In 2004, the AAN and the Child Neurology Society (CNS) issued a practice parameter that concluded that adrenocorticotropic hormone (ACTH), which is administered intramuscularly, is probably most effective for short-term treatment of infantile spasms and that vigabatrin, an oral medication, is a viable option. However the 2004 analysis was hampered by a shortage of larger randomized and controlled studies of these and other treatment options.
Now an update to the original guideline by the AAN Guideline Development Subcommittee and the Practice Committee of the CNS found that while vigabatrin — which was approved by the FDA in 2009 for infantile spasms — may be effective in short-term treatment, two Class III studies show that ACTH is possibly more effective than vigabatrin for short-term treatment of infantile spasms (except in children with tuberous sclerosis). In addition, there is insufficient evidence that vigabatrin or corticosteroids — other than ACTH — are as effective as ACTH in improving neurodevelopmental outcomes.
Infantile spasms, an epilepsy syndrome of infancy and childhood, are characterized by developmental regression and hypsarrhythmia (chaotic brain waves) on EEG. The onset of infantile spasms is usually in the first year of life, typically between 4–8 months. Spasms tend to occur upon awakening or after feeding, and often occur in clusters of up to 100 spasms at a time. Infants may have dozens of clusters and several hundred spasms per day.
The AAN's four-tiered rating scheme was used to establish therapeutic evidence, with Class I studies having the most robust data, and Class IV studies the least, in terms of design, methodology, study size, and analysis.
Neurology Today asked the guideline's lead author Cristina Y. Go, MD, assistant professor of pediatric neurology at the Hospital for Sick Children of the University of Toronto, to review the panel's new findings.
WHAT ARE THE MOST SIGNIFICANT CHANGES IN THE UPDATED GUIDELINE?
There is considerable variation in how infantile spasms are treated but a shortage of really good studies evaluating the options. [The committees reviewed studies from 2002 to 2011, and did a detailed analysis of 26 papers that had a clearly stated diagnosis of infantile spasms and an EEG demonstrating hypsarrhythmia or modified hypsarrhythmia.] Fortunately two major clinical trials — one has been completed and another is under way may help further our understanding, but the results have yet to be published and therefore could not be included in our review.
Nonetheless, this update provides evidence that for short-term treatment, ACTH is more effective than vigabatrin. We also found that low-dose ACTH is as effective as high-dose treatment. One Class II study and one Class III study also show that a shorter lag time to treatment with either hormonal therapy or vigabatrin potentially improves long-term cognitive outcomes. It also suggests that ACTH or prednisolone may be considered in preference to vigabatrin in cryptogenic infantile spasms to improve long-term developmental outcomes.
WHY IS ACTH BETTER THAN OTHER FORMS OF CORTICOSTEROIDS?
We still don't know the reason why ACTH works better. A single short-term Class III study compared high-dose oral prednisolone (40–60 mg/day) with intramuscular ACTH and found that 76 percent of patients responded to synthetic ACTH compared with 70 percent to prednisolone. However neither treatment agent showed any significant difference in the EEG response rate at 14 days (p=0.61). Most other studies used different forms of corticosteroids and are mostly Class IV studies.
Overall, there was insufficient evidence to recommend the use of prednisolone, dexamethasone, or methylprednisolone as being as effective as ACTH for short-term treatment.
WHAT BARRIERS EXIST WITH THE USE OF ACTH?
ACTH imposes a burden of treatment because of its prohibitive cost and mode of administration, by intramuscular injection. It is usually initiated in a hospital-based setting under nursing supervision.
WHAT ARE THE POTENTIAL SIDE EFFECTS OF THESE DRUGS?
The most frequent adverse effects with hormonal therapy include hypertension (37 percent), irritability (37 percent), infection (14 percent), and cerebral atrophy (62 percent). Vigabatrin also carries a black box warning that use may result in permanent visual impairment, however the risk appears to be lower with short-term use.
