Abstracts

Rationale: Clobazam has been used as an add-on therapy for several seizure types and epilepsy syndromes with satisfactory results. Clobazam treatment tailored to the patient's timing of seizures may provide improved seizure control. We evaluated patients who used clobazam as an add-on therapy with a higher-evening differential dose for treatment of predominantly nighttime and early-morning seizures and compared seizure reduction rates between patients who received differential and equal dosing. Methods: We retrospectively reviewed patients with refractory epilepsy who used clobazam differential dosing at a tertiary center between 2001 and 2013. Differential dosing was defined as a higher-evening dose of clobazam after 6 p.m and providing more than 50% of the total daily dose at that time. Differential dose patients had a high proportion of seizures (>80%) at nighttime or early-morning (6 p.m. to 6 a.m.). Each differential dose patient was matched to 2 non-differential dose controls by age, etiology, seizure type, and MRI-lesion. Seizure reduction was calculated from baseline (3 months prior to clobazam initiation) to 1^st follow-up. The main outcome was seizure frequency at 1^st follow-up between patients who received differential and non-differential dosing. A sub-analysis for response in seizure type subgroups was performed. Results: Twenty-seven patients with refractory epilepsy were treated with clobazam differential dosing as an add-on therapy. The median age was 9.1 years (SD: 3.9, IQR: 5.5-10.3), 40.7% of the patients were female and median follow-up was 9 months (SD: 28.7, IQR: 5-19). Genetic etiology was observed in 5 (18.5%), structural/metabolic in 10 (37%), and unknown etiology in 12 (44.5%) patients (Table 1). Patients with differential dosing tolerated a median overall higher clobazam dose of 0.8 mg/kg/d at 1^st follow-up (SD: 0.5, IQR: 0.7-1.1 mg/kg/d), as compared to 0.6 mg/kg/d in controls (SD: 0.4, IQR: 0.3-0.8 mg/kg/d, Two-sample t-test, p<0.05). In differential dose patients, the median percentage of the total clobazam dose administered in the evening was 66.7% (SD: 6.7, IQR: 66.7-70.6%). Patients were treated with a median of two concomitant AEDs (IQR: 2-3). Differential dose patients exhibited a median seizure reduction of 75% (SD: 156.6, IQR: 60-100%), compared to 50% (SD: 169.3, IQR: 20-83.3%) seizure reduction in controls (Mann-Whitney U Test, p<0.005, Figure 1). Patients with generalized seizures benefited the most from differential dosing with a 77.5% (SD: 166.2, IQR: 63.3-100%) median seizure reduction, as compared to 50% (SD: 177.6, IQR: 20-93.0%) in controls (X², p=0.017). Conclusions: A higher-evening differential dose of clobazam, based upon times of highest seizure susceptibility, improved seizures in patients with predominantly nighttime and early-morning seizures. Chronotherapy tailored to the patients' seizure susceptibility patterns may improve care in epilepsy patients, specifically also because differential dosing may permit higher overall treatment doses with a similar side-effect profile. This research was funded as an investigator-initiated study by Lundbeck LLC.