscles (left greater than right), the left lateral and inferior rectus muscles, and the right superior rectus muscle. Although the most common pattern of extraocular muscle enlargement is symmetric, asymmetric involvement is not uncommon in Graves disease. This patient had known hyperthyroidism secondary to Graves disease. (Courtesy of Dr. S. Chan.)

Treatment of thyroid ophthalmopathy is controversial. Radiation therapy of the pituitary or thyroid has no effect; neither does surgical removal of the thyroid. Surgical decompression of the orbit is of disputed benefit. Methylcellulose drops, shields, or partial suturing of the lids is recommended to protect the eye. Prednisone is favored by some clinicians. Limb myopathy is common with hyperthyroidism. Thyrotoxic myopathy is characterized by weakness and wasting of the muscles of the pelvic girdle, particularly the iliopsoas, and, to a lesser extent, the muscles of the shoulder girdle. Tendon reflexes are normal or hyperactive, and sensation is normal. Fasciculations or myokymia may be noted. Thyrotoxic myopathy needs to be distinguished from myasthenia gravis (MG), which may accompany hyperthyroidism. Improvement of the myopathy follows effective treatment of the hyperthyroidism. The occurrence of hyperthyroidism and periodic paralysis seems more common in people of Asian ancestry. Thyrotoxic periodic paralysis is similar to hypokalemic periodic paralysis in terms of precipitants and treatment. Propranolol may temporarily reduce the number of attacks. Symptoms disappear when the treated patient becomes euthyroid. There is an association between hyperthyroidism and MG. About 5% of patients with MG have hyperthyroidism. In most patients, MG precedes or occurs simultaneously with the hyperthyroidism. Differential diagnosis between thyrotoxic myopathy and MG is primarily made on the clinical features, response to edrophonium chloride, and electrophysiologic abnormalities of MG. If there are cranial symptoms (dysarthria, dysphagia, ptosis) in a hyperthyroid patient, MG should be suspected. Interpretation of ocular signs may be complicated by thyrotoxic ophthalmopathy, but even with exophthalmos, the presence of ptosis suggests concomitant MG, which may respond to edrophonium.

PARATHYROID Hypoparathyroidism Hypoparathyroidism results in a disturbance of calcium and phosphorus metabolism that is manifested especially by tetany. Hypoparathyroidism may be due to primary deficiency of parathyroid hormone or from lack of peripheral responses as a result of defective action at cellular hormone receptors. Hypoparathyroidism may follow thyroidectomy or may be part of an idiopathic autoimmune syndrome, which sometimes includes primary adrenal failure. In pseudohypoparathyroidism, symptoms of hypocalcemia result from the ineffective action of parathyroid hormone at cellular receptors. Patients have a characteristic habitus, with short stature, stocky physique, rounded face, and shortening of the metacarpal and metatarsal bones. Common clinical features of hypoparathyroidism and pseudohypoparathyroidism include mental deficiency, cataracts, tetany, and seizures ( Table 146.2). Lesions of ectodermally derived tissue include scaly skin, alopecia, or atrophic changes in the nails. Other neurologic manifestations are directly related to the effects of hypocalcemia on the nervous system.

TABLE 146.2. INCIDENCE OF SIGNS AND SYMPTOMS IN PSEUDOHYPOPARATHYROIDISM

Tetany is the most distinctive sign that may be manifested by carpopedal spasm. Latent tetany can be demonstrated by contracture of the facial muscles on tapping the facial nerve in front of the ear ( Chvostek sign), evoking carpal spasm by inducing ischemia in the arm with an inflated blood pressure cuff ( Trousseau sign), or demonstrating the lowered threshold of electrical excitability of the nerve ( Erb sign). Convulsions are a symptom of hypocalcemia regardless of cause. Seizures are usually generalized, tend to be frequent, and respond poorly to anticonvulsant drugs. EEG changes are nonspecific and typically revert to normal with correction of the serum calcium levels. Although hypoparathyroidism is a rare cause of seizures, the diagnosis should be considered when seizures are frequent or bizarre and difficult to control with medication. Intracranial calcifications are common in hypoparathyroidism ( Fig. 146.8). The basal ganglia are the predominant site for calcium deposition, but other regions may be affected. The calcifications are usually not associated with symptoms, but a variety of hypokinetic and hyperkinetic movement disorders have been seen in hypoparathyroidism. Symptoms may be reversible with appropriate treatment.

FIG. 146.8. Pseudohypoparathyroidism. A: Dense areas of calcification are evident in the head of the caudate nucleus (anterior putamen and globus pallidus (middle pair) and pulvinar (posterior). The fine densities in the occipital horns are calcifications in the choroid plexus. B: Calcification is also seen in subcortical areas of the cerebellar hemispheres. (Courtesy of Dr. S.K. Hilal and Dr. M. Mawad.)

Increased intracranial pressure with papilledema has been reported with hypoparathyroidism. The mechanism is unexplained. CSF pressure returns to normal with correction of serum calcium values. Hypoparathyroid myopathy may be accompanied by high values of serum creatine kinase. The diagnosis of hypoparathyroidism is made based on clinical symptoms, hypocalcemia, and low or undetectable plasma parathyroid hormone levels. In pseudohypoparathyroidism, parathyroid hormone levels are elevated. Hypocalcemia may be associated with electrocardiogram changes, including prolongation of the QT interval and T-wave changes. Vitamin D and calcium supplements are the primary therapy for most forms of hypoparathyroidism. They are effective in relieving tetany and in restoring the serum calcium and phosphorus values to normal. Dosage needs to be adjusted to the needs of the patient. Hyperparathyroidism Primary hyperparathyroidism is most commonly due to the oversecretion of parathyroid hormone by a solitary adenoma of the parathyroid glands. The classic syndrome of hyperparathyroidism is hypercalcemia with a combination of renal lithiasis, osteitis, and peptic ulcer disease ( Table 146.3). Modern-day hyperparathyroidism, however, is frequently seen with minimal symptoms.

TABLE 146.3. CLUES TO THE DIAGNOSIS OF HYPERPARATHYROIDISM IN THE FIRST 343 CASES AT THE MASSACHUSETTS GENERAL HOSPITAL

Neuromuscular symptoms include symmetric proximal limb weakness and muscle wasting. Tendon reflexes may be normal or hyperactive. Abnormal movements of the tongue may be seen. Electromyography and muscle biopsy may show evidence of neuropathic disease. Mental status changes include memory loss, irritability, and depression, which improve with return to normal of serum calcium levels. The diagnosis of hyperparathyroidism is now often made by automated blood chemistry tests in routine examinations, before there are clinical signs. Calcium levels are not as elevated as in the past, and the classic neuromuscular symptoms and signs are less frequently observed. Limb weakness, paresthesia, and muscle cramps may be seen. Neurologic abnormalities are now uncommon. Differential diagnosis includes the conditions that cause hypercalcemia, including secondary hyperparathyroidism.

PANCREAS Hypoglycemia The central nervous system (CNS) depends almost entirely on glucose for its metabolism; dysfunction develops rapidly when the amount of glucose in the blood falls below critical levels. Hypoglycemia may be associated with an overdose of insulin in the treatment of DM. Spontaneous hypoglycemia is usually the result of pancreatic hyperinsulinism. Hypersecretion of insulin by the pancreas may be due to a tumor of the islet cells or functional overactivity of these cells. Hypoglycemia may also occur when liver function is impaired or when there is severe damage to the pituitary or adrenal glands. The symptoms of hyperinsulinism are paroxysmal, tending to occur when the blood glucose could be expected to be low (in the morning before breakfast, after a fast, or after heavy exercise). Occasionally, symptoms follow a meal. The duration of symptoms varies from minutes to hours. The severity also varies. There may be only nervousness, anxiety, or tremulousness, which is relieved by the ingestion of food. Severe attacks last for hours, during which the patient may perform automatic activity with complete amnesia for the entire period or seizures may be followed by coma. The frequency of attacks varies from several per day to infrequent episodes. Spontaneous hypoglycemia is occasionally seen in infants. Risk factors include immaturity, low birthweight, or severe illness. Infants of diabetic mothers may exhibit hyperinsulinism. A host of genetic or metabolic defects may cause hypoglycemia, including galactosemia, fructose intolerance, or leucine sensitivity. The symptoms of infantile hypoglycemia are muscular twitching, myoclonic jerks, and seizures. Mental retardation results if the condition is not recognized and adequately treated. Hypoglycemic symptoms can be divided into two groups: autonomic and cerebral. Sympathetic symptoms are present in most patients at the onset of hypoglycemia, usually preceding the more serious cerebral manifestations. Autonomic symptoms include lightheadedness, sweating, nausea, vomiting, pallor, palpitations, precordial oppression, headache, abdominal pain, and hunger. Cerebral symptoms usually occur with the sympathetic phenomena but may be the only manifestations. The most common manifestations are paresthesia, diplopia, and blurred vision, which may be followed by tremor, focal neurologic abnormalities, abnormal behavior, or convulsions. After prolonged, severe hypoglycemia, coma may ensue. Episodic confusion and abnormal behavior may simulate complex partial epilepsy. Although generalized or partial seizures may be a common manifestation of hypoglycemia, hyperinsulinism only rarely causes epilepsy. The neurologic examination is usually normal, except during attacks of hypoglycemia when there may be findings as described. The diagnosis is established by documentation of hypoglycemia during a symptomatic episode, but the timing of the specimen is important because homeostatic mechanisms may return the blood glucose level to normal. The level of blood glucose at which symptoms appear varies from person to person. The EEG shows focal or widespread dysrhythmia during an attack of hypoglycemia and, in some patients, even in the interval between attacks. The diagnosis of hyperinsulinism is made by the paroxysmal appearance of signs of autonomic and cerebral dysfunction in association with a low blood glucose level and an inappropriately high circulating insulin level. Factitious hypoglycemia may be caused by self-administration of insulin or inappropriate use of oral hypoglycemic agents. If it is not possible to obtain a blood specimen during an attack, a diagnostic fast should be considered. After 12 to 14 hours, 80% of patients with islet cell tumors have low glucose and high insulin levels. Longer fasts may be needed. The diagnosis of islet cell adenoma can be difficult; additional endocrine tests and imaging studies may be needed. Hypoglycemia associated with diseases of the liver, adrenal, or pituitary can usually be distinguished by other signs and symptoms of disease in these organs. Early, intensive treatment of acute hypoglycemia is important to prevent CNS damage. Sugar can be given orally in conscious patients. Comatose patients should be given glucose intravenously. Functional hyperinsulinism is treated by diet modifications to avoid excessive insulin secretion by the pancreas. Long-term management of hyperinsulinism is directed at identification and correction of the underlying cause. Diabetes Mellitus DM is a systemic metabolic disorder characterized by hypoinsulinism or peripheral resistance to the action of insulin. Current classification systems broadly divide DM into two types defined by clinical characteristics and pattern of insulin deficiency. Insulin-dependent DM usually occurs in young, nonobese people with insulin deficiency. Noninsulin-dependent DM is generally encountered in older, obese individuals with peripheral resistance to the action of insulin. The neurologic complications in both types of DM are similar; the presence of neurologic disease is roughly correlated with the duration and severity of the disease and is commonly associated with other tissue complications of DM, such as retinopathy and nephropathy. The primary neurologic complication of DM is peripheral neuropathy. This includes mononeuropathies (peripheral and cranial nerves), polyneuropathy, autonomic neuropathy, radiculopathies, and entrapment neuropathy (median, ulnar, and peroneal) (see Chapter 105). The cause of these neuropathies is uncertain; metabolic, vascular, and hypoxic mechanisms have been advanced. Mononeuropathies are attributed to vascular lesions of peripheral nerves. Onset of symptoms is rapid, and pain is common in both mononeuropathies and radiculopathies caused by DM. Common cranial neuropathies involve the oculomotor and abducens nerves and are also due to vascular lesions. Pupillary sparing is common but not invariable because of the pattern of vascular damage to the oculomotor nerve. The prognosis for recovery from mononeuropathy or radiculopathy is good. Symmetric polyneuropathy of DM is the one most commonly encountered. There is typically a gradual onset of symptoms, the character of the symptoms depending on the type of peripheral nerve fiber affected. Numbness and burning are common complaints. Rarely, a patient may present with a Charcot joint or skin ulcer if nociceptive fibers have sustained the predominant damage. Distal sensory loss may be accompanied by weakness; tendon reflexes are usually lost. Diagnosis of diabetic polyneuropathy is aided by nerve conduction studies that show an axonal neuropathy. CSF protein content is usually elevated but may be normal. Autonomic neuropathy may be prominent in DM. Cardiovascular symptoms include arrhythmias or orthostatic hypotension. These may complicate diagnosis and treatment of concurrent myocardial disease. Gastrointestinal motility problems can produce nausea, vomiting, or diarrhea, depending on the severity and distribution of the autonomic neuropathy. Diabetic neuropathy may lead to bladder dysfunction or erectile and ejaculatory failure in men. CNS complications of DM are primarily due to the metabolic derangements of hypoinsulinism and hypoglycemia that may follow administration of insulin. Cerebrovascular disease is an important problem in diabetics because of accelerated atherosclerosis of cerebral blood vessels and related cardiovascular disorders of heart failure, hypertension, and coagulation abnormalities. Hypoinsulinism or insulin resistance may also be a secondary feature of other neurologic disorders (e.g., Friedreich ataxia) and may share common etiologic features with some genetic or familial diseases.

ADRENAL The adrenal gland is composed of two distinct parts: the mesodermally derived cortex and the neuroectodermally derived medulla. The cortex synthesizes and secretes steroid hormones, including mineralocorticoids, glucocorticoids, progestins, estrogens, and androgens. Aldosterone is the principal mineralocorticoid and is

involved in sodium and potassium homeostasis by the kidney. Glucocorticoids play an important role in metabolic and immunologic processes. Under normal circumstances, sex steroid production by the adrenal plays a relatively minor role compared with the contribution by the gonads. The adrenal medulla contains chromaffin cells, the most important source of circulating catecholamines. These catecholamines, epinephrine and norepinephrine, have important cardiovascular, metabolic, and neural effects. Hypoadrenalism Hypofunction of the adrenal cortex is usually due to atrophy of the gland of unknown cause. The gland may be destroyed by tuberculosis, neoplasms, amyloidosis, hemochromatosis, or fungal or human immunodeficiency virus infection. Addison disease, or chronic insufficiency of the adrenal cortex, is characterized by weakness, weight loss, increased pigmentation of the skin, hypotension, behavioral changes, and hypoglycemia. Chronic adrenal insufficiency may be an autoimmune disorder, occasionally in association with other autoimmune disorders, such as MG. It may also be a feature of the abnormal metabolism of long-chain fatty acids in X-linked adrenoleukodystrophy. It may be the only clinical expression in about 10% of cases, including both the cerebral and adrenomyelopathic forms of the disease. In one study, one-third of young males diagnosed with primary adrenal failure (Addison disease) were found to have adrenoleukodystrophy after measurement of long-chain fatty acids. Secondary adrenal insufficiency follows pituitary failure, in which symptoms are less severe because of the relative preservation of mineralocorticoid function, which is not regulated by ACTH. CNS manifestations of Addison disease are common, primarily in cognition and behavior. Psychotic symptoms are rare. Elevated CSF pressure is sometimes accompanied by cerebral edema. Autopsy studies of the brain in Addison disease indicate that glucocorticoids play an important trophic function in the CNS, sustaining the granule cells of the hippocampus. (The loss of hippocampal neurons with adrenocortical hormone receptors in aging is accelerated in Alzheimer disease and appears to be associated with hypercortisolism.) Diagnosis is suggested by the clinical features and is confirmed by low plasma levels of cortisol with elevated ACTH levels (in primary adrenal failure), decreased excretion of 17-hydroxycorticosteroids, and failure of the adrenal cortex to respond to ACTH. Treatment is based on administration of a glucocorticoid preparation and replacement of mineralocorticoids with sodium. The latter may not be needed if the pituitary is the source of adrenal insufficiency. Hyperadrenalism Hyperfunction of the adrenal cortex produces Cushing syndrome, which was attributed by Cushing to a basophilic adenoma of the pituitary. The clinical symptoms of Cushing disease can be reproduced by the administration of corticosteroids. Mental status changes, including difficulties with memory, and myopathy are two of the more common neurologic symptoms. The syndrome of idiopathic intracranial hypertension with headache, nausea, vomiting, and papilledema may occur with reduction or withdrawal of corticosteroids being used as therapy. Symptoms resolve with reinstatement of steroid dosage, and withdrawal is accomplished more gradually. The differential diagnosis of Cushing syndrome may be difficult because there are several potential sources of hyperadrenalism (pituitary, adrenal, or ectopic source of ACTH production) and also because of the effects of common clinical conditions, such as obesity and depression, on the production and suppressibility of corticosteroids. These conditions may make interpretation of diagnostic tests challenging ( Table 146.4). Treatment is directed at control of corticosteroid secretion and the underlying pathology.

TABLE 146.4. EVALUATION OF HYPERCORTISOLISM (CUSHING SYNDROME)

Primary Hyperaldosteronism In 1955, Conn described a syndrome caused by production of aldosterone from a tumor of the adrenal cortex. The clinical manifestations include recurrent attacks of muscular weakness simulating periodic paralysis, tetany, polyuria, hypertension, and a striking imbalance of electrolytes with hypokalemia, hypernatremia, and alkalosis. Paresthesia may occur as a result of the alkalosis. Diagnosis is made by finding increased aldosterone secretion and excretion, with reduced activity of plasma renin. Treatment involves removal of the adrenal tumor coupled with use of an aldosterone inhibitor. Familial glucocorticoid-remediable aldosteronism may be associated with intracranial aneurysms at about the same frequency as in inherited polycystic kidney disease. Bartter syndrome is a related disorder characterized by hyperreninemia, hyperaldosteronism, and hypokalemic alkalosis without hypertension or peripheral edema. Hypomagnesemia is often present, and treatment with potassium chloride and magnesium may restore potassium levels. Recent genetic studies have begun to define the nature of the ion channel defects in these renal tubular disorders of the Bartter-like syndromes, including the Gitelman variant, which also has hypocalciuria. Pheochromocytoma Hyperfunction of the adrenal medulla as a result of a tumor of the chromaffin cells is accompanied by increased secretion of catecholamines. The tumor may be familial, alone or in conjunction with other endocrine tumors. Pheochromocytoma may be seen with neurofibromatosis, von Hippel-Lindau disease, ataxia-telangiectasia, or Sturge-Weber syndrome, consistent with the neuroectodermal origin of the adrenal medulla. Familial pheochromocytoma is associated with bilateral adrenal tumors, while sporadic cases are nearly always unilateral. Hypertension of a moderate or severe degree is characteristic. The hypertension may be paroxysmal or sustained and is associated with palpitations, episodic hyperhidrosis, headaches, and other nonspecific systemic symptoms, such as nausea, emesis, or diarrhea. Anxiety attacks are common. Death may result from cerebral hemorrhage, pulmonary edema, or cardiac failure in one of the acute attacks or as a result of one of these complications from sustained hypertension. Diagnosis and treatment are directed at establishing the increased excretion of catecholamine metabolites in the urine and localization and removal of the tumor. The tumor may occur in sites other than the adrenal; imaging techniques are helpful in localization.

GONADS Neurologic disorders associated with diseases of the ovary or testes are not well-defined. However, the primary secretions of the gonads—estrogens, progestins, and androgens—have been reported to influence a variety of neurologic symptoms. Cyclic or phasic fluctuations in gonadal secretion (during the menstrual cycle or pregnancy) have been linked to common problems such as migraine headache and epilepsy and to less common disorders such as porphyria. Therapeutic use of estrogen–progestin preparations in oral contraceptives poses potential risks for neurologic complications, notably cerebrovascular disease. Although migraine has been frequently reported in association with menstrual periods, the true incidence of catamenial migraine is difficult to determine. Somerville (1975) demonstrated that some women have headaches precipitated by the rapid decline in circulating estradiol during the late-luteal phase and that these

headaches can be prevented by administration of estrogen, but not progesterone. The mechanism of action is not clear, but the role of estrogens in catamenial migraine may explain the onset and variation of headaches during pregnancy or with the use of oral contraceptives. Although long-term estrogen treatment is said to be useful in catamenial migraine, this is not practical for most women. Premenstrual administration of prostaglandin inhibitors may be helpful. Discontinuation of estrogen-containing oral contraceptives usually relieves the symptoms. The relation of oral contraceptive use and the occurrence of stroke has been a controversial topic. Numerous epidemiologic studies indicate that age greater than 35 years and cigarette smoking increase the risk of ischemic and hemorrhagic stroke in women using oral contraceptives. Contraceptive preparations with lower doses of synthetic estrogens are thought to be safest. Hypercoagulability associated with estrogens is thought to be an important etiologic factor in arterial strokes, as well as in the syndromes of cerebral venous thrombosis that may complicate pregnancy or contraceptive use. Direct effects of sex steroids on the CNS may explain the effects of estrogens (epileptogenic) and progestins (anticonvulsant) on seizure frequency in epilepsy. Oral contraceptives or pregnancy may unmask latent chorea (chorea gravidarum), and menstrual cyclicity or exogenous administration of estrogen has been reported to be associated with functional changes in parkinsonism, myoclonus, and other movement disorders. Sex steroid receptors on CNS neoplasms may influence growth characteristics of the tumor. Clinically evident enlargement of meningioma may be seen with pregnancy. The developmental effects of estrogens and androgens on the brain are extensive. Many behavioral characteristics, sexual and otherwise, may be directed by the influence of these hormones on the morphology of neurons and the creation of neural networks. Studies of cognitive function in hypothalamic hypogonadism emphasize the linkages between endocrine and neural function. Clinical interventions may be forthcoming. SUGGESTED READINGS Pituitary Abrams GM, Schipper HM. Neuroendocrine syndromes of the hypothalamus. Neurol Clin 1986;4:769–782. Barzilay J, Heatley GJ, Cushing GW. Benign and malignant tumors in patients with acromegaly. Arch Intern Med 1991;151:1629–1632. Bauer HG. Endocrine and other clinical manifestations of hypothalamic disease: a survey of 60 cases with autopsies. J Clin Endocrinol Metab 1954;14:13–31. Brada M, Ford D, Ashley S, et al. Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. BMJ 1992;304:1343–1346. Brunner HO, Ollen BJ. Precocious puberty in boys. N Eng J Med 1999;341. Chan TY. Drug-induced syndrome of inappropriate antidiuretic hormone secretion: causes, diagnosis and management. Drugs Aging 1998;11:27–44. Chanson P, Weinbraub BD, Harris AG. Octreotide therapy for thyroid-stimulating hormone-secreting pituitary adenomas: a follow-up of 52 patients. Ann Intern Med 1993;119:236–240. Damaraju SC, Rajshekhar V, Chandy MJ. Validation study of a central venous pressure-based protocol for the management of neurosurgical patients with hypontremia and natriuresis. Neurosurgery 1997;40: 312–317. Dash RJ, Gupta V, Suri S. Sheehan's syndrome: clinical profile, pituitary hormone responses and computed sellar tomography. Aust N Z J Med 1993;23:26–31. DeSouza B, Brunetti A, Fulham MJ, et al. Pituitary microadenomas: a PET Study. Radiology 1990;177:39–44. Doppmen JL, Frank JA, Dwyer AJ, et al. Gadolinium DTPA-enhanced MR imaging of ACTH-secreting microadenomas of the pituitary gland. J Comput Assist Tomogr 1988;12:728–735. Harrigan MR. Cerebral salt wasting syndrome: a review. Neurosurgery 1996;38:152–160. Hartog M, Hull MG. Hyperprolactinaemia. BMJ 1988;297:701–702. Hirshberg B, Ben-Yehuda A. The syndrome of inappropriate antidiuretic hormone secretion in the elderly. Am J Med 1997;103:270–273. Hua F, Asati R, Miki Y, et al. Differentiation of suprasellar non-neoplastic cysts from cystic neoplasms by Gd-DTPA MRI. J Comput Asst Tomogr 1992;16:744–749. Khaleeli A, Lerg RD, Edwards RHT, et al. The neuromuscular features of acromegaly: a clinical and pathological study. J Neurol Neurosurg Psychiatry 1984;47:1009–1015. Kivela T, Pelkonen R, Heiskanen O. Diabetes indipidus and blindness caused by a suprasellar tumor: Pieter Pauw's observations from the 16th century. JAMA 1998;279:48–50. Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases including 48 with pituitary tumors. N Engl J Med 1977;296:589–600. Klibanski A, Zervas NT. Diagnosis and management of hormone-secreting pituitary adenomas. N Engl J Med 1991;342:822–830. Kovacs K. Necrosis of anterior pituitary in humans. I Neuroendocrinology 1969;4:170–199. Kovacs K. Necrosis of anterior pituitary in humans. II. Neuroendocrinology 1969;4:201–241. Lam KS, Wat MS, Choi KL, Ip TP, Pang RW, Kumana CR. Pharmacokinetics, pharmacodynamics, long-term efficacy and safety of oral 1-deamino-8-D-arginine vasopressin in adult patients with central diabetes insipidus. Br J Clin Pharmacol 1996;42:379–385. Lee BCP, Deck MDF. Sellar and juxtasellar lesion detection with MR. Radiology 1985;157:143–147. Loli P, Berselli ME, Tagliaferri M. Use of ketoconazole in the treatment of Cushing's syndrome. J Clin Endocrinol Metab 1986;63:1365–1371. Mantello MT, Schwartz RB, Jones KM, et al. Imaging of neurologic complications associated with pregnancy. AJR 1993;160:843–847. Martin JB, Reichlin S. Clinical neuroendocrinology, 2nd ed. Philadelphia: FA Davis Co, 1987. Melmed S. Acromegaly. N Engl J Med 1990;322:966–977. Molitch ME. Pituitary incidentalomas. Endocrinol Metab Clin North Am 1997;26;724–740. Molitch ME, Thorner MO, Merritt C. Management of prolactinomas. J Clin Endocrinol Metab 1997;26:996–1000. Moses AM, Notman DD. Diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Adv Intern Med 1982;27:73–100. Newman CB, Melmed S, Snyder PJ, et al. Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial of 105 patients—a clinical research center study. Endocrinol Metab 1995;80:2668–2675. Erratum: J Clin Endocrinol Metab 1995;80:3238.

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insipidus. Am J Hum Genet 1996;58:107–117. Robinson DB, Michaels RD. Empty sella resulting from the spontaneous resolution of a pituitary macroadenoma. Arch Intern Med 1992;152:1920–1923. Ruitshauser J, Boni-Schnetzler M, Boni J, et al. A novel point mutation in the translation initiation codon of the pre-pro-vasopressin-neurophysin II gene: cosegregation with morphological abnormalities and clinical aymptoms in autosomal dominant neurohypophyseal diabetes insipidus. J Clin Endocrinol Metab 1996;81:192–198. Saito T, Ishikawa S, Abe K, et al. Acute aquaresis by the nonpeptide arginine vasopressin (AVP) antagonist OPC-31260 improves hyponatremia in patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Clin Endocrinol Metab 1997;82:1054–1057. Singer I, Oster JR, Fishman LM. The management of diabetes insipidus in adults. Arch Intern Med 1997;157:1293–1301. Styne D, Grumbach MM, Kaplan SL, et al. Treatment of Cushing's disease in childhood and adolescence by transsphenoidal microadenomectoma. N Engl J Med 1984;310:889–893. Tanigawa K, Yamashita S, Nagataki S. Acute quadriplegia in acromegaly. Ann Intern Med 1992;117:94–95. Vidal E, Cevallos R, Vidal J, et al. Twelve cases of pituitary apoplexy. Arch Intern Med 1992;152:1893–1899. Woo MH, Smythe MA. Association of SIADH with selective serotonin reuptake inhibitors. Ann Pharmacother 1997;31:108–110. Young WF, Scheithauer BW, Kovacs KT, et al. Gonadotropin adenoma of the pituitary gland: a clinicopathologic analysis of 100 cases Mayo Clin Proc 1996;71:649–656. Zimmerman EA. Neuroendocrine disorders. In: Rosenberg R, ed. Atlas of clinical neurology. Philadelphia: Current Medicine, 1998:3.1–3.15. Thyroid Anasti JN, Flack MR, Nelson LM, et al. A potential novel mechanism for precocious puberty in juvenile hypothyroidism. J Clin Endocrinol Metab 1995;80:276–279. Atchison JA, Lee PA, Albright AL. Reversible suprasellar pituitary mass secondary to hypothyroidism. JAMA 1989;262:3175–3177. Barnard RD, Campbell MJ, McDonald MI. Pathologic findings in a case of hypothyroidism with ataxia. J Neurol Neurosurg Psychiatry 1971;34:755–760. Beghi E, Delodovici ML, Bogliun G, et al. Hypothyroidism and polyneuropathy. J Neurol Neurosurg Psychiatry 1989;52:1420–1423. Bellman SC, Davies A, Fuggle PW, et al. Mild impairment of neuro-otological function in early treated congenital hypothyroidism.

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Tallstedt L, Lundell G, Torring O, et al. Occurrence of ophthalmopathy after treatment for Graves' hyperthyroidism. N Engl J Med 1992;326:1733–1738. Trobe JD, Glaser JS, Laflamme P. Dysthyroid optic neuropathy. Arch Ophthalmol 1978;96:1199–1209. Trokel SL, Hilal SK. Recognition and differential diagnosis of enlarged extraocular muscles in computed tomography. Am J Ophthalmol 1979;87:503–512. Van Dop C, Conte FA, Koch TK. Pseudotumor cerebri with initiation of levothyroxine therapy for juvenile hypothyroidism. N Engl J Med 1983;308:1076–1080. Wise MP, Blunt S, Lane RJ. Neurological presentations of hypothyroidism: the importance of slow-relaxing reflexes. J R Soc Med 1995;88:272–274. Wong PS, Hee FL, Lip GY. Atrial fibrillation and the thyroid. Heart 1997;78:623–624. Parathyroid Abe S, Tojo K, Ichida K, et al. A rare case of idiopathic hypoparathyroidism with varied neurological manifestations. Intern Med 1996;35:129–134. Burch WM, Posillico JT. Hypoparathyroidism after I-131 therapy with subsequent return of parathyroid function. J Clin Endocrinol Metab 1983;57:398–401. Cogan MG, Covey CM, Arieff AI, et al. Central nervous system manifestations of hyperparathyroidism. Am J Med 1978;65:563–630. Cope O. The story of hyperparathyroidism at the Massachusetts General Hospital. N Engl J Med 1966;274:1174–1182. Mallette LE, Bilezikian JP, Heath DA, Aurback GD. Primary hyperparathyroidism: clinical and biochemical features. Medicine (Baltimore) 1974;53:127–146. Mallette LE, Patten BM, Engel WK. Neuromuscular disease in secondary hyperparathyroidism. Ann Intern Med 1975;82:474–483. McKinney AS. Idiopathic hypoparathyroidism presenting as chorea. Neurology 1962;12:485–491. Muenter MD, Whisnant JP. Basal ganglia calcification, hypoparathyroidism and extrapyramidal motor manifestations. Neurology 1968;18:1075–1083. Nusynowitz ML, Frame B, Kolb PO. The spectrum of hypoparathyroid states. Medicine 1976;55:105–119. Patten BM, Bilezikian JP, Mallette LE, et al. Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 1974;80:182–194. Roisin AJ. Ectopic calcification around joints of paralyzed limbs in hemiplegia, diffuse brain damage and other neurological diseases. Ann Rheum Dis 1975;34:499–505. Spiegel AM, Weinstein LS. Pseudohypoparathyroidism. In: Scriver CR, Beaudet AL, Sly WS, Valle, D, eds. The metabolic and molecular basis of inherited disease, 5th ed. New York: McGraw-Hill 1995;3073–3089. Tabaee-Zadeh MJ, Frame B, Kappahn K. Kinesiogenic choreoathetosis and idiopathic hypoparathyroidism. N Engl J Med 1972;286:762–763. Turken SA, Cafferty M, Silverberg S, et al. Neuromuscular involvement in mild asymptomatic primary hyperparathyroidism.

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CHAPTER 147. HEMATOLOGIC AND RELATED DISEASES MERRITT’S NEUROLOGY

CHAPTER 147. HEMATOLOGIC AND RELATED DISEASES KYRIAKOS P. PAPADOPOULOS AND CASILDA M. BALMACEDA Erythrocyte Disorders Platelet Disorders Blood Cell Dyscrasias Coagulation Disorders Cerebrovascular Complications of Cancer Other Disorders Suggested Readings

ERYTHROCYTE DISORDERS Sickle Cell Disease Sickle hemoglobin (HbS) is characterized by an abnormal b-globin chain in which the sixth amino acid valine is substituted by glutamic acid. The disorder is prevalent in blacks of African descent. Individuals with sickle cell anemia are homozygous for HbS (SS); their hemoglobin contains two normal alpha chains and two abnormal beta chains. In the deoxygenated condition, the hemoglobin tetramer polarizes and the cell shape becomes distorted, resulting in rigid red blood cells. Cell damage leads to hemolytic anemia and to occlusion of vessels in the kidney, bone, lung, liver, heart, spleen, peripheral nerves, and brain. Other common sickle genotypes having neurologic sequelae include sickle cell-hemoglobin C (SC) disease and the sickle-b-thalassemia syndromes. Stroke is the second leading cause of death after infection, occurring in 7% to 15% of homozygous children. According to the Cooperative Study of Sickle Cell Disease, the incidence of first cerebrovascular accident is 0.6 per 100 patient years for SS, 0.15 per 100 patient years for SC, and 0.08 per 100 patient years for sickle-b-thalassemia. Isolated case reports describe patients with sickle cell trait as having otherwise unexplained strokes, particularly with subcortical infarction. In large series, however, the incidence of cerebrovascular disease in these patients was the same as for the general African-American population. The risk of stroke in children with sickle cell disease is 250 to 400 times more than in the general population. The cumulative risk of stroke by age 45 is about 24% for SS patients and 10% for SC patients. About 60% of strokes are ischemic; the others are hemorrhagic. Mean age at development of cerebral infarcts is 8 years, but they also occur in older patients, whereas hemorrhage is most frequent in patients between ages 20 and 29 years. Most strokes do not occur at the time of painful crisis, dehydration, fever, or infection. Preceding transient ischemic attacks (TIAs) are uncommon. Low hemoglobin concentration and high leukocyte count are risk factors for hemorrhagic stroke. In ischemic stroke, the primary vascular lesion is occlusive disease of the intracranial portion of the distal internal carotid, proximal middle cerebral, or anterior cerebral artery. Vascular damage includes segmental thickening caused by intimal proliferation of fibroblasts and smooth muscle. Both large and small vessels are affected. Many infarcts occur in watershed distributions, attributed to large vessel disease compounded by anemia and hemodynamic insufficiency or hypoperfusion in the border zone. Cerebral blood flow studies show hyperemia, but the vessels fail to dilate further with hypercapneic stimulation. The vessels may be maximally dilated, and a drop in perfusion cannot be compensated by further vasodilatation. Therefore, damage is attributed to a combination of both perfusion failure and intraarterial embolization. Strokes occur when the hypoperfusion exceeds adaptive mechanisms and further vasodilatation is not possible. The second mechanism of stroke is the resistance to the passage of sickle cells in the small distal penetrating arterioles, with rigid red cell sludge and stasis. Small vessels in the distal fields are the most vulnerable because the cells adhere and are trapped in the areas of already decreased perfusion. In large vessels, damage from the abnormal red cells leads to large vessel hyperplasia and thrombus formation at the bifurcation. Subarachnoid hemorrhage is more common in children, whereas intraparenchymal hemorrhage is seen in adults. The causes of hemorrhage include aneurysmal dilatation of large vessels, moyamoya-like disease with fragile collateral circulation, and hemorrhage into infarcted tissue. Aneurysms are found at the bifurcation points of large vessels, which are also the sites of endothelial hyperplasia. The chronically abnormal rheology is thought to weaken the mural integrity of the blood vessel walls, leading to aneurysmal dilatation and rupture. Magnetic resonance imaging (MRI) shows infarcts, often asymptomatic, in small vessel territory in 28% and large vessel territory in 72%. Angiography shows a high incidence of large vessel pathology, but intraarterial injections increase the risk of stroke or sickle cell crisis. Preparation for angiography includes transfusions to reduce the HbS concentration to less than 30%. An 11% incidence of stenosis has been shown by MR angiography in children younger than 4 years. Carotid and transcranial Doppler studies are sensitive in detecting arterial vasculopathy. Positron emission tomography shows higher regional blood flow in sickle cell patients than in age-matched control subjects. The incidence of stroke recurrence is lower in patients who receive transfusions regularly. In those who receive chronic transfusion therapy, 10% have recurrent stroke; without transfusions, stroke recurrence is 46% to 90% usually within 3 years of the first event. The goal of transfusion with HbA cells is an HbS concentration less than 30% of the total hemoglobin. The transfusion regimen is maintained for 2 to 4 years; some advocate long-term transfusion indefinitely. Younger patients with strokes tend to have residual symptoms, and survivors may be neuropsychologically impaired. Cognitive abnormalities occur even in the absence of MRI abnormalities or clinical stroke, and the IQ may be lower than in asymptomatic carriers. Transcranial Doppler ultrasonography identifies SS children at risk of stroke. Elevated time-averaged mean blood flow velocity in the intracranial internal carotid or middle cerebral artery is associated with a 46% risk of cerebral infarction in 39 months. The randomized Stroke Prevention Trial in Sickle Cell Anemia of prophylactic transfusion for prevention of first stroke in patients with abnormal transcranial Doppler ultrasonography showed a 92% decrease in stroke occurrence. Ultimately, the benefits of long-term transfusion in preventing a first or recurrent stroke must be weighed against the complications of transfusions, including alloimmunization, infection, and iron overload. Other therapies include efforts to increase the concentration of fetal hemoglobin with butyric acid and hydroxyurea and bone marrow transplantation. The incidence of seizures varies from 6% to 12%. Seizures may accompany strokes or meningitis and may be precipitated by dehydration or by commonly used medications such as meperidine. Computed tomography (CT) or MRI only rarely shows a lesion responsible for the seizures. Infections are common for several reasons: splenic infarction, local tissue hypoxia, or abnormalities in complement activation. Bacterial meningitis, most commonly caused by streptococcus pneumonia, cerebral abscesses, and tuberculomas, have all been seen. Headache is reported in 28% of children. It is often not associated with sickle cell crisis, intracerebral hemorrhage, skull infarction, or osteomyelitis. An acute or chronic progressive encephalopathy may be seen. In individuals with SC disease, visual disturbances due to retinopathy is seen in 58% and hearing loss is more common than with SS disease. Myelopathy is rare but may follow spinal cord infarction or spinal cord compression by extramedullary hematopoiesis. Peripheral neuropathy is also unusual but may manifest as an acute mononeuropathy affecting the mental, peroneal, or multiple cranial nerves. Thalassemia b-Thalassemia is an inherited hemolytic anemia resulting from defective b-globin chain synthesis. It usually occurs in individuals of Mediterranean or Asian extraction and is characterized by hepatosplenomegaly, skin changes, and growth retardation. Transient dizziness and visual blurring are seen in up to 20%. The transient symptoms characteristically occur between transfusions and improve when the anemia is ameliorated. Other manifestations are headaches (13%) and seizures (13%). Twenty percent develop a mild peripheral, mainly motor, neuropathy in the second decade of life. A syndrome consisting of myalgia, paroxysmal muscle

weakness, and myopathic electromyography changes has also been reported. Stroke is rare, seen in those receiving multiple transfusions and attributed to thrombocytosis after splenectomy or to intravascular hemolysis. Spinal cord and cauda equina compression resulting from extramedullary hematopoiesis responds to transfusion and radiation therapy. Skull x-ray films show characteristic abnormalities ( Fig. 147.1).

FIG. 147.1. Skull in chronic hemolytic anemia (thalassemia). A: Thickening of vault. B: Magnified view of “hair-on-end� appearance as a result of extramedullary hematopoiesis in the widened diploic space. (Courtesy of Dr. William H. McAlister.)

Polycythemia Polycythemia, an abnormal increase in the number of circulating erythrocytes, occurs with the myeloproliferative disorder polycythemia vera or may be secondary to pulmonary hypoventilation or high altitude. Rarely, cerebellar hemangioblastoma or hepatoma causes polycythemia by elaborating erythropoietin. Blood viscosity increases and may cause headache. Other symptoms, occurring in 50% to 80% of patients, include dizziness, tinnitus, visual disturbances, and cognitive impairment. These symptoms respond to reduction in the red blood cell count by phlebotomy or chemotherapy. Circulation returns to normal as the hematocrit is reduced to 40% to 45% and blood viscosity is lowered. Hyperviscosity also predisposes to large and small vessel cerebral infarction and may accelerate atherosclerosis. In polycythemia vera, transient ischemic attacks and ischemic stroke account for 70% of arterial thromboses. Aseptic cavernous sinus thrombosis is rare. Both thrombocytosis and a platelet disorder that leads to a hemorrhagic diathesis may be seen. Cerebral thrombosis is fatal in 15% and cerebral hemorrhage in 3% of patients with this condition. Patients may complain of limb pain or paresthesias that are attributed to ischemia and often recede promptly with phlebotomy. Peripheral neuropathy, predominantly sensory axonal, occurs in up to 46% of patients.

PLATELET DISORDERS Essential Thrombocytosis (Thrombocythemia) Essential thrombocytosis is an acquired myeloproliferative disorder characterized by splenomegaly, elevated platelet count, platelet dysfunction, and a predisposition to both hemorrhage and thrombosis involving the arterial and venous circulation. The Polycythemia Vera Study Group established specific criteria for diagnosis: persistent thrombocytosis (platelet count greater than 600,000/mm 3), megakaryocytic hyperplasia in the bone marrow, absence of the Philadelphia chromosome, marrow fibrosis or myeloid metaplasia, and absence of increased erythrocyte mass in the presence of normal iron stores. Other causes of secondary thrombocytosis, such as underlying systemic illness, iron deficiency, and neoplasia, must be excluded. Onset is in the sixth or seventh decade of life, and the mean platelet count at diagnosis is 1 Ă— 10 6/mm3. Neurologic episodes occur in about 30% of patients. The most common neurologic manifestation is headache, followed by paresthesias, TIAs, cerebral infarction, and seizures. Bleeding complications are mild, primarily gastrointestinal, and rarely of neurologic consequence. It is not known whether the qualitative platelet abnormalities or the thrombocytosis is responsible for symptoms. Most neurologic episodes occur at onset or with hematologic relapse. Microvasculature occlusion may be responsible. Some authorities recommend treatment with aspirin or dipyridamole in asymptomatic patients. After serious thromboembolic events, urgent platelet pheresis is recommended. Hydroxyurea and anagralide are effective in reducing the platelet count. The clinician should check the platelet count in all patients with ischemic episodes and in those with headaches, visual symptoms, or paresthesias. Thrombotic Thrombocytopenic Purpura Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, nephropathy, and neurologic manifestations. The mean age at onset is 40 years as an acute process that causes damage by microvasculature occlusion, with anoxic injury, in kidney and brain. Seventy percent of the patients have neurologic symptoms, most commonly as hemiparesis in 25% or an organic mental syndrome in 50%. Aphasia, hemisensory loss, seizures, ataxia, and field defects are less common. The symptoms are transient, usually lasting less than 48 hours. Permanent neurologic symptoms occur in a few patients. Hemiparesis tends to improve more readily than mental status changes. Neuropathologic changes may or may not be symptomatic. Hyaline thrombotic occlusion of arterioles and capillaries without inflammation results in small infarcts and petechial hemorrhages, usually in the gray matter ( Fig. 147.2). Rarely, there is large vessel occlusion or subarachnoid or subdural hemorrhage. Symptoms are attributed to episodes of focal ischemia. The majority of cases of TTP are associated with an acquired IgG inhibitor of von Willebrand factor cleaving protease. Ticlopidine therapy has been associated with TTP.

FIG. 147.2. Thrombotic thrombocytopenic purpura. Occlusion of small cerebral vessels by amorphous hyaline material. (Courtesy of Dr. Abner Wolf.)

Normal findings on CT suggest the possibility of full clinical recovery in 70% of the patients. If CT findings are abnormal, death or permanent neurologic disorder follows in 80% of the patients. Cerebrospinal fluid (CSF) is usually normal except for elevated protein content. Treatment includes chemotherapy, steroids, or plasma exchange, leading to remission in 75%. Dialysis is used to treat the renal dysfunction, and heparin may be used but may cause cerebral hemorrhage. Death from neurologic complications in TTP is not as common as from other organ failure. Malaria may be mimicked by

TTP. Heparin-induced Thrombocytopenia Heparin-induced thrombocytopenia is an immune-mediated disorder typically occurring 5 or more days after initiation of therapy in a patient not previously exposed to heparin. The pathogenic IgG immunoglobulin binds a heparin/platelet factor 4 complex, causing platelet activation. This prothrombotic state is characterized by a 50% or greater decrease in platelet count, and up to 50% of patients develop thrombotic complications, including cerebral infarction in 3% to 4% of all patients. Heparin therapy should be discontinued immediately, and warfarin withheld until platelets recover to avoid venous limb gangrene. Danaparoid, a heparinoid mixture of anticoagulant glycosaminoglycans, is an effective therapy.

BLOOD CELL DYSCRASIAS Leukemia All forms of leukemia may lead indirectly to neurologic symptoms because of complications of therapy, especially hemorrhage due to thrombocytopenia or infection due to low white blood cell counts. With markedly elevated white blood counts (greater than 150,000/mm 3), leukostasis may occlude cerebral blood vessels. Furthermore, leukemic blasts can infiltrate the arteriole endothelial walls to cause hemorrhage. Patients at risk for central nervous system (CNS) leukostasis are treated with emergency leukapheresis to lower the blast count. Leukemic nodules may also predispose to intracerebral hemorrhage, which may be fatal. Direct CNS manifestations of leukemia depend on the specific cell type involved. In acute myelogenous leukemias, CNS involvement is uncommonly the first manifestation. Patients at risk for CNS symptoms include those with high circulating blast counts and the monocytic M4 subtype. The M4 Eo variant in particular, with eosinophilia and the inv(16)(p13q22) inversion of chromosome 16, is commonly associated with leptomeningeal and intracerebral lesions. Cranial nerve palsies due to infiltration are rare in acute myelogenous leukemias, mostly involving the fifth and seventh nerves. Unless CNS symptoms require therapy, lumbar puncture is deferred until the peripheral blood is cleared of blast cells to avoid possible CNS seeding. Acute myelogenous leukemias may affect the CNS in the form of a chloroma (or granulocytic sarcoma), a local collection of blast cells that appears green because of a high myeloperoxidase content. Chloromas may be seen 1 year before the overt onset of acute leukemia, originating in subperiosteal sites in bone and characteristically causing unilateral or bilateral exophthalmos simulating orbital lymphoma. Other sites include the cranial and facial bones, commonly causing facial palsy, and the spinal epidural space, causing paraplegia. Acute lymphocytic leukemia involves the CNS in 5% to 10% of patients at time of diagnosis, often without symptoms. Risk factors for CNS leukemia include a high lymphocyte count, T-ALL phenotype, and L3 (Burkitt) morphology. Without prophylactic chemotherapy directed at the CNS, the CNS relapse rate is up to 50%. Leukemic cells invade the meninges; tumor spreads from the bone marrow centripetally along arachnoid veins, giving rise to leptomeningeal metastases. The infiltrate spreads along the arachnoid into the Virchow-Robin spaces, secondarily affecting the adventitia of arterioles. With leptomeningeal seeding, the CSF cytology is invariably abnormal. As with meningeal involvement by carcinoma, all levels of the CNS are affected, with cranial nerve signs (IIIrd, IVth, VIth, and VIIth), seizures, cognitive deficit, or hydrocephalus. Uncommon syndromes with leukemic infiltration include hypothalamic infiltration with hyperphagia and obesity or diabetes insipidus. The prognosis for acute leukemia was poor before therapy directed at eradication of leptomeningeal metastasis was introduced in the early 1960s. The CNS is a sanctuary because most systemic antileukemic chemotherapy does not achieve adequate therapeutic CSF levels to eradicate tumor cells. Surviving leukemia cells in the CSF may reenter the marrow and reestablish the disease. With combined craniospinal radiation and intrathecal chemotherapy (methotrexate or cytosine arabinoside), the incidence of CNS relapse has declined dramatically, with improved quality of life and survival. Although cranial irradiation is neurotoxic (see Chapter 71), intrathecal chemotherapy is less satisfactory. Current protocols attempt to eliminate spinal radiation, reduce the cranial dose, and treat more intensively with intrathecal medications. Bone marrow transplantation in patients with leukemia may be complicated by posttransplant leukoencephalopathy. In contrast, chronic leukemia rarely affects the CNS. When chronic myelogenous leukemia enters into blast crisis, leptomeningeal metastases may occur. Chronic lymphocytic leukemia is common but only exceptionally invades the meninges or brain, most often with late-stage disease. Plasma Cell Dyscrasias Several conditions, both neoplastic and nonneoplastic, are characterized by the appearance of monoclonal gamma globulins (M protein) in the serum. The monoclonal proteins are produced by cells of B-cell lineage, and the associated plasma cell dyscrasias include multiple myeloma, Waldenstrรถm macroglobulinemia (with IgM paraprotein), and amyloidosis. If monoclonal gammopathy is the only manifestation, this is termed monoclonal gammopathy of unknown significance (MGUS). MGUS may persist in asymptomatic people for years or decades. In 20% of patients, a plasma cell dyscrasia or one of the lymphoproliferative diseases (chronic lymphocytic leukemia [CLL], lymphoma) later appears. Differentiation of MGUS from more serious disease depends on bone marrow examination, urinary excretion of light chains (Bence-Jones protein), and survey for bone lesions. Peripheral neuropathy is a common neurologic manifestation of MGUS. In most cases the paraprotein is IgM and less commonly IgG or IgA. In about half of the patients with IgM neuropathy, the monoclonal protein has antibody activity against myelin-associated glycoprotein and results in a demyelinating peripheral neuropathy. These patients show large-fiber sensory loss and late-onset distal limb weakness. Some patients with a sensory axonal neuropathy have IgM antibodies that recognize axonal sulfatides or chondroitin sulfate. The role of the M protein in the pathogenesis of these syndromes is debated, but experimentally antibodies to myelin-associated glycoprotein can induce peripheral nerve demyelination. In myeloma, the most frequent neurologic complication is thoracic or lumbosacral radiculopathy, resulting from nerve compression by a vertebral lesion or collapsed bone. A syndrome of spinal cord compression may appear when there are epidural myeloma masses within the spinal canal. The intraspinal lesions are treated with combinations of radiotherapy or chemotherapy. Intracranial plasmacytomas are usually extensions of myeloma skull lesions. Characteristic multiple osteolytic lesions are seen on radiographs of the skull and other bones ( Fig. 147.3). Leptomeningeal invasion is also seen with myeloma. Peripheral neuropathy is uncommon and usually associated with axonal degeneration and amyloidosis. One unusual multisystem disease is POEMS ( p olyneuropathy, o rganomegaly, e ndocrinopathy, M protein, and s kin changes), which is associated with osteosclerotic myeloma or plasmacytoma. The M protein is usually IgG or IgA, invariably associated with a lambda light chain. Surgical removal of the plasmacytoma may reverse the neuropathy.

FIG. 147.3. Multiple myeloma. Myriads of osteolytic lesions. (Courtesy of Dr. Lowell G. Lubic.)

The peripheral neuropathy in Waldenstrรถm macroglobulinemia is similar to the demyelinating neuropathy of MGUS. Leukoencephalopathy with macroglobulinemia is called the Bing-Neel syndrome; there may be plasma cell invasion of perivascular spaces, but there is no cerebral mass lesion. A hyperviscosity syndrome with IgM paraproteinemia is associated with headache, blurred vision, tinnitus, vertigo, and ataxia. Serum viscosity can be reduced by chemotherapy or by plasmapheresis to

lower the paraprotein concentration. The neuropathies are treated with immunosuppressive drugs, intravenous immunoglobulin therapy, or plasmapheresis. Myelofibrosis Extramedullary hematopoiesis often accompanies myelofibrosis or polycythemia vera and may cause extradural spinal cord compression, cerebral compression by calvarial-based intracranial masses, or orbital lesions with exophthalmos. The neurologic signs are usually painless and develop insidiously. The syndrome occurs more frequently after splenectomy and responds to radiotherapy.

