2004 Mauriello_bleph_hemi spasm_book chapter

In: Brin Mitchell F, ed. Scientific and Therapeutic Aspects of botulinum Toxin Philadelphia PA: Lippincott Williams & Wilkins; 2002:pp. 197-205 2004020225 Scientific and Therapeutic Aspects of Botulinum Toxin edited by M.F. Brin, J. Jankovic, and M. Hallett Lippincott Williams & Wilkins, Philadelphia, 䉷 2002.

19 The Role of Botulinum Toxin Type A (BOTOX威) in the Management of Blepharospasm and Hemifacial Spasm Joseph A. Mauriello, Jr.

Local injections of botulinum toxin type A (BTX-A) remain the treatment of choice for blepharospasm and hemifacial spasm (1–24).

BTX-A has a local effect on the treated skeletal muscle. The toxin does not appear to affect brainstem interneurons that mediate the bilateral blink reflex recovery cycle in patients with blepharospasm (25). Single-fiber electromyography suggests that new neuromuscular junctions and their functional maturation are responsible for muscle recovery after treatment with BTX-A (26).

TREATMENT OF BLEPHAROSPASM AND CRANIAL DYSTONIA WITH BTX-A

apparent remission of their disease after injection. Three patients (1.3%) ultimately obtained relief from orbicularis muscle extirpative surgery and required no additional therapy. Of the 11 patients (4.6%) who chose not to receive BTX-A injections, one patient was successfully managed with psychotherapy and another with oral trihexyphenidyl.

In a study in which BTX types A and F were combined, there was no apparent potentiation of the clinical effectiveness of the two drugs.

However, the duration of action with the combined drugs was longer than with type F alone and shorter than with type A alone (27).

Treatment Outcomes

Pharmacologic Adjuvant Therapy Combined with BTX Therapy

A study of 239 patients with blepharospasm and cranial dystonia (Meige’s syndrome) over an 11year period demonstrated (a) the long-term acceptance of BTX-A injections by patients and (b) the role of other treatment modalities including oral medications and surgery in treating blepharospasm (26). Of 239 patients evaluated, 228 patients received local injections of BTXA into the eyelid and facial musculature (16).

Of the 228 patients, 202 (72.1%) were still treated with BTX-A at the end of the 11-year period. Four patients (1.8%) no longer received BTX-A injections because of difficulty in obtaining transportation for medical treatment.

Fourteen patients (6.1%) sought no additional treatment of any type. Five patients (2.2%) had

Of the 228 patients who received BTX-A, 99 patients received adjunctive drug therapy prescribed by their neurologist or primary care physician (16). Drugs used included minor anxiolytics (51 patients) such as alprazolam (25 patients), diazepam (16 patients), and lorazepam (10 patients); anticholinergic medication, trihexyphenidyl (14 patients); antiseizure medications, clonazepam (12 patients) and carbamazepine (6 patients); and a muscle relaxant, baclofen (16 patients). Because antianxiety medications were the most common drugs taken along with botulinum toxin, it was inferred from the data that control of stress by any technique may similarly augment the therapeutic effects of BTX-A. The authors (16) concluded that BTX-A is the

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most highly effective treatment for blepharospasm and Meige’s syndrome over a long period of time. In addition, adjunctive oral drug therapy including minor tranquilizers as well as eyelid surgery to excise pretarsal and preseptal orbicularis oculi muscle of the upper eyelid and redundant upper eyelid skin (functional blepharoplasty) may increase the toxin’s effectiveness.

Any upper eyelid ptosis should be treated by concomitant levator dehiscence repair. It has been the author’s impression that after a decade or more of BTX-A injections, eyelid surgery becomes increasingly more likely. In another study, it was found that facial pain and headache may occur with blepharospasm. These symptoms may be similarly relieved by treatment of the blepharospasm with BTX-A (28).

Initial Ophthalmologic Examination A history and complete ophthalmologic examination are performed. Of particular significance is a history of dry eye. A family history of blepharospasm or other focal dystonia is obtained. A pharmacologic history of neuroleptics, antihistamines, and/or antiepileptic medications including lamotrigine is important as such drugs predispose to blepharospasm. In addition, the role of serotonin reuptake inhibitors is unclear and unsubstantiated to date (29–32). Topical anesthetic is instilled into each eye, and any improvement noted in eyelid spasm may then be attributed to underlying dry eye. Any preexisting ptosis or excess upper eyelid skin should be noted.

