The Neurotoxin Institute

Advisory Editor
Mark Hallett, MD
Chief, Human Motor Control Section
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, Maryland

Introduction to blepharospasm

Blepharospasm is a focal dystonia characterized by excessive involuntary contraction of the orbicularis oculi muscles, leading to repetitive blinking or sustained closure of the eyelids. In severe cases, tonic eyelid closure can lead to functional blindness and can have significant negative impact on the patient’s quality of life (Langlois et al, 2003; Hallett, 2002). Inability to open the eyes can also occur as a result of failure of levator palpebrae muscle activation (“apraxia of eyelid opening”). Primary, essential, or idiopathic blepharospasm, often referred to as benign essential blepharospasm, is not associated with any known etiology (Hallett, 2002). Blepharospasm occurs spontaneously but can be triggered by exposure to bright lights, watching television, reading, driving, or fatigue. Contractions may be ameliorated with sensory tricks such as touching the forehead or the eyebrow or talking (Langlois et al, 2003; Defazio and Livrea, 2004). Blepharospasm may occur alone or it may be accompanied by dystonia of the lower face and jaw (Meige syndrome) or other focal dystonias such as cervical dystonia (spasmodic torticollis) (Hallett, 2002).

Blepharospasm is chronic, progressive, and frequently disabling, with age of onset typically in the fifth or sixth decade (Hallett, 2002; Defazio and Livrea, 2004). In their review of published epidemiologic data, Defazio and Livrea concluded that the crude estimates of prevalence range from 16 to 133 per million (Defazio and Livrea, 2002). Women are more than two times more likely to be affected than men and are typically older at onset (Hallett, 2002; Defazio and Livrea, 2002). Prior head trauma with loss of consciousness, family history of dystonia, and prior eye disease may also increase the risk of developing blepharospasm (Defazio and Livrea, 2002). Older age at onset, female gender, and prior head/face trauma are also thought to be risk factors for the spread of dystonia to other muscles (Defazio and Livrea, 2002). Causes of secondary blepharospasm include acquired conditions (eg, brain-stem lesions of inflammatory or vascular origin) or, less frequently, inherited metabolic/neurodegenerative conditions, such as Wilson’s disease, Huntington’s disease, and parkinsonian disorders in which blepharospasm may be a neurological sign of either the disease or treatment with dopaminergic drugs (Defazio and Livrea, 2004).

Current therapeutic approaches

The goal of blepharospasm treatment is to reduce or prevent unwanted, repeated, forced closure of the eyelids. Approved in 1989 for the treatment of blepharospasm, botulinum neurotoxin (BoNT) is now the treatment of choice for this disorder (Hallett, 2002; Defazio and Livrea, 2004). BoNT therapy is highly effective in patients with spasm of the orbicularis oculi muscles and can be used for many years without loss of efficacy (Hallett, 2002; Defazio and Livrea, 2004). Apraxia of eyelid opening is more difficult to treat than blepharospasm, but some patients with apraxia of eyelid opening improve with BoNT injections, particularly if the apraxia of eyelid opening is triggered by blepharospasm (Forget et al, 2002). Patients with involuntary levator inhibition, alone or in combination with blepharospasm, are less responsive to BoNT (Aramideh et al, 1994; Aramideh et al, 1995; Forget et al. 2002).

For the minority of patients refractory to BoNT therapy, treatment alternatives include trihexyphenidyl, clonazepam, baclofen, and tetrabenazine (Balash and Giladi, 2004; Defazio and Livrea, 2004), although these are generally not very efficacious. Patients who are unresponsive to these medications are candidates for myectomy of the eyelid protractors (Hallett, 2002; Defazio and Livrea, 2004).

