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Botulinum toxin A for the treatment of strabismus is not a new concept; in fact, the first case series was published by Alan B. Scott, MD, more than 30 years ago.1 Since FDA approval of Botox (onabotulinumtoxinA) in 1989, it has been used as both an adjunct and an alternative to traditional surgery for treating certain types of strabismus in adults.2
What is new is the growing interest in its use in young children. “Many children have a dramatic and permanent response to Botox,” said David G. Hunter, MD, PhD, vice chairman of ophthalmology at Harvard Medical School and ophthalmologist-in-chief at Boston Children’s Hospital. “It’s not a replacement for incisional surgery, but it is a valuable additional tool.”
Despite promising recent research on the use of botulinum toxin in children, clinicians must carefully weigh the drug’s benefits and risks, as with any therapy that has not been approved for pediatric use. To assist in that process, three experts discuss the latest research and their approach to treatment.
State of the Research
Despite several new papers supporting its efficacy in children, botulinum toxin is often thought to have no role in pediatric strabismus practice. “Early studies were very small and reported either contradictory results or Botox’s inferiority to traditional surgery,” said Alejandra de Alba Campomanes, MD, MPH, assistant professor of ophthalmology at the University of California, San Francisco, and director of pediatric ophthalmology and strabismus at San Francisco General Hospital. “Many strabismus specialists continue to quote those early studies as the reason they don’t use Botox in children today.”
Yet the 2012 Cochrane review on botulinum toxin for strabismus reported comparable results between surgery and botulinum toxin for re-treatment of acquired or infantile esotropia.2 A 2012 study on augmentation of medial rectus recessions with botulinum toxin injection demonstrated its effectiveness for infants with large-angle infantile esotropia (more than 60 prism diopters [PD]), with stable results over time.3 And, more recently, a study comparing bilateral botulinum toxin injections versus bilateral recessions of the medial rectus muscles for treating infantile esotropia reported no difference in binocular alignment between the approaches at a minimum of 48 months of follow-up, concluding that botulinum toxin may be considered a primary treatment for infantile esotropia.4
|(1) With the child under general anesthesia, the medial rectus muscle is grasped with forceps and injected with Botox.
Why Consider Botox for Kids?
Long-lasting effects in children. Unlike in other conditions, in which the effects of botulinum toxin are transient and can be sustained only with repeated injections, its effects in some types of strabismus can be permanent.
“Sometimes with just one injection or—most of the time—two, there is a long-lasting effect,” said Dr. de Alba. Before the paralytic effect wears off, it somehow alters the mechanism of the underlying strabismus in a way that makes it disappear altogether.
“One of the beliefs about why Botox has long-lasting effects in kids is that we’re jump-starting the brain mechanisms that stabilize alignment,” said Dr. de Alba. “The child relearns very early how to use both eyes together.”
Preserving muscle preserves surgical options. Early surgery for strabismus in children is the treatment of choice in the United States and remains the definitive approach.2 “But always with strabismus surgery, we’re thinking about what we’re going to be doing next if this doesn’t work,” said Dr. Hunter. “The more [muscle] you can preserve with each step, the better.”
Unlike traditional surgery, botulinum toxin therapy does not alter the anatomy of the eye. “If a muscle hasn’t been repositioned, you have a greater ability to predict what the effect of further surgery will be on that muscle,” said Gregg T. Lueder, MD, professor of ophthalmology and visual sciences and professor of pediatrics at St. Louis Children’s Hospital, Washington University. Using Botox can minimize the number of muscles operated on, thus preserving future surgical options.
|CHANGES OVER TIME. (2) Botox case study, in family photos. (A) 3.5-year-old girl with acute, acquired, comitant esotropia of 30 PD and no measurable stereopsis. (B) Two weeks after injection of 5 units of Botox into both medial rectus muscles, she has a large exotropia and right ptosis. (C) Four months after injection, she has no measurable strabismus but still lacks stereopsis; however, at the one-year follow-up, she continues to have excellent alignment and has recovered 100 arc seconds of stereopsis.
Clinical Scenarios for Botox
If the eyes are misaligned in infants, binocular vision cannot develop. “The most critical prognostic factor is the duration between when the crossing starts and when you get the eyes straight,” said Dr. Lueder. “The best results occur when the eyes are realigned within a couple of months.” With that in mind, there are several scenarios in which botulinum toxin can speed up alignment while preserving muscles.
