Pharmacologic treatment of strabismus

Pharmacologic treatment of the deviation

Botulinum toxin A

Scott introduced pharmacologic treatment in the management of eye deviations.¹ Initially, he presented his results of botulinum injection for the treatment of strabismus,²^–⁴ later those for the treatment of blepharospasm.⁵ The safety and effectiveness of this treatment was subsequently documented.⁶ In 1989, Botox was approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old.

The drug is effective not only in strabismus, but also in several other specialties: neurology, urology, cosmetics, and orthopedics. Botulinum toxin now has specific indications in the treatment of strabismus. In our experience, the best indication is in recent sixth nerve paralysis, in order to avoid medial rectus contracture. This treatment is definitively part of the present management of strabismus.

Crotoxin

In the last few years, colleagues in Brazil have tested crotoxin, the major toxin of the venom of the South American rattlesnake. It causes a blockade of the neurotransmitters at the neuromuscular junction, just like botulinum toxin. It has been tested in ocular motor muscles of animals,⁷ and human beings. In the treatment of strabismus and blepharospasm, it provides similar results to botulinum toxin.⁸ No patient has shown any systemic effect due to crotoxin injection. The data suggest that crotoxin may be a useful and less expensive new option for the treatment of strabismus and blepharospasm, as well as in other medical areas.

It will be good if, in the future, someone discovers a drug with this effect which can be administered by mouth or intramuscular injection, in order to avoid the unpleasant “injections in the eye.”

Bupivacaine

Bupivacaine injection of muscle in animals produces immediate and massive degeneration of muscle fibers with dissolution of myofibrils at the Z-band.^9,¹⁰ Other structures around them are unchanged, including the satellite cells, which form the muscle fibers.¹¹ Inflammatory cells and macrophages remove the degenerated muscle fibers in a few days.^10,¹¹ Two days after injection, satellite cells are activated and regeneration begins with the muscle reaching preinjection size and strength; continued growth is seen for about 180 days,^12,¹³ with the final muscle size exceeding the initial size. Goldchmit et al. suggested that strabismus after cataract surgery with retrobulbar anesthesia results from muscle hypertrophy induced by bupivacaine.¹⁴ Fibrosis and scarring, the current suggested causes for such strabismus, has not been documented by biopsy, or found in animal studies.

Based on this observation, Scott et al. employed bupivacaine for correcting strabismus, thus enhancing the force of a weak muscle ¹⁵ or of the muscle opposite to the deviation in comitant strabismus,¹⁶ the inverse effect of the botulinum toxin. They injected 1.0 to 4.5 mL of bupivacaine into the lateral rectus muscles of six patients with esotropia.¹⁶ The drug improved alignment in four of the six patients. They observed a positive correlation between the improved eye alignment and the increase in muscle size. Clinical and laboratory studies are underway to determine optimal dosages and its effects in other strabismus conditions.

Scott et al. have injected botulinum toxin into the antagonist muscle of that which was injected with bupivacaine.¹⁷ They treated seven patients with comitant horizontal strabismus; the treatment corrected an average of 19.7Δ, about twice the correction reported from bupivacaine alone. The muscle injected with bupivacaine increased its size by 5.8%. This approach may be a useful option in the treatment of strabismus.

Pharmacologic treatment of amblyopia

For more than a century, the treatment of amblyopia has been limited to occlusion of the dominant eye, except for a short usage of pleoptics and the restricted, but growing, use of penalization. Because occlusion treatment is not always effective and depends on several factors, including age of onset of the treatment, etiology of the amblyopia (anisometropia, strabismus, or deprivation), its “deepness”, and the presence of eccentric fixation, a pharmacologic treatment has been sought.