COAGULATION DISORDERS Hematologic disorders or coagulopathies may be responsible for stroke in 4% to 17% of young patients and 1% of all patients with ischemic stroke. The role of prothrombotic disorders in older stroke patients is not known. Most prothrombotic disorders are associated with venous thrombosis in unusual sites (mesentery, sagittal sinus), but arterial thrombosis, mainly in the carotid artery, has been described. Women with hereditary prothrombotic conditions using oral contraception are at a three- to fourfold risk of cerebral sinus thrombosis. Cerebral thrombosis can occur without systemic manifestations. A hematologic abnormality is attributed a causal role in stroke if the abnormality persists months after the event or is seen in other family members. Antithrombin III Deficiency Antithrombin III (ATIII) is a plasma glycoprotein synthesized by the liver and endothelial cells. It binds to endogenous heparan on the surface of endothelial cells or to exogenous heparin. ATIII is required for the anticoagulant action of heparin, increasing its ability to inhibit thrombin and other activated clotting factors. The activity of ATIII can be measured by its ability to inactivate factor Xa or thrombin. Heparin accelerates this interaction. Deficiency of ATIII is inherited or acquired, with a prevalence of 1:2,000 to 1:5,000 in the general population. There are two types of familial ATIII deficiency. Type I accounts for about 90% of inherited cases; both antigen level and functional activity of ATIII are decreased. In type II, levels are normal, but there is dysfunction of ATIII. The disease is inherited in an autosomal dominant fashion, affecting both sexes equally. Penetrance is variable. The most common manifestation is leg thrombosis and pulmonary embolus. In heterozygote individuals, symptomatic thrombosis increases after the age of 15, and by age 55 it is estimated to occur in 85% of gene carriers. More than half of the thrombotic episodes occur with triggering events: pregnancy, surgery, or infection. It is an isolated event in 42%. Cerebral venous thrombosis is more common, but arterial thrombosis may occur. For homozygotes, venous thrombosis is usually seen during the first year of life. Clues to diagnosis are family history of thromboembolism, thrombosis during pregnancy, resistance to heparin therapy, or unusual sites of thrombosis (brain, mesentery). There are several causes of acquired ATIII deficiency. Decreased synthesis is seen with liver cirrhosis. Drug-induced ATIII deficiency occurs with L-asparaginase, heparin, or oral contraceptives containing estrogen. Increased excretion in protein-losing enteropathy, inflammatory bowel disease, or nephrotic syndrome results in low ATIII levels. Accelerated consumption in disseminated intravascular coagulopathy (DIC) or after major surgery can lead to ATIII deficiency. ATIII deficiency is resistant to anticoagulation with heparin. ATIII concentrate is given to deficient patients with a thrombotic event or at times of maximal risk, such as surgery or delivery. After a thrombotic event, lifelong warfarin therapy is indicated. The value of prophylactic anticoagulation for all carriers during high-risk events is debated. Protein S Deficiency Protein S is a vitamin K-dependent plasma protein synthesized in the liver. It facilitates the binding of protein C to the platelet membrane, acting as a nonenzymatic cofactor for the anticoagulant activity of activated protein C. Only 40% of protein S is in a free form; the rest is in an inactive form, bound to C4-binding protein. C4-binding protein levels are elevated during acute inflammation or stress, increasing the inactivation of protein S and thus the risk of thrombosis. The complex of proteins C and S inhibits the clotting cascade. Protein S deficiency can be acquired or congenital, inherited as autosomal dominant with partial expressivity. Acquired deficiency is caused by liver dysfunction, vitamin K deficiency, warfarin therapy, nephrotic syndrome, oral contraceptives, or chemotherapy. Up to 20% of patients with stroke have protein S deficiency, but the significance of this figure has been challenged by case-control studies. Thrombosis, both cerebral venous and arterial system, has been described. In evaluating protein S deficiency, it is necessary to determine both the free and the total protein S levels. Most patients with protein S deficiency and stroke are given anticoagulation therapy for a predetermined period. Prophylactic anticoagulation is not advocated for asymptomatic protein S deficiency. Protein C Deficiency Protein C is a serine protease and an important inhibitor of plasma coagulation. Similar to protein S, its synthesis by the liver depends on vitamin K. Protein C in the plasma is inactive; it is activated by a thrombin–thrombomodulin complex when clotting is initiated at the endothelial surface. Protein S enhances the activity of protein C. Once activated, protein C inactivates factors Va and VIIIa, inhibiting coagulation and enhancing fibrinolytic activity. Deficiency can be inherited or acquired. The trait is autosomal dominant with incomplete penetrance. Homozygous individuals develop purpura fulminans and severe thrombotic complications in the neonatal period. Heterozygotes have recurrent thrombosis in early adult years. Members of the family may have subnormal protein C levels but may be asymptomatic. Additional risk factors for thromboembolism, such as smoking or oral contraceptives, may be contributory. Acquired protein C deficiency may occur with vitamin K malabsorption or warfarin therapy or with malignancy or chemotherapy. Either quantitative or qualitative protein C deficiency can lead to cerebral thrombosis. Protein C deficiency is found in 6% to 8% of patients who have a stroke before age 40. Strokes are usually attributed to venous thrombosis. Occlusion of the cerebral arteries is rare, as is cerebral sinus thrombosis. Anticoagulation with heparin or warfarin is recommended only for clinical thrombosis and not for those with subnormal levels. Warfarin necrosis of skin and subcutaneous tissues, particularly breast and adipose tissue, may be seen in patients 2 to 5 days into treatment and has been attributed to loading doses. Protein C deficiency may be associated with homocysteinemia, which itself can lead to thrombosis. Factor V Leiden and Prothrombin G20210A Mutations Factor V Leiden is the most common known genetic risk factor for thrombosis. A mutation of the factor V gene causing replacement of arginine 506 by glycine results in factor Va resistance to degradation by activated protein C. The resultant imbalance between pro- and anticoagulant factors predisposes to venous thrombosis. The incidence of heterozygous factor V Leiden is 2% to 8.5%, depending on the ethnicity and geographic location of the population studied. Heterozygosity for the factor V mutation alone does not appear to increase the risk for ischemic stroke. There is conflicting data as to whether the prothrombin G20210A mutation, which is associated with thrombosis, confers an increased risk of ischemic stroke in young patients heterozygous for this mutation. Spinal cord infarction in young women smokers on oral contraception having the prothrombin G20210A mutation has been described. Recent data suggest that the frequent coexistence of factor V Leiden; the prothrombin 20210A allele; and hereditary deficiencies of ATIII, protein C, and protein S may significantly contribute to the risk of thrombotic events. Hereditary Abnormalities of Fibrinolysis There are four inherited abnormalities of fibrinolysis. Plasminogen deficiency is autosomal dominant, with patients predisposed to venous thrombosis, including cortical vein thrombosis. Tissue plasminogen activator deficiency has been associated with venous thrombosis but not stroke. Patients with dysfibrinogenemia can have strokes rarely. Those with factor XII deficiency have elevated activated partial thromboplastin time, and some have had strokes.

Autoantibodies Antiphospholipid antibodies, encompassing the lupus anticoagulant and anticardiolipin antibodies, are the most common acquired defects associated with thrombosis. IgG anticardiolipin antibodies have been associated with ischemic stroke, often recurrent, particularly in young adults. Other neurologic presentations in patients with antiphospholipid antibodies include cerebral venous sinus thrombosis, dementia, and chorea. The presence of a lupus anticoagulant should be suspected if the activated partial thromboplastin time (and prothrombin time in some cases) is prolonged and fails to correct with mixing studies. Paroxysmal Nocturnal Hemoglobinuria This clonal myelodysplastic syndrome is characterized by the absence of glycosylphosphatidylinositol, which anchors proteins to the cell surface. Patients are prone to hepatic vein and sagittal sinus thrombosis and may have hemolytic anemia, cytopenia, and headache. Hemophilia Twenty-five percent of hemorrhagic deaths in hemophiliacs are due to intracranial bleeding, often without precedent trauma. Bleeding can be subdural, epidural, intracerebral, or infrequently intraspinal. In a study of 2,500 patients followed for 10 years, the incidence of intracranial bleeding was 3%, with a 34% mortality rate and 47% of survivors having residual mental retardation, motor impairment, or seizures. Treatment with factor concentrate should not be delayed for diagnostic procedures if there is a clinical suspicion of intracranial bleeding. Peripheral neuropathies may follow intaneural bleeding or nerve compression by hematomas.

CEREBROVASCULAR COMPLICATIONS OF CANCER At autopsy, as many as 15% of patients with systemic malignancy have evidence of cerebrovascular disease. Cancers cause vascular complications by several indirect or direct mechanisms. Nonbacterial thrombotic endocarditis with sterile platelet-fibrin heart valve vegetations is the most common cause of cerebral infarction in patients with systemic malignancy. Most patients have disseminated malignancy and have multiple strokes, with ischemic or hemorrhagic infarctions in different vascular territories, often preceded by TIAs. The lesions are differentiated from brain metastases by CT or MRI. The most common tumors are lymphomas and adenocarcinomas, particularly mucin-producing adenocarcinomas. Emboli to other organs (pulmonary embolism, limb arterial emboli, or myocardial infarction) may call attention to the diagnosis, especially in patients with neurologic symptoms. There is thought to be a coagulopathy, but this has not been clarified. Therapy is directed toward eradication of the primary tumor; the role of anticoagulation is unsettled. Tumor emboli uncommonly cause cerebral infarction, usually with atrial myxoma or lung carcinoma. Neoplastic angioendotheliomatosis was formerly attributed to tumor emboli or diffuse spread of endothelial cells with strokelike symptoms, but neoplastic angioendotheliomatosis is a systemic lymphoma with intravascular dissemination (see Chapter 56). Coagulation disorders may be due to the underlying tumor, chemotherapy, or radiotherapy. Coagulopathy is often seen with hepatic metastases and depletion of coagulation factors. Many chemotherapeutic agents depress stem cell function to cause thrombocytopenia. Colony-stimulating factors stimulate leukocyte production and permit more intensive chemotherapy, but thrombocytopenia may require platelet transfusions. Spontaneous intraparenchymal or subarachnoid hemorrhage may occur when the platelet count is less than 20,000/mm 3, a common problem in the cancer patient with sepsis. The combination of coagulopathy and thrombocytopenia, often seen with leukemia, predisposes to cerebral hemorrhage. In contrast, subdural hemorrhage is less common than parenchymal or subarachnoid hemorrhage in patients with coagulopathy or thrombocytopenia and occurs more frequently in the presence of dural metastases from carcinoma of breast, lung, or prostate. Even with normal coagulation and platelet function, some metastatic tumors (melanomas, lung carcinomas, choriocarcinomas, and hypernephromas) are likely to cause hemorrhage into a tumor. With gliomas, the likelihood of intratumor hemorrhage increases with increasing grade of malignancy. To avert intratumor hemorrhage, patients with known primary or metastatic brain tumors should receive platelet transfusions if the count falls below 20,000/mm 3, and coagulation functions should be maintained with transfusions of fresh frozen plasma. Intracranial or subarachnoid hemorrhage may result from rupture of a neoplastic (oncotic) aneurysm caused by atrial myxomas or direct destruction of arterial walls as a result of invasion by a metastatic lung carcinoma or choriocarcinoma or glioblastoma. DIC is readily detected in its acute fulminant form when patients bleed profusely after venipuncture and have intracranial hemorrhage. Acute promyelocytic leukemia is associated with fulminant DIC, probably secondary to release of granules from leukemic cells. A more indolent form of DIC may also cause neurologic manifestations. Autopsy examinations reveal evidence of thrombosis in situ, intravascular coagulation. In contrast to nonbacterial thrombotic endocarditis, in which multifocal neurologic signs predominate, the main neurologic manifestation of DIC is diffuse encephalopathy. The diagnosis of chronic DIC is difficult but should be considered if the level of fibrin split products is elevated. Heparin anticoagulation is a logical but unproven therapy. Occlusion of the superior sagittal sinus may follow direct spread of tumor to the dura. The cardinal symptoms of venous sinus thrombosis include headache secondary to increased intracranial pressure and seizures. It may also be a nonmetastatic complication, presumably caused by coagulopathy. The diagnosis is made by MRI, which shows loss of the typical signal flow void in the superior sagittal sinus at the site of the thrombosis. Heparin therapy is frequently beneficial but must be monitored, particularly if there is hemorrhagic cortical infarction. Leptomeningeal metastasis infrequently produces TIA or infarction by compromising vessels near the meningeal infiltrate. Radiation-induced vasculopathy of the carotid artery may be delayed for years after radiation therapy for tumors of the head or neck. Symptoms of TIAs or infarction point to the involved vessel, and angiography reveals intimal irregularity. Radiotherapy may accelerate atherosclerosis, and appropriate patients benefit from endarterectomy.

OTHER DISORDERS Hypereosinophilic Syndrome Hypereosinophilia has been associated with a number of disorders, including allergies, parasitic infections, Hodgkin and T-cell lymphomas, and some forms of vasculitis. When eosinophilia (greater than 1,500/mm 3) persists for more than 6 months without an apparent underlying cause, with evidence of tissue damage by eosinophils, the disorder is termed the hypereosinophilic syndrome. The pathogenesis may be related to T-cell overexpression of cytokines, particularly interleukin-5. Eosinophils contain a number of granule proteins that damage tissue, including the eosinophil-derived neurotoxin that can cause Purkinje cell degeneration, ataxia, and paralysis in experimental animals. Multiple organs are affected, including the heart (endomyocardial fibrosis), lungs, liver, spleen, and skin. The CNS is affected in 15% of cases as encephalopathy, TIA, embolic infarction, or peripheral neuropathy. Behavioral changes, confusion, memory loss, ataxia, and upper motor neuron signs may be the first manifestation. Cerebral embolism is attributed to the cardiac disorder and responds poorly to anticoagulation. Patients with hypereosinophilia and peripheral neuropathy raise the possibility of the Churg-Strauss syndrome. Steroids and hydroxyurea are the mainstay of therapy for the eosinophilic syndrome. Langerhans Cell Histiocytosis Histiocytes include the antigen-presenting dendritic cells and antigen-processing phagocytic cells. Disorders of dendritic cells, previously called histiocytosis X, are now termed Langerhans cell histiocytosis. They may arise from clonal proliferation of cells but malignant histiocytosis, a true neoplasm, is rare. A localized form is the eosinophilic granuloma (Fig. 147.4); a multifocal form is the Hand-Schรถller-Christian disease, and a disseminated disease in children under age 2 is the Letterer-Siwe disease. The diagnosis of Langerhans cell histiocytosis is made by biopsy of affected tissues and immunohistochemical analysis with surface markers that are expressed by Langerhans cells.

FIG. 147.4. Eosinophilic granuloma of optic chiasm. A: T1-weighted coronal magnetic resonance (MR) image shows enlargement of optic chiasm. B and C: T1-weighted coronal and sagittal MR images after gadolinium enhancement demonstrate focal enhancing nodule involving optic chiasm and hypothalamus, consistent with known eosinophilic granuloma. Incidentally noted are several small enhancing lesions in left temporal lobe (an unusual site for eosinophilic granuloma). (Courtesy of Drs. S. Chan and S.K. Hilal.)

Eosinophilic granuloma is a painless destructive bone lesion that frequently involves the calvarium but is detected on CT performed for other reasons. Excision and local radiation therapy are often curative. Hand-Schöller-Christian disease is characterized by the triad of calvarial lesions, exophthalmos, and diabetes insipidus. Otitis media and constitutional symptoms of fever or weight loss may occur. The hypothalamus is likely to be affected, most often with diabetes insipidus, especially in children and young adults. CT or MRI reveals both gray and white matter contrast and noncontrast-enhancing intraparenchymal lesions that are not specific; biopsy is needed unless tissue diagnosis can be obtained from a calvarial lesion. Therapy consists of localized irradiation and corticosteroids. Chemotherapy is given for those with resistant disease. Letterer-Siwe disease causes a granulomatous rash, lymphadenopathy, hepatosplenomegaly, fever, and weight loss, usually without neurologic involvement. The prognosis for this form is quite poor; cytotoxic chemotherapy has been recommended. Neurolymphomatosis In 1934, Lhermitte and Trelles described lymphomatous infiltration of peripheral nerves or neurolymphomatosis. Of more than 40 histologically proven cases reported subsequently, most have had non-Hodgkin lymphoma with progressive sensorimotor peripheral neuropathy. Some also had cranial neuropathy (45%), bowel or bladder incontinence (25%), gait ataxia (18%), or mental change (13%). The CSF protein content was above 100 mg/dL in 57% of patients, and 70% had lymphocytic CSF pleocytosis. CSF cytology was abnormal in 33%. Electrodiagnostic studies show axonal neuropathy, mixed, or pure demyelinating neuropathy. Sural nerve biopsy shows equal numbers of patients with purely axonal degeneration or demyelinating lesions. MRI may be useful in identifying appropriate biopsy sites. At postmortem examination, there is often B-lymphocytic infiltration of leptomeninges, dorsal root ganglia, and spinal roots. The histopathologic pattern is indistinguishable from that of primary leptomeningeal lymphoma. Neurolymphomatosis is readily discernible from the polyclonal T-cell infiltration in human immunodeficiency virus-associated diffuse infiltrative lymphocytosis syndrome. The neurologic disorder sometimes improves with corticosteroids, chemotherapy, or radiation therapy. Angiocentric Immunoproliferative Lesions These disorders are discussed in Chapter 56. Chediak-Higashi Syndrome This rare autosomal recessive disorder is characterized by partial oculocutaneous albinism, immunologic defects, a bleeding diathesis, and progressive neurologic dysfunction. Mutation of the CHS1 gene on chromosome 1q42-q44 appears to result in defective transport of intracellular proteins, producing giant lysosomal granules in granule-containing cells, including neutrophils, monocytes, hepatocytes, and renal tubular cells. The granules are easily recognized on a peripheral blood smear. Impaired neutrophil function and defective T-cell and natural killer cell cytotoxicity predisposes to infections that lead to death, usually within the first decade of life. Neurologic syndromes include a spinocerebellar disorder and peripheral neuropathy. The neurologic symptoms may be associated with neuronal or Schwann cell inclusions or by lymphohistiocytic infiltration of peripheral nerves. CT brain findings include diffuse atrophy and decreased periventricular density. Bone marrow transplant is a potentially curative avenue for therapy. SUGGESTED READINGS Sickle Cell Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5–11. Earley CJ, Kittner SJ, Feeser BR, et al. Stroke in children and sickle-cell disease: Baltimore-Washington Cooperative Young Stroke Study. Neurology 1998;51:169–176. Fabian R, Peters B. Neurological complications of hemoglobin SC disease. Arch Neurol 1984;41:289–292. Greenberg J, Massey E. Cerebral infarction in sickle cell trait. Ann Neurol 1985;18:354–355. Hart RG, Kanter MC. Hematologic disorders and ischemic stroke. A selective review. Stroke 1990;21:1111–1121. Liu JE, Gzesh DJ, Ballas SK. The spectrum of epilepsy in sickle cell anemia. J Neurol Sci 1994;123:6–10. Moser FG, Miller ST, Bello JA, et al. The spectrum of brain MR abnormalities in sickle-cell disease: a report from the Cooperative Study of Sickle Cell Disease.

AJNR 1996;17:965–972.

Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998;91:288–294. Preul MC, Cendes F, Just N, Mohr G. Intracranial aneurysms and sickle cell anemia: multiplicity and propensity for the vertebrobasilar territory. Neurosurgery 1998;42:971–977. Reyes M. Subcortical cerebral infarctions in sickle cell trait. J Neurol Neurosurg Psychiatry 1989;52:516–518. Wang WC, Langston JW, Steen RG, et al. Abnormalities of the central nervous system in very young children with sickle cell anemia. J Pediatr 1998;132:994–998. Thalassemia Kaufmann T, Coleman M, Giardina P, Nisce LZ. The role of radiation therapy in the management of hematopoietic neurologic complications in thalassemia.

Acta Haematol 1991;85:156–159.

Logothetis J, Constantoulakis M, Economidou J, et al. Thalassemia major (homozygous beta-thalassemia). A survey of 138 cases with emphasis on neurologic and muscular aspects. Neurology 1972;22:294–304. Papanastasiou DA, Papanicolaou D, Magiakou AM, et al. Peripheral neuropathy in patients with beta-thalassaemia. J Neurol Neurosurg Psychiatry 1991;54:997–1000. Wong V, Yu Y, Liang R, et al. Cerebral thrombosis in b-thalassemia/hemoglobin E disease. Stroke 1990;21:812–816. Polycythemia

Gruppo Italiano Studio Policitemia. Polycythemia vera: the natural history of 1213 patients followed for 20 years. Ann Intern Med 1995;123:656–664. Newton LK. Neurologic complications of polycythemia and their impact on therapy. Oncology 1990;4:59–64. Poza JJ, Cobo AM, Marti-Masso JF. Peripheral neuropathy associated with polycythemia vera. Neurologia 1996;11:276–279. Yiannikas C, McLoed JG, Walsh JC. Peripheral neuropathy associated with polycythemia vera. Neurology 1983;33:139–143. Essential Thrombocytosis (Thrombocythemia) Koudstaal PJ, Koudstaal A. Neurologic and visual symptoms in essential thrombocythemia: efficacy of low-dose aspirin. Semin Thromb Hemost 1997;23:365–370. Martin EA, Lavin PJ, Thompson AJ. Painful extremities and neurological disorder in essential thrombocythaemia. J R Soc Med 1984;77:372–374. Mitus AJ, Tiziano B, Shulman LN, et al. Hemostatic complications in young patients with essential thrombocythemia. Am J Med 1990;88:371–375. Thrombotic Thrombocytopenic Purpura Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, et al. Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases. Ann Intern Med 1998;128:541–544. Kay AC, Solberg LA Jr, Nichols DA, Petitt RM. Prognostic significance of computed tomography of the brain in thrombotic thrombocytopenic purpura. Mayo Clin Proc 1991;66:602–607. Tardy B, Page Y, Convers P, et al. Thrombotic thrombocytopenic purpura: MR findings. AJNR 1993;14:489–490. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585–1594. Heparin-induced Thrombocytopenia Becker PS, Miller VT. Heparin-induced thrombocytopenia. Stroke 1989;20:1449–1459. Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Organan (Org 10172). Thromb Haemost 1993;70:554–561. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996;101:502–507. Myelofibrosis Landolfi R, Colosimo CJ, De Candia E, et al. Meningeal hematopoiesis causing exophthalmos and hemiparesis in myelofibrosis: effect of radiotherapy. Cancer 1988;62:2346–2349. Rice GPA, Assis LJP, Barr RM, et al. Extramedullary hematopoiesis and spinal cord compression complicating polycythemia rubra vera. Ann Neurol 1980;7:81–84. Leukemia Azzarelli B, Roessmann U. Pathogenesis of central nervous system infiltration in acute leukemia. Arch Pathol Lab Med 1977;101:203–205. Balis FM, Savitch JL, Bleyer WA, et al. Remission induction of meningeal leukemia with high-dose intravenous methotrexate. J Clin Oncol 1985;3:485–489. Cramer SC, Glaspy JA, Efird JT, Louis DN. Chronic lymphocytic leukemia and the central nervous system: a clinical and pathological study. Neurology 1996;46:19–25. Dekker AW, Elderson A, Punt K, Sixma JJ. Meningeal involvement in patients with acute nonlymphocytic leukemia. Incidence, management, and predictive factors.

Cancer 1985;56:2078–2082.

Freeman AI, Weinberg V, Breecher ML, et al. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. J Med 1983;308:477–484. Holmes R, Keating MJ, Cork A, et al. A unique pattern of central nervous system leukemia in acute myelomonocytic leukemia associated with inv(16)(p13q22). Blood 1985;65:1071–1078. McCarthy LJ. Leukostasis thrombi. JAMA 1985;254:613. McKee LC, Collins RD. Intravascular leukocyte thrombi and aggregates as a cause of morbidity and mortality in leukemia. Medicine (Baltimore) 1974;53:463–478. Pinkel D, Woo S. Prevention and treatment of meningeal leukemia in children. Blood 1994;84:355–366. Pui CH, Dahl GV, Kalwinsky DK, et al. Central nervous system leukemia in children with acute nonlymphoblastic leukemia. Blood 1985;66:1062–1067. Steinherz PG, Miller LP, Ghavimi F, et al. Dural sinus thrombosis in children with acute lymphoblastic leukemia. JAMA 1981;246:2837–2839. Plasma Cell Dyscrasias Delauche-Cavallier MC, Laredo JD, Wybier M, et al. Solitary plasmacytoma of the spine. Cancer 1988;61:1707–1714. Gordon PH, Rowland LP, Younger DS, et al. Lymphoproliferative disorders and motor neuron disease: an update. Neurology 1997;48:1671–1678. Kelly JJ Jr, Kyle RA, Miles JM, et al. Osteosclerotic myeloma and peripheral neuropathy. Neurology 1983;33:202–210. Latov N. Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies. Ann Neurol 1995;37[Suppl 1]:S32–S42. Neau JP, Guilhot F, Dumas P, et al. Formes nerologiques centrales de la maladie de Waldenstrom. Syndrome de Bing-Neel. Trois cas. Rev Neurol (Paris) 1991;147:56–60. Nobile-Orazio E, Barbieri S, Baldini L, et al. Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies. Acta Neurol Scand 1992;85:383–390. Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med 1998;338:1601–1607. Schey S. Osteosclerotic myeloma and “POEMS” syndrome. Blood Rev 1996;10:75–80. Schulman P, Sun T, Shareer L, et al. Meningeal involvement in IgD myeloma with cerebrospinal fluid paraprotein analysis. Cancer 1980;46:152–155. Sherman WH, Olarte MR, McKiernan G, et al. Plasma exchange treatment of peripheral neuropathy associated with plasma cell dyscrasia. J Neurol Neurosurg Psychiatry 1984;47:813–819. Spiers ASD, Halpern R, Ross SC, et al. Meningeal myelomatosis. Arch Intern Med 1980;140:256–259. West SG, Pittman DL, Coggin JT. Intracranial plasma cell granuloma. Cancer 1980;46:330–335. Disorders of Coagulation Antiphospholipid Antibodies in Stroke Study (APASS) Group. Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurology 1993;43:2069–2073. de Bruijn SF, Stam J, Koopman MM, Vandenbroucke JP. Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in [correction of who are] carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group. BMJ 1998;316:589–592. De Stefano V, Chiusolo P, Paciaroni K, et al. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998;91:3562–3565. Grewal RP, Goldberg MA. Stroke in protein C deficiency. Am J Med 1990;89:538–539.

N Engl

Harris M, Exner T, Rickard K, et al. Multiple cerebral thrombosis in Fletcher factor (prekallikrein) deficiency: a case report. Am J Hematol 1985;19:387–393. Hathaway WE. Clinical aspects of antithrombin III deficiency. Semin Hematol 1991;28:19–23. Israel S, Seshia S. Childhood stroke associated with protein C or S deficiency. J Pediatr 1987;111:562–564. Jorens PG, Hermans CR, Haber I, et al. Acquired protein C and S deficiency, inflammatory bowel disease and cerebral arterial thrombosis. Blut 1990;61:307–310. Kohler J, Kasper J, Witt I, et al. Ischemic stroke due to protein C deficiency. Stroke 1990;21:1077–1080. Kwaan HC. Protein C and protein S. Semin Thromb Hemost 1989;15:353–355. Lee MK, Ng SC. Cerebral venous thrombosis associated with antithrombin III deficiency. Aust N Z J Med 1991;21:772–773. Leone G, Graham JA, Daly HM, Carson PJ. Antithrombin III deficiency and cerebrovascular accidents in young adults. J Clin Pathol 1992;45:921–922. Levine SR, Brey RL, Sawaya KL, et al. Recurrent stroke and thrombo-occlusive events in the phospholipid syndrome. Ann Neurol 1995;38:119–124. Martinez HR, Rangel-Guerra R, Marfil LJ. Ischemic stroke due to deficiency of coagulation inhibitors. Report of 10 young adults. Stroke 1993;24:19–45. Matsushita K, Kuriyama Y, Sawada T, et al. Cerebral infarction associated with protein C deficiency. Stroke 1992;23:108–111. Mayer S, Sacco R, Hurlet-Jensen A, et al. Free protein S deficiency in acute ischemic stroke. A case-control study. Stroke 1993;24:224–227. Munts AG, van Genderen PJ, Dippel DW, et al. Coagulation disorders in young adults with acute cerebral ischaemia. J Neurol 1998;245:21–25. Prats JM, Garaizar C, Zuazo E, et al. Superior sagittal sinus thrombosis in a child with protein S deficiency. Neurology 1992;42:2303–2305. Pratt CW, Church FC. Antithrombin: structure and function. Semin Hematol 1991;28:3–9. Rich C, Gill JC, Wernick S, et al. An unusual cause of cerebral venous thrombosis in a four-year-old child. Stroke 1993;24:603–605. Ridker PM, Hennekens CH, Lindpaintner K, et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995;332:912–917. Shinmyozu K, Ohkatsu Y, Maruyama Y, et al. A case of congenital antithrombin III deficiency complicated by an internal carotid artery occlusion. Clin Neurol 1986;26:162–165. Vomberg P, Breederveld C. Cerebral thromboembolism due to antithrombin III deficiency in two children. Neuropediatrics 1987;18:42–44. Cerebrovascular Complications of Cancer Amico L, Caplan LR, Thomas C. Cerebrovascular complications of mucinous cancers. Neurology 1989;39:522–526. Atkinson JL, Sundt TM, Dale AJD, et al. Radiation associated atheromatous disease of the cervical carotid artery: report of seven cases and review of the literature. Neurosurgery 1989;24:171. Biller J, Challa VR, Toole JF, et al. Nonbacterial thrombotic endocarditis: a neurologic perspective of clinicopathologic correlations in 99 patients. Arch Neurol 1982;39:95–98. Edoute Y, Haim N, Rinkevich D, et al. Cardiac valvular vegetations in cancer patients: a prospective echocardiographic study of 200 patients. Am J Med 1997;102:252–258. Feehs RS, McGuirt WF, Bond MG, et al. Irradiation. A significant risk factor for carotid atherosclerosis. Arch Otolaryngol Head Neck Surg 1991;117:1135–1137. Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985;64:16–35. Green KB, Silverstein RL. Hypercoagulability in cancer. Hematol Oncol Clin North Am 1996;10:499–530. Helmer FA. Oncotic aneurysm. J Neurosurg 1976;45:98–100. Hickey WF, Garnick MB, Henderson IC, et al. Primary cerebral venous thrombosis in patients with cancer—a rarely diagnosed paraneoplastic syndrome. Am J Med 1982;73:740–750. Ho K-L. Neoplastic aneurysm and intracranial hemorrhage. Cancer 1982;50:2935–2940. Klein P, Haley EC, Wooten GF, et al. Focal cerebral infarctions associated with perivascular tumor infiltrates in carcinomatous leptomeningeal metastases. Arch Neurol 1989;46:1149. Murros KE, Toole JF. The effect of radiation on carotid arteries. Arch Neurol 1989;46:449. O'Neill BP, Dinapoli RP, Okazaki H. Cerebral infarction as a result of tumor emboli. Cancer 1987;60:90–95. Rogers LR, Cho E, Kempin S, et al. Cerebral infarction from non-bacterial thrombotic endocarditis. Am J Med 1987;83:746. Hypereosinophilic Syndrome Bell D, Mackay IG, Pentland B. Hypereosinophilic syndrome presenting as peripheral neuropathy. Postgrad Med J 1985:61:429–432. Brito-Babapulle F. Clonal eosinophilic disorders and the hypereosinophilic syndrome. Blood Rev 1997;11:129–145. Durack DT, Sumi SM, Klebanoff SJ. Neurotoxicity of human eosinophils. Proc Natl Acad Sci USA 1979;76:1443–1447. Monaco S, Lucci B, Laperchia N, et al. Polyneuropathy in hypereosinophilic syndrome. Neurology 1988;38:494–496. Rosenberg HF, Tenen DG, Ackerman SJ. Molecular cloning of the human eosinophil-derived neurotoxin: a member of the ribonuclease gene family. Proc Natl Acad Sci USA 1989;86:4460–4464. Langerhans Cell Histiocytosis Adornato BT, Eil C, Head GL, Loriaus L. Cerebellar involvement in multifocal eosinophilic granuloma: demonstration by computerized tomographic scanning.

Ann Neurol 1980;7:125–129.

George JC, Edwards MK, Smith RR, et al. MR of intracranial Langerhans cell histiocytosis. J Comput Assist Tomogr 1994;18:295–297. Grois NG, Favara BE, Mostbeck GH, Prayer D. Central nervous system disease in Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998;12:287–305. Ladisch S. Langerhans cell histiocytosis. Curr Opin Hematol 1998;5:54–58. Neurolymphomatosis Diaz-Arrastia R, Younger DS, Hair L, et al. Neurolymphomatosis: a clinicopathologic syndrome re-emerges. Neurology 1992;42:1136–1141. Gherardi RK, Chretien F, Delfau-Larue MH, et al. Neuropathy in diffuse infiltrative lymphocytosis syndrome: an HIV neuropathy, not a lymphoma. Neurology 1998;50:1041–1044. Gordon PH, Younger DS. Neurolymphomatosis. Neurology 1996;46:1191–1192. Van den Bent MJ, de Bruin HG, Beun GD, Vecht CJ. Neurolymphomatosis of the median nerve. Neurology 1995;45:1403–1405. Chediak-Higashi Syndrome

Ballard R, Tien RD, Nohria V, Juel V. The Chediak-Higashi syndrome: CT and MR findings. Pediatr Radiol 1994;24:266–267. Misra VP, King RHM, Harding AE, et al. Peripheral neuropathy in the Chediak-Higashi syndrome. Acta Neuropathol 1991;81:354–358. Pettit RE, Berdal KG. Chediak-Higashi syndrome. Arch Neurol 1984;41:1001–1002. Spitz RA. Genetic defects in Chediak-Higashi syndrome and the beige mouse. J Clin Immunol 1998;18:97–105.

CHAPTER 148. HEPATIC DISEASE MERRITT’S NEUROLOGY

CHAPTER 148. HEPATIC DISEASE NEIL H. RASKIN AND LEWIS P. ROWLAND Clinical Features Pathophysiology Differential Diagnosis Treatment Neurologic Complications of Liver Transplantation Suggested Readings

The terms hepatic coma and encephalopathy have led to imprecision of both clinical and pathophysiologic concepts. The often fatal comatose state associated with acute hepatic necrosis is usually attended by striking elevation of serum ammonia content; coma is usually a single event of rapid onset and fulminant course that is characterized by delirium, convulsions, and, occasionally, decerebrate rigidity. The mechanism of this encephalopathy is not clear. Hepatic encephalopathy usually develops in patients with chronic liver disease when portal hypertension induces an extensive portal collateral circulation; portal venous blood bypasses the detoxification site, which is the liver, and drains directly into the systemic circulation to produce the cerebral intoxication that is properly termed portal-systemic encephalopathy. Several examples of portal-systemic encephalopathy have been reported in which the hepatic parenchyma was normal, underlining the anatomic importance of bypassing the liver as the mechanism. The offending nitrogenous substance arising in the intestine has not been identified with precision, but ammonia is the prime suspect. The clinical syndrome resulting from shunting is an episodic encephalopathy comprising admixtures of ataxia, action tremor, dysarthria, sensorial clouding, and asterixis. The episodes are usually reversible, although they may recur. Cerebral morphologic changes are few except for an increase in large Alzheimer type II astrocytes. In a few patients with this disorder, a relentlessly progressing neurologic disorder occurs in addition to the fluctuating intoxication syndrome, including dementia, ataxia, dysarthria, intention tremor, and a choreoathetotic movement. The brains of these patients show zones of pseudolaminar necrosis in cerebral and cerebellar cortex, cavitation and neuronal loss in the basal ganglia and cerebellum, and glycogen-staining inclusions in enlarged astrocytes. This irreversible disorder has been termed acquired chronic hepatocerebral degeneration, but it is probably the ultimate morphologic destruction that may result from the chronic metabolic defect that attends portal-systemic shunting.

CLINICAL FEATURES Thought processes are usually compromised insidiously, although an acute agitated delirium may occasionally usher in the syndrome. Mental dullness and drowsiness are usually the first symptoms; patients yawn frequently and drift off to sleep easily yet remain arousable. Cognitive defects eventually appear. Asterixis almost always accompanies these modest changes of consciousness. As encephalopathy progresses, bilateral paratonia appears, and the stretch reflexes become brisk; bilateral Babinski signs are usually found when obtundation becomes profound. Convulsions are decidedly uncommon in this disorder, in contrast to uremic encephalopathy. Spastic paraparesis may be seen. Decerebrate and decorticate postures and diffuse spasticity of the limbs frequently accompany deeper stages of coma. In the patient with overt hepatocellular failure with jaundice or ascites, the diagnosis of this disorder is not difficult. When parenchymal liver disease is mild or nonexistent, however, an elevated serum ammonia level or an elevation of cerebrospinal fluid glutamine content has high diagnostic sensitivity. The cerebrospinal fluid is otherwise bland. The ultimate diagnostic test is clinical responsiveness to ammonium loading; the risks of this procedure in patients with intact hepatocellular function are minimal. Ten grams of ammonium chloride is given in daily divided doses for 3 days; the appearance or worsening of asterixis, dysarthria, or ataxia or a further slowing of the electroencephalogram is diagnostic. Early in the course of encephalopathy, when the only evidence is seen on neuropsychologic tests, computed tomography may show cortical atrophy, cerebral edema, or normal patterns. Magnetic resonance imaging usually shows increased signal in the globus pallidus in T1-weighted studies. Manganese deposition may account for this. Sometimes there is calcification, and there may be abnormalities in the mesencephalon and pons. Cerebral edema is more common in chronic encephalopathy than once believed.

PATHOPHYSIOLOGY Several substances have been considered the putative neurotoxin in portal-systemic encephalopathy. These include methionine, other amino acids, short-chain fatty acids, biogenic amines, indoles and skatoles, and ammonia. None of these has succeeded in explaining the condition better than ammonia. Ammonia, a highly neurotoxic substance, is ordinarily converted to urea by the liver; when this detoxification mechanism is bypassed, levels of ammonia in the brain and blood increase. Occasionally, blood ammonia levels are normal or only slightly elevated in the face of full-blown coma. This has been used as a powerful argument against the implication of ammonia in this disorder; however, at physiologic pH, almost all serum ammonia in the NH 4+ NH 3 + H+ system is in the form of NH4+, with only traces of NH 3 present. NH 3 crosses membranes with facility and is far more toxic than NH 4+; thus, it is possible that when methods become available to measure circulating free ammonia levels in portal-systemic encephalopathy, they will be strikingly consistently elevated. Ammonia is detoxified in brain astrocytes by conversion to the nontoxic glutamine. Following up on the observation that levodopa benefited patients in hepatic coma, Fischer and Baldessarini (1971) proposed the false neurotransmitter hypothesis to explain the mechanism of this effect and other features of the disorder. They suggested that amines such as octopamine (or their aromatic amino acid precursors tyrosine and phenylalanine), which are derived from protein by gut bacterial action, might escape oxidation by the liver and flood the systemic and cerebral circulations. Octopamine could then replace norepinephrine and dopamine in nerve endings and act as a false neurotransmitter; the accumulation of false neurotransmitters might then account for the encephalopathy, and the amelioration could be achieved by restoring “true� neurotransmitters through an elevation of tissue dopamine levels. L-Dopa administration, however, has a powerful peripheral effect, inducing the renal excretion of ammonia and urea; this probably accounts for the beneficial effects of L-dopa in some encephalopathic patients. Further, octopamine concentration in rat brain has been elevated more than 20,000-fold, along with depletion of both norepinephrine and dopamine, without any detectable alteration of consciousness. Although false neurotransmitters do accumulate in portal-systemic encephalopathy, there is little reason to hold them responsible for the encephalopathy. It has also been suggested that increased sensitivity to inhibitory neurotransmitters such as GABA and glycine may underlie the encephalopathy.

DIFFERENTIAL DIAGNOSIS Among the numerous causes of encephalopathy, several affect abusers of alcohol, including acute ethanolic intoxication and delerium tremens, Wernicke encephalopathy, Korsakoff syndrome, drug intoxication, other metabolic disorders (uremia, hyponatremia), and consequences of head injury, such as subdural hematoma. Another consideration is Wilson disease.

TREATMENT Administration of antibiotics (especially neomycin or metronidazole) decreases the population of intestinal organisms to decrease production of ammonia and other cerebrotoxins. Lactulose is also beneficial for reasons that are not clear, but it lowers colonic pH, increases incorporation of ammonia into bacterial protein, and is a cathartic. The effects of neomycin and lactulose, given together, seem better than the effects either gives alone. Although recovery is expected in patients with mild acute encephalopathy, cerebral edema occurs in about 75% of patients in acute coma and may be the cause of death. Intracranial pressure monitoring is often carried out in transplantation centers despite the risk of bleeding. If cerebral perfusion pressure is less than 40 mm Hg and does not respond to mannitol therapy, transplantation is deemed futile. In some cases of fulminant hepatic failure, emergency hepatectomy has been performed, followed by support with an extracorporeal bioartificial liver and then orthoptic liver transplantation.

NEUROLOGIC COMPLICATIONS OF LIVER TRANSPLANTATION Neurologic problems arise in 8% to 47% of liver transplant recipients. The complications range from mild encephalopathy to akinetic mutism or coma. Psychiatric syndromes range from mild anxiety or depression to hallucinatory psychosis. Other syndromes include seizures, myoclonus, tremor, cortical blindness, brachial plexopathy, and peripheral neuropathy ( Table 148.1). Cerebral hemorrhage is sometimes responsible. Recovery from these disorders is often excellent and has no effect on survival, which is the same for those with or without neurologic syndromes. The acute leukoencephalopathy caused by tacrolimus (FK506) is reversed promptly on withdrawal of drug.

TABLE 148.1. NEUROLOGIC COMPLICATIONS OF LIVER TRANSPLANTATION

The necessary immunosuppression may lead to the opportunistic infections, and cyclosporine itself is held responsible for some cerebral disorders, possibly including central pontine myelinosis and leukoencephalopathy. Instead of the intravenous administration of cyclosporine, use of an oral formulation has reduced the severity of neurotoxicity. Both cyclosporine and OKT3 may cause seizures, and OKT3 may cause aseptic meningitis. Epileptiform activity in the electroencephalogram is seen much more often in patients who die than in those who survive. In an autopsy study of 21 patients who had seizures, Estol et al. (1989) found combinations of ischemic or hemorrhagic strokes in 18, central pontine myelinosis in 5, and central nervous system infections in 5. Metabolic abnormalities were also responsible for the seizures in these patients. Graft-versus-host reactions may include polyneuropathy, myasthenia gravis, and polymyositis. Infected donor tissue may transmit cytomegalovirus or Creutzfeldt-Jakob disease. SUGGESTED READINGS Hepatic Encephalopathy Asconape JJ. Use of antiepileptic drugs in the presence of liver and kidney diseases: a review. Epilepsia 1982;23[Suppl 1]:S65–S79. Butterworth RF, Spahr L, Fontaine S, Layrargues GP. Manganese toxicity, dopaminergic dysfunction and hepatic encephalopathy. Metab Brain Dis 1995;10:259–267. Crippen JS, Gross JB Jr, Lindor KD. Increased intracranial pressure and hepatic encephalopathy in chronic liver disease. Am J Gastroenterol 1992;87:879–882. Donovan JP, Schafer DF, Shaw BW, Sorrell MF. Cerebral oedema and increased intracranial pressure in chronic liver disease. Lancet 1998;351:719–721. Ferenci P, Pappas SC, Munson PJ, et al. Changes in the status of neurotransmitter receptors in a rabbit model of hepatic encephalopathy. Hepatology 1984;4:186–191. Fischer JE, Baldessarini RJ. False neurotransmitters and hepatic failure. Lancet 1971;2:75–80. Haseler LJ, Sibbitt WL Jr, Mojtahedzadeh HN, Reddy S, Agarwal VF, McCarthy DM. Proton MR spectroscopic measurement of neurometabolites in hepatic encephalopathy during oral lactulose therapy. AJNR 1998;19:1681–1686. Jones EA, Weissenborn K. Neurology and the liver. J Neurol Neurosurg Psychiatry 1997;63:279–293. Lockwood AH, Yap EW, Wong WH. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metab 1991;11:337–341. Lunzer M, James IM, Weinman J, et al. Treatment of chronic hepatic encephalopathy with levodopa. Gut 1974;15:555–561. Raskin NH, Bredesen D, Ehrenfeld WK, et al. Periodic confusion caused by congenital extrahepatic portacaval shunt. Neurology 1984;34:666–669. Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med 1997;337:473–479. Rozga J, Podesta L, LePage E, et al. Control of cerebral oedema by total hepatectomy and extracorporeal liver support in fulminant hepatic failure. Lancet 1993;342:898–899. Shady H, Lieber CS. Blood ammonia levels in relationship to hepatic encephalopathy after propranolol. Am J Gastroenterol 1988;83:249–255. Sherlock S. Chronic portal systemic encephalopathy: update 1987. Gut 1987;28:1043–1048. Summerskill WHJ, Davidson EA, Sherlock S, et al. The neuropsychiatric syndrome associated with hepatic cirrhosis and an extensive portal collateral circulation. Q J Med 1956;25:245–266. Victor M, Adams RD, Cole M. The acquired (non-Wilsonian) type of chronic hepatocerebral degeneration. Medicine (Baltimore) 1965;44:345–396. Zieve L, Doizai M, Derr RF. Reversal of ammonia coma in rats by L-dopa: a peripheral effect. Gut 1979;20:28–32. Liver Transplantation Bird GLA, Meadows J, Goka J, et al. Cyclosporin-associated akinetic mutism and extrapyramidal syndrome after liver transplantation. J Neurol Neurosurg Psychiatry 1990;53:1068–1071. Campellone JV, Lacomis D, Kramer DJ, Van Cott AC, Giuliani MJ. Acute myopathy after liver transplantation. Neurology 1998;50:45–53. De Groen PC, Aksamit AJ, Rakela J, et al. Central nervous system toxicity after liver transplantation: role of cyclosporin and cholesterol. N Engl J Med 1987;317:861–866. Estol CJ, Faris AA, Martinez AJ, et al. Central pontine myelinosis after liver transplantation. Neurology 1989;39:493–498. Estol CJ, Lopez O, Brenner RP, et al. Seizures after liver transplantation: a clinicopathologic study. Neurology 1989;39:1297–1301. Fisher NC, Ruban E, Carey M et al. Late-onset fatal acure leukoencephalopathy in liver transplant recipient. Lancet 1997;349:1884–1885. Garg BP, Walsh LE, Pescovitz MD, et al. Neurologic complications of pediatric liver transplantation. Pediatr Neurol 1993;9:44–48. Martin MA, Massanari RM, Ngheim DD, et al. Nosocomial aseptic meningitis associated with administration of OKT3. JAMA 1988;259:2002–2005. Small SL, Fukui MB, Bramblett GT, et al. Immunosuppression-induced leukoencephalopathy from Tacrolimus (FK506). Ann Neurol 1996;40:575–580. Stein DP, Lederman RJ, Vogt DP, et al. Neurological complications following liver transplantation. Ann Neurol 1992;31:644–649.

Torocsik HV, Curless RG, Post J, et al. FK506-induced leukoencephalopathy in children with organ transplants. Neurology 1999;52:1497–1500. Truwit CL, Denaro CP, Lake JR, et al. MRI of reversible cyclosporin A-induced neurotoxicity. AJNR 1991;12:651–659. Wijdicks EFM, Dahlke LJ, Wiesner RH. Oral cyclosporine decreases severity of neurotoxicity in liver transplant recipients. Neurology 1999;52:1708–1710. Wijdicks EFM, Wiesner RH, Krom RAF. Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression. Neurology 1995;45:1962–1964. Wszolek ZK, Aksamit AJ, Ellingson RJ, et al. Epileptiform EEG abnormalities in liver transplant recipients. Ann Neurol 1991;130:37–41.

CHAPTER 149. CEREBRAL COMPLICATIONS OF CARDIAC SURGERY MERRITT’S NEUROLOGY

CHAPTER 149. CEREBRAL COMPLICATIONS OF CARDIAC SURGERY ERIC J. HEYER AND LEWIS P. ROWLAND Magnitude of the Problem Disorders of Cognition Other Complications of Open-Heart Surgery Interventional Cardiac Procedures Suggested Readings

MAGNITUDE OF THE PROBLEM In one series of 1,487 cardiac operations performed between 1984 and 1989, the mortality rate was 8.54%. Additionally, 16 patients (1.1%) had major neurologic syndromes of four types: unresponsive after surgery, awoke with signs of cerebral infarction, initially intact but had a stroke later, or dementia without focal signs. Among those who were unresponsive in the postoperative period, half died or remained comatose. The problems were attributed to atheromatous embolism, perioperative hypotension, or air embolism. In another series, up to 4% had cerebral symptoms if reactions included chronic anxiety and depression. Clinically detectable encephalopathy results in 3% to 12% of operations, but permanent cognitive disability is less common.

DISORDERS OF COGNITION In the early days of heart surgery, intellectual decline seemed inordinately common after operations performed with cardiopulmonary bypass support, even when the procedure seemed to be uncomplicated. In prospective studies, cognitive problems were seen in up to 70% of survivors, depending on the criteria used; neuropsychologic testing is most sensitive. Six months after surgery, Shaw et al. (1987) found that 3 of 259 (2%) patients seemed seriously disabled and were dependent on family members. The pathogenesis of this disorder is probably influenced by more than one of the following during cardiopulmonary bypass: type of oxygenator, type of cardiopulmonary bypass circuit, body temperature, arterial blood gas management, and use of arterial line filters. Before 1985, cardiopulmonary bypass was achieved with bubble oxygenators that produced particulate or gaseous bubbles, which could have occluded small cerebral vessels. Capillary membrane oxygenators were substituted to avoid this complication, and the frequency of serious intellectual loss occurs less often. Also, hypothermia is maintained as a protective measure, but there is uncertainty about the exact temperature (“mild,” 32 to 34°C, versus “moderate,” 28 to 32°C) to be used, although normothermia (37°C) is potentially harmful. Solid emboli are held responsible for the cerebral injury. Arterial line filters, however, reduce the number of emboli from the cardiopulmonary bypass system. The fraction of cardiac output going to the brain also determines the fraction of the embolic load reaching the brain. Maintaining cerebral blood flow by supporting autoregulation would provide sufficient but not excessive flow to support cerebral metabolism. To maintain autoregulation during cardiopulmonary bypass, blood gas values must be kept near normal when measured at 37°C even though the patient may actually be colder. In contrast, correcting the blood gases for the lower temperature would lead to the addition of carbon dioxide to the cardiopulmonary bypass system to normalize the blood gas values at the patient's hypothermic temperature; under those conditions, autoregulation would be lost. If heparin is bonded to the cardiopulmonary bypass circuit there is considerably less activation of platelets, white cells, and endothelial cells, resulting in attenuation of coagulation and the inflammatory response. Consequently, less anticoagulation may be required and blood loss decreases. The incidence of cerebral dysfunction may also decrease. Despite these precautions, however, some patients note forgetfulness, mental slowing, or difficulty concentrating. Performance on neuropsychologic tests is worst in the first week or so after surgery; months later, most patients have returned to preoperative levels. Moody et al. (1990) found many focal dilatations or small aneurysms in 90% of patients who died after cardiac surgery on bypass. The dilated areas were empty and were therefore assumed to have been sites of gas bubbles or fat emboli. In living patients, continuous transcranial or carotid Doppler measurements have detected emboli in operations performed with either membrane or bubble oxygenators. With either membrane or bubble oxygenators, emboli also arise when the aortic cannula is inserted and when the aorta is unclamped. Emboli also arise during bypass when the bubble oxygenator is used. In coronary artery bypass graft (CABG) operations, carotid Doppler studies demonstrated a mean of 62 emboli for each operation. In open-chamber cardiac operations, carotid and transcranial Doppler studies demonstrated even more cerebrally directed emboli. Times of danger included removal of the aortic side clamp, aortic cannulation, onset of cardiopulmonary bypass, and resumption of ventricular contraction. Emboli and cerebral injuries are even more numerous with aortic disease. Other monitoring systems have not been successful. Quantitative electroencephalogram does not detect impending brain damage, partly because cerebral hypothermia reduces the electroencephalogram amplitude. Infrared detection of cerebral oxygenation is beset by technical problems, including contamination of the signal with extracranial blood.

OTHER COMPLICATIONS OF OPEN-HEART SURGERY Patients with active infective endocarditis and those having a second cardiac operation are at high risk for stroke or other cerebral complications. Risk factors include impaired left ventricular function, low cardiac output, sepsis, toxemia, and impaired hemostasis. Use of aprotinin for hemostasis may decrease morbidity. Heparin-bonded cardiopulmonary bypass circuits may circumvent this issue. Controversy exists about the advantages of pulsatile or nonpulsatile perfusion during bypass.

INTERVENTIONAL CARDIAC PROCEDURES Cardiac Catheterization Strokes or transient ischemic attacks after cardiac catheterization are rare, encountered in 0.1% to 1.0% of procedures. The posterior circulation is affected more than the carotid territory. Cerebral blindness and visual field defects result. About half of those with occipital symptoms have a confusional state or memory problems that are attributed to temporal lobe ischemia. Carotid syndromes of hemiparesis, with or without language disorders, occur in 30% to 40%. About half of the syndromes abate within 48 hours. The episodes are attributed to emboli released by the guidewire or in flushing the catheter in the ascending aorta. Systemic hypotension may be responsible for some. Showers of cholesterol emboli after catheterization or cardiac surgery can cause peripheral occlusive vascular disease, with gangrene and peripheral neuropathy (cholesterol emboli syndrome). Coronary Angioplasty Transient ischemic attacks occur in about 0.2% of these procedures, presumably embolic in origin. Valvuloplasty Percutaneous balloon valvuloplasty is used to treat stenosis of pulmonary, mitral, and aortic valves. In one series, embolic stroke occurred in 3 of 26 aortic valve procedures and none of 6 mitral procedures.

Coronary Artery Bypass Graft Stroke is the major complication of CABG, and although the rate has declined, it is still reported in 1% to 5% of operations, affecting 1,000 to 3,000 people annually in the United States. Many of these patients are elderly. More than half of the episodes are transient or mild, but that leaves many with serious disability. The major recognized factors are cardiac arrhythmia during surgery, carotid artery disease, and air embolism from the left ventricle. Attention has focused on the carotid arteries, assuming that hypotension during surgery in the presence of arterial narrowing induces focal cerebral ischemia. Many strokes, however, occur in people with normal carotids or after, not during, surgery. There seems to be no advantage to defer CABG for prophylactic endarterectomy. In one series, stroke occurred in 1 of 90 patients with 50% to 90% asymptomatic carotid stenosis and 1 of 16 with 90% stenosis. Even symptomatic carotid stenosis does not seem to increase the risk prohibitively, but conclusive data are not available. A history of stroke increases the likelihood of a second stroke as a complication of CABG. Among 127 CABG patients with a history of stroke, 17 (13.4%) had a new one with surgery; 3.2% were deemed serious. Many were thought to be embolic because of atrial fibrillation. Postoperative cardiac arrhythmia is a common problem even in patients who have not had prior stroke. Persistent postoperative coma is encountered in 1% of patients. In half the cases, the cause is not apparent. The others are attributed to global ischemia or hypoxia, major hemisphere infarction with herniation, or multiple infarcts. Cardiac Transplantation In the early days of heart transplantation, neurologic complications were seen in 54% of the cases, and 20% were fatal. With time, both figures have been much reduced. Because the patients have advanced atherosclerosis, stroke is still a major risk, occurring in up to 9%. Other problems include reversible encephalopathy and seizures. Cerebral hemorrhage is rare, linked to anticoagulation or uncontrolled hypertension. Vascular headache is common. Encephalopathy occurs in about 10% of cases and is attributed to renal or hepatic failure or sepsis. Later, because of the necessary immunosuppression, opportunistic infection is the most common cause of neurologic disorder; with new antibiotics, the rate has dropped from 15% to 5%. Aspergillus, toxoplasma, and other uncommon organisms are encountered. Cytomegalovirus and herpes zoster may cause problems. Aseptic meningitis may have no detectable cause. The incidence of primary central nervous system lymphoma is increased. Osteoporosis and other complications of steroid therapy are common, and cyclosporine may cause tremor, seizures, and confusional states. SUGGESTED READINGS Aldea GS, O'Gara P, Shapira OM, et al. Effect of anticoagulation protocol on outcome in patients undergoing CABG with heparin-bonded cardiopulmonary bypass circuits. Ann Thorac Surg 1998;65:425–433. Barbut D, Lo YW, Hartman GS, et al. Aortic atheroma is related to outcome but not numbers of emboli during coronary bypass. Ann Thorac Surg 1997;64:454–459. Bendixen BH, Younger DS, Hair LS, et al. Cholesterol emboli neuropathy. Neurology 1992;42:428–430. Fessatidis I, Prapas S, Havas A, et al. Prevention of perioperative neurological dysfunction: six year prospective study of cardiac surgery. J Cardiovasc Surg 1991;32:570–574. Furlan AJ, Sila CA, Chimowitz MI, et al. Neurologic complications related to cardiac surgery. Neurol Clin 1992;10:145–166. Grote CL, Shanahan PT, Salmon P, et al. Cognitive outcome after cardiac operations. J Thorac Cardiovasc Surg 1992;104:1405–1409. Heyer EJ. Neurologic assessment and cardiac surgery. J Cardiothorac Vasc Anesth 1996;10:99–103. Hotson JR, Enzman DR. Neurological complications of cardiac transplantation. Neurol Clin 1988;6:349–365. Kirkham FJ. Recognition and prevention of neurological complications in pediatric cardiac surgery. Pediatr Cardiol 1998;19:331–345. Kosmororsky G, Hanson MR, Tomsak RL. Neuro-ophthalmic complications of cardiac catheterization. Neurology 1988;38:483–485. Lane RJM, Roche SW, Leung AAW, et al. Cyclosporine neurotoxicity in cardiac transplant recipients. J Neurol Neurosurg Psychiatry 1988;51:1434–1437. Montero C, Martinez AJ. Neuropathology of heart transplantation. Neurology 1986;36:1149–1156. Moody DM, Bell MA, Challa VA, et al. Brain microemboli during cardiac surgery or aortography. Ann Neurol 1990;28:477–486. Prevost S, Deshotels A. Quality of life after cardiac surgery. AACN Clin Issues Crit Care Nurs 1993;4:320–328. Riggle KP, Oddi MA. Spinal cord necrosis and paraplegia as complications of the intra-aortic balloon. Crit Care Med 1989;17:75–76. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 1996;335:1857–1863. Robinson M, Blumenthal JA, Burker EJ, et al. Coronary artery bypass grafting and cognitive function;a review. J Cardiopulm Rehab 1990;10:180–189. Rorick M, Furlan AJ. Risk of cardiac surgery in patients with prior stroke. Neurology 1990;40:835–837. Shapira OM, Aldea GS, Zelingher J, et al. Enhanced blood conservation and improved clinical outcome after valve surgery using heparin-bonded cardiopulmonary bypass circuits. J Cardiol Surg 1996;11:307–317. Shaw PJ, Bates D, Cartilidge NEF, et al. Long-term intellectual dysfunction following coronary artery bypass graft surgery: a six-month follow-up study. Q J Med 1987;62:259–268. Shaw PJ, Bates D, Cartilidge NEF, et al. An analysis of factors predisposing to neurological injury in patients undergoing coronary bypass operations. Q J Med 1989;267:633–646. Sila CA. Spectrum of neurologic events following cardiac transplantation. Stroke 1989;20:1586–1589. Sotaniemi KA, Mononen H, Hokkanen TE. Long-term cerebral outcome after open-heart surgery. Five-year neuropsychological follow-up study. Stroke 1986;17:410–416. Taylor KM. Improved outcome of seriously ill open-heart surgery patients: focus on reoperation and endocarditis. J Heart Lung Transplant 1993;12:S14–S18. Van der Linden J, Casimir-Ahn H. When do cerebral emboli appear during open-heart operations? Transcranial doppler study. Ann Thorac Surg 1991;51:237–241.

