10 Neurology by Urvi Trivedi

SECTION 10

Neurology 80.

Primary Headache Disorders - An Update Anup Kr Bhattacharya, Agnibha Maity

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81.

Approach to Hyperkinetic Movement Disorders Balamurugan Namasivayam

384

82.

Management Tips of Epilepsy: A Physicianâ&#x20AC;&#x2122;s Perspective Sudhir V Shah

388

83.

Management of Epilepsy in Special Situations Jaslovleen Kaur, Gagandeep Singh

391

84.

Recent Advances in Epilepsy Sushil Tandel

394

85.

Surgery for Parkinsonâ&#x20AC;&#x2122;s disease and Epilepsy Paresh Doshi, Raghvendra Ramdasi, Smita Thorve

398

86.

Thrombolysis in Stroke - Experience In India Apratim Chatterjee, Subhodeep Gupta, Bhaskar Ghosh, Biman Kanti Ray

407

87.

Tough Calls in Neurology K Mugundhan

412

88.

Motor Neuron Diseases Joy D Desai

418

89.

A Case Based Approach to Acute Flaccid Paralysis Salil Gupta

423

90.

Approach Towards a Patient with Vertigo Sanjiv Maheshwari, Ravi Kumar Meena

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C H A P T E R

Primary Headache Disorders An Update

Headache is nearly universal symptom with a complex & heterogeneous set of causes. Nearly half of the worldâ&#x20AC;&#x2122;s population has an active headache disorders.1 In the second edition of ICHD -2, headache is divided into secondary disorders, attributable to a specific aetiology and primary disorders without an underlying cause.2 Primary headache classification is split into three sections: migraine, tension type headache & trigeminal autonomic cephalgia.

MIGRAINE

Migraine is a common disabling primary headache disorder. Epidemiological studies have documented its high prevalence and high socioeconomic and personal ssimpacts. In the global burden of disease survey 2010, it was ranked as the third most prevalent disorder and seventh highest specific cause of disability worldwide. Its prevalence in women far exceeds that of men in adulthood, with female: male ratio 2.8:1, peaking at 3.3:1 between age 40 & 45 years. The female predominance is maintained in the postmenopausal age group.3-6 Prior to puberty, migraine prevalence is higher in boys than in girls.7,8 Migraine has two major subtypes. 1.1 Migraine without aura is a clinical syndrome characterised by headache with specific features and associated symptoms. 1.2 Migraine with aura is primarily characterised by the transient focal neurological symptoms that usually precede or sometimes accompany the headache. Migraine Without Aura: In a population based series up to 12% of individuals with migraine without aura experienced premonitory symptoms.9 Premonitory symptoms were reported by prospective electronic diary documentation. The most common symptoms were tiredness (72%), difficulty with concentration (51%), and a stiff neck(50%).10 The most reliable predictors of an attack were yawning, difficulties with speech, difficulties with reading & increased emotion. Premonitory symptoms accurately predicted the onset of migraine headache within 72 hours in 72% of the time. In about 60% of patients the headache is unilateral.11 Whether unilateral or bilateral, the pain is predominately in the distribution of the first division of the trigeminal nerve. Most commonly the pain tends to be frontotemporal and periorbital, often spreading to parietal and occipital areas. A quarter to a third of patients experience pain in one or both regions of the occiput and neck.12,13 The relevance of this is paramount. It is not infrequent that the cervical spine is erroneously implicated in generating the pain in primary headache disorders. However involvement of regions of

Anup Kr Bhattacharya, Agnibha Maity

the occiput and neck are consistent with the physiological nociceptive connections which sub serve the head & neck.14,15 Functionally the trigeminal nucleus extends beyond the traditional nucleus caudalis to the dorsal horn of the high cervical region. The sensory innervations of the superior sagittal sinus are mainly from the ophthalmic i.e. first division of trigeminal. In human volunteers local anaesthetic block of the greater occipital nerve results in modulation of the ipsilateral nociceptive blink response.16 This is the basis for the therapeutic success of occipital nerve blockade17 and neurostimulation18 in headache.

MIGRAINE WITH AURA19-23

Recurrent attacks, lasting minutes, unilateral, fully reversible visual, sensory or other CNS symptoms that usually develop gradually and are usually followed by headache and associated migraine symptom.

Diagnostic criteria A.

At least two attacks fulfilling criteria B & C

1 or more of the following fully reversible aura symptoms: 1.Visual 2.Sensory 3.Speech. 4. Motor 5.Brainstem. 6. Retinal.

At least two of the following four characteristics:1. At least one aura symptom spreads gradually over >=5 min, and/or two or more symptoms occur in succession.2.Each individual aura symptom lasts 5-60 minutes.3.At least one aura symptom is unilateral.4.Aura is accompanied, or followed within 60 min, by headache.

Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded.

The aura is a complex neurological symptom that occurs usually before the headache, but it may begin after the pain phase has commenced, or continue into the headache phase. Visual aura is the most common type of aura, occurring in over 90% of patients. It often presents as a fortification spectrum: a zigzag figure near the point of fixation that may gradually spread right or left and assume a laterally convex shape with an angulated scintillating edge, leaving absolute or variable degrees of relative scotoma in its wake. Next in frequency are sensory disturbances, in the form of pins & needles moving slowly from the point of origin and affecting a greater or smaller part of one side of the body, face and/ or tongue. Less frequent are speech disturbances, usually aphasic but often hard to categorise. When aura includes

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motor weakness, disorder should be coded as hemiplegic migraine or one of its sub forms.

Diplopia

Ataxia

MIGRAINE WITH TYPICAL AURA24-25

Decreased level of consciousness

At least two of the following four characteristics:

At least one aura symptom spreads gradually over >= 5 minutes, and/or two or more symptoms occur in succession

Each individual aura symptom lasts 5-60 minutes

At least one aura symptom is unilateral

The aura is accompanied, or followed within 60 minutes, by headache

Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded.

Migraine with typical aura in which aura consists of visual and/or sensory and/or speech/language symptoms, but no motor weakness, and is characterised by gradual development, duration of each symptom no longer than 1 hour, a mix of positive & negative features and complete reversibility.

NEUROLOGY

Diagonistic Criteria A.

At least two attacks fulfilling criteria B & C.

Aura consisting of visual, sensory, and/or speech/ language symptoms, each fully reversible, but no motor, brainstem or retinal symptoms.

At least two of the following four characteristics:

At least one aura symptom spreads gradually over >=5 minutes, and/or two or more symptoms occur in succession.

Each individual aura symptom lasts 5-60 minutes.

At least one aura symptom is unilateral.

Aura is accompanied or followed within 60 min by headache.

Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded.

TYPICAL AURA WITH HEADACHE

Migraine with typical aura -- aura is accompanied or followed within 60 min by headache with or without migraine characteristics.

Diagnostic Criteria

HEMIPLEGIC MIGRAINE 30-39

Migraine with aura associated with motor weakness.

Diagnostic Criteria A.

At least two attacks fulfilling criteria B and C

Aura consisting of both of the following:

Fully reversible motor weakness.

Fully reversible visual, sensory and/or speech/ language symptoms

At least two of the following four characteristics:

At least one aura symptom spreads gradually over>=5 minutes, and/or two or more symptoms occur in succession

Each individual non-motor aura symptom lasts 5-60 minutes and symptoms last <72 hours

Fulfils criteria for migraine with typical aura.

At least one aura symptom is unilateral

Headache, with or without migraine characteristics, accompanies or follows aura within 60 min.

The aura is not accounted for by another ICHD-3 diagnosis and transient ischemic attack and stroke have been excluded

TYPICAL AURA WITHOUT HEADACHE

Migraine with typical aura - not associated with headache during next 60 min.

MIGRAINE WITH BRAINSTEM AURA26-29

Migraine aura suggestive of originating from the brainstem but no motor weakness.

Diagnostic Criteria

FAMILIAL HEMIPLEGIC MIGRAINE

Migraine with aura including motor weakness, and at least one first-or second-degree relative has migraine aura associated with motor weakness.

Diagnostic Criteria A.

Fulfils criteria for hemiplegic migraine At least one first-or second-degree relative has had attacks fulfilling criteria for hemiplegic migraine.

At least two attacks fulfilling criteria B-D

Aura consisting of visual, sensory and/or speech/ language symptoms, each fully reversible, but no motor or retinal symptoms

Fulfils criteria for familial hemiplegic

At least two of the following brainstem symptoms:

A causative mutation on the CACNA1A gene has been demonstrated.

FAMILIAL HEMIPLEGIC MIGRAINE TYPE 1(F H M 1)

1. Dysarthia 2.

Vertigo

Tinnitus

Hypacusis

FAMILIAL HEMIPLEGIC MIGRAINE TYPE 2(F H M 2)

Fulfils criteria for familial hemiplegic migraine

A causative mutation on the ATP1A2 gene has been demonstrated.

STATUS MIGRAINOSUS41

A debilitating migraine attack lasting for more than 72 hours.

Diagnostic Criteria

A headache attack fulfilling criteria B and C

Occurring in a patient with migraine without aura and/or migraine with aura, and typical of previous attacks except for its duration and severity

Both of the following characteristics:

Unremitting for >72 hours

Pain and/or associated symptoms are debilitating.

Not better accounted for by another ICHD-3 diagnosis.

Attacks occur >=1 week apart

Complete freedom from symptoms between attacks

Not attributed to another disorder.

ABDOMINAL MIGRAINE

An idiopathic disorder seen mainly in children as recurrent attacks of moderate to severe midline abdominal pain, associated with vasomotor symptoms, nausea and vomiting, lasting 2-72 hours and with no symptom in between episodes. Headache does not occur during these episodes.

Diagnostic Criteria A.

At least five attacks of abdominal pain, fulfilling criteria B-D

One or more migraine aura symptoms associated with an ischemic brain lesion in the appropriate territory demonstrated by neuroimaging.

Pain has at least two of the following three characteristic:

Midline location, periumbilical or poorly localized

Dull or ‘just sore’ quality

Diagnostic Criteria:

Moderate or severe intensity

A migraine attack fulfilling criteria B and C

During attacks, at least two of the following:

Occurring in a patient with Migraine with aura and typical of previous attack except that one or more aura symptoms persists for >60 minutes.

a. Anorexia

MIGRAINOUS INFARCTION42

Neuroimaging demonstrates ischemic information in a relevant area

Not better accounted for by another diagnosis.

MIGRAINE TRIGGERED SEIZURE

A seizure triggered by an attack of migraine with aura.

Diagnostic Criteria A.

A seizure fulfilling diagnostic criteria for one type of epileptic attack, and criterion B below

Occurring in a patient with migraine with aura, and during, or within 1 hour after, an attack of migraine with aura

Not better accounted for by another diagnosis.

CYCLIC VOMITING SYNDROME

Recurrent episodic attack of intense nausea and vomiting, usually stereotypical in the individual and with predictable with timing of episodes. Attacks may be associated with pallor and lethargy. There is complete resolution of symptoms between attacks. Diagnostic Criteria A. At least five attacks of intense nausea and vomiting, fulfilling criteria B and C

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Nausea

Vomiting

d. Pallor

RETINAL MIGRAINE43

Repeated attacks of monocular visual disturbances, including scintillations, scotoma or blindness, associated with migraine headache.

Diagnostic criteria A.

At least two attack fulfilling criteria B and C

Aura consisting of fully reversible monocular positive and/or negative visual phenomena (e.g. scintillations, scotoma or blindness) confirmed during an attack by either or both of the following:

Clinical visual field examination

The patient’s drawing (made after clear instruction) of a monocular field defect.

At least two of the following three characteristics

The aura spreads gradually over>5 minutes

Aura symptoms last 5-60 minutes

The aura is accompanied or followed within 60 minutes by headache.

Not better accounted for by another ICHD-3 diagnosis and other causes of amaurosis fugax have been excluded.

Stereotyped in the individual patient and recurring with predictable periodicity.

All of the following:

Nausea and vomiting occur at least four times per hour

Based on clinical symptoms, pathophysiology of migraine can be divided into three phases:

Attacks last>=1 hour and up to 10 days

PATHOPHYSIOLOGY OF MIGRAINE44

The trigger phase characterised by neuronal

CHAPTER 80

NEUROLOGY

triggering migraine than is widely believed. A food is a trigger when: A>Migraine onset occurs within 6 hours of intake. B. The effect is reasonably reproducible. C. Withdrawal leads to improvement. Most migraineurs can eat whatever they like as long as they keep up with their energy demands. A few susceptible individuals note a definite relationship between consumption of certain foods, particularly alcohol, and the onset of migraine. The foods may not always trigger an attack but tip the balance when the person is vulnerable.

hyperexcitibility.

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The aura phase possibly involving spreading depression and finally

cortical

The headache phase due to cranial vasodilatation precipitated by activation and sensitization of the trigeminal system at the peripheral and central levels.

Exploring each phase of migraine reveals unique mechanisms and divulges novel therapeutic targets. Sensory fibres innervate the cranial vessels arising from trigeminal ganglion which contain neuropeptides. Trigeminovascular inputs from dural meninges have reflex connections between neurons in the pons in the superior salivatory nucleus and are a part of cranial parasympathetic outflow that in part is mediated through the pterygopalatine ganglion. In addition certain genetic abnormalities may be responsible for altering the threshold to migraine specific triggers in the brain, e.g. mutations of the P/Q type calcium channel gene that plays an important role in familial hemiplegic migraine. The subsequent events following the trigger phase lead to the symptoms observed during the aura and headache phases can be explained on the basis of neurovascular involvement. Clinical & experimental considerations suggest that the pathogenesis of the migraine headache is intimately linked to the trigeminal innervations. When activated following cortical spreading depression causes dilatation of cranial vessels, including arteriovenous shunts. Thus, migraine pain is due to activation of the nociceptors in intracranial structures, in concert with a reduction in the function of endogenous pain control pathways. This nociceptive information from cranial blood vessels is conveyed to central neurons in the trigeminal sensory nucleus that in turn relay the pain signals to higher centres and headache is perceived. In addition trigeminal pathway may get sensitized and release CGRP, this reinforces vasodilatation and enhances the relay of nociceptive impulses to the central nervous system.

MANAGEMENT OF MIGRAINE 45-47

Managing Aggravating factors: 1.

Anxiety & Emotion=Most migraineurs cope well with stresses but many have attacks when they relax. Stress may induce other triggers such as missed meals, poor sleep and muscle tension.

Hormonal Triggers=About 50% of female migraine sufferers experience troublesome migraine headaches associated with menstruation. Migraine can worsen in first trimester of pregnancy but improve thereafter. The menopause, oral contraception and hormone replacement therapy can be associated with worsening, improvement or no change in the disorder.

Missed meals=May trigger attacks. Regular meals should be encouraged.

Specific foods=Less commonly implicated in

Too much and too little sleep= can both play a role. Sleepless nights results in overtiredness which triggers migraine. Conversely, sleeping in for even half an hour longer than usual, often at the weekend, can trigger migraine. In both cases, the cause of the altered sleep pattern may be the true trigger.

Strenuous exercise=Can precipitate an attack in a person unaccustomed to it. This puts many people off exercise when in fact regular exercise may help prevent migraine attacks. This is because it improves blood sugar balance, helps breathing, stimulates the body to release its own natural pain killers and promotes a general sense of wellbeing.

DRUG INTERVENTION (ACUTE)

The evidence base for many acute antimigraine drug is poor. For aspirin/metoclopramide combination the evidence is better and for the triptans it is generally good. Whilst, logically, drug treatment should be selected for each patient according to his or her need. Consequently there is a treatment ladder which begins with drugs chosen because they are safest and cheapest whilst being known to have efficacy. All patients should start on the first step of this ladder. As a general rule all acute drug therapy should be combined with rest and sleep. STEP ONE: Simple Oral Analgesic Âą antiemetic. Recommended analgesic doses for acute migraine are typically greater than standard doses to achieve rapid therapeutic levels against a background of gastric stasis. NSAID + a prokinetic antiemetic: Aspirin 600-900mg up to 4 doses in 24 hours. or Ibuprofen 400-600 mg up to 4 doses in 24 hours or Tolfenamic Acid rapid release 200 mg repeated once if necessary after 1-2 hours or Naproxen 750-825mg with a further 250-275mg up to twice in 24 hours or Diclofenac-potassium 50-100mg repeated up to a total of 200 mg in 24 hours. There is a little evidence for the efficacy of paracetamol alone. For nausea & vomiting :-Prochlorperazine 3-6mg buccal tablet, dissolved between gum & cheek up to twice in 24 hrs OR Domperidone 10 mg up to 4 times in 24 hours. MIGRAMAX (Lysine Acetylsalicylate 1620 mg plus metoclopramide 10 mg per sachet up to three sachets in 24 hours) is a convenient preparation. An alternative to those who cannot tolerate aspirin is Paramax sachets (paracetamol 500 mg plus metoclopramide 5 mg per sachet, up to 3 doses in 24 hours.

Step Two: Rectal Analgesic Âą Antiemetic=Diclofenac suppositories 100 mg (upto 200 mg in 24 hours) for pain plus Domperidone suppositories 30-60 mg when needed for nausea or vomiting. Peptic ulcer or lower bowel disease is contraindication to step two. The occurance of diarrhoea during acute migraine may prevent effective use.

Ergotamine Tartrate 1-2 mg has shown significantly lower relapse rate which may be due to its prolonged duration of action. STEP 3 is contraindicated if there is uncontrolled hypertension, risk factors for CAD or cerebrovascular disease, advanced age and in children below12 yrs. Step Four: There is some evidence that the combination of sumitriptan 50 mg and Naproxen 500 mg is superior to either drug alone. Other combinations of STEP ONE+THREE may be worth trying, followed by steps TWO+THREE. In all cases NARCOTICS are not recommended for the emergency treatment of migraine and their use can be associated with delayed recovery. Patient in whom there is potential contraindication to take triptan may benefit from Sumatriptan 6mg S/C or Diclofenac 75 mg I/M which can be given alone or in combination with chlorpromazine 25-50 mg I/M or I/V. Metoclopropamide 10-20 mg or Prochlorperazine 12.5 mg are alternative options but can cause acute dystonia including oculogyric crisis, which can be reversed by Procyclidine 5-10 mg I/M or I/V.

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There is some evidence that this occurs more in those whose untreated attacks last longer than 24 hrs. Naratriptan, Eletriptan, Frovatriptan are associated with relatively low recurrence rates. Ergomatrine is associated with significantly less relapse. Naproxen or tolfenamic acid may be used pre-emptively if relapse is anticipated.

LONG DURATION MIGRAINE

Migraine lasting longer than 3 days is uncommon (status migrainous). Apparently long duration attacks may be migraine with a superseding tension type headache for which Naproxen or Diclofenac preferable to specific antimigraine drugs.

PROPHYLACTIC TREATMENT OF MIGRAINE

Unfortunately at present there is no cure for migraine. Thus who suffer from frequent migraine attacks may require preventive therapy. First Line: Beta adrenergic blocker without partial agonism is first line if not contraindicated by asthma, heart failure, peripheral vascular disease or depression. Atenolol 25-100 mg bid is to preferred over metoprolol 50100 mg and Propanolol LA 80 mg-160 mg bd. Bisoprolol 5-10 mg od may be the choice but evidence of its efficacy is needed. Amitriptyline 10-150 mg daily, at 1-2 hours before bedtime is first line when migraine coexists with : troublesome tension type headache, another chronic pain condition, disturbed sleep or depression. Common adverse effect is dry mouth, sedation, dizziness, nausea. Second Line: Topiramate 25 mg-50 mg bid and Sodium valproate 300-1000 mg bd are second line. Adverse effect reported for sodium valproate include nausea, asthenia, somnolence, weight gain, alopecia. Liver dysfunction is reported rarely. About 50% patient taking topiramate for migraine experience tingling sensation which usually resolve with continued use. Third Line: There is some clinical justification for considering other antiepileptics such as Gabapentin 300 mg od -800 mg tds, although evidence of efficacy is far from robust. The most common adverse effect reported are dizziness & sedation. Methylsergide 1-2 mg tds is generally considered to be most effective prophylactic, but is held in reserve. This is partly because of its association with retroperitoneal fibrosis although it is said not to have this side effect in courses of less than 6 month. Beta blockers and Amitriptyline can be used together, and a synergistic effect is claimed for this combination. Other Drugs Used in Prophylaxis but with Limited or Uncertain Efficacy: Pizotifen and Clonidine widely used for many years but with little clinical trial. Verapamil MR 120-240mg bid also had limited clinical trial evidence of efficacy. SSRI like Fluoxetine 20-40 mg are of uncertain value. Other drugs including lisinopril, montelukast, candesartan, riboflavin and Co-enzyme Q10 show potential benefit but further research is necessary. Onabotulinumtoxin A is licensed for prophylaxis of patients with more than 15 headache days per month, of which at least eight days are with migraine.

CHAPTER 80

Step Three: Specific anti-migraine drugs=The marketed triptans differ in ways that might rationally suggest one rather than another for a particular patient. Clinical trials indicate that they range in comparative efficacy. About 30% of patients fail to respond to any particular one, with nonresponsive attributable to a variety of factors including low and inconsistent absorption, use of medication at wrong time(too early or too late in an attack), inadequate dose and individual biological variability. Triptans should be taken at the start of headache phase. There is increasing evidence of greater efficacy when taken whilst pain is still mild, but triptans appear to be ineffective if administered during aura. SUMATRIPTAN was first launched, and clinical experience of its use is greatest. The 50mg tablet and the rapidly dispersing RADIS 50mg tablet are equally appropriate for first use of triptan. When response to these is inadequate, RADIS 100 mg tablet or 20 mg nasal spray may be used according to preference. Total dosage in 24 hours should not exceed 300 mg orally or 40 mg intranasally. If a rapid response is expected then 6 mg subcutaneously, is the triptan of choice. ZOLMITRIPTAN 2.5mg are also equally effective for first use of triptan. A second dose may be taken for lack of effect after two hours if needed. Total dose in 24 hrs should not exceed 10 mg. Zolmitriptan 5mg nasal spray produces a rapid response and may be useful if vomiting is already occurring since upto 30% is absorbed through the nasal mucosa. Rizatriptan 10 mg are alternative to Sumatriptan 100 mg. The total dose in 24 hrs should not exceed 20 mg. NARATRIPTAN, ALMOTRIPTAN, . ELETRIPTAN, FROVITRIPTAN are other triptans being used in the treatment of migraine.

PATIENT WHO PERSISTENTLY EXPERIENCE RELAPSE

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Hormone Related Migraine: An effect of hormones on migraine is common, and greater for migraine without aura. Evidence suggests estrogen withdrawal triggers migraine in some women. More than 50% women report an association between migraine & menstruation. Depending on need for contraception, several options can be tried in whatever orders seems appropriate. Prophylaxis should be tried for a minimum of three cycles at maximum dose before it is deemed ineffective.

NEUROLOGY

Nonhormonal prophylaxis does not depend on regular menstruation. Mefenamic acid 500 mg tds or qds can be given from the onset of menstruation until last day of bleeding. It is recommended as first line in migraine occurring with menorrhagia and/or dysmenorrhoea.

CLUSTER HEADACHE

Cluster headache is a relatively common condition by neurological standards, probably affecting about 1 in 1000 people, although compared to other more common primary headaches, such as migraine, it is clearly rare in clinical practice. Cluster headache is certainly the most prominent and most common of the TACs and is considered one of the most severe pain syndromes in humans—in fact, women have described the headache worse than childbirth.

Diagonistic Criteria A.

At least five headache attacks fulfilling criteria B–D:

Severe or very severe unilateral orbital, supraorbital and/or temporal headache attacks, which last untreated for 15–180 minutes. During part (but less than half) of the time course of the cluster headache, attacks may be less severe, less frequent, or of shorter or longer duration.

The headache is accompanied by at least one of the following symptoms ipsilateral to the pain:

C. Hormones for menstrual migraine are supplements, if the woman has an intact uterus and is menstruating regularly, no progesterones are necessary. Transdermal estrogen 100 microgram is used from 3 days before onset of mens for 7 days.

Conjunctival Injection or lacrimation

Nasal congestion and/or rhinorrhea

Eyelid edema

Forehead and facial sweating

Miosis and/or ptosis

A sense of restlessness and agitation

The attacks have a frequency from one every other day to 8 per day

History or physical and neurological examination do not suggest any other disorder, and/or they are ruled out by appropriate investigations.

Triptans have been studied in clinical trials of short term prophylaxis of menstrual attack of migraine. The greatest evidence of efficacy is for Frovatriptan for 6 days (5mg bd on day 1, 2.5 mg bd on day 2-6) starting 2 days before the expected onset of migraine.

Combined hormonal contraceptive and the progesterone only oral desogestrel, subdermally implanted etonogestrel and injectable depot progestogens inhibit natural ovarian cycle, which can benefit menstrual migraine.

ADVANCES IN MIGRAINE PREVENTION48

While there have been a number of target receptors and molecules identified as potentially related to migraine there is not much progress in relation to therapy..The latest foray in migraine prevention is antibodies either to calcitonin gene related peptide (CGRP) or to its receptor. It is suggested that antimigraine site should reside in areas not limited by the BBB such as intra & extra cranial vessels, dural mast cells and the trigeminal system.

NONDRUG INTERVENTION

Improving physical susceptibility.

fitness

Relaxation therapy, stress reduction, coping strategies are first line treatments where a specific indication exists.

Yoga and medication are said to enhance stress management and appeal to some people.

TRIGENIMAL AUTONOMIC CEPHALGIAS49-51

may

reduce

It is now an accepted clinical term, first proposed by Goadsby and Lipton, for a group of primary headaches with pain and autonomic involvement in the facial area of the trigeminal nerve.All these headache syndrome have 2 features in common: short lasting,unilateral,extremely severe headache attacks accompanied by typical autonomic symptoms.

Episodic cluster headache: At least two cluster periods lasting 7 days to 1 year separated by pain-free periods lasting ≥1 month. Chronic cluster headache: Attacks occur for more than one year without remission or with remission of <1 month. Probable cluster headache: Attacks fulfilling all but one of the criteria for cluster headache. Treatment: Many patients with acute cluster headache respond very well to oxygen inhalation. This should be given as 100% oxygen at 10-12L/min for 15-20 min. It appears that high flow and high oxygen content are important. Sumatriptan 6mg S/C is rapid in onset and will usually shorten an attack to 10-15 min.Sumatriptan 20 mg and Zolmitriptan 5mg nasal spray are both effective in acute cluster headache. The choice of preventive treatment in chronic cluster headache depends in part on the length of the bout. A 10 day course of prednisolone,beginning at 60 mg daily for 7 days and followed by a rapid tapper may interrupt pain bout for many patients. Lithium 400800mg appears to be particularly useful for the chronic form of the disorder. Many experts favor verapamil as first line preventive treatment. Initial dose range 40-

80mg twice daily.Effective dose may be as high as 960 mg/day. Methylsergide 3-12 mg, Topiramate 100-400 mg, Gabapentin 1200-3600mg, Melatonin 9-12 mg are also used for long term prevention of episodic and prolonged chronic cluster headache.

At least 20 attacks fulfilling criteria B–D

Attacks of severe unilateral orbital, supraorbital or temporal pain lasting 2–30 minutes

Headache is accompanied by at least one of the following:

ipsilateral conjunctival injection and/or lacrimation

ipsilateral nasal congestion and/or rhinorrhea

ipsilateral eyelid edema

ipsilateral forehead and facial sweating

ipsilateral miosis and/or ptosis

Attacks have a frequency above 5 per day for more than half the time, although periods with lower frequency may occur

Attacks are prevented completely by therapeutic doses of indomethac

Attacks are not attributed to another disorder

Treatment: Indomethacin (25-75mg tid) can completely suppress attacks of PH,is treatment of choice.Verapamil an effective treatment for cluster headache,does not appears to be effective for PH.Topiramate useful in some cases. Piroxicam has been used although not effective as indomethacin. Secondary PH has been reported with lesions in the region of sella turcica, including AV malformation, cavernous sinus meningioma, pituitary pathology, epidermoid tumors. Secondary PH patients requires high dose of indomethacin(200mg/day). SUNCT/SUNA (Short lasting unilateral neuralgiform headache attacks with conjunctival injection & tearing): It is rare primary headache syndrome characterized by severe,unilateral orbital or temporal pain that is stabbing or throbbing in quality. Diagnostic Criteria: A. At least 5 attacks fulfilling criteria B-D. B.

