T18. High dose phenobarbital is safe and effective treatment for SCN2A related epilepsy

Introduction Voltage-gated sodium channels play major role in neuronal excitability. Nav1.1, Nav1.2, Nav1.3 and Nav1.6 sodium channels found in the brain differ in α -subunits, encoded by SCN1A, SCN2A, SCN3A, and SCN8A genes respectively. NaV1.2 Channels is the only sodium channel expressed during early development at nodes of Ranvier and in the axon initial segment (AIS) in developing and mature neurons, particularly cortical glutamatergic pyramidal cells. NaV1.2 channel has relatively high exictation threshold. NaV1.2 is regulated developmentally by alternative splicing to produce ‘neonatal’ and ‘adult’ isoforms. ‘Neonatal’ form is less excitable than ‘adult’ conferring reduced neuronal excitability and seizure susceptibility. Most dominantly inherited missense genetic variants of NaV1.2 manifests as familial epilepsy while de novo mutations as severe epileptic encephalopathy, both have gain of function with increased excitability and lowered seizure threshold. Cortical pyramidal neurons AIS receives exclusively inhibitory GABA-ergic input from specific set of interneurons called chandelier cells. Methods A FT, WF child born via planned caesarian to a healthy 27 yr G2P2A0L2 with APGAR 8, 9 at 1, 5 min at OSH. On DOL 2, developed seizure manifested as chocking, left arm forced flexion with leftward head deviation, right arm extension evolve into whole body jerking with apnea. Ictal EEG documented left frontal-temporal onset focal seizure. She received two loading doses of Phenobarbital followed by maintenance of 5 mg/kg/day. At therapeutic level of 44 mcg/ml, seizures remained under controlled. On DOL 22, presented to OSH with right arm twitching. Random PHB level was 27.5 mcg/ml. She received load of PHB and Levetiracetam 20 mg/kg each. Seizures continued overnight leading to transfer to our institute. Patient physcial and neurologic exam was normal. Ictal EEG re-demonstrated left central onset rhythmic spike-wave seizure evolution pattern clinically manifesting wide-eyed gaze with right face and upper extremity clonic jerking. Patient received total dose of 40 mg/kg of levetiracetam without improvement. Later, two 10 mg/kg doses of PHB given at couple of hours interval stopped seizures. Maintenance dosing of PHB was increased to 6 mg/kg/day. PHB level obtained was 54.2mcg/ml. It was tolerated well without sedation, hypotonia or adverse effects. She has been weaned off PHB at 7 months of age and has been seizure free with normal development at 14 months of age. Gene DX Comprehensive Epilepsy Panel revealed pathogenic variant of the SCN2A gene ( p . Val261Met). Results We described infant with de novo SCN2A mutation presenting as benign familial neonatal infantile epilepsy well controlled with high therapeutic phenobarbital level without experiencing adverse side effects. Conclusion Phenobarbital at very high therapeutic level exerted seizure control probably via inhibitory effects of Chanderlier cell counterbalancing increased excitability of genetic missense variant of NaV1.2 at the AIS.