Initial Eyelid Treatment with BTX-A Freeze-dried BTX-A (as BOTOX) is reconstituted by diluting a vial of 100 U with 4 cc of 0.9% saline that is preservative free. The technique involves using a 1-cc tuberculin syringe and a 30-gauge needle.

The toxin is injected into the pretarsal orbicularis muscle of the upper eyelid medially and laterally (2.5 U or 0.1 cc in each location) (Fig. 19.1) (29A). Similarly, the lower eyelids (2.5 U or 0.1 cc in each location) are injected in the same pretarsal location. The lateral canthus (2.5

FIG. 19.1. Medial pretarsal injection (0.1 cc of freeze-dried botulinum toxin type A that was reconstituted with 4 cc of saline) of toxin is given as close to eyelid margin as possible.

U) is injected at the initial treatment session (16).

A total of 12.5 U is injected into the eyelids on each side.

Injections are performed bilaterally and symmetrically for blepharospasm. Because the orbicularis muscle is located just below the thin skin of the eyelid and there is no intervening subcutaneous fat, electromyographic (EMG) guidance is unnecessary.

In general, treatment of facial areas other than the eyelids is deferred until the effect of the initial eyelid injections is determined 2 weeks after treatment.

Follow-up Evaluation and Treatment Two weeks after initial injection, patients return for follow-up examinations and are asked to assess their subjective percentage of improvement as compared to pretreatment (16). They are queried about their response relative to the anatomic areas involved: the eyebrow, eyelids, midface (from the cheek to the upper lip), and neck. On examination, the relative weakness on forced closure of the eyelids is objectively graded on a scale from Ⳮ1 to Ⳮ4 where Ⳮ1 is the leastgenerated forced closure and Ⳮ4 is the pretreatment level of generated forced closure. The relative weakness of the eyebrow musculature is also assessed.

Patients satisfied with the response and who demonstrate no residual spasm receive no further treatment at that time. Such patients are asked to return for reinjection when the spasms return and become moderate to severe.

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Treatment of Residual Eyelid and Eyebrow Spasms As stated earlier, the physician objectively observes the eyelid and face for evidence of residual spasm. If present, additional drug is given in the upper lid (5 U in each lid). Additional injections are prohibited if upper eyelid ptosis or superior rectus extraocular muscle weakness is present. Generally, the amount of drugs injected into the lower lid and lateral canthal musculature do not need to be increased.

Brow spasms are similarly evaluated. Significant brow spasm is evidenced by marked vertical furrows between the brows medially as well as by downward contraction of the entire brow. Patients who are not satisfied with the result of the first treatment for blepharospasm and have brow spasms receive injections above the medial eyebrows (5 U in two sites above the medial aspect of the brow) (Fig. 19.2). This treatment weakens the corrugator muscle, the depressor supercilii, and the procerus muscles as well as the orbital portion of the orbicularis oculi muscle. These muscles contribute to eyelid closure. Contraction of the corrugator muscle actually raises the head of the brow (medially), but depresses the tail (laterally). More importantly, the depressor supercilii muscle pulls the entire brow downward and contributes to vertical lines between eyebrows. In addition, the procerus muscle contributes to the vertical frown lines between the

FIG. 19.2. Five units of botulinum toxin type A are injected just above the brow to weaken the procerus, depressor supercilii, and corrugator muscles.

FIG. 19.3. Note descent of entire brow. Vertical lines between brows are mainly a result of corrugator muscle. Patient required eyelid and brow injections for relief.

eyebrows and the horizontal furrows of the radix of the nose (33). The procerus muscle causes descent of the head of the brow (Fig. 19.3). The orbicularis muscle pulls the entire brow downward and creates vertical wrinkles above the medial brow. Residual spasms in the temporal brow area just above the lateral canthus are treated with 2.5 to 5 U depending on the severity of the spasms. Approximately, 20% of patients require brow injections (17).

It is important that the brow injections not weaken the frontalis muscle, which counteracts the brow spasm. In addition, any injections in the frontalis muscle should avoid weakening of the levator muscle. Frontalis muscle activity is evidenced by horizontal furrows across the forehead with concomitant elevation of the eyebrow (Fig. 19.4). The injections should be given just above the medial brow. The middle and upper forehead should be avoided in order to maintain the contractile ability of the frontalis muscle.

