albertoalbaneseAlberto Albanese, MD

Istituto Nazionale Neurologico Carlo Besta
Universita Cattalica del Sacro Cuore
Milan, Italy

Alberto Albanese graduated from the Catholic Univer­sity Medical School in Rome, Italy, in 1977; he received his certification in Neurology in 1981 and in Psychiatry in 1985. From 1978 to 1979, Dr. Albanese was recipient of a Fulbright-Hays fellowship at the Brain Research Institute, University of California Los Angeles. In 1985-86, he was visiting professor at the Maudsley Hospital, London, with the late Professor David Marsden. In 1990, he received the Roussel prize for research on Ageing. In 1997, he was appointed visiting professor at the University of Cordoba (Argentina) and in 2003, he was nominated Membre d’honneur à titre étranger by the French Neurological Society.

Career

In 1984, Alberto Albanese was appointed Assistant Professor in Neurology and Director of the Movement Disorders Clinic at the Gemelli hospital in Rome, and in 1992, was appointed Associate Professor of Neurology. In 1996, he was appointed Professor of Neurology and co-Chairman of the Department of Neurology, University of Lausanne, Switzerland, where he stayed until 2000. In 2000, Alberto Albanese returned to his native country, where he was appointed Professor of Neurology and Head Neurologist at the National Neurological HospitalCarlo Besta," Milan. He currently holds the same position.

Research interests

His first research interests were in basic science. Using morphological staining and tract-tracing techniques in the 1970s, he studied the normal and abnormal activity of dopaminergic and cholinergic CNS neurons. He also evaluated animal models of disease developed using inbred mouse strains and monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydro­pyridine (MPTP).

From the 1980s, Dr. Albanese became progressively more engaged in patient care and clinical research in the field of movement disorders and was a fellow in London with the late David Marsden, first in Denmark Hill and then in Queen Square. His research interest became focused mainly on dystonia, Parkinson’s disease, and other parkinsonian syndromes (such as multiple system atrophy). His publications cover an ample spectrum of movement disorders, including choreas and tics. He has been a pioneer in the introduction of botulinum toxins in Italy and has pioneered the use of deep brain stimulation in Parkinson’s disease and other movement disorders. In this clinical capacity, Prof. Albanese has raised several generations of Italian neurologists with expertise in movement disorders and has mentored medical graduates who now hold neurological positions of international stance, such as: Prof. Enza Maria Valente (Rome), Dr. Anna Rita Bentivoglio (Rome), Dr. Carlo Colosimo (Rome), Dr. Elena Moro (Toronto).


Scientific activity

Alberto Albanese has published over 200 publications, including more than 170 scientific papers on indexed journals and several chapters on multi-authored books. His H index is 40. He has coordinated nationwide scientific projects in Italy and Switzerland and has received grants from a number of Italian and international granting agencies. He is Editor in Chief of Frontiers in Movement Disorders, Associate Editor of the European Journal of Neurology since 2007, and of Therapeutic Advances in Neurological Disorders since 2008, and has been on the editorial board of Movement Disorders and of European Neurology from 1996 to 2000, and currently is on the editorial board of Current Neuropharmacology. He is a member of the Faculty of 1000, and has peer reviewed a number of neurological journals, including: Brain, Brain Dysfunction, Brain Research Bulletin, Electroencephalography and Clinical Neurophysiology, European Journal of Neurology, European Neurology, Fundamental & Clinical Pharmacology, Journal of Neurology, Lancet, Nature, Journal of Neurology Neurosurgery and Psychiatry, Movement Disorders, Neurology, Neurological Sciences, Neuroscience Letters, and New England Journal of Medicine.

Prof. Albanese has chaired the International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins (Baveno, Italy, 2008), and has been a member of the organizing committee of several international congresses, including the 8th MDS Congress (Rome, 2004), the Nineteenth Meeting of the European Neurological Society (Milan, 2008) and the XVIII WFN World Congress on Parkinson’s Disease and Other Movement Disorders (Miami Beach, 2009).

Prof. Albanese is an honorary member of the French Neurological Society and of the Swiss Neurological Society. He is a regular member of several scientific societies, including the Italian Neurological Society (since 1980; repeatedly member of the executive committee), the Italian Movement Disorders Society (founder, President 2006-2007), the Movement Disorders Society (co-chair of the Task Force on DBS in Dystonia), and the American Academy of Neurology (corresponding fellow since 1991).


