Abstracts

Rationale: Sudden Unexpected Death in Epilepsy (SUDEP) is defined as the sudden, unexpected and unexplained death of a person with epilepsy and accounts for between 8 and 17% of epilepsy-related deaths. This statistic rises to 50% for patients with refractory epilepsy. Our laboratory utilizes two unique SUDEP model mice, each generate with knock-in of a Scn8a gene mutations that were identified in epileptic patients with documented SUDEP. The mice reproduce many of the pathological hallmarks seen in the patients, including spontaneously occurring generalized tonic-clonic seizures and SUDEP-like deaths. In order to develop better biomarkers and therapies for SUDEP, we must understand the mechanism(s) that lead to death. We hypothesize failure of breathing and/or cardiac function is the cause of SUDEP. Methods: Two mouse lines were used. One with a germline mutation of N1678D in Scn8a ('D/+'). The other line has an R1872W mutation of Scn8a expressed conditionally under control of the EMX1 promoter ('W/+EMX1-Cre') To determine the cause of SUDEP in our model mice we chronically recorded video, electroencephalogram (EEG), electrocardiogram (ECG), and breathing via whole body plethysmography. Seizures were identified and scored using standard video-EEG protocols. Heart rate was determined using ECG waveform analysis (LabChart software) and respiratory frequency with threshold analysis (Spike2 software). Results: In our W/+EMX1-Cre line, we observed that SUDEP occurred primarily due to apnea that began during a tonic-clonic seizure (Fig. 1B). Significant bradycardia was also observed; however, heart function did continue for several minutes after breathing stopped. Many non-terminal tonic-clonic seizures also presented with apnea and bradycardia, but breathing and heart rate recovered postictally in these cases (Fig. 1A). In one patient with SCN8A epileptic encepholopathy we observed a tonic-clonic seizure that presented with profound apnea and bradycardia during the tonic phase (Fig. 2). Conclusions: Apnea is the primary cause of SUDEP; however, bradycardia may also play a role. Future experiments determining the mechanism of apnea and recovery from apnea during seizures will be important for developing better therapies for SUDEP. Funding: No funding