Mechanism of action of BoNT in blepharospasm

The effect of BoNT in blepharospasm is largely attributable to the muscle relaxation produced as a result of the inhibition of acetylcholine release at the neuromuscular junction. The first use of neurotoxins to treat eye movement disorders was reported in an animal study in the early 1970s showing that injection of low doses of neurotoxic agents into the extraocular muscles, under electromyographic control, reduced the activity of hyperactive muscles (Calace et al, 2003). This finding prompted subsequent human studies of BoNT type A (produced as BOTOX® by Allergan, Inc., Irvine, CA, and Dysport® by Ipsen, Slough, UK) in ocular motility disorders including blepharospasm. Early studies explored the activity of BoNT in patients with blepharospasm using single-fiber electromyography, compound motor action potential of the orbicularis oculi muscle (measured by stimulation of the facial nerve), blink reflex, and blink reflex recovery curve (Girlanda et al, 1996). These measurements were carried out before injection and at 1, 2, and 4 weeks after unilateral BoNT injection. Postinjection facial compound motor action potential decreased bilaterally and single-fiber electromyography indicated abnormal neuromuscular junction function bilaterally. The excitability curve of blink reflex was not altered by therapy. These results confirmed the actions of BoNT at the neuromuscular junction and provided evidence of bilateral clinical and neurophysiologic effects following unilateral administration, presumably as a result of local toxin spread (Girlanda et al, 1996).

Clinical data

The safety and efficacy of BoNT in the treatment of blepharospasm has been demonstrated by a small number of double-blind studies and a considerable number of open case-control studies. A double-blind, placebo-controlled study by Jankovic and Orman demonstrated the beneficial effects of BoNT type A (BOTOX®, then known as Oculinum), in 11 patients with blepharospasm (Jankovic and Orman, 1987). This study found that all patients with blepharospasm improved after a total of 14 series of BoNT injections, with 72% improvement over baseline on severity rating score (0 = absent, 4 = most severe) and a mean duration of beneficial effect of 12.5 weeks. There was no improvement in patients who received placebo.

As noted by Jost and Kohl, the total number of patients studied in randomized controlled trials is small; however, results were consistent across trials and concordant with the positive findings of open-label studies (Jost and Kohl, 2001). One weakness noted in some of these clinical trials is the inclusion of patients with blepharospasm and patients with hemifacial spasm without a clear delineation between the two disorders. Although Jost and Kohl concluded that blepharospasm qualified for evidence-based medicine Ia classification (systematic review of randomized clinical trials with homogeneity among trials), there are only 3 Class I studies involving only 22 patients (Table 1).

*The BOTOX® formulation was known as Oculinum at the time these studies were conducted.

A recent systematic review by Costa and colleagues found no randomized controlled trials with sufficient numbers of patients to fit the inclusion criteria. The authors therefore concluded that no high-quality data support the use of BoNT for treatment of blepharospasm, but that studies have indicated that BoNT type A is effective and safe for treatment of blepharospasm, benefiting 90% of patients. They further note that this considerable effect size makes placebo-controlled trials of blepharospasm treatment with BoNT type A impractical and perhaps unethical (Costa et al, 2005).

Several studies have assessed the dose of BoNT required for efficacy in blepharospasm. In an open-label, uncontrolled study, 115 patients with cervical dystonia, blepharospasm, or facial hemispasm were treated over a period of 2 years to evaluate the effects of low-dose BoNT treatment (Rollnik et al, 2000). BOTOX® was diluted in 20 mL of 0.1% albumin solution to arrive at a concentration of 25 MU/mL. The mean duration of beneficial effects was 11.7 weeks and patient-evaluated clinical global improvement was 2.7 points on a 0 to 4 scale. A study that examined the qualitative changes from BOTOX® treatment over time found that the mean interval of symptom relief was longer with a low dose (4.0 months, 16 U) than with a high dose (3.2 months, 24.2 U) (Snir et al, 2003). In a hospital-based study comprising 215 injections of BoNT type A in patients with focal dystonias, the lowest dosages of Dysport were required for patients with blepharospasm (122 U) and writer’s cramp (92.5 U), whereas a dosage of over 500 U was required for patients with generalized dystonia. The best treatment response was observed in patients with blepharospasm (>98%) and hemifacial spasm (97%), whereas patients with generalized dystonia showed the poorest response (Gupta et al, 2003).