Attacks of unilateral orbital, supraorbital or temporal stabbing or pulsating pain lasting 5-240 seconds.

Pain is accompanied by ipsilateral conjunctival injection & lacrimation.

Attacks occur with a frequency 3-200 per day.

Attacks are not attributed to another disorder.

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Treatment: Therapy of acute attack is not a useful concept bcoz attack is of short duration. However IV Lidocaine which arrest the symptom can be used in hospitalized patients. Long term prevention to minimize disability and hospitalization is goal of treatment. The most effective treatment for prevention is Lamotrigine 200-400mg/ day. Topiramate and Gabapentin may also be effective. Carbamazepine, 400-500 mg/day has been reported by patients to offer modest benefit. Hemicrania Continua: The essential features of hemicrania continua are moderate and continuous unilateral pain associated with fluctuation of severe pain,complete resolution of pain with indomethacin and exacerbation that may be associated with autonomic features, including conjunctival injection, lacrimation and photophobia on affected side.The age of onset ranges from 11-58 years. Women are affected twice as often as men.The cause is unknown.

CHRONIC TENSION TYPE HEADACHE52

A disorder evolving from frequent episodic tension – type headache, with daily or very frequent episodes of headache, typically bilateral, pressing or tightening in quality and of mild to moderate intensity, lasting hours to days, or unremitting. The pain does not worsen with routine physical activity, but may be associated with mild nausea, photophobia or photophobia.

Diagnostic Criteria A.

headache occurring on > 15 days per month on average for more than three months ( > 180 days per year) and fulfilling criteria B through D.

Lasting hours to days, or unremitting

At least two of the following characteristics:

Bilateral Location

Pressing or tightening (non-pulsating) quality

Mild or moderate intensity

Not aggravated by routine physical activity such as walking or climbing stairs.

Both of the following:

No more than one of photophobia, or mild nausea.

Neither moderate or severe nausea nor vomiting

Not better accounted for by another ICHD-3 diagnosis

Treatment: The pain in TTH can be managed by simple analgesics such as acetaminophen,aspirin,or NSAIDs. Behavioral approaches including relaxation can also be effective. For chronic TTH amitriptyline is the only proven treatment.

MEDICATION OVERUSE HEADACHE52

Headache occurring on 15 or more days per months developing as a consequence of regular overuse of acute or symptomatic headache medication (on 10 or more, or

CHAPTER 80

Paroxysmal hemicranias was first described by Sjaastad and Dale and is characterized by relatively short bouts of severe unilateral pain in the orbital and temporal area. The typical attack duration is 10–20 minutes, and the typical frequency is more than 5 attacks per day, but there are reports of between 1 and 40 attacks per day. The age of onset is usually in the twenties, with a 3:1 female to male ratio.

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15 or more days per month, depending on the medication) for more than 3 months. It usually, but not invariably, resolves after the overuse is stopped. A. Headache occurring on 15 or more days per month in a patient with a pre-existing headache disorder.

NEUROLOGY

B. Regular overuse for more than three months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache:

observations have led to great strides in comprehending mechanisms underlying uncommon primary headache disorders. Finally conceptualising primary headache has led to important reasarch questions addressing disease progression and transformation in multiple realms: clinically, physiologically and anatomically.

REFERENCES

Stovner Lj, Hagen K, Jensen R, et al. The Global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalagia 2007; 27: 193-210.

Headache Classification Subcommittee of the International Headache Society. The International classification of headache disorders, 2nd edition. Cephalagia 2004; 24:9-160.

Stewart WF, Lipton RB, Celentano DD, Reed MI, Prevalence of migraine headache in the United States, Relation to age, income, race, and other sociodemographic factors. JAMA 1992; 267:64-69.

ICHD-3: International Classification of Headache Disorders, 3rd edition; NSAID: nonsteroidal antiinflammatory drug.

Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalance and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001; 41:646-657.

PRIMARY COUGH HEADACHE

Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence.

Abu-Arfeh I, Russell G. Prevalence of headache and migraine in school children. BJM 1994; 309:765-769.

Mortimer MJ, Kay J, Jaron A. Epidemiology of headache and childhood migraine in an urban general practice using ad hoc, Vahlquist and HIS criteria. Dev Med Child Neurol 1992; 34:1095-1101.

Blau NJ.Adult migraine:London:Chapman and Hall;1987:330.

Russell MB,Andersson PG,Iselius L.Cluster headache 1996; 36:608.

Regular intake for > 10 days per month for > 3 months of ergotamines, triptans, opioids, or combination analgesics, or any combination of ergotamines, triptans, simple analgesics, NSAIDs and opioids without overuse of any single drug or drug class alone or when the pattern of overuse cannot be reliably established. Regular intake for > 15 days per month for > 3 months of simple analgesics (ie, acetaminophen, aspirin, or NSAID). C. Not better accounted for by another ICHD -3 diagnosis.

It is a generalised headache that begins suddenly, lasts for several minutes, sometimes up to few hours and precipitated by coughing and it is preventable by avoiding coughing. Indomethacin 25-50 mg two to three times daily is treatment of choice. There are reports cough headache has got a increased propensity for development of cerebrovascular diseases.

PRIMARY EXERCISE HEADACHE

It has features resembling both cough headache & migraine.It may be precipitated by any form of exercise. Often has the pulsatile quality of migraine.Exercise regimen should begin modestly and progress gradually to higher levels of intensity. Indomethacin at daily doses from 25-150 mg is generally effective.

PRIMARY HEADACHE ASSOCIATED WITH SEXUAL ACTIVITY

3 types of sex headache are reported: A dull bilateral ache in head & neck that intensifies as sexual excitement increases; a sudden severe, explosive headache occurring at orgasm; a postural headache developing after coitus that resembles the headache of low CSF pressure. Management can often be limited to reassurance. Propanolol is used, dose varies from 40-200mg/day. An alternative is CCB like Diltiazem 60 mg tid.

CONCLUSION

Our current understanding regarding the primary headache disorder has greatly accelerated in recent years. Clarity in population prevalence of the most common primary headache disorders, TTH & migraine has been restored by eloquent and well designed epidemiological studies like AMPP. Migraine comorbidity, and in particular, its relationship with CVD, has become an intense area of investigation, thanks to large cohort studies of the WHS and PHS increasing clinical and radiologic

10. Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedkov JF, et al. Premonitory symptoms in migraine: An electronic diary study. Neurology 2003; 60:935-40. [Pub Med] 11. Rasmussen BK, Jensen R,Olesen J. Ppulation-based analysis of the diagnostic criteria of the International Headache Society. Cephalagia 1991; 11:129-34. [Pub Med] 12. Kalman L. Migraine pain location: A tertiary care study of 1283 migraineures. Headache 2005; 45:1038-47. .[Pub Med] 13. Chakravarty A, Mukherjee A, Roy D. Migraine pain location in adult patients from eastern India. Annals Indian Acad of Neurol 2008; 11:98-102. [PMC free article] [Pub Med] 14. Kaube H, Keay KA, Hoskin KL, Bandler R, Goadsby PJ. Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical spinal cord following stimulation of the superior sagittal sinus in the cat. Brain Res 1993; 629:95-102 [Pub Med] 15. Couch JR, Diamond S. Status migraineosus: Causative and therapeutic aspects. Headache 1983; 23:94-101. [Pub Med] 16. Busch V, Jakob W, Juergens T, Schulte-Mattler W, Kaube H, May A. Occipital nerve blockade in chronic cluster headache patients and functional connectivity between trigeminal and occipital nerves. Cephalalgia 2007; 27:126-14 [Pub Med]. 17. Afridi SK, Shields KG, Bhola R, Goadsby PJ. Greater occipital nerve injections in primary headache syndromesprolonged effects from a single injection. Pain 2006; 122:1269. [Pub Med]

18. Saper JR, Dodick DW, Silberstein SD, McCarville S, Sun M et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia 2010; 31:271-85. [PMC free article] [Pub Med] 19. Cao Y. Weich KM. Aurora S. et al. Fundamental MRI-BOLD of visually trigerred headache in patients with migraine. Arch Neurol 1999; 56:548-554. 20. Charles A and Brennan K. Cortical spreading depression –new insights and persistent questions. Cephalagia 2009; 29:1115-1124.

22. Cutrer FM Sorensen AG, Weisskoff R.M. et al. Perfusion weighted imaging defects during spontaneous aura Ann Neurol 1998; 43:25-31.

36. Hansen JM, Thomsen LL, Olesen J, et al. Coexisting typical migraine in familial hemiplegic migraine. Neurology 2010; 74:594-600. 37. Lizuka T, Takhahashi Y, Sato M, et al. Neurovascular changes in prolonged migraine aura in FHM with a novel ATPIA2 gene mutation J Neurol Neurosurg Psychiat 2012; 83:205-212. 38. Jurkat-Rott K, Freilinger T, Dreier JP, et al. Variability of familial hemiplegic migraine with novel AIA2 Na + /K+ATPase variants. Neurology 2004; 62:1857-1861. Kirchmann M, Thomsen LL, and Olesen J. Basilar –type migraine: clinical, epidemiologic and genetic features. Neurology 2006; 66:880-886.

23. Eriksen MK Thomsen LL. Andersen I. et al. Clinical characteristics of 362 patients with familial migraine with aura. Cephalagia 2004; 24:564-575.

39. Leo L, Gherardini L, Barone V, et al, Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type-2. PloS Genet 2011; 7:el002129.

24. Eriksen MK, Thomsen LL and Olesen J. Implications of clinical subtypes of migraine with aura. Headache 2006:46:286-297. Matharu MJ and Goadsby PJ. Posttraumatic chronic paroxysmal hemicranias (CPH) with aura. Neurology 2001:56:273-275. Morrison DP, Abnormal perceptual experiences in migraine Cephalagia 1990; 10:273-277.

41. Akhtar ND, Murray MA and Rothner AD. Status migrainosus in children and adolescents. Semin pediatr Neurol 2001; 8:27-33.

25. Silberstein SD. Niknam R. Rozen TD et al. Cluster headache with aura. Neurology 2004; 54219-221. Wijinan CA. Wolf PA. Kase CS. et al. Migraines visual accompaniments are not rare in late life: The Framingham Study. Stroke 1998; 29:1539-1543. 26. Ambrosini A. D’Onofrio M, Greco GS et al, Famillial basilar migraine associated with a new mutation in the ATPIA2 gene. Neurology 2005; 65:1826-1828. 27. Bickerstaff E. R. Basilar artery migraine Lancet 1961;1:15 Caplan LR. Migraine and vertebrobasilar ischemia. Neurology 1991; 4155:61. 28. Enksen MK. Thomsen LL and Olesen. J Implecations of clinical subryptes of migraine with aura. Headache 2006; 46:286-297. 29. Kirchman M. Thomsen LL and Olesen J. Basilar-type migraine: Clined epidomlogic and genetic features. Neurology 2006; 66:880-886. 30. Ambrosini A, D’ Onofrio M, Grieco GS, et al Familial basilar migraine associated with a new mutation in the ATPIA2 gene. Neurology 2005; 65:1826-1828. 31. De Fusco M, Marconi R, Silvestri L, et al. haploinusfficiency of ATPIA2 encoding the NA+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type2. Nat Genet 2003; 33:192-196. 32. Discharge M, Freilinger T, Eskstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCNIA in familial hemiplegic migraine. Lancet 2005; 366:371-377. 33. Dreier JP, Jurkat-Rott K, Petzoid GC, et al. Opening of the blood brain barrier proceeding cortical edema in a severe attack of FHM type II. Neurology 2005; 64:2145-2147. 34. Eriksen MK, Thomsen LL and Olesen J. Implications of clinical subtypes of migraine with aura. Headache 2006; 46:286-297.

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40. Carroll D. Retinal migraine Headache 1970;10:9-13, Chronicle EP and Mulleners WM. Visual system dysfunction in migraine: A review of clinical and psychological findings Cephalalgia 1996; 16: 525-535.

42. Bono G, Minonzio G, Mauri M and Clerrici AM. Complications of migraine: Migrainous infarction Clin Exp Hyper tens 2006; 28:233-242. 43. Carroll D. Retinal migraine Headache 1970;10:9-13, Chronicle EP and Mulleners WM. Visual system dysfunction in migraine: A review of clinical and psychological findings Cephalalgia 1996; 16:525-535. 44. Prameela B et al., Sch Acad J Pharm 2014; 3:285-289. 45. Wikinson M,Williams K,Leyton M.Observations on treatment of an acte attack of migraine.Res Clin Stud Headache 1978; 6:141-146. 46. Johnson ES,Ratcliffe DM,Wilkinson M.Naproxen sodium in treatment of migraine. Cephalagia 1985; 5:5-10. 47. Bates D,Ashford E,Dawson R,et al.Subcutaneous sumatriptan during migraine aura.Sumatriptan Aura Study Group. Neurology 1994; 44:1587-1592. 48. Walter S,Bigal ME CGRP receptor antagonist and antibodies against CGRP and its receptor in migraine treatment.Br J Clin Pharmacol 2015; 80:193-19. 49. May A. Cluster headache: pathogenesis, diagnosis & management. Lancet 2005; 366:843-855. 50. Drummond PD. Dysfunction of the sympathetic nervous system in cluster headache. Cephalgia 1988; 8:181-186. 51. Sjaastad O, Editor. Cluster headache syndrome. London: W.B. Saunder; 1992. 52. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33:629.

CHAPTER 80

21. Cologno D. Torelli P and Manzoni GC, Migraine with aura: A review of 81 patients at 10-20 years’ follow-up. Cephalagia 1998; 18:690-696.

35. Plansen JM, Schytz HW, Larsen VA et al. Hemiplegic migraine aura begins with cerebral hypoperfusion : imaging in the acute phase. Headache 2011; 51:1289-1296.

Approach to Hyperkinetic Movement Disorders

C H A P T E R

Balamurugan Namasivayam

Movement disorders is a group of neurologic conditions that can be divided phenomenologically into slow movements(hypokinetic) and abnormal involuntary movements(hyperkinetic) (Table 1). The hypokinetic disorders are characterized not only by slowness of movement but also by paucity of movements. The most characteristic feature of hypokinetic movement disorder is bradykinesia, typically present in Parkinsonian disorders. Hyperkinetic disorders are subdividided into tremor, tics, myoclonus, athetosis, ballismus, chorea, dystonia, sterotype an akathisia. Furthermore ataxia, gait disorders and spasticity are also often included among movement disorders. While the basal ganglia and their connections have been implicated in the pathophysiology of most of the movement disorders, some are caused by altered peripheral input as exemplified by hemifacial spasm and other peripherally induced movement disorders. A subset of movement disorders with varied phenomenology is caused by psychological factors , hence referred to as â&#x20AC;&#x2DC;psycogenic movement disordersâ&#x20AC;&#x2122;. Because the diagnosis of a movement disorder is based on recognition of specific phenomenological features, clinicians who encounter patients with movement disorder must use their powers of observation to carefully categorize the disorder. The phenominological categorization is absolutely critical for formulation of etiological diagnosis and selection of the appropriate treatment. Many hyperkinetic movement disorders manifest with multiple types of movements, which may include a combination of the various hyperkinesias. The basal ganglia regulate the initiation, scaling, and control of the amplitude and direction of movement.

Table 1 : Classification of Movement Disorders Hypokinetic

Hyper kinetic

Parkinsonism

Tremor

Apraxia

Tics

Blocking tics

Myoclonus

Catatonia

Athetosis

Cataplexy and drop attacks

Ballismus

Hypothyroid slowness

Chorea Dystonia Dyskinesia

Movement disorders can result from biochemical or structural abnormalities in these structures. The basal ganglia are a complex of deep nuclei that consist of the corpus striatum, globus pallidus, and substantia nigra. The corpus striatum, which includes the caudate nucleus and the putamen, receives input from the cerebral cortex and the thalamus and, in turn, projects to the globus pallidus. The substantia nigra is divided into the dopamine-rich pars compacta and the less dense pars reticularis. The pars reticularis is similar histologically and chemically to the medial segment of the globus pallidus, and both project via the thalamus to the premotor and motor cortex. The substantia nigra pars compacta gives rise to the nigralstriatal pathway, which is the main dopaminergic tract. The output of the basal ganglia projects by way of the thalamus to the cerebral cortex and then to the pyramidal system. Basal ganglia output is sometimes referred to as the extrapyramidal system because it was formerly thought to be in parallel with the pyramidal system. Integration of the basal ganglia with the cortex facilitates motor control.

PHYSIOLOGICALLY MOVEMENTS CAN BE CATEGORIZED INTO ONE OF FOUR CLASSES

1. Automatic 2.

Voluntary

Semivoluntary or unvoluntary

Involuntary

Automatic movements are learned motor behaviors that are performed without conscious effort. Eg: The act of walking or speaking ;the swing of arms during walking Voluntary movements are intentional (planned or self initiated) or externally triggered Eg: Turning the head toward a loud noise or withdrawing a hand from a hot plate. Intentional voluntary movements are preceded by the Bereitschafts potential (or readiness potential), a slow negative potential recorded over the supplemental motor area and contralateral motor cortex appearing 1 to 1.5 seconds prior to the movement. The Bereitschafts potential does not appear with other movements including externally triggered voluntary movements. In some cases learned voluntary motor skills are incorporated within in the repertoire of the movement

disorders such as camouflaging choeric movements or tics by immediately following them with voluntary executed movements so called parakinesias.

Step 2: Sustained Versus Non Sustained Sustained 1.

Rigidity

Dystonia

Oculogyric crisis

Paroxysmal dystonia

Dystonia tics

Sandifer syndrome

Step 1: Rhythmic Versus Arrhythmic

Stiff person syndrome

Rhythmic

Congenital torticollis

Tremor

Orthopedic torticollis

Resting

Non Sustained

Posturing

Action

Step 3 : Paroxysmal Versus Continual Versus Continuous

Intention

Dystonic tremor *

Dystonic myorhythmia*

Myoclonus,segmental*

Epilepsia partialis continua

Myoclonus,oscillatory

Moving toes/ fingers

Myorhythmia*

Periodic movements in sleep

10.

Tardive dyskinesia(tardive stereotypy)*

Involuntary movements are often non suppressible (Eg most tremors and myoclonus) but some can be partially suppressible (Eg some tremors., chorea, dystonia, stereotypies and some tics).

STEPWISE APPROACH TO MOVEMENT DISORDERS

Arrhythmic 1.

Akathitic movements

Athetosis

Ballism.

Chorea

Hemifacial spasm

Hyperekplexia

Arrhthmic myoclonus

Stereotypy

Tics

10.

Dystonia*

*Dystonias often, but not always, has repetitive movements, which were coined as myorhythmia by Herz and now labeled as dystonic tremor and patterned

385

All others

Paroxysmal 1.

Tics

PKD

PNKD

PED

Paroxysmal ataxia

Paroxysmal tremor

Hypnogenic dystonia

Stereotypies

Akathitic movements

10.

Jumpy stumps

11.

Moving toes

12.

Myorrhythmia

Continual 1.

Ballism

Chorea

Dystonic movements

Myoclonus,arrhythmic

Some stereotypies

Akathitic moaning

Continuous 1.

Abdominal dyskinesias

2. Athetosis

CHAPTER 81

Semivoluntary or unvoluntary movements are induced by an inner sensory stimulus (Eg; need to stretch a body part or need to scratch an itch ) or by an unwanted feeling or compulsion (Eg: compulsive touching or smelling). Many of the movements occurring as tics are as a response to various senasation (Eg; akathesia and the restless leg syndrome) can be considered unvoluntary because the movemets are usually the result of an action to nullify an unwanted , unpleasant sensation. Unvoluntary movements are suppressible.

movements. Today , myorhythmia refers to the slow , rhythmic movements, most classically seen in Whipple disease. Segmental myoclonus is typically rhythmical, whereas other forms of myoclonus are arrhythmic. Stereotypies can occur at irregular intervals, and these are in the right hand column above. In contrast, classical tardive dyskinesia movements are continuous, and these stereotypies are placed in the left hand column.

NEUROLOGY

386

Tremors

Dystonic postures

7. Minipolymyoclonus

Minipolymyoclonus

Myoclonus, rhythmic

9. Myoclonus*

Tardive stereotypy

10.

Tic status

11. Pseudodystonias*

Jumpy stumps Moving toes/ fingers Myokymia

9. Myokymia

12.

•

*Paradoxical dystonias refers to dystonias refers to dystonias that is present only at rest disappears with action; orthostatic tremor is tremor of the thighs and legs (spreading to the trunk) that occurs only on prolonged standing and disappears with walking or sitting ; most dystonias and myoclonus that are present at rest are also present and often worse with action as well; pseudodystonias refer to neuromyotonia and other causes of stiff musclaes or postures that are not due to dystonia (common are orthopredic deformities and pain).

Continual means over and over again; Continuous means without stopping or unbroken.

Step 4: Present While Asleep Or Awake

Appears during sleep and disappears when awakened 1.

Hypogenic dyskinesias

Periodic movements in sleep

Persists during sleep 1.

Secondary palatal myoclonus

Ocular myoclonus

Ocu;ofacialmasticatory myorhythmia

Moving toes

Myokymia

Neuromyotonia(Isaacs syndrome)

Diminishes during sleep 1.

All others

Step 5: Present At Rest Or With Action

At rest only (disappears with action) 1.

Akathitic movements

Paradoxic dystonia*

Resting tremor

Restless legs

Orthostatic tremor(only on standing)

With action only 1. Ataxia 2.

Action dystonia

Action myoclonus

Orthostatic tremor*

Tremor: postural,action,intention

Task- specific tremor

Task- specific dystonia

At rest and continues with action 1.

Abdominal dyskinesias

2. Athetosis 3.

Ballism

Chorea

Dystonia*

Tics

Step 6: Patterned and Non Patterned Movements Patterned (i.e., same muscle groups) 1.

Abdominal dyskinesias

2. Dystonias 3.

Hemifacial spasm

Moving toes/fingers

Segmental myoclonus

Myorhythmia,Myokymia

Tardive stereotypy

Tremor

Non patterned 1.

All others

Step 7: Combination of Varieties of Movements 1.

Psychogenic movement disorders

Tardive syndromes

Neuroacanthocytosis

Wilson disease

Huntington disease

DRPLA

7. Dystonia* *Patients with dystonia have additional dyskinesias that are part of the spectrum of classical torsion dystonia. These include tremor,myoclonus and choreic – like movements. Dystonia – plus syndromes can have features of parkinsonism or myoclonus in addition to dystonia.

Step 8: Speed (Fast Versus Slow) Fastest 

1. Minipolymyoclonus 2.

Myoclonus

Hyperekplexia

Hemifacial spasm

Intermediate  1.

Chorea

Ballism

Jumpy stumps

4. 5.

Lesch- Nyhan Syndrome

2. Neuroacanthocytosis

Tremors

Psychogenic movement disorders

Tardive steretypy

Step 14: With Complex Movements

Moving toes/fingers

Myorhythmia

Akathitic movements

Step 9: Amplitude Ballistic

Ballism

Not Ballistic Chorea and all others

Very Small 1. Minipolymyoclonus

Tics

Akathitic movements

Compulsions

Stereotypies

Psychogenic movements

Note: Each of the above can have simple movements as well.

Step 15: Presence Of Sensory Component 1. Akathisia 2.

Moving toes,painful legs

Restless legs

Tics

Step 16: Presence Of Ocular Movements 1.

Tics

Powerful

Oculogyric crises

Stiff person

Opsoclonus

Jumpy stumps

Ocular myoclonus

Intermediate

Ocular myorhythmia

Ocular dysmetria

Step 10: Force

Dystonia

Easy to overcome 1.

All others

Step 11: Suppresibility Suppressible 1.

Stereotypies>tics,akathitic movements>chorea>ball ism>dystonia>tremor>moving toes

7. Nystagmus

REFERENCES

1. 2. 3.

Not suppressible 1.

Hemifacial spasm

2. Minipolymyoclonus 3.

Myoclonus

Hyperekplexia

Myorhythmia

Moving toes

Step 12: Vocalizations

Vocal tics: simple or complex

Akathisia: moaning

Huntington disease

Neuroacanthocytosis

Joseph Jankovic and Randilph W Evans. Movement Disorders , Neurology clinics, Elsevier 2015. Stanley Fahn and Joseph Jankovic Principles and Practice of Movement Disorders Elseiver 2007. Joseph Jankovic and Eduardo Tolosa, Parkinsons disease and movement disorder ; Lippincott Williams & Wilkins 1988. Alvarez MV, Evidente VG, Driver-Dunckley ED. Differentiating Parkinson’s disease from other parkinsonian disorders. Semin Neurol 2007; 27:356–62. Dekker MCJ, Bonifati V, van Duijn CM. Parkinson’s disease: piecing together a genetic jigsaw. Brain 2003; 126:1–12. Jankovick J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatr 2008; 79:368–76. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on tremor. Ad Hoc Scientific Committee. Mov Disord 1998; 13(Suppl 3):2–23. Elble RJ. Diagnostic criteria for essential tremor and differential diagnosis. Neurology 2000; 54(11 Suppl. 4):S2–6. Dressler D, Benecke R. Diagnosis and management of acute movement disorders. J Neurol 2005; 252:1299–306.

CHAPTER 81

387

Step 13: Presence of Self Mutilation

Tourette Syndrome

1. Athetosis

Cranial dystonia

Slowest

C H A P T E R

Management Tips of Epilepsy: A Physician’s Perspective

Epilepsy is a ubiquitous disease and is known to antiquity. It is characterized by occurrence of recurrent seizures secondary to disease or dysfunction of the central nervous system. Seizures occur due to abnormal hyper synchronous discharges of cortical neurons and the clinical features depend upon the location and extent of the propagation of the discharging neurons. Acute symptomatic/provoked seizures are defined as clinical seizures occurring at the time of a systemic insult or inclose temporal relationship with an acute CNS insult e.g. metabolic,toxic,structural,inflammatory or infectious causes. Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized byan enduring predisposition to generate epileptic seizures. This definition is usuallypractically applied as having two unprovoked seizures >24 h apart. Physician should be able to initiate management, alleviate misunderstandings and refer appropriately when required. The latest practical definition accepted byThe InternationalLeague Against Epilepsy (ILAE) considers epilepsy to be a diseaseof the brain defined by any of the following conditions: 1.

At least two unprovoked (orreflex) seizures occurring >24 h apart;

one unprovoked (or reflex) seizure and aprobability of further seizures similar to the general recurrence risk (at least 60%) aftertwo unprovoked seizures, occurring over the next 10 years;

diagnosis of an epilepsysyndrome. This revised definition of epilepsy brings the term in concordancewith common use.

DIAGNOSIS

Diagnosis of epilepsy requires detailed history especially information from eyewitness regarding the semiology of seizure. Several conditions like convulsive syncope, transient ischemic attacks, parasomnias and psychogenic episodes (dissociative attacks) may mimic seizures. A correct diagnosis, rational treatment, reassurance and family education can lead toimproved quality of life for an epileptic patient. Though diagnosis of epilepsy is clinical, EEG is an important part of the workup. Neuroimaging preferably MRI is helpful to evaluate for structural lesions. Video EEG is the simultaneous recording of video and EEG of seizures in patients with epilepsy. It helps to localize the epileptic focus in the presurgical evaluation of epilepsy. It can also help to differentiate dissociative attacks from true epileptic seizures.

