Abstracts

Rationale: The leading cause of death in patients who are refractory to conventional medical treatment is sudden unexpected death in epilepsy (SUDEP). The cause of death in SUDEP cases appears to be some form of cardiorespiratory arrest. The conditions which make a seizure more or less likely to precipitate fatal cardiorespiratory aberrations are unclear; however, seizures which result in death typically happen at night. There are a number of possible explanations for the increased frequency of SUDEP at night. Sleep, a state at which breathing is unstable, usually occurs at night. Additionally, people are less likely to be monitored by others during the night; However, there are also physiological changes associated with certain times of day which may increase SUDEP vulnerability. The goal of this investigation was to test the hypothesis that time of day is an independent risk factor for seizure induced death. Methods: Six groups of 12 adult male wild-type C57BL/6J mice housed in normal 12:12 light-dark cycle were equipped with EEG, EMG and EKG recording electrodes. Maximal electroshock seizures (MES; 50 mA; 0.2 sec; 60 Hz sine wave pulses) were induced in these animals during wakefulness, NREM sleep, or REM sleep during the day or during the night. EEG, EMG, EKG, video recording and whole-body plethysmograph were conducted before during and after each seizure. Sleep state was determined live using EEG, EMG and video feeds. The extension to flexion ratio (E/F Ratio) of the motor seizure was scored by video and used to assess seizure severity. Results: Seizures induced during wake and NREM sleep during the day (the inactive phase of rodents) had higher mortality than the corresponding sleep state during the night (12 mice per sleep state at each time point, p < 0.05). Seizures induced during REM sleep were universally fatal regardless of time of day. There was a greater degree of respiratory suppression following nonfatal seizures induced during the day compared to the night (p < 0.05). There was also a longer duration of EEG suppression following nonfatal seizures induced during the day compared to the night (p < 0.05). Conclusions: Data from this investigation shows that time of day has an effect on postictal respiratory outcomes and mortality across multiple sleep states. This suggests that time of day may be an independent risk factor for seizure induced death. In the future, it will be necessary to investigate the mechanism by which circadian phase alters postictal respiratory outcomes which may be a target for interventions to prevent seizure induced death. Funding: This work was supported by The Christopher Donalty and Kyle Coggins Memorial SUDEP Research Fund from Citizens United for Research on Epilepsy (CURE; GFB), NIH/NINDS T32 NS007421 (BSP), 5K08NS069667 from NIH/NINDS (GFB), and TL1 TR000151 from NIH/NCATS (MAH). Dr. Buchanan is also supported by the Beth and Nathan Tross Epilepsy Research Fund.