CHAPTER 150. BONE DISEASE MERRITT’S NEUROLOGY

CHAPTER 150. BONE DISEASE ROGER N. ROSENBERG Osteitis Deformans (Paget Disease) Fibrous Dysplasia Achondroplasia Ankylosing Spondylitis Atlantoaxial Dislocation Suggested Readings

OSTEITIS DEFORMANS (PAGET DISEASE) This chronic disease of the adult skeleton is characterized by bowing and irregular flattening of the bones. Any or all skeletal bones may be affected, but the tibia, skull, and pelvis are the most frequent sites. Except for the skeletal deformities and pain, the disease causes disability only when the skull or spine is involved. Pathology In affected bones, there is an imbalance between formation and resorption of bone. In most cases, there is a mixture of excessive bone formation and bone destruction. The areas of bone destruction are filled with hyperplastic vascular connective tissue. New bone formation may occur in the destroyed areas in an irregular disorganized manner. The metabolic disturbance is unknown. Incidence There is a postmortem incidence of 3% in patients over 40 years of age. Men and women are equally affected. The common age at onset is in the fourth to sixth decades; it is rare before age 30. Symptoms and Signs Two types of neurologic symptoms appear: those due to the abnormalities in bone and those due to arteriosclerosis, a common accompaniment. The cerebral manifestations that occur with arteriosclerosis are identical to those seen in patients with arteriosclerosis in the absence of Paget disease. The neurologic defects of osteitis deformans are usually related to pressure on the central nervous system or the nerve roots by the overgrowth of bone. Convulsive seizures, generalized or neuralgic head pain, cranial nerve palsies, and paraplegia occur in a few cases. Deafness caused by pressure on the auditory nerves is the most common symptom; unilateral facial palsy is the next most common symptom. Loss of vision in one eye, visual field defects, or exophthalmos may occur when the sphenoid bone is affected. Compression of the spinal cord is more common than compression of the cerebral substance, which is extremely rare except when there is sarcomatous degeneration of the lesions. Platybasia may occur in advanced cases. Paget disease has been described in a patient with basilar impression and Arnold-Chiari type 1 malformation. Laboratory Data The serum calcium content is normal, and the serum phosphorus is normal or only slightly increased. Serum alkaline phosphatase activity is increased; the level varies with the extent and activity of the process. It may be only slightly elevated when the disease is localized to one or two bones. Diagnosis The diagnosis of Paget disease is made from the patient's appearance and the characteristic radiographic changes. Involvement of the skull in advanced cases is manifested by a generalized enlargement of the calvarium, anteroflexion of the head, and depression of the chin on the chest. When the spine is involved, the patient's stature is shortened; the spine is flexed forward and its mobility is greatly reduced. Radiographically, the skull shows areas of increased bone density with loss of normal architecture, mingled with areas in which the density of the bone is decreased (Fig. 150.1). The margins of the bones are fuzzy and indistinct. The general appearance is that of an enormous skull with the bones of the vault covered with “cotton wool.” In advanced cases, there may be a flattening of the base of the skull on the cervical vertebrae ( platybasia) with signs of damage to the lower cranial nerves, medulla, or cerebellum. Both computed tomography (CT) and magnetic resonance imaging (MRI) aid diagnosis ( Fig. 150.2).

FIG. 150.1. Osteitis deformans (Paget disease) of the skull. (Courtesy of Dr. Juan Taveras.)

FIG. 150.2. Paget disease. Basilar invagination. A: Using bone windows, axial computed tomography shows the foramen magnum projected within the posterior fossa. Intradiploic calcific density with “cotton wool” appearance is typical of Paget disease. B: Higher section, using soft tissue windows, demonstrates obliteration of basal cisterns and brainstem compression caused by basilar invagination. C: Axial T2-weighted magnetic resonance image shows prominent mottled signal in the diploic space. D: Sagittal T1-weighted magnetic resonance image confirms impingement of brainstem by dens. (Courtesy of Drs. J.A. Bello and S.K. Hilal.)

Diagnosis may be difficult if the clinical symptoms are mainly neurologic. In these instances, radiographs of the pelvis and legs or a general survey of the entire skeleton may establish the diagnosis. Rarely, it may be impossible to distinguish monophasic Paget disease of the skull from osteoblastic metastases. Search for a primary neoplasm, particularly in the prostate or biopsy of one of the lesions in the skull may be necessary in those cases. Course The course is variable but usually extends over decades. The neurologic lesions seldom lead to serious disability other than deafness, convulsive seizures, or compression of the spinal cord. Treatment There is no specific therapy. Calcitonin is given to inhibit the osteolytic process. Salmon calcitonin is given in subcutaneous injections of 50 to 100 units daily. Improvement of osteolytic lesions and reversal of neurologic manifestations have been noted with long-term therapy. About 25% of the patients develop serum antibodies to salmon calcitonin, sometimes in titers high enough to make the person resistant to the hormonal action of calcitonin; under these circumstances, human calcitonin may be effective. An alternate therapy is disodium editronate in a dosage of 5.0 mg/kg body weight daily for 6 months. The value of either medical therapy can be evaluated by reduction of serum levels of alkaline phosphatase measured at 4-month intervals and annual radiographs of specific lesions. Decompression of the spinal cord may be indicated for myelopathy secondary to stenosis created by the enlarged vertebrae. Similarly, platybasia may lead to decompression of the posterior fossa.

FIBROUS DYSPLASIA The skull and the bones in other parts of the body are occasionally involved by a process characterized by small areas of bone destruction or massive sclerotic overgrowth. The clinical picture of fibrous dysplasia is related to the site and extent of the bone overgrowth. Sassin and Rosenberg (1968) described involvement of bones of the skull in 50 cases as follows: frontal, 28; sphenoid, 24; frontal and sphenoid, 18; temporal, 8; facial, 15; parietal, 6; and occipital, 8. Diffuse involvement of the entire skull produces leontiasis ossea, with exophthalmos, optic atrophy, and cranial nerve palsies ( Fig. 150.3).

FIG. 150.3. Fibrous dysplasia. Computed tomographies. A: Axial contrast-enhanced scan shows proptosis on right with abnormal soft tissue enhancement within orbit and middle cranial fossa. B: Bone window depicts pronounced thickening of sphenoid bone. (Courtesy of Dr. T.L. Chi.)

In addition to the disfiguration of the skull in the polyostotic form, symptoms of the monostotic form of the disease include headache, convulsions, exophthalmos, optic atrophy, and deafness. Symptoms may begin at any age, but onset usually occurs in early adult life. The family history is negative, and there is no racial or sexual predominance. A polyostotic form of the disease is characterized by cafe-au-lait spots, endocrine dysfunction with precocious puberty in girls, and involvement of the femur (shepherd's crook deformity). Mutations in the Arg201 codon of the Ys G protein subunit have been described in patients with fibrous dysplasia. These Ys G as mutations may be seen in monostotic or polyostotic patients and in the McCune-Albright syndrome that includes multiple endocrinopathies and cafe-au-lait lesions with fibrous dysplasia.

ACHONDROPLASIA Achondroplasia (chondrodystrophy) is the most frequent form of skeletal dysplasia causing dwarfism. It is characterized by short arms and legs, lumbar lordosis, and enlargement of the head caused by mutations in the fibroblast growth factor receptor 3 gene (FGFR3). The disease is rare and is estimated to occur in 15 of 1 million births in the United States. It is usually inherited as an autosomal dominant trait. Symptoms of involvement of the nervous system sometimes develop as a result of hydrocephalus, compression of the medulla and cervical cord at the level of the foramen magnum, compression of the spinal cord by ruptured intervertebral disk, and bone compression of the lower thoracic or lumbar cord. Convulsive seizures, ataxia, and paraplegia are the most common symptoms. Mental development is usually normal. The diagnosis is made from the characteristic body configuration of short arms and legs, normal-size trunk, enlargement of the head, and changes in the radiographs of the skeleton (Fig. 150.4). Many affected infants die in the perinatal period, although a normal lifespan is possible for patients with less severe involvement of the bones.

FIG. 150.4. Skull radiograph showing typical malformation of achondroplasia. The clivus is shortened.

Shunting procedures may be needed for hydrocephalus caused by involvement of the bones at the base of the skull. Laminectomy is indicated for signs of cord compression. The mutations described in 1994 in the FGFR3 gene at 4p are usually new mutations and result in autosomal dominant inheritance. The gene product is expressed in cartilage. A frequent FGFR3 mutation is a G1138A codon mutation with GGG to AGG or CGG substitutions, resulting in an exchange of glycine at position 380 in the FGFR3 protein to arginine. As a result of this mutation, a gain of negative function results, producing an inactive fibroblast growth factor receptor and resultant dwarfism.

ANKYLOSING SPONDYLITIS This inflammatory disorder affects ligamentous insertions into bones; at first, it usually affects the sacroiliac joints and lumbar spine. In some patients, the entire spine is involved, with ossification of the ligaments and fusion of the vertebra. The spine becomes rigid and susceptible to a variety of disorders that may affect the spinal cord, including fractures and dislocations, atlantooccipital dislocation, and spinal stenosis. The condition is common, affecting an estimated 1.4% of the general population. It only rarely, however, causes symptoms and signs of myelopathy. A cauda equina syndrome may appear in patients with long-standing spondylitis. Signs and symptoms are symmetric, with weakness, wasting, and sensory loss in lumbosacral myotomes. Bladder and bowel are commonly affected, and pain may be severe. The mechanism is not clear. Although concomitant arachnoiditis has been suspected as the cause, the syndrome appears late, when there is little evidence that the underlying spondylitis is active. Moreover, there is little inflammation at postmortem examination, which is likely to show chronic fibrosis. There is erosion of posterior bone elements, and, in earlier days, myelography showed enlargement of the caudal sac and prominent diverticulae of the arachnoid. CT shows similar pathology, but MRI is more illuminating, showing nerve root thickening and sometimes enhancement of dura and nerve roots; that pattern suggests inflammation of the arachnoid structures, supporting the earlier theory. Surgery is generally ineffective and has sometimes been deleterious, although there have been rare reports of some relief. Steroid therapy has been similarly without benefit.

ATLANTOAXIAL DISLOCATION Subluxation of C-1 on C-2 occurs in many conditions that render the odontoid process of C-2 ineffective as a stabilizing post. This occurs most often as a complication of cervical trauma but also occurs as a congenital malformation (alone or in combination with other anomalies of the cervical spine or cranium) and is seen with disproportionate frequency with Down syndrome, ankylosing spondylitis, and rheumatoid arthritis. It can be demonstrated with plain spine films, CT, or MRI. There is risk of cervical myelopathy or medullary compression, and sudden death has been reported. For symptomatic cases, surgical stabilization is indicated. For asymptomatic cases, there has to be consideration of the risks of surgery against uncertain risks of no surgery. A general recommendation is to consider stabilization or decompression if imaging shows deformation of the neuroaxis, symptomatic or not. A closed reduction and brace immobilization was successfully applied to a patient with traumatic bilateral rotatory dislocation of the atlantoaxial joints. SUGGESTED READINGS Osteitis Deformans (Paget Disease) Boutin RD, et al. Complications in Paget disease at MR imaging. Radiology 1998;209:641–651. Chen J-R, Rhee RSC, Wallach S, et al. Neurologic disturbances in Paget disease of bone: response to calcitonin. Neurology 1979;29:448–457. Davis DP, et al. Coccygeal fracture and Paget's disease presenting as acute cauda equina syndrome. J Emerg Med 1999;17:251–254. Douglas DL, Duckworth T, Kanis JA, et al. Spinal cord dysfunction in Paget's disease of bone. Has medical treatment a vascular basis? J Bone Joint Surg Br 1981;63B:495–503. Douglas DL, Kanis JA, Duckworth T, et al. Paget's disease: improvement of spinal cord dysfunction with diphosphate and calcitonin. Metab Bone Dis Relat Res 1981;3:327–335. Gandolfi A, Brizzi R, Tedesghi F, et al. Fibrosarcoma arising in Paget's disease of the vertebra: review of the literature. Surg Neurol 1983;13:72–76. Ginsberg LE, Elster AD, Moody DM. MRI of Paget disease with temporal bone involvement presenting with sensorineural hearing loss. J Comput Assist Tomogr 1992;16:314–316. Goldhammer V, Braham J, Kosary IZ. Hydrocephalic dementia in Paget's disease of the skull: treatment by ventriculoatrial shunt. Neurology 1979;29:513–516. Hadjipavlou A, Lander P. Paget disease of the spine. J Bone Joint Surg Am 1991;73:1376–1381. Iglesias-Osma C. Paget's disease of bone and basilar impression with an Arnold-Chiari type-1 malformation. Ann Med Intern 1997;14:519–522. Roberts MC, Kressel HY, Fallon MD, et al. Paget disease: MR imaging findings. Radiology 1989;173:341–345. Singer F, Krane S. Paget's disease of bone. In: Avioli L, Krane S, eds. Metabolic bone disease and clinically related disorders, 2nd ed. Philadelphia: WB Saunders, 1990. Wallach S. Treatment of Paget's disease. Adv Neurol 1982;27:1–43. Weisz GM. Lumbar spinal canal stenosis in Paget's disease. Spine 1983;8:192–198. Fibrous Dysplasia Albright F. Polyostotic fibrous dysplasia: a defense of the entity. J Clin Endocrinol Metab 1947;7:307–324. Candeliere GA, Roughley PJ, Glorieux FH. Polymerase chain reaction-based technique for the selective enrichment and analysis of mosaic Arg201 mutations in G alpha S from patients with fibrous dysplasia of bone. Bone 1997;21:201–206. Casselman JW, DeJong I, Neyt L, et al. MRI in craniofacial fibrous dysplasia. Neuroradiology 1993;35:234–237. Cole DE, Fraser FC, Glorieux FH, et al. Panostotic fibrous dysplasia: a congenital disorder of bone with unusual facial appearance, bone fragility, hyperphosphatasemia, and hypophosphatemia. Am J Med Genet 1983;14:725–735. Finney HL, Roberts JS. Fibrous dysplasia of the skull with progressive cranial nerve involvement. Surg Neurol 1976;6:341–343. Katz BJ, Nerad JA. Ophthalmic manifestations of fibrous dysplasia: a disease of children and adults. Ophthalmology 1998;105:2207–2215. Mohammadi-Araghi H, Haery C. Fibro-osseous lesions of craniofacial bones. The role of imaging. Radiol Clin North Am 1993;31:121–134. Saper JR. Disorders of bone and the nervous system: the dysplasias and premature closure syndromes. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. New York: Elsevier-North Holland, 1979. Sassin JF, Rosenberg RN. Neurologic complications of fibrous dysplasia of the skull. Arch Neurol 1968;18:363–376. Tehranzadeh J, et al. Computed tomography of Paget disease of the skull versus fibrous dysplasia. Skeletal Radiol 1998;27:664–672. Achondroplasia Aryanpur J, Hurko O, Francomano C, et al. Craniocervical decompression for cervicomedullary compression in pediatric patients with achondroplasia. J Neurosurg 1990;73:375–382. Dandy WF. Hydrocephalus in chondrodystrophy. Bull Johns Hopkins Hosp 1921;32:5–10.

Denis JP, Rosenberg HS, Ellsworth CA Jr. Megalocephaly, hydrocephalus and other neurological aspects of achondroplasia. Brain 1961;84:427–445. Duvoisin RC, Yahr MD. Compressive spinal cord and root systems in achondroplastic dwarfs. Neurology 1962;12:202–207. Hamamci N, Hawran S, Biering-Sorensen F. Achondroplasia and spinal cord lesion. Three case reports. Paraplegia 1993;31:375–379. Hecht JT, Butler IJ. Neurologic morbidity associated with achondroplasia. J Child Neurol 1990;5:84–97. Horton WA. Fibroblast growth factor receptor 3 and the human chondrodysplasias. Curr Opin Pediatr 1997;9:437–442. Kahandovitz N, Rimoin DL, Sillence DO. The clinical spectrum of lumbar spine disease in achondroplasia. Spine 1982;7:137–140. McKusick VA. 1997 Albert Lasker Award for Special Achievement in Medical Science. Observations over 50 years concerning intestinal polyposis, Marfan syndrome, and achondroplasia. Nat Med 1997;3:1065–1068. Shiang R, Thompson LH, Zhu Y-Z, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994;78:335–342. Thomas IT, Frias JL. The prospective management of cervicomedullary compression in achondroplasia. Birth Defects 1989;25:83–90. Thompson NM, et al. Neuroanatomic and neuropsychological outcome in school-age children with achondroplasia. Am J Med Genet 1999;88: 145–153. Wynne-Davies R, Walsh WK, Gormley J. Achondroplasia and hypochondroplasia. Clinical variation and spinal stenosis. J Bone Joint Surg Br 1981;63B:508–515. Ankylosing Spondylitis Bruining K, Weiss K, Zelfer B, et al. Arachnoiditis in the cauda equina syndrome of longstanding ankylosing spondylitis. J Neuroimag 1993;3:55–57. Fox MW, Onofrio BM, Kilgore JE. Neurological complications of ankylosing spondylitis. J Neurosurg 1993;78:871–878. Mitchell MJ, Sartoris DJ, Moody D, et al. Cauda equina syndrome complicating ankylosing spondylitis. Radiology 1990;175:521–525. Rowed DW. Management of cervical spinal cord injury in ankylosing spondylitis: intervertebral disc as a cause of cord compression. J Neurosurg 1992;77:241–246. Rubenstein DJ, Alvarez O, Ghelman B, et al. Cauda equina syndrome complicating ankylosing spondylitis. J Comput Assist Tomogr 1989;13: 511–513. Shaw PJ, Allcutt DA, Bates D, et al. Cauda equina syndrome with multiple lumbar arachnoid cysts in ankylosing spondylitis: improvement following surgical therapy. J Neural Neurosurg Psychiatry 1990;53:1076–1079. Sparling M, Bartelson JD, McLeod RA, et al. MRI of arachnoid diverticula associated with cauda equina syndrome in ankylosing spondylitis. J Rheumatol 1989;16:1335–1337. Tullous MW, Skerhut HEI, Story JL, et al. Cauda equina syndrome of long-lasting ankylosing spondylitis. J Neurosurg 1990;73:441–447. Atlantoaxial Dislocation Crockard HA, Heiman AE, Stevens JM. Progressive myelopathy secondary to odontoid fractures: clinical, radiological, and surgical features. J Neurosurg 1993;78:579–586. Elliott S, Morton RE, Whitelaw RA. Atlantoaxial instability and abnormalities of the odontoid in Down's syndrome. Arch Dis Child 1988;63:1484–1489. Floyd AS, Learmouth ID, Mody G, et al. Atlantoaxial instability and neurologic indicators in rheumatoid arthritis. Clin Orthop 1989;241:177–182. Martich V, Ben Ami T, Yousefzadeh DK, et al. Hypoplastic posterior arch of C1 in children with Down syndrome: a double jeopardy. Radiology 1992;183:125–128. Rowland LP, Shapiro JH, Jacobson HG. Neurological syndromes associated with congenital absence of the odontoid process. Arch Neurol Psychiatry 1958;80:286–291. Sorin S, Askari I, Moskowitz RW. Atlantoaxial subluxation as a complication of early ankylosing spondylitis. Arthritis Rheum 1979;22:273–276. Stevens JM, Chong WK, Barber C, et al. A new appraisal of abnormalities of the odontoid process associated with atlantoaxial subluxation and neurological disability. Brain 1994;117:133–148. Wise JJ, Cheney R, Fischgrund J. Traumatic bilateral rotatory dislocation of the atlanto-axial joints: a case report and review of the literature. J Spinal Disord 1997;10:451–453. Yamashita Y, Takahashi M, Sakamoto Y, et al. Atlantoaxial subluxation. Radiography and MRI correlated to myelopathy. Acta Radiol 1989;10:135–140.

CHAPTER 151. RENAL DISEASE MERRITT’S NEUROLOGY

CHAPTER 151. RENAL DISEASE NEIL H. RASKIN Uremic Encephalopathy Uremic Neuropathy Dialysis Dysequilibrium Syndrome Dialysis Dementia Pseudotumor Cerebri Neurologic Complications of Renal Transplantation Suggested Readings

Uremia is a term used to describe a constellation of signs and symptoms in patients with severe azotemia caused by acute or chronic renal failure; symptomatic renal failure is an acceptable definition. The clinical features of the neurologic consequences of renal failure do not correlate well with any single biochemical abnormality but seem to be related to the rate of development of renal failure. This chapter summarizes the features of uremic encephalopathy and neuropathy and the distinctive neurologic complications of dialysis and renal transplantation.

UREMIC ENCEPHALOPATHY In uremia, as in other metabolic encephalopathies, there is a continuum of signs of neurologic dysfunction, including dysarthria, instability of gait, asterixis, action tremor, multifocal myoclonus, and sensorial clouding. One or more of these signs may predominate, but fluctuation of clinical signs from day to day is characteristic. The earliest most reliable indication of uremic encephalopathy is sensorial clouding. Patients appear fatigued, preoccupied, and apathetic; they have difficulty concentrating. Obtundation becomes more apparent as perceptual errors, defective memory, and mild confusion become evident. Illusions and perceptions sometimes progress to frank visual hallucinations. Asterixis is almost always present once sensorial clouding appears: It is most effectively elicited by having the patient hold the arms outstretched in fixed hyperextension at the elbow and wrist, with the fingers spread apart. After a latency of up to 30 seconds, flexion-extension (“flapping”) of the fingers at the metacarpophalangeal joints and at the wrist appears arrhythmically and at irregular intervals. Multifocal myoclonus refers to visible twitching of muscles that is sudden, arrhythmic, and asymmetric, involving muscles first in one locus and then in another and affecting chiefly the face and proximal limbs. It is a strong indication of a severe metabolic disturbance and usually does not appear until stupor or coma has supervened. In uremia, asterixis and myoclonus may be so intense that muscles appear to fasciculate, giving rise to the term uremic twitching. This form of myoclonus probably signifies cortical irritability; it is, at times, difficult to distinguish from a multifocal seizure. Tetany is commonly associated with myoclonus and other signs of encephalopathy. It may be overt, with spontaneous carpopedal spasms, or latent, manifested by a Trousseau sign. The spasms originate in abnormal peripheral nerve discharges. In uremic patients, tetany does not usually respond to injections of calcium and occurs despite metabolic acidosis (which inhibits hypocalcemic tetany). The restless-legs syndrome occurs in 40% of uremic patients and probably is an encephalopathic symptom. This syndrome comprises creeping, crawling, prickling, and pruritic sensations deep within the legs. These sensations are almost always worse in the evening; they are relieved by movement of the limbs. Clonazepam, levodopa, dopamine agonists, opioids, and some anticonvulsants are effective in terminating this syndrome. Alterations in limb tone appear as encephalopathy progresses and brainstem function is compromised. Muscle tone is usually heightened and is sometimes asymmetric. Eventually, decorticate posturing may appear in preference to decerebrate attitudes. Focal motor signs are present in about 20% of patients; these signs often clear after hemodialysis. Convulsions are usually a late manifestation of uremic encephalopathy. In the older literature, convulsions were thought to occur far more often than is now reported; this may have been the result of failing to distinguish hypertensive encephalopathy from uremia, which may coexist. Hypertensive retinopathy and papilledema are major signs that distinguish the two conditions; further, focal signs such as aphasia or cortical blindness are much more common in hypertensive brain disease than in uremia. The treatment of recurring uremic convulsions is not straightforward because the pharmacokinetics of phenytoin are altered in uremic patients. In uremia, plasma protein binding of phenytoin is decreased so much that the unbound fraction of the drug is two to three times more than that found in normal plasma. In uremic patients, however, the volume of distribution of the drug is larger, and there is an increased rate of conversion of phenytoin to hydroxylated derivatives, resulting in lower total serum concentrations of the drug for any given dose. This combination of factors allows the physician to administer the usual dosage of phenytoin (300 to 400 mg daily) to a uremic patient and attain therapeutic unbound levels of the drug despite lower total serum levels (i.e., 5 to 10 mg/L rather than 10 to 20 mg/L). Meningeal signs occur in about 35% of uremic patients; half of those affected have cerebrospinal fluid (CSF) pleocytosis. CSF protein elevations greater than 60 mg/dL occur in 60% of uremic patients; in 20%, the CSF protein exceeds 100 mg/dL. CSF protein content may return to normal in the immediate posthemodialysis period. The increase in CSF protein is caused by an alteration in the permeability properties of the brain's capillary endothelial cells adjacent to the CSF, which have tight intercellular junctions. There are no specific pathologic alterations of brain in uremic encephalopathy; cerebral use of oxygen is depressed, as it is in other metabolic encephalopathies, because of a primary interference with synaptic transmission. Depressed cerebral metabolic rate and clinical state usually change together but are probably independent reflections of generally impaired neuronal functions. The profundity of uremic encephalopathy correlates only in a general way, and sometimes poorly, with biochemical abnormalities in the blood. Cerebral acidosis has been suggested as a possible mechanism, but CSF pH is usually normal. Brain calcium is increased by 50% and seems to be due to excess circulating parathyroid hormone, which is nondialyzable. It is not clear whether calcium changes are related to the cerebral dysfunction. The rapid clearing of uremic encephalopathy after dialysis suggests that small to moderately sized water-soluble molecules are responsible for the encephalopathy. Excessive accumulation of toxic organic acids overwhelms the normal mechanisms for excluding such compounds from the brain and may be important. These organic acids may block transport systems of the choroid plexus and of glia that normally remove metabolites of some neurotransmitters in brain. Furthermore, there is a nonspecific increase in cerebral membrane permeability in uremia, and this may permit greater entry into brain of uremic toxins such as the organic acids, which further derange cerebral function. Erythropoietin is often given to patients on long-term dialysis to correct the anemia. In the process, cognitive functions may improve.

UREMIC NEUROPATHY Peripheral neuropathy is the most common neurologic consequence of chronic renal failure. It is a distal, symmetric, mixed sensorimotor neuropathy affecting the legs more than the arms. It is clinically indistinguishable from the neuropathies of chronic alcohol abuse or diabetes mellitus. The rate of progression, severity, prominence of motor or sensory signs, and prevalence of dysesthesia vary. It is several times more common in men than in women. The symptom of burning feet was considered a common feature of uremic neuropathy but probably resulted from removal of water-soluble thiamine by hemodialysis, and with near universal B vitamin replacement, this syndrome is now rare. The rate of progression of uremic neuropathy varies widely; in general, it evolves over several months but may be fulminant. Among most patients who enter chronic hemodialysis programs, the neuropathy stabilizes or improves slowly. Patients with mild neuropathy often recover completely, but those who begin dialysis with severe neuropathy rarely recover even after several years. Lack of improvement or progression of symptoms while on hemodialysis may suggest an alternative diagnosis, such as chronic inflammatory demyelinating polyneuropathy. Patients in chronic renal failure are also more susceptible to drugs that are normally excreted in the urine; for this reason, there may be prolonged paralysis after administration of neuromuscular blocking agents as an aid to endotracheal intubation, and the prolonged paralysis may be mistaken for peripheral neuropathy. An accelerated neuropathy of renal failure may progress so rapidly that it is mistaken for the Guillain-Barré syndrome.

Successful renal transplantation has a clear, predictable, and beneficial effect on uremic neuropathy. Motor nerve conduction velocities increase within days of transplantation. There is progressive improvement for 6 to 12 months, often with complete recovery, even in patients with severe neuropathy before transplantation. Pathologically, this neuropathy is usually a primary axonal degeneration with secondary segmental demyelination, probably as a result of a metabolic failure of the perikaryon; there is also a predominantly demyelinative type. Because uremic neuropathy improves with hemodialysis, it seems evident that the neuropathy results from the accumulation of dialyzable metabolite. These substances may be in the “middle molecule� (300 to 2,000 Da) range; compounds of this size cross dialysis membranes more slowly than smaller molecules such as creatinine and urea, which are the usual measures of chemical control of uremia. Supporting this contention are observations that control of neuropathy in some patients depends on increased hours of dialysis each week (beyond that necessary for chemical control of uremia) and that peritoneal dialysis seems to be associated with a lower incidence of neuropathy. The peritoneal membrane seems to permit passage of some molecules more readily and selectively than the cellophane membrane used in hemodialysis. The transplanted kidney deals effectively with substances of different molecular size; the resulting elimination of middle molecules could explain the invariable improvement of the neuropathy after transplantation. There is a parathormone-induced increase in calcium in peripheral nerves in experimental uremia, which causes slowed nerve conduction velocity; these changes can be prevented by prior parathyroidectomy. In human uremic patients, circulating parathormone levels correlate inversely with nerve conduction velocities. It seems unlikely, however, that parathormone is involved in uremic neuropathy because the hormone is nondialyzable, and hyperparathyroidism itself is not usually associated with neuropathy.

DIALYSIS DYSEQUILIBRIUM SYNDROME Headache, nausea, and muscle cramps attend hemodialysis in more than 50% of patients; in somewhat over 5%, obtundation, convulsions, or delirium may occur. The cerebral sequelae are usually seen with rapid dialysis at the outset of a dialysis program; symptoms usually appear toward the third or fourth hour of a dialysis run but occasionally appear 8 to 24 hours later. The syndrome is usually self-limited, subsiding in hours, but delirium may persist for several days. Some patients become exophthalmic because of increased intraocular pressure at the height of the syndrome. Other clinical correlates include increased intracranial pressure, papilledema, and generalized electroencephalographic slowing. Shift of water into brain is probably the proximate cause of dysequilibrium. Rapid reduction of blood solute content cannot be paralleled by brain solutes because of the blood–brain barrier. An osmotic gradient is produced between blood and brain causing movement of water into brain, which results in encephalopathy, cerebral edema, and increased intracranial pressure. The osmotically active substances retained in brain have not yet been identified.

DIALYSIS DEMENTIA A distinctive, progressive, usually fatal encephalopathy may occur in patients who are chronically dialyzed for periods that exceed 3 years. The first symptom is usually a stammering, hesitancy of speech, and, at times, speech arrest. The speech disorder is intensified during and immediately after dialysis and at first may be seen only during these periods. A thought disturbance is usually evident, and there is a consistent electroencephalogram abnormality, with bursts of high-voltage slowing in the frontal leads. As the disorder progresses, speech becomes more dysarthric and aphasic; dementia and myoclonic jerks usually become apparent ( Table 151.1) at this time. The other elements of the encephalopathy include delusional thinking, convulsions, asterixis, and occasionally focal neurologic abnormalities. Early in the course, diazepam is effective in lessening myoclonus and seizures and in improving speech; it becomes less effective later. The CSF is unremarkable. Increased dialysis time and renal transplantation do not seem to alter the course of the disease. No distinctive abnormalities have been found in brain at autopsy.

TABLE 151.1. CLINICAL FEATURES OF DIALYSIS DEMENTIA

The geographic variation in the incidence of dialysis dementia suggests a neurotoxin. Aluminum content is consistently elevated in the cerebral gray matter of patients who die from this condition. Municipal water supplies heavily contaminated with aluminum have been linked to the syndrome in epidemiologic studies. Another possible source is absorption of aluminum from orally administered phosphate-binding agents that are given to uremic patients. Plasma protein binding of aluminum retards the removal of aluminum during dialysis even when an aluminum-free dialysate is used. Nevertheless, there have been several reports of remission of dialysis dementia when deferoxamine was used to remove aluminum from the diet, from the dialysate, or from the patient. Cerebral aluminum intoxication, still an unconfirmed hypothesis, seems to be the most likely possibility at this time. Brain GABA levels are reduced in numerous regions, but the meaning of this finding is not clear.

PSEUDOTUMOR CEREBRI Patients in chronic renal failure may be at increased risk for benign intracranial hypertension. There has been no formal epidemiologic study, but several cases have been reported. In the experience of Guy et al. (1990), patients in renal failure seem more likely to lose vision, but fenestration of the optic nerve sheath was effective in improving vision in several of them.

NEUROLOGIC COMPLICATIONS OF RENAL TRANSPLANTATION A curious vulnerability to certain brain tumors and unusual infections of the nervous system occur in patients who have undergone transplantation; however, cerebral infarction is the most common neurologic complication. The risk that a lymphoma will develop after a transplant is about 35 times greater than normal; this increased risk depends almost entirely on the increased incidence of primary central nervous system lymphoma. Brain tumors appear between 5 and 46 months after transplantation. The resulting clinical syndromes include increased intracranial pressure, rapidly evolving focal neurologic signs, or combinations of these. Convulsions are rare. A remarkable characteristic of primary lymphomas is the response to radiotherapy; survivals of 3 to 5 years are not unusual. Systemic fungal infections are found at autopsy in about 45% of patients who have been treated with renal transplantation and immunosuppression; brain abscess formation occurs in about 35% of these patients. In almost all cases, the primary source of infection is in the lung. Chest radiographs and the presence of fever aid in differentiating fungal brain abscess from brain tumor in recipients of transplants. Aspergillus has a unique predilection for dissemination to brain and accounts for most fungal brain abscesses; candida, nocardia, and histoplasma are found in the others. The clinical syndrome resulting from these infections is usually delirium accompanied by seizures. Headache, stiff neck, and focal signs also occur but not commonly. The CSF is often remarkably bland, and brain biopsy may be the only reliable way to establish a diagnosis. The distinction of fungal brain abscess from possibly radiosensitive brain tumor makes it important to consider this procedure. SUGGESTED READINGS

Adams HP, Dawson G, Coffman TJ, Corry RI. Stroke in renal transplant recipients. Arch Neurol 1986;43:113–115. Altmann P, Al-Salihi F, Butter K, et al. Serum aluminum levels and erythrocyte dihydropteridine reductase activity in patients on hemodialysis. N Engl J Med 1987;317:80–84. Babb AL, Ahmad S, Bergstrom J, Scribner BH. The middle molecule hypothesis in perspective. Am J Kidney Dis 1981;1:46–50. Bolton CF, Young GB. Neurological complications of renal disease. London: Butterworths, 1990. Bucher SF, Seelos KC, Oertel WH, et al. Cerebral generators involved in the pathogenesis of the restless legs syndrome. Ann Neurol 1997;41:639–645. Guy J, Johnston PK, Corbett JJ, et al. Treatment of visual loss in pseudotumor cerebri with uremia. Neurology 1990;40:28–32. Hamed LM, Winward KE, Glaser JS, et al. Optic neuropathy in uremia. Am J Ophthalmol 1989;108:30–35. Healton EB, Brust JCM, Feinfeld DA, Thomson GE. Hypertensive encephalopathy and the neurologic manifestations of malignant hypertension. Neurology 1982;32:127–132. Lederman RJ, Henry CF. Progressive dialysis encephalopathy. Ann Neurol 1978;4:199–204. Mattana J, Effiong C, Gooneratne R, Singhal PC. Outcome of stroke in patients undergoing hemodialysis. Arch Intern Med 1998;158:537–541. McCarthy JT, Milliner DS, Johnson WJ. Clinical experience with desferrioxamine in dialysis patients with aluminum toxicity. Q J Med 1990;74:257–276. Nissenson AR, Nimer SD, Wolcott DL. Recombinant human erythropoietin and renal anemia: molecular biology, clinical efficacy, and nervous system effects. Ann Intern Med 1991;114:402–416. Pastan S, Bailey J. Dialysis therapy. N Engl J Med 1998;338:1428–1437. Patchell RA. Neurological complications of organ transplantation. Ann Neurol 1994;36:688–703. Raskin NH, Fishman RA. Neurologic disorders in renal failure. N Engl J Med 1976;294:143–148, 204–210. Ropper AH. Accelerated neuropathy of renal failure. Arch Neurol 1993;50:536–539. Russo LS, Beale G, Sandroni S, et al. Aluminum intoxication in undialyzed adults with chronic renal failure. J Neurol Neurosurg Psychiatry 1992;55:697–700. Said G, Boudier L, Selva J, et al. Patterns of uremic polyneuropathy. Neurology 1983;33:567–574. Sidhom OA, Odeh YK, Krumlovsky FA, et al. Low-dose prazosin in patients with muscle cramps during hemodialysis. Clin Pharm Ther 1994;56:445–451. Wills MR, Savory J. Aluminum and chronic renal failure; sources, absorption, transport, and toxicity. Crit Rev Clin Lab Sci 1989;27:59–107.

CHAPTER 152. RESPIRATORY CARE: DIAGNOSIS AND MANAGEMENT MERRITT’S NEUROLOGY

CHAPTER 152. RESPIRATORY CARE: DIAGNOSIS AND MANAGEMENT STEPHAN A. MAYER AND MATTHEW E.FINK Respiratory Physiology Neurologic Diseases with Primary Respiratory Dysfunction Management of Respiratory Failure in Neurologic Diseases Suggested Readings

Many different problems are encountered in a neurologic intensive care unit (ICU); all patients share a common need for meticulous nursing care and cardiorespiratory monitoring to prevent a life-threatening complication. Diagnosis is rarely a problem; the major concern in the ICU is treatment of neurologic disease and the medical complications that determine survival and recovery. Neurologic patients who require ICU treatment frequently have a depressed level of consciousness, impaired airway protection due to depressed cough and gag reflexes, immobilization and paralysis, or oropharyngeal and respiratory muscle weakness, all of which predispose to pulmonary complications and respiratory failure. In fact, respiratory monitoring and support is the most common reason for admission of neurologic patients to the ICU.

RESPIRATORY PHYSIOLOGY Respiratory failure occurs when gas exchange is impaired. The diagnosis of respiratory failure depends on arterial blood gas analysis. PaO 2 less than 60 mm Hg or PaCO 2 greater than 50 mm Hg unequivocally defines respiratory failure. There are warning signs, however, of deteriorating ventilatory function before respiratory failure is overt. Patients with neurologic disease often do not complain of dyspnea. The premonitory signs of mild respiratory failure include restlessness, insomnia, confusion, tachycardia, tachypnea, diaphoresis, asterixis, and headache. When muscle weakness is the problem, use of accessory muscles, dysynchronous breathing, and paradoxical respirations (inward movement of the abdomen with inspiration) may be observed. Advanced respiratory failure leads to cyanosis, hypotension, and coma. It is impossible to predict PaO 2 and PaCO2 from clinical signs; measurement of arterial blood gases is essential. Normal PaO 2 is a function of age. A healthy 20 year old has a PaO 2 of 90 to 95 mm Hg. With each decade, PaO 2 decreases by 3 mm Hg. Normal PaCO2 is 37 to 43 mm Hg and is not affected by age. Hypoxemia is caused by five conditions: a low inspired oxygen concentration, alveolar hypoventilation, ventilation-perfusion mismatch, intracardiac right-to-left shunting, and impaired diffusion. Accurate interpretation of PaO 2 requires calculation of the alveolar-arterial (A-a) oxygen tension difference, or “A-a gradient.” Alveolar oxygen tension (PaO 2) can be calculated from the equation PaO 2 5 (FiO2 2 713) 2 (PaCO 2/0.8), where FiO2 is the inspired fraction of oxygen (0.21 in room air) and Paco 2 is the arterial carbon dioxide tension. An A-a gradient exceeding 20 mm Hg usually results from ventilation-perfusion mismatching, which in turn comes in two forms. “Dead space ventilation” occurs when ventilated lung segments do not come in contact with pulmonary capillary blood flow; this occurs when the alveolar-capillary interface is destroyed (e.g., emphysema) or when blood flow is reduced (e.g., pulmonary embolism). “Intrapulmonary shunting” occurs when perfused lung segments do not come in contact with ventilated alveoli; this occurs when small airways are occluded (e.g., asthma, chronic bronchitis), when alveoli are filled with fluid (e.g., pulmonary edema, pneumonia), or when alveoli collapse (atelectasis). In most conditions, these two processes occur in combination. Hypoxemia with an A-a gradient less than 20 mm Hg strongly suggests an extrapulmonary cause of hypoxemia (hypoventilation or a low inspired oxygen concentration). Hypercapnia is caused by three conditions: increased CO 2 production or inhalation, alveolar hypoventilation, and ventilation-perfusion mismatching with dead space ventilation. Hypoventilation is identified by high PaCO 2 with a normal A-a gradient. Acute hypercapnia leads to acidosis and cerebral vasodilation, which in turn can cause depressed level of consciousness (“CO 2 narcosis”), aggravation of elevated intracranial pressure, and blunted respiratory drive leading to further hypoventilation. Pulmonary function testing is the simplest and most reliable way to evaluate respiratory function in patients with neuromuscular respiratory failure ( Table 152.1). Arterial blood gases are also important to monitor, but abnormalities (hypoxia and hypercarbia) usually develop late in the cycle of respiratory decompensation and thus are not sensitive for detecting early ventilatory failure. Vital capacity, the volume of exhaled air after maximal inspiration, normally ranges from 40 to 70 mL/kg. Reduction of vital capacity to 30 mL/kg is associated with a weak cough, accumulation of oropharyngeal secretions, atelectasis, and hypoxemia. A vital capacity of 15 mL/kg (1 L in a 70-kg person) is generally considered the level at which intubation is required ( Table 152.2). Negative inspiratory pressure, normally more than 80 cm H 2O, measures the strength of the diaphragm and other muscles of inspiration and generally reflects the ability to maintain normal lung expansion and avoid atelectasis. Positive expiratory force, normally more than 140 cm H 2O, measures the strength of the muscles of expiration and correlates with strength of cough and the ability to clear secretions from the airway.

TABLE 152.1. PULMONARY FUNCTION TESTS IN NEUROMUSCULAR RESPIRATORY FAILURE

TABLE 152.2. CRITERIA FOR INTUBATION AND MECHANICAL VENTILATION

The pathophysiology of neuromuscular respiratory failure resembles a vicious cycle. Mild hypoxemia usually precedes hypercapnia because atelectasis (and mild

intrapulmonary shunting) is an early development. As weakness progresses, inability to maintain normal lung expansion results in reduced lung compliance and an increase in the work of breathing, which is often further aggravated by a weak cough and inability to clear secretions from the airway. As vital capacity approaches 15 mL/kg, rapid shallow breathing and hypercapnia develop. At this stage, the situation can rapidly and unexpectedly deteriorate once muscle fatigue develops and the patient can no longer compensate with increased respiratory effort.

NEUROLOGIC DISEASES WITH PRIMARY RESPIRATORY DYSFUNCTION Brainstem Disease Reticular formation neurons, sensitive to hypoxemia and hypercarbia, are located in the brainstem and may be affected by ischemia, hemorrhage, inflammation, or neoplasms. The medullary center is responsible for initiation and maintenance of spontaneous respirations, whereas the pontine pneumotaxic center helps to coordinate cyclic respirations. Forebrain damage, often from metabolic causes, can lead to Cheyne-Stokes respirations (regular, cyclic crescendo-decrescendo respiratory pattern with intervening apnea), as respiratory drive becomes dependent on changes in PCO 2. Hypothalamic or midbrain damage, particularly in the setting of brainstem herniation, may cause central neurogenic hyperventilation (low PCO 2 with normal A-a gradient). Lower pontine tegmental damage may lead to apneustic (inspiratory breath holding) or cluster breathing (irregular bursts of rapid breathing alternating with apneic periods). Medullary damage may cause ataxic breathing (irregular pattern with hypoxemia and hypercarbia), gasping, or apnea. Documentation of total apnea in the face of a hypercarbic stimulus is an essential component in the diagnosis of brain death. Formal apnea testing requires preoxygenating the patient with 100% oxygen and normalizing the PCO 2 to 40 mm Hg, turning off the ventilator, and allowing the PCO 2 to rise above 55 mm Hg (the PCO2 will rise 3 to 6 mm Hg/min). Arterial blood gases are checked at both the beginning and end of the test to confirm the eventual extent of hypercarbia. The physician must stand at the bedside during the apnea test to observe the chest wall and diaphragm to confirm the absence of respiratory muscle movement. In addition to abnormalities in respiratory rate and pattern and synchronization of diaphragm and intercostal muscles, brainstem damage often alters consciousness and causes paralysis of pharyngeal and laryngeal musculature, predisposing to aspiration pneumonitis. Patients with severe brainstem dysfunction should have nasotracheal or orotracheal intubation, electively, to prevent respiratory complications. Brainstem respiratory centers may be depressed (lose responsiveness to CO 2 or O2) by narcotics or barbiturates, metabolic abnormalities such as hypothyroidism, and by starvation or metabolic alkalosis. Idiopathic primary alveolar hypoventilation and “central sleep apnea syndrome” are due to brainstem malfunction. These disorders are easily distinguished from structural brainstem pathology by the lack of associated neurologic signs. Spinal Cord Disease The respiratory system is affected depending on the segmental level and severity of the spinal injury. In spinal cord trauma, the most common cause of death is acute respiratory failure due to apnea, aspiration pneumonia, or pulmonary embolism. The long-term care of a quadraplegic patient heavily depends on the degree of respiratory impairment. A lesion at C-3 abolishes both diaphragmatic and intercostal muscle activity, leaving only accessory muscle function. The result is severe hypercapnic respiratory failure. Acute spinal cord lesions at the C-5 to C-6 level produce an immediate fall in vital capacity to 30% of normal. Several months after injury, however, the vital capacity will increase to 50% to 60% of normal. High thoracic lesions will compromise intercostal and abdominal muscles, causing a limitation of inspiratory capacity and active expiration. Midthoracic lesions have little impact on respiratory muscle function because only the abdominal muscles are affected. Most spinal cord diseases cause respiratory impairment by interrupting the suprasegmental impulses that drive the diaphragm and intercostal muscles. There are two notable exceptions, however, strychnine poisoning and tetanus. Both of these toxins block the inhibitory interneurons within the spinal cord, causing simultaneous increases in the activity of muscles that are normally antagonists. Apnea and respiratory failure can result from intense muscle spasms of the upper airway muscles, diaphragm, and intercostal muscles. In rare cases, severe generalized dystonia can lead to a similar picture. Motor Neuron Diseases Amyotrophic lateral sclerosis is the main form of motor neuron disease that causes respiratory failure (see Chapter 117). Respiratory failure usually develops late in course of amyotrophic lateral sclerosis, as the respiratory muscles and strength of cough progressively weaken. If symptoms begin with limb weakness, the disorder may progress to respiratory failure in 2 to 5 years. If oropharyngeal symptoms appear first, respiratory complications may be caused by recurrent aspiration pneumonitis. Frequent pulmonary function testing can identify patients at risk for respiratory complications. The earliest changes are decreases in maximum inspiratory and expiratory muscle pressures, followed by reduced vital capacity. When vital capacity falls below 30 mL/kg, the ability to cough and maintain lung expansion is impaired, increasing the risk of aspiration pneumonia. Blood gases remain normal until the patient is near respiratory arrest. Peripheral Neuropathies The Guillain-Barré syndrome, or acute inflammatory demyelinating polyneuropathy, is the prototype neuropathy with respiratory complications (see Chapter 105). Of patients with this syndrome, 20% require tracheal intubation and mechanical ventilation. There is a 5% mortality rate with the best possible treatment. Most deaths are due to pulmonary embolism, severe pneumonia, or other medical complications. Some degree of respiratory insufficiency must be expected in all patients with severe disease; therefore, during the 2- to 4-week period of progression, there should be frequent measurements of inspiratory and expiratory pressures and vital capacity. Intubation is usually required when the vital capacity falls below 15 mL/kg. Plasmapheresis or intravenous immunoglobulin therapy should be initiated as soon as possible in all Guillain-Barré patients with respiratory muscle weakness. Critical illness neuropathy is an acquired axonal neuropathy that usually presents as failure to wean from mechanical ventilation. Sepsis and multisystem organ failure are risk factors. Neurologic examination reveals flaccid, areflexic quadraparesis, or quadraplegia. Recovery occurs gradually over months, if the patient's underlying medical problems are stabilized. Disorders of Neuromuscular Transmission Myasthenia gravis, botulism, and neuromuscular blocking drugs may affect respiratory muscles. Myasthenia gravis almost always affects cranial muscles, causing ptosis, weakness in the ocular and oropharyngeal muscles, and symmetric facial weakness (see Chapter 120). As in Guillain-Barré syndrome and other neuromuscular diseases, blood gas abnormalities are a late manifestation of respiratory failure. Frequent measurement of inspiratory and expiratory pressures and vital capacity is essential; tracheal intubation is carried out if the vital capacity is less than 15 mL/kg. Myasthenia gravis is a treacherous disease because fluctuations may be sudden and unpredictable. Patients with severe dysarthria and dysphagia are at greatest risk. Myasthenic crisis is defined an exacerbation of weakness that requires mechanical ventilation. It occurs in 15% to 20% of patients overall, and one-third of these will experience two or more episodes of crisis. As with Guillain-Barré syndrome, mortality is approximately 5%. Infection (usually pneumonia or viral upper respiratory infection) is the most common precipitant (40%), followed by no obvious cause (30%) and aspiration (10%). As a general rule, 25% of patients in crisis can be extubated after 1 week, 50% after 2 weeks, and 75% after 1 month. Plasmapheresis leads to short-term improvement of weakness in 75% of patients and should be performed in all patients unless otherwise contraindicated, although its efficacy for reducing the duration of crisis has not been tested in a randomized controlled trial. Muscle Disease Muscular dystrophies, myotonic disorders, inflammatory myopathies, periodic paralyses, metabolic myopathies (especially acid maltase deficiency), endocrine disorders, infectious myopathies, mitochondrial myopathies, toxic myopathies, myoglobinuria, critical illness myopathy, and electrolyte disorders may cause widespread skeletal muscle weakness. Respiratory failure may appear in acute fulminant attacks or after a period of progression. Rarely, respiratory failure may be the first manifestation of a generalized myopathy.

MANAGEMENT OF RESPIRATORY FAILURE IN NEUROLOGIC DISEASES Examination The initial management of the patient with impending neuromuscular respiratory failure is directed toward assessing the adequacy of ventilation and possible need for immediate intubation. The patient's overall comfort level and the rapidity with which the dyspnea has developed are both important. Rapid shallow breathing, with inability to generate adequate tidal volumes, is a danger sign of significant respiratory muscle fatigue. Diaphragmatic strength can be estimated by palpating for normal outward movement of the abdomen with inspiration; with severe weakness, inspiration is associated with spontaneous inward movement of the diaphragm (paradoxical respirations). Ventilatory reserve can be assessed by checking the patient's ability to count from 1 to 25 in a single breath. The strength of the patient's cough should be observed. A wet gurgled voice and pooled oropharyngeal secretions are the best clinical signs of significant dysphagia. When severe, weakness of the glottic and oropharyngeal muscles can lead to stridor, which is indicative of potentially life-threatening upper airway obstruction. Dysphagia is best screened for by asking the patient to sip 3 ounces of water; coughing is diagnostic of aspiration, and if present, oral feedings should be held until swallowing can be formally assessed. Mechanical Ventilation Mechanical ventilation may be positive pressure or negative pressure. Until the mid-1950s, all mechanical ventilation was negative pressure. The most common device was the Drinker tank respirator (“iron lung”), which created a cyclical subatmospheric pressure around the patient's chest, causing chest expansion. Today, there are several types of negative-pressure devices, cuirass ventilators, that can be used on a long-term basis to assist the patient's own respiratory efforts without tracheal intubation. Patients with motor neuron disease and chronic myopathies are sometimes able to live at home with these devices. Small suitcase-sized portable and battery-powered volume-cycled ventilators are also available for ambulatory use. Ventilator-dependent patients may go home and remain mobile. Mechanical ventilation is the primary treatment for respiratory failure. The trachea may be intubated orally or nasally; a soft air-filled cuff is then inflated in the trachea to prevent leakage of air around the tube. Indications for endotracheal intubation include physiologic parameters ( Table 152.2) and the rate of respiratory deterioration and the patient's overall comfort level. In some cases, positive-pressure ventilation can be delivered for short periods (e.g., overnight) with the use of a tight-fitting face mask. Positive pressure ventilation may be pressure cycled or volume cycled; the latter mode is usually preferred because it delivers a precise tidal volume over a wide range of pressures. Synchronous intermittent mandatory ventilation is the initial mode of ventilation in most patients. With this mode, a predetermined number of volume-cycled positive pressure breaths are delivered per minute. The patient can initiate a spontaneous breath at any time and receive either a volume-assisted breath or an unsupported breath, depending on the phase of the ventilator cycle. Initially, the tidal volume is set at 10 mL/kg with a respiratory rate of 8 to 12 breaths/min, and 3 to 5 cm H2O of positive end-expiratory pressure is maintained to prevent atelectasis. The fraction of inspired air is gradually adjusted downward from 100% until the Pao2 is 70 to 90 mm Hg. Weaning from the ventilator can be considered when pulmonary function tests show improvement and there are no significant medical complications ( Table 152.3). Weaning can be accomplished in three ways: a gradual reduction of the rate of intermittent mandatory ventilation, enabling the patient to take over the spontaneous respirations; “pressure support” weaning with continuous positive airway pressure; and complete removal of the patient from the respirator, allowing free breathing for short periods with oxygen supplementation alone (weaning with a T-tube). Breathing through a ventilator circuit can sometimes increase the work of breathing because of the internal resistance of the machine. Thus, some patients with respiratory muscle weakness wean more easily on a T-tube. Pressure support is a preset level of airway pressure delivered with each inspiratory effort, which reduces the overall work of breathing; the level (usually 5 to 15 cm H 2O) should be adjusted to attain spontaneous tidal volumes of 300 to 500 mL and a comfortable breathing pattern. Whatever the mode of weaning, an increasing respiratory rate with decreasing tidal volumes indicates tiring, at which point the weaning trial should be stopped and the patient returned to synchronous intermittent mandatory ventilation for rest overnight. The ability of the patient to tolerate a T-tube or continuous positive airway pressure with minimal pressure support (5 cm H 2O) for extended periods of time, while maintaining a ratio of respiratory rate (breaths/min) to tidal volume (L) below 100, is probably the single best predictor of successful extubation.