WHAT DID THE PANEL CONCLUDE ABOUT USING VIGABATRIN ALONE OR IN COMBINATION WITH OTHER DRUGS?
We found that vigabatrin is possibly effective for short-term treatment of infantile spasms, which remains unchanged from the 2004 practice parameter. Since then there have been no new studies except for a Class III study comparing low to high dose vigabatrin and an international multicenter study comparing hormonal therapy alone to hormonal therapy plus VGB that is still under way.
WHEN SHOULD A LOW-DOSE/HIGH-DOSE ACTH OR VIGABATRIN REGIMEN BE CONSIDERED?
Most centers have their own dosing regimen for ACTH, and this has made it difficult to answer questions regarding optimal ACTH formulation, dose, and treatment duration. However, in this update we have two studies using the same low-dose regimen of 20–30 IU daily, which has shown similar clinical and EEG response rates to those for high-dose ACTH.
In terms of vigabatrin, it is possibly effective for short-term treatment of infantile spasms and also for treatment of children with infantile spasms secondary to tuberous sclerosis.
One study, a single large Class III randomized, controlled trial comparing low-dose and high-dose vigabatrin, found that more than twice as many patients in the high-dose group achieved spasm cessation within 14 days compared with those in the low-dose group (15.9 percent versus 7 percent). In a subgroup of children with tuberous sclerosis complex, the high-dose vigabatrin regimen was associated with fewer spasms overall than in patients treated with a lower dose (25 percent versus 16.7 percent). In these patients high-dose treatment was associated with 30.8 percent resolution of hypsarrhythmia, compared to 13.2 percent in those taking a lower dose.
WHAT IS ADVISED FOR CRYPTOGENIC SPASMS?
Evidence from one Class II study shows that hormonal therapy may be considered for use in preference to vigabatrin in this subgroup of patients, to possibly improve their long-term neurodevelopmental outcomes.
WHAT IS THE KETOGENIC DIET AND WHAT EVIDENCE SUPPORTS ITS USE?
It is a high-fat, adequate-protein and low-carbohydrate diet that forces the body to burn fat instead of carbohydrates. It is used primarily to treat difficult-to-control epilepsy in children, but has also been used to treat infantile spasms. All of the available studies are mainly Class IV studies — the least robust — so we don't have sufficient evidence to recommend it at this time.
IS THERE ANY EVIDENCE THAT SHORT-TERM TREATMENT WITH ACTH OR VIGABATRIN LEADS TO BETTER LONG-TERM DEVELOPMENTAL OUTCOMES?
Evidence from one Class II study and one Class III study shows that shorter lag time to treatment (with hormonal therapy or vigabatrin) may lead to better long-term neurodevelopmental outcomes.
WHAT ARE THE PROMISING AREAS OF RESEARCH?
The International Collaborative Infantile Spasms Study, a multicenter randomized controlled trial comparing hormonal therapy alone with hormonal therapy plus vigabatrin, is currently under way. Having data on standardized dose, formulation and duration of treatment agents being used in a multicenter study will help provide evidence for an optimal treatment regimen for this devastating condition.
A recently concluded Canadian randomized, double-blind trial of add-on flunarizine to prevent cognitive deterioration associated with 20 infantile spasms should provide further evidence regarding the use of combination therapy. The data have not been published yet.
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• Go CY, Mackay MT, Weiss K, et al. Evidence-based guideline update: Medical treatment of infantile spasms: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology
• Mackay MT, Weiss SK, Adams-Webber T, et al. Practice parameter: Medical treatment of infantile spasms: Report of the American Academy of Neurology and the Child Neurology Society. Neurology
• Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet
• Haberlandt E, Weger C, Sigl SB, et al. Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes. Pediatr Neurol
• Elterman RD, Shields WD, Bittman RM, et al. Vigabatrin for the treatment of infantile spasms: final report of a randomized trial. J Child Neurol 2010;25:1340–1347.