 

I. CME Information for Blepharospasm and Strabismus:

Abstract

Benign Essential Blepharospasm (BEB) is a disabling focal dystonia marked by involuntary blinking or sustained eyelid closure. It may be caused by spasms of the orbicularis oculi muscle or failure of the superior levator palpebrae muscle to contract. Blepharospasm has a substantial impact on quality of life and may lead to depression and anxiety. No medical or surgical treatments for blepharospasm were effective before the introduction of botulinum neurotoxin A (BoNT-A). Currently, two BoNT-A formulations are approved by the FDA for the management of BEB, and BoNT-A is considered standard of care. BoNT-A provides high response rates and improves patient quality of life with minor adverse events, including ptosis, epiphora, keratitis, dry eyes, and diplopia. Other BoNT formulations are being studied as well. Strabismus, misalignment of the eyes, is a disabling condition that frequently affects pediatric populations but can also affect adults. With a range of presentations, the treatments for strabismus vary and include corrective lenses, eye exercises, occlusive therapy, and surgery. BoNT-A is frequently used as an adjunct and alternative to strabismus surgery. BoNT-A therapy improves vision in more than 50% of patients for 6 months or longer after injection. Optimal strategies for dosing and injecting BoNT are discussed.

Educational Objectives

Upon completion, participants should be able to:

  • Describe the epidemiology and pathophysiology of blepharospasm and strabismus in order to understand the clinical scope of these disorders
  • Recognize important clinical features of blepharospasm and strabismus to better assess patients
  • Explain the principles of patient management for blepharospasm and strabismus in order to develop an appropriate treatment plan
  • Recognize the role of botulinum neurotoxin (BoNT) preparations in the management of blepharospasm and strabismus in order to optimize therapeutic benefit and reducecomplicationsarget Audience

Target Audience

This activity is directed to neurologists, ophthalmologists, oculoplastic surgeons, family practitioners,  pediatricians, and other healthcare providers involved in the treatment of benign essential blepharospasm and/or strabismus using neurotoxin therapy. 

Method of Participation

To receive a maximum of 1.0 AMA PRA Category 1 Credit(s)™ you should:

  • View the presentations in this CME activity and evaluate the content presented
  • Complete and submit the posttest, CME registration, and activity evaluation forms

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Beth Israel Medical Center and Scientiae, LLC. The provider is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Statement

Beth Israel Medical Center & St. Luke’s and Roosevelt Hospitals designate this online educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Term of Approval

November 2010 through November 2012.   Original Release Date November 2010.

Program Director

Alberto Albanese, MD [bio]

Professor of Neurology
Istituto Nazionale Neurologico Carlo Besta
Università Cattolica del Sacro Cuore
Milan, Italy

CME Program Reviewer

Susan Bressman, MD
Chairman of the Department of Neurology
Beth Israel Medical Center
New York, New York
Professor of Neurology
Albert Einstein College of Medicine
New York, New York

Disclosure Statement

It is the policy of Beth Israel Medical Center & St. Luke’s and Roosevelt Hospitals that faculty and providers disclose real or apparent conflicts of interest relating to the topics of this educational activity, and also disclose discussions of unlabeled/unapproved uses of drugs or devices during their presentation(s). Beth Israel Medical Center & St. Luke’s and Roosevelt Hospitals have established policies that will identify and resolve all conflicts of interest prior to this educational activity.

This CME activity discusses the off-label use of botulinum neurotoxin.

Susan Bressman MD, Program Reviewer

Dr. Bressman has indicated no conflict of interest.

Alberto Albanese, MD Program Director

Consultant:  Allergan, Inc., Lundbeck, Inc.

Acknowledgement of Support

This activity is jointly sponsored by Beth Israel Medical Center & Scientiae, LLC.

It is supported by an unrestricted educational grant from Allergan, Inc.

 

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II. ABSTRACT

Benign Essential Blepharospasm (BEB) is a disabling focal dystonia marked by involuntary blinking or sustained eyelid closure. It may be caused by spasms of the orbicularis oculi muscle or failure of the superior levator palpebrae muscle to contract. Blepharospasm has a substantial impact on quality of life and may lead to depression and anxiety. No medical or surgical treatments for blepharospasm were effective before the introduction of botulinum neurotoxin A (BoNT-A). Currently, two BoNT-A formulations are approved by the FDA for the management of BEB, and BoNT-A is considered standard of care. BoNT-A provides high response rates and improves patient quality of life with minor adverse events, including ptosis, epiphora, keratitis, dry eyes, and diplopia. Other BoNT formulations are being studied as well. Strabismus, misalignment of the eyes, is a disabling condition that frequently affects pediatric populations but can also affect adults. With a range of presentations, the treatments for strabismus vary and include corrective lenses, eye exercises, occlusive therapy, and surgery. BoNT-A is frequently used as an adjunct and alternative to strabismus surgery. BoNT-A therapy improves vision in more than 50% of patients for 6 months or longer after injection. Optimal strategies for dosing and injecting BoNT are discussed.

