Abstracts

Rationale: Clobazam was approved in 2011 as an adjunctive therapy for the treatment of seizures assocaited with Lennox-Gastaut syndrome. Unlike the classic 1,4-benzodiazepines (such as diazepam, clonazepam, lorazepam, and midazolam), clobazam is structurally different as a long-acting 1,5-benzodiazepine with a greater binding affinity for GABA alpha-2 than alpha-1 receptors. Our study examines the effects of frequent prior 1,4-benzodiazepine use on the efficacy of clobazam on seizure control. Methods: We reviewed all charts of patients that were placed on clobazam at our epilepsy center Pediatric Neurology, PA from 2005-2014. Data collected included general demographics, 1,4-benzodiazepine use prior to clobazam initiation, and change in seizure frequency at last follow-up. Patients were statistically analyzed into two groups: improved seizure control (>50% seizure reduction) and not improved seizure control (<50% seizure reduction or worsening). Frequent 1,4-benzodiazepine use was defined as at least once daily use. Statistical analysis included Fisher's exact test and unpaired t-test. Results: Thirty-four patients (21 males, 13 females) were prescribed clobazam with mean start age of 9.2 years (range 9 months to 15.8 years) and mean starting dose of 10.4mg (range 2-35mg). Mean follow-up period was 15.3 months (range 8 days to 55 months), and mean final clobazam dose was 20.3mg (range 3.75-50mg). Seventeen patients (50%) had significant improvement. There were no statistically significant differences between the group that improved and the one that did not in terms of gender, age at clobazam initiation, seizure type, history of infantile spasms, seizure frequency prior to clobazam initiation, presence of concurrent hepatic inhibiting/inducing antiepileptic drugs, and follow-up period. Fourteen patients (82.4%) used 1,4-benzodiazepines frequently in the group that did not have seizure reduction vs. one patient (0.06%) in the group that had significant seizure reduction (p<0.0001). One patient who had frequent prior 1,4-benzodiazepine use went into status epilepticus after initiation of clobazam. Conclusions: Clobazam and 1,4-benzodiazepines both act on the GABA receptors. Structural similarities result in competitive binding for alpha receptors, but variation in placement of the nitrogen atom on the diazepine ring results in different affinities for the various alpha receptor subunits. Our retrospective study shows a large statistical significance in patients who respond poorly to clobazam are the ones who use 1,4-benzodiazepine frequently prior to initiation of clobazam. Our study suggests that a wash-out period of 1,4-benzodiazepines prior to clobazam initiation could be warranted and should be considered. Future studies should examine an appropriate wash-out period for benzodiazepines prior to starting clobazam.