Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death in patients with refractory epilepsy. SUDEP results in more years of potential life lost due to disease than any other neurological condition with the exception of stroke. There are no known ways of reliably predicting or preventing SUDEP. It is generally agreed that SUDEP typically happens as the result of cardiorespiratory failure following a convulsive seizure; however, it is not clear what circumstances differentiate SUDEP from the many other seizures that a patient may experience in their life. SUDEP happens more during the night and the early hours of the morning. There are a number of possible explanations for the increased nocturnal incidence of SUDEP. Patients are more likely to be alone, asleep, and in the presence of bedding during the night, all of which might make a seizure more dangerous. Another possibility is that circadian rhythms alter the likelihood of seizure induced death independent of sleep. Many aspects of mammalian physiology which might be relevant to SUDEP such as breathing and cardiac activity, sleep, and even some seizures are regulated in a circadian fashion. The hypothesis of this investigation was that circadian rhythmicity alters vulnerability to seizure induced death. Methods: The approach to testing this hypothesis was to induce maximal electroshock seizures at different circadian time points and compare seizure severity, mortality, and respiratory sequalae. Male C57BL/6J mice (7-10 weeks old) were singly housed in cages equipped with running wheels, with the wheel locked on the first day to prevent novelty induced phase shifts. Mice were kept under 12:12 light-dark schedule and allowed to entrain normally to the ambient lighting conditions for 7-10 days. Mice were then transferred into conditions of constant darkness and handled only under dim red light. The animals were kept in constant darkness until their circadian free running period could be determined on the basis of running wheel activity (10-14 days). Maximal electroshock seizures were induced at six circadian time points (circadian time [CT] 2, 6, 10, 14, 18, and 22. n = 9 per time point). Motor seizure severity, as assessed by extension/flexion ratio, was determined for each seizure using video from an infrared camera. The animals breathing was quantified during and after the seizure using whole body plethysmography. Results: We found that seizure induced death was not uniformly distributed across the experimental time points with an increased rate towards the end of the subjective night (p = 0.04, V test for circular uniformity). Conclusions: These results indicate that the circadian time point at which a seizure occurs might alter the likelihood of seizure induced death. It may be that circadian rhythmicity contributes to the nocturnal pattern of SUDEP. Determining the mechanism by which circadian phase might alter vulnerability to SUDEP may provide insights into why SUDEP happens more during the night and what can be to prevent it. Funding: This work was supported by the NIH/ NINDS (R01NS095842 to GFB and F31NS106819 to BSP), the Beth L. Tross Epilepsy Professorship to GFB, and the University of Iowa Graduate College Post-Comprehensive Research Fellowship to BSP.