The clinical effectiveness of botulinum A toxin is related to the completeness and duration of the paralysis of the injected muscle and to the condition that is treated (i.e., nonparalytic versus paralytic strabismus). Prior to the use of botulinum A toxin it had been observed that patients who recovered from sixth-nerve palsies often had a residual esotropia even though lateral rectus muscle function had apparently returned to normal. In such cases, the longer the paralysis persisted the more likely it was that a permanent deviation would occur. This change in ocular alignment was thought to be secondary to a mild residual weakness of the involved muscle (i.e., lateral rectus) plus contracture of its antagonist muscle (i.e., medial rectus). A similar mechanism is postulated to be responsible for the effects seen after botulinum A toxin injection, that is, weakness of the injected muscle plus contraction of its antagonist.

Once injected into the extraocular muscle botulinum A toxin binds rapidly to the nerve terminals, thereby limiting exposure to the systemic circulation. Until recently, antibodies could not be detected in humans exposed to therapeutic botulinum A toxin injections. However, an in vivo mouse neutralization assay has been developed that can detect serum antibodies to botulinum A toxin.⁸ Although not yet documented in patients treated for strabismus, clinical resistance to the effects of subsequent injections of botulinum A toxin has been correlated with the presence of antibodies to botulinum A toxin detected by this bioassay.⁹

The commercial preparation of botulinum A toxin (Oculinum) is distributed by Allergan Pharmaceuticals, Inc. (Irvine, CA) in a frozen, lyophilized form that is very stable. Once reconstituted into a solution, it must be used within hours because its effectiveness deteriorates rapidly. Care must be used in handling the reconstituted toxin because of its susceptibility to damage from preservatives, fluctuations in pH, heat, vigorous shaking, and rapid injection.¹⁰ The standard unit for measuring the potency of botulinum A toxin is derived from a mouse assay.¹¹ One unit of botulinum A toxin is the lethal dose for 50% of a group of 18- to 20-g female Swiss-Webster mice. The median lethal dose (LD₅₀) for humans is estimated at approximately 40 U/kg.¹ The toxin available in the United Kingdom (Dysport, Ipsen Limited, Slough, Berkshire, UK) is much more potent; 1 ng of British toxin contains 40 mouse units, whereas 1 ng of American toxin contains 2.5 mouse units.¹² This may explain the higher incidence of side effects with the more potent British toxin. The doses used in strabismus applications are roughly proportional to the mass of the muscle being injected and are less than 1/100 of the estimated human LD₅₀.¹³

TABLE 1. Strabismus Categories Treatable with Botulinum A Toxin

Botulinum A toxin can also be a useful alternative in those patients in whom general or local anesthesia is contraindicated. Those individuals with a history of malignant hyperthermia, chronic obstructive pulmonary disease, or significant cardiac abnormalities can often be treated successfully with botulinum A toxin avoiding anesthesia and its potential hazards in these high-risk patients.

Anatomic considerations must also be considered in selecting patients for botulinum A toxin injection. Those patients with an abnormal orbital anatomy caused by posttraumatic (e.g., blowout fractures) or congenital conditions (e.g., Crouzon's disease), must be approached with caution because the extraocular muscles are often in abnormal positions. The presence of other orbital abnormalities such as tumors, vascular malformations, or bony defects may make botulinum A toxin injection difficult, thereby increasing the risk of significant complications after injection.

Until the ophthalmologist is familiar and experienced with the injection procedure, consideration should be given to treating only the horizontal rectus muscles. The vertical rectus muscles, because they have opposite functions from the nearby oblique muscles, require a higher level of expertise to avoid unwanted complications. Likewise, experience should be gained on adults before attempting injections in children.

When inhalation anesthesia with nitrous oxide or halothane is used, the EMG recording is diminished or extinguished. Placement of the drug in the muscle belly can be done under direct visualization or during the waking-up process. If this is attempted, careful attention to eye position and anatomy are important. Usually the medication is delivered approximately 2.5 cm posteriorly in the muscle. Without the use of EMG, a more anterior injection may minimize adjacent muscle involvement. If EMG guidance is desired, an alternative approach requires waiting until the child is coming out of light stage (stage 2–3) anesthesia. At the point when extraocular movements are seen, the electrode is inserted rapidly in an attempt to locate the muscle before the patient becomes completely awake. This requires considerable skill and is somewhat cumbersome if mask anesthesia is used. In infants under 12 months of age injections can be performed using topical anesthesia and restraint. A hungry infant can sometimes be fed a bottle and remain quiet and comfortable throughout the entire procedure.¹⁷