Sudhir V Shah

DRUG THERAPY FOR EPILEPSY- BASIC PRINCIPLES

Medical therapy for seizures is started if patient clearly has proven unprovoked seizures. The principle of AED therapy is to use appropriate monotherapy in full doses before a second drug is added if the response is suboptimal. When starting drug therapy one should start at a lower dose and should gradually titrate to full dose.Selection of the antiepileptic drug is based on the seizure type and side effect profile of the drug, comorbid illnesses in the patient, and cost of long term therapy. Remarkable nonspecificity of therapy is a striking feature of most partial and tonic – clonic epilepsies of adult life, regardless of cause. This is perhaps because the antiepileptic drugs act on the final physiological processes of epilepsy which are similar whatever the cause. Side effects vary, however, more than efficacy,and the choice of drugs is often influenced more by them. Certain AEDs themselves aggravate or precipitate seizures. Carbamazepine, phenytoin, and phenobarbitone can aggravate absence seizures. Carbamazepine, phenytoin, vigabatrin, and lamotrigine can aggravate myoclonic seizures. Benzodiazepine can exacerbate tonic seizures.

CHOICE OF ANTIEPILEPTIC DRUG THERAPY BASED ON SEIZURE TYPE Type of seizure

Drug

Primary generalized tonic– clonic seizures

Valproate, lamotrigine, levetiracetam

Partial seizures, secondary Carbamazepine, generalized tonic-clonic oxcarbazepine, phenytoin, seizures valproate, lamotrigine Typical absence seizures

Valproate, lamotrigine, levetiracetam

Myoclonic seizures

Valproate, levetiracetam

Atypical absence, tonic and atonic seizures

Valproate, Lamotrigine, levetiracetam, topiramate

About 60% of all epilepsies respond to the first appropriate monotherapy. An additional 10% respond to addition of a second AED. The added value of seizure control of a third AED is to only 3-4% of patients. 25% of patients continue to have seizures despite 2 or 3 AEDs. This constitutes medically refractory epilepsy. Common substrates of refractory epilepsy like cortical dysplasia and cavernomas, mesial temporal sclerosis (MTS) can sometimes be identified only on 3 Tesla MRI with special imaging protocols. MTS constitutes over 50% of all refractory epilepsy. The typical history is of childhood

Stage-1 first 30 minutes

Stage-2 30-120 minutes

Stage-3 >120 minutes

• Stage 2 - Established SE • IV AED- eg. phenytoin,phenobarbitone, valoproate

• Stage 3 - Refractory SE • General anaesthesia- propofol, midazolam, thiopentone • Super-refractory SE- SE which has continued or recurred despite treatment with general anaesthesia for 24 hours or more

Fig. 1 : Algorithm for Management of Status Epilepticus febrile seizures followed by refractory focal seizures with dyscognitive features with rare secondary generalization. Many of these patients can be treated by anterior temporal lobectomy, after proper presurgical evaluation. Ketogenic diet consists of a fat to carbohydrate and protein ratio of 3:1 or 4:1. It may be tried in children with intractable seizures, with AED intolerance or side effects, and with specific metabolic defects, or as a bridge to control seizure when patient is considered for surgery.

SINGLE UNPROVOKED SEIZURE- WHEN TO TREAT?

5-10% of the population suffer from at least one seizure during lifetime. Not all first seizures mean the beginning of epilepsy. Risk of recurrence of seizure after first event is 40% during lifetime. Most recurrences occur early- 50% of seizures recur within first 6 months. 2 year risk of being seizure free is about the same whether or not AEDs are started after first unprovoked seizure. Most important indicators of recurrence include structural lesions on MRI (strongest predictor), abnormal EEG, partial seizure type, seizure in sleep, postictal motor paralysis and positive family history. Normal routine EEG doesn’t rule out epilepsy. First EEG is abnormal in 30-50% of patients and 2 serial EEGs are abnormal in 70-80% of patients after first seizure.

HOW TO DISCONTINUE AED?

Decision to withdraw AED in patient with controlled epilepsy needs expertise and has to be individualized. Continuing or discontinuing the treatment depends upon the risk-benefit ratio. JME may need low dose AED for lifelong. Successful withdrawal of AED is likely in childhood onset epilepsy, in patient with normal EEG, and in adult who is seizure free on AED for 2 or more years. The persistence of spike – wave inthose with IGE is the most useful prognostic EEG feature, suggesting a higher chance of relapse. AED should be withdrawn slowly with reduction by 25% of daily dose every 5 elimination halflife. Taper a single AED over 4 – 6 wks. For the patient on 2 drugs first taper one drug and if seizure free, second withdrawal can be attempted. Of patients who are going to experience a recurrence of seizures on withdrawal, 50%

do so during the reduction phase and 25% in the first 6 months after withdrawal.

389

NEWER AEDS

Rufinamide, lacosamide, clobazam, zonisamideand Ezogabine are the drugs which are recently approved in epilepsy. Lacosamide acts on slow inactivation of voltage gated Na channels.Rufinamide acts on fast inactivation of Na channels which is useful in Lenox-Gastaut syndrome. Clobazam is benzodiazepine acting on chloride channels. Other drugs include brivaracetam, eslicarbazapine, stiripentol, perampanel and a few others.

RECENT ADVANCES AND FUTURE TRENDS

Vagus nerve stimulation has been used as an adjunctive treatment for medically refractory partial-onset seizures in adolescents and adults. One third of patients had a 50% or greater reduction in seizure frequency. Gamma knife surgery, deep brain stimulation, gene therapy, polymer based therapy, and medical use of marijuana are also being considered for seizures.

STATUS EPILEPTICUS

As per latest definition given by neurocritical care society in 2012, status epilepticus is definedas >5 min of (a) continuous clinical and/or electrographic seizure activity or (b) recurrent seizure activity without recovery between seizures. Etiology is the main determinant of outcome of status epilepticus. IV Benzodiazepines (Lorazepam / Diazepam / Midazolam) are clearly the first line of treatment. IV lorazepam is easily available and at dose of 0.1 mg/kg it has superior efficacy, short latency, prolonged effect> 6 hours, and minimal respiratory depression, while diazepam has lower efficacy and effect lasts up to 20 minutes. IV midazolam is also short acting and requires additional drug/dosage (Figure 1).

EPILEPSY IN ELDERLY PEOPLE

Epilepsy is a frequent and generally under – recognized problem in elderly people. It can be difficult to differentiate seizures from syncope, hypoglycemia, transient ischemic attacks and transient global amnesia in them. Uncontrolled seizures are likely to be more hazardousin an elderly patient. In elderly patients, choice of AED and dosing will have to be adjusted to comorbid disease. Therapy should generally beinitiated with lower doses than in the young adult. Adequate calcium and vitamin D supplementation is essential especially with enzyme inducing drugs. Renal and hepatic function and plasma protein concentrations should be measured before therapy is started. Blood level measurements should be made at regular intervals,for relevant drugs, at least until stable regimens have been achieved. Drug combinations should be avoided especially in elderly where possible. Elderly patients are more vulnerable to druginduced impairment of gait and tremor. Initiate carbamazepine therapy slowly inindividuals aged > 65 years, slowly increase the dose. The slow - release formulation causes fewer side effects. The lack of drug interactions, and the

CHAPTER 82

After 24 hours

• Stage 1- Early status epilepticus(SE) • Treat with BZD- eg. IV lorazepam, buccal midazolam, IV or rectal diazepam

NEUROLOGY

390

simple pharmacokinetics,of levetiracetam are advantages in elderly people. Levetiracetam is useful and safe although they should be monitored for behavioral side effects. Lamotrigine is better tolerated in elderly but its clearance is reduced by a third when compared to young. The metabolism of phenytoin can be saturated at lower levels that in young. Frequent serum level measurements are essential. Valproate is effective for generalized tonicclonic seizures in elderly but its half-life can be doubled in them. Encephalopathic side effects of valproate are more common in elderly. Chrono (slow release) formulation has doubtful advantage if any.

ISSUES FOR WOMEN WITH EPILEPSY (WWE)

Estrogen has neuroexcitatory properties and progesterone has neuroinhibitory properties. Therefore, changes in endogenous and exogenous female hormone levels can influence seizure control. Enzyme inducing drugs increase metabolism of hormones. OC pills have significant drug interaction with carbamazepine, phenobarbitone, phenytoin, topiramate and lamotrigine. Oestrogen is enzyme inducer especially of glycosylation and decreases level of lamotrigine by 30%. Levetiracetam, gabapentin, zonisamide, and valproate donâ&#x20AC;&#x2122;t affect contraception. Depot medroxyprogesterone levels are not affected by enzyme inducing drugs. Infertility is particularly common in women taking polytherapy. Up to 60% women on valproate get PCOS, usually if drug is started below age of 26.

The major congenital malformations (MCM) most commonly associated with AED exposure include congenital heart disease, cleft lip/palate, urogenital defects and neural tube defects. MCM rates in the general population is around 2%,and women with epilepsy who are not receiving AEDs show similar rates. The Lowest rates of malformation were seen with LTG doses of <300 mg/day(2%) and CBZ doses of <400 mg/day(3.4%). The risks of malformation were significantly higher at all evaluated doses of valproate and phenobarbitone. With AED exposure and pregnancy the rates vary between 3.1% to 9%. Usually MCM occurs before 60 days. Preconception counseling and folate therapy is essential in WWE. High resolution Ultrasound screening or fetal MRI at 18-20 weeks gestation can identify many fetal anomalies. Fetal exposure to valproate is associated with lower IQ and increased risk of autism. Pre pregnancy seizure frequency has important relation with seizure recurrence during pregnancy. Seizure free period over previous 9 months provides over 90% chance of seizure free pregnancy. AEDs are excreted into breast milk to a variabledegree. Due to the overall benefits of breast-feeding, mothers with epilepsy can be encouraged to breast-feed. If there is presence of lethargy or poor feeding in infant, change of AED should be considered.

C H A P T E R

Management of Epilepsy in Special Situations

INTRODUCTION

Epilepsy poses a great challenge to physicians in its management when it is associated with special situations. In these special situations, epilepsy can occur either as an index disease with other diseases or there can be concurrent occurrence of several chronic disorders requiring treatment. Furthermore it has been suggested that prevalence of cardiovascular disorders, infections, pulmonary disease and gastrointestinal hemorrhage is increased in people with epilepsy. Here, we review the management of epilepsy in these various situations where epilepsy is either as an index disease or present concurrently with other chronic diseases. The recognition and treatment in such situations strengthen the comprehensive care of epilepsy.

ORGAN DYSFUNCTION AND EPILEPSY

Epilepsy can occur concomitantly with organ (e.g., hepatic, renal or endocrine) dysfunction and it may or may not be related to the latter. The presence of concurrent organ dysfunction in epilepsy has various implications in its management, which are as follows: 1.

Organ dysfunction may occur as a complication of epilepsy or its treatment.

Organ dysfunction may have an effect on treatment.

Seizures may occur as a manifestation of organ dysfunction or as a manifestation of a disorder that affects the brain as well as the body organ.

Epilepsy may impact treatment of the organ disorder.

HEPATIC AND RENAL DISEASE

Antiepileptic drug (AED) metabolism occurs largely in the liver while elimination of drugs usually occurs via either the liver or the kidney or both. Besides, the liver and kidney are involved in synthesis and regulation of plasma proteins and many AEDs are extensively protein-bound. Hence, both hepatic and renal dysfunction may affect AED pharmacokinetics through a variety of mechanisms. Hepatic dysfunction can be divided into acute and chronic. On the basis of previous data, acute hepatic dysfunction (due to toxins and viral hepatitis) does not significantly alter AED pharmacokinetics. Midazolam, in view of its short duration of action, can be used for aborting the seizures and phenytoin (with a loading dose), phenobarbital, gabapentin and levetiracetam may be used for status epilepticus or recurrent seizures in the setting of acute hepatic dysfunction. However, dosage adjustments

Jaslovleen Kaur, Gagandeep Singh

are required in chronic liver disease (i.e., cirrhosis), mainly due to the proportion of AED being metabolized or eliminated in the liver or the degree of protein binding. Most of the available AEDs have low hepatic extraction ratios, except conventional AEDs, including phenytoin, valproate, carbamazepine, phenobarbital and primidone, which are chiefly metabolized in the liver. In many liver disorders, impaired protein synthesis results in reduced fraction of the protein-bound drug and elevated free levels of the drug. Hence, dosage considerations in chronic hepatic dysfunction should be based on clinical response to AED (i.e., degree of seizure control) and estimation of free drug levels, along with slower titrations and lower maintenance doses of AEDs. In renal dysfunction, reduced glomerular filtration and tubular secretion may result in reduced drug elimination. To add to this, there are both quantitative (i.e., protein loss in nephrotic syndrome) and qualitative changes in plasma proteins. This may result in elevated free drug levels. Furthermore, the need of dialysis in both acute and chronic renal dysfunction, may also lead to loss of AED from the body. For certain AEDs, dosage guidelines have been reviewed regarding supplemental doses in immediate post-dialysis period. (Table 1)

CARDIAC DISEASE

A variety of life-threatening cardiac arrhythmias have been described in epilepsy. They may be present either as effects of seizures on cardiac rhythm or various cardiac disorders associated with epilepsy. Ictal tachycardia is seen with intense sympathetic discharge during seizures, while excessive parasympathetic discharge results in ictal asystole. For various cardiac rhythm disorders with epilepsy, a genetic basis involving sodium and potassium ion channel disorders has been suggested. The most common cardiac rhythm disorder seen is atrio-ventricular heart block (AV block) associated with carbamazepine and lacosamide. QT interval abnormalities inherited or as a consequence of AED (such as carbamazepine and phenytoin), may account for a proportion of cases of sudden unexpected death in epilepsy (SUDEP). A baseline electrocardiogram should be ordered, for QT interval abnormalities and AV blocks, before commencing AED treatment. Barbiturates, valproate and most of newer AEDs are safer in such situations.

PULMONARY DISEASE

Obstructive sleep apnoea has been encountered in people with epilepsy (PWE). The high frequency of sleep apnoea

392

Table 1: Dosage Adjustments for Newer Antiepileptic Drugs in Patients with Reduced Kidney Function Supplementary Dose After Hemodialysis

Total Daily Dose (GFR, in mL/min)

NEUROLOGY

AED

60-89

30-59

15-29

<15

Gabapentin

400-600 mg TID

200-300 mg BID

200-300 mg/day

100-150 mg/day or 300 mg every other day

125-250 mg

Levetiracetam

500-1000 mg BID

250-750 mg BID

250-500 mg BID

250-500 mg

Topiramate

100-200 mg BID

50-100 mg BID

50-100 mg

Oxcarbazepine

300- 600 mg BID

50% of original dose

Insufficient data; use with caution

100-400 mg

Zonisamide

in people with epilepsy has been attributed to depressive effect of nocturnal seizures and AEDs on airway muscle tone. Treatment of sleep apnoea with continuous positive airway pressure (CPAP) ventilation has been shown to improve seizure control. Bronchodilator treatment with theophylline in pulmonary airway disease can result in seizures, usually in extremes of age and with over-dosages. Theophylline therefore should be used cautiously in PWE. A rare complication of seizures and status epilepticus is neurogenic pulmonary edema, occurring within a few hours of the seizure and may present with dyspnea, breathing difficulty and hemoptysis, leading to cardiovascular collapse and SUDEP. Intensive cardiopulmonary support is the mainstay of this emergency.

THYROID DISEASE AND EPILEPSY

Subclinical hypothyroidism due to carbamazepine, phenytoin and valproate has been reported. These effects have been attributed to enzyme inducing effects of AEDs or effects on the hypothalamic centers regulating thyroid function. However, the abnormalities revert upon withdrawal of the AED. In individuals with pre-existing thyroid dysfunction, such AEDs with demonstrated effects on thyroid function should best be avoided.

CANCER AND EPILEPSY

Limited data is available regarding the incidence of seizures in people with cancer. However there appear to be some differences between adults and children for the etiology of seizures. In children, the myelo-ablative therapy (busulphan for leukemia) has been related with high frequency of seizures, and in adults, intracranial metastasis is mostly the culprit. Anti-cancer drug induced seizures and metabolic disturbances are the other common causes, and such seizures do not require long term AED treatment. In the treatment of such acute seizures, a drug with rapid onset

Insufficient data; use with caution

Supplement 50% dose if seizure occurs after hemodialysis

Table 2: Cancer Chemotherapeutic Agents that are Substrates for Enzyme-Inducing Action of Aeds Agent

Reference

Methotrexate

Relling et al., 2000

Busulfan

Hassan et al., 1993

Cyclophosphamide Alberts et al., 1976, 1978 Ifosfamide

Lu et al., 1998

Vincristine

Villikka et al., 1999

Doxorubicin

Cusack et al., 1988; Sturgill et al., 2000

Paclitaxel Tamoxifen

Fetell et al., 1997; Chang et al., 1998 Moorthy et al., 1997

of action is preferred. Oral benzodiazepines (lorazepam or clonazepam) are routinely administered prophylactically before and until 24 hours after high dose busulphan as myelo-ablative treatment. Many cancer chemotherapeutic agents are substrates for the enzyme inducing action of AEDs. In the presence of conventional AEDs, higher doses of anti-cancer agents (e.g. paclitaxel) are recommended when given concomitantly. Newer AEDs that do not induce hepatic microsomal enzyme systems may be preferred for seizure control in people with cancer (Table 2).

INFECTIONS AND EPILEPSY

Human Immunodeficiency Virus Infection and Seizures

Seizures are common in human immunodeficiency virus (HIV) infection and these typically occur in the later stages of HIV infection. In about half of the HIV-infected individuals, the primary HIV infection itself is considered the cause of seizures and in others, it is attributed to a variety of opportunistic infections. Due to multiple co-morbidities and concurrent use of several medications for HIV treatment and other

opportunistic infections, several drug-drug and diseasedrug interactions should be carefully considered in prescribing the AED.

CONNECTIVE TISSUE DISORDERS

Systemic lupus erythematosus (SLE) may result in seizures with many underlying mechanisms including anti-neuronal antibodies, vascular infarctions, metabolic disturbances or complicating CNS infections. Newer nonenzyme inducing AEDs may be preferred, in view of long term and multiple classes of medications being required in SLE.

OBSTETRIC OUTCOME

The occurrence of seizures during pregnancy have been associated with low birth weight, pre-term labor and increased gestational age. However there is no contraindication to the use of regional anaesthesia including spinal or epidural. A multi-disciplinary approach consisting of anaesthesiologist, obstetrician and neurologist is critical in order to minimize obstetric and perinatal risk in women with epilepsy.

REFERENCES

Gaitatzis A, Carroll K, Majeed A, W Sander J. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 2004; 45: 1613-1622.

Very often, determination of pregnancy leads to impulsive revision of AED regimen in seeking a safe AED with low teratogenic potential. All AEDs with exception of valproate have a reasonable teratogenic profile; therefore, there is perhaps no absolutely safe AED during pregnancy. Preconceptional folic acid supplementation reduces risk of major congenital malformations.

Brockmoller J, Thomsen T, Wittstock M, et al. Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child Pugh classes A, B and C): characterization by dynamic liver function tests. Clin Pharmacol Ther 2005; 77:529-541.

Ahmed SN, Siddiqi ZA. Antiepileptic drugs and liver disease. Seizure 2006; 15:156-164.

Israni RK, Kasbekar N, Haynes K, et al. Use of antiepileptic drugs in patients with kidney disease. Seminars in dialysis 2006; 19:408-416.

Kwon S, Lee S, Hyun M, Choe BH, et al. The potential for QT prolongation by antiepileptic drugs in children. Pediatr Neurol 2004; 30:99-101.

Desai J. Perspectives on interactions between anti-epileptic drugs and anti-microbial agents. Epilepsia 2008; 49:47-49.

Crawford P. Management of epilepsy in pregnancy. Future Neurol 2006; 1:303-310.

Ohman I, Vitols S, Thomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate during lactation. Epilepsia 2000; 41:709-713.

SEIZURE CONTROL IN PREGNANCY

Hyperventilation, sleep deprivation, pain, emotional stress can increase the risk of seizure during labor. AEDs should be continued during labor and oral clobazam can be added to reduce the risk of seizure as well as to allay anxiety. Convulsive seizures during labor should be treated with intravenous benzodiazepines such as lorazepam and if needed, intravenous phenytoin or levetiracetam be used. Status epilepticus in pregnancy is managed as otherwise. The levels of many AEDs decline by average of 50% during third trimester of pregnancy, and an increase in dosage is recommended during this time. Drug dosage should be reduced to pre-pregnancy dosage within 10 days after delivery.

CHAPTER 83

PREGNANCY & EPILEPSY

Pre-Conceptional Care

393

C H A P T E R

Recent Advances in Epilepsy

INTRODUCTION

With 65 million people affected worldwide, epilepsy is the most common, chronic, serious neurological disease.1 People with epilepsy suffer from discrimination, misunderstanding, social stigma,2 and the stress of living with a chronic unpredictable disease that can lead to loss of autonomy for activities of daily living. Although epilepsy can be successfully treated in most cases, the treatment gap is enormous, especially in low-income and middle-income countries,3 because antiepileptic drugs are inaccessible or too expensive.4 Nevertheless, not all patients respond to available medical treatments, with increasing evidence that surgery and other treatments (eg, neurostimulation and diet) can be beneficial. As medicine is an ever changing field, it is customary for the clinicians to stay updated hence here we have focussed on recent advances in the field of epilepsy research.

TERMINOLOGY

Deﬁnitions

Seizure is deﬁned by the International League against Epilepsy (ILAE) as “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain”. While Epilepsy is characterised conceptually as an “enduring predisposition of the brain to generate epileptic seizures, with neurobiological, cognitive, psychological, and social consequences”.5 Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained

Sushil Tandel

seizure free for the last 10 years and oﬀ anti-seizure medicines for at least the last 5 years.”6

CLASSIFICATION

Figure 1: Proposed ILAE organisation of epileptic seizures in 2016 The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types and to adopt more transparent names.Because current knowledge is insufficient to form a scientifically-based classification, the 2016 classification is operational (practical) and based upon the 1981 Classification, extended in 2010. Changes include: 1. “partial” becomes “focal”; 2. Seizures of unknown onset can still be classified; 3. Awareness is used as a classifier of focal seizures; 4. The terms dyscognitive, simple partial, complex partial, psychic, secondarily generalized are eliminated; 5. Focal tonic, clonic, atonic, myoclonic and epileptic spasms seizure types are recognized, along with bilateral versions of these seizure types. 6. Addition of new generalized seizure types: absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, clonic-tonic; clonic, epileptic spasms. Epileptic spasms can thus be focal, generalized or unknown. 7. Bilateral tonic-clonic seizure replaces secondarily generalized seizure. Significance: The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types7.

EPIDEMIOLOGY

The prevalence of active epilepsy is 5–8 per 1000 population in high-income countries and 10 per 1000 population in low-income countries, where even higher rates have been reported in rural areas. These regional differences probably result from differences in risk factors for epilepsy, including infections and inadequate antenatal and perinatal care. Similar differences exist for the incidence of epilepsy: findings from a 2011 metaanalysis17 showed that annual incidence is 45 per 100 000 population in high-income countries and 82 per 100 000 population in low-income and middle-income countries.8

Etiology Fig. 1: ILAE Seizure Classification 2016 Expanded Scheme

The increasing role that genetic factors play in the aetiology of the epilepsies has become increasingly apparent but environmental factors, including infection, also play a

needs diﬀerent investigations depending on the suspected disorder.

Epilepsy genetic

Family and personal history, age of onset, seizure type, neurological and cognitive status, 12-lead ECG to rule out cardiac abnormalities, and an interictal EEG are mandatory. A brain MRI is generally needed, except for patients presenting with typical syndromes such as childhood or juvenile absence epilepsy, juvenile myoclonic epilepsy, or self-limited childhood epilepsy with centrotemporal spikes. Blood tests, lumbar puncture, and other investigations can be helpful when speciﬁ c causes are suspected.

New techniques such as whole exome sequencing have helped many new discoveries in genetics. With regards to epilepsy, one exciting project completed in 2013 on patients with Lennox–Gastaut syndrome as two classic forms of epileptic encephalopathies. In addition to what are known currently, the authors found mutations in two new genes, GABRB3 and ALG13, which have previously not been linked to epileptic encephalopathy. It is possible that targeting the function of these genes is pivotal for major breakthroughs in therapeutic approaches.9

Febrile seizures

Epileptic encephalopathies are devastating syndromes, which are distinct from the most frequent cause of drug resistant epilepsy—mesial temporal lobe epilepsy. However, some epileptic encephalopathies, such as epileptic encephalopathies due to SCN1A mutations (Dravet syndrome and GEFS plus spectrum epilepsies) share common features with mesial temporal lobe epilepsies. In both epilepsies, febrile seizures are often found in the past medical history raising the question whether they may share some genetic similarities. This has been addressed by a recent study which sheds light on the association of SCN1A, febrile seizures and temporal lobe epilepsy. A recent study done recently revealed a association for mesial temporal lobe epilepsy with hippocampal sclerosis and febrile seizures within an intron of the SCN1A gene.10

PRRT2 and LGI1

Another advance in 2013 in epilepsy genetics, has been of new mutations within PRRT2. PRRT2 itself has been discovered in 2012 as the gene underlying paroxysmal kinesigenic dyskinesia with infantile convulsions.11,12

HPV16 in focal cortical dysplasia

Focal cortical dysplasias are common pathologies encountered in pharmacoresistant epilepsy. Within the umbrella term of malformations of cortical development, focal cortical dysplasias have been mainly classiﬁed according to morphological characteristics. The presence of balloon cells is a deﬁning feature of focal cortical dysplasia type IIB (FCDIIB), yet further characteristerization of ballon cells and their function is warranted.13

Major diagnostic advances over the past decade include improved imaging technology and application of epilepsy targeted protocols for image acquisition and analysis (including three-dimensional FLAIR and voxelbased analyses of multiple contrasts), allowing detection of previously unrecognised subtle epileptogenic lesions; identiﬁcation of new forms of autoimmune encephalitis, including those associated with anti-NMDA receptors,49 anti-GABAB receptors,50 and antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein (anti-Lgi-1), and contactinassociated protein-2 (anti-Caspr2);and application of genetic advances (including array comparative genomic hybridisation, candidate epilepsy gene panels, and whole-exome sequencing), leading to discovery of new gene mutations in rare epileptic disorders (either sporadic or familial).8

MANAGEMENT

Pharmacotherapy

There have been lots of advances in medical management of epilepsy. Since the 1990s, 15 new AEDs have been added to the pharmacologic armamentarium of epilepsy. These have been separated into second- and third-generation AEDs; the former include felbamate, gabapentin, lamotrigine, levetiracetam,oxcarbazepine, pregabalin, tiagabine,topiramate, vigabatrin, and zonisamide. Third-generation AEDs introduced in the last 5 years include lacosamide, (LCM), rufinamide (RFN), ezogabine (EZG), eslicarbazepine (ESL), and perampanel (PER). These AEDs will be reviewed in brief below: 1.

Lacosamide-LCM is an AED that enhances the slow inactivated state of voltage-gated sodium channels (VGSCs) [5],LCM recently received monotherapy approval by the U.S. Food and Drug Administration (FDA) in 2014 for focal epilepsy. Common side effects include dizziness, ataxia, double vision, nystagmus, and nausea. LCM should be used with caution in patients who have known cardiac conduction problems, such as firstdegree atrioventricular (AV) block, second-degree or higherAVblock and sick sinus syndrome without pacemaker, or who are on concomitant medications that prolong PR interval.

Rufinamide-RFN is a structurally unique triazole

DIAGNOSIS

Diagnosis of the epileptic nature of a seizure can be based on a precise description of the episode semiology by the patient and witnesses, and might not need any speciﬁc investigation. The most important recent advance stems from the availability of smartphones, with which relatives can video-record the seizures. Unfortunately, many doctors lack knowledge of the semiology that allows diﬀerentiation between epileptic seizures and other disorders such as convulsive syncope and psychogenic non-epileptic attacks, resulting in much misdiagnosis. Correct diagnosis of the underlying epilepsy syndrome

395

CHAPTER 84

critical role. Here, we review some of the recent genetic findings from epilepsy studies.

derivative that prolongs the inactive state of sodium channels and slows sodium channel recovery. Although it has been shown to have efficacy in focal epilepsy, it is used primarily in the treatment of drop attacks in Lennox Gastaut Syndrome (LGS).

