6.2.1 BTXA Products

Licensed commercial BTXA products in the United States and the European Union include Botox (onabotulinumtoxinA; Allergan), Dysport (abobotulinumtoxinA; Ipsen), and Xeomin (incobotulinumtoxinA; Merz). Dosage equivalence is similar for extraocular muscle usage, although Dysport requires higher doses for other muscles. RimabotulinumtoxinB (Myobloc) has been used effectively for strabismus in cases with developed immunity to type A toxin, but results data have not been reported.

6.2.2 Mechanisms of Effect

BTXA blocks acetylcholine release and creates a “chemodenervation” effect. The maximal paralytic effect is reached 5 to 7 days after injection, persists for 1 to 2 months (depending on dose), then gradually declines, and is fully gone at 6 to 9 months (Fig. 6‑1). ^{2 ,​ 3} Although BTXA paralysis is temporary, it may result in a permanent change of the deviation (Fig. 6‑2). Possible mechanisms for this permanent effect of BTXA are as follows:

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  Paralysis changes the eye position, similar to traction sutures. ⁴

  
  
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  Added sarcomeres lengthen the stretched chemodenervated extraocular muscle (EOM) and removed sarcomeres shorten its slackened antagonist EOM. ⁵

  
  
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  Alterations within the EOM, which have been shown by histochemical techniques. ^{6 ,​ 7}

  
  
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  Central adaptive mechanism: Improved alignment leads to restoration of binocularity and improved fusional vergence amplitudes.

  

  

6.2.3 Dosage

The usual dosage range is 2.5 to 10 U of BTXA, and it is usually delivered via electromyographic (EMG) guidance. ⁸ Sensitivity to BTXA, angle of deviation due to paralysis, and EOM lengthening or shortening response to the misalignment position are factors that vary between individuals. The long-term alignment response to BTXA is therefore also variable. For the normal EOM, 0 to 4.0 U of BTXA usually covers the range from no effect to 90% paralysis. Our routine dose is 5 U to produce full paralysis. We use lower doses in infants and up to 10 U per injection in thyroid-associated eye disease. Increased dosages create unwanted effects on adjacent muscles including the levator, and these side effects do not warrant a slightly increased effectiveness. ⁹ As with all medications, repeat injection after an inadequate initial response requires increased dosage.

6.2.4 Advantages of BTXA Treatment

The main advantage of BTXA treatment is its minimal invasiveness and lack of scar tissue formation. The application of BTXA is uncomplicated and there is no limit on repeat injections, allowing lifetime maintenance treatment for some patients. It is an outpatient treatment for adults and does not preclude future strabismus surgery. The dose required to treat strabismus is small, which keeps the costs low in busy clinics.

The temporary effect of BTXA is an advantage in treatment of acute paralytic strabismus, as well as restrictive or unstable deviations. It also affords a test of the potential function of the paretic muscle by paralyzing its antagonist (Fig. 6‑3, Fig. 6‑4). BTXA injection also helps to assess postoperative diplopia risk, as well as to test the capacity for fusion in central fusion disruption.

6.2.5 Diagnostic Use of BTXA

In paralytic strabismus, spontaneous recovery of the paralyzed muscle may not fully restore normal alignment due to contracture of its antagonist muscle. Where active force tests or saccadic performance indicates possible recovery of function, injection of BTXA into the antagonist EOM allows the assessment of the functional capacity of the paretic EOM, provided there is not fully established fibrosis in the antagonist EOM (Fig. 6‑3, Fig. 6‑4). ¹⁰ Testing for the potential of postoperative diplopia with preoperative prisms is not always reliable, and those who report diplopia may overcome diplopia once their eyes are aligned. BTXA provides a temporary orthophoric period and allows assessment of the postoperative diplopia risk. ¹¹

Fusional ability may be lost in adults with binocular sensory deprivation due to cataract or uncorrected aphakia of greater than 2 years’ duration, as well as intracranial pathology that causes disruption of central fusion. Options to regain alignment include prisms, surgery, and BTXA. The loss of contrast sensitivity and decreased visual acuity due to increasing prism power create unreliable responses. ^{12 ,​ 13} Strabismus surgery may increase symptoms if the patient cannot fuse postoperatively, as the diplopia becomes more noticeable when the images are closer. In central fusion disruption, BTXA allows the assessment of the potential for fusion by providing a period of alignment which potentially allows the visual system to recover without the distortions of prisms. BTXA therefore provides useful information about a patient’s potential for fusion.

6.2.6 Therapeutic Use of BTXA

BTXA injection has been used in nonparalytic deviations after multiple previous surgeries, residual or consecutive deviations, intermittent deviations, convergence insufficiency, convergence spasm, small angle deviations, sensory eso- or exodeviations, acute comitant esotropia, decompensated phorias, cyclic deviations, deviations with neurologic impairment, and infantile esotropia.

