Vigabatrin and Felbamate for Infantile Spasms
ABSTRACT & COMMENTARY
Source: Viegevano F, Cilio M. Vigabatrin versus ACTH as first-line treatment for infantile spasms: A randomized, prospective study. Epilepsia 1997;38:1270-1274.
Treatment with adrenocorticotrophic hormone (ACTH) is the standard of care for infantile spasms (IS). However, ACTH has severe side effects (irritability, agitation, hypertension, weight gain, and infection). Over the last five years, vigabatrin (VGB) has emerged as a less toxic alternative to ACTH. VGB was initially tested as an add-on agent for IS refractory to ACTH. Viegevano and Cilio now report on a prospective, randomized trial of ACTH vs. VGB for new-onset IS.
Forty-two children with newly diagnosed IS (ages 2-9 months) were randomized to treatment with ACTH or VGB within three weeks of seizure onset. If spasms did not cease on the initial treatment after 20 days, or intolerance to the medication developed, the patient was crossed over to the alternative drug. Video-EEG evaluation was performed every 10 days.
Twenty-three infants initially received VGB. In seven of these, IS disappeared within three days, in three more IS stopped by eight days of treatment, and in one patient, IS ended after 14 days of therapy. One child had VGB stopped due to irritability and agitation. Two others experienced drowsiness and mild hypotonia but continued the medication.
Nineteen infants initially received ACTH. In 14 patients, IS disappeared within 2-12 days of treatment. Ten of these responded in less than five days. Seven children developed extreme irritability and hypertension on ACTH, but only in one was it necessary to stop the ACTH.
Fourteen of the ACTH-treated cases had video-EEGs. By 10 days of treatment, the EEG had normalized in eight patients, with multifocal spikes present in the other six. After 20 days of ACTH, 11 children had normal EEGs, and two still had multifocal spikes. Eleven of the VGB-treated cases had video-EEGs. By 10 days of treatment, two children continued to exhibit hypsarrhythmia, and nine had multifocal spikes. No normal EEGs were recorded in this group after 10 days on VGB. After 20 days, four children had normal EEGs, and seven continued to exhibit multifocal spikes. Thus, both the seizure rates and EEGs improved more on ACTH than on VGB.
COMMENTARY
This report from Viegevano and Cilio demonstrates that VGB is an effective treatment for new-onset IS. While VGB stopped IS in only two-thirds as many cases as ACTH, and did so more slowly than ACTH, VGB was tolerated better than ACTH.
We and these authors suggest that VGB should be considered for first-line therapy for new-onset IS. If, after 10 days, the clinical response on VGB is unsatisfactory, ACTH should be substituted. VGB seems particularly effective for IS due to tuberosclerosis, where a response rate as high as 96% has been described (Aicardi, et al. Epilepsia 1996;37:638-642).
ACTH can be administered safely for only 30 days. Riikonen and Donner (Arch Dis Child 1980;55:664-672) found mortality of 4.9% and morbidity of 37% (hypertension and infection) among 162 patients treated with ACTH for IS. After a limited-duration course of ACTH, long-term VGB may be substituted to prevent IS relapse and treat any residual or developing other seizure types.
We recently published our results using felbamate to treat IS resistant to other medications (Hosain, et al. J Child Neurol 1997;12:466-468). Eleven children ages 7-32 months (median, 20 months), with IS persisting despite two or more antiepileptic drugs, were given felbamate for 4-42 weeks (median, 22 weeks). We counted seizures on pre- and post-treatment video-EEGs, which we reviewed blindly concerning the phase of the study in which they were recorded. Felbamate reduced seizures a median of -72% (range, 0% to -100%). Parents also reported less IS on felbamate. Parental reports indicated complete disappearance of seizures in one child, a reduction of more than -90% in four, more than -75% in two, and more than half in three.
This efficacy of felbamate for IS must be compared with its hematological and hepatic toxicity. Felbamate produced aplastic anemia in 1/7875 exposures and hepatic failure in a similar, but less well-defined, number of patients. Less than half of those patients died. By contrast, ACTH treatment has been associated with a mortality rate of nearly 5% (Riikonen, Donner. Arch Dis Child 1980;55:664-672).
VGB and felbamate are effective, and safer, alternatives to ACTH for IS. Felbamate is still FDA approved for the medication-resistant mixed seizures of the Lennox-Gastaut syndrome but not for the related and similar West syndrome and IS. Vigabatrin has received an "approvable" letter from the U.S. FDA for IS and is on the market in Canada and Europe. -drl
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