TABLE 152.3. CRITERIA FOR WEANING FROM MECHANICAL VENTILATION

Most clinicians perform a tracheostomy if mechanical ventilation is required for more that 2 weeks. Tracheostomy has several advantages over long-term endotracheal intubation, including increased comfort, reduced risk of permanent tracheolaryngeal injury, increased ease of weaning from the ventilator (reduced dead space and less resistance to flow from the endotracheal tube), and improved ability to manage and suction secretions. The latter two considerations are of particular importance when weaning patients with neuromuscular respiratory failure from mechanical ventilation. If some patients with severe persistent oropharyngeal muscle weakness, a tracheostomy is necessary to manage secretions and prevent aspiration, even though respiratory muscle function is adequate. SUGGESTED READINGS American Thoracic Society Symposium Summary. Respiratory muscles: structure and function. Am Rev Respir Dis 1986;134:1078–1093. Bach JR, O'Brien J, Krotenberg R, Alba A, et al. Management of end stage respiratory failure in Duchenne muscular dystrophy. Muscle Nerve 1987;10:177–182. Bolton CF. Assessment of respiratory function in the intensive care unit. Can J Neurol Sci 1994;21:S28–S34. Borel CO, Tilford C, Nichols DG, et al. Diaphragmatic performance during recovery from acute ventilatory failure in patients with Guillain-Barre syndrome and myasthenia gravis. 1991;99:444–451.

Chest

Chevrolet JC, Deleamont P. Repeated vital capacity measurements as predictive parameters for mechanical ventilation and weaning success in the Guillain-Barré syndrome. Am Rev Respir Dis 1991;144:814–818. Cohen CA, Zagelbaum G, Gross D, et al. Clinical manifestations of inspiratory muscle fatigue. Am J Med 1982;73:308–316. Hall JB, Wood LDH. Liberation of the patient from mechanical ventilation. JAMA 1987;257:1621–1628. Hirano M, Ott BR, Raps EC, et al. Acute quadriplegic myopathy: complication of treatment with steroids, nondepolarizing blocking agents, or both. Neurology 1992;42:2082–2087. Howard RS, Wiles CM, Hirsch NP, et al. Respiratory involvement in primary muscle disorders: assessment and management. Q J Med 1993;86:175–189.

Hughes RAC, Bihari D. Acute neuromuscular respiratory paralysis. J Neurol Neurosurg Psychiatry 1993;56:334–343. Hund EF, Borel CO, Cornblath DR, et al. Intensive management and treatment of severe Guillain-Barre syndrome. Crit Care Med 1993;21:433-446. Karpel JP, Aldrich TK. Respiratory failure and mechanical ventilation: pathophysiology and methods of promoting weaning. Lung 1986;164:309–324. Kelley BJ, Luce JM. The diagnosis and management of neuromuscular diseases causing ventilatory failure. Chest 1991;99:1485–1494. Make BJ, Gilmartin ME. Rehabilitation and home care for ventilator-assisted individuals. Clin Chest Med 1986;7:679–691. Mayer SA. Intensive care of the myasthenic patient. Neurology 1997;48[Suppl 5]:S70–S75. Ropper AH, Kehne SM. Guillain-Barré syndrome: management of respiratory failure. Neurology 1985;35:1662–1665. Strumpf DA, Millman RP, Hill NS. The management of chronic hypoventilation. Chest 1990;98:474–480. Thomas CE, Mayer SA, Gungor Y, et al. Myasthenic crisis: clinical features, mortality, complications, and risk factors for prolonged intubation. Neurology 1997;48:1253–1260. Tobin MJ. Mechanical ventilation. N Engl J Med 1994;330:1056–1061. Wijdicks EFM, Borel CO. Respiratory management in acute neurologic illness. Neurology 1998;50:11–20. Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med 1991;324:1445–1450.

CHAPTER 153. PARANEOPLASTIC SYNDROMES MERRITT’S NEUROLOGY

CHAPTER 153. PARANEOPLASTIC SYNDROMES LEWIS P. ROWLAND Definition Epidemiology Pathogenesis Clinical Syndromes Laboratory Data Treatment Suggested Readings

DEFINITION A paraneoplastic syndrome is one that occurs more frequently than expected by chance in association with neoplasm, most often a malignant tumor. It is called “paraneoplastic” because the neurologic disorder is not the result of tumor invasion or metastasis, chemotherapy, radiotherapy, malnutrition, or coincidental infection.

EPIDEMIOLOGY If only clinically symptomatic syndromes are considered (and not, say, subclinical peripheral neuropathy determined by nerve conduction studies), all syndromes are rare. For instance, all syndromes together occur in less than 1% of all patients with small cell lung cancer. Conversely, among patients diagnosed with a recognized paraneoplastic syndrome, 10% to 60% prove to have a tumor ( Table 153.1). The possible presence of a tumor cannot be totally eliminated without postmortem examination.

TABLE 153.1. FREQUENCY OF ASSOCIATED TUMOR WITH CLINICAL SYNDROMES THAT ARE OFTEN PARANEOPLASTIC

PATHOGENESIS The dominant theory holds that most paraneoplastic disorders are autoimmune in origin. This is based primarily on the frequent presence of characteristic antibodies against neuronal antigens. Presumably, the host mounts an antibody attack against antigens in the tumor and, by a process of molecular mimicry, the immune response is directed against central or peripheral neural antigens. However, the antibodies have limited specificity and sensitivity. Also, there is no evidence of complement-mediated autoimmunity. Attention has therefore been directed to the possibility of T-cell–mediated neurotoxicity. Because the syndromes are so rare, genetic susceptibility is thought to play a role. In contrast to the central nervous system syndromes, antibodies are thought to be pathogenic in the peripheral neuromuscular disorders of the Lambert-Eaton syndrome with neoplasm and myasthenia gravis with thymoma and the anti–myelin-associated glycoprotein (MAG) peripheral neuropathies with lymphoproliferative disease. These syndromes are discussed in Chapter 103, Chapter 120, and Chapter 121. Other recognized paraneoplastic mechanisms include hormones secreted by a tumor, such as corticotropin, resulting in Cushing syndrome, or parathyroid hormone-related protein, causing hypercalcemic encephalopathy. Carcinoid tumors may compete with tryptophan to cause a pellagra-like encephalopathy. Immunodeficiency may lead to opportunistic infection, especially by the JC virus in progressive multifocal leukoencephalopathy.

CLINICAL SYNDROMES Paraneoplastic Cerebellar Degeneration Symptoms and signs are dominated by cerebellar pathways: ataxia of gait and limbs, dysarthria, nystagmus, and oscillopsia. Other manifestations are encountered in half the cases, with hearing loss, bulbar syndromes, corticospinal tract signs, dementia, and peripheral neuropathy. Computed tomography (CT) and magnetic resonance imaging (MRI) show no specific lesions. Cerebrospinal fluid (CSF) abnormalities may include modest pleocytosis and high protein content, sometimes with high IgG and oligoclonal bands. Associated antibodies may be anti-Yo (with cancer of the ovary), anti-Hu (with small cell lung cancer), Hodgkin antibody with Hodgkin disease, or anti-Ri with cancer of the breast. The differential diagnosis includes viral encephalitis, multiple sclerosis, Creutzfeldt-Jakob disease, alcoholic cerebellar degeneration, and hereditary spinocerebellar atrophy. Treatment is not satisfactory. Subacute Sensory Neuropathy/Encephalitis Among patients with idiopathic sensory neuropathy, at least one-third prove to have an associated malignant tumor. Neurologic symptoms usually precede those of the tumor, which is likely to be small. Painful paresthesias are the dominant symptoms and progress for days or weeks on all four limbs, the trunk, and sometimes the face. Unlike cisplatinum neuropathy, which spares pain and temperature, paraneoplastic neuropathy affects all forms of sensation, resulting in a severe sensory ataxia. Tendon reflexes are lost and CSF pleocytosis is characteristic. Nerve conduction studies show loss of sensory evoked potentials, with normal motor functions. Inflammation is seen in the dorsal root ganglia. Limbic Encephalitis Personality and mood changes progress rapidly, and within weeks the syndrome is dominated by delirium and dementia with severe memory loss. The disorder may occur alone or with other signs of encephalitis or sensory neuropathy. Computed tomography and magnetic resonance imaging are usually normal at first, but enhancing lesions may be seen in the temporal lobes. CSF pleocytosis is characteristic. Pathologic signs of inflammation are limited at first to the limbic and insular cortex, but other gray matter may be affected. The changes include loss of neurons, perivascular infiltration by leukocytes, and microglial proliferation. Brainstem Encephalitis Symptoms of brainstem encephalitis are usually part of a more widespread encephalitis but may be the first manifestations. The manifestations are those of the cranial nerves or basal ganglia. Common findings are oculomotor disorders, including nystagmus and supranuclear vertical gaze palsy as well as hearing loss,

dysarthria, dysphagia, and abnormal respiration. Movement disorders may be prominent. Opsoclonus-Myoclonus This syndrome is seen most often in children with neuroblastoma, which has a favorable prognosis. The term implies constant motion of the eyes—arrhytmic, irregular in direction, or tempo. There may be evidence of encephalomyelitis or cerebellar disorder. The disorder of eye movements is attributed to dysfunction of the paramedian pontine reticular formation. In adults, opsoclonus may be part of a complex syndrome with cerebellar signs and encephalomyelitis, tumors of several types, and anti-Ri antibodies. Myelitis Spinal cord symptoms evolve in days or weeks with clinical evidence of a level lesion. The CSF may show pleocytosis with high protein content and normal sugar; oligoclonal bands may be present. Myelitis may occur with or without encephalomyelitis. Acute necrotizing myelopathy may be an extreme form of the inflammatory demyelinating myelitis. Motor Neuron Diseases It is uncertain whether there is a higher frequency of malignant tumor in patients with forms of motor neuron disease. Most epidemiologic studies have shown no such relation. Yet there have been reports of patients whose neurologic symptoms disappeared with treatment of the tumor. Also, there have been more than 60 reports of patients with motor neuron diseases and lymphoproliferative disease. Lower motor neuron signs (“amyotrophy”), including fasciculation, are seen in combination with paraneoplastic encephalomyelitis. A pure upper motor neuron syndrome (“primary lateral sclerosis”) has been reported in women with breast cancer, but several patients also developed lower motor neuron signs (i.e., they developed amyotrophic lateral sclerosis). Sensorimotor Peripheral Neuropathy Sensorimotor peripheral neuropathy with or without slow conduction velocity is common after age 50. Among the diverse causes are anti-MAG paraproteinemic peripheral neuropathy and paraneoplastic neuropathy. Prominent features may include glove-stocking paresthesias and sensory loss, distal limb weakness, or both. Autonomic failure may be prominent, with disorders of gastrointestinal motility, especially diarrhea or pseudo-obstruction. Cranial symptoms are lacking and the syndrome is slow in evolution; it may responde to immunotherapy, as described in Chapter 105. Vasculitis is found in some acute neuropathies. Neuromuscular Disorders The association of myasthenia gravis with thymoma is described in Chapter 120. There is no known paraneoplastic form of myasthenia with cancers; the neuromuscular disorder may occur by chance with a malignant tumor. Lambert-Eaton myasthenic syndrome (LEMS) is discussed in Chapter 121. Paraneoplastic neuromyotonia, as described in Chapter 129 is associated most often with thymoma but also with small cell lung cancer or other tumors. The Moersch-Woltman or stiff-man syndrome is sometimes associated with cancer of lung or other organs. Myopathies About 20% patients with dermatomyositis starting after age 40 have an associated tumor, which can be almost any type. Whether there is a higher than expected association of tumor with polymyositis has not been proven. These syndromes are described in Chapter 130 and Chapter 131.

LABORATORY DATA Few laboratory tests point to the diagnosis of a paraneoplastic syndrome. MRI may or may not show abnormalities of white or gray matter; scans are often normal. Similarly, the CSF may or may not show high CSF protein or pleocytosis, but the CSF sugar content should be normal or some other diagnosis suspected. The diagnosis of peripheral neuropathy depends in part on the demonstration of conduction abnormalities, and LEMS is virtually defined by the demonstration of an incrementing response to repetitive nerve stimulation, as described in Chapter 121. Demonstration of a characteristic antibody can accelerate diagnosis of the several paraneoplastic syndromes. Antibodies Anti-amphiphysin is found in nerve terminals. Antibodies are found in diverse syndromes, including LEMS, sensory neuropathy, and limbic encephalitis. The associated tumors are also diverse, including lung, breast, and ovary. Anti-Hu was the first antibody to be identified with small cell lung carcinoma. Like several of the others that followed, it was named after the patient who provided the first serum. It is also called “type 1 antineuronal nuclear autoantibody” or ANNA-1. In a few patients, the tumor was one other than small cell lung cancer. Specificity for sensory neuropathy is given as 99%, with a sensitivity of 82%. The clinical syndrome is most often encephalomyelitis or sensory neuropathy, and the neurologic symptoms usually precede discovery of the tumor. Anti-Ri is an RNA-binding protein. The clinical syndrome is opsoclonus-myoclonus and the tumors are mostly breast and small cell lung cancer. In anti-ta, the antigen, Ma2, is a member of a family of proteins in brain, testis, and some tumors. The antibody has been found primarily in patients with testicular cancer associated with limbic and brainstem encephalitis. Anti-Tr reacts with Purkinje cells of the cerebellum. The clinical syndrome is primarily a subacute cerebellar disorder, often with dysarthria and nystagmus. The neoplasm is almost always Hodgkin disease. Anti-VGCC reacts with voltage-gated calcium channel of muscle and is found in patients with LEMS. The antibody is not found in other types of paraneoplastic syndromes. Anti-Yo is a DNA-binding protein, and the antibody is found most often with a cerebellar disorder or brainstem encephalitis in association with a tumor of the ovary, uterus, or breast.

TREATMENT The peripheral disorders of sensorimotor polyneuropathy and LEMS often respond to intravenous immunoglobulin therapy or immunosuppressive drug therapy. The central nervous system syndromes are refractory to treatment. Corticosteroid therapy is often effective for the opsoclonus-myoclonus syndrome in children, and treatment of the associated tumor may ameliorate the syndrome in adults. SUGGESTED READINGS Albert M, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med 1998;4:1321–1324. Antoine JC, Absi L, Honnorat J, et al. Antiamphiphysin antibodies ae associated with various paraneoplastic neurological syndromes and tumors. Arch Neurol 1999;56:172–177. Bennett JL, Galetta SL, Friedman LP, et al. Neuro-ophthalmologic manifestations of a paraneoplastic syndrome and testicular carcinoma. Neurology 1999;52:864–867. Burns TM, Juel VC, Sanders DB, Phillips LH II. Neuroendocrine lung tumors and disorders of the neuromuscular junction. Neurology 1999;52:1480–1491.

Camerlingo M, Nemni R, Ferraro B, et al. Malignancy and sensory: neuropathy of unexplained cause. Arch Neurol 1998;55:981–984. Dalmau J, Gultekin SH, Posner JB. Paraneoplastic neurologic syndromes: pathogenesis and pathophysiology. Brain Pathol 1999;9:275–284. Dalmau J, Gultekin SH, Voltz R, et al. Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain 1999;122:27–39. Dropcho EJ. Neurologic paraneoplastic syndromes. J Neurol Sci 1998;153:264–278. Forsyth PA, Dalmau J, Graus F, Cwik V, Rosenblum MK, Posner JB. Motor neuron syndromes in cancer patients. Ann Neurol 1997;41:722–730. Giometto B, Taraloto B, Graus F. Autoimmunity in paraneoplastic neurological syndromes. Brain Pathol 1999;9:261–273. Gordon PH, Rowland LP, Younger DS, et al. Lymphoproliferative disorders and motor neuron disease. Ann Neurol 1997;48:1671–1678. Ichimura M, Yamamoto M, Kobayashi Y, et al. Tissue distribution of pathological lesions and Hu antigen expression in paraneoplastic sensory neuropathy. Acta Neuropathol 1998;95:641–648. Klawaja S, Sripathi N, Ahmad BK, Lemmon VA. Paraneoplastic motor neuron disease with type 1 Purkinje cell antibodies. Muscle Nerve 1998;2:943–945. Lieberman FS, Odel J, Hirsch J, Heinemann M, Michaaeli J, Posner J. Bilateral optic neuropathy with IgGk multiple myeloma improved after myeloablative chemotherapy. 1999;52:414–416.

Neurology

Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 1998;50:652–657. Molinuevo JL, Graus F, Serrano C, Rene R, Guerrero A, Illa I. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann Neurol 1998;44:976–980. Posner JB. Neurologic complications of cancer. Philadelphia: FA Davis, 1995:353–385. Posner JB, Dalmau JO. Paraneoplastic syndromes affecting the central nervous system. Annu Rev Med 1997;48:157–166. Rees J. Paraneoplastic syndromes. Curr Opin Neurol 1998;11:623–637. Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med 1998;338:1601–1607. Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA. Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol 1997;28:284–288. Scaravilli F, An SF, Groves M, Thom M. The neuropathology of paraneoplastic syndromes. Brain Pathol 1999;9:251–260. Sodeyama N, Ishida K, Jaeckle KA, et al. Pattern of epitopic reactivity of the anti-Hu antibody on HuD with and without paraneoplastic syndrome. J Neurol Neurosurg Psychiatry 1999;66:97–99. Tabarki B, Palmer P, Lebon P, Sebire G. Spontaneous recovery of opsoclonus-myoclonus syndrome caused by enterovirus infection. J Neurol Neurosurg Psychiatry 1998:64:406–407. Voltz R, Carpentier AF, Rosenfeld MR, Posner JB, Dalmau J. P/Q type voltage-gated calcium channel antibodies in paraneoplastic disorders of the central nervous system. Muscle Nerve 1999;22:119–122. Wakabyashi K, Horikawa Y, Oyake M, Suzuki S, Morita T, Takahashi H. Sporadic motor neuron disease with severe sensory neuronopathy. Acta Neuropathol 1998;95:426–430.

CHAPTER 154. NUTRITIONAL DISORDERS: VITAMIN B12 DEFICIENCY, MALABSORPTION, AND MALNUTRITION MERRITT’S NEUROLOGY

CHAPTER 154. NUTRITIONAL DISORDERS: VITAMIN B12 DEFICIENCY, MALABSORPTION, AND MALNUTRITION LEWIS P. ROWLAND AND BRADFORD P. WORRALL Vitamin B12 (Cobalamin) Deficiency Malnutrition Malabsorption Suggested Readings

Many neurologic syndromes are ascribed to lack of vitamins or other essential nutrients. The most common are pernicious anemia (lack of vitamin B and malabsorption syndromes.

12),

malnutrition,

VITAMIN B12 (COBALAMIN) DEFICIENCY History Although not the first to describe the disorder, in 1849 Thomas Addison made pernicious anemia well known. By the turn of the century, the diagnostic triad was recognized: anemia, neurologic symptoms, and atrophy of the epithelial covering of the tongue. In 1900, Russell, Batten, and Collier introduced the term combined degeneration of the spinal cord. The disease was lethal until 1926, when Minot and Murphy used replacement therapy without knowing what had to be replaced; they found that supplementing the diet with liver was therapeutic. Castle administered liver extract parenterally, and in 1948 vitamin B 12 completely reversed the symptoms. Additionally, the automation of blood counts and measurement of blood vitamin B 12 levels has made early diagnosis the rule. As a result, the neurologic disorder is now rarely seen in major medical centers of industrialized countries. Although the condition was once thought to affect Nordic people primarily, it is seen in all racial groups. The prevalence of undiagnosed pernicious anemia after age 60 is about 2%. Physiology Cobalamin is synthesized only in specific microorganisms, and animal products are the sole dietary sources for humans. Gastric acid is needed for peptic digestion to release the vitamin from proteins. Achlorhydria of the elderly may suffice to cause B 12 deficiency, but an intrinsic factor is usually missing as well. The freed B 12 is bound by R proteins (R for “rapid” movement on electrophoresis) and then by gastric intrinsic factor, a glycoprotein produced by gastric parietal cells, which is needed for absorption of B 12 and which is absent in people with pernicious anemia. The combined intrinsic factor–cobalamin complex is transported across the terminal ileum and binds to transcobalamin, with a half-life of 6 to 9 minutes. The complex enters cells by endocytosis, and the vitamin enters red blood cells in an energy-dependent process. Cobalamin is converted to adenosyl or methyl coenzymes, which are necessary for normal neural metabolism. If they are missing, abnormal fatty acids may accumulate in myelin or methylating reactions may be defective. A congenital form of methylcobalamin deficiency leads to developmental delay, microcephaly, and seizures, with delayed myelination. However, the details of B 12 dependency in the mature nervous system are not well known, and it is not clear why the spinal cord and peripheral nerves are so vulnerable when B 12 levels are low. Pathogenesis About 80% of adult-onset pernicious anemia is attributed to lack of gastric intrinsic factor secondary to atrophic gastritis ( Table 154.1). The disorder is thought to be autoimmune in origin because antibodies to gastric parietal cells are found in 90% and antibodies to intrinsic factor occur in up to 76%. The parietal cell antigen is gastric H +/K+-ATPase. Supporting the view that autoimmunity is important is the frequent association of pernicious anemia with some other autoimmune disease, such as myasthenia gravis, Hashimoto thyroiditis, vitiligo, or polyglandular deficiency. A murine model of the immune disorder has been developed. In those with normal intrinsic factor, the vitamin is not absorbed because of jejunal diverticulosis, tropical sprue, or loss of the stomach or ileum by surgical resection. Rarely, the vitamin cannot be liberated from dietary animal proteins because peptic digestion is inadequate.

TABLE 154.1. CAUSES OF COBALAMIN DEFICIENCY IN 143 PATIENTS

Pathology In the spinal cord, white matter is affected more than gray. Symmetric loss of myelin sheaths occurs more often than axonal loss; changes are most prominent in the posterior and lateral columns ( combined system disease) (Fig. 154.1 and Fig. 154.2). The thoracic cord is affected first and then the process extends in either direction. Patchy demyelination may be seen in the frontal white matter ( Fig. 154.3).

FIG. 154.1. Subacute combined degeneration. Sections of spinal cord at various levels showing segmental loss of myelin, which is most intense in the dorsal and

lateral columns.

FIG. 154.2. Subacute combined degeneration. Destruction of myelin predominating in the posterior and lateral columns. Swelling of affected myelin sheaths causes spongy appearance.

FIG. 154.3. Subacute combined degeneration. Partial loss of myelin of white matter of frontal lobe. (Courtesy of Dr. L. Roizin.)

Clinical Features Today most patients are probably asymptomatic. If the deficiency persists, symptoms may be those of anemia, neurologic disorder, or other problems such as vitiligo, sore tongue, or prematurely gray hair. Anorexia and weight loss may be prominent. About 40% of all patients with B 12 deficiency are said to have some neurologic symptoms or signs, and these are often the first or most prominent manifestations of the disease. Only 20% of patients are younger than age 50; most are over 60. Usually, there are features of both myelopathy and peripheral neuropathy. The most common symptom, attributed to the neuropathy, is acroparesthesia, burning and painful sensations that affect the hands and feet. There may be sensory ataxia. Memory loss, visual loss (due to optic neuropathy), orthostatic hypotension, anosmia, impaired taste (dysgeusia), sphincter symptoms, and impotence are other symptoms. On examination, there is glove-stocking sensory loss, and almost all patients show loss of vibratory sensation and of position sense. The Romberg sign is often present; the patient can stand with feet together if the eyes are open but sways and falls on closing the eyes because of the loss of position sense. There may or may not be weakness of limb muscles; the neuropathy is predominantly sensory, but there are upper motor neuron signs: increased tone, impaired alternating movements, and hyperactive tendon jerks, with Babinski and Hoffmann signs. Cognitive loss may be evident as florid dementia or may be manifest only on neuropsychologic tests. Optic atrophy is found in fewer than 1% of patients. As a measure of the efficacy of modern diagnosis and treatment, even symptomatic patients are usually independent in activities of daily living. Fewer than 10% are restricted to chair or bed. Diagnosis The diagnosis rests on demonstration of blood levels of vitamin B 12 less than 200 pg/mL, but low normal values (200 to 350 pg/mL) may be found in people who respond to therapy. Some people with low values are not deficient, and additional tests may be useful. Both methylmalonic acid and homocysteine accumulate when there is impairment of cobalamin-dependent reactions; both metabolites are abnormally increased in serum in more than 99% of patients with true cobalamin deficiency. The Schilling test, a measure of the absorption of orally ingested labeled B 12, is technically difficult and unreliable because it may be normal in vegetarians and nitrous oxide abusers. Sometimes a therapeutic trial is the only way to determine whether a neurologic syndrome is in fact due to B 12 deficiency. Magnetic resonance imaging (MRI) may show increased T2-weighted signal and contrast enhancement of the posterior and lateral columns of the spinal cord, with return to normal on treatment. Nerve conduction tests show a sensorimotor neuropathy that may be either axonal or demyelinating. Visual, brainstem, and somatosensory evoked responses may be normal or abnormal. Computed tomography and MRI may show no abnormality, or there may be cerebral atrophy in patients with dementia. In patients with neurologic signs, only about 20% show severe anemia. Both the hematocrit and mean corpuscular volume may be normal, although they are the traditional abnormalities. Bone marrow biopsy, however, reliably shows megaloblastic abnormalities. B 12 deficiency must be considered in any sensorimotor neuropathy, myelopathy, autonomic neuropathy, dementia, or optic neuropathy. Several of these disorders arise in acquired immunodeficiency syndrome, but a possible role of B 12 is doubted. Dentists may be at special risk because recreational abuse of nitrous oxide can interfere with cobalamin metabolism and cause neuropathy or combined system disease. Treatment B12 is given intramuscularly in a dosage of 1,000 Âľg daily for the first week, followed by weekly injections for the first month, and then monthly injections for life. Oral therapy is less reliable largely because absorption without intrinsic factor is inefficient. After parenteral injection of B 12, hematologic improvement may be evident within 48 hours, and there is a subjective sense of general improvement. Paresthesias are often the first neurologic symptoms to improve and do so within 2 weeks; corticospinal abnormalities are slower to respond. If there is no response in 3 months, the condition is probably not due to B 12 deficiency. About half of the patients are left with some abnormality on examination; the residual disability depends on the duration of symptoms.

MALNUTRITION

Malnutrition is still a serious problem throughout the world. In poor countries, dietary deficiency is common. In industrial countries, nutritional syndromes are more likely to be seen in alcoholics, in patients with chronic bowel disease, or in patients after some medical treatment that interferes with essential elements of diet ( Table 154.2). Even if the acute disorders are corrected, there may be long-term effects. Maternal malnutrition may affect the fetus and cause mental retardation; on another level, chronic neurologic syndromes persisted in World War II prisoners long after they had resumed a normal diet.

TABLE 154.2. NEUROLOGIC SYNDROMES ATTRIBUTED TO NUTRITIONAL DEFICIENCY

Dietary therapy may be important in the management of some inborn errors of metabolism to prevent accumulation of some toxic substances (as in phenylketonuria) or to amplify the activity of a mutant enzyme (as in vitamin B 6-responsive homocystinuria). Diseases of malnutrition may arise if essential nutrients are not provided because the diet is inadequate. The result may be the same if nutrients are lost by vomiting or diarrhea, if there is malabsorption, if use of a nutrient is impaired, or if the target organ is unresponsive to a mediating hormone. Examples of different syndromes are found in other chapters of this book; a simple listing or table is a gross oversimplification for two reasons. First, vitamin deficiency is likely to be multiple and often accompanied by protein-calorie malnutrition and thus the resulting syndromes are complex. Second, it is possible to tabulate the major target system of a particular syndrome, although most involve more than one system; spinal cord syndromes and encephalopathy, for example, may be more prominent than the peripheral neuropathy of pellagra. In contrast, peripheral neuropathy, optic neuropathy, or dementia may be seen in patients with combined system disease of the spinal cord secondary to vitamin B 12 deficiency. Some neurologic syndromes are attributable to dietary excess ( Table 154.3). For this reason, too, the syndromes are likely to be complex.

TABLE 154.3. NEUROLOGIC SYNDROMES ATTRIBUTED TO DIETARY EXCESS

A common cause of malnutrition in industrialized countries is anorexia nervosa. In addition to the conventional neuropathy and other syndromes of multiple vitamin deficiency, there may be a myopathy. Here, however, the nutritional disorder is often complicated by the ingestion of emetine to induce vomiting. An epidemic of peripheral and optic neuropathy in Cuba was seen in 1991 after the collapse of support from the Soviet Union and enforcement of an embargo by the United States. As many as 50,000 may have been affected. This combination of disorders had earlier been seen in prisoners of war and other malnourished populations. In Cuba, some patients had mutations of mitochondrial DNA of the kind seen in Leber hereditary optic neuropathy, which may have made them more susceptible to dietary deprivation. Many patients improved with supplemental vitamin therapy. Viral infection may have been responsible for some cases. Only a brief overview is offered of disorders of the stomach and intestine. The major neurologic syndrome of stomach disease results from lack of intrinsic factor and B12 deficiency. There are no major neurologic consequences of peptic ulcer (other than those that might result from shock after massive hemorrhage), but treatment of the ulcer may lead to a neurologic disorder. Antacids may cause a partial malabsorption syndrome. Cimetidine therapy avoids these problems but may cause an acute confusional state. Antacids that contain aluminum or phosphate-binders can cause encephalopathy, especially in the presence of renal disease. Surgical therapy may cure the ulcer but may also create a neurologic disorder as a result of malabsorption.

MALABSORPTION Malabsorption syndromes may arise for any of several reasons ( Table 154.4). In patients with these disorders, neurologic abnormalities seem to be disproportionately frequent. Alone or in combination, there may be evidence of myopathy, sensorimotor peripheral neuropathy, degeneration of corticospinal tracts and posterior columns, and cerebellar abnormality. Optic neuritis, atypical pigmentary degeneration of the retina, and dementia are less common signs of malabsorption syndromes.

TABLE 154.4. SOME CAUSES OF NEUROLOGIC DISORDER DUE TO MALABSORPTION

There have been three waves of explanation. First, the syndromes were attributed to vitamin B 12 deficiency, which probably accounted for some but not all cases; many patients had normal serum B12 levels and did not respond to vitamin B 12 therapy. Second, there was considerable interest in the relation of the neurologic abnormality to osteomalacia, which often appeared in the same patients. Osteomalacia also accompanied similar neurologic syndromes in patients who had dietary problems other than malabsorption (e.g., lack of sunlight or dietary vitamin D, resistance to vitamin D, renal disease, ingestion of anticonvulsant drugs). Osteomalacia or vitamin D deficiency, however, was hard to prove in some cases, and there was often no response to vitamin D therapy. Third, now the main culprit is lack of vitamin E, which can arise in several different ways: fat malabsorption, colestatic liver disease, abetalipoproteinemia, and autosomal recessive absence of the tocopherol transfer protein. In these disorders, ataxia and sensorimotor polyneuropathy are prominent clinical signs and may improve with vitamin E replacement, giving up to 4 g daily of alpha tocopherol. The main bowel diseases associated with neurologic symptoms are celiac disease and inflammatory bowel disease (Crohn disease or ulcerative colitis). Celiac disease is characterized by the triad of malabsorption, abnormal small bowel mucosa, and intolerance to gluten, a complex of wheat proteins. Gluten sensitivity can be documented by finding antibodies to gliadin. Neurologic complications arise from osteomalacic myopathy, B 12 deficiency with neuropathy or myelopathy, hypokalemia, or hypocalcemia. In some patients, severe ataxia of gait has been related to the gluten sensitivity, with changes in peripheral nerves, posterior columns, and cerebellum. Both Crohn disease and ulcerative colitis are associated with increased risk of thromboembolism that may affect other parts of the body but includes arteries and veins of the brain or spinal cord. Neuromuscular disorders are diverse ( Table 154.5). Peripheral neuropathy is found with Crohn disease for reasons that are uncertain; acute or chronic demyelinating neuropathy is found more often with ulcerative colitis. Myopathy may occur with either disorder, but symptomatic central nervous system disease is exceptional even though white matter lesions are found by MRI.

TABLE 154.5. NEUROLOGIC SYNDROMES IN 19 PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Another unusual syndrome of malabsorption is episodic abnormality of sleep, thirst, hunger, and mood, a combination that suggests a hypothalamic disorder. Other manifestations are episodes of weakness, ataxia, slurred speech, confusion, and nausea. This is attributed to bacterial overgrowth with production of D-lactic acid. D-Lactic acidosis is seen in patients with a short small intestine and an intact colon. Excessive production of d-lactate by abnormal bowel flora overwhelms normal metabolism of D-lactate and leads to an accumulation of this enantiomer in the blood. The condition may be fatal, but oral antibiotic treatment has abolished the syndrome in some patients. Chronic diarrhea from any cause, including malabsorption or abuse of laxatives, may cause hypokalemia with resulting chronic myopathy, acute paralysis, or acute myoglobinuria. Acute hypophosphatemia may arise in alcohol abusers treated for loss of fluids and electrolytes, after treatment of diabetic ketoacidosis, or after hyperalimentation. In these circumstances, limb weakness may simulate Guillain-Barré syndrome, or the acute electrolyte disorder may actually precipitate the neuropathy; seizures and coma may be part of the picture. In some conditions, diarrhea accompanies but is not thought to cause the neurologic disorder. The combination of diarrhea, orthostatic hypotension, and peripheral neuropathy suggests the possibility of amyloid disease or diabetes mellitus. The combination of chronic diarrhea, arthritis, and dementia or other cerebral disorder suggests Whipple disease (see Chapter 34). The disease is often diagnosed only at autopsy because there is no characteristic clinical picture and steatorrhea may be lacking. An unusual sign is oculomasticatory myorhythmia, a term that describes rhythmic convergence of the eyes and synchronous contractions of the masticatory muscles. Diagnosis can be made reliably by a polymerase chain reaction test. Recognition is important because Whipple disease can be cured by treatment with trimethoprim-sulfamethoxazole. SUGGESTED READINGS General Glickman R. Malabsorption syndromes. In: Wyngaarden JB, Smith LH Jr, eds. Cecil's textbook of medicine, 16th ed. Philadelphia: WB Saunders, 1982. Keane JR. Neurologic symptoms mistaken for gastrointestinal disease. Neurology 1998;50:1189–1190. Malouf R, Brust JCM. Hypoglycemia: causes, neurological manifestations, and outcome. Ann Neurol 1985;17:321–430. Pallis CA, Lewis PD. The neurology of gastrointestinal disease. Philadelphia: WB Saunders, 1974. Perkin GD, Murray-Lyon I. Neurology and the gastrointestinal system. J Neurol Neurosurg Psychiatry 1998;65:291–300. Winick M. Malnutrition and the brain. New York: Oxford University Press, 1976. Vitamin B12 Deficiency Al-Shubali AF, Farah SA, Hussein JM, Trontelj JV, Khuraibet AJ. Axonal and demyelinating neuropathy with reversible proximal conduction block, an unusual feature of vitamin B Nerve 1998;21:1341–1343. Anonymous Editorial. Still time for rational debate about vitamin B

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Brantigan CO. Folate supplementation and the risk of making vitamin B

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Chanarin I, Metz J. Diagnosis of cobalamin deficiency: the old and the new. Br J Haematol 1997;97:695–700. Elia M. Oral or parenteral therapy for B 12 deficiency. Lancet 1998;352:1721–1722. Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin therapy. Neurology 1995;45:1435–1440. Hall CA. Function of vitamin B 12 in the central nervous system as revealed by congenital defects. Am J Hematol 1990;34:121–127. Healton EH, Savage DG, Brust JCM, et al. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 1991;70:228–245. Holloway KL, Alberico AM. Postoperative myelopathy: a preventable complication in patients with B

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deficiency. Neurosurgery 1990;72:732–736.

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Kinsella LJ, Green R. “Anesthesia paresthetica”: nitrous oxide-induced cobalamin deficiency. Neurology 1995;45:1608–1610. Layzer RB. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 1978;2:1227–1230. Layzer RB, Fishman RA, Schafer JA. Neuropathy following abuse of nitrous oxide. Neurology 1978;28:504–506. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720–1728. Lindenbaum J, Savage DG, Stabler SP, et al. Diagnosis of cobalamin deficiency. II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Hematol 1990;34:99–107. Locatelli ER, Laureno R, Ballard P, Mark AS. MRI in vitamin B

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Robertson KR, Stern RA, Hall CD, et al. Vitamin B 12 deficiency and nervous system disease in HIV infection. Arch Neurol 1993;50:807–811. Russell JSR, Batten FE, Collier J. Subacute combined degeneration of the spinal cord. Brain 1900;23:39–110. Sigal SH, Hall CA, Antel JP. Plasma R binder deficiency and neurologic disease. N Engl J Med 1987;317:1330–1332. Stabler SP. Vitamin B 12 deficiency in older people: improving diagnosis and preventing disability. J Am Geriatr Soc 1998;46:1199–1206. Stojsavljevic N, Levic Z, Drulovic J. 44-month clinical-brain MRI follow-up in a patient with B

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Toh B-H, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med 1997;337:1441–1448. Victor M, Lear AA. Subacute combined degeneration of the spinal cord. Am J Med 1956;20:896–911. Malnutrition and Malabsorption Albers JW, Nostrant TT, Riggs JE. Neurologic manifestations of gastrointestinal disease. Neurol Clin 1989;7:525–548. Alloway R, Reynolds EH, Spargo E, et al. Neuropathy and myopathy in two patients with anorexia and bulimia nervosa. J Neurol Neurosurg Psychiatry 1985;48:1015–1020. Dastur DK, Manghani DK, Osuntokun BO, et al. Neuromuscular and related changes in malnutrition. A review. J Neurol Sci 1982;55:207–230. Flannelly G, Turner MJ, Connolly R, et al. Persistent hyperemesis gravidarum complicated by Wernicke's encephalopathy. Irish J Med Sci 1990;159:89. Gill GV, Bell DR. Persisting nutritional neuropathy amongst former war prisoners. J Neurol Neurosurg Psychiatry 1982;45:861–865. Hadjivassilou M, Grunewald RA, Chattopadhyay AK, et al. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 1998;352:1582–1585. Hart PE, Gould SR, MacSweeney JE, Clifton A, Schon F. Brain white matter lesions in inflammatory bowel disease. Lancet 1998;351:1558. Hedges TR 3rd, Hirano M, Tucker K, Caballero B. Epidemic optic and peripheral neuropathy in Cuba: a unique geopolitical public health problem. Surv Ophthalmol 1997;41:341–353. Hirano M, Cleary JM, Stewart AM, et al. Mitochondrial DNA mutations in an outbreak of optic neuropathy in Cuba. Neurology 1994;44:843–845. Johns DR. Cerebrovascular complications of inflammatory bowel disease. Am J Gastroenterol 1991;86:367–370. Lloyd-Still JD, Tomasi L. Neurovascular and thromboembolic complications of inflammatory bowel disease in childhood. J Paediatr Gastroenterol Nutr 1989;9:461–466. Lossos A, River Y, Eliakim A, Steiner I. Neurologic aspects of inflammatory bowel disease. Neurology 1995;45:416–421. Mitchell JE, Seim HC, Colon E, et al. Medical complications and medical management of bulimia. Ann Intern Med 1987;107:71–77. Palmer EP, Guary AT. Reversible myopathy secondary to abuse of ipecac in patients with major eating disorders. N Engl J Med 1985;313:1457–1459. Patchell RA, Fellows HA, Humphries LL. Neurologic complications of anorexia nervosa. Acta Neurol Scand 1994;89:111–116. Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P. Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features. 1999;66:32–35.

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Harding AE, Muller DPR, Thomas PK, et al. Spinocerebellar degeneration secondary to chronic intestinal malabsorption: a vitamin E deficiency syndrome. Ann Neurol 1982;12:419–424. Mauro A, Orsi L, Mortara P, et al. Cerebellar syndrome in adult celiac disease with vitamin E deficiency. Acta Neurol Scand 1991;84:167–170. Sitrin MD, Lieberman F, Jensen WE, et al. Vitamin E deficiency and neurologic disease in adults with cystic fibrosis. Ann Intern Med 1987;107:51–54. Sokol RJ. Vitamin E and neurologic deficits. Adv Pediatr 1990;37:119–148. D-Lactic Acidosis Carr DB, Shih VE, Richter JM, et al. D-lactic acidosis simulating a hypothalamic syndrome after bowel bypass. Ann Neurol 1982;11:195–197. Vella A, Farrugia G. D-Lactic acidosis: pathologic consequence of saprophytism. Mayo Clin Proc 1998;73:451–456. Vitamins and Minerals Insogna KL, Bordley DR, Caro JF, et al. Osteomalacia and weakness from excessive antacid ingestion. JAMA 1980;244:2544–2546. Parry GJ, Bredsen DE. Sensory neuropathy with low-dose pyridoxine. Neurology 1985;35:1466–1468. Rosenberg M, McCarten JR, Snyder BD, et al. Hypophosphatemia with reversible ataxia and quadriparesis. Am J Med Sci 1987;293:261–264. Schott GD, Wills MR. Muscle weakness in osteomalacia. Lancet 1976;1:626–629. Weintraub MI. Hypophosphatemia mimicking acute Guillain-Barré-Strohl syndrome. A complication of parenteral alimentation. JAMA 1980;235:1040–1041.

CHAPTER 155. VASCULITIS SYNDROMES MERRITT’S NEUROLOGY

CHAPTER 155. VASCULITIS SYNDROMES LEWIS P. ROWLAND Polyarteritis Nodosa Temporal Arteritis and Polymyalgia Rheumatica (Giant Cell Arteritis) Temporal Arteritis Polymyalgia Rheumatica Antineuronal Cytoplasmic Autoantibody-Positive Granulomatous Giant Cell Arteritis: Churg-Strauss Syndrome and Wegener Granulomatosis Granulomatous Angiitis of the Brain Systemic Lupus Erythematosus Other Collagen-Vascular Diseases Suggested Readings

Several syndromes are commonly linked because they are characterized by a combination of arthritis, rash, and visceral disease. Because arthritis is common to all and fibrinoid degeneration of blood vessels is common, they are called collagen-vascular diseases. Inflammatory lesions of the blood vessels, however, are the dominant pathologic changes in some syndromes. Periarteritis nodosa was the model vasculitis, but the classification of related syndromes depended on autopsy evaluation of histologic changes in the arteries, whether large or small vessels were involved, and which organs were most affected. Similar classifications were applied to clinical diagnosis, but overlap between syndromes and lack of knowledge of pathogenesis obscured the area. Some of these diseases were attributed to the deposition of circulating immune complexes within vessel walls, and some seemed related to viral infection. With the discovery of antineuronal cytoplasmic autoantibodies (ANCA) and other antibodies, a new classification was adopted by an international consensus conference in 1994 ( Table 155.1). An older classification describes syndromes that have characteristic clinical and neurologic manifestations and warrant individual discussion ( Table 155.2). Clinical disorders of brain, spinal cord, peripheral nerve, and muscle are prominent in these diseases. All these conditions are said to be rare except for temporal arteritis and polymyalgia rheumatica after age 60 and Kawasaki disease in children.

TABLE 155.1. VASCULITIS SYNDROMES: CHAPEL HILL CONSENSUS CRITERIA

TABLE 155.2. SYNDROMES ASSOCIATED WITH SYSTEMIC VASCULITIS

ANCA tests have had a major impact in clinical practice and in theory, bolstering the view that these diseases are autoimmune in origin. In the United Kingdom, the annual incidence of systemic vasculitis other than temporal arteritis was 42 per million population, and 50% of patients tested positive for ANCA. They are especially prevalent in Wegener granulomatosis, microscopic polyangiitis, and the Churg-Strauss syndrome. The test depends on immunofluorescence that gives either of two patterns, cytoplasmic ANCA or perinuclear ANCA. The cytoplasmic antigen is a proteinase (PR3-ANCA) and the perinuclear antigen is myeloperoxidase (MPO-ANCA); 90% of patients with Wegener disease have the cytoplasmic PR3-ANCA, and 90% of patients with Churg-Strauss have the perinuclear MPO-ANCA. However, the missing 10% is important because a negative test does not exclude either diagnosis.

POLYARTERITIS NODOSA Polyarteritis nodosa is an inflammatory arteritis that affects primarily the medium-sized arteritis. It is characterized by nonspecific symptoms commonly associated with an infection or signs and symptoms involving abdominal organs, joints, peripheral nerves, muscles, or central nervous system (CNS). Etiology The cause of periarteritis is unknown; reactions to bacterial or viral infection have been postulated. Association of the disorder with asthma, serum sickness, or drug reactions suggests autoimmunity. Rich reproduced the lesions in rabbits by repeated injections of horse serum. Immune complexes may play a role; in some cases, immune complexes have been found in vessel walls without vasculitis but with chronic aggressive hepatitis attributed to hepatitis B virus. Pathology There is widespread panarteritis. The pathology in the nervous system includes infiltrates in the adventitia and vasa vasorum, polymorphonuclear leukocytes, and eosinophils. Necrosis of the media and elastic membrane occurs and may lead to formation of multiple small aneurysms. As these become fibrotic, they may rupture; proliferation of intima may lead to thrombosis of vessels. Repair and fibrosis of the aneurysms lead to a characteristic beading appearance caused by the nodules. Incidence Polyarteritis nodosa is rare, but when it occurs, the CNS is involved in about 25% of cases. Both sexes are affected. The disease may occur at any age, but more than 50% of the reported cases are in the third or fourth decades of life. Signs and Symptoms Onset may be acute or insidious. Fever; malaise; tachycardia; sweating; fleeting edema; weakness; and pains in the joints, muscles, or abdomen are common early

symptoms (Table 155.3 and Table 155.4). Blood pressure may be elevated, and there may be a moderate or severe anemia with leukocytosis.

TABLE 155.3. CLINICAL FEATURES IN PATIENTSa WITH POLYARTERITIS NODOSA

TABLE 155.4. SYMPTOMS AT ONSET IN PATIENTS WITH POLYARTERITIS NODOSA

Visceral lesions occur in most cases. Kidney involvement produces symptoms and signs of acute glomerular nephritis. Cutaneous hemorrhages, erythematous eruptions, and tender red subcutaneous nodules may appear in the skin of the trunk or limbs. Gastrointestinal, hepatic, renal, or cardiac symptoms may develop. Peripheral neuropathy is the most common neurologic disorder. Periarteritis is probably one of the most common causes of mononeuritis multiplex, but there may also be a diffuse sensorimotor peripheral neuropathy. Both forms of neuropathy are attributed to ischemia effected by the arteritis of nutrient vessels. Damage to cerebral arteries may lead to thrombosis or hemorrhage; spinal syndromes are exceptional. The most common manifestations of cerebral involvement are headache, convulsions, blurred vision, vertigo, sudden loss of vision in one eye, and confusional states or organic psychosis. A disorder characterized by keratitis and deafness in nonsyphilitic individuals is called the Cogan syndrome. It occurs predominantly in young adults with negative blood and cerebrospinal fluid (CSF) tests for syphilis and no stigmata of congenital syphilis. The cause of the keratitis and deafness is not known, but in some cases, the syndrome was one feature of polyarteritis nodosa. Symptoms begin suddenly, involving the cornea and both divisions of the eighth nerve. The eye and the eighth nerve are usually involved simultaneously, but there may be weeks or months between the onset of symptoms in the eye and the ear. Involvement of the eighth nerve is usually signaled by nausea, vomiting, tinnitus, and loss of hearing. With progression of the hearing loss to complete deafness, the vestibular symptoms subside. Laboratory Data There is a leukocytosis with an inconstant eosinophilia. Nontreponemal serologic tests for syphilis may be positive, and there may be positive skin and serologic tests for trichinosis. CSF is normal unless there has been a meningeal hemorrhage. Diagnosis Diagnosis of polyarteritis nodosa should be considered in all patients with an obscure febrile illness with systemic symptoms and chronic peripheral neuropathy. The diagnosis can often be established by biopsy of sural nerve, muscle, or testicle. Course and Prognosis Prognosis is poor. Death usually occurs because of lesions of the kidneys, other abdominal viscera, or the heart; occasionally, lesions in the brain or peripheral nerves may cause death. Duration of life after onset of symptoms varies from a few months to several years. Spontaneous healing of the arteritis may occur and is followed by remission of all symptoms and signs, including those due to involvement of the peripheral nerves. Treatment There is no specific therapy. Treatment is chiefly supportive, including blood transfusions and symptomatic therapy for associated conditions. Corticosteroids may be of temporary benefit in some cases.

TEMPORAL ARTERITIS AND POLYMYALGIA RHEUMATICA (GIANT CELL ARTERITIS) Temporal arteritis and polymyalgia rheumatica are inextricably linked because they overlap in clinical features, high erythrocyte sedimentation rate (ESR), pathology in the temporal artery (giant cell arteritis), course, and response to steroid therapy. Both affect people older than age 50, and dominant features include malaise and myalgia. The major difference is the prominent headache in temporal arteritis and the threat of visual loss. However, temporal artery biopsy may be positive in patients who lack the cranial symptoms. It is not clear whether the two syndromes are slightly different manifestations of the same etiology and pathogenesis or there are two separate conditions with overlapping manifestations. Doppler studies may provide a noninvasive mode of diagnosis, but sensitivity and specificity must be assessed. The lesions are characterized by the presence of activated CD4+ T cells, macrophages that produce transforming growth factor-b, and absence of B cells. If temporal artery biopsy samples are implanted in severe combined immunodeficiency mice, patterns suggest that persistence of the transforming growth factor-b macrophages accounts for the chronicity of disease and that steroid therapy suppresses the function of these cells as assessed by histology and also by interleukin production.

TEMPORAL ARTERITIS This syndrome was first described by Horton in 1934. The pathology is similar to that of periarteritis nodosa except that the inflammatory reaction is more severe and there are more multinucleated giant cells in the media ( giant cell arteritis). It is usually restricted to the temporal artery, but other vessels are sometimes affected. The syndrome occurs after age 50 equally in men and women. It is said to occur exclusively in whites and primarily those of Nordic descent. In Sweden, the incidence rate was 18.3 cases per 100,000 inhabitants over age 50. In

Italy, the comparable figure was 6.9 per 100,000. The low frequency in blacks parallels the distribution of HLA-DR4. The pathogenesis is uncertain. Immune complexes are not found consistently, and it is thought that local T cells are activated, many bearing peceptors for interleukin-2. There is also evidence, however, of depletion of circulating T-suppressor CD8 cells, implying a general abnormality of immune function. Also, the antigen is unknown. Symptoms include headache, which is typically centered on the affected temporal artery but may be more generalized. Systemic symptoms include malaise, fever, anorexia, weight loss, and myalgia. The ESR is almost always above 50 mm/hr. The affected temporal artery may be prominent, nodular, tender, and noncompressible. Unilateral visual loss, found in 14% to 33% of patients in different series, is attributed to occlusion of the central retinal artery. The disk may appear pale, normal, or swollen with retinal hemorrhages. Ophthalmoparesis may be prominent, but other cranial nerve palsies are uncommon. Coronary and limb arteries are sometimes affected. Cerebral symptoms are mostly those of cerebral infarction, which is seen in few cases. However, it is also one of the rare forms of reversible dementia. Diagnosis is simple when all typical findings are present. The ESR, however, may not be elevated, and the temporal artery biopsy specimen may be normal in otherwise typical cases. The diagnosis should be considered whenever a person older than 50 begins to have new headaches, unilateral visual loss, or ophthalmoparesis. Diagnosis is then made by the high ESR or typical findings on biopsy. Typical abnormalities on temporal artery biopsy are diagnostic because inflammatory cells are not seen at autopsy of control subjects. If the clinical picture includes headache, jaw claudication, and myalgia with high ESR, it is more likely that the biopsy will support the diagnosis, but not always. It is difficult to substantiate the diagnosis if clinical manifestations are not typical and the ESR or biopsy is normal. It is now difficult to determine the natural history because the threat of visual loss leads to steroid treatment as soon as the diagnosis is made; it is truly emergency treatment. It is difficult to justify a placebo-controlled trial under these circumstances. However, it is believed that the disease is self-limited, lasting months or a year or two. In the past, when daily prednisone doses were about 60 mg, few patients could stop steroid therapy. In the 1980s, the dose gradually dropped without losing efficacy. The adverse effects of steroid therapy are dose and duration dependent; with “standard” doses, at least a third of the patients had serious adverse effects of steroids. With maintenance doses of 5 to 10 mg prednisone, the frequency of side effects is much less, and therapy can often be discontinued in 6 to 12 months. In the past decade, the recommended starting dose has dropped from 60 mg daily to 20 to 40 mg daily. Taylor and Samanta recommend a starting dose of 40 mg daily if there has been no visual loss. They reduce the dose by 10 mg/day each month for 3 months, then from 20 to 10 mg daily over another 3 months, and slower tapering thereafter. If vision is already affected, the dose is 60 to 80 mg daily, and some add 250 mg hydrocortisone intravenously if vision has already been affected; there is no evidence that these higher doses are more effective. In the only controlled trial of steroids and cyclophosphamide, neither was superior. Early steroid therapy seems to prevent the most feared consequence of temporal arteritis, loss of vision. If therapy is started when one eye is affected, vision in the other eye is protected. If vision has already been lost, chances of recovery are low. Aiello et al. (1993) found that 34 of 245 patients (14%) lost vision; in 32 of them, the visual loss occurred before steroid therapy commenced. The mortality rate is low, and most deaths that do occur are encountered in the first 4 months of the disease.

POLYMYALGIA RHEUMATICA This condition is defined by the combination of myalgia, malaise, weight loss, and increased ESR in a person older than 50. In many patients, temporal artery biopsy shows the changes of temporal arteritis, even if there is no headache or other symptomatic indication that cranial vessels are affected. The threat of visual loss is lower if there are no cranial symptoms, but the similarities require the same steroid therapy. The symptoms of polymyalgia rheumatica are nonspecific and could be reproduced by someone with an occult malignant tumor. It becomes a matter of clinical judgment to decide whether there is time for a diagnostic therapeutic trial of steroid therapy (as described for temporal arteritis) with or without search for the possible tumor. The other major consideration in differential diagnosis is polymyositis. In polymyalgia, however, there is no limb weakness, serum levels of creatine kinase are normal, and there are no myopathic changes in muscle biopsy or electromyography; if any of these tests gave abnormal results, the syndrome would be indistinguishable from polymyositis. Treatment is the same as for temporal arteritis, but there may be more consistent symptomatic relief with even smaller doses of prednisolone, 15 to 20 mg daily, dropping to 10 mg daily by 3 months. The long-term outlook is excellent, but there are recurrences in some patients.

