 |
Slide 1 |
An Update on the Use of Botulinum Toxin Type A for Strabismus
Rudolph S. Wagner, MD
In the late 1970s, the pharmacologic treatment of strabismus was pioneered by Scott,1,2 who experimented with the direct injection of various neurotoxins into the extraocular muscles. Scott correctly theorized that the temporary paralysis of an extraocular muscle produced by chemodenervation could result in a change in eye alignment. During a 10-year investigational period regulated by the U.S. Food and Drug Administration (FDA), more than 8,000 injections of botulinum toxin type A were administered in patients.1 In 1990, botulinum toxin type A (Botox, Allergan Pharmaceuticals, Irvine, Calif) was granted FDA approval and removed from investigational status. Approved indications for the toxin included the treatment of strabismus in patients age 12 years and older, blepharospasm, cervical dystonia, and primary axillary hyperhidrosis. Subsequently, in 2004, Botox Cosmetic received approval for the treatment of glabellar folds. Based on the accumulated data from more than 200 investigators treating more than 4,000 patients with strabismus and numerous published clinical research reports, the role of chemodenervation in the treatment of strabismus is now more clearly defined.3
Botulinum toxin type A is a large protein molecule (150,000 d) that is bound to the receptor sites on motor nerve terminals within 24 hours of intramuscular injection. The toxin enters and remains at the nerve terminal for several days to weeks and inhibits the release of the neurotransmitter acetylcholine, which functionally denervates the muscle. The toxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine in vesicles located within the nerve endings. When injected in therapeutic doses, botulinum toxin type A remains localized to the injected region, which results in a chemical denervation muscle weakness or paralysis within 3 to 5 days after injection.
Although an irreversible binding occurs when the muscle is chemically denervated, extrajunctional acetylcholine receptors may develop in the atrophied muscle. The nerve, therefore, can reinnervate the muscle with a reversal of the paralysis and eventual recovery. The dose-related extraocular muscle paralysis usually lasts from 2 to 8 weeks. Toxin-induced paralysis lasting for several weeks can result in permanently changed ocular alignment as the injected muscle lengthens and its antagonist contracts. It is now believed the muscles alter alignment of the eyes by adapting their length through the addition and deletion of sarcomeres. The toxin places the eye in a new position, and the muscles are stretched or shortened.3
Botulinum toxin type A is prepared in units for clinical use. The lyophilized drug is supplied in 100-U vials and is reconstituted with nonpreserved saline solution (0.9% sodium chloride injection), resulting in doses from 1 U/0.1 mL to 12 U/0.1 mL. The dose can be increased or decreased to modify the effect. The estimated systemic toxic dose is 40 U/kg body weight. Two nanograms (2×10-9 g), an amount frequently used in treating strabismus, is 1 per 1,000 of the lethal dose (LD 50) of the macaque monkey. No systemic paralytic effect has been observed or suspected in any patient treated with the small doses used for strabismus. Antibodies to the toxin have not been detected in patients given small doses for ocular use. Therefore, repeat injections can be given when necessary.1
|
Botulinum toxin type A is injected transconjunctivally under topical anesthesia in an outpatient setting (Slide 1). Topical vasoconstrictors are administered to help avoid local hemorrhaging at the injection site. An electromyogram (EMG) electrode needle is attached to a 1-mL syringe containing 0.1 mL of toxin. The needle is connected to an audible EMG amplifier.
The needle is passed along the surface of the globe posteriorly and into the belly of the extraocular muscle. The tip of the needle is approximately 2.5 cm into the muscle from its insertion. This approximates the location of the motor end plate, which is the desired injection site for minimal diffusion into adjacent structures. Once the needle is in the muscle, the patient is asked to perform a version to cause the muscle to contract. For example, when the needle is in the medial rectus muscle, the patient is asked to perform a version that will result in adduction of the eye.
A characteristic noise from the amplifier is heard as the muscle contracts and the injection is given. This technique involves minimal discomfort to the patient but necessitates a certain level of cooperation. There is a minimal recovery period (minutes) in most patients, and they can resume normal activities on the day of injection.
|
Treatment of horizontal forms of strabismus with botulinum toxin is the area in which the greatest amount of experience exists.1 It is unfortunate that the study results are derived from a heterogenous group, and it is often difficult to draw specific conclusions from the available data. There is no question botulinum toxin is effective in reducing the angle of strabismus in the acute postinjection period. However, there is also a tendency for recurrence of the strabismus with time, and many patients require more than one injection during the course of their therapy. Selection of appropriate patients greatly influences final results. In the early phases of the FDA investigation, strabismus of many etiologies was treated. As the investigation progressed, specific uses for the toxin became evident (Table 1).