LOCATION

The patient should be made comfortable in the supine position (Fig. 3). Although this can be performed in an office chair, a flat examination table or similar setup is advisable both for patient comfort and stability of the head during the procedure. The room should be as free as possible from electrical signals that can interfere with the audio EMG recording device. Certain fluorescent fixtures and overhead wiring produce signals that can be picked up by the recorder, thereby interfering with assessment during the injection process. Loud background noise often occurs when the EMG device is turned on prior to inserting the needle into the conjunctiva. However, as soon as the needle touches the conjunctiva, this noise is greatly diminished. If this does not occur, then accurate localization of the muscle will be difficult. In this situation, reducing the illumination or turning off nonessential lights can be helpful.

PREINJECTION PREPARATION

The dosage to be administers should be calculated (Table 2). Nonpreserved saline 0.9% is used to mix the Oculinum so that the desired number of units to be given are in a volume of 0.1 mL or less. Two milliliters of the reconstituted fluid is drawn into a tuberculin syringe; the monopolar electrode needle should not be used for this process. The 27-gauge, 1½-inch, Teflon-coated, monopolar electrode needle is then attached to the end of the tuberculin syringe. The total volume in the tuberculin syringe is reduced to to one-tenth of a milliliter by injecting the excess drug through the needle end. Because of the size of the needle and the small volume used, the needle barrel must be loaded with the drug to avoid undermedicating the patient. The location of the attachment of the wire onto the needle hub can be used as a reference point to determine the position of the needle bevel.

TABLE 2. Botulinum Toxin Dosage for Horizontal and Vertical Rectus Muscles (in units)

A pediatric electrocardiographic electrode is then attached to the patient's forehead, making sure that a good contact is present (see Fig. 3). It should be placed medially for the medial rectus and laterally for the lateral rectus. If not already done, the patient should be informed that an audio signal will be used during the procedure so that he or she will not become startled when the amplifier is turned on. Next, turn on the amplifier and test the connections by touching the needle tip to the conjunctiva. Any background noise should become extinguished and an audible click should be heard. If this does not happen, the ground connection to the needle hub should be checked and possible interference from overhead lights, etc., investigated. This is also the time to make sure that adequate topical anesthesia has been achieved.

INJECTION TECHNIQUE

Before beginning, it should be explained to the patient that he or she will have to move the eyes into various gaze positions during the procedure. Therefore, it is important that the patient keep both eyes open and fixed on some target. It is helpful to have an assistant during the injection procedure. Standing at the head of the patient, the lids are held open with the fingers. The patient should look away from the field of action of the injected muscle, for example, when injecting the medial rectus have the patient begin by looking laterally with that eye (Fig. 4). The assistant can use a hand or other fixation target for this purpose. The patient should be reminded to keep both eyes open so that fixation is maintained.

With the bevel facing the muscle, the needle is inserted through the conjunctiva 8 to 10 mm from the limbus. Once through the conjunctiva, the needle is advanced several more millimeters until the tip is beyond the equator. The assistant should move the fixation target slowly to the primary position so that the injection-muscle EMG signal can be activated. If the medial rectus is being injected, continue to advance the needle straight posteriorly aiming for the optic canal (Fig. 5). When injecting the lateral rectus the syringe has to be angled toward the ear at approximately a 45-degree angle to avoid touching the periosteum of the lateral orbital wall with the needle point, which is quite uncomfortable (see Fig. 5). A slight angle is also necessary when injecting the superior rectus. The inferior rectus is often easier to inject through the lower lid rather than the conjunctiva. As the needle is advanced and while listening to the EMG signal, continue to advance until a loud crackling noise occurs. If uncertainty exists as to whether this is from the appropriate muscle, have the patient slowly look out of the field of action of the muscle to be injected. The signal should decrease. Care must be taken to ensure that slow eye movements are made. This may be somewhat difficult because the patient may be anxious or apprehensive and may experience some discomfort. When the electrode is at the appropriate location, the reconstituted toxin is injected slowly. The EMG signal should diminish at this point as the tissue is pushed away from the tip by the entering fluid. Allow the needle to remain in this position for 10 to 15 seconds and then slowly withdraw the needle. The patient should be checked for signs of hemorrhage or other potential complications.

POSTINJECTION MANAGEMENT

Once finished, the patient should be asked to sit up on the edge of the examination table but should not be allowed to stand until postinjection anxiety and bradycardia have subsided. Often the patient is so relieved that the process is over that an episode of lightheadedness or even syncope can occur. One to two minutes is usually all that is necessary at this time. It is not necessary to patch the eye or use antibiotics unless there is some concern about the injection process. The patient should be informed that topical anesthesia has been applied to the eye and ocular manipulation for the next 30 to 45 minutes should be discouraged. The patient should be observed for 5 to 10 minutes to make sure that no retrobulbar bleeding has occurred. Acetaminophen should suffice for any postinjection discomfort.