The long-term efficacy of BoNT in the treatment of blepharospasm has also been examined. Jankovic and Schwartz analyzed the long-term effects of repeated BoNT (BOTOX®) treatments in 42 patients with blepharospasm who underwent at least 5 different treatment sessions. The total treatment dose and peak efficacy rating were constant over time, but the duration of action increased and the frequency of side effects diminished over time. They concluded that chronic treatment was not associated with any decline in benefit, and that efficacy may improve slightly with repeat treatments (Jankovic and Schwartz, 1993).

A more recent long-term follow-up study analyzed data from 235 patients treated with BoNT (BOTOX®) for a variety of different movement disorders and dystonias, including blepharospasm, over a 10-year period (Hsiung et al, 2002). After 5 years and a total of 2616 treatment cycles, substantial clinical benefit was noted in 90% of patients with blepharospasm, 88% with hemifacial spasm, 63% with cervical dystonia, 100% with jaw closing and lower limb dystonia, and 56% with writer’s cramp. There was an increase in patient satisfaction after 5 years of treatment, with a benefit of 75.8% and with efficacy maintained for over 10 years in some patients. The most common reasons for discontinuing treatment were development of primary resistance (defined as less than 25% improvement after 2 or 3 consecutive trials with increasing doses of BoNT type A) in 9.1% of patients and development of secondary resistance (defined as achievement of at least 50% improvement for at least 2 treatment cycles followed by less than 25% improvement after 2 or more subsequent treatment cycles) in 7.5% of patients. Adverse effects, mostly minor, included dysphagia, pain, and bruising, and were the cause for discontinuation in 1.3% of patients. The results demonstrated that efficacy and tolerability were well maintained after long periods of treatment.

Another study that examined the long-term effects of BoNT type A (BOTOX®) in blepharospasm followed 168 patients from 1980 to 2001 (Calace et al, 2003). A total of 1264 treatment cycles (range,1-41 cycles per patient) were conducted during the study period. A total of 93% of patients reported improvement after treatment, with a mean duration of improvement of 3.6 months (range, 0-16 months). Three patients (1.7%) had a total remission of spasm. Twelve patients (7%) who underwent more than 14 treatments and were followed for 10 years or more (range, 10-18 years) showed no reduction in duration of relief over time, demonstrating that BoNT therapy is effective over the long term. All side effects were local in nature.

Clinical considerations

Injection procedures

The position of the injection sites around the orbicularis oculi muscle is thought to influence the efficacy and side effects of BoNT type A (Cakmur et al, 2002). A wide range of injection techniques have been reported, but there is no standard treatment protocol. Typically, injections are made in the upper eyelid above the eyebrow, medially and laterally, and in the lower eyelid laterally to weaken the orbital preseptal part of the orbicularis oculi. To weaken the pretarsal part of the orbicularis oculi, BoNT is injected subcutaneously into the mid upper eyelid close to the eyelash line (Defazio and Livrea, 2004) (Figures 1 and 2). A study by Cakmur and colleagues compared the impact of different injection sites on BoNT type A (BOTOX®) treatment of involuntary eyelid closure. Patients with blepharospasm who received pretarsal injections of BoNT type A experienced a higher response rate and longer duration of maximum response (97% response, 11.4-week duration of maximum response) than did patients who received preseptal injections (90% response, 8.2-week duration of maximum response). Moreover, major side effects (eg, ptosis) were less frequent with pretarsal injections than with preseptal injections. This study was limited by the fact that it was not prospective or blinded; nevertheless it clearly supports that the location of the injection site can impact BoNT efficacy (Cakmur et al, 2002). Because BoNT can diffuse from the site of injection into surrounding tissue, it is recommended that injection dose and volume should be adequate to weaken specific portions of the orbicularis oculi muscle while limiting diffusion to nearby muscle (Defazio and Livrea, 2004).