There are two groups of patients to consider regarding the usefulness of BTXA injection. The first group has a long-term benefit with one or two injections only. Their alignment is restored once binocular fusion is regained, leading to a long-term benefit. In the second group, which requires repeated injections, the interval between injections does increase over time, and the deviation angle decreases over time. There have been no reported adverse effects from repeated injections. ^{14 ,​ 15}

Results in childhood concomitant strabismus are similar to those in adults. ^{16 ,​ 17 ,​ 18 ,​ 20} The best results have been reported in small angle deviations in children. Those with binocularity achieved long-term stable results. ²¹ BTXA is a good choice for small deviations in children without binocularity with their high risk of consecutive deviations after surgery. The common side effects of ptosis and vertical deviations, 24% and 9% in our study, occur mostly after medial rectus (MR) injection, last a few weeks, and leave no amblyopia due to ptosis, and only rare vertical deviation.

In infantile esotropia the results with BTXA vary with patient selection and angle of deviation. A recent meta-analysis summarizing seven reported series showed an average strabismus correction rate of 77%, requiring an average of 1.6 injections. ²² The subset of neurologically normal infants treated with bilateral MR muscle injection before 7 months of age, had a correction rate of 88%, ²³ but other studies reported lower success rates than this for both injection and surgery. ^{21 ,​ 24 ,​ 25 ,​ 26} In another series, in which a second injection was required in half the cases, the success rate of correction by injection for deviations over 30 PD was 45% as compared to a surgical success rate of 69%. For deviations under 30 PD, injection and surgical success rates were the same at 60% each. ²⁷

6.2.7 BTXA to Augment Strabismus Surgery

To augment recession, BTXA may be injected into the recessed EOM during surgery. ²⁸ This weakens the muscle and reduces tension without crippling the muscle’s mechanics, which may occur with large recession. ²⁹ In large deviations, the addition of BTXA at the time of muscle recession may augment recession enough to avoid operating on a third horizontal muscle. Confining surgery to two muscles, and adding BTXA, resulted in successful correction in six of eight patients with esotropia (ET) of 70 to 100 prism diopters (PD). ³⁰ In a recent study the effect of BTXA-augmented recessions was evaluated in a group of 13 patients with large sensory deviations, avoiding supramaximal surgery and confining surgery to the deviating eye. The long-term success rate was 87.5% and 80% in exo- and esodeviations, respectively. ³¹ In a series of 23 patients with infantile ET of 65 to 100 PD, bilateral MR muscle recession surgery augmented with bilateral MR BTXA corrected 74% to within 10 PD, with an average of 6.6 years and minimum of 2 years of follow-up. ³² A recent comparative series reported only an 18% success rate of surgical correction of infantile ET greater than 60 PD. A companion cohort using slightly less surgery but adding bilateral MR muscle BTXA corrected 48%. The effect of adding BTXA on surgical dosage was to increase the effect by 42%, from 4 PD/mm to 5.7 PD/mm. The 4-month postoperative results had hardly changed by 12 months. ³³ These reports support the addition of BTXA to recession surgery for large deviations in both adults and children.

In recent onset cyclic ET in children, and in accommodative esotropia with recent loss of fusion, BTXA is the first line of treatment by these authors. A study of children with new onset ET showed BTXA to be as effective as surgery, with frequent recovery of binocular fusion. ³⁴

In esotropia due to microphthalmia and cerebral palsy, BTXA is our first line treatment. Surgical results are unpredictable, averaging two operations per child in one recent series, and multiple procedures in several cases. ³⁵

BTXA was shown to be as effective as surgery in childhood intermittent exotropia in several series with success rates of 69 to 77%. ^{36 ,​ 37}

To decrease of the risk of anterior segment ischemia (ASI), BTXA injection rather than surgical recession can be used to release a tight MR in combination with full vertical muscle transposition (Video 35.1). BTXA injection can be done at the time of transposition if the MR is found to be tight and restricting, or postoperatively when the effect of the transposition can be assessed and the need for BTXA evaluated. Injection preserves the muscle’s arc of contact and anatomy, potentially resulting in a larger range of motion than would be present after recession.

6.2.8 BTXA in Paralytic Strabismus

6.2.8.2 Fourth Cranial Nerve Palsy

In fourth CN palsy the injection sites utilized may be the ipsilateral inferior oblique (IO) or the contralateral inferior rectus (IR) to relieve vertical diplopia. Surgical over- and undercorrections may be ameliorated with BTXA, similar to its use with other strabismus surgery (Fig. 6‑5, Fig. 6‑6, Fig. 6‑7, Fig. 6‑8). ^{40 ,​ 41 ,​ 42 ,​ 43 ,​ 44}

We reported on a small group of patients with fourth CN palsy with superior rectus (SR) contracture and a large vertical deviation who underwent IO disinsertion in combination with BTXA injection into the ipsilateral SR. ⁴⁵ The results remain stable without overcorrection, but the patients must be warned about the possibility of transient ptosis.

