Long-term control of epileptic drop attacks with the combination of valproate, lamotrigine, and a benzodiazepine: A "proof of concept,'' open label study

Purpose: Long-term medical management of epileptic drop attacks is usually unsatisfactory and more effective antiepileptic drug (AED) regimens are needed. The present study aimed at providing proof of concept that previously refractory epileptic drop attacks could be significantly and safely controlled by the specific combination of valproate, lamotrigine, and a benzodiazepine. Methods: An open label trial providing class IV evidence of efficacy, including 32 patients with cryptogenic/symptomatic, generalized or multifocal epilepsies, and refractory drop attacks. Following baseline, the combination under study was introduced and patients followed for 12 months. Frequency of drop attacks was compared at 3-month intervals with that during baseline and correlated with clinical, electroencephalography (EEG), and imaging variables. A list of putative side effects was read to patients and caregivers at each visit. Key Findings: Four patients were excluded, one due to a Stevens-Johnson syndrome (SJS). Median number of drop attacks decreased 96% between baseline and the fourth trimester of the study (from 50 to 2; p < 0,001). Intentionto- treat (ITT) analysis showed that 15 patients (47%) had complete control, 7 (21%) had a 75% and 5 (15%) had a 50-74% reduction in the frequency of falls in the fourth trimester. Twenty-two patients (68%) had side effects, but except for the three excluded because of early rash, caregivers did not consider discontinuation. Mean final dose of valproate was 35.9 mg/kg/day and that of lamotrigine 4.9 mg/kg/day. Twenty patients used clobazam, eight nitrazepam, and the other four clonazepam as the elected benzodiazepine. Outcome did not correlate with clinical, EEG, and imaging variables. Significance: This open label study suggests that the combination of valproate, lamotrigine, and a benzodiazepine can markedly reduce the frequency of epileptic drop attacks in patients with generalized or multifocal epilepsies. Careful clinical monitoring for early signs of SJS is needed.