ANTINEURONAL CYTOPLASMIC AUTOANTIBODY-POSITIVE GRANULOMATOUS GIANT CELL ARTERITIS: CHURG-STRAUSS SYNDROME AND WEGENER GRANULOMATOSIS The arterial lesions in these rare syndromes differ from those of periarteritis in that granuloma formation is more prominent, and they may be more necrotizing. There are other differences. For instance, eosinophilia and asthma define the Churg-Strauss syndrome. Sensorimotor neuropathy is seen in about 70% of patients and, sometimes, visual loss. Microscopic polyangiitis resembles periarteritis nodosa clinically and neurologically but affects smaller vessels, especially in the kidneys and lungs (Table 155.5).

TABLE 155.5. FREQUENCY OF MANIFESTATIONS IN SMALL-VESSEL VASCULITIS (PERCENT OF PATIENTS)

Wegener granulomatosis has a predilection for the respiratory system and kidneys. According to criteria of the American Academy of Rheumatology, the diagnosis can be made if there are two of the following four criteria: oral ulcers or purulent bloody nasal discharge; abnormal chest film showing nodules, fixed infiltrates, or cavities; microhematuria; and biopsy evidence of granulomatous inflammation in the wall of an artery or perivascular tissue. “Limited” Wegemer disease shows the typical pathology but spares lungs and kidney. Ninety percent of typical Wegener patients are ANCA positive; 50% to 80% have the C-ANCA pattern with anti-proteinase 3, and 10% to 18% show the P-ANCA pattern with anti-myeloperoxidase. Neurologic manifestations, as in other vasculitis syndromes, more often indicate a sensorimotor peripheral neuropathy than a CNS syndrome. The disease was once thought to be uniformly fatal, but survival is reported with modern immunosuppressive therapy, including cyclophosphamide.

GRANULOMATOUS ANGIITIS OF THE BRAIN In one form of granulomatous angiitis, clinical manifestations are restricted to the brain. Thus, this is appropriately called granulomatous angiitis of the brain (GAB). In a few cases, the spinal cord is similarly affected, alone or with cerebral lesions. Therefore, the more comprehensive term is granulomatous angiitis of the nervous

system (GANS). This disorder is essentially defined by the characteristic histologic lesion, a granulomatous change that includes multinucleated giant cells; it is seen in small or larger named cerebral blood vessels. Lesions of this nature are found in some patients with clinical evidence of a cerebral infarct ipsilateral to herpes zoster ophthalmicus. Otherwise, there is no clinical clue to the nature of the disease. A few patients have had evidence of immunosuppression with sarcoidosis, Hodgkin disease, or acquired immunodeficiency syndrome. After herpes zoster, the clinical manifestations may be those of an uncomplicated stroke, with severe or mild manifestations in different cases. When there is no evidence of zosterian infection, the symptoms include two invariable but nonspecific sets, focal cerebral signs and mental obtundation, which may be preceded by dementia. The course is subacute, so this can be regarded as a progressive encephalopathy. Characteristically, there is CSF pleocytosis, up to 500 mononuclear cells per high-power field. CSF protein content is usually increased, exceeding 100 mg/dL in 75% of cases, but CSF glucose content is normal. There has been doubt about the necessity or desirability of brain biopsy for diagnosis. Advocates believe that pathologic proof is needed and that the risks of meningeal biopsy are about 1%. On the other hand, the risks of immunotherapy are much higher and may be given for an erroneous diagnosis. Analyzing 30 biopsies for presumed GANS, Goldstein and associates found that 50% had some other disease. Moreover, angiographic evidence of arteritis is unreliable when “positive” and is absent in most cases of histologically proven granulomatous angiitis of the brain. Others contend that a negative biopsy does not exclude the diagnosis and believe that sufficient evidence is given by angiographic “beading” of arteries. Cases so diagnosed have been treated with cyclophosphamide, and, if the outcome was favorable, the authors concluded that the likely catastrophic outcome had been averted. In autopsy-proven cases, however, the arteriogram is usually normal or shows evidence of an infarct or local tissue swelling but not beading. Moreover, the clinical, arteriographic, and CSF manifestations can be caused by infiltration of meninges by tumor cells or viral infection; beading of cerebral arteries is a nonspecific finding. These different perspectives can be seen in a comparison of series defined by pathologic diagnosis (the “neurologist's view”) or by cerebral angiography and pathology (the “rheumatologist's view”) ( Table 155.5). Neurologists do not consider diagnosis by arteriography reliable because beading is found in only 10% of pathologically proven cases. Strokes are found in only 15%. In contrast to arteriographic diagnosis, pathologic diagnosis leads to a reasonably consistent picture: encephalopathy (obtundation, cognitive loss); headache; onset over days or weeks, not apoplectic; and CSF protein content greater than 100 mg/dL. Other problems of diagnosis include subacute bacterial, yeast, or neoplastic meningitis; these conditions are more likely if CSF glucose content is less than 40 mg/dL, and if the glucose content is normal, CSF cytology is needed. GAB may simulate prion disease by causing severe dementia within a few weeks. If GAB produces a mass lesion, brain biopsy makes the distinction from tumor. The diagnosis of GANS implies myelopathy, which is difficult to diagnose in life unless there is concomitant evidence of herpes zoster or sarcoid. The neurologists' consensus is that diagnosis in living patients can be verified only by a brain biopsy that includes meningeal vessels. In histologically proven cases (without zoster), the outcome has been fatal in most cases within a few years. About half the patients die within 6 weeks, but a third live longer than 1 year after onset. Treatment with immunosuppressive drugs has not been effective in most proven cases, but control of GAB has been documented in patients with biopsy-proven GAB who were treated with immunosuppression, died later, and had no autopsy evidence of lingering inflammation; two of those patients also had amyloid angiopathy.

SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus (SLE) is characterized by widespread inflammatory change in the connective tissue (collagen) of the skin and systemic organs. The primary damage is to the subendothelial connective tissue of capillaries, small arteries, and veins; the endocardium; and the synovial and serous membranes. Etiology and Incidence The cause is not known, but immune complexes are deposited in small vessels. The initiating event could be a persistent viral infection, but sometimes serologic and clinical manifestations follow administration of drugs, such as procainamide. Although rare, the incidence may be increasing. Most cases begin between ages 20 and 40, but the disease may be seen in children. Some 95% of adult patients are women. Symptoms and Signs The chief clinical manifestations are prolonged irregular fever, with remissions of variable duration (weeks, months, or even years); erythematous rash; recurrent attacks with evidence of involvement of synovial and serous membranes (polyarthritis, pleuritis, pericarditis); depression of bone marrow function (leukopenia, hypochromic anemia, moderate thrombocytopenia); and, in advanced stages, clinical evidence of vascular alteration in the skin, kidneys, and other viscera. Neurologic manifestations can be divided into several major categories. The most common form, affecting up to 25% of all patients with SLE, is cerebral lupus, an encephalopathy manifest by seizures, psychosis, dementia, chorea, or cranial nerve disorder. SLE is one of the few remaining causes of chorea in young women. Other neurologic syndromes are transverse myelopathy, sensorimotor peripheral neuropathy, and polymyositis ( Table 155.6). These symptoms are often attributed to thrombosis of small vessels or petechial hemorrhages. Microinfarcts may be related to fibrinoid degeneration of small vessels with deposition of antibodies to a platelet membrane glycoprotein. The same neurologic symptoms are encountered in pediatric lupus.

TABLE 155.6. COMPARISON OF TWO CONCEPTS OF GRANULOMATOSIS ANGIITIS OF THE BRAIN: DIAGNOSIS BY HISTOPATHOLOGY OR ARTERIOGRAPHY

Evidence of cerebral vasculitis is meager. The cause of cerebral symptoms is not known but they are attributed to mixed pathogenesis: antineuronal antibodies of unknown type, microvascular occlusions from vasculitis, antiphospholipid antibodies, and noninflammatory vasculopathy. Although strokes are a feature of the “antiphospholipid syndrome,” there is little evidence they are responsible for cerebral lupus. Antibodies to ribosomal protein P are said to be highly specific for cerebral lupus but of poor sensitivity, found in only 20% of patients. Stroke caused by occlusion of large cerebral vessels is distinctly uncommon. In 1994, Mitsias and Levine found only 30 reported cases, and they were due to diverse mechanisms, including thrombus, dissection, fibromuscular dysplasia, vasculitis, and premature atherosclerosis. The short-term death rate was 40%, and recurrences occurred in 13% of the survivors. Venous sinus thrombosis is also recognized. In general, little information has been provided by brain imaging of any kind, including

positron emission tomography and single-photon emission computed tomography. The cause of cerebral lupus is therefore uncertain. In some cases, cerebral emboli arise from endocarditis or thrombotic thrombocytopenia. Laboratory Data In addition to anemia and leukopenia, there is often hematuria or proteinuria, signs of renal damage. Biologic false-positive tests for syphilis may be encountered. The most important diagnostic test is the search for antinuclear antibodies (ANA), especially antibodies to double-stranded DNA, which are also used as a measure of activity of the disease. Antibodies to a particular antigen (“Sm” for Smith) may be found more often in patients with cerebral disease. Although not used often these days, phagocytic polymorphonuclear leukocytes ( LE cells) are found in 80% of all cases and are considered pathognomonic by some authorities. Serum complement levels may be decreased in patients with renal disease; deposits of globulin and complement may be found in renal biopsy specimens. CSF is usually normal, but there may be a modest increase in protein content. For reasons not known, the CSF glucose content is often decreased in SLE patients with myelitis. Computed tomography and magnetic resonance imaging show nonspecific changes in cerebral lupus. Positron emission tomography may show lesions in brain in SLE patients with normal magnetic resonance imaging; functional abnormality may precede structural abnormality. Diagnosis Diagnosis may be difficult. Fever; weight loss; arthritis; anemia; leukopenia; pleuritis; and cardiac, renal, or neurologic symptoms in a young woman should lead to a consideration of this diagnosis. An erythematous rash on the bridge of the nose and the malar eminences in a butterfly-like distribution facilitates the diagnosis. Finding LE cells or ANA in the blood is of value in establishing the diagnosis. Neurologic manifestations are only rarely the first manifestation of SLE, but the diagnosis should be kept in mind when there is an acute encephalopathy in a young woman. Acute psychosis in a woman with known SLE may be due to the disease or the effects of steroid therapy, which may be difficult to unravel. Mixed connective tissue disease is an overlap syndrome with features of SLE, systemic sclerosis, and polymyositis. At first, there seemed to be an association with antibodies to ribonucleoprotein, but the specificity disappeared. Also, polymyositis can be a manifestation of any collagen-vascular or vasculitis syndrome, with little specificity. It is primarily systemic sclerosis that overlaps with both SLE and dermatomyositis. For instance, the multisystem disease described in Case Record 24-1995 may show polymyositis, with evidence of SLE (rash more like that of SLE than that of dermatomyositis) and high titer of ANA, and features of systemic sclerosis (esophageal dysmotility, Raynaud phenomenon, and severe lung disease), but no skin lesions of scleroderma. SLE patients may also show features of rheumatoid arthritis or Sjögren syndrome. It seems unlikely that mixed connective tissue disease is a unique condition, but the multisystem diseases are a diagnostic and therapeutic challenge. Course, Prognosis, and Therapy Cerebral lupus is a medical catastrophe with poor prognosis. Recommendations include intravenous doses of methylprednisolone (1 g daily for 3 days), followed by low-dose oral prednisolone. Some authorities add intravenous cyclophosphamide in the initial treatment. Plasmapheresis has not been established as beneficial, and intravenous immunoglobulin therapy is still experimental. Cases are so few and the disease is so devastating that it has been difficult to carry out a therapeutic trial. Treatment is equally uncertain for the less-threatening syndromes of peripheral neuropathy, myelitis, or polymyositis. Steroid therapy is the accepted treatment but not established by therapeutic trial. In the long run, death may result from renal failure or infection.

OTHER COLLAGEN-VASCULAR DISEASES Neurologic syndromes may complicate other collagen-vascular diseases, usually when the systemic disorder is evident. Sometimes, there are characteristic syndromes. For instance, an aggressive polyneuropathy may be seen in patients with rheumatoid arthritis. Some clinicians believe the neuropathy may be precipitated by steroid therapy. Another neurologic syndrome of rheumatoid arthritis is atlantoaxial dislocation with resulting cord compression; the syndrome is attributed to resorption of the odontoid process. Sjögren syndrome is defined clinically by internationally accepted criteria. There must be at least two of the following: xerostomia (dry mouth), which can be documented by scintigraphy; xerophthalmia (dry eyes; pathologic documentation of abnormality in salivary gland biopsy); or keratoconjunctivitis sicca, as demonstrated by the Shirmer test for tear production. Lip biopsy may show sialoadenitis. If the neurologic manifestations dominate, the term “sicca complex” has been used. Sensorimotor peripheral neuropathy (primarily sensory or sensorimotor) and polymyositis are the most common neurologic manifestations. Sjögren disease is one of the causes of trigeminal sensory neuropathy. CNS complications are rare, but venous sinus thrombosis, myelopathy, a form of motor neuron disease, or aseptic meningitis is seen. The origin of the neuropathy is not known. Antineuronal antibodies have been found in some cases. Treatment, as usual in these diseases, focuses on steroids in uncontrolled trials. In Sjögren syndrome, peripheral neuropathy and polymyositis may be prominent. Peripheral neuropathy is also seen in more than half the patients with the idiopathic hypereosinophilic syndrome, and there may be evidence of vasculitis in the nerve biopsy. SUGGESTED READINGS General Cupps TR, Fauci AS. The vasculitic syndromes. Adv Intern Med 1982;27:315–344. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997;337:1512–1523. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides:proposal of an international consensus conference. Arthritis Rheum 1994;37:187–192. Olney RK. Neuropathies associated with connective tissue disease. Semin Neurol 1998;18:63–72. Savage COS, Harper L, Adu D. Primary systemic vasculitis. Lancet 1997;349:553–558. Polyarteritis Nodosa Bicknell JM, Holland JV. Neurologic manifestations of Cogan syndrome. Neurology 1978;28:278–281. Ford RG, Siekert RG. Central nervous system manifestations of periarteritis nodosa. Neurology 1965;15:114–122. Gayraud M, Guillevin L, Cohen P, et al. Treatment of good-prognosis polyarteritis nodosa and Churg-Strauss syndrome: comparison of steroids and oral or pulse cyclophosphamide in 25 patients. French Cooperative Study Group for Vasculitides. Br J Rheumatol 1997;36:1290–1297. Lande A, Rossi P. The value of total aortography in diagnosis of Takayasu arteritis. Radiology 1975;114:287–297. Lovelace RE. Mononeuritis multiplex in polyarteritis nodosa. Neurology 1964;14:434–442. Moore PM, Cupps TR. Neurological complications of vasculitis. Ann Neurol 1983;14:155–167. Oren S, Besbas N, Saatci U, et al. Diagnostic criteria for polyarteritis nodosa in childhood. J Pediatr 1992;120:206–209. Rose AG, Sinclair-Smith CC. Takayasu's arteritis? A study of 16 autopsy cases. Arch Pathol Lab Med 1980;104:231–234. Wicki J, Olivieri J, Pizzolato G, et al. Successful treatment of polyarteritis nodosa related to hepatitis B virus with a combination of lamivudine and interferon alpha. 1999;38:183–185.

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CHAPTER 156. NEUROLOGIC DISEASE DURING PREGNANCY MERRITT’S NEUROLOGY

CHAPTER 156. NEUROLOGIC DISEASE DURING PREGNANCY ALISON M. PACK AND MARTHA J. MORRELL Biology of Pregnancy Epilepsy Preeclampsia and Eclampsia Stroke Cerebral Hemorrhage Multiple Sclerosis Migraine Neoplasms Neuropathies Myasthenia Gravis Movement Disorders Suggested Readings

Pregnancy and the postpartum period are times of major biologic and social changes. Pregnancy may be associated with alterations in preexisting neurologic conditions, such as epilepsy or migraine, or herald the emergence of neurologic disorders such as peripheral nerve entrapment or a movement disorder. This chapter addresses the diagnosis, management, and treatment of neurologic disorders arising in or altered by pregnancy.

BIOLOGY OF PREGNANCY Some physiologic changes during pregnancy may influence the expression of neurologic disease and complicate management. Alterations in neuroactive steroid hormones may influence the phenotypic appearance of the disease. Changes in pharmacokinetics, compliance, and sleep patterns may make disease management more challenging. The concentration and type of circulating steroid hormones change during pregnancy. Estrogen production increases. In the nonpregnant state, the main circulating estrogens are estradiol, which is synthesized by ovarian thecal cells, and estrone, which is produced by the extraglandular conversion of androstenedione. Estriol is a peripheral metabolite of estrone and estradiol. In pregnancy, the concentrations of all these estrogens, particularly estriol, increase. As pregnancy progresses, maternal steroids and dihydroisoandrostene from developing fetal adrenal glands are converted principally to estriol. Progesterone production also increases dramatically. These hormonal changes may affect neurologic conditions that are hormone-responsive, including migraine, epilepsy, and multiple sclerosis. Drug pharmacokinetics are affected by the physiologic changes of pregnancy ( Table 156.1). Renal blood flow and glomerular filtration increase as a function of increased cardiac output. Plasma volume, extravascular fluid, and adipose tissue increase to create a larger volume of distribution. Serum albumin decreases, which reduces drug-binding and increases drug clearance. These pharmacokinetic alterations may affect drug concentrations. The changes are most important for drugs that are highly protein bound, hepatically metabolized, or renally cleared.

TABLE 156.1. PHYSIOLOGIC CHANGES DURING PREGNANCY

Other events of pregnancy that may compromise management are hyperemesis gravidarum, sleep deprivation, and poor compliance. Hyperemesis gravidarum can make it difficult to maintain adequate concentrations of oral medications. Sleep deprivation aggravates many neurologic conditions and can be a particular problem in the third trimester. Compliance may deteriorate because of a woman's concern that taking medication might harm her baby. Women are often advised by friends, relatives, and even medical personnel to minimize fetal drug exposure. This may lead to skipped doses, reduced doses, or even self-discontinuation of an indicated medication.

EPILEPSY Each year 20,000 women with epilepsy become pregnant. This number has grown as marriage rates have increased for women with epilepsy, as parenting has become more socially supported, and as the medical management of pregnancy in women with epilepsy has improved. Seizure frequency may change during pregnancy. In women with preexisting epilepsy, 35% experience an increase in seizure frequency, 55% have no change, and 10% have fewer seizures. Changes responsible for this include changes in sex hormones, antiepileptic drug (AED) metabolism, sleep schedules, and medication compliance. AED concentrations may change. The total AED concentration falls because of an increase in volume of distribution, decreased drug absorption, and increased drug clearance. Although the total concentration decreases, the proportion of unbound or free drug increases because albumin levels and protein binding decline. Therefore, it is necessary to follow the nonprotein-bound drug concentrations for AEDs that are highly protein-bound, including carbamazepine (Tegretol), phenytoin sodium (Dilantin), and sodium valproate (Depakene). Dose adjustments should maintain a stable nonprotein-bound fraction. The older AEDs (benzodiazepines, phenytoin, carbamazepine, phenobarbital, and valproate) are teratogenic in humans. Major malformations related to AED exposure include cleft lip and palate and cardiac defects (atrial septal defect, tetralogy of Fallot, ventricular septal defect, coarctation of the aorta, patent ductus arteriosus, and pulmonary stenosis). The incidence of these major malformations in infants born to mothers with epilepsy is 4% to 6%, compared to 2% to 4% for the general population. These malformations can occur with exposure to any of the older AEDs. Neural tube defects (spina bifida and anencephaly) occur in 0.5% to 1% of infants exposed to carbamazepine and 1% to 2% of infants exposed to valproate during the first month of gestation. Minor congenital anomalies associated with AED exposure include facial dysmorphism and digital anomalies, which arise in 6% to 20% of infants exposed to AEDs in utero. This is a twofold increase over the rate in the general population. However, these anomalies are usually subtle and may often be outgrown. Since 1993, seven new AEDs have been introduced, with little information about effects on the developing fetus. A prospective registry has been established to learn more about pregnancy and fetal outcome in women using AEDs (Table 156.2). The registry should be contacted regarding any woman who becomes pregnant while taking AEDs.

TABLE 156.2. NORTH AMERICAN ANTIEPILEPTIC DRUG PREGNANCY REGISTRY

Several mechanisms have been postulated to explain the teratogenicity of AEDs. Some may be teratogenic because of free radical intermediates that may bind with ribonucleic acid and disrupt deoxyribonucleic acid synthesis and organogenesis. Higher concentrations of oxide metabolites increase the risk of fetal malformations. Some AEDs may cause folic acid deficiency, which is associated with higher occurrence and recurrence rates of neural tube defects. The American Academy of Neurology (AAN) and the American College of Obstetric and Gynecologic Physicians (1996) recommend that all women of childbearing age taking AEDs should receive folic acid supplementation of 0.4 to 5.0 mg per day. Management of epilepsy in women of reproductive age should focus on maintaining effective control of seizures while minimizing fetal exposure to AEDs. This applies to dosage and to number of AEDs. Medication reduction or substitution should be achieved prior to conception. Altering medication during pregnancy increases the risk of breakthrough seizures and exposes the fetus to an additional AED. The recommended AED management in pregnancy is monotherapy at the lowest effective dose. The drug of choice is the one most likely to be effective and well tolerated. Current information is not sufficient to identify a particular AED as favored in pregnancy. If there is a family history of neural tube defects, an agent other than carbamazepine or valproate might be considered. Once a woman is pregnant, prenatal diagnostic testing includes a maternal serum alpha-fetoprotein and a level II (anatomic) ultrasound at 14 to 18 weeks. This combination will identify more than 95% of infants with neural tube defects. In some instances, amniocentesis may be indicated. AEDs have also been associated with an increased risk for early fetal hemorrhage. This may be due to an AED-drug related vitamin K deficiency. Therefore, the AAN recommends vitamin K supplementation (vitamin K1 at 10 mg per day) for the last month of gestation. For pregnant women with new-onset seizures, the diagnostic strategy is similar to that for any patient with a first-time seizure. A complete neurologic history and examination should be obtained, with attention to signs of a specific etiology, such as acute intracranial hemorrhage or central nervous system (CNS) infection. The evaluation should also screen for hypertension, proteinuria, and edema to exclude eclampsia. Follow-up studies include serologic tests for syphilis and human immunodeficiency virus, electroencephalogram (EEG), and magnetic resonance imaging (MRI). MRI is the preferred imaging technique for pregnant woman. As in nonpregnant women with a first-time seizure, treatment depends on seizure type and etiology.

PREECLAMPSIA AND ECLAMPSIA Preeclampsia and eclampsia are most often seen in young primigravida women. Preeclampsia is a multisystem disorder that is diagnosed clinically by hypertension, proteinuria, and edema. Preeclampsia is associated with hepatic and coagulation abnormalities, hypoalbuminemia, increased urate levels, and hemoconcentration. Eclampsia is manifested by seizures, cerebral bleeding, and death. The incidence in Europe and other developed countries is 1 per 2,000. In developing countries, the incidence varies from 1 in 100 to 1 in 1,700. Worldwide, eclampsia probably accounts for 50,000 deaths annually. Neurologic abnormalities associated with eclampsia include confusion, seizures, cortical blindness, visual-field defects, headaches, and blurred vision. Seizures are most often generalized but may be partial. Cortical blindness and visual-field defects may occur with bilateral occipital lobe involvement. The differential diagnosis of eclampsia includes subarachnoid hemorrhage and cerebral venous thrombosis. The diagnosis is established by increased blood pressure plus proteinuria, edema, or both. A significant increase in blood pressure is defined as an increase of more than 15 mm Hg diastolic or 30 mm Hg systolic above baseline measurements obtained before or early in pregnancy. If no early reading is available, a blood pressure of 140/90 mm Hg or higher in late pregnancy is significant. Neuroimaging, EEG, cerebrospinal fluid (CSF) analysis, and angiography may help in diagnosis. Computed tomography (CT) is usually normal in eclampsia but may show hypodense regions in areas of cerebral edema. MRI permits better detection of edema in the cortical mantle. During an eclamptic convulsion, the EEG shows spike-and-wave discharges. The CSF is usually normal in preeclampsia. In eclampsia, the CSF protein content is often moderately elevated, and the pressure may be increased. In some patients, angiography shows arterial spasm. Pathologic examination of eclamptic brains reveals petechial hemorrhages in cortical and subcortical patches. Microscopically, these petechial hemorrhages are ring hemorrhages about capillaries and precapillaries occluded by fibrinoid material. Areas that are predisposed include the parietooccipital and occipital regions. Treatment of eclampsia is controversial. The most accepted treatment is delivery of the fetus, if appropriate. Hypertension should be treated with antihypertensive agents. The National Blood Pressure Education Program recommends magnesium sulfate for the treatment and prevention of eclamptic seizures. In the United States, obstetricians have traditionally used magnesium sulfate. However, in the United Kingdom, they use phenytoin or diazepam. Randomized trials have compared these agents for seizure prevention in women with preeclampsia/eclampsia. The results suggest that magnesium is the agent of choice, but no study has evaluated the treatment of eclamptic seizures with both magnesium sulfate and an AED.

STROKE Pregnancy is a risk factor for stroke, and the postpartum period is the most vulnerable time. Presumptive mechanisms include changes in the coagulation and fibrinolytic systems leading to a hypercoagulable state and an increase in viscosity and stasis, which can promote thrombosis. In the postpartum period, the large decrease in blood volume at childbirth, rapid changes in hormone status that alter hemodynamics and coagulation, and the strain of delivery may predispose to a stroke. Arterial occlusion causes 50% to 80% of ischemic strokes in pregnant women. Cerebral venous thrombosis is the next most common etiology. Arterial occlusion occurs primarily in the second and third trimesters, whereas venous thrombosis most often occurs in the postpartum period. Arterial strokes most often occur as a consequence of identifiable risk factors, including premature atherosclerosis, moyamoya disease, Takayasu arteritis, fibromuscular dysplasia, and primary CNS vasculitis. Hematologic disorders can play an etiologic role in arterial and venous strokes. Such disorders include sickle-cell disease, antiphospholipid syndrome, thrombotic thrombocytopenic purpura, and deficiencies in antithrombin III, protein C, protein S, and factor V Leiden. Other etiologies are cardiogenic and paradoxic emboli. Treatment of strokes in pregnancy is directed to the specific cause. Heparin does not cross the placenta and is the anticoagulant of choice in pregnancy. However, long-term use (greater than 1 month) is associated with osteoporosis. Warfarin sodium (Coumadin) crosses the placenta and is a known teratogen. It is therefore recommended only for women who cannot tolerate heparin or who have recurrent thromboembolic events. Aspirin complications in pregnancy include teratogenic effects and bleeding in the neonate. However, low-dose aspirin (less than 150 mg) is safe in the second and third trimesters, with no increase in maternal or neonatal adverse effects. Use of low-molecular-weight heparin is gaining acceptance during pregnancy. Like heparin, low-molecular-weight heparin does not cross the placenta. The risk of bleeding with these compounds is small, and the development of osteoporosis is less likely, although there is little information about appropriate

doses in pregnancy.

CEREBRAL HEMORRHAGE The risk of cerebral hemorrhage increases in pregnancy. Cerebral hemorrhage occurs in 1 to 5 pregnancies per 10,000, with an associated mortality of 30% to 40%. Factors that predispose to hemorrhage include physiologic changes of pregnancy such as hypertension, high concentrations of estrogens causing arterial dilation, and increases in cardiac output, blood volume, and venous pressure. Pregnancy-related conditions also increase the risk of hemorrhage. These include eclampsia, metastatic choriocarcinoma, cerebral emboli, and coagulopathies. Subarachnoid hemorrhage accounts for 50% of all intracranial bleeding in pregnancy and carries a high mortality. Cerebral aneurysms and arteriovenous malformations cause most subarachnoid hemorrhages in pregnancy. Other causes include eclampsia, cocaine use, coagulopathies, ectopic endometriosis, moyamoya disease, and choriocarcinoma. Aneurysmal bleeding usually occurs in older patients in the second and third trimesters. In contrast, hemorrhages from arteriovenous malformations occur in younger women throughout gestation, with the highest risk during labor and the puerperium. The diagnosis and treatment of subarachnoid hemorrhage and intracerebral hemorrhage in pregnant women are similar to those in nonpregnant patients. Subarachnoid hemorrhage is diagnosed by clinical manifestations and CT. If brain CT is normal and the clinical signs are consistent with intracranial hemorrhage, lumbar puncture should be performed. Once intracranial hemorrhage is detected, follow-up studies include MRI and four-vessel angiography. Noncontrast CT is also the most sensitive means of diagnosing intracerebral hemorrhage. Treatment of these conditions is directed to supporting the mother and fetus and preventing complications. Blood pressure should be carefully monitored, and fetal monitoring is indicated. The specific treatment depends on the etiology of the hemorrhage.

MULTIPLE SCLEROSIS Multiple sclerosis (MS) affects 1 in 10,000 people in Western countries, primarily women in the childbearing years. A multicenter, prospective observational study (Pregnancy in Multiple Sclerosis Study; Confavreux, 1998) and other surveys found that the rate of relapse declines in pregnancy, especially in the third trimester, and increases in the first 3 months postpartum. Long-term disability was not affected. The mechanisms responsible for the change in the rate of relapses include humoral and immunologic changes, as seen also in pregnant women with other autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. There is no correlation of relapse rate with the physical stress of childbirth and caring for the newborn, sleep deprivation, type and dose of anesthesia, breast-feeding, or socioeconomic factors. Many women with relapsing-remitting MS are treated with interferon beta-1b (Betaseron), interferon beta-1a (Avonex), or glatiramer acetate (Copaxone). None of these has been tested formally in pregnant women and discontinuation of these agents is recommended. In addition, there have been no controlled trials addressing the safety of medication for MS relapses. If a severe relapse does occur with pregnancy, a short course of corticosteroid therapy is recommended. However, neonatal adrenal suppression may follow maternal corticosteroid use, and large prenatal doses in animals caused growth retardation and compromised development of the CNS.

MIGRAINE Migraine is diagnosed in 18% of women of childbearing years, and 60% to 80% of migraine headaches improve during pregnancy. Women who had migraine onset at menarche or who have had menstrual migraines are more likely to experience improvement, especially in the first or second trimester. Higher levels of estrogen are probably responsible for this improvement during pregnancy. The subsequent fall in estrogen levels may cause postpartum headaches. It is not known why migraine may start or become worse in pregnancy. If migraine arises in pregnancy, the differential diagnosis must be considered. A new-onset migraine with aura can be a symptom of vasculitis, brain tumor, or occipital arteriovenous malformation. Subarachnoid hemorrhage can cause headache any time during pregnancy or delivery. Other disorders with headache include stroke, cerebral venous thrombosis, eclampsia, pituitary tumor, and choriocarcinoma. Medication use during pregnancy should be limited. If necessary, acetaminophen, nonsteroidal antiinflammatory drugs, codeine, or other narcotics may be used; low-dose aspirin may also be given. Antiemetics such as metoclopramide or prochlorperazine may relieve the headache and associated nausea and vomiting. These agents are generally safe and effective. Ergotamine, dihydroergotamine mesylate (D.H.E. 45), and sumatriptan succinate (Imitrex) should be avoided. For someone with recurrent headaches, a beta-adrenergic blocker, such as propanolol, may be used prophylactically. However, adverse effects including intrauterine growth retardation have been reported with beta-adrenergic blockers. Therefore, the choice of medication for migraine in pregnant women should balance the the mother's comfort with the least fetal risk.

NEOPLASMS Brain tumors rarely become symptomatic during pregnancy. The types of tumors arising in pregnancy differ from those in nonpregnant women. Glioma is the most common, followed by meningioma, acoustic neuroma, and then a variety of other tumors, including pituitary tumors. Tumor growth may be exacerbated by pregnancy, especially meningioma. Possible mechanisms include increased blood volume, fluid retention, and stimulation of tumor growth by hormones. Systemic cancer is unusual in young women and rarely begins during pregnancy. Choriocarcinoma is the only systemic tumor specifically associated with pregnancy. Brain metastases are common in choriocarcinoma; among patients diagnosed with choriocarcinoma, 3% to 20% have brain disease at diagnosis. Cerebral neoplasms cause headaches, seizures, focal signs, or symptoms of increased intracranial pressure. The seizures may be partial or generalized. Nausea and vomiting in the first trimester can be confused with morning sickness. All women suspected of having a brain tumor should be examined with MRI.

NEUROPATHIES During pregnancy and the puerperium, women are at an increased risk for peripheral neuropathy. Backache or poorly localized paresthesia is common. At least 50% of pregnant women have back pain, Among the specific rare neuropathies that occur with a higher incidence during pregnancy are carpal tunnel syndrome, facial nerve palsy, meralgia paresthetica, and chronic inflammatory demyelinating polyneuropathy (CIDP) (see Chapter 63 and Chapter 105). Carpal tunnel syndrome is the most frequent neuropathy of pregnancy. It usually begins in the third trimester and disappears after delivery; it is attributed to generalized edema. Bell palsy appears with a slightly higher frequency during pregnancy, mostly in the third trimester. Prognosis for recovery is excellent and is similar to that in nonpregnant women. Treatment is symptomatic, including protection of the eye. Meralgia paresthetica, a sensory neuropathy of the lateral femoral cutaneous nerve of the thigh, is attributed to compression of the nerve under the lateral part of the inguinal ligament. Swelling during pregnancy, increased body weight, and increased lordosis during pregnancy are possible causes. Numbness, burning, tingling, or pain in the lateral thigh suggests the diagnosis. A local anesthetic with or without steroids is usually all that is necessary. Most women improve in the postpartum period. The incidence of CIDP is slightly higher during pregnancy. As in nonpregnant women, treatment includes plasmapheresis, intravenous gamma globulin, or steroids.

MYASTHENIA GRAVIS Symptoms of myasthenia gravis (MG) may increase during menstruation, pregnancy, or the puerperium. About one-third of MG patients become worse, one-third show no change, and one-third show improvement. If symptoms begin during pregnancy, the diagnosis is established, and treatment is symptomatic, with plasmapheresis and intravenous immunoglobulin. Thymectomy is deferred until long after delivery. Neonatal MG affects 12% to 20% of infants born to mothers with MG. The symptoms clear within a few weeks.

MOVEMENT DISORDERS Movement disorders are unusual in young women, but those that specifically occur during pregnancy include the restless leg syndrome, chorea, and drug-induced movement disorders. The restless leg syndrome is probably the most common movement disorder of pregnancy. It is characterized by a crawling, burning, or aching sensation in the calves with an irresistible urge to move the legs. It occurs in 10% to 20% of pregnant women. Treatment includes massage, flexion and extension, walking, benzodiazepines, opiates, or levodopa. Chorea gravidarum occurs in pregnancy (see Chapter 109). Treatment is reserved for those with violent and disabling chorea and includes haloperidol or benzodiazepines. Drugs that block dopamine receptors are often used to treat the nausea and vomiting of pregnancy. These drugs can cause new-onset chorea, tremor, dystonia, or parkinsonism. Idiopathic Parkinson disease is uncommon in women younger than 40 years. More common is secondary parkinsonism caused by medication or toxins. There is no definite evidence that Parkinson disease worsens during pregnancy, and there is little information about the toxicity of antiparkinson medications. Successful pregnancies have been reported in women taking levodopa. SUGGESTED READINGS Biology of Pregnancy Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995;50:222–239. Neuroendocrinology.In: Speroff L, Glass RH, Kase NG, eds. Clinical gynecologic endocrinology and fertility. Baltimore: Williams & Wilkins, 1994:141–182. Silberstein SD. Drug treatment and trials in women. In: Kaplan PW, ed. Neurologic disease in women. New York: Demos Medical Publishing, 1998:25–44. Epilepsy Brown JE, Jacobs DR, Hartman TJ, et al. Predictors of red cell folate level in women attempting pregnancy. JAMA 1997;277:548–552. Buehler BA, Delimont D, Van Waes M, Finnell RH. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990;322:1567–1572. Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993;168:923–928. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832–1835. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects: implications for treatment. JAMA 1995;274:1698–1702. Dansky L, Andermann E, Roseblatt D, Sherwin AL, Andermann F. Anticonvulsants, folate levels, and pregnancy outcome. Ann Neurol 1987;21:176–182. Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992;42[Suppl 5]:149–160. Finnell RH, Buehler BA, Kerr BM, Agler PL, Levy RH. Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis. Neurology 1992;42:25–31. Gaily E, Granstrom ML. Minor anomalies in children of mothers with epilepsy. Neurology 1992;42[Suppl 5]:128–131. Gordon N. Folate metabolism and neural tube defects. Brain Dev 1995;17:307–311. Guidelines for the care of women of childbearing age with epilepsy. Commission on Genetics, Pregnancy, and the Child, International League Against Epilepsy. Epilepsia 1993;34:588–589. Kaneko S, Otani K, Fukushima Y, et al. Teratogenicity of antiepilepsy drugs: analysis of possible risk factors. Epilepsia 1988;29:459–467. Koch S, Loesche G, Jager-Roman E, et al. Major birth malformations and antiepileptic drugs. Neurology 1992;42[Suppl 5]:83–88. Laurence KM, James N, Miller MH, Tennant GB, Campbell H. Double-blind, randomised controlled trial of folate before conception to prevent the recurrence of neural tube defects. 1981;282:1509–1511.

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CHAPTER 157. ALCOHOLISM MERRITT’S NEUROLOGY

SECTION XXIII. ENVIRONMENTAL NEUROLOGY CHAPTER 157. ALCOHOLISM JOHN C.M. BRUST Ethanol Intoxication Ethanol–Drug Interactions Ethanol Dependence and Withdrawal Wernicke-Korsakoff Syndrome Alcoholic Cerebellar Degeneration Alcoholic Polyneuropathy Alcoholic Amblyopia Pellagra Alcoholic Liver Disease Hypoglycemia Alcoholic Ketoacidosis Infection in Alcoholics Trauma in Alcoholics Alcohol and Cancer Alcohol and Stroke Alcoholic Myopathy Central Pontine Myelinolysis and Marchiafava-Bignami Disease Alcoholic Dementia Fetal Alcohol Syndrome Treatment of Chronic Alcoholism Suggested Readings

In the United States, 7% of all adults and 19% of adolescents are “problem drinkers”: addicted to ethanol or, even if abstinent most of the time, likely to get into trouble when they drink. Ethanol-related deaths exceed 100,000 each year, accounting for 5% of all deaths in the United States. The devastation is direct (from intoxication, addiction, and withdrawal) or indirect (from nutritional deficiency or other ethanol-related diseases).

ETHANOL INTOXICATION Ethanol acts at many levels of the neuraxis and affects a number of neurotransmitter systems, especially t-aminobutyric acid and glutamate. Like general anesthetics, ethanol disrupts (“fluidizes”) the phospholipid bilayer of cell membranes. How much of its actions on neurotransmitter receptors and protein channels is indirectly the result of this less specific effect is uncertain. To obtain a mildly intoxicating blood ethanol concentration (BEC) of 100 mg/dL, a 70-kg person must drink about 50 g (2 oz) of 100% ethanol. Following zero-order kinetics, ethanol is metabolized at about 70 to 150 mg/kg of body weight per hour, with a fall in BEC of 10 to 25 mg/dL per hour. Thus, most adults require 6 hours to metabolize a 50-g dose, and the ingestion of only 8 g of additional ethanol per hour would maintain the BEC at 100 mg/dL. Symptoms and signs of acute ethanol intoxication are due to cerebral depression, possibly at first of the reticular formation with cerebral disinhibition and later of the cerebral cortex itself. Manifestations depend not only on the BEC but also on the rate of climb and the person's tolerance, which is related less to increased metabolism than to poorly understood adaptive changes in the brain. At any BEC, intoxication is more severe when the level is rising than when it is falling, when the level is reached rapidly, and when the level has only recently been achieved. A single BEC determination therefore is not a reliable indicator of drunkenness, and the correlations of Table 157.1 are broad generalizations. Death from respiratory paralysis may occur with a BEC of 400 mg/dL and survival may occur at 700 mg/dL; a level of 500 mg/dL would be fatal in 50% of individuals.

TABLE 157.1. CORRELATION OF SYMPTOMS WITH BLOOD ETHANOL CONCENTRATION (BEC)

Low-to-moderate BECs cause slow saccadic eye movements and interrupted jerky pursuit movements that may impair visual acuity. Esophoria and exophoria cause diplopia. With a BEC of 150 to 250 mg/dL, there is increased electroencephalogram (EEG) beta activity (“beta buzz”); higher BECs cause EEG slowing. During sleep, suppression of the rapid eye movement (REM) stage is followed by REM rebound after a few hours. The term pathologic intoxication refers to sudden extreme excitement with irrational or violent behavior after even small doses of ethanol. Episodes are said to last for minutes or hours, followed by sleep and, on awakening, amnesia for the events that took place. Delusions, hallucinations, and homicide may occur during bouts of pathologic intoxication. Some cases are probably psychologic dissociative reactions; others may be due to the kind of paradoxic excitation that sometimes follows barbiturate administration. The term alcoholic blackout refers to amnesia for periods of intoxication, sometimes lasting several hours, even though consciousness at the time did not seem to be disturbed. Although sometimes considered a sign of physiologic dependence, blackouts also occur in occasional drinkers. Their nature is uncertain. Acute ethanol poisoning causes more than 1,000 deaths each year in the United States. In stuporous alcoholic patients, subdural hematoma, meningitis, and hypoglycemia are important diagnostic considerations, but it is equally important to remember that ethanol intoxication alone can be fatal. Blood ethanol causes a rise of blood osmolality, about 22 mOsm/L for every 100 mg/dL of ethanol; however, there are no transmembrane shifts of water, and the hyperosmolarity does not cause symptoms. Ethanol overdose should be considered in any comatose patient whose serum osmolarity is higher than predicted by calculation of the sum of serum sodium, glucose, and urea. Patients stuporous or comatose from ethanol intoxication are generally managed similarly to those poisoned by other depressant drugs ( Table 157.2). Death comes from respiratory depression, and artificial ventilation in an intensive care unit is the mainstay of treatment. Hypovolemia, acid–base or electrolyte imbalance, and abnormal temperature require attention, and if there is any uncertainty about the blood glucose level, 50% glucose is given intravenously, along with parenteral thiamine. Because ethanol is rapidly absorbed, gastric lavage does not help unless other drugs have been ingested. In obstreperous or violent patients, sedatives (including phenothiazines and haloperidol) should be avoided because they may push patients into stupor and respiratory depression. When a patient is being addressed, he or she may be alert but then lapse into stupor or coma when stimuli are decreased.

TABLE 157.2. TREATMENT OF ACUTE ETHANOL INTOXICATION

In a nonhabitual drinker, a BEC of 400 mg/dL takes 20 hours to return to zero. The only practical agent that might accelerate ethanol metabolism and elimination is fructose, but this causes gastrointestinal upset, lactic acidosis, and osmotic diuresis. (An imidazobenzodiazepine drug has been developed that reverses symptoms of mild-to-moderate ethanol intoxication; it is available for experimental use only.) Hemodialysis or peritoneal dialysis can be used for BECs greater than 600 mg/dL; for severe acidosis; for concurrent ingestion of methanol, ethylene glycol, or other dialyzable drugs; or for severely intoxicated children. Analeptic agents such as ethamivan, caffeine, or amphetamine have no useful role and can cause seizures and cardiac arrhythmia. Although patients are often depleted of magnesium, administration of magnesium sulfate may further depress the sensorium in intoxicated patients. Reports suggesting that naloxone hydrochloride (Narcan) benefits patients with ethanol intoxication require confirmation.

ETHANOL–DRUG INTERACTIONS The combination of ethanol with other drugs, often in suicide attempts, causes 2,500 deaths annually, or 13% of all drug-related fatalities. Ethanol is often taken with marijuana, barbiturates, opiates, cocaine, hallucinogens, and inhalants—with varying interactions. Alcoholics often abuse barbiturates, and although ethanol and barbiturates are cross-tolerant, they lower the lethal dose of either alone or when taken acutely in combination. Ethanol with chloral hydrate (Mickey Finn) may be especially dangerous. Impaired judgment and respiratory depression are also hazards when ethanol is combined with hypnotics, such as methaqualone (Quaalude), sedating antihistamines, antipsychotic agents, and tranquilizers such as meprobamate and benzodiazepines. Hypnotic drugs with long half-lives may cause potentially dangerous incoordination when ethanol is consumed the following day. The cross-tolerance of ethanol with general anesthetics such as ether, chloroform, or fluorinated agents raises the threshold to sleep induction, but synergistic interaction then increases the depth and length of the anesthetic stage reached. Tricyclic antidepressants do not have a consistent effect; desipramine hydrochloride antagonizes the effects of ethanol, and amitriptyline potentiates them. Ethanol and morphine, repeatedly used, can increase each other's potency, and methadone addicts not only frequently become alcoholics but also can then develop a characteristic encephalopathy. Death has followed ethanol taken with propoxyphene hydrochloride. A mild reaction resembling that caused by disulfiram (Antabuse) occurs when patients combine ethanol with sulfonylureas such as tolbutamide (Orinase) or with some antibiotics, including chloramphenicol, griseofulvin, isoniazid, metronidazole, and quinacrine hydrochloride.

ETHANOL DEPENDENCE AND WITHDRAWAL The term hangover refers to the headache, nausea, vomiting, malaise, nervousness, tremulousness, and sweating that can occur in anyone after brief but excessive drinking. Hangover does not imply ethanol addiction, but ethanol withdrawal does imply addiction and encompasses several disorders ( Table 157.3), which may occur alone or in combination after reduction or cessation of drinking. Severity depends on the length and degree of a particular binge.

TABLE 157.3. ETHANOL WITHDRAWAL SYNDROMES

Tremulousness, the most common ethanol withdrawal symptom, usually appears in the morning after several days of drinking. It is promptly relieved by ethanol, but if drinking cannot continue, tremor becomes more intense, with insomnia, easy startling, agitation, facial and conjunctival flushing, sweating, anorexia, nausea, retching, weakness, tachypnea, tachycardia, and systolic hypertension. Except for inattentiveness and inability to fully recall the events that occurred during the binge, mentation is usually intact. Symptoms subside in a few days, but it may be 2 weeks before they completely disappear. Perceptual disturbances, with variable insight, occur in about 25% of ethanol-addicted patients and include nightmares, illusions, and hallucinations, which are most often visual but may be auditory, tactile, olfactory, or a combination of these. Imagery includes insects, animals, or people. Hallucinations are usually fragmentary, lasting minutes at a time for several days. Sometimes, however, auditory hallucinations of threatening content last much longer, and occasionally, a persistent state of auditory hallucinosis with paranoid delusions that resembles schizophrenia develops in these patients and may require care in a mental hospital. Repeated bouts of acute auditory hallucinosis may predispose to the chronic form. Ethanol can precipitate seizures in any epileptic; seizures usually occur the morning after weekend or even single-day drinking rather than during inebriation. Alcohol-related seizures affecting alcoholics not otherwise epileptic have traditionally been considered a withdrawal phenomenon, usually occurring within 48 hours of the last drink in persons who have abused ethanol chronically or in binges for months or years. The minimal duration of drinking sufficient to cause seizures is uncertain, but the risk is dose-related, beginning at only 50-g absolute ethanol daily. Seizures usually occur singly or in a brief cluster; status epilepticus is infrequent. Focal features are present in 25% and do not consistently correlate with evidence of previous head injury or other structural cerebral pathology. Alcohol seizures sometimes accompany tremulousness or hallucinosis, but they may occur in otherwise asymptomatic individuals. Their frequent appearance during active drinking or after more than 1 week of abstinence suggests that mechanisms other than withdrawal play a role in some individuals. The diagnosis of alcohol-related seizures depends on an accurate history and exclusion of other cerebral lesions. Because reliable follow-up is unlikely, a seizure workup should be done, including computed tomography (CT) or magnetic resonance imaging and examination of cerebrospinal fluid (CSF). Fewer than 10% of patients with rum fits have spontaneous EEG abnormalities, compared with 50% of those with idiopathic epilepsy. A reported high frequency of electrographic photomyoclonic and photoconvulsant responses during ethanol withdrawal was not borne out by subsequent studies. In contrast to tremor, hallucinosis, or seizures, which usually occur within 1 or 2 days of abstinence, delirium tremens usually begins from 48 to 72 hours after the last drink. Patients with delirium tremens are often hospitalized for other reasons. Delirium tremens may follow withdrawal seizures either before the postictal period has

cleared or after 1 or 2 asymptomatic days, but when seizures occur during a bout of delirium tremens, some other diagnosis (e.g., meningitis) should be considered. Symptoms typically begin and end abruptly, lasting from hours to a few days. There may be alternating periods of confusion and lucidity. Infrequently, relapses may prolong the disorder for a few weeks. Patients are typically agitated, inattentive, and grossly tremulous, with fever, tachycardia, and profuse sweating. They pick at the bed clothes or stare wildly about and intermittently shout at or try to fend off hallucinated people or objects. “Quiet� delirium is infrequent. Mortality is as high as 15%; death is usually due to other diseases (e.g., pneumonia or cirrhosis), but it may be attributed to unexplained shock, lack of response to therapy, or no apparent cause. Treatment of ethanol withdrawal includes prevention or reduction of early symptoms, prevention of delirium tremens, and management of delirium tremens after it starts (Table 157.4). Sedatives have been recommended for recently abstinent alcoholics or those with mild early withdrawal symptoms, with theoretical consideration given to cross-tolerance with ethanol. Popular agents include paraldehyde, barbiturates, and benzodiazepines. With any of these agents, the aim is to give a loading dose likely to cause symptoms of mild intoxication (calming, dysarthria, ataxia, fine nystagmus), and then to adjust subsequent doses to avoid intoxication and tremulousness. After 1 or 2 days, dosage is gradually tapered, with reinstitution of intoxicating doses should withdrawal symptoms reappear. Beta-adrenergic blocking agents dampen alcohol withdrawal tremor and have been reported to decrease agitation and autonomic signs as well, reducing the need for benzodiazepines or other sedatives.

TABLE 157.4. TREATMENT OF ETHANOL WITHDRAWAL

Ethanol, when used parenterally, has the disadvantage of a low therapeutic index. Because ethanol is directly toxic to many organs, it should be avoided during hospitalization, even though most patients resume drinking on discharge. Neither haloperidol nor phenothiazines have a specific effect on hallucinations; theoretically, they are less likely to prevent hallucinosis or delirium tremens than drugs cross-tolerant with ethanol, and they can exacerbate seizures. Phenytoin sodium (Dilantin) appears to be of no value in preventing seizures during withdrawal. Status epilepticus during ethanol withdrawal is treated as in other situations; intravenous phenobarbital or diazepam has an advantage, compared with phenytoin, of reducing other withdrawal symptoms when the patient awakens. Long-term anticonvulsants in patients with ethanol withdrawal seizures are superfluous; abstainers do not need them, and drinkers do not take them. An epileptic whose seizures are often precipitated by ethanol abuse unfortunately does need treatment, even though compliance is unlikely. Hypomagnesemia is common during early ethanol withdrawal, and although it may not be the primary cause of symptoms, magnesium sulfate should be given to hypomagnesemic patients. Hypokalemia and hypocalcemia may also be present, and the latter may respond to treatment only when hypomagnesemia is corrected. Parenteral thiamine and multivitamins are given even if there are no clinical signs of depletion. Delirium tremens, once it appears, cannot be abruptly reversed by any agent, and specific cross-tolerance of a sedative with ethanol is less important in full-blown delirium tremens than in early abstinence. Parenteral diazepam is more effective than paraldehyde in rapid calming and has fewer adverse reactions (including apnea) and lower mortality. The required doses might be fatal in a normal person (see Table 157.4), but one cannot predict in any individual patient how high the tolerable dose is. Liver disease decreases the metabolism of diazepam, and patients with cirrhosis are more vulnerable to the depressant effects of sedatives; as delirium tremens clears, hepatic encephalopathy takes its place. General medical management in delirium tremens is intensive. Although dehydration may be severe enough to cause shock, patients with liver damage may retain sodium and water. Hypokalemia can cause cardiac arrhythmias. Hypoglycemia may be masked, as may other serious coexisting illnesses, such as alcoholic hepatitis, pancreatitis, meningitis, or subdural hematoma. Occasionally encountered during abstinence is either parkinsonism or chorea, which tends to clear over days or weeks. Such movement disorders are presumably related to ethanol effects on striatal dopamine.

WERNICKE-KORSAKOFF SYNDROME Although pathologically indistinguishable, Wernicke and Korsakoff syndromes are clinically distinct. Wernicke syndrome, when full-blown, consists of mental, eye movement, and gait abnormalities. Korsakoff syndrome is only a mental disorder that differs qualitatively from Wernicke syndrome ( Table 157.5). Both are the result of thiamine deficiency.

