STRABISMUS

Botulinum Neurotoxins in the Management of Strabismus

Advisory Editor
A. B. Scott, MD
Smith-Kettlewell Eye Research Institute
San Francisco, California

Introduction

Strabismus, or misalignment of the eyes, affects approximately 3% to 4% of the adult population in the United States (Ticho, 2003; Beauchamp et al, 2003). The condition is also one of the most common causes of pediatric referrals to ophthalmologists, affecting 2% to 5% of the preschool-age population (Chatzistefanou and Mills, 2000; Ticho, 2003). Strabismus is characterized by a constant or intermittent ocular deviation that is often associated with amblyopia, reduced or absent binocular vision, or other sight-threatening diseases and can present as either exotropia (an eye turned outward) or esotropia (an eye turned inward, or crossed eyes) (Ticho, 2003; Charles, 2004; Michaelides and Moore, 2004). Approximately half of adults with strabismus had onset during infancy or childhood and were either not treated or treated unsuccessfully (Beauchamp et al, 2003). Adult-onset strabismus may result from paralytic conditions (fourth or sixth cranial nerve palsies), orbital trauma, thyroid ophthalmopathy, or other orbital or neurologic diseases, or it may be secondary to ophthalmic procedures (Beauchamp et al, 2003; Mills et al, 2004).

Despite the misconception that adult strabismus is "merely cosmetic" and is difficult to treat, good treatment outcomes, with significant improvement of central and peripheral binocular vision, have been reported (Beauchamp et al, 2003). Moreover, there is growing awareness of the social prejudices and socioeconomic problems faced by adults with strabismus; a recent report suggested that women with strabismus were significantly less likely to be hired by prospective employers than those without (Coats et al, 2000). Thus, in addition to anatomical benefits, ocular realignment may have a positive impact on the patient's self-esteem and quality of life.

Current treatment approaches

Childhood strabismus is frequently associated with amblyopia and lack of binocular fusion. Surgery is typically recommended to restore normal eye alignment and facilitate development of binocularity. In adults, normal binocularity may have been present before the onset of strabismus. Adults may have symptoms that include diplopia, visual confusion, and abnormal head posture or abnormal facial appearance owing to eye misalignment (Mills et al, 2004). Potential benefits of surgical treatment in adults include improved diplopia, improved binocularity, and improved head position, as well as improved self-esteem and ability to communicate with others.

Surgical treatment of strabismus is usually performed in an outpatient setting under general or local anesthesia. Because of differences in binocularity and sensory adaptation to abnormal ocular alignment, surgical complications may differ in adults and children. Postoperative diplopia is most likely to occur in visually mature patients (Mills et al, 2004).

Pharmacological means for treating strabismus include topical autonomic agents (eg, atropine, miotics) to manipulate the refractive status of the eye and thereby affect alignment, focus, and amblyopia; centrally acting agents such as levodopa and citicholine, which affect the central visual system abnormalities in amblyopia; and botulinum neurotoxin (BoNT) (Chatzistefanou and Mills, 2000).

Botulinum neurotoxin in the treatment of strabismus

The use of BoNT in humans was pioneered by the ophthalmologist Alan Scott in 1979 (Scott, 1981). Initial animal experiments showed that injection of BoNT into the horizontal rectus muscles of rhesus monkeys produced ocular realignment. Subsequent human experiments showed that injection of BoNT into the extraocular muscles of 42 strabismus patients had a uniformly beneficial effect that lasted up to 411 days without systemic effect or local complications (Scott, 1981). The angle of deviation in strabismus is measured in prism diopters, whereby 1 prism diopter denotes the prism strength that will bend a light ray 1 centimeter at a 1-meter distance from the prism; horizontal deviations greater than 10 diopters are considered clinically significant (Ticho, 2003). An open-label clinical trial demonstrated that BoNT type A (BoNT-A) injections in 677 patients with strabismus resulted in improvement in 55% of patients to an alignment of 10 prism diopters or less when evaluated at 6 months or more after injection (BOTOX® package insert). In 1989, the Food and Drug Administration (FDA) approved the first BoNT-based product for the treatment of strabismus. Since that time, in further studies, BoNT-A reduced ocular deviation in >50% of patients, and positive responses to BoNT-A injections were reported in the treatment of patients with strabismus secondary to central neurologic damage, myasthenia, trauma, brain infection, psychomotor deficiency, prematurity, hematologic diseases, and endocrinopathies (Moguel-Ancheita et al, 2003; Carruthers and Carruthers, 2004). The successful use of BoNT-A to correct strabismus paved the way for its therapeutic application in the treatment of a number of disorders, including hyperhidrosis, cervical dystonia, and blepharospasm (BOTOX® package insert).

The effectiveness of BoNT-A in strabismus depends on accurate injection near the motor endplate of the appropriate rectus muscle (Denniston and Reuser, 2001). Application of the toxin to the eye muscles is performed under electromyographic guidance of a monopolar needle electrode containing a channel for the toxin. Following application of a topical anesthesia to the conjunctiva, preferably with the addition of a vasoconstrictor, the needle is inserted through the conjunctiva and into the target muscle until it is in the area of the neuromuscular junction (as recognized by maximum electrical activity on the oscilloscope or noise from the connected loudspeaker). Muscle paralysis develops within 3 to 5 days of toxin injection (Huber, 2002).