Since early 2000, the author has injected BTX-A on each side of the nose 8 mm medial to the medial commissure of the eye. These injections weaken the procerus and the depressor supercilii muscles. The injections are in a plane approximately 5 mm above the level of the medial canthus adjacent to the horizontal nasal wrinkles. These wrinkles are most evident on active contracture, but also tend to be present when the affected muscles are at rest. Treatment includes 2.5 to 5 U injected bilaterally. While

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FIG. 19.4. Note use of frontalis muscle to elevate eyebrows to break eyelid spasms. Ten years after successful treatment with botulinum toxin, patient underwent limited myectomy because of decreased duration of toxin effect (less than 2 months). Patient does not have excess dermatochalasis or ptosis.

this treatment is directed specifically at the procerus muscle, diffusion of the toxin also affects the depressor supercilii muscle, which also contracts the eyebrows downward. Such injections effectively control residual blepharospasm that is recalcitrant to the standard protocol outlined above for treatment of the eyelids and medial brow. Marked brow contractures in the medial brow may be treated on the initial visit depending on the overall severity of the eyelid and eyebrow contractures.

Residual midfacial and mandibular spasms initially are treated with a total of 5 U injected in two separate locations: (a) in the upper face in the area of the malar eminence and (b) just medial to the mid-aspect of the inferior orbital rim.

In patients with spasms of the jaw, 5 U are given at the angle of jaw in the muscle just above the condyle of the jaw (below the zygomatic arch) but not into the joint space. Five to 7.5 U are injected into two to three sites along the ramus of the jaw. Injections may be given in areas where persistent contracture is of concern to the patient (Fig. 19.5). Facial skin, except in the eyelid area, has intervening fat between the dermis and the underlying facial musculature. The target muscle is, therefore, deep to the fat.

Treatment to control spasms in the lower face and mouth should be performed judiciously and incrementally, sometimes in several follow-up treatment sessions as outlined below. Injections adjacent to the corner of the mouth or above the upper lip should be staged in order to avoid excessive muscular weakness with associated drooling, slurred speech, asymmetric facial animation, and biting of the resultant, flaccid buccal mucosa.

Treatment of Subsequent Residual Eyelid and Facial Spasms (4 Weeks After Initial Treatment) Optimally, patients with significant residual eyelid and facial contractures are reexamined in 2 weeks (4 weeks after the initial injection). At

Treatment of Residual Facial Spasms Facial spasms are evaluated 2 weeks after the initial eyelid injections. Eyelid treatment may improve facial spasms and, therefore, treatment of the face may be deferred until the patient is examined 2 weeks after initial eyelid injection.

FIG. 19.5. Patient with marked spasm above mouth was treated with 2.5 U and gained relief.

BOTULINUM TOXIN TYPE A WITH BLEPHAROSPASM AND HEMIFACIAL SPASM this time, eyelid injections (five additional units in each upper lid) are repeated a third, and even a fourth, time 2 weeks later, if necessary, to obtain a therapeutic effect. The cumulative dose of the previous weeks’ injections is given on reinjection several months later after the effect of all the injections dissipates.

In general, patients are requested to return for another treatment session when the effects of the drug are sufficiently dissipated that involuntary eyelid and facial spasms are almost at the pretreatment level. A second treatment session is generally delayed at least 90 days to allow for the production of new receptor sites at the muscle end-plate and for new drug to be effective.

As with any drug therapy, the goal of treatment is to control symptoms with the lowest dose and least frequency of injections to minimize complications.

Duration of Action of BTX-A In our study (16), the mean duration of action was 14.9 weeks for 18 patients with blepharospasm, 16.3 weeks for 7 patients with hemifacial spasm, and 11 weeks for cranial dystonia patients.

Side-Effects of Treatment of Blepharospasm with BTX-A Acute side-effects include pain on injection.

Local bruising resolves within 10 to 14 days.

Medications such as coumadin, aspirin, and other anticoagulant medications that predispose to bruising do not need to be discontinued prior to treatment. Garlic, ginseng, and gingko may also cause bleeding.

Resulting lagophthalmos from incomplete involuntary as well as weakened forced eyelid closure may cause symptoms of dry eye. Symptoms include ocular itching, burning, tearing, foreign body sensation, pain in and around the eye, conjunctival injection, photophobia, and blurred vision, and were present in 36% of our patients.

Usually, these symptoms are transient and minimal. Dry eye results from an incomplete casual upper eyelid blink. A decreased lacrimal pump from pharmacologic weakening of the orbicu-

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laris muscle leads to an increased lacrimal lake and tear meniscus present on the lower eyelid margin. Again, transient tearing and blurred vision without other symptoms of dry eye occur.

Such symptoms are generally improved by increased forced and complete blinking and topical lubricating eye drops every 2 to 4 hours as needed and usually decrease in intensity 2 to 4 weeks after treatment.