396

NEUROLOGY

Ezogabine-First neuronal potassium channel opener developed for the treatment of epilepsy acts by enhancement of potassium currents mediated by KCNQ ion channels, thereby reducing hyper excitability. Also potentiates GABA-A receptors via activation of beta 1 & beta 2 subtype of GABA receptor and weakly blocks sodium and calcium channels.Was FDA approved in 2011 as an adjunctive treatment in refractory partial-onset seizures. Eslicarbazepine- Third generation AED which is an effective component of carbamazepine with, fewer cognitive and psychiatric adverse effects.It crosses BBB more effectively, lacks a toxic epoxide unlike its prodrug and has minimal interaction with the cytochrome P450 liver enzymes. In Nov 2013 US FDA approved it as an adjunctive treatment for partial onset seizures. Parampanel-First-in-class drug, a highly selective, non competitive AMPA type glutamate receptor antagonist which was FDA in 2012 approved for treatment of refractory partial-onset seizures in patients 12 years and older, in the dose 4 – 12 mg OD. It has boxed warning about the risk for serious neuropsychiatric events.

New drugs in pipeline Drugs decreasing neuronal excitation A.

Blockade of sodium channel

Brivaracetam

Carisbamate

Inhibition of glutamate release/ AMPA antagonist

•

NS 1209

•

BGG 492

•

ICA 105665

Melatonin

5HT receptor agonist: Naluzotan.14

Cannabidiol (partial agonist of central cannabinoid receptor type 1 (CB1) receptors)15

Novel non-drug treatments for epilepsy

Despite advances in imaging and the accumulation of neurological and surgical experience,20–40% of patients with epilepsy are considered refractory to medical treatment.1 Less than 50% of these are candidates for focal resective surgery, with rates of long-term seizure freedom ranging from 30% to 60% depending on the operation.2 However, there is widespread agreement that there remains great potential to improve nonpharmacological management, to achieve either better seizure control or complete seizure freedom. Few non-pharmacological methods which are being used world-wide are described below.

NEUROABLATION

Radiofrequency (RF) thermo coagulation

This procedure is done using a RF generator connected to the electrode contacts. It is well tolerated by the patient and does not require general anaesthesia. Multiple sites can be lesioned, with realtime clinical and electrophysiological feedback. Finally, this method does not preclude the possibility of subsequent conventional open surgery. One disadvantage with this technique is that RF thermocoagulation is known to be an inherently imprecise mode of thermal energy delivery.

MR-guided focused ultrasound

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is an accurate method of delivering high doses of transcranial ultrasound energy to a discrete intracranial focal point. consists of a clinical 3 T MRI, with a transcranial hemispheric array transducer that has 1024 ultrasound elements.

Laser ablation

Novel agents

Ablation can also be achieved by MRI-guided laser interstitial thermal therapy (MRgLITT). The commercially available Visualase Thermal Therapy System combines a 15W 980 nm diode laser and cooled laser application system with an image processing workstation. The applicator is inserted to reach the target by a stereotactic method, and laser treatment is applied in the MR scanner, with MR thermal imaging to visualise the thermal ablation. MRgLITT avoids the complications associated with radio surgery. The ablation is more precise than that achieved with RF thermo coagulation.

Anti-inflammatory: Belnacasan (VX 765)

Stereotactic radio-surgery

Pro-drug of Valproic acid: SPD 421, Valnoctamide

Chloride importer blockade: Bumetanide

Drugs acting on potassium channels

•

YKP 3089

Drugs enhancing neuronal inhibition • Ganalaxone •

Stiripentol

•

CPP 115

•

Valrocemide

(SRS) is a well-established technique that uses focused ionising radiation to target deep-seated lesions, sparing damage to surrounding tissue. The ionising radiation breaks chemical bonds and results in the production of free radicals. Ionising radiation can be generated by proton beam accelerators and photon accelerators. The

most widely used sources of ionising radiation are photon accelerators, such as Cyberknife and Gamma Knife.

REFERENCES

Thurman DJ, Beghi E, Begley CE, et al, and the ILAE Commission on Epidemiology. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia 2011; 52 (suppl 7): 2–26.

Quintas R, Raggi A, Giovannetti AM, et al. Psychosocial diﬃculties in people with epilepsy: a systematic review of literature from 2005 until 2010. Epilepsy Behav 2012; 25:60– 67.

Meyer AC, Dua T, Ma J, Saxena S, Birbeck G. Global disparities in the epilepsy treatment gap: a systematic review. Bull World Health Organ 2010; 88: 260–66.

Cameron A, Bansal A, Dua T, et al. Mapping the availability, price, and aﬀ ordability of antiepileptic drugs in 46 countries. Epilepsia 2012; 53:962–69.

Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: deﬁ nitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005; 46:470–72.

Fisher R, Acevedo C, Arzimanoglou A, et al. A practical clinical deﬁnition of epilepsy. Epilepsia 2014; 55:475–82.

Scheffer IE, French J, Hirsch E, Jain S, Mathern GW, Moshé SL, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM. Classification of the epilepsies: New concepts for discussion and debate—Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology. Epilepsia Open 2016 Jul 1.

Solomon L Moshé, Emilio Perucca, Philippe Ryvlin, Torbjörn Tomson.Epilepsy: new advances.www.thelancet. com.Published online September 24, 2014 http://dx.doi. org/10.1016/S0140-6736(14)60456-6.

Allen AS, Epi4 K Consortium, Epilepsy Phenome/ Genome Project et al. De novo mutations in epileptic encephalopathies. Nature 2013; 501:217–221. doi:10.1038/ nature12439.

NEUROMODULATION

Functional neurosurgery refers to the surgical manipulation of brain behaviour by the stimulation or removal of a population of neurones.This includes:

VAGAL NERVE STIMULATION

This is a well-established palliative treatment for epilepsy, in patients who are not candidates for resective surgery. Although VNS is unlikely to offer any advance in epilepsy surgery, the elucidation of the mechanism of action may have important consequences for other related treatments. Current evidence points towards a deactivation of the nucleus of the solitary tract, with widespread projections to the dorsal raphe nucleus, locus coeruleus, hypothalamus, thalamus, amygdala and hippocampus. Trigeminal nerve stimulation Trigeminal nerve stimulation (TNS) is similarly used for deactivation of certain brain nuclei.

DEEP BRAIN STIMULATION

There is a long history of interest in the use of deep brain stimulation (DBS) for epilepsy control. The postulated mechanism of action is by interrupting the propagation of seizure activity, or by increasing the overall seizure threshold. Multiple targets have been put forward, centred in and around the circuit of Papez. The current results with DBS for the treatment of epilepsy remain modest, even accounting for the difﬁcult patient group with highly refractory epilepsy.

CLOSED-LOOP LOCAL DRUG DELIVERY

It is an attractive possibility that localised intracerebral delivery of antiepileptic drugs (AED) can improve the efﬁcacy of pharmacological treatment of epilepsy, without systemic side effects.36 Several groups are, therefore, engaged in research developing automated local drug delivery systems, comprising of seizure detection technology coupled with intracranial delivery of AED.16 Thus, epilepsy surgery remains a signiﬁcantly underused resource. It is often perceived as a treatment of last resort. Perhaps the most important advance for the future would be to increase awareness in the general population, and education among health professionals, on the safety and efficacy of epilepsy surgery as an early intervention in medically refractory focal epilepsy.

CONCLUSION

There continue to be considerable advances in epilepsy research that will possibly translate into therapies to prevent epilepsy and its co-morbidities and to treat people with pharmaco-resistant epilepsy. However, despite the size of the problem (over 50 million people with epilepsy worldwide of whom 30 % do not respond adequately to our present therapies), epilepsy research remains poorly funded, and there is a continued need for investment.

10. Kasperaviciute D, Catarino CB, Matarin M et al. Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A. Brain 2013; 136:3140–3150. 11. Lee H-Y, Huang Y, Bruneau N et al. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep 2012; 1:2–12. doi:10.1016/j. celrep.2011.11.001 8. 12. Becker F, Schubert J, Striano P et al. PRRT2-related disorders: further PKD and ICCA cases and review of the literature. J Neurol 2013; 260:1234–1244. doi:10.1007/s00415012-6777. 13. Chen J, Tsai V, Parker WE et al. Detection of human papillomavirus in human focal cortical dysplasia type IIB. Ann Neurol 2012; 72:881–892. doi:10.1002/ana.23795. 14. Enrique Serrano and Andres M. Kanner. Recent treatment advances and novel therapeutic approaches in epilepsy. F1000Prime Reports 2015, 7:61 (doi:10.12703/P7-61). 15. Saipetch C, Sachs E, Haneef Z. Epilepsy Five new things. Neurology: Clinical Practice 2016 Aug 3:10-212. 16. Nowell M, et al. Advances in epilepsy surgery .J Neurol Neurosurg Psychiatry 2014;85:1273–1279. doi:10.1136/ jnnp-2013-30706.

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C H A P T E R

Surgery for Parkinson’s disease and Epilepsy Paresh Doshi, Raghvendra Ramdasi, Smita Thorve

SURGICAL TREATMENT FOR PARKINSON’S DISEASE

Rigidity

Parkinson’s disease (PD) is second most common neurodegenerative disease after Alzheimer’s disease. It is characterised by with motor symptoms and nonmotor features including cognitive and neuropsychiatric symptoms. Here we review various treatment modalities for Parkinson’s disease with special emphasis on bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). We review the indications, advantages, disadvantages of STN DBS and future of the same in the treatment of PD.

Bradykinesia

Abstract

INTRODUCTION

Parkinson’s disease is a movement disorder characterized by tremor, rigidity and bradykinesia. The first line therapy for the same is medical. But with advancement of this degenerative disease motor fluctuations, dyskinesia and other drug related side effects disable the patient’s life. In this situation DBS can improve the motor symptoms, reduce the drug requirements and improve the quality of life.1 The patient selection, methodology, complications and outcome of the same is discussed here.

PARKINSONIAN DISORDERS

In 1817, James Parkinson described in his essay on the Shaking Palsy the symptoms of Parkinsonian disorder.2 Subsequently other features of this disorder were identified. He described four cardinal features of this disorder i.e. rest tremor, bradykinesia, rigidity, and postural instability. His description included Parkinson’s disease and Parkinson plus syndrome.

PARKINSON’S DISEASE

PD usually affects the patients in fifth decade.3 However, disease onset before fourth decade is not uncommon, and such patients are designated as Young onset PD. PD symptoms before the age of 20 years is even rarer and these patients are known as Juvenile PD patients. Both these conditions are rare affecting 5% of PD patients. 4,5 In our personal operated series, 25% of patients are young onset PD and only 1% patients of Juvenile PD.

Tremor

Rest tremor is the first symptom in 70% of PD patients. It has frequency of approximately 5 Hz and variable amplitude. It is typically more distal than proximal. It may be intermittent and is almost always asymmetric. Like most tremors, it is worsened by distraction and strong emotion.6

Parkinsonian rigidity is due to enhanced static or postural reflexes. The rigidity may be of either a “lead pipe” or “cogwheel” quality and is typically asymmetric.7 The appendicular rigidity is more marked than the axial rigidity. Of the cardinal features of PD, bradykinesia has the best correlation with disease severity.8

Postural and gait instability

The parkinsonian gait is characterized by shuffling of the feet, decreased arm swing and flexion of the neck and spine. Patients are unable to turn in a single step and break their turns into multiple small increments. But the body remains aligned with the feet during this process (“en bloc turns”). Both festination and retropulsion may be seen. Festination arises from an inability to return to an erect posture once leaning forward. Patients appear to chase their center of gravity. Retropulsion occurs as a result of patients’ inability to recover from a backwardleaning posture.2

PATHOPHYSIOLOGY OF PARKINSON’S DISEASE

PD is manifested only after approximately 80% of striatal dopamine and 50% of nigral neurons are lost. It can occur because of both genetic predisposition and environmental exposure.8 Bradykinesia and rigidity can be explained by current models. According to the Alexander, DeLong, and Strick model, bradykinesia arises from excessive inhibition of the thalamus by the globus pallidus (pars) interna (GPi), either direct pathway of GPi overactivity or indirect pathway of overactivation of the GPi by an overactive subthalamic nucleus.9

DIAGNOSIS

PD has to be differentiated from Parkinson’s Plus syndrome. These include, Dementia with Lewy Bodies, Progressive Supranuclear Palsy, Corticobasal Degeneration and Multiple System Atrophy. Some of indicators of Parkinson’s Plus syndrome include, Symmetrical signs and symptoms; rapid progression of the disease; poor response to medications, including levodopa; repeated falls; vertical gaze restriction; early memory loss and cognitive decline; presence of cerebellar deficits, corticospinal tract signs; early autonomic dysfunction or postural instability; and dysphasia and pseudobulbar palsy. It is important to know these

symptoms as the treatment options and prognosis for the Parkinson’s Plus syndrome is poor.10

MEDICAL THERAPY

The initial choice of medical treatment for the Parkinson’s disease is invidualised. Young patients, patients with early PD; mild symptoms are offered centrally-acting anticholinergic medications, selective irreversible MAO-B inhibitors and amantidine. As the disease advances dopamine agonsist and levodopa are introduced. In elederly patients, above 65 years, one can start levodopa from the beginning.

Selective irreversible MAO-B inhibitors (selegiline and rasagiline) inhibit degradation of dopamine. They have mild therapeutic effects as a monotherapy and augment L-DOPA given exogenously. Multiple additional neuroprotective mechanisms of action are proposed.11

Amantidine –This antiviral reduces all symptoms of PD though modestly.12 It also reduces L-DOPAinduced dyskinesia in advanced PD. 13

D2/3 dopamine agonists (ropinerole, pramipexole) bind post-synaptic striatal dopamine receptors and exert effect. Though the effect is inferior to L-DOPA, they are preferred for initial treatment as they have less dyskinesia or motor fluctuations.14

L-DOPA- It is the gold-standard of medical therapy. This dopamine precursor is converted to dopamine in CNS by enzyme aromatic amino acid decarboxylase (AAAD).15 The AAAD inhibitors (carbidopa or benserazide) reduce peripheral dopamine production and increase dopamine concentration. Adjunctive treatment with COMT enzyme inhibitors (entacapone and tolcapone) can improve the CNS delivery of L-DOPA through inhibition of degradation to 3-O-methyldopa (3OMD).16

Selection criteria

Proper patient selection is critical to the success of deep brain stimulation surgery (DBS). The selection of the patients for DBS is based on: 1.

Diagnosis: The patient should have confirmed diagnosis of idiopathic Parkinson’s disease. The criteria for the same is presence of bradykinesia with atleast one of the other three symptoms namely: rigidity, resting tremor and postural instability. The patient with atypical PD (Parkinson’s plus) should not be offered this therapy.19

Age: The age is debatable predictor factor but increased age will cause cognitive decline, associated co-morbidities and overall increase in surgical risk.20 We carefully evaluate patients above 70 years and if we find them fit to undergo treatment, do not hesitate to offer them surgery. The oldest patient that has undergone DBS at our centre was 82 years old.

Disease duration- In order to avoid misdiagnosis of PD we offer surgery after 5 years of disease. The only exception being patients with severe tremors not controlled with levodopa or other medications, and in such cases we have offered surgery before five years.21

Disease severity- The motor fluctuations in response to dopaminergic drugs in the form of wearing off effect and dyskinesias are the most common indication for the DBS. Disabling tremor in the absence of above despite drug treatment is also an indication for DBS.22

L-DOPA responsiveness- It is the single most important predictive factor for positive outcome of DBS. A 30% improvement in the Unified Parkinson Disease Rating Scale III score has been used as one useful marker of positive outcome. The severe tremor resistance to L-DOPA is an exception to this.23

Cognitive impairment- Dementia is the most important and common exclusion criterion for DBS surgery.24

Psychiatric illness- Untreated psychiatric illness should be treated before the procedure. Treated depression will not exclude surgical option but adds to the caution.25

ADVANCED PARKINSON’S DISEASE

Few years into the treatment patients of PD develop motor fluctuations. These are in the form ON-OFF phenomenon, sudden OFF periods, dyskinesias and hallucinations. It is believed that the pulsatile nature of the dopamine replacement therapies is the cause for this motor fluctuations. Patient progressively require higher doses, however, every incremental dose brings in its share of side effects, limiting its value.1 This can now be addressed by surgical treatment.

SURGICAL THERAPY

The breakthrough in the treatment came when Benabid and colleagues found high frequency (above 100Hz)

399

TARGET FOR DBS

The globus pallidus internus (GPi) and the subthalamic nucleus (STN) are the two most commonly used targets.

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a. Centrally-acting anticholinergic drugs (e.g. trihexyphenidyl and benztropine) can be effective at reducing tremor and dystonia but less effect on other symptoms. They should not be given to patients older than 65. The common side effects include dryness of mouth and urinary hesitancy.

stimulation of thalamic nuclei produce lesion like effect and suppress tremors. During thalamic lesioning procedures stimulation below 100 Hz was found to augment and above 100 Hz was found to suppress tremor.17 This was successfully applied to treat PD through both the targets, i.e. the subthalamic nucleus and internal pallidum (nuclei with known increased firing rates in PD).18

NEUROLOGY

400

Initially, the GPi was preferred. But subsequently STN was found to be the superior target and STN DBS is considered to be gold standard surgical therapy.24,25, 26 Both targets have equal effect in reducing off-time motor symptoms and tremors. STN is superior to Gpi in reducing rigidity and bradykinesia, it has lesser battery usage and medication reduction is achievable to the extent of 40-100%. However, GPi is superior in dyskinesia suppression and gait stability. It has lesser impact on cognitive function.27Drug reduction is not achievable with GPi stimulation. We prefer to offer GPi stimulation to those elderly patients, who are significantly disabled by PD and have borderline cognitive deficits.

SURGERY

DBS surgery is best performed by an experienced surgeon with expertise in stereotactic and functional neurosurgery who is a part of team that includes a movement disorder neurologist, neuropsychologist, psychiatrist, and neurophysiologist. We will go on to describe the protocols followed at our centre.

Presurgical Assessment

Patient is admitted two days prior to surgery. The Unified Parkinson’s disease Rating Scale (UPDRS) is carried out with best on and 12 hours off medication. The Video recordings using standard protocols are performed during on and off medical condition. Mini-Mental examination is performed to know the cognitive status. The fitness for surgery is done during this phase.

Preoperative anatomical target localisation

STN is localized using a 3T magnetic resonance imaging. First an inversion recovery, sagittal sequence is performed anterior commissure (AC) and posterior commissure (PC) identified. Mid-commissural point identified. The STN is typically identified on a slice 2 mm posterior to the mid-commissural point. At this point STN is 11-12 mm lateral and 4 mm inferior to the intercommissural plane. The preoperative planning to reach the STN through precoronal trajectory is done and co-ordinates obtained.

Surgery

Frame fixation-The surgery is performed using CRW (Cosman-Robert Wales) stereotactic system. The computed topography is performed with frame in situ. Axial computerized tomography (CT) scan is fused with the preoperative MRI using Framelink software. The trajectory is planned through precoronal burr hole avoiding vessels, ventricle and other eloquent structures. The co-ordinates obtained and verified with preoperative ones to rule out major discrepancy. Once this is done, the stimulating microelectrode is inserted through a precoronal burr hole through the predetermined trajectories. Usually three to four trajectories, separated radially around a central trajectory, are used for exploring the STN region. Microelectrode recording (MER) obtained. The position of STN is calculated depending on best MER recording. This is then followed by stimulation of STN at 130 Hz to look for clinical improvement in the PD symptoms. This is done by the neurologist in

the theatre. Similarly, the side effects are noted in each trajectory. The final position is confirmed at optimal improvement in rigidity and bradykinesia without any motor side effects. Once the confirmation of the STN target is obtained, the stimulating electrode is replaced with DBS electrode. Both the electrodes are implanted on the same day. Postoperative CT scan is performed to confirm the position of the electrodes. We implant the IPG (Implantable Pulse Generator) on the next day, under general anesthesia.

PROGRAMMING

We keep the patient off medication overnight and do the programming the next day. First the monopolar programming is performed where singe chosen contact point negative and IPG is on the positive side. The width of 60 msec and frequency of 130 Hz is kept. Each and every contact is assessed for improvement and side effects. The best contact with low threshold for improvement and high threshold for side effects is selected for final continuous stimulation. Drug reduction is commenced on day 3 or 4 postoperatively.1

RESULTS

Meta-analysis of studies of patients undergoing DBS between 1993-2004 was performed by Kleiner-Fishman et al. They identified 37 cohorts with 921 patients. The mean improvement in the off phase UPDRS III symptoms was 52%, UPDRS II was 50% and the levodopa reduction was around 56%. The average reduction in dyskinesias was 69%. The quality of life (PDQ-39) scores also improved. The scores that significantly improved were stigma (54.4%), activities of daily living (51.6%), mobility (38.5%), bodily discomfort (35.8%), and emotional well-being (32.1%). Dimensions with modest benefit included social support (17.0%), cognition (16.5%) and communication (13.0%).28 In our series the UPDRS II and III scores improved by 62% and 61% respectively at one year follow up. The levodopa reduction was 54%.1

Complications

The complications rate reported in the literature varies between various series. The rates of surgical complications are quite variable in the literature and include intracranial hemorrhage (0%-10%), stroke (0%-2%), infection (0%15%), lead erosion without infection (1%-2.5%), lead fracture (0%-15%), lead migration (0%-19%), and death (0%-4.4%).29,30-32 The consensus statement on DBS in PD states that “There was consensus that the incidence of symptomatic intracranial hemorrhage is likely less than 2% for most centers and that lead fracture and migration are likely much lower in recent times owing to improved technology”.33 In our personal series the vascular and hardware complication rates were 0.6% and 4% respectively.34

SUBTHALAMOTOMY

Although thalamotomy and pallidotomy are not used for treatment of PD, there is still a role of STN lesioning. Here a permanent lesion is created along the dorsolateral region of STN where kinesthetic neurons are located. The results

of subthalamotomy are similar to STN DBS in the short and long term.35The improvement however is variable and not as consistent as DBS. The added advantage of titrability and adjustability of the stimulation parameters offered by DBS makes it a more superior treatment. We offer subthalamotomy to patients who either cannot travel for follow up and programming or who cannot afford the surgery.

STN DBS IN EARLY MOTOR COMPLICATIONS (NEJM TRIAL)

CONCLUSION

Patient with idiopathic Parkinson’s disease with motor fluctuations should be referred to centers with an experienced team of experts in DBS surgery for surgical evaluation. In an appropriate candidate STN DBS is treatment of choice which effectively treats motor symptoms, reduce drug requirements and improve the quality of life. The benefits of DBS are sustained for several years. There is still role of STN lesioning for the treatment of Parkinson’s disease.

SURGICAL TREATMENT FOR EPILEPSY

Abstract

Epilepsy is a common neurological disorder. Patients who are refractory to 2 anticonvulsants for more than 2 years are to be evaluated further for the feasibility of surgery. The assessment battery includes detailed clinical history, 3T magnetic resonance imaging (MRI), Video EEG, neuropsychological assessment and functional MRI if needed. The surgical options include resective surgeries (anterior temporal lobectomy, Selective amygdalohippocampectomy, lesional surgery), disconnection surgeries (Subpial transaction, callosotomy) and resective plus disconnection surgery (Hemispherectomy). The indications, technique and effectiveness of each is discussed here.

The main criteria for epilepsy surgery have been formulated by Walker in 1974. According to his suggestions, the following criteria have to be met to qualify for curative epilepsy surgery: (1) focal or regional seizure onset, (2) drug intractability with 2 anticonvulsants (3) seizures represent a severe handicap, (4) seizures exist for at least 2 years without tendency for remission and despite adequate medical treatment, (5) sufficient general and mental health state of the patient who is sufficiently motivated and compliant in order to collaborate preoperatively, intraoperatively (if necessary) and postoperatively.39 According to evidence-based guidelines the first indication for epilepsy surgery in all age groups is resistance to antiepileptic drugs. 40,41 Some modifications of Walker’s criteria are (1) the demand for early surgery (at least in certain epilepsy syndromes such as mesial temporal lobe epilepsy, MTLE), (2) indications for ‘‘palliative’’ surgery, and (3) a more liberal indication in children. 40,42.

CONTRAINDICATIONS

There are no evidence-based contraindications to epilepsy surgery, although the existence of a severe active psychiatric condition (e.g., active psychosis) or medical comorbidities precluding surgery are generally accepted as contraindications. However, surgery should be considered in such individuals with drug-resistant epilepsy if these conditions resolve. Failure to identify an epileptic focus after a complete surgical evaluation by an epilepsy specialist is usually a contraindication to surgery, except for patients with drop attacks. Here, corpus callosotomy may be beneficial in reducing the frequency of drop attacks.40

PHILOSOPHY OF EPILEPSY SURGERY

The knowledge of various zones where the seizure originates and spreads remains essential for the success of epilepsy surgery •

The lesional zone: The area where the lesion is situated in case of lesional epilepsy is lesional zone.

It is generally accepted that the epileptogenic zone lies within or in close spatial neighbourhood of the macroscopic lesion (if present) in the majority of patients. But in few cases it may be away from the lesion.43

•

The symptomatogenic zone – seizure semiology: It is the area of cortex that, when activated, produces the initial ictal symptoms or signs. It might include cortical areas at distance to the actual seizure onset zone that become activated (in the case of ‘‘positive’’ symptoms) or deactivated (in the case of ‘‘negative’’ symptoms) due to seizure spread.44,45

•

The irritative zone: The irritative zone has been defined as the area of cortex that generates interictal spikes. It can be measured by non-invasive or invasive EEG, MEG and fMRI. The irritative zone

INTRODUCTION

Epilepsy is the second most commonly reported neurologic condition worldwide and affects people of both sexes and of all ages and socioeconomic statuses.37 About 40% of newly diagnosed epilepsies are drug refractory and may be considered potential candidates for epilepsy surgery. 38 Despite development in neuroimaging, microneurosurgical techniques and proven effectiveness of epilepsy surgery, it is very much underutilized. Spectrum of surgical procedures from curative to palliative is discussed herewith.

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Recently a randomized multicentric study was conducted across Europe. 251 patients with less than 3 years of motor fluctuations and more than or equal to 4 years of disease duration were randomized between medical and surgical treatment. The study found that neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01).36

INDICATIONS OF SURGERY

is usually more extended than the seizure onset zone.44

402

NEUROLOGY

•

Seizure onset zone: It is the cortical area that initiates clinical seizures. It can be of two types according to Lu¨ders distinguished between the actual seizure onset zone and the potential seizure onset zone (Figure 1). Lu¨ders suggested that incomplete resection of both the actual or the potential seizure onset zone may result in incomplete seizure control.46

PREOPERATIVE EVALUATION

It includes: a.

Detailed clinical history semiology of the seizure.

with

Interictal 3T MRI to study abnormalities in the brain structure constitutes the primary investigation.

Video EEG monitoring to record typical seizures,

Neuropsychological cognitive function

Novel investigations novel functional imaging (e.g., functional MRI, PET, SPECT, functional connectivity) and neurophysiological diagnostic modalities (e.g., detection of high-frequency oscillations or assessment of neuronal connectivity using intracranial EEG recording, magnetoencephalography) have greatly enhanced presurgical planning by increasing the likelihood of identifying lesions not seen on MRI of the patient’s brain.40

assessment

emphasis

baseline

RESECTIVE SURGERY

Surgical resection of the epileptogenic focus is the preferred surgical approach when possible. The extent of resection may range from simple lesionectomy to single or multiple lobectomies and is tailored based on the individual patient’s seizure semiology, imaging findings, and ictal and functional mapping.