Acute acquired esotropia. One example is acute acquired esotropia. “A typical scenario is a 4- or 5-year-old child who wakes up one morning with his or her eyes crossed,” said Dr. Hunter. “Usually those kids will end up having a neuroimaging study to rule out a brain tumor, but assuming those studies are negative, you would typically wait to see if it resolves on its own in a few months before rushing to recess the medial rectus muscles. But most of these kids don’t get better: They stay the same; they develop amblyopia; and, if they spend too much time with their eyes misaligned, they can lose binocular vision as well. Botox is a way to go right in, even within a few weeks of onset, and get the eyes straight without repositioning any muscles.”
Follow-up or adjunct to traditional surgery. Dr. Lueder said, “I find Botox helpful for children who’ve had previous surgery for esotropia or exotropia but who have mild to moderate residual misalignment and some evidence of binocular vision, for example, as with intermittent deviations.”
He also uses it as an adjunct to traditional surgery. In a recent study on the concomitant use of botulinum toxin and surgery for large-angle infantile esotropia, he and his colleagues found that the combination established alignment in 74 percent of patients, with a mean follow-up of 6.6 years.3 Only the two medial rectus muscles were operated on, decreasing the duration of the anesthesia and the risk of surgical complications; and the lateral rectus muscles were preserved for additional surgery, if necessary.
Because he wants to align the eyes as soon as possible, Dr. Lueder doesn’t use Botox alone for new-onset strabismus, even small-angle deviations. “Frequently, one injection is not sufficient, so the procedure needs to be repeated. This increases the time between presentation and correction.”
Primary treatment. Dr. de Alba does use Botox alone for small-angle esotropia. As lead author of the first head-to-head comparison of botulinum toxin versus surgery as a primary treatment for infantile esotropia, she reported that the two therapeutic approaches had comparable success rates in patients with pretreatment angles of less than 30 PD.5 She noted several advantages to using botulinum toxin: “It’s a much, much faster procedure—three minutes in the OR (in adults, it can be done in the clinic). Although it requires general mask anesthesia, complications are minimal because it takes only a few minutes.”
The greatest benefit is that there’s very little scarring and minimal effect on the anatomy in these infants, said Dr. de Alba. “When we do muscle surgery for infantile esotropia, the child often develops exotropia later in life—three, five, maybe 10 years after surgery—probably because of the permanent anatomic alterations. Botox has a very low rate of those long-term effects because we think it allows for a more physiologic correction as opposed to anatomic change in the eye muscles. As a result, we’re less likely to see those late overcorrections or consecutive deviations that we see frequently with surgery.”
Caveats for Botulinum Toxin
Results take time. One reason some strabismus specialists don’t use botulinum toxin is the time needed for the treatment to take effect. “With surgery, you pretty much know in a week or week-and-a-half what the response is going to be,” said Dr. de Alba. “For Botox, you have to be more patient, waiting six weeks or so to see the full effect.”
Uncertainty about dosing. Because of the many different types of strabismus with varying treatment approaches—as well as the dearth of randomized controlled trials—there is not yet a standardized regimen for children.2 In addition, Dr. Hunter cautioned, several proprietary formulations of botulinum toxin are available, and their dosages are not interchangeable. “In the United Kingdom, they use Dysport (abobotulinumtoxinA), so their research is reported with that formulation, making it difficult to interpret dosages.”
With Botox, “Most of us think of 5 units as a standard dosage to achieve a moderate effect in children and adults,” he said. “But, in some cases, I might only use 2.5 to 3 units to gain a small effect and avoid overcorrection. Or I will sometimes go up to 7.5 to 10 units if there’s a lot of inflammation or fibrosis. The more medication injected, the higher the risk of side effects.”
Expense. Whatever dosage the ophthalmologist uses—usually 5 to 10 units—it is considerably smaller than for other indications. Because Botox is packaged in 100- or 200-unit vials, there’s a lot of waste, and it can get expensive for a practice. “Although you can cluster your [adult] patients as best you can in clinics, most hospitals only allow one vial per patient. So for children, who receive Botox in a hospital setting, clustering isn’t possible,” said Dr. de Alba.