Patients may have an incomplete casual upper eyelid blink that is somewhat counteracted by the increased lacrimal lake inferiorly as a result of a decreased lacrimal pump. These patients should be queried specifically about symptoms of dry eye, including itching, burning, and foreign-body sensation. Corneal epithelial staining with fluorescein may reveal the need for punctal occlusion by silicone plugs or thermal cautery may be necessary. In my experience, only a handful of patients with severe underlying dry eye have required punctal plugs. Rarely, frank recurrent corneal erosion requires prompt ophthalmologic referral.

Mild, transient ptosis lasting for 2 to 4 weeks occurred in 14% of patients (16). Lower-lid ectropion and entropion each occurred in one patient (2%). Such patients may have predisposition of such eyelid malpositions because of preexisting lower-lid laxity.

Tolerance to the drug was not a problem in this series (16). Patients who responded to two or more injections rarely developed tolerance to the drug. Antibodies have not been found in a small number of patients treated for blepharospasm in whom they were sought (12). Theoretically, toxin that is incorrectly formulated, dried, or rehydrated may form inactive, antigenic toxin (toxoid).

In patients with continued blepharospasm after treatment, the poor response is evaluated by assessing forced eyelid closure. In patients with weakened forced closure, the toxin appears to be effective. Such patients should be evaluated for excess dermatochalasis or upper lid ptosis. Other patients in this subgroup have apraxia of eyelid opening that tends to respond to limited myectomy. In my experience, additional BTXA injections are always necessary.

In patients who continue to show little or no

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orbicularis muscle weakness despite repeat botulinum injections, presumed antibodies should be considered as the cause of the failure to respond. No further serum testing is recommended.

Spontaneous Resolution of Blepharospasm After BTX-A Injections In our study, five patients had spontaneous resolution of the blepharospasm after BTX-A injections (16). While the reason for the resolution is unclear, physicians should probably counsel their patients with blepharospasm and Meige’s syndrome that symptoms may rarely abate after treatment with BTX-A. It is impossible to ascertain whether the BTX-A itself influenced the natural history of the disease.

Treatment Choices Other than BTX-A of Patients with Blepharospasm and Meige’s Syndrome Alternative treatments to BTX-A, including radical orbicularis myectomy surgery (three patients), psychotherapy (one patient), and oral medication (one patient), were ultimately chosen as the primary treatment by a small minority of the 239 patient population (16).

Adjunctive treatments included eyelid surgery and oral anxiolytic medications. Six patients underwent excision of excess skin and plication of the levator aponeurosis but continued to receive botulinum treatment. Complications of surgery were minimal and well tolerated.

MANAGEMENT OF HEMIFACIAL SPASM WITH BTX-A In a retrospective study of patients with hemifacial spasm (HFS), the long-term treatment choices of patients were local BTX-A injections, oral pharmacologic agents, and surgery (neurosurgical decompression of the seventh nerve at the brainstem level and upper eyelid blepharoplasty) (17). Of 119 patients diagnosed with hemifacial spasm, 108 were initially treated with 735 BTX-A injections over an 11-year period

(18). Forty-seven of the 108 patients (43.5%) received 459 injections for a median treatment period of 59 months per patient (17). Eight patients (7.4%) continued treatment elsewhere, and four other patients were injected by the author until their death from other causes. Twentytwo patients (20.4%) were lost to follow-up after receiving 117 injections. Five patients (4.6%) had spontaneous resolution of their condition after BTX-A therapy and nine patients (8.3%) chose not to receive any additional injections or other treatment.

Pharmacologic Adjuvant Therapy Combined with BTX Therapy In addition to BTX injections, 15 patients required adjunctive minor tranquilizers and/or antiseizure medications. BTX-A is an excellent long-term treatment of hemifacial spasm. As with blepharospasm, patients with hemifacial spasm inexplicably, but only occasionally, experience spontaneous resolution after botulinum therapy (34–36).

Treatment Choices Other than BTX-A in 119 Patients with Hemifacial Spasm Thirteen patients (12.0%) did not respond adequately to botulinum injections and did not opt for retreatment. Ten of the 13 patients obtained relief from treatments other than BTX: oral pharmacologic agents (two patients), neurosurgical decompression of the seventh nerve (two patients), and upper-eyelid blepharoplasty (one patient).

Duration of Action of BTX-A The average duration of the therapeutic effect of BTX-A in the treatment of hemifacial spasm is 16 to 18 weeks (8,9,16).