HORIZONTAL STRABISMUS

As a group, patients with horizontal strabismus as respond well to treatment with botulinum A toxin injection (Fig. 6).^18–24 The results of several large studies are summarized in Table 3. As a general rule botulinum A toxin injections reduce a deviation by approximately 65%, and a little over half of patients have their deviation reduced to less than 10 △. The larger the deviation the greater the prism diopter change, but the less likely that the total deviation will be reduced to 10△ or less. Overcorrections are rare and have occurred in fewer than 1% of patients. A single injection can be expected to reduce a deviation to less than 10△ in approximately 30% to 35% of patients.²⁰ Most patients, however, need more than one injection with the average number of injections varying anywhere from 1.3 to 2, depending on the type of strabismus and the size of the original deviation.^19,20,23 After the toxin effect has disappeared, the stability of the postinjection deviation appears to be comparable to that achieved with surgery and is enhanced if there is potential to establish or regain fusion.

TABLE 3. The Effect of Botulinum A Toxin Injection on Horizontal Strabismus

VERTICAL STRABISMUS

There is little information in the literature about the results from injections into vertical rectus or oblique muscles. The superior rectus is rarely treated because ptosis occurs in almost every patient. Similarly, inferior and superior oblique injections are rarely attempted because of the high incidence of undesirable associated effects on the adjacent muscles. The inferior rectus is the only muscle routinely injected for vertical deviations. Many of these patients are status postretinal detachment surgery or have thyroid myopathy and are discussed later in the chapter. In uncomplicated vertical deviations, injection into the inferior rectus tends to result in the same amount of correction as seen in horizontal deviations. In a recent series of 20 patients with a vertical hypotropia the average preinjection deviation was 30 △. Botulinum A toxin reduced the deviation to an average of 17△ resulting in a 41% reduction. These patients received on the average of 1.7 injections and were followed for at least 6 months. Forty percent of these patients were able to regain fusion postinjection (E.G. Buckley, unpublished data).

SIXTH-NERVE PALSY

The effectiveness of botulinum A toxin to correct an esotropia caused by sixth-nerve palsy is determined by the amount of residual function of the lateral rectus muscle, the amount of medial rectus muscle contracture, and the duration of the palsy prior to injection. During the acute phase, botulinum A toxin can be injected into the medial rectus to prevent permanent contracture and restore binocularity (Fig. 7). Because the time to recovery after botulinum A toxin injections and sixth-nerve palsies are approximately the same, reinjection is usually not necessary and up to 75% of patients have complete recovery of their ocular motility^25–29 Botulinum A toxin can also be used as an adjunct to transposition surgery in patients with a complete lateral rectus palsy.^30–32 In these patients, botulinum A toxin is injected into the medial rectus either prior to or during the surgical procedure (Fig. 8). In this role it functions as a chemical traction suture. It allows the transposition procedure to achieve its maximum lateral position and enables the tissue to heal before it is subjected to the pulling forces of the medial rectus (Fig. 9). It also reduces the chances of anterior segment ischemia by limiting the incisional surgery to movement of only two extraocular muscles. The size and location of the field of single binocular vision has been shown to be larger and more central with this technique when compared with other procedures (Table 4).

TABLE 4. Comparison of Results of Methods of Treating Unilateral Acquired Sixth Nerve Paralysis

RETINAL DETACHMENT

Persistent strabismus after retinal reattachment surgery is difficult to correct and has additional surgical risks over other types of strabismus surgery. Recent reports have established the effectiveness of botulinum A toxin in eliminating diplopia and restoring binocular vision in these patients (Table 5).^33–35 The effectiveness of botulinum A toxin injections depends on a variety of factors including visual acuity, macular abnormalities, retinal reoperations, and the presence of significant restrictions. Even with all these obstacles, approximately 70% of patients obtain significant benefit. The injection procedure itself is more difficult because the normal anatomic position of the extraocular muscles has been altered by the retinal detachment surgery. Theoretically this increases the possibility of globe perforation with the electrode needle and extra care should be exercised when injecting these patients.

