George B Richerson, Detlev Boison, Carl L Faingold, Philippe Ryvlin

The mechanisms of sudden unexpected death in epilepsy (SUDEP) have been difficult to define, as most cases occur unwitnessed, and physiologic recordings have been obtained in only a handful of cases. However, recent data obtained from human cases and experimental studies in animal models have brought us closer to identifying potential mechanisms. Theories of SUDEP should be able to explain how a seizure starting in the forebrain can sometimes lead to changes in brainstem cardiorespiratory control mechanisms. Herein we focus on three major themes of work on the causes of SUDEP. First, evidence is reviewed identifying postictal hypoventilation as a major contributor to the cause of death. Second, data are discussed that brainstem serotonin and adenosine pathways may be involved, as well as how they may contribute. Finally, parallels are drawn between SIDS and SUDEP, and we highlight similarities pointing to the possibility of shared pathophysiology involving combined failure of respiratory and cardiovascular control mechanisms. Knowledge about the causes of SUDEP may lead to potential pharmacologic approaches for prevention. We end by describing how translation of this work may result in future applications to clinical care.