In the FDA study, for patients with follow-up of 6 months or longer after their last injection, horizontal strabismus was reduced an average of 63% (range: 50% to 81%) depending on the type of strabismus.1 Fifty-six percent of adults injected achieved a deviation of 10 prism diopters (PD) or less, with some requiring more than one injection. Overcorrections occurred in fewer than 1% of patients. The results showed 35% of adults with horizontal strabismus were corrected to within 10 PD of orthophoria after one injection.
In a similar mixed group of patients, Biglan and colleagues7 achieved a 38% correction rate after an average of 1.3 injections. Carruthers and colleagues8 reported a 29% correction rate after a single injection in a series of patients with large-angle deviations (average deviation: 35 PD). It should be noted their group of patients did not have fusional potential. Similarly, Biglan and colleagues7 achieved satisfactory alignment in only 50% of their patients with sensory strabismus. The injection can reduce, but usually does not eliminate, larger deviations, and all results were better for smaller angles (<40 PD) of strabismus7 (Table 2).
Esotropia
In 261 patients with esotropia who underwent botulinum injections, a 68% reduction of the deviation was achieved.1 Sixty-eight percent of patients had a final deviation of 10 PD or less after an average follow-up of 27 months (range: 6 to 65 months). One hundred fifteen of these patients required more than one injection to obtain this result.
Biglan and colleagues7 injected 32 patients for the primary treatment of comitant esotropia. Only 11 (34%) patients achieved control after injection. Eleven patients required additional injections to improve alignment. Lingua9 injected 33 patients for esotropia and reported an early recurrence of the strabismus in nine (37.4%) patients. Early recurrence was defined as a return of the original strabismus (at least 15 PD with full ductions) within 3 months of attaining alignment after one to four injections. In 19 patients injected for esotropia, Lingua (unpublished data) achieved an 87% reduction of the strabismus after 8 weeks, but after 2 years, reduction was retained in only 47%.
Exotropia
Results of botulinum treatment for exotropia have not been as good as those for esotropia. Scott reported a 50% reduction of the angle of exotropia in 95 patients after injection, with 49% achieving a final deviation of 10 PD or less. Twenty-nine patients in this group required more than one injection. Biglan and colleagues7 injected 15 patients with botulinum toxin for the primary treatment of intermittent and constant comitant exodeviations. Five (33%) patients required one or more reinjections, and 12 (79%) patients eventually underwent traditional strabismus surgery to achieve satisfactory alignment. Only two (13%) patients achieved control with the injections alone. The mean reduction in the magnitude of the deviation was only 5 PD in their study. Similarly, Lingua9 reported an early recurrence of exotropia in 12 (55%) of 22 patients.
Biglan and colleagues7 found botulinum toxin to be an unsatisfactory primary treatment for constant or intermittent exotropia. Their results did not compare favorably with success rates for traditional surgery in similar patients. Although good results might be anticipated with intermittent exotropia, the data suggest definitive alteration of the muscle-tension relationship with traditional surgery is necessary to treat patients with intermittent exotropia. As with esotropia, large angles tended to return to preinjection position and required repeat injections more frequently than smaller angles.
Although better results have been obtained with injection of the medial rectus muscle for esotropia, the lateral rectus muscle can be injected to treat exotropia. Scott and colleagues10 attributed the increased success with esotropia to the greater concentration of singly innervated fibers in the medial rectus muscle, which are singularly and profoundly affected by botulinum.
Postoperative adjustment using botulinum toxin
Surgical treatment of strabismus may produce overcorrection or undercorrection. In patients with persistent overcorrection and diplopia following lateral rectus recessions for intermittent exotropia, injection of botulinum into the medial rectus muscle should be considered. Biglan and colleagues7 found injection of the medial rectus muscle for consecutive esotropia to be the most valuable application of the drug. Seven of eight patients had a satisfactory lasting response to treatment of their overcorrected deviation with botulinum toxin.
