Adjuvant Vigabatrin in Refractory Epilepsy: A Ceiling to Effective Dosage in Individual Patients?

Abstract

A double-blind, randomized, cross-over study of additional vigabatrin (gamma-vinyl-GABA, VGB, 1.0 g twice daily for 6 weeks, followed by 1.5 g twice daily for 6 weeks) and matched placebo was undertaken in 24 patients with refractory epilepsy. Nineteen completed the trial satisfactorily. Fewer seizure days were reported during VGB treatment [placebo 41, VGB 23, p < 0.05, 95% confidence interval (CI) -1.5 to -14]. An overall reduction in median seizure numbers failed to reach statistical significance (n = 19; placebo 52, VGB 32, NS, 95% CI -18 to +24). Subgroup analysis, however, showed a significant reduction in partial seizures (n = 17) with 2 g VGB daily (placebo 22, VGB 13, p < 0.05, 95% CI -0.5 to -16.5), but not with higher dosage (placebo 28, VGB 22, NS, 95% CI -18 to +11). A deterioration in control of partial seizures as compared with the equivalent placebo phase was observed when patients were changed from 2 to 3 g/day VGB (2 g VGB 13, 3 g VGB 22, p = 0.05, 95% CI 0 to +20). Loss of efficacy was noted in 3 patients, and seizure control worsened slightly in 5 others. One previously resistant patient developed a therapeutic response, and 2 other patients reported an additional useful reduction in seizures. In the remaining 8 patients, seizure frequency did not change. VGB did not appear to benefit tonic-clonic seizures. Serum VGB concentrations were higher during treatment with 3 g (15.5 +/- 8.9 mg/L) daily than with 2 g (13.5 +/- 11.2 mg/L). No important alterations were noted in the concentrations of concomitantly administered antiepileptic drugs (AEDs) throughout the trial. VGB is useful adjuvant therapy for treatment of partial seizures. There may be a ceiling to effective dosage. This demands individual dose titration for each patient.

Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation

“…In all but four of the trials, which involved patients with both generalised and partial seizures, 54,83,85,86 all patients had partial seizures. The trials recruited between 23 and 182 (mean = 72) patients and followed them up for periods of 4-18 weeks (mean = 10 weeks).…”

“…However, they reported the number of patients who achieved at least a 50% reduction in seizure frequency with VGB, which ranged from 33 to 67%. 49,54,83,[85][86][87] In the trial that reported the largest benefit, it was unclear if an appropriate paired analysis was performed or if patients had constant and predictable seizure frequencies. 49 That study and two others 83,85 did not report a washout period but the possible effects on the reported findings were not mentioned.…”

“…Where applicable, the majority of the studies (100) did not report whether the success of the blinding procedure was assessed and only three studies reported assessing the success of blinding. [54][55][56] 10. Were details of the baseline comparability of the treatment groups presented?…”

“…Six crossover studies 49,54,83,[85][86][87] and four parallel studies 38,[153][154][155] compared adjunctive VGB with placebo in patients with refractory seizures. In all but four of the trials, which involved patients with both generalised and partial seizures, 54,83,85,86 all patients had partial seizures.…”

Do Antiepileptic Drugs Exacerbate Seizures?

“…The study by Perucca et al (1) nicely reviews the probable role of VGB in increasing seizure frequency or inducing new seizure types. An effective "therapeutic ceiling dose" has been postulated for VGB with deterioration in seizure control possible when this dosage is exceeded (25). In one series, increased numbers of seizures were clearly related to escalations in VGB dose in one-fourth of pediatric patients (26).…”