ANTERIOR TEMPORAL LOBECTOMY (ATL)

Indications

Whereas mesial temporal sclerosis is the most common pathologic basis of focal epilepsy in adults, 47 children demonstrate this finding less commonly and are more likely to have neoplastic lesions, 48 or congenital brain anomalies, such as cortical dysplasia, as the underlying substrate of refractory seizures.49

Technique

Our technique is based on the technique described by Spencer et al. in 1984.50 We perform 6 cm resection of temporal lobe (based on the anatomy of the vein of Labe) on the non-dominant side and 5 cm resection of middle and inferior temporal gyrus on the dominant side of the temporal lobe. We spare the superior temporal gyrus on the dominant side. There are several variations to this techniques based on individual centres experience and expertise.51 Mortality after the ATL procedure is very

low, with reported rates ranging from 0 to 0.5% in large series.52,53 Morbidity rates in a recent review ranged from 0 to 9.3% ,with the most common complications being visual field disturbance, infection, and neuropsychological changes, most notably declines in verbal memory when the dominant hemisphere was resected.52

SELECTIVE AMYGDALOHIPPOCAMPECTOMY (SAH)

Indications

One school of thoughts believe that sparing the neocortex, by performing SAH, reduces the cognitive morbidity and improved neuropsychological outcome. However, this theory has not been confirmed and various studies have shown equivocal results in postoperative neuropsychological function when comparing these SAH with standard ATL.54-56 In centres not having adequate expertise in patient selection, the seizure control has been inferior with SAH than with ATL with amygdalohippocampectomy.

Technique

SAH can be performed through several techniques including transsylvian , transcortical , and subtemporal approaches, with the selection dependent on the patient and the surgeon. Two large meta-analyses of studies comparing the two procedures head to head found higher rates of seizure freedom after ATL than after SAH.57,58 One study found no significant difference in intelligence quotient scores between patients receiving the two procedures, and one was unable to make significant conclusions regarding differences in neuropsychiatric outcomes between the two groups. The fact that seizure freedom after SAH may be lower in children than in adults.59

Effectiveness of resective surgeries

Cohort studies and RCTs consistently show that, in focal drug-resistant epilepsy, resective brain surgery results in seizure freedom for about 57% of patients who undergo neocortical resections and for 70% of those who undergo anteromesial temporal resections, compared with 5%–8% of patients receiving optimum medical therapy.60-63 In a recent RCT comparing medical therapy to early surgery in patients with temporal lobe epilepsy, 73% of patients in the surgical group became seizure free during the second year of follow-up, compared with 0% in the medical group.61 A meta-analysis of one RCT and 19 observational studies comparing surgery with medical therapy found an absolute risk reduction of 42% (95% CI 32%–51%) for any seizure recurrence in patients who underwent surgery.64 Similar surgical outcomes have been reported in cohort studies involving older patients.65

Hemispherectomy

The use of cerebral hemispherectomy for control of seizures implies that the pathological processes of the epileptogenic brain, the seizure foci, are lateralized to one hemisphere, and that the other hemisphere has preserved its anatomical and physiological integrity. The causes can be congenital or acquired.

Congenital etiologies regroup conditions such as infantile hemiplegia from prenatal vascular insult, hemimegalencephaly, diffuse non-hypertrophic dysplasia and Sturge-Weber disease, while acquired conditions such as cerebrovascular accident (hemorrhagic or embolic), head injury, cerebral infection, or chronic encephalitis of Rasmussen occur after early normal development.66 Anatomical hemispherectomy: It consists in the anatomic removal of one cerebral hemisphere with or without the basal ganglia.66

Hemidecortication: It consists in the removal of the whole cerebral cortex with sparing of the white matter, thus avoiding opening of the lateral ventricle.67

Modified hemispherectomy: It is developed by Adams consisting of anatomical hemispherectomy followed by occlusion of the ipsilateral foramen of Monro with muscle to prevent communication between ventricular CSF and the hemispherectomy cavity, adding the reduction of the volume of the hemispherectomy cavity by tacking the convexity dura to the falx, the basal dura, and the tentorium, thus creating a large extradural space.68

Functional hemispherectomy: It consists of an anatomical subtotal but physiologically complete hemispherectomy is based on principles of disconnection rather than excision.69

Hemispherotomy: It consists in disconnecting the hemisphere with minimal brain tissue removal.

Two approaches have been described. Delalande and colleagues proposed a vertical approach where the hemisphere is disconnected through a posterior frontal transcortical approach to the lateral ventricle.70-72 The lateral approach (Peri-insular hemispherotomy) is part of a continuum with the highest disconnectionversus-excision ratio in the technical variations of functional hemispherectomy.73,74 Long-term improvement in seizure control following hemispherectomy is anticipated in 90–95% of patients. This benefit can be further divided into two categories: those patients who become and remain seizure-free (70–85%) and those who continue to have some seizures but benefit from at least an 80% reduction in seizure frequency (10–20%). These figures reflect the experience of different surgeons, using different techniques, for different pathologies and are useful for discussion with patients and their families.75

SUBPIAL TRANSACTION

Indications 1.

Focal seizures arising in eloquent cortex (with or without resective surgery of the adjoining area when the epileptogenic zone extends away from the eloquent cortex).76 Landau-Kleffner

Syndrome.

Laundau-Kleffner

Malignant Rolandic-Sylvian Epilepsy Syndrome. Malignant Rolandic-Sylvian Epilepsy (MRSE) syndrome was described by Otsubo et al. in children presenting with intractable sensorimotor partial seizures that progress to secondary generalization.78

Rationale and technique

Rationale of MST consists of linear and parallel cuts 5 mm apart across the region defined as the epileptogenic zone. The principle is based on the selective destruction of the short horizontal fiber connections with preservation of vertically oriented neuronal elements.76

CALLOSOTOMY

Rationale

Corpus callosum is the largest white matter bundle connecting two cerebral hemispheres. In multifocal epilepsies seizure originate from various areas of brain and spread through corpus callosum to cause secondary generalization. Sectioning of corpus callosum can therefore reduce the generalization or bilateral synchronization. 79

Indication

The categories of patients considered for corpus callosotomy include those with multifocal or unresectable focal generalized epilepsy, progressive epileptic hemiplegic encephalitis (Rasmussen’s syndrome), FormeFruste infantile hemiplegia with a functional hand, and the Lennox-Gastaut syndrome and Sturge-Weber syndrome.80,81

Technique

The callosotomy can be partial (anterior 2/3rd resected) or complete (entire corpus callosum resected). 79 We advocate partial callosotomy to avoid complications of major disconnection syndrome.

Seizure control

Spencer et al. reported that total corpus callosotomy prevented secondarily generalized seizures in at least 75% of patients, which is consistent with other series.82 They found that total callosotomy was more than twice as effective as partial section. Fuiks et al. found that 70% of their 80 patients undergoing anterior callosotomy had significant improvement in their seizures, and 12.8% were cured. 83

Neuromodulation

It includes vagal nerve stimulation, direct cortical electrical stimulation (DCS), transcranial magnetic stimulation (TMS) which have shown promising results. Deep brain stimulation (hippocampal, anterior thalamic and STN)

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Syndrome (LKS) has been traditionally one of the main indications for MST in children. LKS is defined as an acute or progressive, acquired epileptic aphasia (AEA) or verbal auditory agnosia in previously normal children associated with the presence of epileptiform discharges over the central and superior temporal regions that become more frequent during sleep.77

404

and RNS are newer modalities under evaluation. Out of these VNS is only approved treatment modality and discussed here.

VAGAL NERVE STIMULATION (VNS)

Indications

NEUROLOGY

VNS is one of the first neuromodulation techniques used for intractable epilepsy. It is an adjunctive therapy aimed at reduction in the frequency of seizures, especially in patients suffering from partial seizures (with or without secondary generalization); or generalized seizures, which are refractory to antiepileptic medications.84

Technical aspects

Left Vagus nerve is selected for stimulation. It is approached through a carotid or transverse neck incision at the mid-neck level. The main vagal trunk is identified and exposed for 3-4 cm in the carotid sheath. Electrode coils are passed around the nerve without putting undue tension on the nerve or the coil. The electrodes are tunneled subcutaneously and connected to a pacemaker (after trial stimulation) implanted in the infraclavicular region.85

Effectiveness

Randomized controlled trials have shown that vagal nerve stimulation can reduce seizures by 25% on average (95% CI 14%–34%),86 and RCTs have also shown a net improvement (active minus control) in seizure frequency of 15% (Interquartile range 2%–24%) with hippocampal stimulation,87 20% (p = 0.01) with recursive cortical stimulation,88 and 26% (p = 0.001) with stimulation of the anterior thalamus.89

Jules Froment to the study of parkinsonian rigidity. Mov Disord 2007; 22:909-914 . 8. Fearnley JM, Lees AJ: Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 1991; 114:22832301. 9. Alexander GE, DeLong MR, Strick PL: Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986; 9:357-381. 10. Gelb DJ, Oliver E, Gilman S: Diagnostic criteria for Parkinson’s disease. Arch Neurol 1999; 56:33-39. 11. Olanow CW, Rascol O, Hauser R et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. New Engl J Med 2009; 361:1268–1278. 12. Schwab RS, England AC Jr, Poskanzer DC et al. Amantadine in the treatment of Parkinson’s disease. JAMA 1969; 208:1168–1170. 13. Shannon KM, Goetz CG, Carroll VS, Tanner CM, Klawans HL. Amantadine and motor fluctuations in chronic Parkinson’s disease. Clin Neuropharmacol 1987; 10:522–526 14. Holloway RG, Shoulson I, Fahn S et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004; 61:1044–1053. 15. Cotzias GC, Papavasiliou PS, Gellene R. Modification of parkinsonism—chronic treatment with L-dopa. New Engl J Med 1969; 280:337–345. 16. Factor SA, Molho ES, Feustel PJ, Brown DL, Evans SM. Long-term comparative experience with tolcapone and entacapone in advanced Parkinson’s disease. Clin Neuropharmacol 2001; 24:295–299.

CONCLUSION

17. Benabid AL, Pollak P, Louveau A et al.Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 1987; 50:344–346.

CONFLICT OF INTEREST

19. Hughes AJ, Daniel SE, Kilford L, et al.: Accuracy of clinical diagnosis of idiopathic Parkinson’s disease. A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55:181-184.

Surgery for epilepsy ranges from resection, disconnection to neuromodulation. It is very effective but underutilised modality of treatment. So it is necessary to spread the awareness regarding the same for the wellbeing patients suffering from this common disorder. None

REFERENCES

Doshi PK, Chhaya NA, Bhatt MA. Bilateral subthalamic nucleus stimulation for Parkinson’s disease. Neurol India 2003; 51:43-8.

Parkinson J: An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci. 2002; 14:223-236.

3. Hoehn MM, Yahr MD: Parkinsonism: onset, progression, and mortality. 1967. Neurology 1998; 50:318-34. 4. Golbe LI: Young-onset Parkinson’s disease: a clinical review. Neurology 1991; 41:168-173. 5. Schrag A, Schott JM: Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol 2006; 5:355-363. 6.

Hohler A, Samii A: Approach to movement disorders. Winn HRYoumans JR Youmans Neurological Surgery 5th ed 2004 WB Saunders Philadelphia. 2729-2744

7. Broussolle E, Krack P, Thobois S, et al.: Contribution of

18. Pollak P, Benabid AL, Gross C et al. Effects of the stimulation of the subthalamic nucleus in Parkinson disease. Rev Neurol (Paris) 1993; 149:175–176.

20. Saint-Cyr JA, Trépanier LL, Kumar R et al. Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’s disease. Brain 2000; 123(pt 10):2091–2108. 21. Schüpbach WM, Maltête D, Houeto JL, et al.: Neurosurgery at an earlier stage of Parkinson’s disease: a randomized, controlled trial. Neurology 2007; 68:267-271. 22. Malhado-Chang N, Alterman R, et al.: Deep brain stimulation. Factor SA Weiner WJ Parkinson’s Disease: Diagnosis and Clinical Management 2nd ed 2007 Demos New York 663-688 23. Lang AE, Houeto JH, Krack P, et al.: Deep brain stimulation: preoperative issues. Mov Disord 2006; 21:171-196 24. Okun MS, Foote KD. Subthalamic nucleus vs globus pallidus interna deep brain stimulation, the rematch: will pallidal deep brain stimulation make a triumphant return? Archives of Neurology 2005; 62:533–536. 25. Weaver FM, Follett KA, Stern M, et al. Randomized trial

sclerosis (ILAE Commission Report). Epilepsia 2004; 45:695714.

26. Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Archives of Neurology. 2005; 62:554– 560.

44. Penfield W, Jasper H. Functional localization in cerebral cortex, In: Penfield W, Jasper H eds. Epilepsy and the functional anatomy of the human brain London: Churchill; 1954. p.88-102.

27. Williams NR, Foote KD, Okun MS. STN vs. GPi Deep Brain Stimulation: Translating the Rematch into Clinical Practice. Mov Disord Clin Pract 2014; 1:24-35.

45. Wieser H-G, Williamson PD. Ictal semiology. In: Engel Jr J, editor. Surgical treatment of epilepsies. New York: Raven Press; 1993. p. 161–71.

28. Kleiner-Fisman G, Herzog J, Fisman DN, et al. : Subthalamic nucleus deep brain stimulation: summary and metaanalysis of outcomes. Mov Disord 2006; 21 Suppl 14:S290304. Review.

46. Lu¨ders HO, Najm I, Nair D, Widdess-Walsh P, Bingman W. The epileptogenic zone: general principles. Epileptic Disord 2006; 8 Suppl 2:S1-9.

29. Weaver FM, Follett K, Stern M, et al; CSP 468 Study Group. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA 2009; 301:63-73. 30. Lang AE, Houeto JL, Krack P, et al. Deep brain stimulation: preoperative issues. Mov Disord 2006; 21(suppl 14):S171-S196. 31. Saint-Cyr JA, Tre´panier LL, Kumar R, Lozano AM, Lang AE. Neuropsycho logical consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’sdisease. Brain 2000; 123(pt 10):2091-2108. 32. Saint-Cyr JA, Tre´panier LL, Kumar R, Lozano AM, Lang AE. Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’s disease. Brain 2000; 123(pt 10):2091-2108. 33. Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann J, et al: Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch Neurol 2011; 68:165-171. 34. Doshi PK. Long-term surgical and hardwarerelated complications of deep brain stimulation. Stereotact Funct Neurosurg 2011; 89:89-95. 35. Alvarez L, Macias R, Lopez G, Alvarez E et al.: Bilateral subthalamotomy in Parkinson’s disease: initial and long-term response. Brain 2005; 128(Pt 3):570-83. 36. Schuepbach WM, Rau J, Knudsen K et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med 2013; 368:610-22 37. Prilipko L, Saxena S. Atlas: Country resources for neurological disorders 2004. Geneva (Switzerland): World Health Organization; 2004. 38. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342:314 -9. 39. Walker AE. Surgery for epilepsy. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. vol. 15. Amsterdam: North-Holland; 1974. p. 739-57. 40. Jette N, Reid AY, Wiebe S. Surgical management of epilepsy. CMAJ 2014; 186:997-1004 41. Labiner DM, Bagic AI, Herman ST, et al. Essential services, personnel, and facilities in specialized epilepsy centers — revised 2010 guidelines. Epilepsia 2010; 51:2322-33. 42. Engel J Jr, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 2012; 307:922-30. 43. Wieser HG. For the ILAE Commission on Neurosurgery of Epilepsy. Mesial temporal lobe epilepsy with hippocampal

47. Asadi-Pooya AA, Sperling MR. Age at onset in patients with medically refractory temporal lobe epilepsy and mesial temporal sclerosis: impact on clinical manifestations and postsurgical outcome. Seizure 2015; 30:42-5. 48. Cataltepe O, Turanli G, Yalnizoglu D, et al. Surgical management of temporal lobe tumor-related epilepsy in children. J Neurosurg 2005; 102:280-7. 49. Marin-Valencia I, Guerrini R, Gleeson JG. Pathogenetic mechanisms of focal cortical dysplasia. Epilepsia 2014; 55:970-8. 50. Spencer DD, Spencer SS, Mattson RH, et al. Access to the posterior medial temporal lobe structures in the surgical treatment of temporal lobe epilepsy. Neurosurgery 1984; 15:667-71. 51. Joo EY, Han HJ, Lee EK, et al. Resection extent versus postoperative outcomes of seizure and memory in mesial temporal lobe epilepsy. Seizure 2005; 14:541-51. 52. Georgiadis I, Kapsalaki EZ, Fountas KN. Temporal lobe resective surgery for medically intractable epilepsy: a review of complications and side effects. Epilepsy Res Treat 2013; 2013:752195. 53. Adelson PD. Temporal lobectomy in children with intractable seizures. Pediatr Neurosurg 2001; 34:268-77. 54. Mansouri A, Fallah A, McAndrews MP, et al. Neurocognitive and seizure outcomes of selective amygdalohippocampectomy versus anterior temporal lobectomy for mesial temporal lobe epilepsy. Epilepsy Res Treat 2014; 2014:306382. 55. Boucher O, Dagenais E, Bouthillier A, et al. Different effects of anterior temporal lobectomy and selective amygdalohippocampectomy on verbal memory performance of patients with epilepsy. Epilepsy Behav 2015; 52:230-5. 56. Suriadi MM, Usui K, Tottori T, et al. Preservation of absolute pitch after right amygdalohippocampectomy for a pianist with TLE. Epilepsy Behav 2015; 42:14-7. 57. Hu WH, Zhang C, Zhang K, et al. Selective amygdalohippocampectomy versus anterior temporal lobectomy in the management of mesial temporal lobe epilepsy: a meta-analysis of comparative studies. J Neurosurg 2013; 119:1089-97. 58. Josephson CB, Dykeman J, Fiest KM, et al. Systematic review and meta-analysis of standard vs selective temporal lobe epilepsy surgery. Neurology 2013; 80:1669-76. 59. Datta A, Sinclair DB, Wheatley M, et al. Selective amygdalohippocampectomy: surgical outcome in children versus adults. Can J Neurol Sci 2009; 36:187-91. 60. Wiebe S, Blume WT, Girvin JP, et al. A randomized,

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of deep brain stimulation for Parkinson disease: thirty-sixmonth outcomes. Neurology 2012; 79:55–65.

406

controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001; 345: 311-8. 61. Engel J Jr, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 2012; 307:922-30. 62. Spencer SS, Berg AT, Vickrey BG, et al. Initial outcomes in the Multicenter Study of Epilepsy Surgery. Neurology 2003; 61:1680-5.

NEUROLOGY

63. Schmidt D, Stavem K. Long-term seizure outcome of surgery versus no surgery for drug-resistant partial epilepsy: a review of controlled studies. Epilepsia 2009; 50:1301-9. 64. Murphy M, Smith PD, Wood M, et al. Surgery for temporal lobe epilepsy associated with mesial temporal sclerosis in the older patient: a long-term follow-up. Epilepsia 2010; 51:1024-9. 65. Dunkley C, Kung J, Scott RC, et al. Epilepsy surgery in children under 3 years. Epilepsy Res 2011; 93:96-106. 66. Rasmussen T. Hemispherectomy for seizures revisited. Can J Neurol Sci 1983; 10:71-8. 67. Ignelzi RJ, Bucy PC. Cerebral hemidecortication in the treatment of infantile cerebral hemiatrophy. J Nerv Ment Dis 1968; 147:14-30. 68. Adams CBT. Hemispherectomy: a modification. J Neurol Neurosurg Psychiatry 1983; 46:617-9. 69. Villemure JG, Rasmussen T. Functional hemispherectomy: methodology. J Epilepsy 1990; 3:177-82 70. Villemure JG, Vernet O, Delalande O. Hemispheric disconnection: callosotomy and hemispherotomy. In Cohadon A, editor. Advances and technical standards in neurosurgery (vol.26). New York/Wien: Springer; 2000. p. 26–69. 71. Delalande O, Pinard JM, Basdevant C, Hemispherotomy:a new procedure for disconnection. Epilepsia 1992; 33 Suppl 3:99-100.

et al. central

72. Delalande O, Bulteau C, Dellatolas G et al.Vertical parasagittal hemispherotomy: surgical procedures and clinical long-term outcomes in a population of 83 children. Neurosurgery 2007; 60:19-32. 73. Villemure JG, Mascott C. Hemispherotomy: the periinsular approach. Technical aspects. Epilepsia 1993; 34:48. 74. Villemure J-G, Mascott CR. Peri-insular hemispherotomy: surgical principles and anatomy. Neurosurgery 1995; 37:97581. 75. Villemure JG, Daniel RT. Peri-Insular hemispherotomy in paediatric epilepsy. Childs Nerv Syst 2006; 22:967-81.

76. Morrell F, Hanberry JW. A new surgical technique for the treatment of focal cortical epilepsy. Electroencephalogr Clin Neurophysiol 1969; 26:120. 77. Morrell F,WhislerWW, Smith M, et al. Landau-Kleffner syndrome. Treatment with subpial intracortical transection. Brain 1995; 118:1529-46. 78. Otsubo H, Chitoku S, Ochi A, et al. Malignant rolandicsylvian epilepsy in children: Diagnosis, treatment and outcomes. Neurology 2001; 57:590-6. 79. Blume WT. Corpus callosum section for seizure control: rationale and review of experimental and clinical data. Cleve Clin Q 1984; 51:319-32. 80. Avila JO, Radvany J, Huck FR et al.Anterior callosotomy as a substitute for hemispherectomy. Acta Neurochir Suppl (Wien) 1980; 30:137-43. 81. Connolly MB, Hendson G, Steinbok P. Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects. Childs Nerv Syst 2006; 22:896908. 82. Spencer SS, Spencer DD, Glaser GH et al. More intense focal seizure types after callosal section: the role of inhibition. Ann Neurol 1984; 16:686-93. 83. Roberts DW, Reeves AG. Effect of commissurotomy on complex partial epilepsy in patients without a resectable seizure focus. Appl Neurophysiol 1987; 50:398-400. 84. Salinsky M, Wernicke J, Rutecki P. A randomized controlled trial of chronic VNS for treatment of medically intractable seizures. Neurology 1995; 51:48-55. 85. Bingaman WW. Vagal nerve stimulation: Surgical techniques. In : Luders HO, editor. Deep brain stimulation and epilepsy. Martin Dunitz: London 2004; 247-54. 86. Tecoma ES, Iragui VJ. Vagus nerve stimulation use and effect in epilepsy: What have we learned? Epilepsy Behav 2006; 8:127-36. 87. Tellez-Zenteno JF, Wiebe S. Hippocampal stimulation in the treatment of epilepsy. Neurosurg Clin N Am 2011; 22:465-75. 88. Morrell MJ. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011; 77:1295-304. 89. Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010; 51:899-908.

Thrombolysis in Stroke Experience In India

C H A P T E R

INTRODUCTION

Stroke is a major health problem worldwide and is associated with high mortality and dependence.1 Stroke was defined by the WHO more than 40 years ago as “rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin.” Acute ischemic stroke (AIS) is an area in neurological clinical practice, which has probably seen the greatest strides as far as an understanding of pathogenesis is concerned.In the December of 1995 there came a paradigm shift in acute ischemic stroke management. National Institute of Neurological Disorders and Stroke (NINDS) in United States of America reported its success in significantly improving the outcome of ischemic stroke by using intravenous recombinant tissue-type plasminogen activator(rtPA), if administered within 3 hours.2 Even after 21 years, rtPA is the most effective treatment in a subset of ischemic stroke patients.

SUMMARY OF THE TRIALS

NINDS Trial 1 and NINDS Trial 2 together randomized 624 subjects within 3 hours of stroke onset to receive 0.9 mg/kg of intravenous tPA or placebo and found that patients treated with tPA within 3 hours of onset had a substantially better chance of functional independence with minimal or no disability 3 months after treatment. The proportion of patients with minimal or no disability increased from 38% with placebo to 50% with tPA, a 12% absolute improvement. The number needed to treat for 1 more patient to have a normal or near normal outcome was 8, and the number needed to treat for 1 more patient to have an improved outcome was 3.1.3 Brain hemorrhages related to tPA caused severe worsened final outcome in 1% of patients.4 Overall, for every 100 patients treated within the first 3 hours, 32 had a better outcome as a result and 3 had a worse outcome. An independent reanalysis of the NINDS trials demonstrated a robust treatment effect in favor of tPA.5 Four other phase 3 IV tPA trials, ECASS 1, ECASS 2, ATLANTIS A, and ATLANTIS B, have enrolled small subsets of patients in the under 3-hour time window. The degree of benefit of lytic therapy in the under 3-hour period observed in these trials was concordant with that found in the 2 NINDS trials.6,7 The use of tPA for acute ischemic stroke was approved by the US Food and Drug

Apratim Chatterjee, Subhodeep Gupta, Bhaskar Ghosh, Biman Kanti Ray

Administration (FDA) in 1996 and subsequently by regulatory agencies in Canada, Europe, South America, and Asia. The European Cooperative Acute Stroke Study 3 (ECASS 3) trial was performed to confirm or disconfirm the findings from initial trials suggesting benefit of IV tPA therapy in the 3- to 4.5-hour window. In ECASS 3, 821 patients were randomized to IV tPA or placebo. Major symptomatic hemorrhages occurred in 2.4% of the tPA group versus 0.2% of the placebo group, with no increase in mortality. Patients treated with tPA had a substantially better chance of functional independence with minimal or no disability 3 months after treatment. The proportion of patients with minimal or no disability increased from 45% with placebo to 52% with tPA, a 7% absolute improvement. The number needed to treat for 1 more patient to have a normal or near normal outcome was 14, and the number needed to treat for 1 more patient to have an improved outcome was 8. Overall, for every 100 patients treated within the 3- to 4.5-hour window, 16 had a better outcome as a result and 3 had a worse outcome.8 The favorable results of the pooled and ECASS 3 trials in the 3- to 4.5-hour window have been duplicated in a large phase 4 study examining the use of intravenous tPA in routine clinical practice. The international Safe Implementation of Treatment in Stroke (SITS) prospective registry identified 2376 patients treated in the 3- to 4.5hour window in regular practice at 650 centers from more than 25 countries. The rates of complications and of favorable outcomes were similar to those in ECASS 3. These findings confirm tPA as effective in clinical practice as it is efficacious in clinical trials in the 3- to 4.5-hour window when inclusion and exclusion guidelines are followed.9

THROMBOLYSIS GUIDELINES

The American Heart Association/American Stroke Association (AHA/ASA) inclusion guidelines for the administration of rt-PA in under 3 hours are as follows6 : •

Diagnosis of ischemic stroke causing measurable neurologic deficit

•

Neurologic signs not clearing spontaneously

•

Neurologic signs not minor and isolated

•

Symptoms not hemorrhage

suggestive

of subarachnoid

NEUROLOGY

408

•

Onset of symptoms less than 3 hours before beginning treatment

•

No head trauma or prior stroke in past 3 months

•

No MI in prior 3 months

•

No GI/GU hemorrhage in previous 21 days

•

No arterial puncture in noncompressible site during prior 7 days

•

No major surgery in prior 14 days

•

No history of prior intracranial bleed

•

Systolic blood pressure under 185 mm Hg, diastolic blood pressure under 110 mm Hg

•

No evidence of acute trauma or bleeding

•

Not taking an oral anticoagulant, or if so, INR under 1.7

•

If taking heparin within 48 hours, a normal activated prothrombin time (aPT)

•

Platelet count of more than 100,000/μL

•

Blood glucose greater than 50 mg/dL (2.7 mmol)

•

No seizure at onset with residual postictal impairments

•

CT scan does not show evidence of multilobar infarction (hypodensity over one-third hemisphere)

•

The patient and family understand the potential risks and benefits of therapy

In May 2009, and again in March 2013, the AHA/ASA guidelines for the administration of rt-PA following acute stroke were revised to expand the window of treatment from 3 hours to 4.5 hours to provide more patients with an opportunity to receive benefit from this effective therapy.3,7,10 Eligible patients should receive rtPA therapy as soon as possible, ideally within 60 minutes of hospital arrival. IV fibrinolysis can be considered in patients with rapidly improving symptoms, mild stroke deficits, major surgery within the past 3 months, and recent myocardial infarction; risks should be weighed against benefits.[19]

CURRENT STATUS IN INDIA

Thrombolytic therapy made a late and slow entry in India, for obvious reasons. These include lack of awareness among public and, among the referring physicians about the existence and usefulness of rtPA treatment. It is found that 8% to 25 % of stroke patients arrived in the hospital within 3 hours.11 All of them were not eligible according to NINDS criteria. Others find the cost very high. But the most important reason which discourages the neurologists to use rtPA is the uncertainty of response and potential for fatal brain hemorrhage. Several Government run institutes in India have reported good outcome with use of rtPA. All India Institute of Medical Sciences, New Delhi, published their experience of 40 thrombolysed patients within a 3h onset between between March 2002 and June 2005.12 The mean age was 66 years (range 32 - 82 years, male : female ratio = 3:2). The mean time to reach the emergency department was 27 min (25 - 45 min). The NIHSS score at admission ranged from 11 to 22 (mean 14.5 minutes). Twenty -six patients (65%) significantly improved on NIHSS at 48 h (> 4 points) (mean change = 10; range 40 - 17). At one month, 32 (79%) improved on Barthel Index (mean change = 45).12 Thirty seven patients were treated with rtPA in a Nizam Institute of Medical Sciences, Hyderabad over 53 months. Twenty –nine (78%) patients had a good outcome at 1 year. 33 Intra-arterial thrombolysis therapy is being used in approximately 10 centers in India. In a tertiary referral center from Kerala, SouthIndia, intra-arterial Urokinase (IA UK) was given in 5 patients. In two patients,there was complete recanalization with excellent recovery. In the remaining three patients, the recanalization rate varied from 0% to 50%, with partial recovery in two and no recovery in one patient.13

BIN EXPERIENCE

First to start thrombolysis in govt. sector in West Bengal •

Thrombolysis started in Aug 2015,

•

Total cases till now 31

•

Eligibility criteria for treatment in the 3 to 4.5 hours after acute stroke are similar to those for treatment at earlier time periods, with any 1 of the following additional exclusion criteria:

Mean time to reach EMERGENCY: 4.14 hours (30 min - 4.5 hrs.)