BoNT serotypes

The vast majority of studies of the effect of BoNT in blepharospasm have been with the A serotype, with similar efficacy and duration of action noted with different type A preparations. The ratio of units of Dysport to BOTOX® for similar efficacy is 4:1, as concluded by the authors of two studies that examined the two available formulations of BoNT type A for the treatment of blepharospasm (Table 2).

Table 2. Comparison of BoNT type A formulations for treatment of blepharospasm.

A limited number of studies have examined the efficacy of other BoNT serotypes. Colosimo and colleagues recently reported an open-label pilot study of BoNT type B (Myobloc®; Solstice Neurosciences, Malvern, PA) in 13 patients with blepharospasm who had positive responses to BoNT type A (Colosimo et al, 2003). Of 13 patients, 5 rated the efficacy of BoNT type B as greater than that of BoNT type A, and chose to continue type B treatment. BoNT type B was generally well tolerated, with pain during injection reported as the most common side effect. BoNT type B is not approved for treatment of blepharospasm. Further studies are needed to establish its efficacy and safety.

Antibody production

A potential consequence of long-term therapy with BoNT is the development of an immune response against the toxin. The literature regarding the frequency of antibodies in patients treated with BoNT contains conflicting reports on this subject. Comparison of studies is difficult owing to variability in methods used to titrate antibodies (Calace et al, 2003), but it does seem that antibodies are more likely with higher doses and regimens where injections are more frequent than every 3 months (Langlois et al, 2003). Since the dose for the treatment of blepharospasm is relatively low, the impact of antibody development on clinical effectiveness of the treatment for this indication is virtually nil (Defazio and Livrea, 2004). It appears that with the new formulation of BOTOX®, antigenic protein content is reduced and antibodies to botulinum toxin are less problematic (Scott, 2004; Langlois et al, 2003).

Recent advances and future directions

Blepharospasm is clearly linked to other dystonias, and many patients with blepharospasm have other involuntary spasms that appear to be dystonias. The contribution of genetic background to the etiology of blepharospasm is an area requiring further investigation, particularly in view of the increasing epidemiological evidence that adult onset focal dystonia is likely the result of an autosomal dominant genetic disorder with markedly reduced penetrance (Defazio and Livrea, 2004; Defazio and Livrea, 2002).

In a recent investigation to clarify the role of abnormalities in dopamine neurotransmission in the generation of dystonic movements, case-control allelic associations were studied in patients with blepharospasm, using polymorphisms in the dopamine receptor and transporter genes as markers (Misbahuddin et al, 2002). Allele 2 of a DRD5 dinucleotide repeat was found to be significantly associated with blepharospasm, suggesting a possible role for this receptor in its pathogenesis.

In addition to increased understanding of the pathophysiology of blepharospasm, other areas for ongoing study include strategies to reduce the risk of antibody production, which can lead to treatment failure, and evaluation of the efficacy and safety of other botulinum toxin serotypes, including type B, which is currently approved for treatment of cervical dystonia.

References and Further Reading

Aramideh M, Bour LJ, Koelman JH, Speelman JD, Ongerbooer de Visser BW. Abnormal eye movements in blepharospasm and involuntary levator palprbrae inhibition. Clinical and pathophysiological considerations. Brain. 1994;117(pt 6)1457-1474.

Aramideh M, Ongerbooer de Visser BW, Brans JW, Koelman JH, Speelman JD. Pretarsal application of botulinum toxin for treatment of blepharospasm. J Neurol Neurosurg Psychiatry. 1995;59:309-311.

Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of botulinum toxin and other cure options. Eur J Neurol. 2004;11:361-370.