Levodopa is a precursor of the catecholamines, dopamine and noradrenalin, both neurotransmitters. Levodopa is used in the treatment of Parkinson’s disease to compensate for reduced dopamine in the brain. Dopamine cannot cross the blood–brain barrier: levodopa is used because it can. It is then transformed to dopamine in the brain. Carbidopa, a peripheral inhibitor of decarboxylase, reduces the systemic side effects of levodopa and increases its availability in the brain.

Some studies suggest the possibility that dopamine is effective in the treatment of amblyopia.¹⁸^–²² The reduction of the size of the scotoma as documented by Gottlob and Stangler-Zuschott¹⁸ is thought-provoking. The theory is that levodopa enhances the plasticity of the visual cortex and hence supplements occlusion therapy in children who are older than the sensitive period.

In Brazil, Procianoy et al. studied four groups of patients with strabismic amblyopia, aged 7 to 17 years, who had already been treated without improvement with occlusion or penalization. Treatment failure was attributed to patient age or poor compliance.²² In children less than 40 kg they gave levodopa/carbidopa (4 : 1) in doses of 5 mg (group I), 10 mg (group II), and 20 mg (group III) or a placebo, three times a day after meals. For patients who weighed 40 kg or more, they gave 10, 20, or 40 mg or placebo. Patients were randomly allocated to these treatment groups or the placebo group after stratification by body weight. All patients had the dominant eye occluded for 3 hours per day. At the end of 7 days, visual acuity improved at least 1 line of Snellen chart in 31.3% of the patients from the placebo group, in 60% of group I, in 40% of group II, and 68% of group III (Pearson’s χ² statistic: P = 0.082).

Bhartiya et al.²³ studied 40 amblyopic children (19 with strabismus with or without anisometropia of less than 3 D and 21 with only anisometropia), 6 to 18 years old (mean age 10.9). Each subject received either levodopa/carbidopa (4 : 1 ratio) or placebo, three times a day after meals over a 4-week period, combined with “full-time” occlusion. Occlusion was continued for the study duration of 3 months (last 2 months without medication). Two strengths of levodopa/carbidopa were used: single strength, 10 mg/2.5 mg of levodopa/carbidopa and double strength, 20 mg/5 mg of levodopa/carbidopa. Children less than 20 kg were given 30 mg of levodopa per day; those whose weight was 21 to 30 kg were given 50 mg of levodopa per day and those whose weight was more than 30 kg were given 60 mg of levodopa per day. The average dose was 1.86 mg/kg/day. The results suggested that levodopa/carbidopa supplementation (in an average dose of 1.8 mg/kg/day) as an adjunct to conventional occlusion in treating amblyopia has no additional benefit over occlusion therapy alone. They did not find any differences in response between strabismic and anisometropic amblyopes. They did demonstrate, however, changes in contrast sensitivity in the occluded eye suggesting that levodopa/carbidopa has some role in modifying the plasticity of the visual system.

These studies show that there is no unanimity as to the utility of levodopa combined with occlusion in the therapy of amblyopia. We hope that in the future a more clearly efficacious pharmacologic treatment for amblyopia will be found. This goal seems extremely difficult when we look at the extent of cortical pathology in amblyopia, but further studies are warranted.

It is possible that any efficacious treatment of strabismic amblyopia will be developed in parallel with a cure of anomalous retinal correspondence (ARC) and achievement of normal fusion. This is another problem related to strabismus that is waiting for cure or prevention. Is ARC always congenital? Can it be acquired?

Some reports have suggested that acupuncture is effective in the treatment of anisometropic amblyopia in children 7 to 12 years old.^24,²⁵ Acupuncture provides an afferent signal to the brain, which may influence certain aspects of neurotransmitter chemistry (including dopamine and acetylcholine) within the central nervous system.²⁶ Its cost-effectiveness has not been proven²⁷ but it is one more piece of evidence suggesting the possibility of extending the sensitive period of the developing visual system.