TABLE 5. Results of Botulinum A Toxin Injections in Strabismus After Retinal Detachment Surgery

DYSTHYROID MYOPATHY

Botulinum A toxin has been shown to be useful in the management of patients with both acute and chronic dysthyroid myopathy. During the acute phase, injections into the involved muscles can relieve contracture, improve ocular rotations, and eliminate diplopia. Repeated injections and larger quantities of drug are required because of the enlargement of the affected muscle.³⁶ With time, fibrotic changes occur in the muscle making botulinum A toxin less effective. In a series of 25 patients with acute thyroid myopathy, only 6 patients had long-term single vision with botulinum A toxin injections alone.³⁷ Scott²⁰ reported similar results with 16 of 27 patients with vertical strabismus initially treated with botulinum A toxin later requiring surgical intervention. Botulinum A toxin injections are less effective if the motility disturbance has been present for more than a year. In patients with small vertical or compound horizontal and vertical deviations, botulinum A toxin injections may reduce the number of operated muscles or decrease the size of the deviation to that which can be corrected by prisms.

NYSTAGMUS

Botulinum A toxin has been used to control severe oscillopsia in patients with acquired nystagmus. Different procedures have been suggested depending on the nature and severity of the nystagmus. Injection into the involved horizontal or vertical muscle has been successful for a uniplanar jerk or pendular nystagmus. In patients with a combined vertical, horizontal, and rotary nystagmus, retrobulbar botulinum A toxin injection has been attempted. Helveston and Pogrebniak³⁸ reported on two patients who developed severe incapacitating oscillopsia after brain stem infarct. Each received 25 units of botulinum A toxin into the retrobulbar space. Visual function improved significantly in both patients. The effect lasted from 5 to 13 weeks and no adverse side effects were observed. As with other entities treated with botulinum A toxin, repeat injections provided similar results. I personally have treated several patients with multiple sclerosis and one patient with oculopalatal myoclonus with similarly good results. Ptosis can occur after retrobulbar botulinum A toxin injection and may be a hindrance to visual function. Concerns about intravascular injection of botulinum A toxin are unwarranted because the dosage is well below the amount necessary to cause systemic toxicity and the molecule is too large to pass through the blood–brain barrier.³⁸

OVERCORRECTIONS AND UNDERCORRECTIONS

Botulinum A toxin can be used when it becomes obvious that a residual deviation after strabismus surgery is not going to improve with time or when other types of supportive therapy such as Fresnel prisms, patching, or exercises yield no benefit. Patients with overcorrections appeared to do exceptionally well with up to 87% obtaining adequate alignment.^19,39 Undercorrections responded the same as other types of horizontal strabismus with a 40% to 60% satisfactory alignment. As might be expected, those patients who had multiple re-operations or had a significant restrictive component to their strabismus, did poorly, but some patients had a permanent improvement in their deviation averaging approximately 10△ of correction.³⁹

CHILDHOOD STRABISMUS

While botulinum A toxin is still considered experimental in children under the age of 12, results to date indicate that it may be effective in this age group and may be a suitable alternative to traditional strabismus surgery (Fig. 10).^14,17,40 Scott and collaborators¹⁵ recently reported that 61% of 362 children who underwent botulinum A toxin injections achieved an alignment of within 10△ of orthophoria. (This is comparable to adults who achieve 65%.) When subdivided into types of strabismus, children with esotropia did better than those with exotropia (65% versus 45%), and smaller deviations (less than 20 △) were more frequently corrected than larger deviations (73% versus 54%) (Table 6). The change in alignment was more stable than that achieved in adults and was felt to be caused by the binocular fusion obtained in children after the injection.^15,17 The frequency of complications was similar to that seen in adults except for ptosis, which occurred in over a third of patients. No amblyopia or visual loss was produced by the injection procedure or by the drug effects in Scott's series. Tejedor and Rodriguez⁴¹ also cite small angle of esotropia, as well as high hypermetropia and minimal amblyopia as best predictors of favorable outcome. In botulinum A toxin treatment of acquired childhood esotropia motor success rates were 53% after one injection and 88% after two or three injections. In regards to binocularity in this group, 47% had at least 400 seconds of arc and 71% had peripheral fusion.⁴¹

TABLE 6. Botulinum Treatment of Childhood Strabismus

Successful treatment of essential infantile esotropia has been described by several authors.^7,13,21,29 Adequate alignment was achieved in 68% to 100% of patients with varying age groups and length of follow-up. In a study of 76 patients, McNeer and coworkers⁴² report successful alignment in 89% with a mean follow-up of 37 months (Table 7). With respect to timing of botulinum A toxin injections, Campos et al.⁴³ conclude that treatment prior to the age of 7 months is optimal while Ruiz et al.⁴⁴ caution against treatment prior to 18 months of age because of a higher rate of decompensated DVD. In addition, it is well known that reoperation rates for infantile esotropia are significant. Tejedor and Rodriguez⁴⁵ compared botulinum A toxin injections to traditional surgery for retreatment of infantile esotropia. Of 55 patients, 28 had surgery and 27 had injections with 3 years of follow-up. Successful alignment within 8△ was achieved in 68% versus 59% (p = 0.72), respectively.⁴⁵