BLEPHAROSPASM

a) Introduction

Blepharospasm is a type of focal dystonia characterized by involuntary, repetitive blinking (clonic spasms) or more sustained eyelid closure (tonic spasms). In severe cases, tonic eyelid closure can result in functional blindness.1 The primary form of blepharospasm is frequently called benign essential blepharospasm (BEB), although the condition is not benign to the patient.2 BEB has a substantial impact on quality of life (QOL) and may lead to depression and anxiety.3

b) Epidemiology

Estimates of the prevalence of blepharospasm vary widely, with rates of 16 to 133 per million reported across different studies.4 BEB is more closely associated with aging than other focal dystonias, with the mean age of onset usually around the sixth decade. The condition is more prevalent among women than men, among patients with a family history of dystonia and/or postural tremor, among those with prior head and face trauma, and among patients with prior eye disease (eg, blepharitis and keratoconjunctivitis).4 The current body of epidemiological literature supports both environmental and familiar (and potentially genetic) factors in the etiology of blepharospasm.4

Regression analysis indicates a significant association between ocular symptoms at disease onset and the development of blepharospasm. The association was stronger for patients with symptoms starting in the year prior to disease onset, particularly among patients 40 to 59 years of age.5 A recent report found that 72% of patients with BEB reported a stressful event immediately prior to development of symptoms.6

c) Clinical Features

Blepharospasm is usually bilateral (exceptionally unilateral).7 The Burke & Fahn Dystonia Rating Scale includes two forms of BEB in four stages related to increased blinking frequency (stages I & II) and increased duration of blinking (stages III & IV) as follows:

  • Stage I:     Occasional blinking (clonic spasms)
  • Stage II:    Frequent blinking without prolonged spasms of eyelid closure
  • Stage III:   Prolonged spasms of eyelid closure with eyes open most of the time
  • Stage IV:   Prolonged spasms of eyelid closure, with eyes closed at least 30% of the time (“functional blindness”)7

Patients with BEB may also experience dystonia in other portions of the face and neck, and it is often accompanied by dystonic movement of adjacent muscles such as the eyebrows and the paranasal muscles.1 The rate of spread is higher than in other dystonias and is likely to occur in the first 1 to 2 years after the onset of blepharospasm.2 Blepharospasm is sometimes preceded by a sensation of eye irritation or photophobia, and may begin unilaterally. Triggers may include watching television, reading, driving, bright lights, or fatigue. Concentration, relaxation, or sensory tricks such as touching the eyelids or talking may ameliorate the condition.1

d) Pathophysiology and Pathogenesis

BEB may be caused by spasms of the orbicularis oculi muscle or failure of the superior levator palpebrae muscle to contract (apraxia of eyelid opening). From a pathophysiologic perspective, patients with BEB have a higher baseline blink rate than control patients. Interestingly, when patients with BEB are engaged in conversation, their blink rates drop off, suggesting that conversation may reduce the excitability of eyelid closure. Beyond the motor disorder, patients with BEB also have a temporal discrimination deficit possibly owing to a loss of short latency inhibition mechanism.

Blepharospasm is thought to be caused by abnormal functioning of the basal ganglia.8 There is also considerable evidence that patients with blepharospasm exhibit increased plasticity of the trigeminal blink reflex circuit.2. A study of cranial dystonia showed overactivity of the sensory cortex, further strengthening the argument for dysfunction of the sensory system in the pathophysiology of BEB.2

e) Diagnosis

The diagnosis of blepharospasm is clinical. Affected individuals have a blink rate above 27 blinks per minute and may also have prolonged lid closures. Several functional rating scales are available to measure the impact of BEB on patient functionality, including the Adenis-Grivet rating scale, which analyzes six items of everyday life on a scale of 0 to 4.9 Videonystagmography, which acquires video images of eye movements, can be used to assess blepharospasm and provide an objective measure of baseline characteristics as well as response to therapy.7

f) Management

The Role of BoNT: The Standard of Care

The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) noted that before the introduction of BoNT, no medical or surgical therapies for blepharospasm were effective. The open-label observations with BoNT were deemed so dramatic that only a few randomized trials have been conducted.10 For this reason, BoNT for blepharospasm has only received a level B (probably effective) recommendation from the AAN based on currently available evidence. However, the clinical experience of BoNT as the treatment of choice has been so strong that investigators suggest it would be unethical to conduct additional placebo-controlled trials to document the efficacy of BoNT for blepharospasm.10