6.2.9 BTXA in Restrictive Strabismus

Restrictive problems exist in Duane’s syndrome, thyroid-associated eye disease (TED), orbital myositis, ⁴⁹ postoperative restriction-adherence syndromes, and strabismus due to retinal detachment surgery. ⁵⁰ BTXA does not correct fibrosis, but fibrosis may be difficult to distinguish from muscle contracture in TED and myositis. ⁵¹ A trial BTXA injection improves about one-fourth of TED cases. In Duane’s syndrome, muscle contracture may increase the deviation and head turn over years. In such cases, BTXA may restore alignment. Four of eight patients age 3 and under with esotropic Duane’s syndrome achieved lasting success from MR injection of BTXA. ⁵² BTXA may also be used for diagnostic purposes in Duane’s syndrome to predict the possible postoperative result. Long-term reduction of deviation was achieved in 53% in a series of 88 patients with Duane’s syndrome. ⁵³

6.2.10 BTXA to Rescue Surgical Failures and Complications

Botulinum toxin is useful to “fine-tune” postoperative over- and undercorrections. This may be termed a “pharmacologic adjustment”. ^{54 ,​ 55 ,​ 56 ,​ 57} It was reported that the results of BTXA were similar to surgery and the BTXA effect was greater when the injection was performed within the first 3 months after surgery (Fig. 6‑5, Fig. 6‑6, Fig. 6‑7, Fig. 6‑8). In its acute phase, the BTXA effect is mostly through the soft tissue healing and mechanical contractile forces, whereas in the chronic phase its effect is mostly through central adaptive mechanisms.

Another major indication for BTXA use is in the surgical complications of adherence syndrome and lost muscle. These authors have previously demonstrated that in adherence syndrome following IO surgery, BTXA injection into the IR muscle may result in orthophoria when done acutely. ⁵⁸ The BTXA effect is due to stabilization of the eye in primary position during fibroadipose tissue proliferation (Fig. 6‑9). With a lost muscle, contracture of the antagonist develops as early as 2 weeks. ⁵⁹ The injection of BTXA into the antagonist EOM during the acute stage prevents secondary contracture, allowing the soft tissues around the lost EOM to attach at a more anterior location, while the eye is maintained in the primary position by the BTXA (Fig. 6‑10). ⁶⁰

6.2.11 BTXA in Posttraumatic Strabismus

BTXA may be useful in posttraumatic EOM damage with ASI risk, posttraumatic adherence problems, and strabismus related to orbital injury. In the acute stage, BTXA injection may maintain the eye in the primary position, thus reducing contracture of the antagonist EOM. This allows soft tissue healing when the eye is in primary position and may reduce the impact of orbital fibrosis on the ocular motility. In the chronic stage it may be used as maintenance therapy or to reduce ASI risk with surgery on multiple rectus muscles (Fig. 6‑11, Fig. 6‑12, Fig. 6‑13).

6.2.12 Complications of BTXA Treatment

The most common side effect of BTXA is ptosis, with a frequency of 9 to 42%. It is dose related, is temporary, and occurs more often after MR injection. The spread of BTXA may affect a neighboring EOM, creating vertical diplopia (frequency 8.3–18.5%). ⁶¹ Diplopia from the induced BTXA paralysis may be bothersome and last many weeks. For this reason we often advise surgical correction for binocular patients with small deviations. Tonic pupil may develop with a frequency of 0.16% to 11%, ⁶² and usually reverses spontaneously. Since tonic pupil does not occur with high doses of 25 U into the orbit, used to paralyze all the muscles for severe oscillopsia (Chapter 17), it is hypothesized to result from needle injury rather than a pharmacologic effect. Accommodative deficiency and retrobulbar hemorrhage are rare complications of BTXA injection. Scleral perforation has an incidence of 0.28% in one report, but it has never occurred in these authors’ hands. ⁶² BTXA is nontoxic to retinal tissue, if injected in error. ⁶³

6.2.13 Disadvantages of BTXA Treatment

There are some disadvantages to treatment of strabismus with BTXA. There may be an inability to reach the target muscle, even using EMG. This occurs especially in postoperative cases and the vertical rectus muscles. Most of these cases, however, prove successful. The effect of injection may be less than the desired full paralysis of the muscle. Re-injection, usually with a higher dose, is required. The frequent lack of effect in established fibrotic strabismus cases, such as in TED, and long-standing paralysis indicates the need for surgery. Long-term reduction of effect of BTXA with recurrence of the deviation may occur.

6.2.14 Ideal Applications for BTXA in Strabismus

Considering all the advantages and disadvantages of BTXA treatment and the experience of the authors with using this agent in clinical practice, the ”first choice” applications of BTXA are as follows: acute phase paralytic/restrictive strabismus, early stages of over- or undercorrections after strabismus surgery, early adherence syndrome, ”intractable diplopia” risk or central fusion disruption, the need to weaken a rectus muscle with the risk of ASI, recurrent deviations despite multiple previous surgeries, as an addition to surgical recession for large angles, cyclic deviations in children, recent onset ET in children, and infantile ET.