McNeer11 also reported excellent results with botulinum toxin in treating consecutive esodeviations. Esodeviation at distance fixation decreased from a mean of 18 PD to 3 PD, and five of 15 patients became orthophoric. In a group of patients with consecutive exodeviations, deviation decreased from 18 PD to 7 PD after approximately 29 months of follow-up. Six of 12 patients in this group became orthophoric. McNeer frequently used botulinum toxin to treat patients who had had traditional strabismus surgery but had been left undercorrected. Botulinum toxin helped reduce the residual deviation in these patients. In many patients, further surgery was avoided, although some patients required multiple injections. The smaller the initial deviation was, the better the response was to the injection both initially and over time.
Vertical strabismus can be corrected or improved with botulinum toxin injection and, in some cases, particularly those with hypotropia, vertical strabismus can be treated with injection of the inferior rectus muscle.6 Dunn and colleagues12 treated patients with vertical strabismus associated with thyroid ophthalmopathy by injecting the inferior rectus muscle. Eleven patients achieved satisfactory results, although multiple injections were necessary in some cases. However, 16 patients eventually required surgery. It is difficult to selectively inject the superior rectus muscle or the superior oblique muscle. Frequently, when injection of these muscles is attempted, a marked ptosis is produced as the toxin diffuses into the levator muscle. It also is difficult to inject the inferior oblique muscle using current techniques.
Dissociated vertical deviation
McNeer13 treated dissociated vertical deviation in five patients with botulinum toxin injections into the superior rectus muscle. Forty-three months after injection, all patients achieved a reduction ranging from 20 PD to 5 PD. Relatively large doses of 5 U to 10 U were used. Ptosis, with the pupil either partially or totally occluded for almost 6 weeks, occurred in all injected eyes. The amblyogenic potential of the ptosis must be considered in young children when contemplating such treatment.
|
|
One of the best indications for the use of botulinum toxin is treatment of esotropia resulting from a sixth cranial nerve palsy7,14-16 (Table 3). In these cases, the antagonist medial rectus muscle in the eye with the palsy is injected. This can balance the paralysis and straighten the eye to correct primary gaze diplopia and prevent secondary contracture of the medial rectus muscle. Future surgery may be obviated in such cases.
Eustis and Parks17 demonstrated that newly acquired constant strabismus in adults can result in irreversible loss of single binocular vision after 2 to 3 months. Injection during the acute period, even in patients expected to recover lateral rectus muscle function, may help prevent this occurrence (Slide 2). Fawcett and colleagues18 have shown early correction of strabismus in adults following the onset of strabismus (within 12 months) can result in superior sensory status.
|
|
Injecting botulinum toxin into the antagonist medial rectus muscle in cases of lateral rectus muscle palsy and paresis has been effective in relieving secondary contracture. In acute sixth nerve palsies, Scott and Kraft15 were able to prevent secondary contracture of the medial rectus muscle in three of four cases injected within 2 to 8 weeks of onset of the palsy. Metz14,19 was able to avoid surgery in 16 of 20 patients treated for acute lateral rectus palsy. Wagner and Frohman16 treated eight patients with sixth nerve palsies by injecting botulinum toxin into the ipsilateral medial rectus muscle. Five of six patients injected within 12 weeks of onset of the palsy achieved orthophoria; however, one later required a modified Jensen procedure without a recession of the medial rectus muscle. In all studies, the best results occurred in patients who had some recovery of lateral rectus function.
Rosenbaum and colleagues20 used botulinum toxin injection in conjunction with strabismus surgery for lateral rectus palsies in 10 patients. Patients with sixth nerve palsy without recovery of function by at least 8 months were included in the study. Total transposition of the superior rectus muscle and inferior rectus muscle to the insertion of the lateral rectus muscle
|
|
Metz14 injected the lateral rectus muscle with botulinum in patients with acute third nerve palsies. All eight patients had recovery of medial rectus function with fusion horizontally in primary gaze after injection. Vertical rotations did not improve in most cases.
|
Strabismus Following Retinal Detachment Surgery
Botulinum toxin has been used successfully to treat patients with strabismus after retinal detachment surgery. Scott22 achieved fusion in 60% of patients injected. Petitto and Buckley23 injected 20 patients (13 with horizontal and seven with vertical strabismus) and achieved fusion in 85%. This is surprising because many patients will have a restrictive strabismus following scleral buckling procedures. Petitto and Buckley postulated that despite muscle restriction, fibrosis, or weakness, botulinum toxin injections may reduce the deviation enough to allow intermittent fusion. By slowly increasing fusional vergence amplitudes, patients can maintain an acceptable ocular motor alignment.