BoNT-A has been used successfully to treat a number of types of paralytic strabismus, including sixth nerve palsy, trochlear nerve palsy, third nerve palsy, early-stage endocrine ophthalmopathy, and combined oculomotor palsies (Huber, 2002). BoNT chemodenervation of the eye muscles is also used diagnostically to simulate eye muscle weakening in preparation for subsequent surgery and to provide information about possible resulting diplopia (Huber, 2002; Marsh, 2003). The toxin can also be used to treat concomitant strabismus, characterized by deviation of the eye axes without any signs of paralysis. BoNT can also be used as an adjunct to strabismus surgery as a means of fine-tuning small operative horizontal misalignments (Denniston and Reuser, 2001). The small dose required for treatment of strabismus (less than 1% of the estimated median lethal dose) has precluded systemic side effects, although local effects such as ptosis are commonly reported. Doses higher than 10 U have been reported to increase the risk of ptosis and vertical deviation (Sener and Sanac, 2000).

Childhood strabismus

Strabismus is one of the most common causes of pediatric referrals to ophthalmologists, and it has been suggested that routine screening for strabismus should be part of all routine well-child examinations (Ticho, 2003). The most common types of childhood strabismus include infantile esotropia, accommodative esotropia, intermittent exotropia, sensory exotropia, cranial nerve palsies, and traumatic strabismus. Comitant strabismus refers to conditions that occur in the absence of identifiable neurologic, mechanical, sensory, or neurotransmitter deficits and includes infantile esotropia, acquired esotropia, infantile exotropia, and intermittent exotropia (Ticho, 2003). These conditions are characterized by an angle of deviation (magnitude of ocular misalignment) that remains the same in all directions of gaze, no matter which eye is fixing on something (Michaelides and Moore, 2004). The precise causes of these conditions remain unknown but are believed to involve primary anomalies of motor innervation to the extraocular muscles and primary anomalies of binocular vision and fusion (Ticho, 2003). Paralytic (incomitant) strabismus is characterized by a degree of ocular misalignment that varies depending on direction of gaze or which eye is fixing on an object (Michaelides and Moore, 2004). It presents when the cranial nerves involved in ocular movement (oculomotor, trochlear, and abducens) are affected by congenital, infectious, traumatic, ischemic, or compressive processes (Ticho, 2003). Recent molecular genetics studies have identified mitochondrial DNA mutations underlying chronic progressive external ophthalmoplegia, a form of incomitant strabismus, and mitochondrial DNA deletions and mutations associated with other forms of incomitant strabismus. Less is known about the pathogenesis of comitant strabismus, but it is believed to involve environmental as well as genetic factors (Michaelides and Moore, 2004).

Treatment options for pediatric strabismus include glasses, eye exercises, and, rarely, occlusion therapy (a mainstay of treatment for strabismic amblyopia, however). Strabismus surgery is usually reserved for those children in whom nonsurgical methods are likely to be unsuccessful; it consists of loosening and tightening procedures (Ticho, 2003).

Use of botulinum toxin in pediatric strabismus

BoNT-A has been used to treat childhood esotropia, although use in the pediatric population is not approved by the FDA (Charles, 2004). Several investigators have recommended injection of BoNT into the medial rectus as an alternative to incisional surgery for children with infantile esotropia. This condition is a common form of strabismus and is defined as a manifest esodeviation in a neurologically normal infant with onset between birth and 6 months (Chatzistefanou and Mills, 2000). A number of studies conducted from 1994 to 2002 showed a high correction rate (60% to 80%) with multiple injections of BoNT for the treatment of infantile esotropia (Scott, 2002; Tengtrisorn et al, 2002). In general, the recommended treatment program comprises simultaneous bimedial injection of 2.5 U of toxin per muscle, injected as early as 3 months of age, and repeat simultaneous injections with recurrence of esotropia exceeding 15 prism diopters, increasing the dose to 3 U per eye unless ptosis is a limiting side effect. Transient partial ptosis occurs in about 25% of children after BoNT injection because of proximity to the levator muscle and typically lasts 2 to 4 weeks (Scott, 2002). The long-term effectiveness of treatment with BoNT injection was demonstrated in a prospective study of 68 children with acquired esotropia (Tejedor and Rodriquez, 2001). At an average 4.8-year follow-up after the last injection, motor success (defined as a distance deviation of no more than 8 prism diopters) was obtained in 53%, 71%, and 88% of children who received one, two, and three injections, respectively. The role of BoNT therapy in other childhood strabismic indications (exotropia, sixth nerve palsy, cerebral palsy) has not been thoroughly evaluated and will require further investigation.

Summary

Since the approval of BoNT-A for the treatment of strabismus by the FDA in 1989, the list of indications for which it is approved has grown to include cervical dystonia, hyperhidrosis, and blepharospasm. The therapeutic use of BoNT has been explored in a number of other disorders as well, including other hypersecretory conditions (eg, hyperlacrimation, nasal hypersecretion) and movement disorders, including tremor and tics. BoNT is also under investigation as treatment for pain caused by headache, backache, and whiplash injury, as well as myofascial pain. Other applications for which the use of BoNT is being investigated include gastroenterological and urological disorders such as achalasia, chronic anal fissure, and detrusor sphincter dyssynergia. Perhaps the most rapidly growing field of use for BoNT is cosmetic surgery.

Although further controlled trials are needed in many of these areas, the safety and efficacy of BoNT-A for the treatment of strabismus is well established. Although results with BoNT-A in children with strabismus look promising, it is not yet approved for use in this age group and additional clinical studies are needed.

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