•

Average NIHSS at presentation – 13

•

Early CT changes prior to thrombolysis : 4

•

MRI done prior to thrombolysis: 27

•

Patients older than 80 years

•

Stroke mimic thrombolysed : 0

•

All patients taking oral anticoagulants are excluded regardless of the international normalized ratio (INR)

•

Average door to needle time : 78 minutes

•

Average NIHSS reduction at discharge – 4.2

•

Patients with baseline NIHSS score > 25

•

Patients with a history of stroke and diabetes

Complications : reperfusion edema-2, intracranial bleeding-1, cardiac arrhythmia -2

•

Patients with imaging evidence of ischemic damage to more than one third of the middle cerebral artery (MCA) territory10

•

Special cases thrombolysed: HIV positive, CKD not on HD----good outcome

•

Total no. of deaths – 4 (2 due to reperfusion edema, 2 due to cardiac arrythmia)

R.G. KAR MEDICAL COLLEGE EXPERIENCE Thrombolysis started in May’16

•

Thrombolysis done in General Medicine Ward and emergency room by General medicine residents under supervision of neurologist.

•

Total no of cases thrombolysed: 20

•

Average time to reach emergency : 3.10 hrs (45 mins to 4 hours)

•

Average NIHSS at presentation – 15.6

•

Early CT changes prior to thrombolysis : 6

•

MRI done prior to thrombolysis: 7

•

Stroke mimic thrombolysed : 2

•

Average door to needle time : 40 mins (only 25 for last 10 cases, least being 15 mins)

•

Average NIHSS reduction at discharge – 8.1 (n=17)

•

Complications : 1 ICH (NIHSS at presentation was 25), 3 Extracranial bleeding

•

Total no of deaths – 3 (2 due to aspiration pneumonitis, 1 due to ICH)

COST EFFECTIVENESS OF THE THERAPY

Initially before starting thrombolysis in govt. sector in West Bengal in BIN in AUG 2015, thrombolysis was only available to select few in private sector where quite a huge cost of therapy was there which was not within the reach of poor people. However after successfully initiating thrombolysis in BIN, IPGMER with a success in the first 12 cases, a plea was made to the state government to make the drug free and make it available in the essential drug list. After a brief wait, luckily enough the government like many other drugs has made it completely free and available in other government institutes as well after which there has been a huge surge of the rate of thrombolysis in Bengal which is widely available to people of all economic background. Even before it was made free it was seen that the use of the drug correctly limited the duration of hospital stay and mortality and morbidity of the patient and thus reduced the overall cost of therapy (compared to ischemic strokes which are not thrombolysed ) coupled with productive numbers of working days lost for the patient. Thus the balance was in any way better cost effective for thrombolysis even if the patient had to buy the drug.

BARRIERS TO THROMBOLYSIS IN INDIA AND WAYS TO OVERCOME

A study was recently conducted (yet in the process of publication) in BIN to find out the barriers to thrombolysis by Chatterjee et al and his colleagues. Out of a total of 147 consecutive patients of acute ischemic stroke 18 could be thrombolysed (12.24%). Out of the 129 patients who could not be thrombolysed 51 patients got enrolled in the ER within 4.5 hours but lost time after emergency entry at various steps. The mean time of onset of stroke

Leaving apart the economic part which we have already overcome much still remains to be done. The most important is the knowledge barrier, the concept that we really do not have any time left even within the window period and the dictum the sooner the better should be emphasized in the ER. A separate triage should be made for the acute ischemic stroke patients in the ER to reduce the waiting time. Separate imaging facility should be made available for the acute ischemic stroke patients so that they will not have to wait at imaging. On call residents should be primed to leave all work apart and attend the ischemic stroke patients as soon as possible. A code should be made with availability of pager system or some alarm to inform the members of the stroke team once an ischemic stroke comes within the window period. This stroke team should constitute of ER physician, neurologist, radiologist, nurse adept with stroke care, ward boys skilled for stroke care. A definite stroke care pathway should exist for every institute to give the best possible care in the simplest and fastest way in their institute.

RECENT ADVANCES IN THRMBOLYSIS AROUND THE GLOBE

Bridging Thrombolysis: Bridging therapy (the combination of intravenous [IV] and intra-arterial [IA] thrombolysis) is part of the therapeutic armamentarium in the daily practice of several stroke centers. As time to recanalization has emerged as a new goal in acute stroke care, combining the speed of IV alteplase administration and the higher recanalization rates of the IA route is a relevant approach. Controlled studies have reported the feasibility and efficacy of bridging therapy in terms of recanalization rates, but a positive clinical impact has only been observed in a select population of IV alteplase nonresponder patients. These findings raise the question of the target population for bridging therapy. It is not yet clear whether it should only be considered for IV alteplase nonresponder patients, or whether the small sample size of the other studies is the main explanation for the absence of any significant clinical benefit. In the study showing a significant favorable outcome at 3 months, higher morbidity and mortality were associated with bridging therapy, with higher symptomatic hemorrhage and death rates. Beyond recanalization rates, favorable clinical outcomes and safety need to be assessed. Pending the results of an ongoing randomized controlled trial comparing the

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•

to ER entry, attending by ER physician, ER to imaging and attending by neurophysician was 4.14 hours, 23.43 min, 41.90 min and 11.91 min respectively. Rest 78 patients could not be thrombolysed because of 51.4 % had economic constraints,28.4% of patients relatives did not give consent,2.4% had refractory high blood pressure,4.8% had logistic problems,5.4% had fluctuating NIHSS scores,seizure at onset was present in 2% of patients, other causes were upper GI.bleed 0.7%,lower GI bleed 0.7%,recent surgery in 1.4%,oral anticoagulant intake in 0.7%, taking loading dose of antiplatelet in 0.7%,superficial bleed and respiratory distress after tpa starting in 0.7% and recent AMI in 0.7%.

410

Sonothrombolysis: Multiple in vitro and animal models

NEUROLOGY

A total of seven retrieval devices were evaluated for stroke applications. Of which two devices have received FDA approval for use. The success of an application in these devices is gauged by percentage of recanalization of the occluded artery.

bridging approach with IV alteplase administration (the unique recommended therapy for patients with acute ischemic stroke), bridging therapy is considered an investigational technique. have demonstrated the efficacy of ultrasound to enhance fibrinolysis. Mechanical pressure waves produced by ultrasound energy improve the delivery and penetration of alteplase (recombinant tissue plasminogen activator [tPA]) inside the clot. In human stroke, the CLOTBUST phase II trial showed that the combination of alteplase plus 2 hours of continuous transcranial Doppler (TCD) increased recanalization rates, producing a trend toward better functional outcomes compared with alteplase alone. Other small clinical trials also showed an improvement in clot lysis when transcranial color-coded sonography was combined with alteplase. In contrast, low-frequency ultrasound increased the symptomatic intracranial hemorrhage rate in a clinical trial. Administration of microbubbles (MBs) may further enhance the effect of ultrasound on thrombolysis by lowering the ultrasoundenergy threshold needed to induce acoustic cavitation. Initial clinical trials have been encouraging, and a multicenter international study, TUCSON, determined a dose of newly developed MBs that can be safely administered with alteplase and TCD. Even in the absence of alteplase, the ultrasound energy, with or without MBs, could increase intrinsic fibrinolysis. The intra-arterial administration of ultrasound with the EKOS NeuroWave® catheter is another ultrasound application for acute stroke that is currently being studied in the IMS III trial. Operator-independent devices, different MBrelated techniques, and other ultrasound parameters for improving and spreading sono thrombolysis are being tested. •

Mechanical thrombolysis: Mechanical thrombectomy devices specifically for AIS intervention were developed in the 1990s concomitant to the advances in bioengineering devices which produced microcatheters and guide-wires amenable and safe to navigate the extremely complex and tortuous cerebral vasculature. Theoretically, mechanical devices provide several advantages over pharmacological thrombolysis, including revascularizations of large artery occlusions, more complete recanalization under observation, lesser amount of lytics to be used, reduced risk of hemorrhage, and a longer time interval for intervention. Six broad groupings classify neurothrombectomy devices: clot retrievers, aspiration or suction devices, snarelike devices, ultrasonography technologies, or lasers, and now stent retrievers. Potential harms associated with navigating mechanical devices into the intracranial circulation may include direct trauma to the neurovasculature (including vasospasm, vessel dissection, perforation or rupture) and fragmenting thrombi into previously unaffected vessels and cerebral territories.

•

Mechanical thrombectomy, in addition to intravenous thrombolysis within 4.5 hours when eligible, is recommended to treat acute stroke patients with large artery occlusions in the anterior circulation up to 6 hours after symptom onset (Grade A, Level 1a, KSU Grade A). Mechanical thrombectomy should not prevent the initiation of intravenous thrombolysis where this is indicated, and intravenous thrombolysis should not delay mechanical thrombectomy (Grade A, Level 1a, KSU Grade A). Mechanical thrombectomy should be performed as soon as possible after its indication (Grade A, Level 1a, KSU Grade A).For mechanical thrombectomy, stent retrievers approved by local health authorities should be considered (Grade A, Level 1a, KSU Grade A). Other thrombectomy or aspiration devices approved by local health authorities may be used upon the neurointerventionists discretion if rapid, complete and safe revascularisation of the target vessel can be achieved (Grade C, Level 2a, KSU Grade C) If intravenous thrombolysis is contraindicated (e.g. Warfarin-treated with therapeutic INR) mechanical thrombectomy is recommended as first-line treatment in large vessel occlusions (Grade A, Level 1a, KSU Grade A) Patients with acute basilar artery occlusion should be evaluated in centres with multimodal imaging and treated with mechanical thrombectomy in addition to intravenous thrombolysis when indicated (Grade B, Level 2a, KSU Grade C); alternatively they may be treated within a randomized controlled trial for thrombectomy approved by the local ethical committee. The decision to undertake mechanical thrombectomy should be made jointly by a multidisciplinary team comprising at least a stroke physician and a neurointerventionalist and performed in experienced centres providing comprehensive stroke care and expertise in neuroanesthesiology (Grade C, Level 5, GCP, KSU Grade C). Mechanical thrombectomy should be performed by a trained and experienced neurointerventionalist who meets national and/ or international requirements (Grade B, Level 2b, KSU Grade B). The choice of anesthesia depends on the individual situation; independently of the method chosen, all efforts should be made to avoid thrombectomy delays (Grade C, Level 2b, KSU Grade C).

PATIENT SELECTION FOR MECHANICAL THROMBOLYSIS

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Intracranial vessel occlusion must be diagnosed with non-invasive imaging whenever possible

before considering treatment with mechanical thrombectomy (Grade A, Level 1a, KSU Grade A). If vessel imaging is not available at baseline, a NIHSS score of ≥ 9 within three, and ≥ 7 points within six hours may indicate the presence of large vessel occlusion (Grade B, Level 2a, KSU Grade B).

•

Patients with radiological signs of large infarcts (for ex. using the ASPECTS score) may be unsuitable for thrombectomy (Grade B, Level 2a, KSU Grade B).

•

Imaging techniques for determining infarct and penumbra sizes can be used for patient selection and correlate with functional outcome after mechanical thrombectomy (Grade B, Level 1b, KSU Grade B).

•

High age alone is not a reason to withhold mechanical thrombectomy as an adjunctive treatment (Grade A, Level 1a, KSU Grade A).

At present mechanical thrombectomy is being successfully done at various centres in the country however a definite published statistics of this procedure across the country is still awaited.

The NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581-7.

[Guideline] Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007; 38:1655-711.

[Guideline] Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945-8.

Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second EuropeanAustralasian Acute Stroke Study Investigators. Lancet 1998; 352:1245-51.

Diedler J, Ahmed N, Sykora M, Uyttenboogaart M, Overgaard K, Luijckx GJ, et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset. Stroke 2010; 41:288-94.

CONCLUSION

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“Miles to go “is still the belief in stroke medicine and it is sure that the future has more to offer and that day is not far when a large burden of morbidity and mortality due to ischemic stroke will be just in history. The advent of stroke thrombolysis has given rise to a new group of neurointerventionalist across the country specialised in stroke. Thrombolysis care and much hope rests upon their shoulder in taking the country ahead in stroke care.

REFERENCES

Warlow C, Sudlow C, Dennis M, Wardlaw J, Sandercock P. Stroke. Lancet 2003; 362:1211-24.

Tissue plasminogen activator for acute ischemic stroke. TheNational Institute of Neurological Disorders and Stroke rtPAStudy Group. N Engl J Med 1995; 333:1581-1587.

Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317-29.

Albers GW, Clark WM, Madden KP, Hamilton SA. ATLANTIS trial: results for patients treated within 3

10. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44:870-947. 11. Indian Collaberative Acute Stroke Study (ICASS). Proceeding of Annual Conference of Andhra Pradesh Neuroscientists Association. Tirupati 2003. 12. Padma V, Soni D, Bhatia R, Srivastava A, Singh M. Thrombolysis in ischemic stroke: experience from a tertiary care hospital in India. J NeurolSci 2005; 238:S428. 13. Sylaja PN, KuruttukulamG,Joseph S, Gupta AK,Radhakrishnan K. Selective intra-arterial thrombolysisin acute carotid territory stroke. Neurol India 2001; 49:153-157.

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hours of stroke onset. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke.Stroke 2002; 33:493-5.

C H A P T E R

INTRODUCTION

Medicine is an ever changing science and more so are neurological sciences with breathtaking developments occurring on a day to day basis. Technological advances have helped us understand and diagnose diseases better. With the advent of various MRI techniques, neurology has received a face change. Newer diagnostic tests have come and helped us diagnose hitherto unknown diseases. Latest drugs have helped us control and cure neurological disorders. Immune-mediated disorders may be mentioned here as an example where new auto-antibodies are being recognized and newer drugs are controlling the disease without the side effects of steroids. Robotic tools have arrived to strengthen the surgeon’s hands. Therapeutic nihilism is no longer warranted in neurology. However the challenges to the clinician are ever increasing. He cannot afford to have rigid ideas and risk missing treatable disorders. He should use all the diagnostic and treatment modalities in his armamentarium judiciously. To top it all, the possibility of getting entangled in legal battles looms large in the case of unhappy patients or relatives. Each case is thus a challenge and the practicing neurologist would agree to at least one humbling experience daily. In other words each patient is a “tough call” unless proved otherwise. To showcase this we present some interesting clinical scenarios which include uncommon presentation of a common disease like Myasthenia Gravis, common presentation of an uncommon disease like Sjogren’s syndrome, uncommon but dreaded complication of surgeries in prone position and treatable disorders masquerading as a degenerative disease like MND. These

Fig. 1: Showing tongue atrophy with fasciculation

Tough Calls in Neurology K Mugundhan

cases highlight the importance of careful and repeated clinical examinations and laboratory investigations before a definitive diagnosis is made.

CASE NO. 1

A 27-year-old female admitted with 20 days history of difficulty in swallowing, change in voice with diurnal variation and fatiguability. There was no history of diplopia, drooping of eyelids, difficulty in eye closure and facial weakness. On examination, patient showed tongue atrophy with fasciculation (Figure 1), minimal limb weakness and absent tendon reflexes. Fatiguability tests were positive. Repetitive nerve stimulation revealed decremental response. Computerized tomography (CT) scan of thorax showed thymic enlargement. Acetylcholine receptor (AChR) antibody was positive (11.3 nmol/lit). Anti-muscle-specific receptor tyrosine kinase (Anti-MuSK) antibody was negative. Patient progressed to respiratory distress within a day of admission required ventilatory support followed by tracheostomy. She was diagnosed as myasthenic crisis. As the patient was not affordable for plasmapheresis and intravenous immunoglobulin, Injection methylprednisolone was given and planned for thymectomy. Patient lost on follow-up. After 3 months, patient presented again with bulbar weakness with minimal limb weakness. On examination, patient showed tongue atrophy with fasciculation. Patient progressed to respiratory failure and required ventilatory support. Plasmapheresis was given. On follow up after 4 weeks tongue fasciculation disappeared and tongue atrophy is improving (Figure 2).

Fig. 2: Showing improvement in tongue atrophy

413

Fig. 3: Showing hyperpigmentation of cheek

aggregates)] were common in MuSK MG patients, whereas fibre type grouping (neurogenic finding) and atrophy were frequent in AChR MG patients¹. The presence of fibre type grouping in AChR positive MG group might be explained by the blockage of AChR receptor binding that causes the internalization and degradation of AChR leading to denervation of affected muscle². In our present case, patient had bulbar onset MG which progressed to myasthenic crisis. Patient was treated with plasmapheresis and steroids after which she recovered. The unusual finding in this case was tongue atrophy with fasciculation which improved with plasmapheresis.

Fig. 4: Showing multiple dental caries Discussion

Myasthenia Gravis (MG) is a reversible autoimmune neuromuscular junction disorder associated with diurnal variation, weakness and fatiguability of voluntary muscles. It commonly affects extraocular muscles first. Bulbar onset myasthenia gravis is relatively rare. Atrophy of muscles is a rare feature of MG. Variety of antibodies are involved in the pathogenesis of MG. Myasthenia Gravis (MG) is an autoimmune disease caused by binding of autoantibodies to receptors involved in neuromuscular transmission. About 80% of patients have detectable serum antibodies against AChR (AChR-Ab). Approximately 15-20% of MG patients do not have any detectable AChR-Ab. Of these patients antibodies against muscle specific tyrosine kinase (MuSK) are positive in 30-50%. 3 types of AChR antibodies are identified which includes acetylcholine binding, blocking and modulating antibodies. Histological examination revealed myopathic changes [(mini-cores and ragged red fibres (mitochondrial

Cranial and bulbar muscle weakness with atrophy including tongue is more common in anti-MuSK MG³´⁴. Tongue atrophy is a rare feature of AChR antibody positive MG⁵. The exact pathogenesis of tongue atrophy is not known.

Conclusion

Bulbar onset MG is relatively rare. Tongue atrophy with fasciculation has been reported in anti-MuSK myasthenia gravis but rare in AChR antibody positive MG. This case highlights AChR antibody positive bulbar onset MG with tongue atrophy and fasciculation and improvement following plasmapheresis. Physician may be easily misled to think about motor neuron disease in the above case.

CASE NO. 2

A 38 year old previously healthy female was admitted with sudden onset severe weakness of all 4 limbs and neck with dyspnea at rest. She gave a history of analgesic intake prior to the illness for dental caries. She had no other systemic illness in the past except for recurrent renal calculi. On examination she was conscious,tachypneic with respiratory rate of 40/minute. Hyperpigmentation of both cheeks were noted (Figure 3). Multiple dental caries were also noted (Figure 4). The blood pressure was 120/70 mm Hg, pulse rate was 84/ min with no pallor, icterus, cyanosis, clubbing, oedema or lymphadenopathy. Neurological examination revealed severe flaccid weakness of all the 4 limbs and involving

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Fig. 5: Showing lymphocytic infiltrate in minor salivary gland and atrophy of acinar cells

related to tubular dysfunction which results from chronic interstitial nephritis.8 The most common presenting symptoms of sjogren syndrome are dryness of mouth and eyes. The most common extra glandular manifestation of sjogren syndrome includes Arthralgia (60%), Raynauds henomenon (37%), lymphadenopathy (14%), Pulmonary involvement (14%), vasculitis (11%) and renal involvement (9%) respectively. This serves to highlight the fact that patients presenting with hypokalemic paralysis with metabolic acidosis can be due to Sjogren syndrome which needs to be investigated and treated appropriately to avoid future recurrences.

NEUROLOGY

414

CASE NO. 3

Fig. 6: Magnetic Resonance Imaging shows enlarged hyper intense extra ocular muscles [left superior rectus, inferior rectus and medial rectus] neck flexors with diminished deep tendon reflexes, absent plantar reflexes without any cranial nerve or sensory involvement. Other systems were normal. ECG showed Prominent U waves, ST depression and Prolonged QTc interval. Blood counts were within normal limits. Blood Urea and Creatinine values were 30 mg/dl and 1.1mg/dl respectively. Severe hypokalemia was noted (serum K+ 1.4mEq/L). Serum sodium was 148.4mEq/L,Bicarbonate was 6.8 mEq/L. ABG revealed metabolic acidosis with compensatory respiratory alkalosis. Diagnosis of distal renal tubular acidosis leading to hypokalemic paralysis with impending respiratory failure was made and managed with potassium replacement and acetazolamide. Patient improved dramatically. Owing to the presence of metabolic acidosis with hypokalemia, nephrocalcinosis and dental caries, the possibility of sjogrensyndrome was considered which was later confirmed by a 3+ positive Anti nuclear antibody showing a nucleoplasm coarse granular pattern. Anti Ro levels were 97 U/ml. Lip biopsy was taken which showed lymphocytic infiltrate in minor salivary gland and atrophy of acinar cells (Figure 5) thereby confirming the diagnosis of sjogren syndrome. Patient is on low dose prednisolone and on regular follow up. The important differential diagnosis of acute areflexic quadriparesis includes Guillaine Barre syndrome, hypokalemic paralysis, transverese myelitis and multiple sclerosis. Sjogren syndrome is a chronic autoimmune disease characterised by progressive lymphocytic infiltration of exocrine glands with varying degrees of systemic involvement.6 Sjogren syndrome presenting as hypokalemic periodic paralysis caused by distal RTA have been rarely reported.7 The spectrum of renal disease includes interstitial nephritis, which can manifest as distal RTA, proximal RTA, tubular proteinuria, nephrogenic diabetes insipidus, glomerular diseases, or renal failure. The most common manifestations are

40 Year old man, non diabetic, not obese, underwent lumbar disc surgery under general anaesthesia in the prone position. In the recovery room, he noticed painless loss of vision in the left eye. 24 hours later neurologist was called to evaluate the cause. Examination of the left eye revealed, no light perception with relative afferent pupillary defect and restriction of extra ocular eye movements. Fundus examination showed normal disc and vessels right side. On affected side, the disc was pale and there was no CRA or CRV occlusion. Ocular tonometry showed intraocular pressure of 18mm Hg. Magnetic Resonance Imaging showed enlarged hyper intense extra ocular muscles[left superior rectus, inferior rectus and medial rectus] (Figure 6). Magnetic Resonance Imaging of Brain did not show any abnormalities in optic nerves, occipital lobes and rest of the visual pathways and cavernous sinus. Blood investigations including blood biochemistry were normal. Diagnosis of ischemic orbital compartment syndrome was made. High dose IV methylprednisolone [1gm] was started. Canthotomy and cantholysis was performed but no improvement in visual acuity or ocular movements.

Discussion

Perioperative ischemic optic neuropathy[ION] is a rare, unexpected and devastating complication occurring overall 1 in 60,000 to 1 in 1,25,000 anaesthetics. Ischemic optic neuropathy[ION] following spinal surgery forms the highest frequency (0.03 percent)9,10. In the above case, patient presented with ischemic orbital compartment syndrome following spinal surgery done in the prone position. Ischemic ocular compartment syndrome is an acute opthalmological emergency requiring prompt decompression to relieve the increased intraocular pressure. It is reported in spine surgery done in prone position. The possible mechanism is the progressive orbital edema secondary to prone position and possible unilateral direct pressure from the headrest device on periorbital structures, resulting in congestion at the orbital apex, with a subsequent compartment syndrome and ischemic orbit.11 The prolonged operation was also a significant factor in the irreversible ischemia and poor overall visual and functional prognosis. Ophthalmologists, as well as neurosurgeons and anaesthesiologists, should be familiar with this rare complication and the mechanism of visual loss in patients

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Fig. 7: Showing left lateral rectus palsy

Fig. 8: Showing wasting and weakness of tongue on both sides undergoing prolonged surgery in prone position. . High risk patients are defined as those who undergo spine procedures while positioned prone and who have prolonged procedures, experience substantial blood loss, or both12. It is essential to monitor these patients during and after surgery and to intervene surgically once the diagnosis of ischemic orbital compartment syndrome is made although the prognosis is poor.

CASE NO. 4

65 year old male, non smoker, non alcoholic, not a known diabetic or hypertensive presented to us with dysphagia with nasal regurgitation, difficulty in marshaling the food and double vision on looking distant objects of 1 month

Fig. 9: MRI (T1Sagittal) Dorsal spine showing multiple well defined hypointense sclerotic secondaries

Fig. 10: HPE of prostatic Biopsy specimen showing irregular small round to oval glands lined by columnar cells with mild to moderate nuclear pleomorphism and hyperchromatism.Sheets of tumour cells with diffuse infiltration of stroma suggestive of grade 2 adenocarcinoma of prostate duration. On examination, the patient was conscious, oriented, afebrile, cervical lymph node enlargement, left lateral rectus palsy was present (Figure 7). Pupil 3mm equally reacting to light on both sides. Fundus examination was normal. Left gag reflex was sluggish. Tongue wasting and weakness was noted on both sides (Figure 8). Left 6th, left 10th and bilateral 12th cranial nerves were involved. Patient did not have florid meningeal signs. There was no limb weakness. All deep tendon jerks were normal. Plantars were flexor. Sensory and cerebellar systems were normal. On rectal examination, hard prostatic mass was felt. Blood investigations including blood biochemistry were

NEUROLOGY

416

normal. Vasculitic profile including ANA were normal. X Ray chest PA view was normal. ENT opinion revealed no lesion in nasopharynx. Ultrasonogram of abdomen and pelvis showed enlargement of prostatic gland (4.6X4.7cm). Serum prostatic specific antigen was more than 1000ng/ ml. MRI Brain( plain and contrast) was normal. MRI (T1Sagittal) Dorsal spine showed multiple well defined hypointense sclerotic secondaries (Figure 9). Fine needle aspiration cytology (FNAC) of left cervical lymph node showed metastatic deposits. Histopathological Examination(HPE) of prostatic gland biopsy showed irregular small round to oval glands lined by columnar cells with mild to moderate nuclear pleomorphism and hyperchromatism. There are other foci showing sheets of tumour cells with diffuse infiltration of stroma. These features were suggestive of grade 2 adenocarcinoma of prostate (Figure 10). CSF analysis showed 40 cells/ cu mm which were predominantly mononuclear cells with mildly elevated protein. CSF sugar was low at 20mg percent. Diagnosis of leptomeningeal metastasis (multiple cranial nerve palsies) due to carcinoma prostate was made based on the hypercellularity, elevated protein and hypoglycorrhachia of the CSF. Patient was subjected to orchidectomy and planned for radiotherapy and antiandrogen therapy. Patient is on follow up.

