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 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
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
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
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
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).
|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
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
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
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.
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
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
- Langlois M, Richer F, Chouinard S: New perspectives on dystonia. Can J Neurol Sci 30 Suppl 1:S34-44, 2003
- Hallett M, Evinger C, Jankovic J, et al: Update on blepharospasm: report from the BEBRF International Workshop. Neurology 71:1275-82, 2008
- 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
- Defazio G, Livrea P: Epidemiology of primary blepharospasm. Mov Disord 17:7-12, 2002
- Martino D, Defazio G, Alessio G, et al: Relationship between eye symptoms and blepharospasm: a multicenter case-control study. Mov Disord 20:1564-70, 2005
- Peckham EL, Lopez G, Shamim EA, et al: Clinical features of patients with blepharospasm: a report of 240 patients. Eur J Neurol, 2011
- Casse G, Adenis JP, Sauvage JP, et al: Videonystagmography as a tool to assess blepharospasm before and after botulinum toxin injection. Graefes Arch Clin Exp Ophthalmol 246:1307-14, 2008
- Jankovic J: Clinical efficacy and tolerability of Xeomin in the treatment of blepharospasm. Eur J Neurol 16 Suppl 2:14-8, 2009
- Adenis JP, Grivet D, Thuret G, et al: [Surgical treatment of blepharospasm: results of a study of 138 patients using an improved disability scale]. Bull Acad Natl Med 190:1007-15; discussion 1016, 2006
- Simpson DM, Blitzer A, Brashear A, et al: Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 70:1699-706, 2008
- Faucett D: Essential blepharospasm, in Yanoff M, Duker J (eds): Ophthalmology, 3rd ed. Maryland Heights, MO, Elsevier Health Sciences, 2008
- Lu DW, Lippitz J: Complications of botulinum neurotoxin. Dis Mon 55:198-211, 2009
- Botox® (onabotulinumtoxinA) for injection [package insert]. Irvine, CA: Allergan Pharmaceuticals; 2010,
- Xeomin® (incobotulinumtoxinA) for injection [package insert]. Greensboro, NC: Merz Pharmaceuticals; 2010.
- Pang N: Muscle force generation comparison after pretarsal and preseptal botulinum toxin A injections in blepharospasm patients, Benign Essential Blepharospasm Canadian Research Foundation Spring Meeting. Toronto, Ontario, Canada, 2006
- Cakmur R, Ozturk V, Uzunel F, et al: Comparison of preseptal and pretarsal injections of botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neurol 249:64-8, 2002
- Cillino S, Raimondi G, Guepratte N, et al: Long-term efficacy of botulinum toxin A for treatment of blepharospasm, hemifacial spasm, and spastic entropion: a multicentre study using two drug-dose escalation indexes. Eye (Lond) 24:600-7, 2010
- Boyles S: Black box warning for Botox. WebMD Health News. April 20, 2009, 2009
- Conte A, Fabbrini G, Belvisi D, et al: Electrical activation of the orbicularis oculi muscle does not increase the effectiveness of botulinum toxin type A in patients with blepharospasm. Eur J Neurol 17:449-55, 2010
- Reich S: Medical Therapy for Blepharospasm. , Blepharospasm Pages, Benign Essential Blepharospasm Research Foundation. Available at http://www.blepharospasm.org/med-therapy.html. Accessed October 15, 2010, 2004
- Georgescu D, Vagefi MR, McMullan TF, et al: Upper eyelid myectomy in blepharospasm with associated apraxia of lid opening. Am J Ophthalmol 145:541-547, 2008
- Sampaio C, Ferreira JJ, Simoes F, et al: DYSBOT: a single-blind, randomized parallel study to determine whether any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type A--Dysport and Botox--assuming a ratio of 4:1. Mov Disord 12:1013-8, 1997
- 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
- 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
- Colosimo C, Chianese M, Giovannelli M, et al: Botulinum toxin type B in blepharospasm and hemifacial spasm. J Neurol Neurosurg Psychiatry 74:687, 2003
- 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
- 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
- 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
- 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
- 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
- Lyons MK, Birch BD, Hillman RA, et al: Long-term follow-up of deep brain stimulation for Meige syndrome. Neurosurg Focus 29:E5, 2010
- 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
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
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.
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
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
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
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 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.
- Engle EC. Genetic basis of congenital strabismus. Arch Ophthalmol. Feb 2007;125(2):189-195.
- 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.
- Ticho BH. Strabismus. Pediatr Clin North Am. Feb 2003;50(1):173-188.
- Beauchamp GR, Black BC, Coats DK, et al. The management of strabismus in adults
- Scott AB. Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Soc. 1981;79:734-770.
- BOTOX [prescribing information]. Irvine, California: Allergan, Inc., August 2009.
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