BoNT Mechanism of Action

There are several serotypes of BoNT, including A, B, C1, D, E, F, and G.11 Currently, only the A and B serotypes have been used clinically. BoNT ameliorates contractions by inhibiting acetylcholine release at the neuromuscular junction and by inhibiting peptide neurotransmitters in the region.12 A recent videonystagmographic analysis of the effect of BoNT-A in patients with BEB showed that BoNT-A reduced both the frequency and the duration of pupillary occlusion greater than 0.3 seconds, that is, blinks that are voluntary or spasms, as opposed to blinks less than 0.3 seconds, which are spontaneous. These results are consistent with a peripheral muscle action and no central effect on neurologic control.7

Clinical Profile of FDA-Approved Agents (OnabotulinumtoxinA and IncobotulinumtoxinA)

The most-studied BoNT agent for the management of blepharospasm is onabotulinumtoxinA (Botox®) (Table 1). Since 1989, this agent has been approved by the FDA for the management of blepharospasm associated with dystonia in patients 12 years of age or older.13 The safety and efficacy of BoNT-A preparations in the treatment of blepharospasm have been assessed by a small number of double-blind studies, a considerable number of open-label, case-control studies, and comparative studies. In general, BoNT-A therapy can be expected to work within 24 to 72 hours, with a response rate in the range of 95% to 98%.11 OnabotulinumtoxinA improves QOL and reduces the severity of depressive symptoms in patients with BEB.3 The duration of effect of BoNT-A is in the range of 3 months.11

Table 1. Studies of BoNT Formulations Used in the Management of Blepharospasm8,10,22-29

Therapies Compared

Study Design Efficacy Outcomes Safety Outcomes

AbobotulinumtoxinA vs onabotolulinumA22

 

 

 

N=91 patients (blepharospasm and hemifacial spasm);single-blind, randomized, parallel-group study

Similar clinical efficacy and tolerability; duration of effect (in those not needing a booster) was 13 weeks for abobotulinumtoxinA vs 11 weeks for onabotulinumtoxinA. However, more patients needed a booster in the abobotulinumtoxinA group than the onabotulinumtoxinA group (23% vs 12%, respectively) AEs in 50% of abobotulinumtoxinA
group vs 47% in the onabotulinumtoxinA group

IncobotulinumtoxinA vs onabotulinumtoxinA
(at 15-80 U)8

 

N=300; double-blind, multicenter trial Both treatments produced statistically significant improvements from baseline in the Jankovic Rating Scale at Week 3 Similar; most common adverse event was ptosis
Chinese botulinum toxin type A vs onabotulinumtoxinA23 N=26; double-blind, randomized, crossover trial; patients with primary blepharospasm or hemifacial spasm Onset of clinical response, duration of effect, patient global assessment of change, and patient preference did not differ between the 2 groups (p >.05). Similar
Chinese BoNT-A vs onabotulinumtoxinA24 N=57; 21 patients with blepharospasm; others had hemifacial spasm The mean effect time length was similar in blepharospasm (11.3 weeks for both toxins); the 26-Item Short Form Health Survey showed improvement from baseline after 16 weeks for both groups Similar pain and burning; no systemic AEs
In an open-label BoNT-B (2500 U) in patients with BEB previously treated with BoNT-A25 N=13 patients with blepharospasm (12 with idiopathic focal dystonia, one with tardive dyskinesia Time course (3.0 day latency) and magnitude of improvement (35% on VAS) were similar to those with BoNT-A, but duration of effect was shorter (63.0 days) with BoNT- Well tolerated, with common AEs such as pain at injection, ptosis, and epiphora; 1 severe anaphylactic reaction
RimabotulinumtoxinB for patients refractory to onabotulinumtoxinA32 N=16, retrospective review from one practice Average dose 3,633 U per treatment session. Mean duration of beneficial effect was 7.3 weeks Side effects for rimabotulinumtoxinB occurred at a higher rate than is  is typical with onabotulinumtoxinA. All patients had ptosis
Korean BoNT-A vs onabotulinumtoxinA26-27 N=60; double-blind, randomized trial in blepharospasm only Improvement in severity of spasm (90.3% for Korean BoNT-A vs 86.2% for onabotulinumtoxinA); other end points (including duration of effect) similar AEs in 16.1% of Korean BoNT-A treated vs 27.6% for onabotulinumtoxin; no serious AEs

Abbreviations:

AE: adverse event;
BEB: benign essential blepharospasm;
BoNT: botulinum neurotoxin;
VAS: visual analog scale.