Surgical treatment of strabismus

Strabismus surgery

Strabismus surgery has not evolved much recently. One development is noteworthy. This improvement occurred when strabismologists started to pay more attention to passive forces that oppose active forces (elasticity, tonus or stiffness of antagonist muscle, fascias, orbital fat, conjunctiva, optic nerve, and adherences). For a thorough examination of the passive forces it is necessary to eliminate the active forces. This has led to the concept that the surgical plan must be confirmed or modified in the surgical room. Passive ductions and the “spring-back balance test” must be done at each stage of the operation. These tests allow the surgeon to recognize and compensate for restrictions of globe movement.

A good example is Hummelsheim’s muscle transposition for sixth nerve paralysis. At the end of surgery, the passive forces must be balanced to place the eye in slight abduction because when the patient wakes, the restored tonus of the medial rectus brings the eye toward adduction. In contrast, when correcting a large angle exotropia with amblyopia, the eye position at the end of surgery must be in primary position for it will tend to remain there.²⁸

Adjustable sutures have improved the prognosis of some types of surgery, but some unpredictability in the strabismus surgery persists. The immediate surgical prognosis depends on the surgeon’s skill in planning and executing the surgery. We hope that in the future we will develop more exact surgical planning based on more informative semiology or new surgical techniques.

The long-term surgical result is a very complicated issue, depending on the long-term reaction of a muscle to surgery, the influence of vision on eye position, the evolution of the AC/A relation, and refraction.

Chemical or biologic adhesives

An option for strabismus surgery may be the substitution of adhesives for sutures, reducing the time of surgery and inflammatory reaction and avoiding the possibility of perforating the sclera. Adhesives, once in contact with tissue, polymerize and fix the tissues together. Improvements in their quality have reduced tissue reactions to them. Available and widely utilized in ophthalmology and in other medical specialties, there are various available adhesives and others are being developed. They are grouped according to their chemical characteristics:

1. Fibrin sealants.

2. Compounds of albumin.

3. Compounds of gelatin–resorcinol–formaldehyde–glutaraldehyde.

4. Cyanoacrylate.

5. Hydrogels.

6. Compounds of collagen.

In ophthalmology, the most common are cyanoacrylate (chemical) and fibrin (biologic) adhesives. Cyanoacrylates have been used in experiments with extraocular muscles in rabbits ²⁹ and in strabismic human beings.^30,³¹

Fibrin, composed of fibrinogen and thrombin, was first used to close corneal wounds in rabbits.³² It has been used in various experimental and ophthalmologic procedures^33,³⁴ and in strabismus surgery.³⁵

Corrêa and Bicas ³⁴ compared the efficacy of sutures of poliglatin-910, cyanoacrylate, fibrin, albumin and glutaraldehyde, and gelatin–resorcinol–formaldehyde–glutaraldehyde. In rabbits, they disinserted the superior rectus and reinserted it with Vicryl® or one of the biologic adhesives. They analyzed:

a. Time of operation.

b. The force required to rupture the muscle–scleral junctions 10 minutes after reinsertion.

c. Postoperative edema, hyperemia, and secretion.

d. Histologic alterations: inflammation, necrosis, granuloma, and fibrosis.

Surgery time was shorter with the biologic adhesives. In resisting rupture of the muscle–scleral junctions, the sutures were best, followed by the adhesive of fibrin and then cyanoacrylate (65%). All the others were deemed not acceptable. On histopathologic examination the fibrin adhesive was best, followed by sutures and then cyanoacrylate. It should be noted that the polymerized product of cyanoacrylate is solid and not absorbable. It may act as an extraneous body that can be extruded. It appears that the fibrin adhesive is the best biologic adhesive for extraocular muscle surgery. However, Moreira et al.³² reported technical difficulties with its preparation and application. In eyes where the superior rectus was reinserted with the adhesive, limitation of elevation was seen. Perhaps this was due to adherence of the muscles belly to sclera, thus shortening the arc of contact. Another disadvantage is that it is very expensive.

We hope that the technical problems and high price will be solved because of the advantages of biologic adhesives.