Initial Treatment with BTX-A In general, 2.5 U are injected into the pretarsal orbicularis oculi muscle in the medial and lateral upper eyelids as well as 12.5 U in the lateral canthus. In patients with only mild disease, 1.25

BOTULINUM TOXIN TYPE A WITH BLEPHAROSPASM AND HEMIFACIAL SPASM U rather than 2.5 U are injected into the four pretarsal sites. The lower face is not initially injected.

Follow-up Treatment When patients are examined 2 weeks after treatment, lower facial spasms are treated with 2.5 to 5 U in the malar eminence region. Lower mouth spasms may be treated with 1.25 to 2.5 U in the corner of the mouth. These injections are given after detailed discussion with the patient about possible asymmetry of smiling and facial weakness with the patient. Occasionally, treatment of the brow protractors including the corrugator muscle and the more central and superficial procerus muscle with 2.5 to 5 U in the medial brow area is helpful.

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blepharoplasty, and 58.33% after levator and/ or blepharoplasty surgery. Average duration of effect of injections increased from 122.1 days in the patients prior to undergoing eyelid surgery to 210.5 days after surgery. One patient in this series had hemifacial spasm and severe bilateral upper-lid dermatochalasis. Upper-eyelid surgery, including limited myectomy, enhanced the effect of the BTX-A in this small group of patients. In patients who have suboptimal response to injections, or who have moderate to marked dermatochalasis with subjective heaviness of the eyelids, upper-eyelid blepharoplasty and/or limited myectomy should be considered. Function and cosmesis are both improved by such surgery (Fig. 19.6).

TREATMENT OF ABERRANT REGENERATION OF THE FACIAL NERVE WITH BTX-A In a study of six patients with the motor and autonomic effects of aberrant regeneration of facial nerve after a peripheral palsy, BTX-A was found to be an effective treatment. The required dose is similar to or slightly lower than the dose for hemifacial spasm. In two patients with tearing, 20 U were injected into the lacrimal gland area with an almost complete amelioration of tearing (37).

A

Role of BTX-A Combined with Limited Myectomy and Other Eyelid Surgery Of 358 patients with focal facial dystonia, 14 underwent (a) upper-eyelid limited myectomy with or without upper-lid blepharoplasty (5 patients), (b) upper-lid blepharoplasty alone (6 patients), or (c) blepharoptosis repair by levator advancement with or without blepharoplasty (3 patients) (38,39). This treatment was reserved for patients who demonstrated orbicularis muscle weakness after BTX injections, but who had a decreased duration of effect or experienced heaviness of the eyelids.

The mean subjective improvement was 68.75% after limited myectomy combined with

B FIG. 19.6. Note patient with left hemifacial spasm and excess skin overhanging the upper eyelid margin (A). After bilateral upper-lid blepharoplasty and left-sided upper-lid limited myectomy, the patient enjoyed both an increased duration of botulinum toxin injections and subjective improvement as well. Note improved cosmesis (B) several months after surgery. A somewhat higher eyelid crease on the left side as compared to the right side is evident as a result of debulking of orbicularis muscle on the left side.

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SCIENTIFIC AND THERAPEUTIC ASPECTS OF BOTULINUM TOXIN tients with presumed serum antibodies to BTXA may respond to other types of toxin.

REFERENCES

FIG. 19.7. Patient has right upper-eyelid ptosis and dermatochalasis of the upper eyelids with diminished response (decreased duration) to BTX as well as heaviness of the upper eyelids (left). Note patient (right) 3 months after bilateral levator advancements, upper-lid blepharoplasty, and limited myectomy. Patient experienced almost immediate improvement in reading and daily visual functions.

Fifteen additional patients have undergone surgical limited myectomy since the original study. Results in this group demonstrate that such surgery has an excellent adjunctive effect to local injections of botulinum for focal facial dystonias (unpublished data). Furthermore, preexisting upper-lid ptosis should be treated in order to improve the effect of the BTX-A injections. In a patient with failure to respond to BTX-A, preexisting should be diagnosed and treated (Fig. 19.7).

CONCLUSION An analysis of these studies (16,18,38) strongly suggests that BTX-A controls blepharospasm, Meige’s syndrome, and hemifacial spasm as well as pharmacologic agents. In patients with eyelid malpositions, including upper-eyelid ptosis, canthal laxity, and upper-lid dermatochalasis, corrective eyelid surgery along with limited myectomy enhances the effectiveness of the injections (16). Because antianxiety medications are the most common drugs taken along with botulinum toxin, control of stress by any other technique may augment the effects of BTX. Pa-

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