Side effects. The side effects of botulinum toxin are common but localized. “Despite our best efforts, we get transient ptosis in about 20 percent of kids, with occasional vertical strabismus. About half of patients develop a transient overcorrection,” said Dr. Hunter.
“For example, a child has esotropia and I do a Botox injection; a week later I might get a call that it’s worse than ever but is now exotropic with ptosis on one side. It just looks awful, and the parents are terribly alarmed.
“But,” he added, “wait another week and the ptosis gets better, the overcorrection starts to wear off, and the child looks good. I’m happy to have avoided an incisional procedure.”
|Suggestions for Botox Use
The experts listed their preferred uses of Botox in children.
DR. DE ALBA
- Small-angle infantile esotropia (less than 35 PD of deviation)
- Very small-angle acquired esotropia (20 to 25 PD), especially within the first three to nine months after onset
- Small-angle residual esotropia following bilateral medial rectus recessions
- Esotropia in children with developmental delays or cerebral palsy, especially with angle variability
- Adjunct to surgery for sixth nerve palsy
- Adjunct to bilateral medial rectus recessions for large-angle strabismus
- Residual or recurrent strabismus after previous bilateral medial rectus recessions
- Any form of strabismus in children with developmental delays, especially if they are already undergoing anesthesia for other surgery
- Small, variable strabismus
- Adjunct to bilateral medial rectus recessions for large-angle infantile esotropia
- Recurrent mild to moderate angle of deviation with some binocular vision after previous traditional surgery
Advice for Practitioners
Many pediatric strabismus specialists have never used botulinum toxin in children and are uncomfortable with the prospect, according to Dr. Hunter. But, as evidence for its efficacy mounts, some may want to start incorporating it into their practices. Following are some considerations:
- “Select your patients carefully because it definitely doesn’t work for everyone,” said Dr. de Alba. Choose children with small to moderate angles of deviation that has persisted for less than six to eight months, without secondary contracture of the involved muscles, who are young at presentation (less than 2 years old; preferably less than 12 months).
- Be prepared for more hand-holding after Botox than after traditional surgery. “No matter how much you educate parents about the chances of ptosis, overcorrection, and vertical misalignment, they will need a lot of reassurance when any of those effects occur,” said Dr. Hunter. “In some ways, it’s easier to just do the surgery, but there are cases where having that ability to do an intervention that’s less definitive than surgery is an advantage (for example, in patients with small, variable esotropia).”
- Be aware that when you’re doing botulinum toxin injections under general anesthesia, you can’t anticipate whether the electromyography amplifier will be helpful, so you may often be injecting into the muscle without its guidance. “As strabismus surgeons, we all know where the muscle is, but you can still be a little apprehensive about exactly where the needle is with respect to the muscle,” said Dr. Hunter. “That’s just something you have to gain experience doing.”
A Complementary Possibility
Injection of the anesthetic bupivacaine into the opposing muscles may complement botulinum toxin therapy.6 Rather than paralyzing the muscle as botulinum toxin does, bupivacaine strengthens it: Although the bupivacaine injection initially causes damage to muscle fibers and myocytes, the new muscle fibers that replace them within the next 10 to 20 days make the muscle larger, stiffer, and stronger than before. Just as surgical recession and resection are used together, bupivacaine and botulinum toxin may augment each other’s effects, said Dr. Hunter.
“It has great potential and great applications,” Dr. de Alba said. “We’re just waiting for data on long-term effects and dosing before we try it.”
1 Scott AB. Ophthalmology. 1980;87(10):1044-1049.
2 Rowe FJ, Noonan CP. Cochrane Database Syst Rev. 2012 Feb 15;2:CD006499.
3 Lueder GT et al. Am J Ophthalmol. 2012;153(3):560-563.
4 Gursoy H et al. J AAPOS. 2012;16(3):269-273.
5 de Alba Campomanes AG et al. J AAPOS. 2010;14(2):111-116.
6 Scott AB et al. Trans Am Ophthalmol Soc. 2009;107:104-109.
Drs. de Alba Campomanes and Lueder report no related financial interests. Dr. Hunter is founder and equity holder in REBIScan, which is developing technology for amblyopia detection in children.