TABLE 157.5. MAJOR NUTRITIONAL DISTURBANCES IN ALCOHOLICS

In acute Wernicke syndrome, mental symptoms most often consist of a global confusional state that appears over days or weeks; there is inattentiveness, indifference, decreased spontaneous speech, disorientation, impaired memory, and lethargy. Stupor and coma are unusual, as is selective amnesia. Disordered perception is common; a patient might identify the hospital room as his or her apartment or a bar. In fewer than 10%, mentation is normal. Abnormal eye movements include nystagmus (horizontal with or without vertical or rotatory components), lateral rectus palsy (bilateral but usually asymmetric), and conjugate gaze palsy (horizontal with or without vertical), progressing to complete external ophthalmoplegia. Although sluggishness of pupillary reaction is common, total loss of reactivity to light does not seem to occur, and ptosis is rare. Whether mental symptoms in acute Wernicke syndrome ever occur without abnormal eye movements is uncertain. Truncal ataxia, present in more than 80% of patients, may prevent standing or walking. Dysarthria and limb ataxia, especially in the arms, are infrequent. Peripheral neuropathy, which occurs to some degree in most patients, may cause weakness sufficient to mask the ataxia. Abnormalities of caloric testing are common, with

gradual improvement, often incomplete, over several months. Patients with Wernicke syndrome frequently have signs of nutritional deficiency (e.g., skin changes, tongue redness, cheilosis) or liver disease. Autonomic signs are common. Although beriberi heart disease is rare, acute tachycardia, dyspnea on exertion, and postural hypotension unexplained by hypovolemia are common, and sudden circulatory collapse may follow mild exertion. Hypothermia is less frequent; fever usually indicates infection. In acute Wernicke syndrome, the EEG may show diffuse slowing, or it may be normal. CSF is normal except for occasional mild protein elevation. Elevated blood pyruvate, falling with treatment, is not specific. Decreased blood transketolase (which requires thiamine pyrophosphate as cofactor) more reliably indicates thiamine deficiency. In most patients, the more purely amnestic syndrome of Korsakoff emerges as the other mental symptoms of Wernicke syndrome respond to treatment. How often Korsakoff syndrome occurs without a background of Wernicke syndrome is disputed and bound up with the question of “alcoholic dementia� (see below). Pathologic changes of Wernicke-Korsakoff are sometimes encountered unexpectedly at autopsy, suggesting the presence of subclinical or atypical forms, including unexplained coma. The amnesia of Korsakoff syndrome is both anterograde, with inability to retain new information, and retrograde, with rather randomly lost recall for events months or years old. Alertness, attentiveness, and behavior are relatively preserved, but there tends to be a lack of spontaneous speech or activity. Confabulation is not invariable and, if initially present, tends gradually to disappear. Insight is usually impaired, and there may be flagrant anosognosia for the mental disturbance. The histopathologic lesions of Wernicke-Korsakoff syndrome consist of variable degrees of neuronal, axonal, and myelin loss; prominent blood vessels; reactive microglia, macrophages, and astrocytes; and, infrequently, small hemorrhages. Nerve cells may be relatively preserved in the presence of extensive myelin destruction and gliosis, and astrocytosis may predominate chronically. Lesions affect the thalamus (especially the dorsomedial nucleus and the medial pulvinar), the hypothalamus (especially the mamillary bodies), the midbrain (especially the oculomotor and periaqueductal areas), and the pons and medulla (especially the abducens and medial vestibular nuclei). In the anterosuperior vermis of the cerebellum, severe Purkinje cell loss and astrocytosis accompany lesser degrees of neuronal loss and gliosis in the molecular and granular layers. The traditional view that the memory impairment of Korsakoff syndrome is the result of lesions in the mamillary body has been challenged by others who attribute amnesia to lesions in the dorsomedial nucleus of the thalamus. The global confusion of Wernicke syndrome may occur without visible thalamic lesions and may be a biochemical disorder. Periaqueductal, oculomotor, or abducens nucleus lesions may explain ophthalmoparesis, which is also seen in patients whose eye movement disorders resolved before death. The cerebellar and vestibular lesions probably contribute to ataxia. Experimental and clinical evidence ascribes a specific role to thiamine in the Wernicke-Korsakoff syndrome. A genetic influence is implied because only a few alcoholic or otherwise malnourished people are affected, and whites seem more susceptible than blacks. Untreated Wernicke-Korsakoff syndrome is fatal, and the mortality rate is 10% among treated patients. Concomitant liver failure, infection, or delirium tremens often makes the cause of death unclear. Postural hypotension and tachycardia call for strict bedrest; associated medical problems may require intensive care. The cornerstone of treatment is thiamine, 50 to 100 mg daily, until a normal diet can be taken; intramuscular or intravenous administration is preferred because thiamine absorption is impaired in chronic alcoholics. Hypomagnesemia may retard improvement after thiamine treatment; magnesium is therefore replaced, along with other vitamins. Protein intake may have to be titrated against the patient's liver status. With thiamine treatment, the ocular abnormalities (especially abducens and gaze palsies) improve within a few hours and usually resolve within 1 week; in about 35% of the patients, horizontal nystagmus persists indefinitely. Global confusion may improve in hours or days and usually resolves within 1 month, leaving Korsakoff amnesia in more than 80%. In less than 25% of these patients, there is eventual clearing of the memory deficit. Ataxia may improve in a few days, but recovery is complete in less than 50% of patients, and nearly 35% do not show improvement at all.

ALCOHOLIC CEREBELLAR DEGENERATION Cerebellar cortical degeneration may occur in nutritionally deficient alcoholics without Wernicke-Korsakoff syndrome (see Table 157.5). Instability of the trunk is the major symptom, often with incoordination of leg movements. Arm ataxia is less prominent; nystagmus and dysarthria are rare. Symptoms evolve in weeks or months and eventually stabilize, sometimes even with continued drinking and poor nutrition. Ataxia without Wernicke disease is less likely to appear abruptly or to improve. Pathologically, the superior vermis is invariably involved, with nerve cell loss and gliosis in the molecular, granular, and especially the Purkinje cell layers. There may be secondary degeneration of the olives and of the fastigial, emboliform, globose, and vestibular nuclei. Involvement of the cerebellar hemispheric cortex is exceptional and limited to the anterior lobes. Pathologic evidence of Wernicke disease may coexist, even though it is unsuspected clinically. CT and autopsies, moreover, have revealed cerebellar atrophy in alcoholics who were not clinically ataxic. Alcoholic cerebellar degeneration is probably nutritional in origin. Identical lesions occur in malnourished nonalcoholics, and ataxia may begin in malnourished alcoholics after weeks of abstinence. The clinical and pathologic similarity to the cerebellar component of Wernicke syndrome suggests shared mechanisms, but most patients with alcoholic cerebellar degeneration do not have pathologic evidence of Wernicke disease.

ALCOHOLIC POLYNEUROPATHY Alcoholic polyneuropathy is a sensorimotor disorder, probably of nutritional origin, that stabilizes or improves with abstinence and an adequate diet (see Table 157.5). Neuropathy is found in most patients with Wernicke-Korsakoff syndrome but more often occurs alone. Paresthesia is usually the first symptom; there may be burning or lancinating pain and exquisite tenderness of the calves or soles. Impaired vibratory sense is usually the earliest sign; proprioception tends to be preserved until other sensory loss is substantial. Loss of ankle jerks is another early sign; eventually, there is diffuse areflexia. Weakness appears at any time and may be severe. Distal leg muscles are affected first, although proximal weakness may be marked. Radiologically demonstrable neuropathic arthropathy of the feet is common, as are skin changes (e.g., thinning, glossiness, reddening, cyanosis, hyperhidrosis). Peripheral autonomic abnormalities are usually less prominent than in diabetic neuropathy but may cause urinary and fecal incontinence, hypotension, hypothermia, cardiac arrhythmia, dysphagia, dysphonia, impaired esophageal peristalsis, altered sweat patterns, or abnormal Valsalva ratio. Pupillary parasympathetic denervation is rare. The CSF is usually normal except for occasional mild elevation of protein content. Pathologically, there is degeneration of both myelin and axons; it is not certain which occurs first. Clinical and experimental evidence suggests that alcoholic polyneuropathy is nutritional in origin and that more than thiamine may be lacking. Peripheral nerve pressure palsies, especially radial and peroneal, are common in alcoholics. Nutritional polyneuropathy may increase the vulnerability of peripheral nerves to compression injury in intoxicated individuals, who tend to sleep deeply in unusual locations and positions. Recovery usually takes days or weeks; splints during this period can prevent contractures.

ALCOHOLIC AMBLYOPIA Alcoholic amblyopia is a visual impairment that progresses over days or weeks, with development of central or centrocecal scotomas and temporal disc pallor (see Table 157.5). Demyelination affects the optic nerves, chiasm, and tracts, with predilection for the maculopapular bundle. Retinal ganglion cell loss is secondary. Ethanol (or tobacco) toxicity plays little or no role; amblyopia clears in patients who receive dietary supplements but continue to smoke and drink ethanol. Alcoholic amblyopia does not progress to total blindness; it may remain stable without change in drinking or eating habits. Improvement, which is often incomplete, nearly always follows nutritional replacement.

PELLAGRA

Nicotinic acid deficiency in alcoholics causes pellagra, with dermatologic, gastrointestinal, and neurologic symptoms. Altered mentation progresses over hours, days, or weeks to amnesia, delusions, hallucinations, or delirium. Nicotinic acid therapy (plus other vitamins, deficiency of which can be contributory) usually results in prompt improvement.

ALCOHOLIC LIVER DISEASE Cirrhosis is the sixth leading cause of death in the United States, and nearly all deaths from cirrhosis in people older than 45 years are caused by ethanol. Altered mentation in an alcoholic therefore always raises the possibility of hepatic encephalopathy, which may accompany intoxication, withdrawal, Wernicke syndrome, meningitis, subdural hematoma, hypoglycemia, or other alcohol states. Hepatic encephalopathy is discussed in detail in Chapter 148. Other neurologic disorders encountered in alcoholic cirrhotics include a poorly understood syndrome of altered mentation, myoclonus, and progressive myelopathy following portacaval shunting, as well as acquired chronic hepatocerebral degeneration, a characteristic syndrome of dementia, dysarthria, ataxia, intention tremor, choreoathetosis, muscular rigidity, and asterixis, which usually occurs in patients who have had repeated bouts of hepatic coma.

HYPOGLYCEMIA Metabolism of ethanol by alcohol dehydrogenase and of acetaldehyde by mitochondrial aldehyde dehydrogenase utilizes nicotinamide adenine dinucleotide (NAD). The resulting elevated NADH-to-NAD ratio impairs gluconeogenesis, and if food is not being eaten and liver glycogen is depleted, there may be severe hypoglycemia with altered behavior, seizures, coma, or focal neurologic deficit. Residual symptoms are common, including dementia. Even after appropriate treatment with intravenous 50% dextrose, these patients require close observation; blood glucose may fall again, with the return of symptoms and possibly permanent brain damage. Ethanol stimulates intestinal release of secretin, which aggravates reactive hypoglycemia, especially in children, by enhancing glucose-stimulated insulin release.

ALCOHOLIC KETOACIDOSIS In alcoholic ketoacidosis, b-hydroxybutyric acid and lactic acid accumulate in association with heavy drinking. The mechanism is unclear. Typical patients are chronic alcoholic young women who increase their ethanol consumption for days or weeks and then stop drinking when they are overcome by anorexia. Vomiting, dehydration, confusion, obtundation, and Kussmaul respiration ensue. Blood glucose may be normal, low, or moderately elevated, with little or no glycosuria. A large anion gap is accounted for by b-hydroxybutyrate, lactate, and lesser amounts of pyruvate and acetoacetate. Serum insulin levels are low, and serum levels of growth hormone, epinephrine, glucagon, and cortisol are high, but glucose intolerance usually clears without insulin and is not demonstrable on recovery. It is not unusual for patients to have repeated attacks of alcoholic ketoacidosis. Alcoholics may have other reasons for metabolic acidosis with a large anion gap (e.g., methanol or ethylene glycol poisoning). When b-hydroxybutyrate is the major ketone present, the nitroprusside test (Acetest) may be negative. Treatment includes infusion of glucose (and thiamine), correction of dehydration or hypotension, and replacement of electrolytes such as potassium, magnesium, and phosphate. Small amounts of bicarbonate may be given. Insulin is usually not needed.

INFECTION IN ALCOHOLICS Alteration of white blood cell function contributes to the alcoholic's predisposition to infection (e.g., bacterial and tuberculous meningitis). Infectious meningitis must always be considered in alcoholics with seizures or altered mental status, even when the clinical picture seems to be that of intoxication, withdrawal, thiamine deficiency, hepatic encephalopathy, hypoglycemia, or other alcoholic disturbances. Alcoholic intoxication is a risk factor for human immunodeficiency virus infection.

TRAUMA IN ALCOHOLICS Thrombocytopenia, a direct effect of ethanol and a consequence of cirrhosis, increases the likelihood of intracranial hematomas after head injury. Abnormalities of clotting factors also increase the possibility of intracranial hematomas. Experimentally, moreover, acute ethanol enhances blood–brain barrier leakage around areas of cerebral trauma. Close observation is essential after even mild head injury in intoxicated patients; an abnormal sensorium must not be dismissed as drunkenness.

ALCOHOL AND CANCER Independently of tobacco, ethanol in moderate amounts increases the risk of carcinoma of the mouth, esophagus, pharynx, larynx, liver, and breast.

ALCOHOL AND STROKE As with coronary artery disease, epidemiologic studies suggest that low-to-moderate amounts of ethanol decrease stroke risk, whereas higher amounts increase it. Reports have been inconsistent, however. Some studies indicate increased risk for hemorrhagic stroke at any dose; some find ethanol protective in whites but not Japanese; and some observe increased stroke risk temporally related to binge drinking. Ethanol could either prevent or cause stroke by several mechanisms. Acutely and chronically, ethanol causes hypertension. It reportedly lowers blood levels of low-density lipoproteins, raises levels of high-density lipoproteins, decreases fibrinolytic activity, increases or inhibits platelet reactivity, dilates or constricts cerebral vessels, and indirectly reduces cerebral blood flow through dehydration. Alcoholic cardiomyopathy predisposes to embolic stroke.

ALCOHOLIC MYOPATHY Alcoholic myopathy is of three types. Subclinical myopathy consists of elevated serum creatine kinase levels and electromyographic changes, sometimes with intermittent cramps or weakness. With chronic myopathy, there is progressive proximal weakness. Acute rhabdomyolysis causes sudden severe weakness, muscle pain, swelling, and myoglobinuria with renal shutdown. Ethanol toxicity rather than nutritional deficiency is the likely cause of myopathy, and symptoms sometimes emerge during a binge. Alcoholic cardiomyopathy often coexists. Whether subclinical, chronic, or acute, myopathy improves with abstinence.

CENTRAL PONTINE MYELINOLYSIS AND MARCHIAFAVA-BIGNAMI DISEASE Central pontine myelinolysis occurs in both alcoholics and nondrinkers and is a consequence of overvigorous correction of hyponatremia. Marchiafava-Bignami disease is nearly always associated with alcoholism (including wine, beer, and whiskey). It is of unknown origin and causes symptoms, including death, that are scarcely explained by the characteristic callosal lesions. Marchiafava-Bignami disease and central pontine myelinolysis are discussed in detail in Chapter 134 and Chapter 135, respectively.

ALCOHOLIC DEMENTIA Alcoholic dementia refers to progressive mental decline in alcoholics without apparent cause, nutritional or otherwise. Symptoms are said to correlate with enlarged cerebral ventricles and widened sulci, and both cognition and radiographic changes allegedly improve with abstinence. The subject is controversial, however. True brain atrophy should not be radiographically reversible, and some workers maintain that most or all cases of alleged alcoholic dementia actually represent other conditions, such as nutritional deficiency, previous trauma, or liver failure. In animals, prolonged administration of moderate amounts of ethanol causes behavioral and neuropathologic abnormalities not found in pair-fed controls. Some studies suggest synergism between ethanol toxicity and thiamine deficiency. The clinical relevance of animal studies to humans is uncertain. If ethanol is indeed neurotoxic, it remains to be seen what constitutes a safe dose.

FETAL ALCOHOL SYNDROME Ethanol ingestion during pregnancy causes congenital malformations and delayed psychomotor development. Major clinical features of the fetal alcohol syndrome include cerebral dysfunction, growth deficiency, and distinctive facies ( Table 157.6); less often, there are abnormalities of the heart, skeleton, urogenital organs, skin,

and muscles. Neuropathologic abnormalities include absence of the corpus callosum, hydrocephalus, and abnormal neuronal migration, with cerebellar dysplasia, heterotopic cell clusters, and microcephaly. These changes occur independently of other potentially incriminating factors, such as maternal malnutrition, smoking, other drug use, or age. Binge drinking, which may produce high ethanol levels at a critical fetal period, may be more important than chronic ethanol exposure, and early gestation appears to be the most vulnerable period.

TABLE 157.6. CLINICAL FEATURES OF FETAL ALCOHOL SYNDROME

Children of alcoholic mothers are often intellectually borderline or retarded without other features of the fetal alcohol syndrome; fetal effects of ethanol thus cover a broad spectrum. Stillbirth and attention deficit disorder seem especially frequent among offspring of heavy drinkers, and each anomaly of the fetal alcohol syndrome may occur alone or in combination with others. The face of a typical patient with the fetal alcohol syndrome is distinctive and as easily recognized at birth as that of the infant with Down syndrome. Irritability and tremulousness with poor suck reflex and hyperacusis are usually present at birth and last weeks or months. Of these children, 85% perform more than two standard deviations below the mean on tests of mental performance; those who are not grossly retarded rarely have even average mental ability. Older children are often hyperactive and clumsy, and there may be hypotonia or hypertonia. Except for neonatal seizures, epilepsy is not a component of the syndrome. Ethanol is directly teratogenic to many animals, but the mechanism is not known. In humans, the risk of alcohol-induced birth defects is established with more than 3 oz of absolute alcohol daily. Below that, the risk is uncertain; a threshold of safety has not been defined. The incidence of fetal alcohol syndrome may be as high as 1 to 2 per 1,000 live births, with partial expression in 3 to 5 per 1,000. It may affect 1% of infants born to women who drink 1 oz of ethanol daily early in pregnancy. More than 30% of the offspring of heavy drinkers are affected by fetal alcohol syndrome, which thus may be the leading teratogenic cause of mental retardation in the Western world.

TREATMENT OF CHRONIC ALCOHOLISM The literature on the treatment of alcoholism is voluminous, and strong opinions outweigh scientific data. Not all problem drinkers consume physically addicting quantities of ethanol, no personality type defines an alcoholic, and the relative roles of genetics and social deprivation vary from patient to patient. (Animal and human studies indicate genetic influences in alcoholism, but the association is complex and undoubtedly involves more than one gene.) Of course, such variability of alcoholic populations means that no treatment modality (e.g., psychotherapy, group psychotherapy, family or social network therapy, drug therapy, behavioral [aversion] therapy) or no single therapeutic setting (e.g., general hospital, halfway house, vocational rehabilitation clinic, Alcoholics Anonymous) is appropriate for all. For example, the success rate of Alcoholics Anonymous has been estimated to be 34%. Use of tranquilizing and sedating drugs is especially controversial because they may lead to switching of dependency or to drug–ethanol interactions. Some clinicians espouse short-term use of these drugs in doses high enough to reduce the psychologic tensions that lead to ethanol use but low enough not to block symptoms of ethanol withdrawal. Disulfiram inhibits aldehyde dehydrogenase and reduces the rate of oxidation of acetaldehyde, accumulation of which accounts for the symptoms that appear soon after someone taking disulfiram drinks ethanol. Within 5 to 10 minutes, there is warmth and flushing of the face and chest, throbbing headache, dyspnea, nausea, vomiting, sweating, thirst, chest pain, palpitations, hypotension, anxiety, confusion, weakness, vertigo, and blurred vision. The severity and duration of these symptoms depend on the amount of ethanol drunk; a few milliliters can cause mild symptoms followed by drowsiness, sleep, and recovery; severe reactions can last hours or be fatal and require hospital admission, with careful management of hypotension and cardiac arrhythmia. Taken in the morning, when the urge to drink is least, disulfiram, 0.25 to 0.5 g daily, does not alter the taste for ethanol and helps only patients who strongly desire to abstain. In the United States, 150,000 to 200,000 patients are maintained on disulfiram, although controlled studies demonstrating substantial long-term benefit are lacking. Side effects of disulfiram that are unrelated to ethanol ingestion include drowsiness, psychiatric symptoms, and cardiovascular problems. Paranoia, impaired memory, ataxia, dysarthria, and even major motor seizures may be difficult to distinguish from ethanol effects, as may peripheral neuropathy. Hypersensitivity hepatitis also occurs. Approved by the U.S. Federal Drug Administration in 1994 as adjunctive therapy for alcoholism, the opiate antagonist naltrexone hydrochloride (ReVia) probably acts at the level of the mesolimbic “reward” circuit to blunt the pleasurable effects of ethanol. In Europe, acamprosate, a drug with an uncertain mechanism of action, is available. Other proposed treatments for alcoholism include lithium, serotonin-uptake inhibitors, dopaminergic agonists, opiates, and psychotherapy. None is scientifically accredited. SUGGESTED READINGS Alcohol-related mortality and years of potential life lost—United States. MMWR 1990;39:173–178. Alldredge BK, Lowenstein DH, Simon RP. A placebo-controlled trial of intravenous diphenylhydantoin for short-term treatment of alcohol withdrawal seizures. Am J Med 1989;87:645–648. Brust JCM. Ethanol. In: Neurological aspects of substance abuse. Boston: Butterworth-Heinemann, 1993:190–252. Brust JCM. Ethanol. In: Schaumburg HH, Spencer PS, eds. Experimental and clinical neurotoxicology, 2nd ed. Baltimore: Williams & Wilkins, 1999. Brust JCM. Stroke and substance abuse. In: Barnett HJM, Mohr JP, Stein BM, et al., eds. Stroke: pathophysiology, diagnosis, and management, 3rd ed. Philadelphia: WB Saunders, 1998:979–1000. Camargo CA. Moderate alcohol consumption and stroke: the epidemiologic evidence. Stroke 1989;20:1611–1626. Charness ME, Simon RP, Greenberg DA. Ethanol and the nervous system. N Engl J Med 1989;321:442–454. Cloninger CR. D2 dopamine receptor gene is associated but not linked with alcoholism. JAMA 1991;266:1793–1800. Day NL, Jasperse D, Richardson D, et al. Prenatal exposure to alcohol: effect on infant growth and morphologic characteristics. Pediatrics 1989;84:536–541. Fisch BJ, Hauser WA, Brust JCM, et al. The EEG response to diffuse and patterned photic stimulation during acute untreated alcohol withdrawal. Neurology 1989;39:434–436. Fuller RK, Branhey L, Brightwell DR, et al. Disulfiram treatment of alcoholism. A Veterans Administration Cooperative Study. JAMA 1986;256:1449–1455. Goldstein DB. Effects of alcohol on cellular membranes. Ann Emerg Med 1986;15:1013–1018. Joyce EM. Aetiology of alcoholic brain damage: alcoholic neurotoxicity or thiamine malnutrition? Br Med Bull 1994;50:99–114.

Lemoine P, Lemoine P. Avenir des infants de meres alcooliques (etude de 105 case retrouves a l'age adult) et quelques constatations d'interet prophylactique. Ann Pediatr 1992;29:226–230. Neiman J, Lang AE, Fornazarri L, Carlen PL. Movement disorders in alcoholism: a review. Neurology 1990;40:741–746. Ng SKC, Hauser WA, Brust JCM, et al. Alcohol consumption and withdrawal in new-onset seizures. N Engl J Med 1988;319:666–673. O'Connor PG, Schottenfeld RS. Patients with alcohol problems. N Engl J Med 1998;338:592–602. Suzdak PD, Glowa JR, Crawley JN, et al. A selective imidazobenodiazepine antagonist of ethanol in the rat. Science 1986;234:1243–1247. Tabakoff B, Hoffman PL. Alcohol addiction: an enigma among us. Neuron 1996;16:909–912. Thompson WL, Johnson AD, Maddrey WL, et al. Diazepam and paraldehyde for treatment of severe delirium tremens: a controlled trial. Ann Intern Med 1975;82:175–180. Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middle-aged and elderly U.S. adults. N Engl J Med 1997;24:1705–1714. Urbano-Marquez AM, Estruch R, Navarro-Lopez F, et al. The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med 1989;320:409–415. Victor M. Persistent altered mentation due to ethanol. Neurol Clin 1993;11:639–661. Victor M, Adams RD. The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 1953;32:526–573. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome, 2nd ed. Philadelphia: FA Davis Co, 1989. Victor M, Adams RD, Mancall EL. A restricted form of cerebellar cortical degeneration occurring in alcoholic patients. Arch Neurol 1959;1:579–688.

CHAPTER 158. DRUG DEPENDENCE MERRITT’S NEUROLOGY

CHAPTER 158. DRUG DEPENDENCE JOHN C.M.BRUST Drugs of Dependence Trauma Infection Seizures Stroke Altered Mentation Fetal Effects Miscellaneous Effects Suggested Readings

There are two kinds of drug dependence. Psychic dependence leads to craving and drug-seeking behavior. Physical dependence produces somatic withdrawal symptoms and signs. Depending on the particular drug and the circumstances of its administration, psychic and physical dependence can coexist or occur alone. Addiction is psychic dependence. In the United States, dependence of one or both types is encountered with a variety of agents, licit and illicit ( Table 158.1). Different classes of drugs produce diverse symptoms of intoxication and withdrawal, as well as medical and neurologic complications. Their legal status has little to do with potential harmfulness.

TABLE 158.1. DRUGS OF DEPENDENCE

DRUGS OF DEPENDENCE Opioids Opioids include agonists (e.g., morphine, heroin, methadone, fentanyl citrate [Sublimaze], meperidine hydrochloride (Demerol HCl), hydromorphone hydrochloride (Dilaudid), codeine, propoxyphene hydrochloride [Darvon]), antagonists (e.g., naloxone hydrochloride [Narcan], naltrexone hydrochloride [ReVia]), and mixed agonist-antagonists (e.g., pentazocine [Talwin], buprenorphine hydrochloride [Buprenex], butorphanol tartrate [Stadol]). At desired levels of intoxication, agonist opioids produce drowsy euphoria, analgesia, cough suppression, miosis, and often nausea, vomiting, sweating, pruritus, hypothermia, postural hypotension, constipation, and decreased libido. Taken parenterally, they produce a “rush,” a brief ecstatic feeling followed by euphoria and either relaxed “nodding” or garrulous hyperactivity. Overdose causes coma, respiratory depression, and pinpoint (but reactive) pupils. For adults with respiratory depression, treatment consists of respiratory support and naloxone, 2 mg intravenously, repeated as needed up to 20 mg; for those with normal respirations, smaller doses (0.4 to 0.8 mg) are given to avoid precipitation of withdrawal signs. Naloxone is short-acting, and so patients receiving it require admission and close observation. Opioid agonist withdrawal symptoms include irritability, lacrimation, rhinorrhea, sweating, yawning, mydriasis, myalgia, muscle spasms, piloerection, nausea, vomiting, abdominal cramps, fever, hot flashes, tachycardia, hypertension, and orgasm. In adults, seizures and delirium are not features of opioid withdrawal, which is rarely life-threatening and can usually be prevented or treated with methadone, 20 mg once or twice daily. By contrast, untreated opioid withdrawal in newborns is severe, protracted, and often fatal; treatment is with titrated doses of methadone, paregoric, or, if additional drug withdrawal is suspected, a barbiturate. Psychostimulants Psychostimulants include amphetamines, methamphetamine, methylphenidate hydrochloride (Ritalin HCl), ephedrine, phenylpropanolamine hydrochloride, other anorectics and decongestants, and cocaine (which, in contrast to other psychostimulants, is also a local anesthetic). Desired effects include alert euphoria with increased motor activity and physical endurance. Taken parenterally or smoked as alkaloidal cocaine (“crack”) or methamphetamine (“ice”), psychostimulants produce a rush clearly distinguishable from that of opioids. With repeated use, there is stereotypic activity progressing to bruxism or other dyskinesias and paranoia progressing to frank hallucinatory psychosis. Overdose causes headache, chest pain, tachycardia, hypertension, flushing, sweating, fever, and excitement. There may be delirium, cardiac arrhythmia, seizures, myoglobinuria, shock, coma, and death. Treatment includes benzodiazepine sedation, bicarbonate for acidosis, anticonvulsants, cooling, an antihypertensive (preferably a direct vasodilator such as sodium nitroprusside [Nitropress]), respiratory and blood pressure support, and cardiac monitoring. Psychostimulant withdrawal produces fatigue, depression, and increased hunger and sleep. Objective signs are few, but depression can require treatment or even hospitalization. Sedatives Sedative agents include barbiturates (e.g., phenobarbital, pentobarbital sodium, amobarbital, secobarbital [Seconal]), benzodiazepines (e.g., diazepam, chlordiazepoxide hydrochloride [Librium], alprazolam [Xanax], lorazepam (Ativan), triazolam [Halcion], flunitrazepam), and miscellaneous products (e.g., glutethimide, ethchlorvynol [Placidyl], methaqualone [Quaalude]). Desired effects and overdose both resemble ethanol intoxication, although respiratory depression is much milder with benzodiazepines. Treatment is supportive; for severe benzodiazepine poisoning, there is a specific antagonist, flumazenil (Romazicon). Withdrawal causes tremor and seizures, which can be prevented or treated with titrated doses of a barbiturate or benzodiazepine. Delirium tremens is a medical emergency requiring intensive care. Marijuana Marijuana, from the hemp plant Cannabis sativa, contains many cannabinoid compounds, of which the principal psychoactive agent is d9-tetrahydrocannabinol. Hashish refers to preparations made from the plant resin, which contains most of the psychoactive cannabinoids. Usually smoked, marijuana produces a relaxed dreamy euphoria, often with jocularity, disinhibition, depersonalization, subjective slowing of time, conjunctival injection, tachycardia, and postural hypotension. High doses cause auditory or visual hallucinations, confusion, and psychosis, but fatal overdose has not been documented. Withdrawal symptoms, other than craving, are minimal; there may be jitteriness, anorexia, and headache. Hallucinogens Hallucinogenic plants are used ritualistically or recreationally around the world. In the United States, the most popular agents are the indolealkylamines psilocybin and

psilocin (from several mushroom species), the phenylalkylamine mescaline (from the peyote cactus), and the synthetic ergot compound lysergic acid diethylamide (LSD). Several synthetic phenylalkylamines are also available, including 3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”), which has both hallucinogenic and amphetamine-like effects. The acute effects of hallucinogens are perceptual (distortions or hallucinations, usually visual and elaborately formed), psychologic (depersonalization or altered mood), and somatic (dizziness, tremor, and paresthesia). Some users experience paranoia or panic, and some, days to months after use, have “flashbacks,” the spontaneous recurrence of drug symptoms without taking the drug. High doses of LSD cause hypertension, obtundation, and seizures, but fatalities have usually been the result of accidents or suicide. Treatment of overdose consists of a calm environment, reassurance, and, if necessary, a benzodiazepine. Withdrawal symptoms do not occur. Inhalants Recreational inhalant use is especially popular among children and adolescents, who sniff a wide variety of products, including aerosols, spot removers, glues, lighter fluid, fire-extinguishing agents, bottled fuel gas, marker pens, paints, and gasoline. Compounds include aliphatic hydrocarbons such as n-hexane, aromatic hydrocarbons such as toluene, and halogenated hydrocarbons such as trichloroethylene; in addition, nitrous oxide is sniffed from whipped-cream dispensers and butyl or amyl nitrite from “room odorizers.” Despite such chemical diversity, desired subjective effects are similar to those of ethanol intoxication. Overdose can cause hallucinations, seizures, and coma; death has resulted from cardiac arrhythmia, accidents, and aspiration of vomitus. Symptoms tend to clear within a few hours, and treatment consists of respiratory and cardiac monitoring. There is no predictable abstinence syndrome other than craving. Phencyclidine Developed as an anesthetic, phencyclidine hydrochloride (PCP or “angel dust”) was withdrawn because it caused psychosis. As a recreational drug, it is usually smoked. Low doses cause euphoria or dysphoria and a feeling of numbness; with increasing intoxication, there is agitation, nystagmus, tachycardia, hypertension, fever, sweating, ataxia, paranoid or catatonic psychosis, hallucinations, myoclonus, rhabdomyolysis, seizures, coma, respiratory depression, and death. Treatment includes a calm environment with benzodiazepine sedation and restraints as needed, gastric suctioning, activated charcoal, forced diuresis, cooling, antihypertensives, anticonvulsants, monitoring of cardiorespiratory and renal function, and, for frank psychosis, haloperidol. Symptoms can persist for hours or days. Withdrawal signs are not seen. Anticholinergics The recreational use of anticholinergics includes ingestion of the plant Datura stramonium, popular among American adolescents, as well as use of antiparkinson drugs and the tricyclic antidepressant amitriptyline. Intoxication produces decreased sweating, tachycardia, dry mouth, dilated unreactive pupils, and delirium with hallucinations. Severe poisoning causes myoclonus, seizures, coma, and death. Treatment includes intravenous physostigmine salicylate (Antilirium), 0.5 to 3 mg, repeated as needed every 30 minutes to 2 hours, plus gastric lavage, cooling, bladder catheterization, respiratory and cardiovascular monitoring, and, if necessary, anticonvulsants. Neuroleptics, which have anticholinergic activity, are contraindicated. There is no withdrawal syndrome.

TRAUMA Trauma may be a consequence of a drug's acute effects, for example, automobile and other accidents during marijuana, inhalant, or anticholinergic intoxication; violence in psychostimulant or PCP users; and self-mutilation during hallucinogen psychosis. Trauma among users of illicit drugs, however, is most often the result of the illegal activities necessary to distribute and procure them. Overprescribing of sedatives is a major contributor to falls in the elderly.

INFECTION Parenteral users of any drug are subject to an array of local and systemic infections, which in turn can affect the nervous system. Hepatitis leads to encephalopathy or hemorrhagic stroke. Cellulitis and pyogenic myositis produce more distant infection, including vertebral osteomyelitis with myelopathy or radiculopathy. Endocarditis, bacterial or fungal, leads to meningitis, cerebral infarction or abscess, and septic or mycotic aneurysm. Tetanus, often severe, affects heroin users, and botulism occurs at injection sites or, among cocaine users, in the nasal sinuses. Malaria has occurred in heroin users from endemic areas. By 1998, nonhomosexual parenteral drug users composed 26% of acquired immunodeficiency syndrome (AIDS) cases reported to the Centers for Disease Control and Prevention; male homosexual drug users accounted for another 6%. Nearly two-thirds of patients receiving methadone maintenance treatment are seropositive for human immunodeficiency virus (HIV). Parenteral drug users experience the same neurologic complications of AIDS as do other groups and are particularly susceptible to syphilis and tuberculosis, including drug-resistant forms. Because of promiscuity and associated sexually transmitted diseases, nonparenteral cocaine users are also at increased risk for AIDS. Heroin and cocaine are themselves immunosuppressants (heroin users were vulnerable to unusual fungal infections before the AIDS epidemic), yet their use in HIV-seropositive individuals does not seem to accelerate the development of AIDS.

SEIZURES Seizures are a feature of withdrawal from sedatives, including, infrequently, benzodiazepines. Methaqualone and glutethimide have reportedly caused seizures during intoxication. Opioids lower seizure threshold, but seizures are seldom encountered during heroin overdose. Myoclonus and seizures more often occur in meperidine users, a consequence of the active metabolite normeperidine. Seizures are also frequent in parenteral users of pentazocine combined with the antihistamine tripelennamine (“T's and blues”). Seizures may occur in cocaine users without other evidence of overdose. In animals, repeated cocaine administration produces seizures in a pattern suggestive of “kindling.” Amphetamine and other psychostimulants are less epileptogenic than cocaine, but seizures have occurred in users of the over-the-counter anorectic phenylpropanolamine hydrochloride. A case–control study found that marijuana was protective against the development of new-onset seizures. In animal studies, the nonpsychoactive cannabinoid compound cannabidiol is anticonvulsant.

STROKE Illicit drug users frequently abuse ethanol and tobacco, increasing their risk for ischemic and hemorrhagic stroke. Parenteral drug users are subject to stroke through systemic complications such as hepatitis, endocarditis, and AIDS. Heroin users develop nephropathy with secondary hypertension, uremia, and bleeding. Heroin has also caused stroke in the absence of other evident risk factors, perhaps through immunologic mechanisms. Stroke in injectors of pentazocine combined with tripelennamine has resulted from embolism of foreign particulate material passing through secondary pulmonary arteriovenous shunts. Amphetamine users are prone to intracerebral hemorrhage following acute hypertension and fever. They are also at risk for occlusive stroke secondary to cerebral vasculitis affecting either medium-sized arteries (resembling polyarteritis nodosa) or smaller arteries and veins (resembling hypersensitivity angiitis). Ischemic and hemorrhagic stroke is also a frequent consequence of cocaine use, regardless of route of administration. Whether stroke is ischemic or hemorrhagic, a common mechanism may be acute hypertension and direct cerebral vasoconstriction, with hemorrhage occurring during reperfusion. Cerebral saccular aneurysms and vascular malformations have been found in more than 50% of patients undergoing angiography for cocaine-related intracranial hemorrhage. LSD and PCP are vasoconstrictive, and occlusive and hemorrhagic strokes have followed their use.

ALTERED MENTATION Dementia in illicit drug users may be the result of concomitant ethanol abuse, malnutrition, head trauma, or infection. Parenteral drug users are at risk for HIV encephalopathy. Whether the drugs themselves cause lasting cognitive or behavioral change is more difficult to establish, for predrug mental status is nearly always uncertain and many drug users are probably self-medicating preexisting psychiatric conditions (e.g., cocaine for depression). The weight of evidence is against chronic mental abnormalities secondary to opioids, marijuana, or hallucinogens. Controversy exists over whether psychostimulants predispose to lasting depression or PCP to schizophrenia. Cerebral atrophy and irregularly decreased cerebral blood flow have been reported in chronic cocaine users. Sedatives can cause “reversible dementia” in the elderly, and their use in small children has been associated with delayed learning. Lead encephalopathy has developed in gasoline sniffers, and toluene sniffers have had cerebral white matter lesions with dementia.

FETAL EFFECTS

The effects of illicit drugs on intrauterine development are also difficult to separate from damage secondary to ethanol, tobacco, malnutrition, and inadequate prenatal care. Infants exposed in utero to heroin have reportedly been small for gestational age, at risk for respiratory distress, and cognitively impaired later in life. Marijuana exposure has been associated with decreased birthweight and length. Cocaine exposure has reportedly caused abruptio placentae, decreased birthweight, congenital anomalies, microcephaly, tremor, perinatal stroke, and developmental delay. A prospective study found diffuse or axial hypertonia more often among cocaine-exposed neonates than controls; this “spastic tetraparesis” cleared by 24 months of age, and there were no differences in mental or motor development.

MISCELLANEOUS EFFECTS Guillain-Barré-type neuropathy and brachial or lumbosacral plexopathy, probably immunologic in origin, have been associated with heroin use. (Brachial plexopathy has also resulted from septic aneurysm of the subclavian artery.) Severe sensorimotor polyneuropathy occurs in sniffers of glue containing n-hexane. Rhabdomyolysis and renal failure have followed use of heroin, amphetamine, cocaine, and PCP. Myeloneuropathy indistinguishable from cobalamin deficiency occurs in nitrous oxide sniffers. Anemia is absent, and serum vitamin B 12 levels are usually normal. The mechanism is inactivation of the cobalamin-dependent enzyme methionine synthetase. Severe irreversible parkinsonism developed in Californians exposed to a meperidine analog contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a metabolite of which is toxic to neurons in the substantia nigra. Symptoms respond to levodopa. Dementia, ataxia, quadriparesis, blindness, and death have occurred in European smokers of heroin pyrolysate. Autopsies show spongiform changes in the central nervous system white matter. The responsible toxin has not been identified. Blindness developed in a heavy heroin user whose mixture contained quinine; however, it improved when he resumed using a quinine-free preparation. Chronic cocaine users experience dystonia and chorea, and cocaine has precipitated symptoms in patients with Tourette syndrome. Marijuana inhibits luteinizing and follicle-stimulating hormones, causing reversible impotence and sterility in men and menstrual irregularity in women. Ataxia and cerebellar white matter changes have occurred in toluene sniffers. SUGGESTED READINGS Breiter HC, Gollub RI, Weisskoff RM, et al. Acute effects of cocaine on human brain activity and emotion. Neuron 1997;19:591–611. Brust JCM. Neurological aspects of substance abuse. Boston: Butterworth Heinemann, 1993. Brust JCM. Stroke and substance abuse. In: Barnett HJM, Mohr JP, Stein BM, et al., eds. Stroke: pathophysiology, diagnosis,and management, 3rd ed. Philadelphia: WB Saunders, 1998:979–1000. Chiriboga CA. Fetal effects. Neurol Clin 1993;11:707–728. Chiriboga CA, Brust JCM, Bateman D, et al. Dose response effect of fetal cocaine exposure on newborn neurological function. Pediatrics 1999;103:79–85. Khanzian EJ, McKenna GJ. Acute toxic and withdrawal reactions associated with drug use and abuse. Ann Intern Med 1979;90:361–372. Levine SR, Brust JCM, Futrell N, et al. Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. N Engl J Med 1990;323:699–704. Lowenstein DH, Massa SM, Rowbotham MC, et al. Acute neurologic and psychiatric complications associated with cocaine abuse. Am J Med 1987;83:841–846. Nestler EJ, Aghajanian GK. Molecular and cellular basis of addiction. Science 1997;278:58–63. Ng SKC, Brust JCM, Hauser WA, et al. Illicit drug use and the risk of new onset seizures: contrasting effects of heroin, marijuana, and cocaine. Am J Epidemiol 1990;132:47–57. Pascual Leone A, Dhuna A, Anderson DC. Cerebral atrophy in habitual cocaine abusers: a planimetric CT study. Neurology 1991;41:34–38. Sloan MA, Kittner SJ, Feeser BR, et al. Illicit drug associated ischemic stroke in the Baltimore Washington Stroke Study. Neurology 1998;50:1688–1698. Stolerman I. Drugs of abuse: behavioral principles, methods and terms. Trends Pharmacol Sci 1992;13:170–176. Weinrieb RM, O'Brien CP. Persistent cognitive deficits attributed to substance abuse. Neurol Clin 1993;11:663–691.

CHAPTER 159. IATROGENIC DISEASE MERRITT’S NEUROLOGY

CHAPTER 159. IATROGENIC DISEASE LEWIS P.ROWLAND Suggested Readings

The growing number of drugs used to treat human disease and the growing number of invasive procedures used for diagnosis and therapy have generated a new class of illness. Twenty years ago, 3% of admissions to Boston hospitals were due to adverse drug reactions, and 30% of all patients in those hospitals had at least one adverse drug reaction. Neurologic reactions accounted for 20% of all adverse reactions in another study. In 1996, Nelson and Talbert found that 16% of admissions to an intensive care unit in Texas were drug-related. In Australia, according to Roughead and associates (1996), 12% of all admissions to medical wards were drug-related, as were 15% to 22% of all emergency admissions. A partial list of the neurologic syndromes seems formidable at first glance ( Table 159.1), and it is important to keep some perspective. The drugs listed do not cause an adverse reaction every time they are used. For example, penicillin is high on the list of drugs that cause convulsive encephalopathies, but only a few cases have been recorded. Most of the other disorders are rare.

TABLE 159.1. ADVERSE NEUROLOGIC REACTIONS DUE TO DRUGS OR PROCEDURES FOR DIAGNOSIS OR THERAPY

Some reactions, however, are common. Tardive dyskinesia is a price paid by many individuals for control of mental disorders, and levodopa-induced dyskinesia is the exchange many make for control of parkinsonism. Cerebral hemorrhage or femoral neuropathy due to retroperitoneal hemorrhage is the price a few patients pay for the prevention of stroke in many other patients. Drug-induced confusion and ataxia are common effects of anticonvulsants, and mental dulling or poor school performance are matters of concern for those who treat epilepsy. The adverse effects of radiotherapy limit our treatment of brain tumors. Control or elimination of these effects by alternative agents or procedures therefore has high priority in the therapeutic needs of neurology. The same must be said for the adverse effects of drugs used to treat neurologic disease that may damage other organs (e.g., corticosteroids, immunosuppressive drugs, antineoplastic drugs). There is even concern that levodopa may accelerate the course of Parkinson disease; on balance this seems unlikely. It is sometimes difficult to list the rare side effects of a drug without inappropriately frightening patients or physicians. When considering the list of adverse reactions, one must consider the relative risks and the benefits expected from the use of specific drugs or specific procedures; patients must understand the tradeoffs involved if they are to be able to give truly informed consent. There is another aspect of these drug reactions: Some have had what might be considered beneficial effects. For instance, the neuroparalytic accidents that followed the use of rabies vaccine led to the discovery of experimental autoimmune encephalomyelitis, and this in turn has had a lasting impact on our concepts of multiple sclerosis. In the meantime, rabies vaccine has been revised and now rarely leads to neurologic disease. Similarly, penicillamine-induced myasthenia gravis (MG) is a rare syndrome, but it has led to valuable observations about the nature of MG. Penicillin has also become important in the study of experimental epileptic neurons. Other drugs have been used to analyze the nature of peripheral neuropathies; some act on Schwann cells or myelin, others on the perikaryon, and others distally on the axon. Understanding the pathogenesis of some adverse reactions may lead to improved medical care in areas beyond the direct impact of the drugs involved. New syndromes have arisen from these reactions. For instance, epidural lipomatosis was first recognized as a complication of steroid therapy, then a consequence of obesity, then an idiopathic disorder and finally a complication of anabolic steroid abuse by body builders. Another example is the serotonin syndrome, which is most often caused by use of serotonin-reuptake inhibitors. The Sternbach (1991) criteria for diagnosis are three: (1) After a serotoninergic drug is started or its dosage increased, three of the following appear: altered mental state, agitation, myoclonus, hyperreflexia, shivering, tremor, diarrhea, or incoordination. (2) Other possible etiologies are excluded, including infection, metabolic aberration, or substance abuse. (3) No other antipsychotic drug has been started or increased in dosage. Although numerous drugs can be responsible, several are often used by neurologists, such as sumatriptan succinate (Imitrex) for migraine and selegeline hydrochloride (Eldepryl) for Parkinson disease. Recognition of the syndrome and withdrawal of the offending drug are followed by reversal of symptoms. The problems do not stop with drugs. Many procedures generate their own problems, including bone marrow transplantation, organ transplantation, brain implants, plasmapheresis, intravenous immunoglobulin therapy, pumps for intrathecal delivery of drugs, and more. The complications of a single therapy may take diverse forms; for instance, bone marrow transplantation may cause a graft-versus-host reaction and immunosuppression may also lead to central nervous system infections by bacteria, fungi, or viruses. Intensive care units are life-saving but also fraught with hazards. Drugs and procedures are not the only iatrogenic disorders. The attitude and behavior of a physician can also contribute to chronic disability in patients. Both physicians and patients seem to prefer a serious diagnosis of nerve or muscle rather than confront the possibility that symptoms may be psychogenic. Modern epidemics of chronic fatigue syndrome, chronic Epstein-Barr syndrome, and chronic Lyme disease are new incarnations of psychasthenia and neurasthenia; physicians have a responsibility in propagating these disorders by emphasizing immunologic and other hypothetical disorders, even though study after study has shown the importance of psychosocial factors. SUGGESTED READINGS Allain T. Dialysis myelopathy: quadriparesis due to extradural amyloid of beta-microglobulin origin. BMJ 1988;296:752–753. Atkinson JLD, Sundt TM Jr, Kazmier FJ, et al. Heparin-induced thrombocytopenia and thrombosis in ischemic stroke. Mayo Clin Proc 1988;63:353–361. Baker GL, Kahl LE, Zee BC, et al. Malignancy following treatment of rheumatoid arthritis with cyclophosphamide: long-term case-control follow-up study. Am J Med 1987;83:1–10. Batchelor TT, Taylor LP, Thaler HT, Posner JB, DeAngelis LM. Steroid myopathy in cancer patients. Neurology 1997;48:1234–1238. Bertorini TE. Myoglobinuria, malignant hyperthermia, neuroleptic malignant syndrome and serotonin syndrome. Neurol Clin 1997;15:649–671. Biller J, ed. Iatrogenic neurology. Boston: Buttterworth-Heinemann, 1998. Bowyer SL, LaMothe MP, Hollister JR. Steroid myopathy: incidence and detection in a population with asthma. J Allergy Clin Immunol 1985;76:234–242. Brannagan TH 3rd, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin treatment in neurologic disease. Neurology 1996;47:674–677.

Caranasos GJ, Stewart RB, Cluff LE. Drug-induced illness leading to hospitalization. JAMA 1974;228:713–717. Chaudry HJ, Cunha BA. Drug-induced aseptic meningitis. Postgrad Med 1991;90:65–70. Cryer PE. Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM: a vicious cycle. Diabetes 1992;41:255–260. Cybulski GR, D'Angelo CM. Neurological deterioration after laminectomy for spondylotic cervical myeloradiculopathy: the putative role of spinal cord ischaemia. 1988;51:717–718.

J Neurol Neurosurg Psychiatry

Dahlquist NR, Perrault J, Callaway CW, et al. D-lactic acidosis and encephalopathy after jejunoileostomy: response to overfeeding and to fasting in humans. Mayo Clin Proc 1984;59:141–145. Denicoff KD, Rubinow DR, Papa MZ, et al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1987;107:293–300. Ericsson M, Alges G, Schliamser SE. Spinal epidural abscess in adults: review and report of iatrogenic cases. Scand J Infect Dis 1990;22:249–257. Evans CDH, Lacey JH. Toxicity of vitamins: complications of a health movement. BMJ 1986;292:509–510. Fadul CE, Lemann W, Thaler HT, et al. Perforations of the gastrointestinal tract in patients receiving steroids for neurologic disease. Neurology 1988;38:348–352. Fahn S. Welcome news about levodopa, but uncertainty remains. Ann Neurol 1998;43:551–554. Fessler RG, Johnson DL, Brown FD, et al. Epidural lipomatosis in steroid-treated patients. Spine 1992;17:183–188. Gardner DM, Lynd LD. Sumatriptan contraindications and the serotonin syndrome. Ann Pharmacother 1998;32:33–38. Gibbons KJ, Guterman LR, Hopkins LN. Iatrogenic intracerebral hemorrhage. Neurosurg Clin N Am 1992;3:667–683. Gilman PK. Serotonin syndrome: history and risk. Fundam Clin Pharmacol 1998;12:482–501. Grafman J, Schwartz V, Dale JK, et al. Analysis of neuropsychological functioning in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry 1993;56:684–689. Graus F, Saiz A, Sierra J, et al. Neurologic complications of autologous and allogeneic bone marrow transplantation in patients with leukemia: a comparative study. Neurology 1996;46:1004–1009. Hunter JM. Adverse effects of neuromuscular blocking drugs. Br J Anaesthiol 1987;59:46–60. Junck L, Marshall WH. Neurotoxicity of radiological contrast agents. Ann Neurol 1983;13:469–484. Kaplan JG, Barasch E, Hirschfeld A, et al. Spinal epidural lipomatosis: a serious complication of iatrogenic Cushing's syndrome. Neurology 1989;39:1031–1034. Kramer J, Klawans HL. Iatrogenic neurology: neurologic complications of nonneuropsychiatric agents. Clin Neuropharmacol 1979;4:175–198. Lacomis D, Petrella JT, Giuliani MJ. Causes of neuromuscular weakness in the intensive care unit: a study of 92 patients. Muscle Nerve 1998;21:610–617. Lane RJM, Mastaglia F. Drug-induced myopathies in man. Lancet 1978;2:562–566. Laschinger JC, Izumoto H, Kouchoukos NT. Evolving concepts in prevention of spinal cord injury during operations on the descending thoracic and thoracoabdominal aorta. Ann Thorac Surg 1987;44:667–674. Lawrie SM, Pelosi AJ. Chronic fatigue syndrome: prevalence and outcome. Psychosocial factors are important for management. BMJ 1994;308:732–733. Lee P, Smith I, Piesowicz A, Brenton D. Spastic paraparesis after anaesthesia. Lancet 1999;353:554. Mack EE, Wilson CB. Meningiomas induced by high-dose cranial irradiation. J Neurosurg 1993;79:28–31. Malouf R, Brust JCM. Hypoglycemia: causes, neurological manifestations and outcome. Ann Neurol 1985;17:421–430. Mattle AH, Sieb JP, Rohner M, et al. Nontraumatic spinal epidural and subdural hematomas. Neurology 1987;37:1351–1356. Miller RR. Hospital admissions due to adverse drug reactions: a report from the Boston Collaborative Drug Surveillance Program. Arch Intern Med 1974;134:219–223. Nelson KM, Talbert RL. Drug-related hospital admissions. Pharmacotherapy 1996;16:701–707. Padovan CS, Yousry TA, Schleuning M, Holler E, Kolb HJ, Straube A. Neurological and neuroradiological findings in long-term survivors of allogeneic bone marrow transplantation. Ann Neurol 1998;43:627–633. Pohl KRE, Farley JD, Jan JE, et al. Ataxia-telangiectasia in a child with vaccine-associated paralytic poliomyelitis. J Pediatr 1992;121:405–407. Rampling R, Symonds P. Radiation myelopathy. Curr Opin Neurol 1998;11:627–632. Richard IH. Acute, drug-induced, life-threatening neurologic syndromes. Neurologist 1998;4:196–210. Richard IH, Kurlan R, Tanner C, et al. Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson's disease. Parkinson Study Group. Neurology 1997;48:1070–1077. Rosenberg M, McCarten JR, Snyder BD, et al. Case report: hypophosphatemia with reversible ataxia and quadriparesis. Am J Med Sci 1987;293:261. Roughead EE, Gilbert AL, Primrose JG, Sansom LN. Drug-related hospital admissions: a review of Australian studies published in 1988-1996. Med J Aust 1998;168:405–408. Schaumberg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome. N Engl J Med 1983;309:445–448. Shintani S, Tanaka H, Irifune A, et al. Iatrogenic acute spinal epidural abscess with septic meningitis: MR findings. Clin Neurol Neurosurg 1992;94:253–255. Siddiqui MF, Bertorini TE. Hypophosphatemia-induced neuropathy: clinical and electrophysiological findings. Muscle Nerve 1998;21:650–652. Steere AC, Taylor E, McHugh GL, et al. The overdiagnosis of Lyme disease. JAMA 1993;269:1812–1816. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705–713. Sterns RH, Riggs JE, Schochet SS Jr. Osmotic demyelination syndrome following correction of hyponatremia. N Engl J Med 1986;314:1535–1542. Watanabe T, Trusler GA, Williams WG, et al. Phrenic nerve paralysis after pediatric cardiac surgery. J Thorac Cardiovasc Surg 1987;94:383–388. Yuen EC, Layzer RB, Weitz SR, Olney RK. Neurologic complications of lumbar epidural anesthesia and analgesia. Neurology 1995;45:1795–1801.

CHAPTER 160. COMPLICATIONS OF CANCER CHEMOTHERAPY MERRITT’S NEUROLOGY

CHAPTER 160. COMPLICATIONS OF CANCER CHEMOTHERAPY MASSIMO CORBO AND CASILDA M.BALMACEDA Antineoplastic Drugs Immunosuppressant Drugs Biologic Response Modifiers Bone Marrow Transplantation Suggested Readings

ANTINEOPLASTIC DRUGS Antitumor chemotherapy may be toxic to both the peripheral and central nervous system (CNS). Several antineoplastic drugs may induce more than one side effect, causing different neurologic disorders ( Table 160.1). The incidence of neurotoxicity may depend on dosage, route and schedule of administration, patient age and general medical condition, and the combination with other neurotoxic drugs or with radiation therapy.

