VIGABATRIN - CLINICAL-EVIDENCE SUPPORTING RATIONAL POLYTHERAPY IN MANAGEMENT OF UNCONTROLLED SEIZURES

Monotherapy is the policy for management of patients with epilepsy. Wi th increasing knowledge of the biology of epilepsy and of the modes of action of antiepileptic drugs (AEDs), this concept must be reevaluate d. When monotherapy fails to control seizures, subsequent treatment sh ould be based on ''rational pharmacology,'' taking into consideration the mode of action of the drugs, to provide improved efficacy with mai ntained tolerance and ease of administration. Introduction of vigabatr in (VGB) as a new AED calls for just such a reevaluation. VGB is an en zyme-activated irreversible inhibitor of gamma-aminobutyric acid (GABA )-transaminase that increases brain and cerebrospinal (CSF) GABA conce ntrations in animals and humans. It has limited efficacy in the classi c animal seizure screening tests, but in many clinical studies has hal ved the incidence of seizures in similar to 50% of patients, especiall y those with partial epilepsies. We evaluated the efficacy of VGB in ' 'socially integrated and active outpatients'' as a likely subset to de monstrate any advantage of rational polytherapy. The criteria for this evaluation included the effects on seizure frequency, patient tolerab ility, and cognitive performance in a battery of psychometric tests. F ourteen of the 19 patients (73%) completing the study had >50% reducti on in seizure frequency, and 10 of 19 (52%) had >70% reduction in seiz ure frequency. Tolerability appeared good; somnolence was the most fre quent adverse event. Three patients complained of a worsening of their seizures, 1 with an increase in frequency and 2 with development of m yoclonic jerks not previously reported. No deleterious effect of VGB o n cognitive function was noted, and performance in late recognition te sts showed significant improvement by the end of the maintenance perio d, which may have been due to the reduction in seizure frequency. The efficacy of VGB in this study in controlling seizures as compared with results of earlier published studies of refractory epilepsy may be re lated to selection of patients with more benign partial epilepsy, but does support the need for further studies in such patients to evaluate the hypothesis of rational polytherapy.