Discussion

Metastatic prostatic carcinoma commonly involves bones and extra pelvic lymph nodes. CNS involvement is unusual and particularly the occurence of leptomeningeal metastasis is extremely rare , with few cases described in the literature13. The reported incidence at autopsy vary from 0.6 to 4.4 percent14. Brain metastasis occurs in 25 percent of patients with malignancies and 50 percent of neoplasms in the brain are metastatic15. The most common sources of metastasis to the brain are carcinoma lung, breast, kidney and melanoma.16,17 The most common sites of prostate cancer metastasis include the bone, lung and liver18. Brain metastasis is very rare in prostate cancer. The intracranial sites of prostate cancer metastasis are the leptomeninges, cerebrum, and cerebellum19. On the other hand, the diagnosis of metastatic prostate carcinoma to the brain has rarely been made in living patients. Brain metastasis in prostate cancer occurs late in the course of the disease. It usually represents the failure of hormonedeprivation therapy and the presence of disseminated disease. The long time between diagnosis and brain involvement strongly favors the cascade theory of tumor spread 20;21. Metastasis to the brain can occur by way of Batsonâ&#x20AC;&#x2122;s plexus or by direct extension from adjacent structures such as the sphenoid bone or sinuses. Other primary cancers, such as lung and breast tumors, are more likely to have intraparenchymal metastases than leptomeningeal involvement. Patients rarely present with neurologic symptoms as the first manifestation of prostate cancer. Presentation with a solitary brain metastasis as the only site of prostate cancer spread is even rarer. Leptomeningeal metastasis is usually clinically silent, although it can present with deficits in multiple anatomic sites22. Gadolinium-enhanced MRI is required to exclude

or confirm the presence of brain metastases. A two-week course of radiotherapy is the most common treatment for patients with multiple brain metastases or leptomeningeal involvement. Brain metastasis is associated with a poor prognosis. Once prostate cancer has spread to the brain, the one-year survival rate is 18 percent, with an average survival of 7.6 months. Our patient presented with multiple cranial nerve palsies. The FNAC of the cervical lymphnode gave clue as metastatic lesion. Inspite of extensive metastasis, there is no evidence of cord compression. CSF analysis showed 40 cells/cumm which were predominantly mononuclear cells with elevated protein. CSF sugar was low at 20mg percent. The diagnosis of leptomeningeal metastasis (multiple cranial nerve palsies) due to carcinoma prostate was made based on the hypercellularity, elevated protein and hypoglycorrhachia of the CSF as per category3 in the National Comprehensive Cancer Network (NCCN) guidelines23. This is the most plausible explanation for cranial nerve involvement in this case. Our emphasis is however on the protean clinical presentations of carcinoma prostate with no clues to the primary site of involvement. A high index of suspicion is needed when an elderly male approaches us with such a clinical presentation.

CONCLUSION

In case no.1, a young lady presented with short duration of recurrent bulbar symptoms. We looked for antibodies to MG and found to be positive. The general teaching is that muscle atrophy is not a feature of MG and is a feature of anterior horn cell disease. It still holds good. It is a typical example of MG masquerading as MND. An interesting feature is reversal of tongue atrophy following immunotherapy (plasmapheresis). Steroids are not useful in GBS. However, in the second case, it proved to be the lifesaving drug since sjogren syndrome was identified as the cause for the clinical presentation of acute flaccid paralysis. Anything can happen in medicine. Surgeries done under prone position is commonly done procedures in neurosurgery and orthopedic surgeries. Nobody would have anticipated this catastrophic complication in this third case. In case no.4, the diagnosis of MND is considered a death sentence due to lack of treatment and the mortality associated with it. It is important to consider MND mimics which could be treatable and may not carry a grave prognosis. Secondary causes should be considered and looked for while dealing with a clinical presentation mimicking MND. In this case, extra ocular muscle involvement (lateral rectus) is the catch point. The subtle CN palsy and careful examination of cervical lymphnode lead us to a treatable malignant disease presenting like MND. Thus all the four cases are examples of tough calls in neurology.

REFERENCES

Society of Anesthesiologists Task Force on Perioperative Visual Loss. Anesthesiology 2012; 116:274-85.

Martignagos, Fanin M, Albertini E, Pegoraro E, Angelinic, Muscle histopathology in myasthenia gravis with antibodies against MuSK and AChR. Neuropathol and Appl Neurobiol 2009; 35:103-110.

13. Domenico Cante, Pierfrancesco Franco, Piera Sciacero, Giuseppe Girelli: Leptomeningeal metastasis from prostate cancer Tu mo ri, 2013; 99:e6-e10.

Appel SH, Anwyl R, Mc Adams MW, Elias S. Accelerated degradation of acetylcholine receptor from cultured rat myotubes with myasthenia gravis sera and globulins. Proc Natl Acad Sci USA 1977; 74:2124-30.

14. Tsai V., Kim S., Clatterbuck R.E., Ewend M.G., Olivi A.: Cystic prostate metastases to the brain parenchyma: report of two cases and review of the literature. J Neurooncol 2001; 51:167-173.

Evoli, A., Tonali,P.A., Padna,L.,et al,2003, Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis, Brain, Vol.126, pp2304-2311.

Farrugia,M.E., Robson,M.D., Clover,L.,et al MRI and clinical studies of facial and bulbar muscle involvement in MuSK antibody associated myasthenia gravis, Brain 2006; 129:1481-1492.

15. Tremont-Lukats IW, Bobustuc G, Lagos GK, Lolas K, Kyritsis AP, Puduvalli VK. Brain metastasis from prostate carcinoma: The M. D. Anderson Cancer Center experience. Cancer 2003; 98:363-368.

J.Burch, C.Warren-Gash, V.Ingham.,et al 2006, Myasthenia gravis- a rare presentation with tongue and fasciculation, Age and Ageing, 35:87-88.

Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. The management of Sjögren’s syndrome. Nat ClinPractRheumatol 2006; 2:252–61.

Soy M, Pamuk ON, Gerenli M, Celik Y. A primary Sjögren’ssyndrome patient with distal renal tubular acidosis, who presentedwith symptoms of hypokalemic periodic paralysis: Report of a casestudy and review of the literature. RheumatolInt 2005; 26:86-9.

16. Chiang PH, Lee TC, Huang CC. Intracranial metastasis of prostate cancer: report of two cases. Chang Gung Med J 2004; 27:770-776. 17. Gilles FH, Sobel EL, Tavare CJ, Leviton A, Hedley-Whyte ET. Age-related changes in diagnoses, histological features, and survival in children with brain tumors: 1930-1979. The Childhood Brain Tumor Consortium. Neurosurgery 1995; 37:1056-1068. 18. Sutton MA, Watkins HL, Green LK, Kadmon D. Intracranial metastases as the first manifestation of prostate cancer. Urology 1996; 48:789-793. 19. Fervenza FC, Wolanskyj AP, Eklund HE, Richardson RL. Brain metastasis: an unusual complication from prostatic adenocarcinoma. Mayo Clin Proc 2000; 75:79-82. 20. Lynes WL, Bostwick DG, Freiha FS, Stamey TA.Parenchymal brain metastases from adenocarcinoma of prostate. Urology 1986; 28:280-7.

Bossini N, Savoldi S, Franceschini F, Mombelloni S, Baronio M, Cavazzana I, et al. Clinical and morphological features of kidneyinvolvement in primary Sjögren’s syndrome. Nephrol Dial Transplant 2001; 16:2328-36.

RothS.perioperative visual loss: What do we know,what can we do. Br J Anaesth 2009; 103:i31-i40.

21. Varkarakis MJ, Winterberger AR, Gaeta J, Moore RH, Murphy GP. Lung metastases in prostatic carcinoma. Clinical significance. Urology 1974; 3:447-52.

10. Roth S,ThistedRA,EricksonJP,BlackS.Eye injuries after non ocular surgery :a study of 60,965 anaesthetics from 1988to 1992. Anaesthesiology 1996; 85:1020-7.

22. Balm M, Hammack J. Leptomeningeal carcinomatosis. Presenting features and prognostic factors. Arch Neurol 1996; 53:626-32.

11. Leibovitch I, CassonR, Laforest C, Selva D. Ischemic ocular compartment syndrome as a complication of spinal surgery in the prone position. Opthalmology 2006; 113:105-8.

23. Brem SS, Bierman PJ, Brem H, Buiowski N, Chamberlain MC, Chiocca EA, et al. National Comprehensive Cancer Network, Central nervous system. J Natl Compr Canc Netw 2011; 9:352–400.

12. Practice advisory for perioperative visual loss associated with spine surgery: an updated report by the American

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C H A P T E R

NOMENCLATURE

Charcot used the term ‘Amyotrophic Lateral Sclerosis’ (ALS), a description based on clinical and neuropathological features in patients assessed by him and studied at autopsy.1 Lord Brain in 1962 used the term Motor Neuron Disease to encompass entities constituting the other clinical manifestations: amyotrophic lateral sclerosis, progressive bulbar palsy, and progressive muscular atrophy.2 Essentially, the two terms ALS and MND are currently considered synonymous and used to describe clinical entities derived from degeneration within the anterior horn cell and the pyramidal tracts to somatic and bulbar musculature with variable segmental involvement producing differing presentations in different patients.3 The clinical phenotype varies according to the segmental dysfunction within these parts of the neuraxis, which occurs at the time of clinical presentation.

AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic Lateral Sclerosis (ALS) is a progressive, relentless, degenerative disorder characterized by a pathological change restricted to the cortical Betz cells, pyramidal tracts, selective brainstem cranial nerve neurons, and the spinal anterior horn cells in variable permutations and combinations. The onset can vary in its topography within the nervous system determining the pattern of initial limb involvement and later its progression. The symptoms of lower motor neuron dysfunction are, weakness, cramps, incoordination and fatigue, while its physical signs are the presence of weakness, atrophy, fasciculations, hypotonia and suppression of deep tendon reflexes. The symptoms of upper motor neuron dysfunction are weakness, incoordination, stiffness and slowing, while the corresponding physical signs are the presence of spasticity, brisk deep tendon reflexes and abnormal reflexes especially the Babinski and Hoffman signs. Depending on the site of onset, the extent of involvement of the neuraxis in the disease process, and the stage of the disease, these symptoms and signs are present in varying combinations. Practically, patients may present with symptoms of difficulty in arising from a chair, tiredness, tripping and inability to button and unbutton clothing, perceived cramps and twitching of muscles. Some may notice and change in speech due to dysarthria and difficulty in swallowing due to bulbar or pseudo-bulbar weakness producing frequent coughing at meal times. Family members may notice slurring of speech due to spastic dysarthria. With the passage of time the whole gamut of

Motor Neuron Diseases Joy D Desai

symptoms and signs may progress variably. In patients in whom the respiratory muscles are affected by ALS, progressive dyspnoea on exertion and later at rest may also compound the clinical challenges. The usual course of progression in ALS is relentless with death occurring in 50% of patients by three to four years from onset.4 The absence of overt sensory, sphincter and oculomotor dysfunction serves to distinguish ALS from other disorders of the lower motor neuron. A variable proportion of patients with ALS may develop personality and behavioural changes. Cognitive assessment reveals impairment in planning ability, execution of strategies and ability to perform complex sequential tasks occasionally associated with frontal lobe release signs.5 Although dementia by the true definition is unusual in ALS, these features of impaired executive functioning, reflect involvement of the frontal lobes in the disease process.6,7 Such frontal lobe dysfunction is more common in patients with predominantly bulbar type of ALS.8 Rarely, some patients exhibit parkinsonian features and loss of postural reflexes (resulting in retropulsion) in addition to the characteristic motor signs of ALS.9,10 Progressive bulbar palsy (PBP) is the nomenclature for a progressive disease presenting with bulbar dysfunction due to destruction of motor neurons in the brainstem. Sometimes this syndrome includes evidence of upper motor neuron dysfunction. Historically, it has been considered a ‘bulbar’ form of ALS/MND. Some patients with progressive bulbar dysfunction of this degenerative kind could evolve into ALS with progression of the disease resulting in limb involvement. Many succumb to aspiration secondary to the bulbar paralysis while clinically restricted to the bulbar dysfunction only. Understandably, this type of MND has a poorer prognosis than ALS. The clinical features of this phenotype of MND often blurs or evolves into ALS. Progressive muscular atrophy (PMA) refers to motor neuron disease presenting with weakness and wasting of muscles of the limb, and trunk muscles without evidence of upper motor neuron dysfunction. This condition may mimic adult onset proximal spinal muscular atrophy (SMA). The more rapid progression, and the later development of brisk reflexes may assist in differentiating PMA from SMA, since in SMA the tendon reflexes are usually reduced, and the plantar responses are always flexor. The prognosis of this form of motor neuron disease

may be different from that of the classical ALS form of motor neuron disease. Primary lateral sclerosis (PLS) typically presents with a slowly progressive spastic gait disorder. Over months or years, the upper limbs are involved and in some a pseudobulbar syndrome develops. Hyper-reflexia, and Babinski and Hoffman signs are characteristic features, while lower motor neuron signs and sphincter dysfunction are absent. The clinical course and survival are much longer than ALS of Charcot type.

DIAGNOSTIC CRITERIA FOR ALS

The diagnosis of ALS is not difficult to make once a clinician is aware of the spectrum of symptoms and signs that constitute the condition. Challenges lie in identifying patients early when all features may not have evolved in a given patient. The current accepted criteria for designation of ALS as a diagnostic entity for research are known as the ‘El Escorial’ criteria. These criteria were proposed after a meeting at the San Lorenzo Monastery in El Escorial near Madrid, Spain by the World Federation of Neurology in May 1990. Understanding of the spectrum of manifestations has changed over the years resulting in proposals to revise these criteria both from the electrodiagnostic point of view and the clinical. The following revised El Escorial criteria serve as a framework to broadly identify categories of patients clinically suspected to suffer from ALS or MND. Some of the original 1990 proposed criteria have been modified to accommodate current understanding ALS.14

REVISED EL ESCORIAL CRITERIA FOR THE DIAGNOSIS OF ALS

Clinically definite ALS •

Evidence of upper motor neuron plus lower motor neuron signs in the bulbar region and at least two spinal regions or

•

The presence of upper motor neuron signs in two spinal regions and lower motor neuron signs in three spinal regions.

Clinically probable ALS •

Evidence of upper motor neuron plus lower motor neuron signs in at least two spinal regions with some upper motor neuron signs rostral to lower motor neuron signs.

Probable, Laboratory supported ALS •

Clinical evidence of upper motor neuron signs and lower motor neuron signs in only one region, or

•

Upper motor neuron signs alone in one region, and lower motor neuron signs defined by EMG criteria in at least two muscles of different root and nerve origin in two limbs.

•

Upper motor neuron plus lower motor neuron signs in one region only, or

•

Upper motor neuron signs alone in two or more regions, or

•

Lower motor neuron signs found rostral to upper motor neuron signs.

419

(Regions: bulbar, cervical, thoracic, and lumbosacral) The differential diagnosis of ALS includes rare presentations due to paraneoplasia, the concordant occurrence of cervical and lumbar radiculopathy due to degenerative spinal disease, and occasionally multifocal motor neuropathy. Most patients undergo routine haematology, biochemistry, endocrine evaluation, CSF examination, EMG/NCV studies, and MRI of the spine.

THERAPY IN ALS

The therapy of ALS till recently was restricted to symptomatic management. However, on the basis of two clinical trials,15, 16 the American FDA has approved Riluzole for the treatment of ALS. The first clinical trial of riluzole in ALS was a multi-centre, stratified, randomized, double-blinded, placebo-controlled study, the results of which were announced in early 1994.15 The study involved 155 patients, of whom 77 were assigned to receive riluzole 100mg/day and 78 placebo. The patients entered in this study were stratified and balanced according to the centre and the type of onset i.e. whether the disease began in the bulbar muscles or in the limbs. The study end-points were either death or tracheostomy. Therefore, the main outcome measure was tracheostomy-free survival. The median survival was 449 days and 532 days in the placebo and riluzole groups, respectively. Overall, riluzole therapy reduced mortality by 38.6% at 12 months and by 19.4% at 21 months (the end of the placebo-controlled period). However, the treatment effect was greater in patients with bulbar-onset disease than in patients with limb-onset disease. The design of the second trial was similar to the first with the addition of a dose-ranging design and a longer period of evaluation.16 In this study, randomization was stratified according to bulbar or limb onset of disease. The trial had a double blind, randomized and placebo-controlled fourarm design. The four groups compared treatments with placebo or 50mg, 100mg and 200mg riluzole daily. A total of 959 patients with clinically probable or definite ALS of less than 5 years duration entered the study. At the end of the study, defined by protocol as a median follow-up of 18 months, 122 placebo-treated patients (50%) and 134 of those who received 100mg of riluzole (57%) were alive without tracheostomy. In the groups receiving 50mg and 200mg riluzole daily, 131 (55%) and 141 (58%) patients were alive without tracheostomy. There was a significant inverse dose response in risk of death. No functional scale used in the study discriminated between the treatment groups. No beneficial effect on muscle strength, assessed by MRC scale, could be discerned in any treatment group.

CHAPTER 88

Based on clinical, radiological and pathological studies11, 12 diagnostic criteria have been laid down. PLS may be a paraneoplastic manifestation of breast carcinoma.13 PLS is a very rare disorder.

Possible ALS

NEUROLOGY

420

Based on these results the ALS/Riluzole Study Group concluded that at a dose of 100mg per day, riluzole was an effective drug in slowing the progression of ALS to death, with an acceptable safety profile and represented the first step in the development of treatments for ALS. The effect was described as a reduction in the risk of death at 18 months of treatment, by about 35%. No difference was noted in the effect of treatment on the bulbar onset group as compared with the limb onset group. Subsequent attempts to evaluate potential therapies for the amelioration of ALS have failed clinical trials. These molecules include anti-glutamate agents, despramipexole, minocycline, and idebenone. Edavarone has been found to be useful by some Japanese investigators but not replicated in trials in the Caucasian populations and its place in the therapy of ALS remains contentious.

MADRAS MOTOR NEURON DISEASE

Meenakshisundaram, Jagganathan, and Ramamurthy designated the term “Madras Motor Neuron Disease” to a cohort of patients described by them in 1970. This term is applied to a sporadic, slowly progressive, juvenile onset of asymmetric weakness and wasting of the limbs accompanied by bilateral facial weakness, weakness and wasting of the tongue leading to bulbar dysfunction, and deafness in varying proportions.17 In contradistinction to ALS the clinical course of this disorder is benign and long-term survival over decades common. Over a period of fifteen years, the original case series reported by Meenakshisundaram had been expanded to forty typical cases.18 70% of these forty patients exhibited clinical signs of lower cranial nerve dysfunction involving the 7th to 12th nerves in varying proportions. The presence of upper motor neuron signs may occur in up to 65% of cases thus making the resemblance to classical ALS very close. Therefore, in most discussions on MND/ ALS, Madras Motor Neuron Disease (MMND) usually finds a place. The absence of reported identical cases from other parts of the world, the lack of established neuropathological correlates of the clinical features, and its rarity has shrouded a cloak of mystery over this elusive entity. In the current understanding, Madras Motor Neuron Disease may be considered as a unique and variant form of anterior horn cell dysfunction with a phenotype that can be clinically recognized and distinguished from the standard motor neuron disease or ALS. Its prognosis and response to any therapeutic intervention are unknown.

HIRAYAMA’S DISEASE/MONOMELIC AMYOTROPHY/ JUVENILE ASYMMETRIC SEGMENTAL MUSCULAR ATROPHY

In 1984, Gourie-Devi and her colleagues from NIMHANS, Bengaluru, described a sporadic condition that mimics motor neuron disease and designated the term “Monomelic amyotrophy” for this condition.19 Japanese neurologists recognize this disorder as identical with that described by Keizo Hirayama in 195920 and in early medical literature it has been eponymously called

Hirayama’s Disease. The disorder reported by Singh et al, in 1980 is possibly the first Indian detailed study of this condition.21 It is believed to be a disorder that occurs more commonly in the Asian sub-continent and Japan than in the Western world, though sporadic reports abound amongst the Caucasian population. Patients with monomelic amyotrophy usually present to the neurologist in the second decade of life. The symptoms are characterised by a slowly progressive, asymmetrical weakness and wasting of the small muscles of the hands. The onset is usually unilateral and remains so for a long time. The wasting is typically restricted to the C7-T1 myotomes and only occasionally involves the C5-6 myotomes. Fasciculations occur and even when seemingly unilateral, electromyography may detect subclinical dysfunction in the opposite limb. Being insidious in onset, the wasting is clinically apparent by the time weakness is noticed by the patient. Often, there is a visible tremor in the outstretched affected limb or when an object is held in the affected limb. The deep tendon reflexes may be sluggish or absent in the symptomatic arm. Lower limbs, bulbar musculature, and the sensory system are unaffected. The tempo of progression in this disorder is characterised by a plateau phase of clinical stabilization after the initial gradual worsening. There has been no documentation of weakness or wasting spreading to involve the lower limbs even decades after the affliction of the upper limbs. In the case series reported by Gourie-Devi et al, lower limb deep tendon reflexes were documented to be brisk in some patients.19 This perhaps drew a close resemblance of this disorder to motor neuron disease. The authors also included three individuals with segmental lower limb weakness and wasting in their report. None of the other publications on this entity previously referred to as Hirayama’s disease have reported lower limb dysfunction of this kind. The aetiology and pathogenesis of this condition remains an enigma. Pradhan et al, from SGPGI, Lucknow performed magnetic resonance imaging (MRI) of the cervical spine in neutral and flexed positions in sixteen patients with Hirayama’s disease, which they preferred to designate as juvenile asymmetric segmental spinal muscular atrophy (JASSMA). They took five normal individuals and five patients with ALS as their controls.22 Focal atrophy of the lower cervical spinal cord was detected in patients with JASSMA. In flexion, there was a marked anterior displacement and antero-posterior flattening of the lower cervical cord against the vertebral bodies. The posterior dura mater also moved forward obliterating the subarachnoid space in all these patients. A large posterior epidural space was observed in flexion, which enhanced on administration of gadolinium in one of their patients. The authors suggested that these MRI characteristics are a hallmark of JASSMA, as such changes were not observed in either in their normal or ALS controls. Hirayama and Tokumaru reported a similar finding of marked forward displacement of the cervical dural sac and compressive flattening of the lower cervical cord

during flexion in seventy-three Japanese patients with Hirayama’s disease.23 Such features were not observed in twenty disease controls. The authors concluded that these radiological findings are supportive of the concept that this condition is a localized cervical poliomyelopathy, as postulated by them earlier.

Restuccia et al, studied somatosensory evoked responses in flexion and extension from the upper limbs in five patients with Hirayama’s disease, six patients with ALS, and fourteen healthy individuals.28 Neck flexion caused a significant amplitude decrease of the N13 cervical response only in patients with Hirayama’s disease (and not in healthy controls or patients with ALS). They suggested that neck flexion resulted in electrophysiologically significant cervical cord dysfunction in patients with Hirayama’s disease. This might be construed to reflect the effects traction on the cervical cord during flexion and its physiological effects on the vulnerable local segments in these patients. In Hirayama’s disease or JASSMA (as is the currently proposed nomenclature), there might be an option of surgically correcting the anatomical aberration of the flexion-extension abnormalities within the cervical cord, by decompressing the affected segments. This has been explored in various manners by speculative neurosurgeons with variable outcomes. While surgical decompression of the cervical cord has not become the standard of care,29 the prospect of potential correction by such an intervention should be borne in mind when dealing with patients with this uncommon condition.

JUVENILE ALS

Ben Hamida et al., described from Tunisia an unusual form of autosomal recessive, childhood onset motor neuron disease characterised by chronic slowly progressive degeneration of both upper and lower motor neurons.30 The anatomical distribution of clinical features is identical to classical ALS. A combination of upper and lower motor neuron dysfunction often associated with pseudo-bulbar changes is characteristic of this form of ‘juvenile ALS’. Cognitive and sensory functions are intact and survival over several decades is the rule. Genetic linkage of a large pedigree with juvenile ALS has defined a disease locus on the distal long arm of chromosome 2, mapping at 2q3335.31 Other Tunisian families with an identical clinical disorder32 have been mapped to chromosome 15q1221. Recently, a dominantly inherited eleven-generation

The variability of clinical combination of features at a given time during the course of the illness, the broad spectrum of sporadic and inheritable disorders with such clinical features, and the occasional occurrence of symptomatic anterior horn cell disorders poses a challenge to most clinicians. A distinct understanding of these specific conditions aids correct nosologic designation and ultimate prognosis.

REFERENCES

Aran FA Recherches sur une maladie non encore décrite du système musculaire (Atrophie musculaire progressive). Arch Gen Med 1850; 24:5-35,172-214.

Brain WR. Motor neuron diseases. In: Brain WR, editor. Diseases of the nervous system, 6th Ed. Ox ford: Oxford University Press,1962:531.

Rowland LP. Diverse forms of motor neuron disease. In: Rowland LP, editor. Human motor neuron diseases. New York: Raven Press:1982;1-13.

Mulder DW, Howard FM. Patient resistance and prognosis in amyotrophic lateral sclerosis. Mayo Clin Proc 1976; 51:537-541.

Neary D, Snowden JS, Mann DMA, et al. Frontal lobe dementia and motor neuron disease. J Neurol Neurosurg Psychiatry 1990; 53:23-32.

Abrahams S, Goldstein LH, Kew JJM, Brooks DJ, Lloyd CM, Firth CD, Leigh PN. Frontal lobe dysfunction in amyotrophic lateral sclerosis. A PET study. Brain 1996; 119:2105-2120.

Jackson M, Lennox G, Lowe J. Motor neuron diseaseinclusion dementia. Neurodegeneration 1996; 5:339- 350.

Abrahams S, Goldstein LH, Al-Chalabi A, Pickering A, Morris RG, Passingham RE, Brooks DJ, Leigh PN. Relation between cognitive dysfunction and pseudobulbar palsy in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1997; 62:464-472.

Qureshi AI, Wilmot G, Dihenia B, Schneider JA, Krendel DA. Motor neuron disease with parkinsonism. Arch Neurol 1996; 53:987-991.

10. Desai J and Swash M. Extrapyramidal involvement in ALS: backward falls and retropulsion. J Neurol Neurosurg Psychiatry 1999; 67:214-216. 11. Younger DS, Chou S, Hays AP. Primary lateral sclerosis: a clinical diagnosis reemerges. Arch Neurol 1988; 45:13041307. 12. Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers GC. Primary lateral sclerosis: clinical features, neuropathology and diagnostic criteria. Brain 1992; 115:495520. 13. Forsyth PA, Dalmau J, Graus F, Cwik V, Rosenblum MK, Posner JB. Motor neuron syndromes in cancer patients. Ann Neurol 1997;41:722730. 14. De Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic

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Based on observations in two autopsied patients24,25 who died from other causes, Hirayama proposed a phenomenon of chronic focal ischaemia of the cervical cord, perhaps as a result of repeated neck flexion in susceptible individuals as the aetiology of the unique neurological features of this disorder. However, other European workers were unable to replicate these MRI abnormalities in such patients26, 27 raising doubts on the utility of performing cervical MRI as a surrogate test when this disorder is clinically suspected. The controversy may be related to the fact that a certain degree of symptomatic progression has to occur before radiological features are discernible.

pedigree with juvenile ALS, having an English ancestry dating back to the 17th century, has been mapped33 to chromosome 9q34. The phenotype of this family is similar to the phenotype of the Tunisian families though the modes of inheritance are different. In 1968, Shrivastava and Garg described a familial form of juvenile ALS34 from North India that might be the only report of juvenile ALS similar to the ones described from Tunisia and USA.

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criteria for the diagnosis of ALS. Clin Neurophysiol 2007; 119:497-503.

of unilateral upper extremity (Hirayama’s disease) [in Japanese]. J Jpn Soc Intern Med 1989; 78:674-675.

15. Bensimon G, Lacomblez L, Meininger V, ALS/Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994; 330:585-591.

26. Schroder R, Keller E, Flacke S, et al. MRI findings in Hirayama’s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease? J Neurol 1999; 246:10691074.