TABLE 160.1. NEUROTOXICITY OF ANTINEOPLASTIC DRUGS

Peripheral Nervous System Toxicity The vinca alkaloids, vincristine sulfate and vinblastine sulfate (Velban), may cause a sensorimotor neuropathy. Vincristine binds to tubulin and disrupts microtubules of the mitotic apparatus of cell division, arresting cells in metaphase. The effect on microtubules involved in axoplasmic transport may be responsible for axonal neuropathy. The severity of symptoms is related to total dose and duration of therapy. Distal paresthesia is the most common symptom, occurring in about 50% of patients. Later, there is distal sensory loss with weakness of the intrinsic hand muscles and the foot and toe dorsiflexors. Sensation is impaired more than motor function. Tendon reflexes are depressed. Although sensory loss tends to persist, paresthesia and weakness improve when dosage is reduced or therapy stopped. Cranial neuropathies tend to be bilateral; unilateral symptoms may suggest metastatic disease. Oculomotor paresis and transient vocal cord paralysis have been reported. Jaw pain results from trigeminal nerve toxicity, occurs suddenly or within 3 days after administration, and resolves spontaneously in a few days, usually without recurring with subsequent doses. An autonomic neuropathy may affect the gastrointestinal tract, causing abdominal pain and constipation in 45% to 60% of patients. Paralytic ileus may follow. Other manifestations include urinary retention, impotence, and orthostatic hypotension. Vincristine neurotoxicity may be more severe in patients with increased age, preexisting neuropathy, and liver dysfunction and in combination with with asparaginase (Elspar) or etoposide (VePesid). Muscle cramps may be the first symptom of neurotoxicity. Patients previously treated with other spindle poisons, such as paclitaxel (Taxol), may not tolerate vincristine. Vinorelbine (Navelbine), a new semisynthetic vinca alkaloid, has less severe neurotoxicity, presumably because of weaker activity on axonal microtubules. Cisplatin (Platinol) causes a dose-dependent, predominantly sensory polyneuropathy when given intravenously or after intraarterial treatment. Neuropathy follows a total cumulative dose greater than 300 to 500 mg/kg and is usually reversible by terminating therapy. Rarely, symptoms begin and progress when cisplatin is discontinued. The dorsal root ganglia are the most vulnerable structures, followed by peripheral nerves. Large myelinated fibers are most susceptible; proprioceptive sensory loss may be profound, with marked sensory ataxia. The motor system is spared. The adrenocorticotropic hormone analogs, glutathione, and nimodipine (Nimotop) may be neuroprotective when given concomitantly. Autonomic neuropathy is rare. Hearing loss is due to toxic effects on cochlear hair cells and may be irreversible. Neuropathies of cranial nerves III, V, and VI may follow intracarotid infusion. Lhermitte symptom is due to drug effects or may suggest spinal cord metastasis. Carboplatin (Paraplatin), a cisplatin analog, has less severe neurologic toxicity but more pronounced hematologic toxicity. Oxaliplatin has a dose-limiting neurotoxicity, producing an acute neuropathy at a dose of 135 mg/m 2. The taxanes, paclitaxel and docetaxel (Taxotere), make microtubules excessively stable and thereby inhibit cell division. Paclitaxel produces a predominantly axonal sensory neuropathy after a single dose of 250 mg/m 2 or at lower doses with repeated treatment. Of treated patients, 50% to 90% are affected, depending on dosing regimens, and axonal sensory neuropathy may be the main dose-limiting toxicity. Early symptoms include distal numbness and tingling; examination reveals loss of tendon jerks and impaired perception of vibration. Proximal limb weakness and myalgia have been described. The neurotoxicity of the combination of docetaxel and cisplatin is more severe than when either medication is given alone. Less frequently, peripheral nerve dysfunction may also be caused by other antineoplastic agents, including suramin, cytarabine (Cytosar-U), fludarabine phosphate (Fludara), procarbazine hydrochloride (Matulane), and etoposide. Central Nervous System Toxicity Most chemotherapeutic agents penetrate the blood–brain barrier poorly, and acute neurotoxicity is uncommon. However, symptoms and signs of CNS dysfunction may be induced by ifosfamide (IFEX) (10% to 30%), fludarabine (10% to 38%), asparaginase (15% to 40%), and procarbazine (less than 14%). 5-Fluorouracil (5-FU) neurotoxicity is rare (5%) but includes an acute cerebellar syndrome with dysarthria, dysmetria, ataxia, vertigo, and nystagmus. The symptoms usually clear within 1 to 6 weeks after drug withdrawal. An inflammatory leukoencephalopathy with enhancing white matter lesions on magnetic resonance imaging (MRI) may follow combined administration of 5-FU and levamisole hydrochloride (Ergamisol). Vacuolar and necrotic lesions are found particularly in the brainstem and cerebellum. A cerebellar syndrome is also the most common neurologic adverse effect of high-dose cytarabine therapy (3 g/m 2 every 12 hours for 12 doses per course). Other manifestations are anosmia, somnolence, optic atrophy, bulbar and pseudobulbar palsies, and hemiparesis. The frequency of CNS side effects is 6% to 47%, usually within 1 week after the first dose. Patients older than 60 years may be at increased risk. Symptoms often subside within weeks. Complications after intrathecal administration of cytarabine include meningismus, seizures, or paraparesis, often with pain and loss of sensation. Although CNS toxicity is uncommon with vincristine treatment, intrathecal administration may cause seizures, encephalopathy, or myelopathy. High doses of chemotherapy in conjunction with stem cell support or bone marrow transplantation may result in neurotoxicity that is not seen with conventional doses. This occurs with the alkylating agents busulfan (Myleran), the nitrosoureas, or thiotepa (Thioplex), as well as with etoposide. High-dose or intracarotid therapy with carmustine (BiCNU) may cause encephalopathy or retinopathy. Carotid artery injection of cisplatin may cause loss of vision or seizures. Drug streaming after intraarterial infusion may expose local areas of brain to extremely high concentrations of the drug, resulting in focal cerebral necrosis. Methotrexate in conventional doses has little or no neurotoxicity when given intravenously, but high-dose therapy may cause an acute strokelike encephalopathy. This syndrome usually occurs abruptly several days after the initiation of therapy and resolves within days after treatment stops. It is characterized by seizures, confusion, hemiparesis, speech disorders, and loss of consciousness. A vascular or embolic etiology has been postulated. Intrathecal methotrexate therapy, used in the prophylaxis of meningeal leukemia and in the treatment of leptomeningeal carcinomatosis, may induce an acute arachnoiditis in 5% to 40% of patients. Starting a few hours after drug administration, the syndrome includes headache, nausea, vomiting, fever, back pain, dizziness, meningismus, and signs of increased intracranial pressure. It usually resolves within a few days. If methotrexate is given intrathecally two to three times a week, a subacute myelopathy or encephalopathy may follow.

Subacute methotrexate neurotoxicity seems to be mediated by release of adenosine, and it is relieved by giving aminophylline, which displaces adenosine from its receptor. A chronic delayed leukoencephalopathy may be caused by intravenous high-dose methotrexate, with symptoms beginning several months after the start of treatment and involving personality changes followed by dementia, focal seizures, spasticity, and alterations in consciousness. Most patients show improvement if treatment ceases. A progressive leukoencephalopathy may also be seen in patients given methotrexate intrathecally combined with prophylactic cranial radiotherapy. Computed tomography (CT) or MRI shows extensive, deep, bilateral white matter lesions. Calcification may be observed in children. The syndrome typically follows a delay of 1 to 2 years and is a major problem in patients successfully treated for leukemia. Although the combined effects of methotrexate and radiation are held responsible rather than the methotrexate alone, this combination is still considered an important strategy for the treatment of acute lymphoblastic leukemia. However, the incidence of leukoencephalopathy (18%) following treatment with intrathecal moderate-dose methotrexate (8 to 12 mg/m 2; cumulative dose, 24 to 90 mg) and prophylactic radiotherapy (18 to 24 Gy) appears to be less than that following treatment with intravenous high-dose methotrexate (50% to 68%). Rarely, a focal leukoencephalopathy is seen if the Ommaya reservoir tip is misplaced in the white matter. Leukoencephalopathy has also been described after oral methotrexate therapy for rheumatoid arthritis.

IMMUNOSUPPRESSANT DRUGS Cyclosporine (Sandimmune) is the mainstay therapy in preventing organ transplant rejection. It acts by inhibiting interleukin-2 (IL-2) production by T cells and is successful in suppressing T-cell response to transplantation antigens and thus prolonging graft survival. In addition to nephrotoxicity and hypertension, neurotoxicity in 8% to 47% of patients includes tremor, paresthesias, seizures, lethargy, ataxia, and quadriparesis. Toxicity, more frequently observed with serum levels greater than 500 ng/mL, may also cause a cerebral blindness that is usually reversible, improving with cessation of therapy or dose reduction. Reversible cerebral white matter lesions are seen on CT or MRI; cortical lesions in both occipital lobes may be present. Hemiparesis may suggest that cyclosporine focally damages blood vessels, but the frequency of cyclosporine neurotoxicity increases in HLA-mismatched and unrelated donor transplants, suggesting that immune factors play a role. Cyclosporine induces activity of the hepatic cytochrome P-450, which also mediates drug oxidation. Consequently, hepatic dysfunction or concomitant administration of agents that induce the P-450 system can cause increased or reduced concentrations of cyclosporine in blood. In the circulation, cyclosporine is bound to lipoproteins; a reduction in serum cholesterol to less than 120 mg/dL may increase free-drug levels and neurotoxicity. Corticosteroids also increase plasma cyclosporine levels. OKT3, a powerful immunosuppressive drug, is the first monoclonal murine antibody to become available for therapy in humans. It is used to treat acute allograft rejection. An asymptomatic cerebrospinal fluid pleocytosis occurs in most patients so treated. Neurologic complications may develop within hours of administration and include altered mental function, seizures, and lethargy. Contrast-enhancing cerebral lesions may be seen on MRI. Aseptic meningitis, visual loss, and transient sensorineural hearing loss are other adverse effects. Tacrolimus (Prograf) has cyclosporine-like activity and is approved for immunosuppression in organ transplantation, particularly if organ rejection is not responsive to OKT3 therapy. It may cause acute tremor, headache, and paresthesias, but neurotoxicity occurs in only 5% to 10% of patients. Neurologic symptoms begin when the tacrolimus level in blood is at a peak, and eventually resolve after the dose is reduced or stopped. In a tacrolimus-related leukoencephalopathy, demyelination in the parietooccipital region and centrum semiovale may be seen on MRI, as in the syndrome caused by cyclosporine. Clinical recovery is usually accompanied by reversal of radiologic abnormalities. Transient cortical blindness and cerebellar symptoms have been described.

BIOLOGIC RESPONSE MODIFIERS Cytokines, such as interferons and IL-2, are used as biologic response modifiers to treat cancer. Neurotoxic effects include vertigo, memory loss, confusion, emotional instability, somnolence, depression, seizures, and hemiparesis. Cytokine-related encephalopathy is self-limited and probably related to increased levels of circulating cytokines after renal allografting. Risk factors include delayed graft function, cadaveric transplantation, and diabetes. Corticosteroid treatment may be helpful.

BONE MARROW TRANSPLANTATION Bone marrow transplantation (BMT) of cells from an HLA-matched donor is widely used to treat refractory leukemia or myelodysplastic conditions. It often results in an immunologic reaction of donor T lymphocytes against recipient tissues, called graft-versus-host-disease (GVHD). Acute GVHD involves the skin, gastrointestinal tract, and liver. Chronic GVHD occurs in 30% to 40% of patients who survive more than 100 days. Manifestations include altered immune function, hypergammaglobulinemia, increased susceptibility to viral infection, and symptoms of collagen-vascular disease. Neurologic disorders of chronic GVHD are polymyositis, myasthenia gravis, sensorimotor neuropathy, aseptic meningitis, or leukoencephalopathy. Remission of neurologic toxicity may follow successful treatment of GVHD with steroids and immunosuppressive drugs. The most common neurologic complications in patients who undergo allogeneic or autologous BMT are cerebral hemorrhage (4%), metabolic encephalopathy (3%), and CNS infections (2%). Hemorrhages are most common with autologous BMT, are mostly subdural, and are attributed to thrombocytopenia. A post-BMT leukoencephalopathy occurs particularly in patients who have had prior cerebral irradiation. It is characterized by focal signs, lethargy, confusion, and progressive deterioration. An acute parkinsonian syndrome has been described. Progressive multifocal leukoencephalopathy may occur in immunocompromised patients after autologous or allogeneic BMT for chronic myelogenous leukemia. The most common neuropathologic findings in patients undergoing BMT are cerebrovascular lesions, including areas of hemorrhagic necrosis and infarction. SUGGESTED READINGS Antineoplastic Drugs Baker WJ, Royer GL Jr, Weiss RB. Cytarabine and neurologic toxicity. J Clin Oncol 1991;9:67–93. Berger T, Malayeri R, Doppelbauer A, et al. Neurological monitoring of neurotoxicity induced by paclitaxel/cisplatin chemotherapy. Eur J Cancer 1997;33:1393–1399. Bernini JC, Fort DW, Griener JC, et al. Aminophylline for methotrexate-induced neurotoxicity. Lancet 1995;345:544–547. Blay JY, Conroy T, Chevreau C, et al. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. 1998;16:864–871.

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Cain JW, Bender CM. Ifosfamide-induced neurotoxicity: associated symptoms and nursing implications. Oncol Nurs Forum 1995;22:659–666. Cain MS, Burton GV, Holcombe RF. Fatal leukoencephalopathy in a patient with non-Hodgkin's lymphoma treated with CHOP chemotherapy and high-dose steroids. Am J Med Sci 1998;315:202–207. Cavaletti G, Bogliun G, Marzorati L, et al. Peripheral neurotoxicity of Taxol in patients previously treated with cisplatin. Cancer 1995;75:1141–1150. Chaudhry V, Rowinsky EK, Sartorious SE, et al. Peripheral neuropathy from Taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol 1994;35:304–311. Fazeny B, Zifko U, Meryn S, et al. Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel: a phase II study. Cancer Chemother Pharmacol 1996;39:150–156. Figueredo AT, Fawcet SE, Molloy DW, et al. Disabling encephalopathy during 5-fluorouracil and levamisole adjuvant therapy for resected colorectal cancer: a report of two cases. Cancer Invest 1995;13:608–611. Forman AR. Peripheral neuropathy in cancer patients: clinical types, etiology and presentation. Oncology 1990;4:85–89. Gregg RW, Molepo JM, Monpetit VJ, et al. Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity. Oncol 1992;10:795–803. Hilkens PH, Pronk LC, Verweij J, et al. Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin. Br J Cancer 1997;75:417–422.

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Kimmel DW, Wijdicks EF, Rodriguez M. Multifocal inflammatory leukoencephalopathy associated with levamisole therapy.

Neurology 1995;45:374–376.

Lovblad K, Kelkar P, Ozdoba C, et al. Pure methotrexate encephalopathy presenting with seizures: CT and MRI features. Pediatr Radiol 1998;28:86–91. Lyass O, Lossos A, Hubert A, et al. Cisplatin-induced non-convulsive encephalopathy. Anticancer Drugs 1998;9:100–104. Macdonald DR. Neurologic complications of chemotherapy. Neurol Clin 1991;9:955–967. Matsumoto K, Takahashi S, Sato A, et al. Leukoencephalopathy in childhood hematopoietic neoplasm caused by moderate-dose methotrexate and prophylactic cranial radiotherapy: an MR analysis. Int J Radiat Oncol Biol Phys 1995;32:913–918. New PZ, Jackson CE, Rinaldi D, et al. Peripheral neuropathy secondary to docetaxel (Taxotere). Neurology 1996;46:108–111. Resar LMS, Phillips PC, Kastan MB, et al. Acute neurotoxicity after intrathecal cytosine arabinoside in two adolescents with acute lymphoblastic leukemia of B-cell type. Cancer 1993;71:117–123. Tuxen MK, Hansen SW. Neurotoxicity secondary to antineoplastic drugs. Cancer Treat Rev 1994;20:191–214. Verschraegen C, Conrad CA, Hong WK. Subacute encephalopathic toxicity of cisplatin. Lung Cancer 1995;13:305–309. Waber DP, Tarbell NJ. Toxicity of CNS prophylaxis for childhood leukemia. Oncology 1997;11:259–265. Worthley SG, McNeil JD. Leukoencephalopathy in a patient taking low-dose oral methotrexate therapy for rheumatoid arthritis. J Rheumatol 1995;22:335–337. Immunosuppressant Drugs: General Martinez AJ. The neuropathology of organ transplantation: comparison and contrast in 500 patients. Pathol Res Pract 1998;194:473–486. Cyclosporine and Tacrolimus Appignani BA, Bhadelia RA, Blacklow SC, et al. Neuroimaging findings in patients on immunosuppressive therapy: experience with tacrolimus toxicity. AJR 1996;166:683–688. Devine SM, Newman NJ, Siegel JL, et al. Tacrolimus (FK506)-induced cerebral blindness following bone marrow transplantation. Bone Marrow Transplant 1996;18:569–572. Hughes RL. Cyclosporine-related central nervous system toxicity in cardiac transplantation. N Engl J Med 1990;323:420–421. Lanzino G, Cloft H, Hemstreet MK, et al. Reversible posterior leukoencephalopathy following organ transplantation: description of two cases. Clin Neurol Neurosurg 1997;99:222–226. Memon M, deMagalhaes-Silverman M, Bloom EJ, et al. Reversible cyclosporine-induced cortical blindness in allogeneic bone marrow transplant recipients. Bone Marrow Transplant 1995;15:283–286. Pace MT, Slovis TL, Kelly JK, Abella SD. Cyclosporin A toxicity: MRI appearance of the brain. Pediatr Radiol 1995;25:180–183. Shutter LA, Green JP, Newman NJ, et al. Cortical blindness and white matter lesions in a patient receiving FK506 after liver transplantation. Neurology 1993;43:2417–2418. Small SL, Fukui MB, Bramblett GT, Eidelman BH. Immunosuppression-induced leukoencephalopathy from tacrolimus (FK506). Ann Neurol 1996;40:575–580. Tezcan H, Zimmer W, Fenstermaker R, et al. Severe cerebellar swelling and thrombotic purpura associated with FK506. Bone Marrow Transplant 1998;21:105–109. Zimmer WE, Hourihane JM, Wang HZ, Schriber JR. The effect of human leukocyte antigen disparity on cyclosporine neurotoxicity after allogeneic bone marrow transplantation. 1998;19:601–610.

AJNR

OKT3 Coleman AR, Norman DJ. OKT3 encephalopathy. Ann Neurol 1990;28:837–838. Parizel PM, Snoeck HW, van den Hauwe L, et al. Cerebral complications of murine monoclonal CD3 antibody (OKT3): CT and MR findings. AJNR 1997;18:1935–1938. Seifeldin RA, Lawrence KR, Rahamtulla AF, Monaco AP. Generalized seizures associated with the use of muromonab-CD3 in two patients after kidney transplantation. Ann Pharmacother 1997;31:586–589. Shihab F, Barry JM, Bennet WM, et al. Cytosine-related encephalopathy induced by OKT3: incidence and predisposing factors. Transplant Proc 1993;25:564–565. Biologic Response Modifiers Bender CM, Monti EJ, Kerr ME. Potential mechanisms of interferon toxicity. Cancer Pract 1996;4:35–39. Licinio J, Kling MA, Hauser P. Cytokines and brain function: relevance to interferon-alpha-induced mood and cognitive changes. Semin Oncol 1998;25:30–38. Michel M, Vincent F, Sigal R, et al. Cerebral vasculitis after interleukin-2 therapy for renal cell carcinoma. J Immunother Emphasis Tumor Immunol 1995;18:124–126. Bone Marrow Transplantation Amato AA, Barohn RJ, Sahenk Z, et al. Polyneuropathy complicating bone marrow and solid organ transplantation. Neurology 1993;43:1513–1518. Anderson BA, Young PV, Kean WF, et al. Polymyositis in chronic graft-versus-host disease. Arch Neurol 1982;39:188–190. Bolger GB, Sullivan KM, Spence AM, et al. Myasthenia gravis after allogeneic bone marrow transplantation: relationship to chronic graft-versus-host disease. Neurology 1986;36:1087–1091. Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324:667–674. Graus F, Saiz A, Sierra J, et al. Neurologic complications of autologous and allogeneic bone marrow transplantation in patients with leukemia: a comparative study. Neurology 1996;46:1004–1009. Lockman LA, Sung JH, Krivit W. Acute parkinsonian syndrome with demyelinating leukoencephalopathy in bone marrow transplant recipients. Pediatr Neurol 1991;7:457–463. Owen RG, Patmore RD, Smith GM, Barnard DL. Cytomegalovirus-induced T-cell proliferation and the development of progressive multifocal leucoencephalopathy following bone marrow transplantation. Br J Haematol 1995;89:196–198. Provenzale JM, Graham ML. Reversible leukoencephalopathy associated with graft-versus-host disease: MR findings. AJNR 1996;17:1290–1294. Seong D, Bruner JM, Lee KH, et al. Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation in a patient with chronic myelogenous leukemia. Clin Infect Dis 1996;23:402–403. Snider S, Bashir R, Bierman P. Neurologic complications after high-dose chemotherapy and autologous bone marrow transplantation for Hodgkin's disease. Neurology 1994;44:681–684. Tahsildar HI, Remler BF, Creger RJ, et al. Delayed, transient encephalopathy after marrow transplantation: case reports and MRI findings in four patients. J Neurooncol 1996;27:241–250.

CHAPTER 161. OCCUPATIONAL AND ENVIRONMENTAL NEUROTOXICOLOGY MERRITT’S NEUROLOGY

CHAPTER 161. OCCUPATIONAL AND ENVIRONMENTAL NEUROTOXICOLOGY LEWIS P.ROWLAND Heavy Metal Intoxication Other Intoxications Suggested Readings

Neurotoxicology commands newspaper attention these days. Is there a Gulf War syndrome? Did exposure there to anticholinesterase nerve gases cause amyotrophic lateral sclerosis (ALS)? Do silicon breast implants cause autoimmune disorders, including multiple sclerosis? Are behavioral changes due to subclinical occupational exposure? Do nearby petrochemical plants or high power electrical lines increase the incidence of brain tumors? Can mercury intoxication result from inhalation of the element from dental amalgams and can that cause multiple sclerosis, ALS, or other diseases? These and similar questions have been debated in an atmosphere of contentious uncertainty. In this chapter we focus on the particular clinical syndromes that result from exposure to heavy metals, solvents, and natural neurotoxins (Table 161.1). Clinical diagnosis, laboratory proof of diagnosis, and treatment are the practical issues. We bypass detailed discussion of behavioral effects from chronic low-level exposures as beyond the scope of this chapter. More detailed information is provided in the General section of Suggested Readings.

TABLE 161.1. NEUROTOXIC SYNDROMES

HEAVY METAL INTOXICATION Pathogenesis The heavy metals have diverse toxic effects on cell nuclei, mitochondria, other organelles, cytoplasmic enzymes, and membrane lipids. Clinical syndromes may result from combinations of these effects that do not readily explain the real-life disorders or why the assault should affect the central nervous system (CNS) in some people, peripheral nerves in others, or both. Lead provides an example of the complexity. It interferes with the sulfhydryl enzymes of heme biosynthesis, especially d-aminolevulinic acid dehydratase, coproporphyrin oxidase, and ferrochetalase. As a result of these partial blocks, several metabolites accumulate in blood and urine: d-aminolevulinic acid, coprophorphyrin III, and zinc protoporphyrin. Other heme-containing enzymes are also affected, including cytochrome P450 in the liver and mitochondrial cytochrome c oxidase. Lead also interferes with calcium-activated enzymes, calcium channels, and Ca 2+-ATPase. Lead has similarly multiple and diverse biochemical ill effects on cell metabolism. Sorting out these interactions and their relationship to the clinical syndromes is not a simple task, and there is even less basic information about other neurointoxicants. Nevertheless, metals and biologic toxins have been used experimentally to analyze the pathogenesis of the neuropathies according to effects on axons, myelin, or Schwann cells. Recognizing Intoxication Clinically The clinical manifestations of an intoxication can result from diverse causes. Other possible causes must therefore be excluded ( Table 161.2) by considering systemic or metabolic disease and evaluating therapeutic drugs the patient may be taking. More reliable diagnosis depends on the recognition of exposure by occupation or recreation, recognition of a specific syndrome and elimination of other causes (as in the acute lead encephalopathy of childhood), or associated laboratory abnormalities. Outbreaks or clusters may be encountered with the relatively mild symptoms of glue sniffing or the devastating encephalomyelopathy of Minamata disease in Japan, which was caused by methyl mercury. The circumstances of attempted suicide or fire usually identify carbon monoxide exposure; a motor running in a parked automobile or a faulty gasoline-fueled heater are most often responsible. For the following discussions, the primary at-risk occupations are listed in Table 161.1 and are not repeated in the text.

TABLE 161.2. CLUES TO THE DIAGNOSIS OF INTOXICATIONS

Acute Encephalopathy Syndromes of confusion, hyperactivity or somnolence, memory impairment, and behavioral change arise from many different disorders, as described under delirium in Chapter 1. The acute encephalopathy of lead poisoning is one that affects children; seizures and increased intracranial pressure without a mass lesion may be clues to diagnosis. The circumstances of intoxication may be evident as in glue sniffing or dialysis dementia. Heavy metal intoxication is not encountered frequently among the causes of delirium but may be the result of attempted murder by poisoning. Chronic Encephalopathy Dementia with or without tremor can be a manifestation of occupational exposure to heavy metals. Therefore, when confronted with a patient who may have been

poisoned, it may be more important to know the occupational history than to order a sweeping laboratory survey of blood and urine. Mercury intoxication may be more often associated with tremor than other exposures, but this is probably not a reliable guide. Parkinsonism can arise in workers in manganese smelters; monitoring guidelines are not always heeded. Parkinsonism may also follow chronic exposure to carbon disulfide. Peripheral Neuropathy Neuropathy may be caused by any heavy metal, almost always the result of occupational exposure. The symptoms are those of any sensorimotor neuropathy with acroparesthesia and distal limb weakness. Optic and autonomic neuropathies seem to be rare. A hallmark of thallium neuropathy is baldness. The neuropathy of organophosphate poisoning may be accompanied by upper motor neuron signs that imply a myelopathy; sometimes the residual signs include those of the lower motor neuron but the occupational history and the sensory loss differentiate the syndrome from motor neuron disease. Cranial Neuropathy Trichlorethylene causes a selective sensory neuropathy of the trigeminal nerve; the syndrome is so specific that it was once seriously evaluated as a treatment for idiopathic trigeminal neuralgia. Visual loss from optic neuropathy or retinopathy is a manifestation of methanol toxicity and many therapeutic drugs. Specific Clinical Syndromes of Intoxication Lead Acute lead encephalopathy in children was first recognized in 1904 and even then was attributed to lead-containing house paint. The syndrome also occurs in adults who are occupationally exposed. The childhood syndrome has been linked to pica, the ingestion of flaking lead-containing paint on the walls of old houses. Inhalation of dust from the ancient paint is another important source of household contamination and makes paint removal hazardous, especially when the paint is burned. Because symptoms are difficult to detect in toddlers, the Centers for Disease Control and Prevention advocates periodic screening of blood lead for all children aged 9 to 36 months. That policy has been debated, but recognition and treatment can prevent the sometimes devastating cerebral consequences. Blood lead levels in U.S. children declined by 78% largely because lead was removed from automobile gasoline and also because lead has been eliminated from house paint. Acute lead encephalopathy is now rare in the United States. However, it is feared that early lead exposure can adversely affect later behavior and school performance. Evidence from several sources suggests that higher blood lead levels are associated with lower IQ. Because of increasing doubt about the efficacy of chelation therapy, prevention is now the goal, as described below. Lead neuropathy is probably restricted to heavy occupational exposure, which is monitored by regulations established by the Occupational Safety and Health Administration; overt neuropathy is rare. Cases attributed to retained bullets in the abdomen or drinking from lead-lined glasses require confirmation by biochemical markers lacking in published reports. Traditionally, the characteristic syndrome of lead neuropathy is confined to motor fibers restricted to or especially involving the radial nerve. However, the presence of visible fasciculation and brisk reflexes or frank upper motor neuron signs suggests that this could be a myelopathy similar to that of ALS. However, there have been no convincing case reports of an ALS-like syndrome in lead workers since 1974. Mercury The relations between elemental, inorganic, and organic forms of mercury involve transformations from one form to another. Chronic occupational exposure to mercury may lead to the “Mad Hatter syndrome,” which is dominated by a tremor resembling essential tremor but which can be severe, even affecting head and trunk. Memory loss, social withdrawal, and emotional lability may be prominent. Similar symptoms may result from exposure to inorganic mercury, which is presumably broken down to elemental mercury in the environment. Inorganic mercury is more likely to cause a sensorimotor neuropathy. Mercury was held responsible for Minamata disease, which affected 2,500 people near the bay of that name in Japan. The outbreak illustrates the conversion of inorganic mercury to more toxic organic mercury by fish. A factory was using mercuric chloride in the manufacture of vinyl chloride. Waste material from the plant was discharged into the bay, ingested by fish, and converted into more toxic methylmercury. The fish were eaten by people, who were also intoxicated. The syndrome comprised cognitive change, cerebellar ataxia, and sensorimotor neuropathy. Visual loss was often severe and may be related to damage of the occipital cortex. Symptoms progressed for 3 to 10 years. Arsenic Acute arsenic poisoning is a multisystem disaster: vomiting, bloody diarrhea, myoglobinuria, renal failure, arrhythmias, hypotension, seizures, coma, and death. In survivors, Mees lines on the fingernails and sensorimotor neuropathy appear in 7 to 14 days. Sensory symptoms dominate, and weakness is more profound in the legs than in the arms and hands. Slow and incomplete recovery takes years. Nerve conduction velocities are typically slow. Cognition may be impaired in some survivors, depending on the severity of the acute encephalopathy. Intoxication by inhalation may be acute or chronic. The chronic version is “blackfoot disease” with vascular changes and gangrene and a less severe peripheral neuropathy. Most arsenic exposure is occupational, but arsenic contamination of groundwater is a growing problem in poverty areas of India and elsewhere. The use of arsenic trioxide to treat leukemia may also be followed by arsenic neuropathy. Thallium A rare syndrome, thallium intoxication is usually the result of unwittingly ingesting a rat poison. The acute episode is dominate by gastrointestinal symptoms. Paresthesias may be noted soon afterward, but overt signs of neuropathy may take 2 weeks to appear. The encephalopathy may include cognitive impairment and choreoathetosis, myoclonus, or other involuntary movements. The unique clue to diagnosis is loss of hair, which begins 1 to 3 weeks after exposure. Neuropathy and dermatitis may be prominent in chronic exposure. Manganese George Cotzias, discoverer of the therapeutic value of levodopa in Parkinson disease, followed an unusual path to that achievement. He was a biochemist, interested in the role of metals in enzyme activity. Manganese was one such metal and that took him to an outbreak of parkinsonism in South American miners. At about that time, Hornykewicz identified the lack of dopamine in the substantia nigra of patients with Parkinson disease; Cotzias gave the precursor in amounts larger than others had used previously. Manganese intoxication reproduces the essential motor features of Parkinson disease but with sufficient clinical and pathologic differences to indicate the conditions are not identical. The outlook is gloomy, including severe cognitive loss. Responses to levodopa and to chelation therapy are limited. Aluminum Dialysis dementia has been attributed to the presence of aluminum in the dialysis water and also in ingested phosphate binders used to control blood phosphorus levels. Treatment of the water and avoidance of the binders have decreased the incidence of the syndrome. Encephalopathy, however, has also occurred in uremic patients dialyzed with deionized water and also in some who took the binders without dialysis, implying that abnormal retention of aluminum is a characteristic of uremia. Paresthesias and weakness were part of potroom palsy, a complex syndrome in workers in a smelter who were exposed to pots that had not been vented properly. Other manifestations included ataxia, tremor, and memory loss. Biochemical Diagnosis

Measurement of blood lead levels is the time-honored diagnostic method even though technical variations render values somewhat uncertain in individual cases. The mean whole blood level in adults who are not exposed to occupational hazards is less than 5 µg/dL. Standard recommendations now consider levels safe up to 30 µg/dL; some consider a higher safe limit, 50 µg/dL. Workers are monitored closely if levels exceed 40 µg/dL. The upper limit of lead in urine is 150 µg/g creatinine. Peripheral neuropathy is usually accompanied by blood lead levels greater than 70 µg/dL. In children, the warning mark is a blood lead level of 10 µg/dL, and estimates suggest that 1.7 million children still have higher levels. Children with levels exceeding 10 µg/dL are more likely to be African-American, poor, and living in large cities. For them, the major source of poisoning is lead paint, followed by contaminated soils and dust. Chelation therapy commences with levels of 40 µg/dL. Testing blood lead levels is recommended for children with presumed autism, attention deficit disorder, pervasive development disorder, mental retardation, or language problems. The blood lead level is considered a more reliable indicator than the biochemical tests mentioned below. A provocative test with Ca-EDTA has been advocated but has been used less and less often. The patient is given 500 mg/m 2 Ca-EDTA in 5% glucose infused in 1 hour. If urinary lead excretion in the next 8 hours exceeds 60% of the amount of EDTA given, the test is positive, that is, the chelator is presumed to have combined with and mobilized excessive body stores of lead. The test is cumbersome, and reliability is debated. A diagnosis of lead intoxication is supported if blood zinc protoporphyrin exceeds 100 µg/dL or if urinary aminolevulinic acid excretion is higher than 15 mg/L. With blood lead levels of 10 µg/dL, the activity of aminolevulinic acid dehydratase is low. At higher lead levels, the activities of coproporphyrinogen oxidase and ferrochetalase are also low. Anemia and basophilic stippling of erythrocytes are characteristic. No other neurotoxin generates similarly specific biochemical abnormalities that can be used diagnostically. Nerve conduction velocities are nonspecifically slow in lead and other neuropathies. The diagnosis of arsenic intoxication is confirmed by urinary levels greater than 75 µg/dL. Hair analysis has been used but is not deemed reliable. The length-dependent neuropathy is primarily axonal with secondary demyelination. After acute exposure, blood tests are not useful for detecting thallium because the metal is taken up by cells so rapidly that blood levels do not rise. Urinary thallium can be detected by atomic absorption spectrometry. Normal urinary values are 0.3 to 0.8 µg/L and levels of 200 to 300 are seen in overt poisoning. A provocative test depends on KCl, which is given orally in a dose of 45 mEq. Potassium displaces thallium from tissue stores and blood levels rise, which can be detected by serial measurement of urinary content. Prevention and Treatment Preventive measures have been most publicized for lead with special concern for the welfare of children. Education programs, paint removal, and deleading house paints have all played a role. Personnel involved in deleading must be protected. Workers in industries at risk have been increasingly monitored and removed from exposure when blood lead levels begin to rise. Motor nerve conduction studies have also been used. Once symptoms of intoxication appear and the diagnosis of lead poisoning is clear, removal from exposure is mandatory. Chelation therapy can be instituted. For children with blood levels less than 45 µg/dL, oral treatment can be instituted with 2,3-dimercaptosuccinic acid and penicillamine. For acute encephalopathy and blood levels more than 70 µg/dL, Ca-EDTA and dimercaprol (2,3-dimercaptopropanol), also called British anti-Lewisite (BAL), can be used together, starting with BAL, 3 to 5 mg/kg intramuscularly; this is followed by simultaneous but separate intramuscular injections of both chelators given every 4 hours for the next 3 to 5 days. For symptomatic neuropathy, Ca-EDTA can be used alone at doses of 50 to 75 mg/kg every 12 hours in a 3- to 5-day course and a 2- to 3-week rest between courses until the blood level is normal. Treatment of the encephalopathy is also symptomatic or surgical. Prevention of mercury intoxication requires monitoring in high-risk occupations, including dental offices, and correction of inadequate ventilation, avoiding vacuuming of spilled mercury, and removal of workers whose urinary level has increased fourfold or is more than 50 µg/L. Control of industrial pollution may require major effort. If the person is symptomatic, treatment commences with dimercaprol, which is given intramuscularly 3 to 5 mg/kg every 4 hours for day 1, every 12 hours on day 2, and then once a day for the next 3 days, followed by a 2-day interruption. Other agents are 2,3-dimercaptosuccinic acid and 2,3-dimercapto-propane-1-sulfonate, a water-soluble form of BAL. All agents are somewhat effective for organic and inorganic mercury poisoning. BAL therapy is also used for acute arsenic poisoning and is most effective before symptoms of neuropathy appear. BAL is considered more effective than penicillamine in treating the chronic neuropathy. Hemodialysis is another treatment for the acute episode. Aside from monitoring occupational exposure to thallium, an important preventive measure is protection of children against the ingestion of candylike pellets. Treatment of acute poisoning depends in part on enhancing urinary and fecal excretion of thallium by giving laxatives and using Prussian Blue or activated charcoal to retard absorption. Urinary excretion is enhanced by forced diuresis and administration of KCl; hemodialysis may be effective.

OTHER INTOXICATIONS Organophosphates Organophosphates, sometimes in combination with carbamates, are used as pesticides by more than 2.5 million agriculture workers and also by amateur gardeners. Also exposed are those engaged in the manufacture of these compounds and military personnel who use or store compounds designed for chemical warfare. It is estimated that 150,000 to 300,000 people have pesticide-induced illness each year. Popular compounds include malathion, parathion, and others. Most are lipid soluble and readily absorbed after ingestion, inhalation, or application to the skin. They are powerful inhibitors of acetylcholinesterase. Three clinical stages follow in sequence. First, acute cholinergic crisis comprises nicotinic effects (limb weakness, fasciculation, tachycardia) and muscarinic manifestations (miosis, lacrimation, salivation). CNS signs include ataxia, seizures, altered consciousness, and sometimes coma. Second, the intermediate syndrome appears in 2 to 4 days after exposure. Weakness may be profound, affecting the proximal limbs, cranial muscles, neck flexors, and respiration; tendon reflexes are lost. The differential diagnosis includes the Guillain-Barré syndrome, periodic paralysis, and myasthenia gravis. Among survivors, recovery may be slow but is the rule. Third, organophosphate-induced delayed neuropathy appears 1 to 5 weeks after exposure. The syndrome was first described during the period of prohibition in the United States when illicit whiskey was made in home stills: 50,000 people consumed “Jamaica Ginger” or “Jinger Jake” that was later found to contain triorthocresyl phosphate. Paresthesias and distal leg weakness appeared weeks later. Triorthocresyl phosphate is not an anticholinesterase, but the syndrome was then seen after exposure to cholinergic organophosphates. The disorder as been attributed to inhibition of “neuropathy target esterase,” disruption of axonal transport, and a dying back neuropathy. Although paresthesias may be noted, the disorder is dominantly motor. Among survivors, upper motor neuron signs implicate the CNS, which in combination with profound lower motor neuron signs may simulate ALS except that there is no progression for years. Exposure can be documented by levels of the drug or its metabolites in blood or urine. Measurement of red cell or plasma cholinesterase is an indirect marker. In electrodiagnostic studies there may be a repetitive response to a single nerve stimulus. The acute disorder is a medical emergency risking death from respiratory paralysis. If the patient has been splashed, clothing must be stripped and the skin washed thoroughly to prevent further absorption. Gastric lavage may be needed. Airway control and ventilation must be ensured and cardiac function monitored. Atropine is the best antidote; subcutaneous doses of 0.5 to 1.0 mg are given every 15 minutes until an effect is observed in the form of dilated pupils, flushed face, dry mouth, and dry skin with cessation of sweating. To suppress airway secretions, some give intravenous doses up to 2 mg every hour. Glycopyrrolate can be added to atropine. Oxime therapy is also recommended in seriously ill patients. These compounds reactivate acetylcholinesterase and should be given as soon as possible after exposure by continuous intravenous infusion. Solvents and Organic Compounds Hexacarbon neuropathy results from mixtures that produce 2,5-hexanedione. Outbreaks arise from industrial exposure to n-hexane, recreational abuse, and industrial exposure to methyl-n-butyl ketone. Paresthesias and weakness appear distally in the legs and only later are the hands affected. Acutely, the syndrome may resemble

the Guillain-Barré syndrome, including slow conduction velocity. Alternatively, progression may be slow. Optic neuropathy is rare. The characteristic pathologic change is neurofilamentous axonal swelling and distal axonal degeneration. Effective measures have been taken to reduce industrial exposure and to eliminate the toxins from glues formerly used for glue sniffing. Epidemics have largely disappeared. Other organic compounds that induce axonal neuropathy by industrial exposure are acrylamide, carbon disulfide, methyl bromide, and triorthocresyl phosphate. A current debate is whether house painters are at risk for solvent-induced behavioral disorders. Carbon Monoxide Carbon monoxide intoxication is more often deliberate than accidental, about 600 a year accidentally in the United States and 5 to 10 times more often in suicide attempts. Accidents are caused predominantly by automobile exhausts and poorly ventilated gasoline-powered heaters. Methylene chloride, a paint remover, is another source. Toxicity results from issue hypoxia and direct damage to cellular structures. CO competes with oxygen for binding to hemoglobin; it binds to other proteins, including myoglobin and cytochrome c oxidase. Symptoms may be mild, simulating viral infection, or it may occur with another emergency, smoke inhalation. Nonspecific symptoms may comprise headache, malaise, dizziness, nausea, difficulty concentrating, and dyspnea. A delayed neuropsychiatric syndrome may follow acute exposure by 3 to 240 days, with cognitive and personality changes, parkinsonism, and psychotic behavior. Although the syndrome seems ominous, 50% to 75% of patients recover. Diagnosis is made by finding high levels of carboxyhemoglobin. However, serum levels may have fallen by the time the patient reaches the emergency room. Measurement of CO in expired air can therefore be useful. Blood taken at the scene by emergency technicians can be used. Rescue from fires is of prime importance. Hospital admission is reserved for the more seriously affected or those with other medical problems. Oxygen is administered because it shortens the half-life of carboxyhemoglobin. Hyperbaric oxygen therapy has been used with increasing frequency, but it is uncertain whether it hastens recovery or reduces the rate of late sequelae. Coma is a clear indication for hyperbaric therapy. Prevention is largely a matter of monitoring equipment, monitoring workers, and education about the hazards of running a motor vehicle in a closed space. Nitrous Oxide Myelopathy (Layzer Syndrome) In 1978, Layzer described 15 patients; 14 were dentists. Thirteen had abused nitrous oxide for 3 months to several years; 2 patients had been exposed only professionally, working in poorly ventilated offices. Symptoms included early paresthesias, Lhermitte symptoms, ataxia, leg weakness, impotence, and sphincter disturbances. Examination showed signs of sensorimotor polyneuropathy, often combined with signs implicating the posterior and lateral columns of the spinal cord in a pattern identical to that of subacute combined system disease (SCD) due to B 12 deficiency. Electrodiagnostic tests showed axonal polyneuropathy; cerebrospinal fluid and other laboratory results were normal. Layzer surmised that the gas interfered with the action of B 12. Subsequent experience proved him correct. Additional cases were reported in abusers of nitrous oxide, and improvement was seen in weeks or months after exposure ceased. Another version of the disorder was seen in people, including a vegetarian, who had hematologic evidence of B 12 deficiency but were asymptomatic until the neurologic disorder was precipitated by nitrous oxide anesthesia for surgery. Magnetic resonance imaging shows the characteristic distribution of lesions in the spinal cord. Scott et al. (1981) reproduced the syndrome by maintaining monkeys in an atmosphere of nitrous oxide. If the diet was supplemented with methionine, the disorder was prevented, but in controls, symptoms progressed to a moribund state; the spinal cord and peripheral nerves of the unsupplemented monkeys showed changes of SCD. Inability to resynthesize methionine from homocysteine seemed responsible, and the primary lesion producing SCD in humans with pernicious anemia may also be impaired synthesis of methionine biosynthesis. Cyanocobalamin is involved in the conversion of l-methylmalonyl coenzyme A to succinyl coenzyme A and the formation of methionine by methylation of homocysteine, a reaction essential for DNA synthesis and for maintenance of the myelin sheath by the methylation of myelin basic protein. Active vitamin B 12 contains cobalt and nitrous oxide produces irreversible oxidation of the Co 2+, rendering B12 inactive. Seafood Intoxication Ciguatera or the marine neurotoxic syndrome is the most common nonbacterial form of food poisoning in the United States and Canada. It is caused by eating tropical reef fish that contain several toxins in edible parts; the toxins are thought to arise in dinoflagellates. It is endemic in subtropical regions, and food shipped to other parts of the world spreads the disease. The acute symptoms are gastrointestinal followed by sensory symptoms, paresthesias, and pruritus. “Sensory inversion” describes the peculiarity that cold feels hot and vice versa. Myalgia, fasciculations, areflexia, trismus, and carpopedal spasm may be noted. Respiratory failure is exceptional. Other systems may be involved prominently, including pain on sexual activity. None of the physical findings is diagnostic, and there are no formal criteria for diagnosis. Most associated toxins open sodium channels, but at least one affects calcium channels. Peripheral nerve conduction velocities are often slow. Bioassays for the ciguatoxins or immunochemical methods are being developed, but none has yet achieved approval by consensus. Treatment is therefore symptomatic. Shellfish poisoning can result from contamination of mollusks by saxitoxin, which blocks sodium channels. The symptoms are similar to ciguatera but more severe, and respiratory depression is a threat. The toxin originates in a dinoflagellate. In the series of De Carvalho et al. (1998), cerebellar ataxia was the dominant finding and peripheral nerve conduction was normal. Recovery was rapid in those patients, but among those described by Gessner et al., 3 of 11 patients were treated with mechanical ventilation and 1 died. Hypertension was also prominent. Binding assays and liquid chromatography identified the toxin in serum and urine. In Japan, the agent of puffer fish poisoning is tetrodotoxin. Treatment of these conditions is symptomatic. Methanol (Methyl Alcohol) Methanol intoxication is seen in drinkers who take it as a substitute for ethanol. Acute poisoning was dominated by gastrointestinal symptoms, drunkenness, and coma. Severe acidosis results from the conversion of methanol to formaldehyde and formic acid. Viscera and brain show petechial hemorrhages and edema. In the series of Liu et al. (1998), the mortality rate was 36%; coma, seizures, and high methanol concentrations were predictors of poor prognosis. Visual loss is attributed to retinal metabolism of methanol (rather than an action of circulating formic acid) because the local oxidation of methanol to formic acid parallels the depletion of retinal ATP. Retinal glial cells may be the first target. It has therefore been suggested that inhibitors of aldehyde dehydrogenase could be therapeutic; here it would mean the administration of ethanol to block the first step of the toxic metabolic pathway. For similar reasons, administration of ethanol blocks the metabolism of methanol in the liver and unchanged toxin is excreted in the urine. 4-Methylpyrazole (fomepizole) has also been used for this purpose. Correction of acidosis and hemodialysis may be used. Exposure to large amounts is fatal within 72 hours. Vision is usually restored in survivors, who incur no other chronic neurologic symptoms. Obsolete Epidemics Many syndromes described here could be eliminated if care were taken to protect the environment. In fact, some epidemics pointed the way to correction. For instance, the outbreak of subacute myelo-optic neuropathy was attributed to an oral antiparasitic agent, clioquinol. The resulting peripheral neuropathy and blindness affected an estimated 10,000 people in Japan. The practice has ceased, and there have been no new cases; investigations indicate that the drug is converted to a potent mitochondrial toxin. Another transient outbreak was the eosinophilia-myalgia syndrome, which involved skin, muscle, lungs, and blood vessels and axonal neuropathy. The disorder was attributed to a toxic contaminant in the preparation of tryptophan, which was taken as a health supplement. That syndrome has also largely disappeared, but it seems likely that new epidemics will appear as new industries and new health fads arise. SUGGESTED READINGS General Baker EL, Feldman RG, French JG. Environmentally related disorders of the nervous system. Med Clin North Am 1990;74:325–345.

Bleecker ML, ed. Occupational neurology and clinical neurotoxicology. Baltimore: Williams& Wilkins, 1994. Feldman RG. Occupational and environmental neurology. Baltimore: Lippincott Raven, 1998. Goyer RA, Klaassen CD, Waalkes MP. Metal toxicology. San Diego: Academic Press, 1995. Kuncl RW, George EB. Toxic neuropathies and myopathies. Curr Opin Neurol 1993;6:695–704. Rom WN, ed. Environmental and occupational medicine, 3rd ed. Philadelphia: Lippincott Raven, 1998. Slikker W, Chang W, eds. Handbook of developmental neurotoxicology. New York: Academic Press, 1998. Spencer PS, Schaumburg HH, Ludolph A. Experimental and clinical neurotoxicology, 2nd ed. New York: Oxford University Press, 1999. Weiss B, O'Donaghue J. Neurobehavioral toxicity. Analysis and intervention. New York: Raven Press, 1994. Aluminum Alfrey AC, Le Gendre GR, Kaehny WD. The dialysis encephalopathy syndrome: possible aluminum intoxication. N Engl J Med 1976;294:184–188. Cannata JB, Briggs JD, Junor BJR, et al. Aluminum hydroxide intake: real risk of aluminum toxicity. Br Med J 1983;286:1937–1938. Garruto RM, Strong MJ, Yanagihara R. Experimental models of aluminum induced motor neuron degeneration. Adv Neurol 1991;56:327–340. Longstreth WT Jr, Rosenstock L, Heyer NJ. Potroom palsy? Neurologic disorders in three aluminum smelter workers. Arch Intern Med 1985;145:1972–1975. Murray JC, Tanner CM, Sprague SM. Aluminum neurotoxicity: a re evaluation. Clin Neuropharmacol 1991;14:179–185. Rastegar A. Dialysis dementia. Neurobase. La Jolla, CA: Arbor, 1999. Van Der Voet GB, Marani E, Tio S, et al. Aluminum neurotoxicity. Prog Histochem Cytochem 1991;23:235–241. White DM, Longstreth WT Jr, Rosenstock L, et al. Neurologic syndrome in 25 workers from an aluminum smelting plant. Arch Intern Med 1992;152:1443–1448. Arsenic Aposhian HV. DMSA and DMPS—water soluble antidotes for heavy metal poisoning. Annu Rev Pharmacol Toxicol 1983;23:193–215. Beckett WS, Moore JL, Keogh JP, et al. Acute encephalopathy due to occupational exposure to arsenic. Br J Ind Med 1986;43:66–67. Gerhardt RE, Crecelius EA, Hudson JB. Moonshine related arsenic poisoning. Arch Intern Med 1980;140:211–213. Huang SY, Chang CS, Tang JL, et al. Acute and chronic arsenic poisoning associated with treatment of acute promyelocytic leukemia. Br J Haematol 1998;103:1092–1095. Nickson R, McArthur J, Burgess W, et al. Arsenic poisoning of Bangladesh groundwater [letter]. Nature 1998;395:338. Quecedo E, Samartin O, Ferber MI, et al. Mees lines: a clue for the diagnosis of arsenic poisoning [Letter]. Arch Dermatol 1996;132:349–350. Lead Aub, JC, Fairhall LT, Minot A, et al. Lead poisoning. Medicine (Baltimore) 1925;4:1–250. Boothby JA, deJesus PV, Rowland LP. Reversible forms of motor neuron disease—lead “neuritis.” Arch Neurol 1974;31:18–23. Byers RK. Lead poisoning, review of the literature and report of 45 cases. Pediatrics 1959;23:585–603. Davoli CT. Childhood lead poisoning. Neurobase. La Jolla, CA: Arbor, 1999. Lifshitz M, Hashkanazi R, Phillip M. The effect of 2,3 dimercaptosuccinic acid in the treatment of lead poisoning in adults. Ann Med 1997;29:83–85. Needleman HL. Lead at low dose and the behavior of children. Acta Psychiatr Scand 1983;303[Suppl]:38–48. Pinkle JL, Brody DJ, Gunter EW, et al. The decline in blood lead levels in the United States. JAMA 1994;272:284–291. Porru S, Alessio L. The use of chelating agents in occupational lead poisoning. Occup Med 1996;46:41–48. Preuss HG. A review of persistent, low grade lead challenge: neurological and cardiovascular consequences. J Am Coll Nutr 1993;12:246–254. Rutter M. Raised lead levels and impaired cognitive/behavioural functioning: a review of the evidence. Dev Med Child Neurol 1980;42[Suppl]:1–36. Ryan D, Levy B, Pollack S, Walker B Jr. Protecting children from lead poisoning and building healthy communities. Am J Public Health 1999;89:822–827. Silbergeld EK. Preventing lead poisoning in children. Annu Rev Public Health 1997;18:187–210. Staudinger KC, Roth VS. Occupational lead poisoning. Am Fam Physician 1998;57:719–726, 731–732. Warren MJ, Cooper JB, Wood SP, Shoolingin Jordan PM. Lead poisoning, haem synthesis, and 5 aminolevulinic acid dehydratase. Trends Biochem Sci 1998;23:217–221. Manganese Abd El Naby S, Hassanein M. Neuropsychiatric manifestations of chronic manganese poisoning. J Neurol Neurosurg Psychiatry 1965;28:282–288. Aschner M, Aschner JL. Manganese neurotoxicity: cellular effects and blood brain barrier transport. Neurosci Behav Rev 1991;15:333–340. Canavan MM, Cobb S, Drinker CK. Chronic manganese poisoning. Arch Neurol Psychiatry 1934;32:501–512. Chandra SV. Psychiatric illness due to manganese poisoning. Acta Psychiatr Scand 1983;303[Suppl]:49–54. Huang C, Chu NS, Lu CS, et al. Long term progression in chronic manganism;10 years of follow up. Neurology 1998;50:698–700. Rosenstock HA, Simons DG, Meyer JS. Chronic manganism. Neurologic and laboratory studies during treatment with levodopa. JAMA 1971;217:1354–1358. Schuler P, Oyanguren H, Maturana V, et al. Manganese poisoning. Environmental and medical study at a Chilean mine. Ind Med Surg 1957;26:167–173. Mercury Adams CR, Ziegler DK, Lin JT. Mercury intoxication simulating amyotrophic lateral sclerosis. JAMA 1983;250:642–643. Albers JW, Kallenbach LR, Fine LJ, et al. Neurologic abnormalities and remote occupational elemental mercury exposure. Ann Neurol 1988;24:651–659. Eto K. Pathology of Minamata disease. Toxicol Pathol 1997;25:614–623. Eyl TB. Organic mercury food poisoning. N Engl J Med 1971;284:706–709.

