Abstracts

Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with maternally-derived mutations of chromosome 15, most commonly deletion of the 15q11-q13 region, which includes 3 genes of the GABA[sub]A [/sub]receptor subunit. The majority of patients have seizures. Increased severity and intractability of epilepsy has been found in those patients with 15q11-13 deletions. Seizure types are typically primary generalized, and can include myoclonus, atypical absence, and generalized tonic-clonic, often with episodes of myoclonic and non-convulsive status epilepticus. Responses have been described to valproate, ethosuximide, topiramate, phenobarbital, and piracetam. Polypharmacy regimens including benzodiazepines, such as clobazam and clonazepam, which act at the GABA[sub]A [/sub]receptor, have also been described as effective. Clorazepate dipotassium is a benzodiazepine which is converted to the active antiepileptic N-desmethyldiazepam and has an apparent half-life of 40-50h. Current indication in epilepsy treatment is adjunctive therapy in the management of partial seizures. Average adult doses are 0.5 to 1 mg/kg/day, with up to 3 mg/kg/day used in children. We report 5 children with AS who became seizure-free on monotherapy with relatively low doses of clorazepate. Retrospective chart review of 5 children with AS and epilepsy seen in Pediatric Neurology at Oregon Health [amp] Science University. Ages ranged 3 to 17 years. Four had the common deletion in the proximal long arm of chromosome 15; one had a mutation of ubiquitin-protein ligase E3A (UBE3A) gene. Ages at seizure onset were 1 [frac12] to 3 years. Seizure types included atypical absence, myoclonic, generalized-tonic-clonic, complex partial, and atonic. All had EEG findings suggestive of AS including 1 to 3 hz generalized spike and slow wave discharges, rhythmic frontal slowing, and rhythmic theta/delta occipital slowing and spikes. Medications tried before initiation of clorazepate in 3 patients included carbamazepine, phenytoin, phenobarbital, and valproic acid. Two patients received clorazepate as initial antiseizure therapy. All patients reported cessation of seizures on doses of clorazepate ranging 0.19 to 1.2 mg/kg/day. No significant sedative or behavioral side effects were reported. Patients were followed for 1 to 6 years. Clorazepate is an effective and well-tolerated long-term monotherapy anticonvulsant for patients with the typical seizures, including primary generalized seizures, associated with Angelman Syndrome. Duration of seizure-freedom, in our children up to 6 years, on clorazepate monotherapy at these relatively low doses suggests that the tachyphylaxis typically seen with chronic benzodiazepine therapy is limited or absent in this population. Monotherapy and once-daily dosing using the sustained release form of clorazepate can improve compliance and reduce potential side effects, compared to alternate anticonvulsant drugs in mono- and polytherapy regimens.