Abstracts

Rationale: Sudden Unexpected Death in Epilepsy (SUDEP) is the most common cause of death in refractory epilepsy patients. Several types of postictal arrhythmia have been associated with seizures, leading some investigators to conclude that cardiac arrest is the principal cause of SUDEP.  However, in monitored cases of SUDEP direct measurements of respiratory function were not made. The recent MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) reported the largest series of SUDEP cases in epilepsy monitoring units (EMUs), and included video, EEG, and EKG. Respiratory activity was assessed indirectly from video recording. In a Dravet Syndrome mouse model (Scn1aR1407X/+; DS) and in DBA/1 mice (audiogenic seizures) fatal postictal apnea has been observed, but the mechanisms of ventilatory arrest have not been defined.  In a refractory epilepsy patient, Dlouhy et al (2015) demonstrated a correlation between seizure spread into the amygdala and apnea induction. The aim of the current work was to determine if the amygdala nucleus is involved in ventilatory arrest in the DBA/1 and DS mouse models of postictal death. Methods: A mouse EMU was used to continuously record EEG, EMG, EKG, whole-body plethysmography (breathing), body temperature, room temperature, humidity and video. To induce seizures, DS mice were exposed to a heat lamp to cause a continuous increase in body temperature from 37°C to 43°C (1°C per 2 minutes), and DBA/1 mice were exposed to a loud noise for 1 minute.  Seizures were first induced in animals before amygdala lesions.  Amygdala lesions were then performed using electrolytic lesions or kainic acid injections following Paxinos and Franklin coordinates, after which seizures were induced again.  The hypercapnic ventilatory response (HCVR; 7% CO2) was measured in a whole-body plethysmography with air flow and gases controlled before and after amygdala lesions. Results: Prior to lesions, both experimental groups of mice had a normal HCVR response compared to control mice. Amygdala ablation did not induce any change in the HCVR in DBA/1 mice. DBA/1 and DS mice showed peri-ictal ventilatory arrest prior to bradycardia and death, consistent with ventilatory arrest as the cause of death. Ventilatory arrest was prevented in 86% and 75% of DBA/1 and DS mice with amygdala lesions respectively. Conclusions: These results indicate that postictal death in Scn1aR1407X/+ and DBA/1 mice is due to respiratory arrest followed by bradycardia. Amygdala ablation did not affect baseline chemoreception in any of these mice. However, ventilatory arrest and death was prevented by amygdala ablation in DBA/1 and DS mouse models, indicating that the amygdala is an important part of the neural pathway involved in ventilatory arrest induced by seizures. Funding: U01NS09041403 SUDEP RESEARCH ALLIANCE:RESPIRATORY AND AROUSAL MECHANISM, APPLICATION.