Haley RM, Hom J, Roland PS, et al. Evaluation of neurologic function in Gulf War veterans: a blinded case control study. JAMA 1997;277:259–261. Hay WJ, Rickards AG, McMenemey WH, et al. Organic mercurial encephalopathy. J Neurol Neurosurg Psychiatry 1963;26:199–202. Korogi Y, Takahashi M, Okajima T, Eto K. MR findings of Minamata disease—organic mercury poisoning. J Magn Reson Imaging 1998;8:308–316. Kurland LT, Faro SN, Siedler H. Minamata disease. World Neurol 1960;1:370–390. Thallium Bank WJ, Pleasure DE, Suzuki K, et al. Thallium poisoning. Arch Neurol 1972;26:456–464. Mahoney W. Retrobulbar neuritis due to thallium poisoning from depilatory cream. JAMA 1932;98:618–620. Nordentoft T, Andersen EB, Mogensen PH. Initial sensorimotor and delayed autonomic neuropathy in acute thallium poisoning. Neurotoxicology 1998;19:421–426. Passarge C, Wieck HH. Thallium polyneuritis. Fortschr Neurol Psychiatr 1965;33:477–557. Rambar AC. Acute thallium poisoning. JAMA 1932;98:1372–1373. Rauws AG, van Heyst AN. Check of Prussian blue for antidotal efficacy in thallium intoxication [Letter]. Arch Toxicol 1979;43:153–154. Shabalina LP, Spiridonova VS. Thallium as an industrial poison (review of literature). J Hyg Epidemiol Microbiol Immunol 1979;23:247–255. Smith DH, Doherty RA. Thallotoxicosis: report of three cases in Massachusetts. Pediatrics 1964;34:480–490. Stein MD, Perlstein MA. Thallium poisoning. Am J Dis Child 1959;98:80–85. Methyl Alcohol Bennet IL Jr, Cary FM, Mitchell GL, et al. Acute methyl alcohol poisoning: a review based on experience in an outbreak of 323 cases. Medicine (Baltimore) 1953;32:431–463. Burns MJ, Graudins A, Aaron CK, McMartin K, Brent J. Treatment of methanol poisoning with intravenous 4 methylpyrazole. Ann Emerg Med 1997;30:829–832. Harrop GA Jr, Benedict EM. Acute methyl alcohol poisoning associated with acidosis. JAMA 1920;74:25–27. Liu JJ, Daya MR, Carrasquillo O, Kales SN. Prognostic factors in patients with methanol intoxication. J Toxicol Clin Toxicol 1998;36:175–181. Organic Solvents Allen N, Mendell JR, Billmaier DJ, et al. Toxic polyneuropathy due to methyl n butyl ketone. Arch Neurol 1975;32:209–218. Baker EL, Fine LJ. Solvent neurotoxicity: the current evidence. J Med 1986;28:126–129. Griffin JW. Hexacarbon neuropathy. Neurobase. La Jolla, CA: Arbor, 1999. Juntunen J, Matikainen E, Antti Poika M, et al. Nervous system effects of long term occupational exposure to toluene. Acta Neurol Scand 1985;72:512–517. Lees Haley PR, Williams CW. Neurotoxicity of chronic low dose exposure to organic solvents: a skeptical review. J Clin Psychology 1997;53:699–712. Schaumberg HH, Spencer PS. Clinical and experimental studies of distal axonopathy—a frequent form of brain and nerve damage produced by environmental chemical hazards. Ann N Y Acad Sci 1979;329:14–29. Struwe G. Psychiatric and neurological symptoms in workers occupationally exposed to organic solvents—results of a differential epidemiological study. Acta Psychiatr Scand 1983;303[Suppl]:100–104. Organophosphate Insecticides Choi PT, Quinonez LG, Cook DJ, Baxter F, Whitehead L. The use of glycopyrrolate in a case of intermediate syndrome following acute organophosphate poisoning. Can J Anesth 1998;45:337–340. De Bleeker J. The intermediate syndrome in organophosphate poisoning: an overview of experimental and clinical observations. Clin Toxicol 1995;33:683–686. de Jager AEJ, van Weerden TW, Houthoff HJ, et al. Polyneuropathy after massive exposure to parathion. Neurology 1981;31:603–605. Ecobichon DJ, Davies JE, Doull J, et al. Neurotoxic effects of pesticides. In: Baker SR, Wilkinson CF, eds. The effects of pesticides on human health . Princeton, NJ: Princeton Scientific, 1990:131–199. Ecobichon DJ, Joy RM. Pesticides and neurological diseases, 2nd ed. Boca Raton, FL: CRC Press, 1994. Good JL, Khurana RK, Mayer RF, et al. Pathophysiological studies of neuromuscular function in subacute organophosphate poisoning induced by phosmet. J Neurol Neurosurg Psychiatry 1993;56:290–294. Landrigan P. Illness in Gulf War veterans. JAMA 1997;277:238–245. Lotti M, Moretto A, Zoppelari R, et al. Inhibition of lymphocytic neuropathy target esterase predicts the development of organophosphate induced delayed polyneuropathy. Arch Toxicol 1986;59:176–179. Moretto A, Lotti M. Poisoning by organophosphorus insecticides and sensory neuropathy. J Neurol Neurosurg Psychiatry 1998;64:463–468. Morgan JP, Penovich P. Jamaica ginger paralysis. 47 year follow up. Arch Neurol 1978;35:530–532. Singh G, Mahajan R, Whig J. The importance of electrodiagnostic studies in acute organophosphate poisoning. J Neurol Sci 1998;157:191–200. Steenland K, Jenkins B, Ames RG, et al. Chronic neurologic sequelae to organophosphate pesticide poisoning. Am J Public Health 1994;84:731–736. Taylor JR, Selhorst JB, Houff S, et al. Chlordecone intoxication in man. Neurology 1978;28:626–630. Thiermann H, Mast U, Klimmeck R, et al. Cholinesterase status, pharmacokinetics, and laboratory findings during obidoxime therapy in organophosphate poisoned patients. Hum Exp Toxicol 1997;16:473–480. Tush GM, Anstead MI. Pralidoxime continuous infusion in the treatment of organophosphorus poisoning. Ann Pharmacother 1997;31:441–444. Wadia RS, Chitra S, Amin RB, et al. Neurological manifestations of organophosphate insecticide poisoning. J Neurol Neurosurg Psychiatry 1987;50:1442–1448. Carbon Monoxide Ernst A, Zibrak JD. Carbon monoxide poisoning. N Engl J Med 1998;339:1603–1608. Neurotoxic Seafood Poisoning DeCarvalho M, Jacinto J, Ramos N, et al. Paralytic shellfish poisoning. Clinical and electrophysiological observations. J Neurol 1998;2245:551–554. DiNubile MJ, Hokama Y. The ciguatera poisoning syndrome from farm raised salmon. Ann Intern Med 1995;122:113–114.

Gessner BD, Bell P, Doucette GJ, et al. Hypertension and identification of toxin in human urine and serum following a cluster of mussel associated paralytic shellfish poisoning outbreaks. Toxicon 1997;35:711–722 Payne CA, Payne SN. Ciguatera. Neurobase. La Jolla, CA: Arbor, 1999. Yasumoto T, Satake M. Chemistry, etiology and determination methods of ciguatera toxins. Annu Rev Pharmacol Toxicol 1988;28:141–161. Nitrous Oxide Beltramello A, Puppini G, Cerini R, et al. Subacute combined degeneration of the spinal cord after nitrous oxide anaesthesia: role of magnetic resonance imaging. J Neurol Neurosurg Psychiatry 1998;64:563–564. Flippo TS, Holder WD Jr. Neurologic degeneration associated with nitrous oxide anesthesia in patients with vitamin B

12 deficiency.

Arch Surg 1993;128:1391–1395.

Gutmann L, Farrell B, Crosby TW, Johnsen D. Nitrous oxide induced myelopathy neuropathy: potential for chronic misuse by dentists. J Am Dent Assoc 1979;98:58–59. Hadzic A, Glab K, Sanborn KV, Thys DM. Severe neurologic deficit after nitrous oxide anesthesia. Anesthesiology 1995;83:863–866. Layzer RB. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 1978;2:1227–1230. Pema PJ, Horak HA, Wyatt RH. Myelopathy caused by nitrous oxide toxicity. AJNR 1998;19:894–896. Rosener M, Dichgans J. Severe combined degeneration of the spinal cord after nitrous oxide anaesthesia in a vegetarian [Letter]. J Neurol Neurosurg Psychiatry 1996;60:354. Scott JM, Dinn JJ, Wilson P, Weir DG. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet 1981;2:334–337. Obsolete Epidemics Anonymous. Eosinophilia myalgia syndrome: review and reappraisal of clinical, epidemiologic and animal studies symposium. J Rheumatol 1996;46[Suppl]:1–110. Arbiser JL, Kraeft SK, van Leeuwen R, et al. Clioquinol zinc chelate: a candidate causative agent of subacute myelo optic neuropathy. Mol Med 1998;4:665–670. Burns SM, Lange DJ, Jaffe IA, Hays AP. Axonal neuropathy in eosinophilia myalgia syndrome. Muscle Nerve 1994;17:293–298. Emslie Smith AM, Mayeno AN, Nakano S, Gleich GJ. 1,1 Ethylidenebis [tryptophan] induces pathologic alterations in muscle similar to those observed in the eosinophilia myalgia syndrome. Neurology 1994;44:2390–2392. Martin RW, Duffy J, Engel AG, et al. The clinical spectrum of the eosinophilis myalgia syndrome associated with l-tryptophan ingestion. Ann Intern Med 1990;113:124–134.

CHAPTER 162. ABUSE OF CHILDREN MERRITT’S NEUROLOGY

CHAPTER 162. ABUSE OF CHILDREN CLAUDIA A. CHIRIBOGA Pediatric Acquired Immunodeficiency Syndrome and Human Immunodeficiency Virus Infection Fetal Alcohol Syndrome Fetal Cocaine Effects The Battered Child Suggested Readings

PEDIATRIC ACQUIRED IMMUNODEFICIENCY SYNDROME AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION Woman and children are the fastest-growing population affected by the acquired immunodeficiency syndrome (AIDS) and the human immunodeficiency virus (HIV). Most children with AIDS in the United States are infected perinatally. In inner cities, about 2% to 4% of live births are HIV-1 antibody positive. Intravenous drug abuse and sexual contact with HIV-infected partners are the maternal risk factors in more than 85% of perinatal cases. Most infections occur during the last trimester of pregnancy and time of delivery. Risk factors for vertical transmission are recent maternal HIV seroconversion, high viral load, and maternal AIDS. Premature infants are also at increased risk of infection. Infection may result from exposure to blood and other body fluids at delivery or transmitted in breast milk. Mother-to-child HIV transmission rates range from 14% to 30%; rates decrease to 8% with prenatal and neonatal zidovudine treatment. Determination of HIV infection in children is complicated because maternal HIV antibody transfers across the placenta and may persist up to age 18 months. HIV-seropositive children are considered HIV infected if they test positive for HIV on two separate occasions by either HIV culture or HIV polymerase chain reaction (PCR) or if they develop AIDS. HIV-seropositive children who do not meet these criteria are considered perinatally exposed, and HIV-seropositive children without AIDS and without laboratory evidence of infection who on testing after age 6 months have negative antibody are seroreverters. The 1994 revised classification system for HIV infection in children has four clinical categories: N, not symptomatic; A, mildly symptomatic; B, moderately symptomatic; and C, severely symptomatic, which includes all AIDS-defining conditions except lymphoid hyperplasia ( Table 162.1). These clinical categories are further classified immunologically depending on the child's age and absolute CD4 count: no evidence of suppression, moderate suppression, and severe suppression ( Table 162.2). For example, A2 indicates mild signs and symptoms of infection with moderate immunosuppression.

TABLE 162.1. REVISED CENTERS FOR DISEASE CONTROL AND PREVENTION CLINICAL CATEGORIES FOR CHILDREN WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION

TABLE 162.2. IMMUNOLOGICAL CATEGORIES BASED ON CHILD'S AGE-SPECIFIC CD4 + T LYMPHOCYTE COUNT AND PERCENT OF TOTAL LYMPHOCYTES

Diagnostic Tests Because of early testing, most HIV-positive children are identified soon after birth. Viral load (i.e., quantified HIV DNA or RNA PCR) is more sensitive than viral cultures and p24 antigen in identifying HIV infection in asymptomatic newborns and infants. By age 4 to 6 months, over 95% of HIV-infected children are identified by a positive PCR. In newborns, a negative PCR test for HIV does not exclude infection but decreases the risk of HIV infection to 3%. Viral load runs higher in asymptomatic children than in asymptomatic adults. Sustained high viral load in adults predicts progression to AIDS. High viral loads in early infancy predict early onset of symptomatic HIV disease. HIV-1 syncytial-inducing phenotypes are linked to aggressive early symptomatic disease. Clinical Manifestations Mild HIV infection includes diarrhea, unexplained persistent fever, lymphadenopathy, and parotitis. Table 162.1 lists the range of signs of symptomatic HIV infection. Lymphoid interstitial pneumonitis and recurrent bacterial infections are seen in children with AIDS but not in adults. Severe manifestations in early infancy, such as progressive encephalopathy or opportunistic infections (e.g., Pneumocystis carinii), carry a poor prognosis for survival. Mechanism of Action HIV infection is maintained by viral persistence in helper T lymphocytes and macrophages. HIV strains with tropism for monocyte-derived macrophages have a predilection to infect cerebral vascular endothelium and central nervous system (CNS). Infected macrophages traverse the blood–brain barrier and infect microglial cells; neurons are spared from direct infestation. Nonproductive infection of astrocytes is reported, but infection of other glial cells has not been firmly established. Neuronal dropout is seen as the disease advances, but it is not known how HIV induces neural damage. Postulated mechanisms include release of soluble neurotoxins by HIV-infected macrophages and lymphocytes (e.g., cytokines, quinolinic acid, viral antigens, or undefined viral products), neurotoxin amplification by astrocyte–macrophage interaction, and impaired blood–brain barrier function secondary to HIV-related endothelial damage. These neurotoxins are thought to produce a reversible metabolic encephalopathy that may disappear with effective antiretroviral treatment. Children with HIV encephalopathy who respond to antiretroviral therapy may show nonprogressive corticospinal tract sequelae.

Pathology Glial nodules and endothelial hyperplasia with calcification, dystrophic calcification, and perivascular mononuclear inflammation are common pathologic findings of subacute encephalitis in HIV-infected brains. The glial nodule comprises a cluster of chronic inflammatory cells in the neurophil and is often associated with multinucleated giant cells that are presumed to arise from coalescent microglia. Human Immunodeficiency Virus Encephalopathy Two types of encephalopathy are seen in children: progressive and static. The evolution of the progressive encephalopathy may be fulminant, inexorably progressive, or stepwise. Progressive encephalopathy is characterized by loss of developmental milestones, progressive pyramidal tract dysfunction, and acquired microcephaly or impaired brain growth. The static encephalopathy is less well defined, and not all cases may be HIV induced. The neurologic abnormalities commonly include abnormalities of muscle tone, hyperreflexia, clonus, and impaired head growth. Hypotonia with corticospinal tract dysfunction may be seen in infants early in the course of the encephalopathy and evolves into a spastic diparesis; with newer antiretroviral treatments, progression to a spastic tetraparesis, with or without pseudobulbar palsy, is seldom seen. Ataxia and rigidity are uncommon. Progressive neurologic dysfunction is the first evidence of progression to AIDS in 10% of infected children. There is always evidence of underlying HIV infection, such as immunologic compromise (low CD4 counts) or high viral load, at the time of onset of neurologic symptoms. Many infected children exhibit global developmental delay, regardless of neurologic findings. In young children, motor development is more impaired than mental development. The incidence of neurologic abnormalities reported in HIV-infected cohorts before the advent of antiretroviral treatments was 30%. Older HIV-infected children may show problems in visual-spatial processing functions and expressive language and may develop AIDS-dementia complex indistinguishable from that described in adults. HIV-associated myelopathy, polyneuropathy, and myopathy are rare in children. Spinal cord pathology shows demyelinating changes of the corticospinal tracts, vacuolar changes, or myelitis attributable to HIV. Acute inflammatory demyelinating polyneuropathy is a rare complication in pediatric HIV. Low-dose treatment with dideoxyinosine causes a painful sensory neuropathy in less than 10% of patients treated. The neuropathy is dose related and usually reverts with cessation of treatment. The mitochondrial myopathy induced by zidovudine has not been seen in children. Focal Manifestations HIV brain infection is nonfocal and subcortical. Seizures are not common. Focal signs or seizures raises the possibility of neoplasm, strokes, or, less likely, opportunistic infections. Primary Central Nervous System Lymphoma This is the most common cause of focal cerebral signs in HIV- infected children, found in 3% to 4% of cases. Seizures are reported in about 33% of patients. It may be difficult to differentiate this tumor from toxoplasma brain abscess; diagnosis requires brain biopsy. Magnetic resonance imaging (MRI) spectroscopy may prove helpful in distinguishing CNS toxoplasmosis from lymphoma. Stroke HIV infection produces inflammation of cerebral vessels, increasing the risk of stroke, which occurs at a rate of 1.3% a year in HIV-infected children. More than 50% of strokes are hemorrhagic and occur with thrombocytopenia (especially immune thrombocytopenic purpura) or CNS neoplasia. Nonhemorrhagic stroke and subarachnoid hemorrhage are attributable to an arteriopathy affecting the large vessels of the circle of Willis or meninges. HIV-related strokes may be clinically silent, so the true incidence is probably higher. Opportunistic Central Nervous System Infection Compared with adults, opportunistic CNS infection is infrequent in HIV-infected children, affecting primarily older children and adolescents. Only a few have had progressive multifocal leukoencephalopathy. Imaging In children with HIV encephalopathy, computed tomography or MRI may show diffuse cerebral atrophy or may be normal. There may be foci of demyelination. Frontal lobe or basal ganglia enhancement and calcifications are late manifestations of HIV encephalopathy and occur primarily in symptomatic infants ( Fig. 162.1). HIV-related myelopathy on spinal MRI may show a high signal but is usually normal. Bilateral cerebral lesions may mimic myelopathy and must be excluded with MRI or computed tomography. Lesions of progressive multifocal leukoencephalopathy are commonly located in the parietooccipital or frontal region affecting both periventricular and subcortical white matter. These lesions may be difficult to distinguish from HIV demyelination.

FIG. 162.1. Computed tomography of an infant with human immunodeficiency virus encephalopathy showing cortical and subcortical atrophy, basal ganglia, and frontal lobe calcifications. (Courtesy of Dr. Ram Kairam.)

Cerebrospinal Fluid Cerebrospinal fluid (CSF) examination is commonly normal in children with HIV infection. In the absence of opportunistic infection, CSF findings in children with progressive encephalopathy are nonspecific, with a lymphocytic pleocytosis and elevated protein content. Intra-blood–brain barrier synthesis of HIV-specific antibody or antigen detection in CSF has not been useful in predicting encephalopathy. CSF viral load, although still experimental, may prove useful in determining HIV encephalopathy in children. Antiretroviral Therapy Combination antiretroviral therapy is needed to avoid emergence of resistant HIV strains. Triple combination antiretroviral therapies that include a protease inhibitor are effective in diminishing viral load and suppressing active viral replication. This in turn correlates with increases in CD4 count, weight gain, improved morbidity

(including CNS symptomatology), and mortality. Whether high systemic viral load predicts the development of HIV encephalopathy has not been firmly established.

FETAL ALCOHOL SYNDROME The fetal alcohol syndrome (FAS) affects children of chronic alcoholic women but also occurs with binge drinking, as defined by five drinks or more on one occasion. Fetal susceptibility to the effects of alcohol is greatest during the first trimester of pregnancy. FAS is characterized by abnormalities of growth, CNS, and facial features; birth defects are common (Table 162.3). FAS rates in the United States are 2 to 4 per 1,000 live births and 2% to 4% among children of alcohol-abusing women. FAS is confined to infants of alcohol-abusing women. Most children with FAS are mildly or moderately retarded, with mean IQ scores of 65 to 70, but intellectual ability varies widely. In families with several affected siblings, the youngest child is usually the most cognitively impaired. Learning disabilities—in particular difficulty with arithmetic, speech delay, and hyperactivity—are commonly observed.

TABLE 162.3. FETAL ALCOHOL SYNDROME

Less severe alcohol-related effects are associated with wide patterns of drinking. These fetal alcohol effects are probably a lower point on the continuum of alcohol effects on the fetus. Maternal alcohol abuse is associated with increased risk of spontaneous abortions, infant mortality, intrauterine growth retardation, and prematurity. Birth defects are common. Minor or major congenital anomalies occur in about a third of infants born to heavy drinkers, compared with 9% of minor anomalies in infants of women who abstain from alcohol. Depressed birth weight has been seen with ingestion of as little as 100 g of alcohol a week (about 1 drink a day); hampered brain growth may be seen with 20 mL (1.5 drinks) a day. Decrease of alcohol intake during pregnancy is beneficial to the offspring, reducing rates of growth retardation and dysmorphic features. Heavy alcohol exposure prenatally, but not mild or moderate exposure, has been linked to decrease in IQ scores, hyperactive behavior, attention problems, learning difficulties, and speech disorders. Postnatal Alcohol Exposure Alcohol transferred through breast milk impairs motor development but not mental development at age 1 year. Ingestion of alcohol by children may lead to hypoglycemic seizures. Withdrawal Syndrome Infants born to women who drink large amounts of alcohol during pregnancy may rarely exhibit signs of withdrawal. Restlessness, agitation, tremulousness, opisthotonus, and seizures are seen shortly after birth and disappear within a few days.

FETAL COCAINE EFFECTS In U.S. cities, about 1 in every 10 newborns is exposed prenatally to cocaine. The long-term consequences of fetal cocaine exposure to the developing nervous system are not well known. Cocaine use during pregnancy has been linked to spontaneous abortion, abruptio placentae, stillbirth, and premature delivery. These events may immediately follow large intakes of cocaine and are attributed to drug-induced vasoconstriction of intrauterine vessels. Women who use cocaine tend to resort to prostitution, increasing risks for syphilis and HIV. They also tend to lack prenatal care, adding to the risks of infant death, low birth weight, and prematurity. Low birth weight and intrauterine growth retardation are common among cocaine-exposed infants. Fetal brain growth is impaired independently of birth weight or gestational age. Sudden infant death syndrome has also been linked to cocaine exposure in utero. Neurobehavior State regulation difficulties are well described among cocaine-exposed newborns, although findings are inconsistent. Some reports describe irritability, excitability, poor feeding, and sleep disturbances among cocaine and cocaine/methamphetamine infants, whereas others describe decreased organizational response and interactive behavior, even if the exposure to cocaine was limited to the first trimester of pregnancy. Modulation of attention is impaired among cocaine-exposed infants who, unlike unexposed infants, prefer higher rates of stimuli when in a high level of arousal. Exposed infants also show motor and movement abnormalities, including excessive tremor and hypertonia. Dose-response effects of cocaine on state regulation and neurologic findings are reported in newborns. Some studies show no neurobehavioral effects, however. Strokes Experimentally, cocaine has a vasoconstrictive effect on fetal cerebral vessels and decreases cerebral blood flow. Neonatal stroke and porencephaly have been associated with prenatal cocaine exposure. Some cases may be related to other neonatal stroke risk factors that accompany fetal cocaine exposure, such as abruptio placentae or birth asphyxia. Intracranial hemorrhage was not associated with cocaine in a prospective study of prematures. Seizures Focal seizures may occur in cocaine-exposed newborns with strokes. Electroencephalograms in cocaine-exposed infants show bursts of sharp waves and spikes that are often multifocal. These findings do not correlate with clinical seizures or neurologic abnormalities and may disappear in 3 to 12 months. Cocaine-exposed premature infants are at increased risk of neonatal seizures. Seizures are rare if there is no stroke. Malformations Prenatal cocaine exposure has been linked with urogenital malformations, limb reduction deformities, and intestinal atresia and infarction. Agenesis of the corpus callosum and septooptic dysplasia have also been noted. These teratogenic effects may result from cocaine-induced vasoconstriction and fetal vascular disruption in early organogenesis. Neurodevelopmental Impact In experiment models, prenatal cocaine has been reported to affect serotonin, norepinephrine, and dopaminergic systems. Lower CSF levels of homovanillic acid found in human newborns exposed to cocaine suggest dopaminergic involvement. In infancy, there may be a high incidence of spastic tetraparesis and diparesis that resolves by age 24 months (Table 162.4). In toddlers and school-aged children, prenatal cocaine exposure did not decrease cognitive abilities, except as mediated

through cocaine effects on brain growth. Cocaine-exposed children seem to suffer from an excess of neurobehavioral abnormalities, including irritability, impulsivity, and aggressive behavior, which may reflect coexisting maternal psychopathology rather than direct cocaine effects.

TABLE 162.4. COCAINE-RELATED EFFECTS

Cocaine Exposure in Childhood Passive intoxication with cocaine may be caused by breast-feeding or passive inhalation of free-base cocaine (“crack”). Seizures are the chief manifestation of symptomatic intoxication, but intoxication may be unsuspected. Urine toxicology screen to detect illicit substances is indicated in evaluating seizures in infants and children, regardless of socioeconomic status. Withdrawal Symptoms There is no evidence of a cocaine-induced withdrawal syndrome. Even with remote prenatal cocaine exposure, cocaine-exposed infants may show hypertonicity and tremor, which are probably cerebral manifestations of fetal cocaine effects.

THE BATTERED CHILD Child abuse may be physical or psychological. Physical abuse includes skin burns, welts, bruises, bone fractures, head trauma, and failure to thrive. Psychological abuse frequently accompanies physical abuse and may lead to growth, behavioral, and developmental impairments. The shaken baby syndrome, an increasingly recognized form of physical abuse, is characterized by bilateral subdural hematomas or subarachnoid hemorrhage, retinal hemorrhages, and the absence of external signs of trauma. It is seen in infants mostly under age 1 year who are shaken repeatedly and violently. The aggressor, usually a parent, shakes the crying infant until he or she quiets and later denies doing so. Depressed mental status, seizures, and signs of increased intracranial pressure are common. Neurogenic pulmonary edema may occur rarely. Bilateral retinal hemorrhages, in the absence of a coagulopathy, are the most specific signs of shaken baby syndrome. Hemorrhages may be flame shaped, round and intraretinal, preretinal, or vitreal. The speed with which blood disappears varies by type: Flame-shaped hemorrhage disappears within a few days, but round intraretinal hemorrhage may last 2 weeks. Retinal folds occasionally are seen. A dilated funduscopic examination should be performed quickly in any child with suspected child abuse to identify retinal hemorrhages before they disappear. Shaken baby syndrome should be suspected with sudden infant death syndrome or near-miss sudden infant death syndrome, with sudden lethargy, with seizures of unknown cause, or if there is a discrepancy between the history and the clinical signs. Broken ribs and chest bruises may be seen in infants held by the chest during shaking, and spiral fractures of the long bones or epiphysial separation may be seen in those shaken by the arms or legs. A skeletal survey showing old fractures helps confirm abuse. Infants with shaken baby syndrome may suffer neurologic sequelae, including hydrocephalus, blindness, developmental delay, mental retardation, microcephaly, and spastic tetraparesis. SUGGESTED READINGS Caffey J. The whiplash shaken baby syndrome: manual shaking by the extremities with whiplashed-induced intracranial and intraocular bleedings, linked with residual permanent brain damage and mental retardation. Pediatrics 1974;54:396–403. Chasnoff IJ, Griffith DR, Freier C, et al. Cocaine/polydrug use in pregnancy. Pediatrics 1992;89:284–289. Chiriboga CA. Neurological correlates of fetal cocaine exposure in cocaine and the developing brain. Ann N Y Acad Sci 1998;846:109–125. Chiriboga CA, Brust JCM, Bateman D, Hauser WA. Dose-response effect of fetal cocaine exposure on newborn neurological function. Pediatrics 1999;103:79–85. Forsyth BW Primary care of children with HIV infection. Curr Opin Pediatr 1995;7:502–512. Gendelman HE, Epstein LG. HIV encephalopathy in children. Curr Opin Pediatr 1995;7:655–662. Park YD, Belman AL, Kim TS, et al. Stroke in pediatric acquired immunodeficiency syndrome. Ann Neurol 1990;28:303–311. Pizzo PA, Wilfert CM. Markers and determinant of disease progression in children with HIV infection. The Pediatric AIDS Siena Workshop II. J Acquir Immune Def Syndr Hum Retrovir 1995;8:30–44. 1994 Revised classification system for human immunodeficiency virus (HIV) infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep 1994;43:RR12. Streissguth AP. Fetal alcohol syndrome: early and long-term consequences. NIDA Res Monogr 1992;119:126–130.

CHAPTER 163. FALLS IN THE ELDERLY MERRITT’S NEUROLOGY

CHAPTER 163. FALLS IN THE ELDERLY LEWIS P. ROWLAND Epidemiology Neurology of Falls Environmental Factors Prevention Suggested Readings

Falls in the elderly are often taken for granted and considered an inevitable consequence of aging. Analysis of the factors that lead to falls, however, raises the possibility of prevention. The problem is certainly serious for individuals, families, and society ( Table 163.1).

TABLE 163.1. FALLS IN THE ELDERLY

EPIDEMIOLOGY It is estimated that 5% to 10% of falls in the elderly result in injury. Most falls occur at home, but the rate of falling is higher in long-term care facilities. Injury is the sixth leading cause of death after age 65, and most injuries result from a fall. Although people over 65 comprise about 12% of the total population, they account for 74% of all deaths caused by falls. Fatality rates increase with age in both men and women ( Table 163.2).

TABLE 163.2. DEATH RATES FROM ACCIDENTAL FALLS IN 1982

The likelihood of admission to a nursing home increases with the number of falls an elderly person has had. Once a person is in a nursing home, the use of antidepressants increases the likelihood of falls. Falls are as likely among those who take selective serotonin reuptake inhibitors as among those taking tricyclics; use of newer drugs does not reduce the higher rates of falling.

NEUROLOGY OF FALLS Few falls seem to be related to syncope, drop attacks, transient ischemic attacks, or overt myopathy. Instead, a propensity to falls is generated by the cumulative handicaps of poor vision, poor balance, unsteady gait, stooped posture, and impaired proprioception. Sensitivity to drugs is another factor; falls are more frequent in people who take more than one drug. Intuitively, it seems likely that the motor impairment of Parkinson disease or previous stroke would increase the likelihood of falls and so would the physical impediments of arthritis or the intellectual failure of dementia. Disequilibrium of unknown cause increases the likelihood of falling. The condition is identified as a triad: Impaired balance is a symptom; gait is impaired on examination; and no cause is discerned by medical, neurologic, and vestibular examination.

ENVIRONMENTAL FACTORS Most falls in the elderly are “accidental.” Examples include missing the last step on descent, slippery surfaces, poor lighting, unexpected appearance of a child or pet, and poorly fitting shoes.

PREVENTION In one study, 46% of fallers were repeaters. The first fall led to loss of mobility and loss of confidence, making the next one more likely. Interventions included walking aids, home nursing visits to assess environmental hazards (including lighting, stairs, bathrooms, and rugs), educating patients, care in taking medications, and physical therapy for gait and balance. The list of medications should be reviewed periodically to be certain that all are needed; this is especially true of all psychoactive drugs. In the Prevention of Falls in the Elderly Trial, these measures reduced the risk of falling and of recurrent falls and the likelihood of hospital admission. Death rates from falls among people over 75 decreased by 50% between 1960 and 1980. SUGGESTED READINGS Avorn J. Depression in the elderly—falls and pitfalls. N Engl J Med 1998;339:918–20. Close J, Ellis M, Hooper R, Glucksman E, Jackson S, Swift C. Prevention of Falls in the Elderly Trial (PROFET): a randomized controlled trial. Fife TD, Baloh RW. Disequilibrium of unknown cause in older people. Ann Neurol 1993;34:694–702.

Lancet 1999;353:93–97.

Kerber KA, Enrietto JA, Jacobson KM, Baloh RW. Disequilibrium in older people: a prospective study. Neurology 1998;51:574–580. Lacomis D, Chad DA, Smith TW. Myopathy in the elderly: evaluation of the histopathologic spectrum and the accuracy of clinical diagnosis. Neurology 1993;43:825–828. Nutt JG, Marsden CD, Thompson PD. Human walking and higher-level gait disorders, particularly in the elderly. Neurology 1993;43:268–279. Saper CB. “All fall down”: the mechanism of orthostatic hypotension in multiple systems atrophy and Parkinson's disease. Ann Neurol 1998;43:149–151. Sorock GS. Falls among the elderly: epidemiology and prevention. Am J Prevent Med 1988;4:282–288. Thajeb P. Gait disorders and multi-infarct dementia. Acta Neurol Scand 1993;87:239–242. Thapa PB, Gideon P, Cost TW, Milam AB, Ray WA. Antidepressants and the risk of falls among nursing homs residents. N Engl J Med 1998;339:875–882. Tinetti ME, Speechley M. Prevention of falls among the elderly. N Engl J Med 1989;320:1055–1059. Tinetti ME, Williams CS. Falls, injuries due to falls and the risk of admission to a nursing home. N Engl J Med 1997;337:1279–1284.

CHAPTER 164. NEUROLOGIC REHABILITATION MERRITT’S NEUROLOGY

SECTION XXIV. REHABILITATION CHAPTER 164. NEUROLOGIC REHABILITATION LAURA LENNIHAN AND GLENN M. SELIGER Occupational Therapy Physical Therapy Dysphagia Therapy Language and Cognitive Therapies Incontinence Therapy Suggested Readings

Neurologic disorders commonly cause temporary or permanent impairments that impede simple daily functions and complex intellectual and physical activities. Neurologists play an important role in prescribing rehabilitation therapies to maximize functional recovery. The proper selection and timing of these therapies make a substantial contribution to optimum quality of life for patient and family despite persistent neurologic impairments. Although it is preferable for rehabilitation to begin soon after a neurologic injury, many people with chronic neurologic conditions have never received adequate rehabilitation therapy. Nevertheless, if they are given proper training and equipment, they may still improve in personal independence, access to the community, or ease with which a caregiver assists them. At a time when neurologists are assuming the role of principal care physicians, experience in neurorehabilitation is essential in the management continuum from acute to chronic neurologic disorders. The World Health Organization definitions of impairment, disability, and handicap ( Table 164.1) provide a structure for understanding the impact of disease on personal independence and integration into society. These criteria help to identify patients who may benefit from rehabilitation. The planning and prescription of a rehabilitation program for a neurologically impaired individual requires characterization of the neurologic disorder with regard to natural history, localization, and extent of nervous system involvement; determination of functional disabilities caused by cognitive and physical impairments; and definition of these disabilities in the context of the patient's physical and social environment. With this information, the type and intensity of rehabilitation therapies can be planned.

TABLE 164.1. WORLD HEALTH ORGANIZATION DEFINITION OF IMPAIRMENT, DISABILITY, AND HANDICAP

Two principal approaches are used in rehabilitation therapy. The first is to bypass the neurologic impediment by teaching adaptive techniques using preserved neurologic function. For example, a person with a paralyzed arm can be trained in one-handed activities using the normal arm. The second approach is to facilitate the return of neurologic function. For example, the person with a paralyzed arm is given tasks to increase effective movement of that arm. Both methods are usually applied in rehabilitation programs. The efficacy of the first approach in improving functional independence and reducing disability is accepted. The second approach is the focus of active clinical research. In a primate model, restraint of the normal arm resulting in forced use of the paretic arm after motor cortex injury leads to better functional recovery of the affected arm than when the normal arm is unrestrained. No functional recovery occurs if the paretic arm is restrained. Case reports in humans similarly support the efficacy of this forced-use paradigm. Gait training on a treadmill while a harness provides partial body weight support is thought to recruit spinal pattern generators for walking. This technique may produce better balance, motor recovery, walking speed, and endurance compared with conventional gait training with patients bearing their full body weight. Current research on the neurobiology of recovery from central nervous system injury and the efficacy of treatments to improve the speed and completeness of recovery is relevant to the practice of neurorehabilitation. For example, norepinephrine plays an important role in modulating central nervous system recovery. In animal models of focal brain injury and in people with strokes, amphetamine administered coincident with physical therapy has resulted in better motor recovery than in placebo-treated subjects. Drugs with central catecholamine antagonist activity, such as haloperidol, prazosin, or clonidine, interfere with motor recovery in animals. Enhancement of activity of the inhibitory neurotransmitter GABA by drugs such as diazapam, phenytoin, or phenobarbital also reduces neurologic recovery in animals. In a retrospective study, stroke patients who received either class of drug had poorer motor recovery than those who did not. Functional outcome is improved by treatment in a comprehensive rehabilitation program. Stroke patients who receive rehabilitation therapies on a stroke rehabilitation unit have better functional outcomes and shorter hospital stays than those treated on a general neurology ward. Similarly, stroke patients admitted to hospital-based acute rehabilitation programs have better functional recovery and are more likely to return home than those treated in a subacute rehabilitation program at a skilled nursing facility. A comprehensive inpatient neurorehabilitation program requires an interdisciplinary team: physician, physical therapist, occupational therapist, speech therapist, neuropsychologist, social worker, and rehabilitation nurse. The physician, as team leader, defines the type and prognosis of the neurologic disorder; is responsible for coordination of rehabilitation services and setting of realistic treatment goals; and provides medical care, especially for the prevention and treatment of complications of a disabling disorder, for instance, deep vein thrombosis or reflex sympathetic dystrophy. The physical therapist's role is to maximize leg function and mobility. The occupational therapist promotes maximum independence in activities of daily living by improving arm function and cognitive skills. The speech therapist characterizes and treats specific language-based cognitive dysfunction and evaluates and treats dysphagia and dysarthria. The neuropsychologist defines cognitive problems and monitors improvement. The rehabilitation nurse, in addition to providing medical nursing care, incorporates into the patients' daily routines skills learned in therapy and institutes treatments to restore sphincter continence. The social worker implements the discharge plan. All team members participate in formulating a discharge plan and in educating and training patient and family in preparation for return home.

OCCUPATIONAL THERAPY Neurologic injury that interferes with use of the arms and hands can be profoundly disabling. Weakness, loss of sensation, ataxia, abnormal tone, and involuntary movements, alone or in combination, can lead to inability to carry out basic activities of daily living, to drive a car, or to work. Occupational therapy promotes recovery from neurologic injury; prevents permanent disability from complications of temporary neurologic impairments, such as wrist-flexor contractures from a radial nerve palsy; teaches new techniques to perform self-care and other tasks; prescribes equipment to increase use of the impaired arm and hand; and, when the impairment is unilateral, teaches performance of one-handed techniques by the normal arm. The approach to restoring function to the neurologically impaired arm is determined in part by central or peripheral site of injury. For example, treatment of weakness caused by an upper motor neuron lesion focuses on reestablishing movement at one joint in isolation from movement at other joints; strengthening exercises follow

later. Strengthening programs are usually instituted early for peripheral injuries, but it is important not to overwork muscles recovering from a nerve injury because weakness may worsen. Wrist and ankle weights can be used to dampen arm and leg ataxia. Improving motor skills is only one of the important components in enhancing performance of the activities of daily living, such as dressing, toileting, washing, grooming, feeding, and community skills. Training to overcome visual and perceptual difficulties, unilateral spatial neglect, memory impairment, inattentiveness, and poor safety judgment may also be important. The occupational therapist selects adaptive equipment and trains patient and family to compensate. Advanced programs may include learning special occupational skills or to drive with the left hand and foot.

PHYSICAL THERAPY Interference with mobility by neurologic disease can be reduced or eliminated by strengthening exercises, gait and balance training, spasticity reduction through stretching or medication, surgical release of shortened tendons, bracing, assistive devices (e.g., cane, walker), and use of a wheelchair. Techniques and orthotics are chosen to maximize safe and independent mobility; to optimize energy efficiency; to prevent decubitus skin ulcers, tendon contractures, and falls; and to enhance recovery. Leg and trunk weakness, impaired postural reflexes, ataxia, proprioceptive loss, and hemineglect may all interfere with walking. Even though a person may not be able to walk immediately after neurologic injury, ambulation usually becomes possible through a combination of bracing at the ankle and sometimes the knee and use of a walker or cane. When ambulation is not possible, mobility is attained through training in the use of a wheelchair of the correct size and height, with a special seat to prevent skin breakdown and cushions for trunk support.

DYSPHAGIA THERAPY Facial, lingual, masticatory, pharyngeal, esophageal, and respiratory muscles participate in swallowing. Neurologic disorders that disturb coordinated contraction of any of these muscles can cause dysphagia and, secondarily, airway obstruction, aspiration pneumonia, and malnutrition. Dysphagia evaluation is indicated for patients with any of these complications; who report coughing, choking, or nasal regurgitation while eating; are dysarthric; or have a disease commonly associated with dysphagia, such as motor neuron disease or myasthenia gravis. This evaluation includes characterization of the neurologic disorder and bedside and fluoroscopic observation of swallowing foods of different consistencies, from thin liquids to chewy meat. Restriction of the diet to consistencies that can be swallowed without aspiration reduces the risk of dysphagia complications. The speech therapist teaches techniques that improve coordinated swallowing and reduce the risk of aspiration, such as tucking the chin before swallowing to close the larynx and open the upper esophagus and swallowing twice after each bite of food to clear the pharynx.

LANGUAGE AND COGNITIVE THERAPIES Brain injuries that cause behavioral, language, and other cognitive dysfunctions may be focal and discrete or generalized and diffuse. In focal injuries, the neurologic dysfunctions may be restricted, with other brain functions preserved, for instance, Broca aphasia with intact attention, memory, and concentration. In contrast, diffuse injury may affect several areas of cognitive function. The therapeutic approach needs to be tailored to the nature and complexity of the symptoms. The first step in implementing a cognitive rehabilitation program is to define the neurobehavioral impediments and how they interfere with function. For example, a short attention span may prevent participation in group activities such as business meetings, or memory impairment may lead to failure at school. Speech therapy for aphasia is a specialized part of cognitive rehabilitation. The speech therapist defines receptive and expressive dysfunction and identifies areas of strength and weaknesses in language. Areas of strength may then be used for compensatory purposes. For instance, if an aphasic patient's written language skills are preserved better than verbal expression, writing may be useful for communication. Training in use of visual imagery as an internal cue may help to overcome the word blocking of Broca aphasia. A picture board may circumvent an expressive language deficit. The use of computer-assisted communication for aphasia is an area of active rehabilitation research. Visual imagery to create memory cues may improve performance on memory tests. Breaking a task into individual steps and then teaching one step at a time helps to overcome constructional problems. In diffuse or multifocal brain injury that impairs attention and behavior and many aspects of cognition and language, a structured program that permits few distractions is necessary. Speech and occupational therapists collaborate on program development and implementation, and all members of the rehabilitation team contribute. Several strategies may compensate for multiple problems. For example, sensory reduction minimizes distractions by controlling the noise and activity in the environment; development of a rigidly structured daily routine helps to overcome poor planning and organizational skills. Education of patient and family about aphasia and other cognitive problems helps to reduce frustration with impaired communication, memory, and abnormal behavior.

INCONTINENCE THERAPY Loss of control of bladder or bowel emptying is a devastating condition and should be addressed by any comprehensive neurorehabilitation program. The cause of impaired emptying or sphincter incompetence, and therefore the treatment, depends on the site of the neural injury. Evaluation includes clinical observations about incontinence and retention; search for nonneurologic factors, such as cystitis or mechanical problems, particularly urethral obstruction by prostatic enlargement; and cystometrographic measurements of bladder and sphincter functions. The neurorehabilitation nurse plays a crucial role in the treatment of bladder and bowel disorders, including implementation of voiding programs and training patient and family to use urethral catheters. Incontinence characterized by bladder hyperreflexia, in which the bladder contracts at low urine volumes and voluntary inhibition of bladder contraction and sphincter relaxation fails, commonly complicates cerebral, particularly frontal lobe, injury. Lack of awareness or indifference may impede achievement of continence, but neurologic recovery usually reduces incontinence. Scheduled voidings at 2-hour intervals contribute to regaining continence. Bladder dyssynergia, in which bladder contraction and sphincter relaxation are dissociated and the bladder contracts against a closed sphincter, is usually a consequence of lower brainstem or spinal cord disorders. Bladder emptying, if it occurs at all, is incomplete and occurs at high pressure. Treatment includes bladder antispasmodic drugs and intermittent catheterization. Hydronephrosis and renal failure are potential complications. Peripheral nerve diseases involving the nerves innervating the bladder may cause bladder flaccidity. Bladder emptying, at low pressures, is incomplete, and incontinence occurs between voluntary voidings. Cholinergic agents may improve emptying, but intermittent catheterization is often necessary. Immobility from any neurologic disorder and loss of cortical control over bowel movements due to spinal cord injury may cause severe obstipation and even bowel obstruction. Prevention combines a high-fiber diet and stool softeners with laxatives or enemas timed to stimulate evacuation on a regular schedule. SUGGESTED READINGS Bennett L, Knowlton GC. Overwork weakness in partially denervated skeletal muscle. Clin Orthop 1958;12:22–29. Goldstein LB, Matchar DB, Morgenlander JC, Davis JN. Influence of drugs on the recovery of sensorimotor function after stroke. J Neurol Rehab 1990;4:137–144. Good DC, Couch JR, eds. Handbook of neurorehabilitation. New York: Marcel Dekker, 1994. International classification of impairments, disabilities, and handicaps. Geneva: World Health Organization, 1980. Kalra L, Dale P, Crome P. Improving stroke rehabilitation: a controlled study. Stroke 1993;24:1462–1467. Kramer AM, Steiner JF, Schlenker RE, et al. Outcomes and costs after hip fracture and stroke. A comparison of rehabilitation settings. JAMA 1997;277:396–404. Selzer ME. Neurological rehabilitation. Ann Neurol 1992;32:695–699. Taub E, Miller NE, Novack TA, et al. Technique to improve chronic motor deficit after stroke. Arch Phys Med Rehabil 1993;74:347–354. Visintin M, Barbeau H, Korner-Bitensky N, Mayo NE. A new approach to retrain gait in stroke patients through body weight support and treadmill stimulation. Stroke 1998;29:1122–1128. Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R. Amphetamine paired with physical therapy accelerates motor recovery after stroke. Stroke 1995;26:2254–2259.

CHAPTER 165. END-OF-LIFE ISSUES IN NEUROLOGY MERRITT’S NEUROLOGY

XXV. ETHICAL AND LEGAL GUIDELINES CHAPTER 165. END-OF-LIFE ISSUES IN NEUROLOGY LEWIS P. ROWLAND Informed Consent Advance Directives Refusal of Life Sustaining Treatment Double Effect Palliative Care Physician Assisted Suicide Terminal Sedation Euthanasia An Overall View Suggested Readings

Neurologic diseases have been at the center of discussions on issues at the end of life. The American Academy of Neurology has set standards for the determination of cerebral death and for the persistent vegetative state (see Chapter 4). Amyotrophic lateral sclerosis and Alzheimer disease have been the focus of debates about assisted suicide. Neurologic intensive care units face the issue of discontinuing mechanical ventilation. Presymptomatic diagnosis is available for incurable conditions like Huntington disease, creating an ethical challenge. These ethical issues could fill a separate book. Here, we set forth some principles and definitions as an introduction for students and physicians as they learn to deal with the problems. The fundamental ethical and legal guidelines are the basis for actions taken or avoided.

INFORMED CONSENT One basis for patient autonomy in decision making is informed consent. A patient may accept or refuse a treatment or diagnostic test after learning about the anticipated benefits and risks and alternative choices. This requires accurate information about prognosis.

ADVANCE DIRECTIVES Individuals may prepare legal documents that specify their preferences for end-of-life treatments under specific circumstances, and they may also appoint surrogate decision makers if the individual is not competent to make decisions at some future time. Most states recognize living wills as instruments for these advance directives, which usually provide a prohibition against life-sustaining treatments that prolong the dying process if the person is in a terminal condition and can no longer make decisions. In the interim, a competent person can change the advance directive at any time.

REFUSAL OF LIFE SUSTAINING TREATMENT The doctrine of informed consent includes the patient's right to refuse life-sustaining treatment. Refusal is a decision not to provide consent, without which the physician usually cannot continue treatment. Respect for patients' autonomy does not require acceptance of all decisions; the decision must be based on adequate understanding of the nature and consequences of the choice ( informed consent) without coercion and with capacity to make a reasoned decision. The patient's right to consent or refuse is not abrogated when the patient loses the capacity to make decisions. It becomes transferred to a legally authorized surrogate decision maker and the physician must ask the surrogate for consent or refusal on behalf of the patient. The surrogate must follow the patient's previously expressed wishes as expressed in advance directives or other reliable statements. If the patient's expressed wishes have not been explicitly stated, the surrogate must use the doctrine of substituted judgment, based on knowledge of the patient's general values and preferences. If the surrogate has no such information, the surrogate must assess the anticipated benefits and burdens, based on the doctrine of best interest. This may be problematic, however, because it is not based on the desires of the patient. Despite widely held beliefs to the contrary, it is not necessary to consult legal counsel before withdrawing life-sustaining therapy.

DOUBLE EFFECT Some actions are morally and ethically acceptable and may have foreseeable but unintended and undesirable outcomes; the morality of the action depends on the morality of the intended outcome, not the unintended one. According to the American Academy of Neurology Ethics Committee statement on assisted suicide, several conditions must be met: the action to be carried out must be morally or ethically acceptable or at least neutral, the good effect must not depend on the undesired or bad effect, and the good effect must be sufficient to justify the risk of the unintended outcome. In practice, this principle makes it possible to administer sufficient analgesic and sedative medication to keep a patient comfortable even though the treatment will not prolong life. The principle of double effect is the basis of the hospice program.

PALLIATIVE CARE According to the World Health Organization definition, palliative care is “the active total care of patients whose disease is not responsive to curative treatment, where the control of pain, of other symptoms and of psychological, social, and spiritual problems is paramount, and where the goal is the achievement of the best quality of life for patients and their families.” More directly stated, palliative care is “comfort care” or treatment intended to relieve pain and suffering rather than to cure the disease, restore the patient to health, or prolong life at all costs. Oral or parenteral morphine is used in amounts sufficient to control pain and maintain comfort. A hospice program is often the venue for palliative care. This is sometimes carried out in a hospital or separate physical facility but is increasingly a home care program. In the United States, a Medicare Disease-Related Group (DRG) provides reimbursement for the care of patients who are not expected to survive for more than 6 months. However, hospice care is used by only 17% of people who are dying, and three reasons are adduced: physicians are uncomfortable about talking with patients about terminal events long enough in advance, sometimes it is difficult to determine precisely the expected time of death, and hospices emphasize home care and family members may not be able to commit the time required or there may be no family members. Most Americans die in hospitals (61%) or nursing homes (17%). Another drawback to the use of home or hospice care is the insensitivity of U.S. physicians to the advance directives of their patients, as detected by the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (support). Fifty percent of the physicians polled did not respect or did not know the advance directives; most do-not-resuscitate (DNR) orders were not written until 24 hours before death; and 40% of the patients had severe pain for several days before death. In a follow-up study, there was no improvement in communication about patients' desires for resuscitation; in the time before death in an intensive care unit; or the incidence or timing of do not resuscitate orders, which were not written in 50% of the patients surveyed. Physicians misunderstood the desires of their patients against do not resuscitate (80%) or the level of pain.

PHYSICIAN ASSISTED SUICIDE As specified by law in the state of Oregon, it is permissible for a physician to prescribe medication to be used by a patient for the purpose of suicide. The physician may not actually administer the drug. This law is restricted to Oregon and the practice is not legal in any other state.

Neurologic diseases generate problems for this policy. Patients may be incompetent with Alzheimer disease and would be unable to give consent. Other patients may lose the use of their hands from multiple sclerosis or amyotrophic lateral sclerosis. Under these circumstances, the patients themselves cannot fill the prescription and take the drug; someone else must assist them physically, which would be euthanasia and specifically banned by the Oregon law. Many authorities have debated the desirability of assisted suicide. Medical and nursing organizations have uniformly opposed legalization.

TERMINAL SEDATION The right to forgo treatment includes food and water. Pain or other discomfort can be ameliorated by standard palliative measures that may include sedation to unconsciousness. The patient then dies as a result of the underlying disease, dehydration, or both. It is believed that some form of terminal sedation is applied in up to 40% of deaths in U.S. hospitals. Discontinuing mechanical ventilation in an intensive care unit is another situation that calls for prevention or relief of suffering. Some believe that terminal dehydration has a stronger moral basis than assisted suicide, based as it is on the right to refuse treatment. A physician is morally obligated to honor a competent patient's refusal of food and water but is not obligated by a request for a lethal drug. Nevertheless, detractors consider terminal sedation a form of “slow euthanasia.”

EUTHANASIA If in compliance with a patient's request a physician administers a lethal drug by injection or other means, the act is “euthanasia,” which is illegal in the United States. The public, physicians, and courts have had difficulty separating refusal or discontinuation of therapy, which are legal, from assisted suicide and euthanasia, which are not. The distinction between assisted suicide and euthanasia is the most controversial of all. The Supreme Court concluded that palliative care and terminal sedation are permissible but referred the question of physician-assisted suicide back to legislation by the states.

AN OVERALL VIEW The issues discussed here are among the most controversial in modern life. Consensus is not easy to achieve, but views are changing and current practices are likely to change as well. Already, pain control and palliative care have come to the fore and provide effective alternatives to assisted suicide. Legal changes may be anticipated but do not seem imminent. SUGGESTED READINGS Almqvist EW, Block M, Brinkman R, Crauford D, Hayden M. A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease. Am J Hum Genet 1999;64:1293–1304. American Academy of Neurology Ethics and Humanities Subcommittee. Certain aspects of the care and management of profoundly and irreversibly paralyzed patients with retained consciousness and cognition. Neurology 1993;43:222–223. American Academy of Neurology Ethics and Humanities Subcommittee. Palliative care in neurology. Neurology 1996;46:870–872. American Academy of Neurology Ethics and Humanities Subcommittee. Ethical issues in the management of the demented patient. Neurology 1996;46:1180–1183. American Academy of Neurology Ethics and Humanities Subcommittee. Assisted suicide, euthanasia, and the neurologist. Neurology 1998; 50:596–598. American Academy of Neurology Quality Standards Subcommittee. Practice parameter: assessment and management of patients in the persistent vegetative state. Neurology 1995;45:1015–1018. Angell M. The Supreme Court and assisted suicide—the ultimate right. N Engl J Med 1997;336:50–53. Bernat JL. Ethical issues in neurology. Boston: Butterworth-Heinemann, 1994. Bernat JL. The problem of physician-assisted suicide. Semin Neurol 1997:17:271–280. Bird TD. Outrageous fortune: the risk of suicide in genetic testing for Huntington disease. Am J Hum Genet 1999;64:1289–1292. Burt RA. The Supreme Court speaks—not assisted suicide but a constitutional right to palliative care. N Engl J Med 1997;337:1234–1236. Doyle D, Hanks GC, Mac Donald N, eds. Oxford textbook of palliative care, 2nd ed. New York: Oxford University Press, 1998. Field MJ, Cassel CK, eds. Institute of Medicine. Approaching death: improving care at the end of life. Washington, DC: National Academy Press, 1997. Foley KM. Competent care for the dying instead of physician assisted suicide. N Engl J Med 1997;336:54–58. Ganzini L, Johnston WS, McFarland BH, Tolle SW, Lee MA. Attitudes of patients with amyotrophic lateral sclerosis and their care givers toward assisted suicide. N Engl J Med 1998;339:967–973. Gostin LO Deciding life and death in the courtroom: from Quinlan to Cruzan, Glucksberg, and Vacco—a brief history and analysis of constitutional protection of the “right to die.” JAMA 1997:278:1523–1528. Mayer SA, Kossoff SB. Withdrawal of life support in the neurological intensive care unit. Neurology 1999;52:1602–1609. Meier DE, Morrison RS, Cassel CK. Improving palliative care. Ann Intern Med 1997;127:223–230. Miller FG, Meier DE. Voluntary death: a comparison of terminal dehydration and physician-assisted suicide. Ann Intern Med 1998;128:559–562. Multisociety task force on persistent vegetative state. N Engl J Med 1994;330:1499–1508, 1572–1579. Newton HB, Malkin MG. Ethical issues in neuro-oncology. Semin Neurol 1997;17:219–226. Orentlicher D. The Supreme Court and physician-assisted suicide—rejecting assisted suicide but embracing euthanasia. N Engl J Med 1997;337:1236–1239. Payne SK, Taylor RM. The persistent vegetative state and anencephaly: problematic paradigms for discussing futility and rationing. Semin Neurol 1997;17:257–264. Quill TE, Lo B, Brock DW. Palliative options of last resort: a comparison of voluntarily stopping eating and drinking, terminal sedation, physician-assisted suicide, and voluntary active euthanasia. JAMA 1997; 278:2099–2104. Quill TE, Meier DE, Block SD, Billings JA. The debate over physician-assisted suicide: empirical data and convergent views. Ann Intern Med 1998;128:552–558. Rowland LP. Assisted suicide and alternatives in amyotrophic lateral sclerosis. N Engl J Med 1998;339:987–989. Ruffin TA. Withdrawing life support. How is the decision made? JAMA 1995;273:738–739. Youngner SJ. Beyond DNR: Fine-tuning end-of-life decision making. Neurology 1995;45:615–616.