Abstracts

Rationale: The N-methyl-D-aspartate (NMDA) receptor plays a major role in neuronal excitation in the central nervous system. The association of NMDA receptor dysfunctions and their pathological roles in a variety of neurodevelopmental disorders, including epilepsy, is well documented. NMDA receptors consist of two GluN1 subunits and two additional GluN2 subunits. GluN2A is encoded by the gene GRIN2A on human chromosome 16. Mutations identified in the GRIN2A gene have been associated with epilepsy-aphasia spectrum (EAS) disorders such as childhood focal epilepsies and epileptic encephalopathies. Within EAS disorders, disease evolution and treatment response are varied and unpredictable. Approximately 33% of patients experience treatment-resistant epilepsy. The potential for understanding pathogenic mechanisms and treatment options in the identification of GRIN2A variations is paramount. Cannabis-based epilepsy treatments have generated great interest in recent years. A small number of open-label and randomized controlled trials suggest a plant-derived pharmaceutical formulation of highly purified cannabidiol may significantly reduce seizure frequency. This is the first report of cannabidiol mediated seizure control in a pediatric patient with a GRIN2A mutation. Methods: We present retrospective clinical data and electroencephalographic features of a unique pediatric case at Nationwide Children’s Hospital.  Results: The patient is a 14-year-old boy who presented with his first seizure at 4 years of age. The initial seizure involved a right focal seizure. He had status epilepticus, myoclonic jerks, and atypical absence seizures; each episode lasting 30 seconds to 15 minutes.  He averaged 50 to 100 seizures daily.  His seizures were refractory despite more than ten AEDs, the ketogenic diet, vitamin B6, and vagus nerve stimulation (VNS). Multiple electroencephalograms (EEG) have shown generalized bisynchronous generalized 2-2.5Hz slow spike waves, left frontotemporal discharges, and electrographic seizures from the left centrotemporal region. Electrical status epilepticus of sleep (ESES) was present. Initially, his development was age appropriate, but significantly regressed. Whole exome testing revealed a V506 A variant in the GRIN2A gene. In 2014, He enrolled in an open-label expanded access program to treat patients with drug-resistant epilepsy with cannabidiol (Epidiolex®) at Nationwide Children’s Hospital. Since starting cannabidiol, the patient has been seizure free without adverse events reported (3 years 8 months).  He remains on clobazam and VNS. 24 hour video EEG showed a normal background with rare epileptiform discharges in the left frontal head region.  ESES was absent. The patient’s cognitive function has improved and he is active in sports. Conclusions: Mutations of the GRIN2A gene have been reported with neuropsychiatric disorders including epilepsy. Our case report data suggest cannabidiol may be an effective treatment for GRIN2A genetic mutations. Further evaluation is needed. Funding: No funding was obtained to support this abstract.