Botulinum toxin has been injected into all four horizontal rectus muscles in an attempt to decrease or eliminate nystagmus and oscillopsia.24 While this can be of some benefit in the short-term, the effect wears off and transient strabismus may be induced. Helveston and Pogrebniak25 injected botulinum toxin into the retrobulbar space in one eye each in two patients with vertical, horizontal, and rotary components to their nystagmus and oscillopsia. They injected 25 U, which is a large dose, and were able to improve visual acuity by reducing the nystagmus. The effect lasted from 5 to 13 weeks, with no adverse side effects.
Although botulinum toxin currently is approved only for patients older than age 12, many children have been and are being treated under the investigative protocol. Although the majority of the data come from the work of Scott and Magoon, others have contributed.4,7,10
Scott and colleagues10 treated 413 children ranging in age from 2 months to 12 years. Average follow-up was 26 months for the majority of patients. The rate of correction to 10 PD or less was 61% in all cases; the rates for all types of esotropia, infantile esotropia, and exotropia were 66%, 65%, and 45%, respectively. It is noteworthy that the results for exotropia were worse than for esotropia, which is similar to findings in adults. Smaller deviations (10-20 PD) were corrected more frequently (73%) than larger deviations (20-110 PD; 54%). No globe perforation, amblyopia, or visual loss was produced by the injection treatment in this series.
In a study of 72 children injected between the ages of 4 months and 13 years, Magoon5 reported 85% had 10 PD or less of deviation at their last examination.5 Complications included transient ptosis and hyperdeviations that all resolved within 6 months, with most resolving within several weeks of the injection.
Magoon reported a subset of 50 patients younger than age 14 had the same alignment 2 years or longer after injection as the original 85 patients between 6 months and 2 years after treatment. The stability of alignment for this subset was greater than that reported for a similar follow-up of adults after botulinum treatment for horizontal strabismus. Magoon speculated the greater stability may be attributed to binocular fusion in children.
There is a great deal of interest in treating infants with congenital esotropia in the first year of life with injection of the medial rectus muscles.4 These children often adopt a horizontal face turn following paralysis of the muscle with botulinum, which indicates they have fusional potential. Such treatment has been associated with long-term stability of alignment in some cases. The reported 65% rate of correction to 10 PD or less in congenital esotropia falls short of the successful 84% surgical rate reported by both Kushner and Morton26 and Helveston and colleagues.27 Biglan and colleagues1 treated 12 patients with congenital esotropia and found 66% returned to an unacceptable deviation and required strabismus surgery. They believe the requirement for frequent reinjection and the prolonged period of misalignment after injection may interfere with the goal of achieving early alignment and binocular vision. Scott and colleagues10 suggest that with further refinement (eg, bilateral injection, use of antitoxin to prevent effects on the antagonist or adjacent muscles, and treatment of younger children age 2 to 4 months), injection results may be improved further for infantile esotropia.
Botulinum toxin is a relatively safe drug. No systemic paralytic effect has been observed or suspected in any patient treated with the doses used for strabismus. Antibodies to the drug have been detected in a few patients who received large experimental doses for spasmodic torticollis but not in patients injected for strabismus. This accounts for the continued effect in patients injected more than once.1
|
|
Scleral perforation occurred in nine (0.11%) of 8,300 injections.3 This tended to occur in large myopic eyes. If there is doubt about needle position, the retina should be examined after withdrawal of the needle. Retrobulbar hemorrhage occurred in 16 (0.2%) cases and resolved without residual effect. Local subconjunctival hemorrhage occurred frequently but was not a problem.
Patients with binocularity frequently experience diplopia, past pointing, and spatial disorientation following injection. It is important to understand patients with the best results following injection often have an initial overcorrection of the strabismus. Patients therefore should be warned that diplopia may accompany this temporary overcorrection and may last for several weeks.
Although not considered a complication, patients also should be informed that the effect of the toxin may not be permanent and they may require additional injections or strabismus surgery. Patients with restrictive strabismus and those with a large recession of the antagonist or ineffective antagonist, such as in Duane retraction syndrome, are poor candidates for botulinum treatments. Patients with myasthenia gravis treated with botulinum toxin may have a prolonged and powerful effect because their acetylcholine receptors also are blocked. This "dual" effect and its resulting paralysis can be remarkable in some patients.
The treatment of strabismus with botulinum toxin type A is an acceptable approach in selected patients. Botulinum injection was never intended to replace traditional strabismus surgery but rather to provide an alternative mode of therapy. When used properly, the toxin can augment traditional surgical results and, in some patients, even substitute for or eliminate the need for strabismus surgery.
