Abstracts

Rationale: Intractable childhood cases of Lennox Gastaut (LGS) show significantly abnormal Interictal EEG patterns that may affect developmental outcome. LGS can be caused by genetic epilepsy syndromes. Ganaxolone (GNX) is a CNS-selective modulator of gamma-aminobutyric acid A (GABA-A). It acts as a positive allosteric modulator of the GABAA receptor with anticonvulsant and anxiolytic effects, Ganaxolone works through its affect on endogenous neurosteroid receptors and may improve EEG and function in certain encephalopathic epilepsy patients. We present two PCDH19 cases and one CDKL5 clinically showing EEG patterns of LGS that were felt to be candidates for GNX therapy trial. Methods: Patients with genetically confirmed PCDH19(2) and CDLK5(1) clinically presenting as LGS with refractive seizures were allowed to participate in an open label trial with GNX (MarinusPharmaceuticals). Sutter IRB consent was obtained and protocol allowed doses up to 1800mg/kg/day. EEG 24 hr baseline tracings were available with follow-up at 8-12 weeks. Seizure control and EEG changes in spike-wave percentage were quantified. Seizure diary for frequency and types of seizures, and Parental and Investigator( CGI-P; CGI-II) were done. Results: Patients with PCDH19 showed respectively reduction in seizure frequency (80%, 75%) after 8 weeks treatment with 1200-1800mg/kg/day of GNX, and EEG improvement of interictal slow-spike and wave frequency of (> 90%, 80%) on awake and asleep EEG. The CDKL5 patients showed seizure reductions respectively of (>67%) and EEG changes (50% reduction of interictal slow-spike wave discharges). . CGI-I and CGI-P were showing much improved for global function and seizure control. No serious adverse events occurred. Conclusions: : This report of GNX treatment for refractive epilepsy cases of clinical LGS with PCDH19 and CDKL5 mutations shows improved CGI and seizure control and correlating EEG improvement in interictal slow-spike and wave activity. More expanded study for other genetic, symptomatic, or idiopathic cases of LGS may be warranted. Funding: Research Grant from Marinus Pharmaceuticals for ganaxolone in PCDH 19 and CDLK 5 patients to Sutter Institute for medical Research ( one of multi-site study by company).