IncobotulinumtoxinA (Xeomin®) is another formulation of BoNT-A that has been studied in various dystonias, including blepharospasm (Table 1). 8 IncobotulinumtoxinA recently received FDA approval for the management of blepharospasm in adults previously treated with onabotulinumtoxinA.14 In a Phase 3 randomized trial conducted in 109 patients with BEB and prior response to onabotulinumtoxinA, patients received incobotulinumtoxinA dosed at a mean of 33 Units per eye. The primary endpoint, change in Jankovic Rating Scale severity subscore from baseline to week 6, showed a statistical improvement in the incobotulinumtoxinA arms vs placebo.14

The most common adverse events associated with onabotulinumtoxinA administration include ptosis (21%), superficial punctate keratitis (6%), and eye dryness (6%).11 In clinical trials with incobotulinumtoxinA, adverse events included ptosis (19%), dry eyes (16%), dry mouth (16%), and visual impairment (12%).14

Optimizing the Outcome With BoNT-A Preparations

Injection Procedures

BoNT-A injections for blepharospasm are frequently made above the eyebrow, medially and laterally in the upper eyelid, and laterally in the lower eyelid.11 Because injections in different sections of the orbicularis oculi muscle differ in efficacy, the clinician should understand the anatomy of that muscle.15-16 A prospective unblinded study that evaluated injections in 53 patients (25 with blepharospasm and 28 with hemifacial spasm) found that pretarsal BoNT-A injections produced a higher response rate and longer duration of response than did preseptal injections. In addition, ptosis was less frequent with pretarsal injections than with preseptal injections (Figure 1).15 These findings and other studies support the benefit of pretarsal injections. The clinician should avoid injecting near the levator palpebrae superioris muscle, which may reduce the complication of ptosis. Furthermore, avoiding injections in the medial lower lid may reduce the diffusion into the inferior oblique muscle, thereby lessening the chances of diplopia. Pressure should be applied immediately after injection to avoid ecchymosis.13

Injection_Sites1

Figure 1. Muscles around the eye are in three sections: a, b, c, and d are orbital muscle; e and f are preseptal muscle, and g and h are pretarsal muscle.

Dosing

The formulations of BoNT-A have different recommended doses. The recommended starting dose for onabotulinumtoxinA in the management of blepharospasm is 1.25 U to 2.5 U (0.05 mL to 0.1 mL volume at each site) injected into each of three sites per affected eye. When administering incobotulinumtoxinA, the dose, number, and location of injections should be based on previous dosing for onabotulinumtoxinA. If the previous dose is not known, the recommended starting dose of incobotulinumtoxinA is 1.25 to 2.5 U per injection site. In clinical trials, the mean dose per injection site was 5.6 U, mean number of injections per eye was 8, and the mean dose per eye was 33.5 U.14

Dose escalation may be required in some patients to maintain a therapeutic benefit. A recent long-term (10 years) study used the botulinum neurotoxin escalation index in Units (BEI-U) and botulinum neurotoxin escalation index percentage (BEI-%) among patients with blepharospasm, hemifacial spasm, and entropion. The results showed increases in mean dosages for BEB patients with no change in duration of relief, as well as mean increases in both dosage and duration of effect in BEB patients =65 years of age. This suggests early underdosing for older BEB patients.17 The Prescribing Information for onabotulinumtoxinA suggests that the dose may be increased up to twofold if the response from initial treatment is considered insufficient (an effect not lasting longer than 2 months).

In general, the goal for dosing BoNT for any indication is to achieve the desired therapeutic end point with the lowest dose possible, and to avoid the risk of distant spread and potential side effects. Even though the onabotulinumtoxinA doses used for blepharospasm are generally lower than those used for some other conditions, patients with blepharospasm should be counseled about the potential for side effects associated with toxin spread and should be given the patient medication guide to read.13-14,18

Adjunctive Therapies

No adjunctive therapies to BoNT treatment have been found to be effective. Based on two studies, one in blepharospasm and one in another dystonia, that show a benefit of muscle activation or electrical stimulation given immediately after BoNT injection to increase the toxin’s pharmacological action, Conte and colleagues tested whether electrically induced activation of injected muscles increases the effectiveness of BoNT-A in patients with BEB. In their trial of 23 patients injected bilaterally in the orbicularis oculi muscle, muscle activation did not increase the effectiveness of BoNT.19

Management in BoNT Nonresponders

The vast majority of patients with BEB respond effectively to BoNT-A injections, although some may require dose escalation over time.8,13-14 When botulinum toxin has not provided enough relief for blepharospasm, it is worth considering adding an oral medication.20 Nonresponse may also be related to anatomical considerations. Apraxia of lid opening is a nonparalytic inability to open the eyes at will, which is the cause of blepharospasm in about 7% of patients. Weakening of the upper pretarsal portion of the eye should be helpful in alleviating lid opening, but this condition is typically refractory to treatment with BoNT. In these cases, upper eyelid myectomy may be helpful.21