Cakmur R, Ozturk V, Uzunel F, Donmez B, Idiman F. Comparison of preseptal and pretarsal injections of botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neurol. 2002;249:64-68.

Colosimo C, Chianese M, Giovannelli M, Contarino MF, Bentivoglio AR. Botulinum toxin type B in blepharospasm and hemifacial spasm . J Neurol Neurosurg Psychiatry. 2003;74:687.

Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type A therapy for blepharospasm. Cochrane Database Syst Rev. 2005;1:CD004900.

Defazio G, Livrea P. Primary blepharospasm: diagnosis and management. Drugs. 2004;64:237-244.

Defazio G, Livrea P. Epidemiology of primary blepharospasm. Mov Disord. 2002;17:7-12.

Fahn S, List T, Moskowitz C, et al. Double-blind controlled study of botulinum toxin for blepharospasm [abstract]. Neurology. 1985;35(suppl 1):271-272.

Forget R, Tozlovanu V, Iancu A, Boghen D. Botulinum toxin improves lid opening delays in blepharospasm-associated apraxia of lid opening. Neurology. 2002;58:1843-1846.

Girlanda P, Quartarone A, Sinicropi S, Nicolosi C, Messina C. Unilateral injection of botulinum toxin in blepharospasm: single fiber electromyography and blink reflex study. Mov Disord. 1996;11:27-31.

Gupta M, Singh G, Khwaja G. Botulinum toxin in the treatment of dystonias – a hospital based study. J Assoc Physicians India. 2003;51:447-453.

Hsiung GY, Das SK, Ranawaya R, Lafontaine AL, Suchowersky O. Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord. 2002;17:1288-1293.

Jankovic J, Fahn S. Dystonic disorders. In: Jankovic J, Tolosa E, eds. Parkinson's Disease and Movement Disorders. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002:331-357.

Jankovic J, Schwartz KS. Longitudinal experience with botulinum toxin injections for treatment of blepharospasm and cervical dystonia. Neurology. 1993;43:834-836.

Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology. 1987;37:616-623.

Langlois M, Richer F, Chouinard S. New perspectives on dystonia. Can J Neurol. 2003;30(suppl 1):S34-S44.

Misbahuddin A, Placzek MR, Chaudhuri KR, Wood NW, Bhatia KP, Warner TT. A polymorphism in the dopamine receptor DRD5 is associated with blepharospasm. Neurology. 2002;58:124-126.

Nussgens Z, Roggenkamper P. Comparison of two botulinum-toxin preparations in the treatment of essential blepharospasm. Graefes Arch Clin Exp Ophthalmol. 1997;235:197-199.

Park YC, Lim JK, Lee DK, Yi SD. Botulinum a toxin treatment of hemifacial spasm and blepharospasm. J Korean Med Sci. 1993;8:334-340.

Rollnik JD, Matzke M, Wohlfarth K, Dengler R, Bigalke H. Low-dose treatment of cervical dystonia, blepharospasm and facial hemispasm with albumin-diluted botulinum toxin type A under EMG guidance. An open label study. Eur Neurol. 2000;43:9-12.

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. 1997;12:1013-1018.

Scott AB. Development of botulinum toxin therapy. Dermatol Clin. 2004;22:131-133.

Snir M, Weinberger D, Bourla D, Kristal-Shalit O, Dotan G, Axer-Siegel R. Quantitative changes in botulinum toxin A treatment over time in patients with essential blepharospasm and idiopathic hemifacial spasm. Am J Ophthalmol. 2003;136:99-105.

Whitaker J, Butler A, Semlyen JK, Barnes MP. Botulinum toxin for people with dystonia treated by an outreach nurse practitioner: a comparative study between a home and a clinic treatment service. Arch Phys Med Rehabil. 2001;82:480-484.

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BLEPHAROSPASM

Botulinum neurotoxins in the management of blepharospasm