TABLE 7. Botulinum Toxin Management of Infantile Esotropia*

Botulinum A toxin has not been found to be useful in childhood strabismus characterized by incomitancy such as in A- and V-patterns or Duane's syndrome. Some success has been achieved with dissociated vertical deviation when it is not associated with inferior oblique overaction. McNeer⁴⁶ injected botulinum A toxin into the superior rectus of the nondominant eye in five patients. A marked reduction in the deviation from 20△ to 5△ occurred. Close follow-up after injection is necessary because all patients developed a significant transient ptosis.

SENSORY STRABISMUS

Achieving ocular alignment in patients with sensory strabismus can be difficult. Botulinum A toxin has been recognized as an alternative to surgical correction in these patients. A recent study of 12 patients with 10△ to 50△ of sensory esotropia or exotropia, who underwent botulinum A toxin injection of either the medial or lateral rectus muscle, reported a 75% success rate with a mean of 7 months of follow-up. The mean number of injections was 1.6 and 3 patients (25%) required surgery.⁴⁷ Long-term follow-up of patients with sensory and consecutive exotropia demonstrated a much higher frequency of surgery (59%) in those previously treated with botulinum A toxin.⁴⁸

Correction of large-angle exotropia (> 80 △) often requires surgery on three or four extraocular muscles. In patients with monocular sensory deprivation, this can present a dilemma because of the preference to operate on the eye with poor vision. Owens et al.⁴⁹ reported three patients with large-angle sensory exotropia (100 to 110 △ who underwent simultaneous botulinum A toxin injection to the lateral rectus muscle followed by a 10-mm recession of the lateral rectus muscle and a 10-mm resection of the medial rectus muscle. Follow-up ranging from 7 months to 4 years demonstrated a satisfactory cosmetic result in all three patients. This technique obviates the need to operate on the normal eye and augmenting the surgical amounts with botulinum A toxin prevented large ductional deficits.⁴⁹

TABLE 8. Complications and Side Effects

The second category encompasses unwanted effects of botulinum A toxin on adjacent muscles. The most common is ptosis that appears to be caused by botulinum A toxin's selective effect on fast-twitch fibers, which are quite abundant in the levator muscle.⁵¹ The incidence of ptosis increases in direct relationship to the injected muscle's proximity to the levator, with superior and medial rectus muscle injections having the highest likelihood.^10,20 While disconcerting to the patient, the ptosis usually clears rapidly and resolves completely by 6 months (see Fig. 6). Only six cases of slight residual ptosis have been reported. The second most common muscle disturbance is a vertical deviation after horizontal rectus injection (Fig. 11). This is seen much more frequently when the muscle anatomy has been altered such as after strabismus or retinal detachment surgery. Most of these vertical deviations will improve, but in a small percentage a residual deviation persists. As with ptosis, it appears to occur more often with medial rectus injections.⁵² Particular caution must be exercised when injecting the inferior rectus. The inferior oblique, because of its close proximity to the inferior rectus and its large size, may be inadvertently injected instead of the inferior rectus. The likelihood of this happening can be decreased by carefully listening to the EMG signal and remembering that the inferior oblique is an elevator muscle and should have a much louder signal on upgaze than the inferior rectus, which is a depressor muscle. Carefully testing the EMG response in both positions helps to avoid this complication. Pupillary dilation is a rare side effect that probably results from injury to the ciliary ganglion. To date, two patients have gone on to develop an Adies tonic pupil.²⁰

Last, sensory symptoms can occur after an extraocular muscle has been paralyzed. In patients with a long-standing strabismus the sudden change from an exotropia to an esotropia may result in extremely bothersome diplopia. Often the potential for this to occur can be detected prior to the injection. In patients with fusion potential the lack of movement in one eye will almost certainly result in diplopia and the patient may adopt a head position in order to correct for it. While most cases of diplopia postinjection are transitory, the possibility should be investigated in the same manner as in patients undergoing strabismus surgery. Spatial disorientation and past pointing can also be seen after botulinum A toxin injection and are particularly common in patients who have a muscle in the preferred eye injected. These effects clear as the botulinum A toxin-induced paresis resolves.

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