Other BoNT Formulations

Although no BoNT preparations other than onabotulinumtoxinA and incobotulinumtoxinA are currently FDA-approved for blepharospasm, studies have been conducted with abobotulinumtoxinA (Dysport®), Chinese botulinum toxin type A (Prosigne®), Korean botulinum toxin type A (Meditoxin®), and rimabotulinumtoxinB (Myobloc®).8,22-29

Even though abobotulinumtoxinA is not FDA approved for blepharospasm, studies have evaluated this agent and the appropriate dosing in cases of BEB. A retrospective chart evaluation was undertaken to determine the responses in patients who received a mean dose per injection session of 34 U of onabotulinumtoxinA and 152 U of abobotulinumtoxinA. No difference was found in mean latency of clinical effect (4.5 vs 5.0 days between the two products). Although efficacy was similar between the two agents, the duration of clinical effect was longer for abobotulinumtoxinA; however, more patients also experienced adverse events with this preparation. These results suggest distinct profiles for these 2 BoNT-A agents.29 In a recent large-scale (N=120), randomized, placebo-controlled trial of multiple doses of abobotulinumtoxinA, the optimal dose was found to be 80 U, at which 97% of patients reported beneficial efficacy and safety outcomes.27

Select studies comparing these other botulinum neurotoxins with onabotulinumtoxinA are discussed in Table 1. In general, these various formulations show good efficacy and safety in the management of blepharospasm, and may provide additional options for patients with blepharospasm. In evaluating the comparative data or trying these alternative formulations clinically, practitioners must recognize that there is no dose equivalency among the BoNT products.28 Studies have demonstrated no reliable dose-equivalency ratios; the FDA emphasized in a recent labeling change/ box warning that different BoNT formulations are not interchangeable and should be treated as different drugs.29 Further study is needed to determine the potential place and optimal dosing of these therapies for blepharospasm.

Other Emerging Therapeutic Options

Methylphenidate is being studied in patients with BEB, and an initial small study in seven patients suggests that it provides objective improvement in mean voltage as well as subjective improvement for patients. A placebo-controlled trial is needed.30 Deep brain stimulation has been studied in patients with Meige syndrome, which is characterized by blepharospasm, cervical dystonia, and facial oromandibular dystonia. In three patients with the condition, 12-month, long-term follow-up Burke-Fahn-Marsdaen scores were substantially improved in these medically-refractory Meige syndrome patients treated with deep-brain stimulation.31  

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REFERENCES

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  3. Ochudlo S, Bryniarski P, Opala G: Botulinum toxin improves the quality of life and reduces the intensification of depressive symptoms in patients with blepharospasm. Parkinsonism Relat Disord 13:505-8, 2007
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  23. Rieder CR, Schestatsky P, Socal MP, et al: A double-blind, randomized, crossover study of prosigne versus botox in patients with blepharospasm and hemifacial spasm. Clin Neuropharmacol 30:39-42, 2007
  24. Quagliato EM, Carelli EF, Viana MA: Prospective, randomized, double-blind study, comparing botulinum toxins type a botox and prosigne for blepharospasm and hemifacial spasm treatment. Clin Neuropharmacol 33:27-31, 2010
  25. Colosimo C, Chianese M, Giovannelli M, et al: Botulinum toxin type B in blepharospasm and hemifacial spasm. J Neurol Neurosurg Psychiatry 74:687, 2003
  26. Yoon JS, Kim JC, Lee SY: Double-blind, randomized, comparative study of Meditoxin versus Botox in the treatment of essential blepharospasm. Korean J Ophthalmol 23:137-41, 2009
  27. Truong D, Comella C, Fernandez HH, et al: Efficacy and safety of purified botulinum toxin type A (Dysport) for the treatment of benign essential blepharospasm: a randomized, placebo-controlled, phase II trial. Parkinsonism Relat Disord 14:407-14, 2008
  28. Badarny S, Susel Z, Honigman S: Effectivity of Dysport in patients with blepharospasm and hemifacial spasm who experienced failure with Botox. Isr Med Assoc J 10:520-2, 2008
  29. Bentivoglio AR, Fasano A, Ialongo T, et al: Fifteen-year experience in treating blepharospasm with Botox or Dysport: same toxin, two drugs. Neurotox Res 15:224-31, 2009
  30. Price KM, Ramey NA, Richard MJ, et al: Can methylphenidate objectively provide relief in patients with uncontrolled blepharospasm? A pilot study using surface electromyography. Ophthal Plast Reconstr Surg 26:353-6, 2010
  31. Lyons MK, Birch BD, Hillman RA, et al: Long-term follow-up of deep brain stimulation for Meige syndrome. Neurosurg Focus 29:E5, 2010
  32. Dutton JJ, White JJ, Richard MJ: Myobloc for the treatment of benign essential blepharospasm in patients refractory to botox. Ophthal Plast Reconstr Surg 22:173-7, 2006