16. Lacomblez L, Bensimon G, Leigh PN, ALS/Riluzole Study Group II. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 1996; 347:1425-1431.

NEUROLOGY

17. Meenakshisundaram E, Jaggannathan K, Ramamurthi B. Clinical pattern of motor neuron disease seen in younger age groups in Madras. Neurol India 1970; 18:109. 18. Jagannathan K and Kumaresan G. Madras pattern of motor neuron disease. In: Gourie-Devi M, editor. Motor Neurone Disease: Global Clinical Patterns and International Research. New Delhi: Oxford & IBH 1987:191-194. 19. Gourie-Devi M, Suresh TG, and Shankar SK. Monomelic amyotrophy. Arch Neurol 1984; 41:388-394. 20. Hirayama K, Toyokura Y, Tsubaki T. Juvenile muscular atrophy of unilateral upper extremity: a new clinical entity [in Japanese]. Psychiatr Neurol Jpn 1959; 61:2190-2198. 21. Singh N, Sachdev KK, Sushila AK. Juvenile muscular atrophy localized to the arms. Arch Neurol 1980; 37:297-299. 22. Pradhan S, Gupta RK. Magnetic resonance imaging in juvenile asymmetric segmental spinal muscular atrophy. J Neurol Sci 1997; 146:133-138. 23. Hirayama K, and Tokumaru Y. Cervical dural sac and spinal cord in juvenile muscular atrophy of distal upper extremity. Neurology 2000; 54:1922-1926. 24. Hirayama K, Tomonaga M, Kitano K, Yamada T, Kojima S, Arai K. Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg Psychiatry 1987; 50:285-290. 25. Araki K, Ueda Y, Michinaka C, Takamasu M, Takino T, Konishi H. An autopsy case of juvenile muscular atrophy

27. Willeit J, Kiechl S, Kiechl-Kohlendorfer U, Golaszewski S, Peer S, Poewe W. Juvenile asymmetric segmental spinal muscular atrophy (Hirayama’s disease): three cases without evidence of “flexion myelopathy”. Acta Neurol Scand 2001; 104:320-322. 28. Restuccia D, Rubino M, Valeriani M, Mirabella M, Sabatelli M, Tonali P. Cervical cord dysfunction during neck flexion in Hirayama’s disease. Neurology 2003; 60:1980-1983. 29. Agundez M, Ruoco I, Barcena J, Mateos B, Barredo J, Zarranz JJ. Hirayama disease: Is surgery an option? Neurologia 2015; 30:502-509. 30. Ben Hamida M, Hentati F, Ben Hamida C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Brain 1990; 113:347-363. 31. Hentati A, Bejaoui K, Pericak-Vance MA, Hentati F, Speer MC, Hung WY, Figlewicz DA, Haines J, Rimmler J, Ben Hamida C. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-35. Nature Genetics 1994; 7:425-428. 32. Hentati A, Ouahchi K, Pericak-Vance MA, Nijhawan D, Ahmad A, Yang Y, et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 1998; 2:55-60. 33. Rabin BA, Griffin JW, Crain BJ, Scavina M, Chance PF, and Cornblath DR. Autosomal dominant juvenile amyotrophic lateral sclerosis. Brain 1999; 122:1359-1550. 34. Garg B, Srivastava G. Familial juvenile amyotrophic lateral sclerosis. Indian Pediatr 1968; 5:119-121.

A Case Based Approach to Acute Flaccid Paralysis

C H A P T E R

Salil Gupta

CASE VIGNETTE

A 24 years old young male is brought to the casualty with 2 days history of acute onset, progressive weakness of all four limbs. At presentation he is bed bound. On examination he has flaccid quadriplegia with swallowing difficulty. What should be the approach to such a patient?

Nerve (acute neuropathies) • Diphtheria •

“Dumb” rabies

• Porphyria •

Drugs & Toxins (arsenic, thallium, lead, gold, chemotherapy - cisplatin / vincristine)

Acute flaccid paralysis (AFP) can be defined as a clinical syndrome characterized by rapid onset (usually hours to days), progressive weakness of at least one, usually two or more limbs. There may be bulbar and respiratory involvement.

•

Vasculitis (incl. lupus, polyarteritis)

Accurate diagnosis of the cause of AFP is important for therapy and prognosis. If untreated, AFP may not only persist but also lead to death due to failure of respiratory muscles. It can also cause complications like aspiration pneumonia, deep venous thrombosis, bed sores and contractures. AFP also is of great public health importance because of its use in surveillance for poliomyelitis in the context of the polio eradication initiative.

INTRODUCTION

NEUROANATOMICAL CORRELATE OF DIFFERENTIAL DIAGNOSIS

•

Inflammatory dermatomyositis)

•

myopathy

•

Guillain-Barre Syndrome

•

HIV

•

Other viruses like CMV

•

Cauda equina syndrome (lumbar disc, tumour, etc.)

•

Sarcoidosis

•

Lyme disease

•

Plexus lesions (brachial plexitis, lumbosacral plexopathy)

Anterior Horn Cell

Before approaching the given case it is useful to keep some common differential diagnoses in mind as per anatomical location starting from one end of the neuraxis.

Muscle:

Nerve Roots (acute polyradiculopathies) and plexus lesions

(polymyositis,

• Poliomyelitis •

Other viruses like HIV

• Paraneoplastic

Spinal Cord •

Inflammatory (Transverse myelitis)

Viral myositis

•

Other myelopathies (epidural abscess or hematoma)

•

Periodic paralyses (hypokalemic, hyperkalemic)

•

Anterior spinal artery syndrome

•

Metabolic derangements (hypophosphatemia, hypokalemia, hypermagnesemia)

CLINICAL CLUES

Neuromuscular Junction •

Myasthenia Gravis

History: Following points in the history must be enquired into so as to classify the presenting pattern of weakness (as given below). This helps not only finding the underlying etiology but also the prognosis and deciding the therapy:

•

Animal toxins (snake bite especially cobra, krait; shellfish, crab etc)

•

Onset & progression of weakness: sudden, acute (over hours), subacute (days to weeks)

•

Botulism

•

duration of weakness (hours to days to weeks)

•

Tick paralysis

•

pattern of weakness (eg: proximal, distal)

•

Organophosphate neuropathy)

•

pattern of progression (eg: onset in arms, “ascending paralysis”)

•

Lambert-Eaton Myasthenic Syndrome (LEMS)

•

sensory involvement (numbness, tingling, loss of balance esp. in dark, pain / burning)

toxicity

(can

also

cause

NEUROLOGY

424

•

bulbar involvement (change in voice or swallowing)

•

facial weakness (trouble chewing, sucking with straw, blowing)

•

Clues to UMN lesion (mostly a spinal cord lesion) could be presence of either: •

Brisk reflexes

extraocular muscle weakness (diplopia) or ptosis

•

Extensor plantar

•

respiratory involvement (iability to complete sentences, dyspnea, orthopnea)

•

Definite sensory level

•

bladder or bowel involvement

•

Bladder or bowel involvement

•

autonomic involvement (diarrhea, orthostatic dizziness, urinary retention, palpitations)

•

systemic symptoms (fever, weight loss, rash, joint pain)

•

recent illness or immunization (diarrheal or respiratory tract infection, anti rabies vaccine, oral polio vaccine)

•

recent travel (out of country, to woods [tick bites])

•

recent h/o dog bite

•

precipitating factors (exertion, loading - with periodic paralyses)

•

fluctuation in weakness (eg. diurnal variation, fatiguability in myasthenia)

•

drug or toxin exposure (canned or ‘bad’ food, pesticides, lead exposure)

•

family history (porphyria)

carbohydrate

A LMN lesion will have absent reflexes with mute plantar. Frequently, an acute onset spinal cord lesion may present with absent reflexes due to spinal shock. But the presence of other differentiating features (extensor plantar, definite sensory level and bladder involvement) help localize the lesion to spinal cord. Step 2: If it is a LMN lesion what is the pattern of weakness? Is it proximal or distal? Lesions localized to the following anatomical locations cause proximal, mostly symmetrical weakness in AFP: • Muscle •

NMJ

• Polyradiculoneuropathies Poly neuropathy will present with distal, mostly symmetrical weakness. Lesions localized to the anterior horn cells can present with symmetrical or asymmetrical, proximal, distal or a combination of both. The reflexes will be absent in both the conditions.

PHYSICAL EXAMINATION

Step 3: Are the reflexes preserved?

•

Distribution and degree of weakness looking specially for extraocular muscles, facial muscles and bulbar involvement

•

Assess for fatiguability

Localization of lesions with proximal weakness and preserved reflexes include muscle or NMJ. Fatigability (appearance of weakness with repeated use) is a prominent feature in NMJ disorders especially myasthenia.

•

Sensory impairment: particular modality (vibration / proprioception vs. pain / temperature) - is there a sensory level?

•

Reflexes: Are the deep tendon reflexes lost? (ie. areflexic), depressed, preserved, or brisk); Do diminished reflexes facilitate with repeated efforts? (LEMS)

•

Autonomic features (postural fall, sweating, pupillary response, ileus)

abnormal

•

Skin: lines on nails with arsenic poisoning (Mee’s lines), ticks, photosensitivity, Gottron’s papules on extensor surfaces & heliotrope discoloration over eyelids (dermatomyositis), fang marks

•

Spinal tenderness (with epidural abscess or hematoma, spinal tumour)

•

Straight leg raise (radiculopathy)

CLINICAL CLUES TO DIFFERENTIAL DIAGNOSIS

Step 1: Is it an upper motor neuron (UMN) or a lower motor neuron (LMN) lesion?

Reflexes would be absent in: •

Anterior horn cell disorders

• Polyradiculoneuropathies • neuropathies Step 4: Are sensations preserved? Neuropathies present with sensory involvement. Polyneuropathy presents with glove and stocking sensory involvement while mononeuritis multiplex would present with patchy sensory loss. Polyradiculoneuropathies may or may not have a sensory loss. Some GBS variants may have sensory loss. Cauda equina may present with a sensory loss in a radicular distribution.

CATEGORIZATION AS PER PATTERN OF INVOLVEMENT

It is useful to classifying the pattern of involvement into any one of the following given below. This approach narrows the differential diagnosis further (Figure 1). 1.

Flaccid symmetric quadripareis (± bulbar and respiratory involvement) with areflexia and minimal to profound sensory loss (but often

425

CHAPTER 89

Fig. 1: Flow diagram of approach to acute flaccid paralysis (AFP) sensory symptoms) - Acute polyradiculopathy (eg GBS) 2.

neuropathy

Symmetric proximal muscle weakness without sensory symptoms or signs and with preserved reflexes: Acute myopathy (eg. polymyositis); periodic paralysis

Fatiguable muscle weakness with diplopia, ptosis and bulbar dysfunction (eg myasthenia and other neuromuscular disorders)

Flaccid Paraparesis with sensory level (often with reduced lower limb reflexes & bladder dysfunction) - Cauda equina syndrome (painful), thoracic spinal cord lesions (eg. transverse myelitis, spinal cord infarct)

•

Paraneoplastic syndromes

•

Organophosphate toxicity (muscarinic cholinergic overstimulation)

•

Botulism

FURTHER INVESTIGATIONS

It is imperative to have a clinical approach as outlined above rather than relying only on electrophysiology, lab parameters or imaging to aid in the diagnosis. After the differential diagnosis is narrowed then tests can be done to confirm diagnosis. Further management strategies will depend on the most probable diagnosis.

MANAGEMENT OUTLINE IN SOME SPECIFIC AFP

Guillain- Barre Syndrome

Bulbar predominant involvement:

Specific Measures:

•

Botulism

•

Myasthenia gravis

IVIg or plasmapheresis are equally effective in reversing the conditions. However the side effect profile of IVIg is better.

•

GBS

•

Snake bite

Ophthalmoplegia with motor weakness:

IVIg is given in dose of 400 mg/kg /day for 5 days while plasmapheresis can be done on alternate day for 5-6 sessions depending on the response.

•

Miller-Fischer variant of GBS (areflexia)

•

Indications include

•

Botulism & Tick paralysis

Rapidly progressive weakness

•

Snake Bite

Presence of respiratory or bulbar involvement

Prominent autonomic dysfunction:

•

GBS

Not indicated if the degree of weakness is non progressive and has been present for more than 2 weeks.

426

Supportive Measures:

Thymic mass is demonstrated on a CT chest

•

If no thymic mass then if age is between 10 to 55 years

Air way protection

NEUROLOGY

• Cardiovascular dysfunction

monitoring

for

autonomic

POLYMYOSITIS

•

Enteral feeding if oropharyngeal dysfunction present

•

Nutrition and daily fluid balance in ICU patients

•

Correction of electrolyte imbalance and conditions like SIADH

On follow up once improvement starts steroid sparing immune suppressants like azathioprine or mycophenolate etc are added.

•

Heparin/ LMWH for prevention of DVT

•

Early rehabilitation is needed

•

Prevention of bed sores

•

Early rehabilitation

MYASTHENIA GRAVIS

•

Steroids are the main stay. However should start at low dose and then gradually build up

•

Immunosuppressants like azathioprine may be added subsequently as steroid sparing agents. Other drugs like mycophenolate also are a good option

•

Acetyl Coline esterase inhibitors like pyridostignine (60 mg tablet) or neostigmine (15 mg tablet) are started along with steroids and titrated as per requirement.

•

IVIg (400 mg/kg / day X 5 days) or plasmapheresis is indicated if patient presents in crisis or impending crisis. Presence of respiratory distress defines the presence of crisis

•

Patient may be referred for thymectomy if they have generalized disease and

Steroids are started as soon as the diagnosis is confirmed.

HYPOKALEMIC PERIODIC PARALYSIS

•

Correction should start with oral therapy of 15 ml solution of KCl (diluted) and can be given as frequent as 30 minutes till improvement starts.

•

IV replacement is usually not necessary and indicated if there is swallowing difficulty or vomiting.

•

Long term therapy consists of acetazolamide in doses from 250 mg-1000 mg/day.

REFERENCES

1. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J (editors). Harrisons Principles Of Internal Medicine.19th Ed.New Delhi:Mc Graw Hill;2015. 2. Campell WW. DeJong’s The Neurologic Examination. 7th Ed. Lippincot Williams Wilkins; 2012. 3. Daroff RB, Jankovic J, Mazziotta JC, Pomeroy SL (editors). Bradley’s Neurology in Clinical Practice. 7th Ed. Elsevier;2016.

Approach Towards a Patient with Vertigo

C H A P T E R

Sanjiv Maheshwari, Ravi Kumar Meena

INTRODUCTION

Otolith organs

Vertigo is an illusion of self or environmental motion. It may be subjective (patient is moving) and objective (environment is moving) or both. Vertigo is a symptom and never a disease and it is very common complaint in clinical practice. It is due to asymmetry of vestibular system due to damage or dysfunction of the labyrinth and vestibular nerve, or central vestibular structures in the brainstem. Vertigo may be physiologic eg. occurring during or after a sustained head rotation.

Vertigo can either be due to peripheral causes (cervical, auditary, ocular) or central causes (brainstem, cortical, psychogenic).

The term vertigo is derived from the Latin word ‘vertere’ meaning ‘to turn’.

VERTIGO V/S DIZZINESS

Dizziness is an imprecise term that means consciousness of disordered orientation of the body in space. Dizziness is a variety of symptoms; it could mean vertigo, dysequilibrium, lightheadedness / presyncope, rocking or swaying as if on a ship, motion sickness, nausea & vomiting, oscillopsia, floating, swimming, spinning inside of head, etc.

ANATOMY AND PHYSIOLOGY

Balance calls upon contributions from vision, vestibular sense, proprioception, musculoskeletal coordination, and even cognitive skills. All these streams of information combine and integrate in central vestibular apparatus in the brain to assess the stability and orientation. Asymmetrical or defective input into the vestibular apparatus or asymmetrical central processing leads to vertigo whereas abnormal bilateral vestibular activation results in truncal ataxia. Vestibular system contributes to our balance system, maintains spatial orientation, stabilizes vision and provides information related to movement and head position. It constitutes:-

Semicircular Canals

The three canals are set at right angle to each other which allow them to perceive rotational or angular acceleration and deceleration in all three planes of three dimensional space. Semicircular canals provide afferent input for the vestibulooccular reflex to keep the eye steady as the head turns. It contains sensory hair cells that are activated by movement of endolymph. As the head moves, hair cells in the semicircular canals send nerve impulses to the brain by way of the vestibular part of IIIV nerve.

The two otolith organs viz. utricle and saccule are oriented roughly perpendicular to each other, utricle in horizontal plane and saccule in vertical plane. Both organs are sensitive to linear rather than rotatory acceleration. The utricle is sensitive to change in horizontal movement. The saccule is sensitive to the change in vertical acceleration (such as going up in an elevator).

CLASSIFICATION OF VERTIGO

Peripheral causes are related to damage of the inner ear receptors or to the vestibulocochlear nerve. Central causes include damage to centers that process vestibular signals in the central nervous system. These may be tabulated as follows:

HISTORY

A careful history remains the cornerstone of diagnosis. A patient complaining of dizziness necessitates a thorough history taking precisely because of the many different meanings the term can have (Table 1). Following protocol is helpful1.

Symptoms - when did the symptoms start?

Describe the symptoms (avoid leading questions),

Time course (resolving, fluctuating),

Persistence (constant, resolving or episodic),

Length and frequency of episodes,

Are episodes spontaneous or provoked (eg. by head movement)?

Are there any associated symptoms (nausea, anxiety, neurological symptoms)?

Do the symptoms go away completely between episodes?

History of any ear symptoms,

Any Ophthalmological symptoms,

Any Neurological symptoms,

Any Other risk factors (head injury, ototoxic drugs, spondylosis, whiplash injury).

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Table 1: History Taking and Mechanism of Dizziness

Table 2: Differences between Peripheral and Central Vertigo

Types of Dizziness

Patient Experiences

Mechanism

Symptoms

Peripheral

Central

Vertigo

Illusion of movement of patient or surroundings.

Disturbance of peripheral or CNS pathways of vestibular system.

Onset

Paroxysmal

Slow or acute

Duration

Seconds to minutes

Weeks to months

Intensity

Severe

Moderates

Frequency

Imbalance or unsteadiness while standing or walking.

Vestibulospinal, propioceptive, visual or motor dysfunction, joint pain or instability, psychological factors.

Episodic, recurrent

Constant, progressive

Nystagmus

Unidirectional - horizontal or rotatory

Bidirectional horizontal or vertical

Triggered by changing head positions

Yes

Unsteadiness

Mild/moderate

Severe

Nausea/ vomiting

Severe

Varying

Auditory symptoms

Common

Rare

Neurological symptoms

Rare

Common

Compensation/ resolution

Rapid

Slow

NEUROLOGY

Dysequilibrium

Syncope or Presyncope

Mal de débarquement

Motion sickness

Impending loss of Consciousness.

Momentary reduction in blood flow to brain eg. cardiac problems.

Sense of rocking or swaying as if on a ship.

Vestibular adaptive process to the continuous, passive motion os lost and is unable to re-adapt once environment is stable.

Episodic dizziness, tiredness, pallor, diaphoresis, salivation, nausea & vomiting.

Nausea & Vomiting Oscillopsia

Visual-vestibular mismatch eg. riding in a car or viewing action sequence in large screen theater.

•

Begin assessing as soon as you meet a patient even in waiting room.

•

Observe the patient while walking along several adjoining hallways, making abrupt turns both to right and left, and traversing an uphill and downhill incline.

•

A patient with a vestibular deficit will often stare at the floor to keep his balance, especially in an unfamiliar setting such as hospital. When patient with vestibular pathology walks, he often veers towards the side of the lesion, and uses a wide based gait. You should be wary of patients who try to “show you how bad my balance is” by using a narrowed base of gait or swaying excessively when standing still.

•

The following list of examination techniques is by no means prescriptive, but is useful when examining a patient with vertigo –

Ears- Otoscopy, tuning fork tests for hearing, audiometry.

Eyes-Examine eye movement for saccades, smooth pursuit, and nystagmus (spontaneous and gaze evoked).

Central nervous system- Examine cranial nerves and look for cerebellar signs.

Vestibulo-occular reflex testing: By asking patients to read letters on a fixed object while they shake their head from side to side.

Head-shake test.

Stimulation of vagus centers in medulla. Subjective illusion of visual motion

Floating, swimming, spinning inside of head

EXAMINATION (TABLE 2)

Spontaneous : acquired nystagmus Head induced : severe, bilateral loss of the VOR Frequently psychological symptoms of anxiety, somatoform disorders, and depression.

Unfortunately there are only few reliable clinical signs to detect or rule out vestibular disease, however, the key points are

Head-impulse test (rapid dolls).

Maneuvers which evoke nystagmus, such as the Dix-Hallpike maneuver, are helpful for diagnosing benign paroxysmal positional vertigo (BPPV).

The differential diagnoses of vertigo are discussed in Table 3. For suppression of vertigo commonly used medications are:I.

ANTIVERTIGO

Vestibular Suppressant

Ca antagonist: Flunarizin (5-10 mg daily),

Vasodilator: Betahistine (24-48 mg/day),

Tranquilizer: Diazepam (2.5 mg 1-3 times daily), Clonazepam (25 mg. 1-3 times daily),

Antihistamine: Dimenhydrinate (50 mg. 1-2 times daily), Meclizine (25-50 mg 3 times daily), Promethazine (25 mg. 2-3 times daily, also can be given rectally and IM), Cinnarizine (25 mg. 2-3 times daily),

NYSTAGMUS

CNS stimulant: Like Ephedrin and Amphetamin not used much.

II.

ANTIEMETIC

Anticholinergic: Atropine, (transdermal patch),

Scopolamine

•

Transient mixed vertical-torsional nystagmus occurs in BPPV, but pure vertical or pure torsional nystagmus is a central sign.

B..

•

Nystagmus from a peripheral lesion may be inhibited by visual fixation, whereas central nystagmus is not suppressed.

Antidopaminergic: Prochlorperazine (5-10 mg. 2-3 times daily), Metoclopramide (10-15 mg. 3-4 times daily).

Antihistamine: Dimenhydrinate (50 mg. 1-2 times daily),

•

Absence of a head impulse sign in a patient with acute prolonged vertigo should suggest a central cause.

III.

PSYCHOAFFECTIVE:

Clonazepam, diazepam, etizolam, etc. for anxiety and panic attacks.

Selective serotonin psychological vertigo

Piracetam a nootropic drug and cyclic derivative of GABA. It is said to have neroprotective and anticovulsant properties, and improves neuroplasticity.

•

Unilateral hearing loss suggests peripheral vertigo. Findings such as diplopia, dysarthria, and limb ataxia suggest a central disorder.

ANCILLARY TESTING

•

Audiometry - Unilateral sensorineural hearing loss supports a peripheral disorder (e.g. vestibular schwannoma). Predominantly low-frequency hearing loss is characteristic of Meniere’s disease.

•

Electronystagmography or videonystagmography.

•

Caloric evaluation.

•

Neuroimaging - CT Scan, MRI, MRA.

SYMPTOMATIC PHARMACOLOGIC TREATMENT

Medical treatment should be reserved for short term control of active vertigo, such as during the first few days of acute vestibular neuritis or for acute attack of Meniere’s disease. One should not prescribe (especially in peripheral causes of vertigo) vestibular suppressant drugs for longer than a few days because they can cause sedation and psychomotor impairment, which hampers central compensation. This central vestibular compensatory mechanism is a faculty of the brain that restores normal balance function after a vestibular assault.

reuptake

inhibitors

for

Betahistine is a histamine analog with an agonistic action. It is a H1 receptor agonist and antagonize the h3 receptors. It increases cochlear and cerebral blood flow and regulates firing activity of the vestibular nuclei. Advantage of betahistine is that only non-sedating anti vertigo drug. All other anti-vertigo drugs have some sedative effect, and therefore depress the CNS, which detrimental to the central vestibular compensatory mechanism. Simultaneously it Has a side effect in form of precipitate preexisting bronchial asthma, precipitation of peptic ulcer, etc.

VESTIBULAR REHABILITATION THERAPY

This is a physiotherapy comprising of various eye movements and head exercises which help central adaptation processes that compensate for vestibular loss and also may help habituate motion sensitivity and other

CHAPTER 90

Dix-Hallpike maneuver - This test consists of a series of two maneuvers: with the patient sitting on the examination table, facing forward, eyes open, the physician turns the patient’s head 45 degrees to the right (A). The physician supports the patient’s head as the patient lies back quickly from a sitting to supine position, ending with the head hanging 20 degrees off the end of the examination table. The patient remains in this position for 30 seconds (B). Then the patient returns to the upright position and is observed for 30 seconds. Next, the maneuver is repeated with the patient’s head turned to the left. A positive test is indicated if any of these maneuvers provoke vertigo with or without nystagmus. Nystagmus from an acute peripheral lesion is unidirectional, with fast phases beating away from the ear with the lesion. Nystagmus that changes direction with gaze is due to a central lesion.

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430

Differential Diagnosis Disorder

Duration of Episodes

Auditory Symptoms

Clinical Features

Treatment

BPPV

Seconds

Commonest cause of vertigo, brief episodes provoked by change in head position relative to gravity,

Canalith repositioning maneuver (BrandtDaroff, Epley, Semont),

Labyrinthitis

Days

Yes

Sudden unilateral loss of vestibular function and hearing, nausea & vomiting,

Antibiotics, removal of infected tissue, vestibular rehabilitation,

Vestibular Neuronitis Days

Tendency to fall and Brief course of highvomiting lasting for days, dose steroids, vestibular rehabilitation,

Meniereâ&#x20AC;&#x2122;s Disease

Yes

Episodes of vertigo, Low-salt diet, diuretic, tinnitus, feeling of surgery, transtympanic fullness or pressure in the gentamicin, ear,

Perilymphatic Fistula Seconds

Yes

Triggered by sound or pressure changes,

Bed rest, avoidance of straining,

Cerebellopontine Angle Tumours (Acoustic Neuroma, Maningiomas)

Months

Yes

Associated symptoms of 5th and 7th cranial nerve,

Surgery,

Cervicogenic Vertigo

Seconds

Vertigo triggered by somatosensory input from head and neck movements,

Conservative, physiotherapy,

Cerebrovascular disease (TIA or stroke)

TIA - seconds to hours, Stroke - days

Usually not

Associated with neurological deficit symptoms,

Control of vascular risk factors, e.g. antiplatelet agents,

Vestibular migraine

Hours

Associated with headache, visual aura,

Beta-blockers, calcium channel blockers, tricyclic amines,

Multiple sclerosis

Months

Sensory and Motor signs and symptoms disseminated in space and time,

Immunomodulatory drugs,

Cerebellar degeneration

Months

Cerebellar sign and symptoms,

Symptomatic,

Cerebellar tumour

Months

Cerebellar sign and symptoms,

Surgery,

Anxiety disorder

Variable

Usually not

Personality usually of an Psycho-educative obsessive-compulsive, therapy, desensitization Attack are precipitated by by self exposure, SSRI typical situations,

Vestibular, Ototoxicity

Months

Yes

History of vestibulo ototoxic drug therapy,

NEUROLOGY

Peripheral Causes

Hours

Central causes

Other causes

Avoid drugs,

symptoms of psychosomatic dizziness. They should only be practiced after the acute episode is over.

Meurer WJ, Low PA, Staab JP. Medical and Psychiatric Causes of Episodic Vestibular Symptoms. Neurol Clin 2015; 33:643-59, ix. doi: 10.1016/j.ncl.2015.04.007.

REFERENCES

Della-Morte D, Rundek T. Front. Dizziness and vertigo. Neurol Neurosci 2012; 30:22-5.

Jahn K, Langhagen T, Schroeder AS, Heinen F. Vertigo and dizziness in childhood - update on diagnosis and treatment. Neuropediatrics 2011; 42:129-34. doi: 10.1055/s-0031-1283158.

Newman-Toker DE, Edlow JA. A Novel, Evidence-Based Approach to Diagnosing Acute Dizziness and Vertigo. Neurol Clin 2015; 33:577-99, viii.

Huh YE, Kim JS. Bedside evaluation of dizzy patients. J Clin Neurol 2013; 9:203-13.

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