IV. STRABISMUS

a) Introduction

Strabismus, or misalignment of the eyes, is marked by constant or intermittent ocular deviation that results in the failure of the two eyes to focus simultaneously on the same object, as well as loss of binocular alignment.1 Strabismus can present as either exotropia (an eye turned outward) or esotropia (an eye turned inward; i.e., crossed eyes).2 Strabismus has a negative impact on self-esteem and can lead to societal prejudices, including employment challenges.3

b) Epidemiology

Strabismus affects 2% to 5% of preschool-age children and is a common cause of pediatric referral to ophthalmologists.3-4 Its prevalence in adults is approximately 4%.4  In about half of adults with strabismus, the condition occurred during infancy or childhood and was either left untreated or treated unsuccessfully.4

c) Clinical Features

Different forms of strabismus vary in their presentation and course. For example, concomitant childhood strabismus typically occurs in children less than 5 months of age and is frequently characterized by a large angle deviation and less-dense amblyopia. Acquired esotropia typically has a later onset—between 1.5 and 4 years of age. This condition can be either accommodative or nonaccomodative. Because of the range of conditions and timing, it is important to reemphasize the eye exam as part of all well-child checkups.

d) Pathophysiology

The causes of strabismus can be characterized as comitant/congenital, paralytic, restrictive, sensory, and syndromic.3 Adult-onset strabismus can occur because of acquired cranial nerve palsies, orbital trauma, thyroid ophthalmopathy, or orbital/neurological diseases, or secondarily from ophthalmic procedures.2

e) Diagnosis

The pediatric care provider should screen for strabismus in all routine well-child checkups. Parents should be given information sheets.3 It is important to determine onset, course, historical risk factors, prenatal drug exposure, and family history. Family photographs can be examined. Specific diagnostic tests that can be employed include the corneal light reflex test and the cover test, which can help determine tropic deviations.3

f) Management

Treatments for pediatric strabismus vary according to the disease mechanism, but they can include corrective lenses, eye exercises, and, rarely, occlusion therapy. Surgery is typically reserved for patients in whom nonsurgical methods are not likely to work. For example, surgery is typically initiated within 12 months of diagnosis of concomitant childhood strabismus. Strabismus surgery consists of loosening (recession) and tightening (resection) procedures. Surgery achieves satisfactory alignment in approximately 75% to 80% of cases.3

Role of BoNT

Scott reported an early experience with botulinum neurotoxin (BoNT) in correcting strabismus. In his 1981 study, 42 patients with strabismus were injected with 132 doses of BoNT-A, providing a positive effect lasting up to 411 days.5 First approved for strabismus in 1989, BoNT-A is used both as an adjunct and an alternative to strabismus surgery. An open-label clinical trial showed that onabotulinumtoxinA injections improved vision in 55% of 677 strabismus patients to an alignment of 10 prism diopters or less when evaluated 6 months or longer following injection.6 As reviewed in Carruthers, additional studies have shown that onabotulinumtoxinA is effective in reducing ocular deviation in more than 50% of patients.7


A Cochrane Review of botulinum neurotoxins for the treatment of strabismus identified four randomized, controlled trials that compared onabotulinumtoxinA or abobotulinumtoxinA to another treatment or no treatment. Two studies found no difference between the use of BoNT-A and surgery for patients requiring retreatment for acquired esotropia or infantile esotropia. BoNT had produced a poorer response compared with surgery for patients treated for horizontal strabismus in the absence of binocular vision. Complications, including ptosis and vertical deviation, occurred in 24% to 56% of patients. No studies involving other serotypes or products were identified, and a dose effect could not be established.8 Specific subsets of patients with positive responses to BoNT include those with strabismus secondary to central neurological damage, endocrinopathies, brain infection, trauma, psychomotor deficiency, prematurity, myasthenia, and hematological disease.9 BoNT-A is a preferred therapy for elderly patients unfit for general anesthesia, when the clinical condition is evolving or unstable, or if surgery is not successful.10

Optimizing BoNT Therapy

Injection Techniques

Several points should be made about appropriate techniques for BoNT-A injection in patients with strabismus:

  • Application should be made to the motor end plate of the appropriate rectus muscle.11 This requires that the needle be injected through the conjunctiva and into the target muscle in the area of the neuromuscular junction (which is recognized by maximal electrical activity on the oscilloscope or noise from the connected loudspeaker)12
  • Drops of a local anesthetic and an ocular decongestant should be given several minutes before injection
  • The injection volume should be between 0.05 and 0.15 mL per muscle6

Dosing

Dosing is based on the muscle type and the disease state and ranges from 1.25 U to 5 U in any one muscle for onabotulinumtoxinA. As is the case with all BoNT injections, the lowest dose possible should be given to achieve therapeutic efficacy, and patients should be counseled about the potential side effects associated with distant toxin spread.6Patients should be reexamined 7 to 14 days after the injection.  The dose can be kept constant if there is an adequate response; subsequent dosing can be increased up to twofold if there is incomplete paralysis. The recommended maximal dose as a single injection for any one muscle (upper limit) is 25 U.6

Pediatric Applications of BoNT-A

Use of BoNT-A therapy for strabismus in children has not been approved by the FDA.6 In children, BoNT-A has been used to treat esotropia. As an alternative to incisional surgery for the treatment of infantile esotropia, multiple injections of BoNT achieve a correction rate greater than 70%.13 The treatment program comprises simultaneous bimedial injection of 1.25 -2.5 U of toxin per rectus muscle. These are to be injected as early as 3 months of age, with repeated simultaneous injections with recurrence of esotropia exceeding 15 prism diopters, increasing the dose to 3 U per eye unless ptosis becomes limiting. Transient partial ptosis, typically lasting 2 to 4 weeks, occurs in about 25% of children after BoNT injection because of proximity to the levator muscle.14 The long-term effectiveness of BoNT treatment was demonstrated in a prospective study of 68 children with acquired esotropia.15At an average of 4.8 years after the last injection, motor success (distance deviation of no more than 8 prism diopters) was obtained in 53%, 71%, and 88% of children who received 1, 2, and 3 injections, respectively.15 The role of BoNT therapy in other childhood strabismic indications (exotropia, sixth nerve palsy, cerebral palsy) requires further investigation.

REFERENCES

  1. Engle EC. Genetic basis of congenital strabismus. Arch Ophthalmol. Feb 2007;125(2):189-195.
  2. Mills MD, Coats DK, Donahue SP, Wheeler DT. Strabismus surgery for adults: a report by the American Academy of Ophthalmology. Ophthalmology. Jun 2004;111(6):1255-1262.
  3. Ticho BH. Strabismus. Pediatr Clin North Am. Feb 2003;50(1):173-188.
  4. Beauchamp GR, Black BC, Coats DK, et al. The management of strabismus in adults
  5. Scott AB. Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Soc. 1981;79:734-770.
  6. BOTOX [prescribing information]. Irvine, California: Allergan, Inc., August 2009.
  7. Carruthers J, Carruthers A. Botox: beyond wrinkles. Clin Dermatol. Jan-Feb 2004;22(1):89-93.
  8. Rowe FJ, Noonan CP. Botulinum toxin for the treatment of strabismus. Cochrane Database Syst Rev. 2009(2):CD006499.
  9. Moguel-Ancheita S, Dixon-Olvera S, Martinez-Oropeza S, Orozco-Gomez LP. [Botulinum toxin as a treatment for strabismus in systemic diseases]. Arch Soc Esp Oftalmol. Jan 2003;78(1):9-14.
  10. Kowal L, Wong E, Yahalom C. Botulinum toxin in the treatment of strabismus. A review of its use and effects. Disabil Rehabil. Dec 15 2007;29(23):1823-1831.
  11. Denniston A, Reuser T. The use of botulinum toxin in ophthalmology. Hosp Med. Aug 2001;62(8):477-479.
  12. Huber A. Botulinum toxin and the eye. Curr Probl Dermatol. 2002;30:227-235.
  13. Tengtrisorn S, Treyapun N, Tantisarasart T. Botulinum A toxin therapy on esotropia in children. J Med Assoc Thai. Nov 2002;85(11):1189-1197.
  14. Scott A, ed. The role of botulinum toxin type A in the management of strabismus. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. Brin M, Jankovic J, Hallett M, eds. Scientific and Therapeutic Aspects of Botulinum Toxin.
  15. Tejedor J, Rodriguez JM. Long-term outcome and predictor variables in the treatment of acquired esotropia with botulinum toxin. Invest Ophthalmol Vis Sci. Oct 2001;42(11):2542-2546.