Pathophysiology of sudden unexpected death in epilepsy: a devasting convergence of dysfunction in brain, respiratory systems, and heart

Sudden Unexpected Death in Epilepsy, or SUDEP, is the leading cause of death in persons with epilepsy. Although extensively studied, the events that result in SUDEP remain poorly understood, with no reliable biomarkers to predict SUDEP risk in an individual. This review synthesizes the literature across many domains, discussing clinical and preclinical studies in brain, cardio-respiratory centers in the brainstem, and intrinsic alterations in cardiac excitability leading to arrhythmia, to provide a comprehensive picture of our current understanding of SUDEP mechanisms. What we do know is that SUDEP involves complex, multi-system dysfunction in persons with epilepsy at baseline, during seizures, and in post-ictal periods. This situation is further complicated by cases of SUDEP Plus, in which pre-existing conditions in addition to epilepsy, e.g. Brugada syndrome or Long-QT syndrome, may contribute to death during a seizure. Finally, it is likely that multiple etiologies lead to SUDEP outcomes. Here, we highlight gaps in the field requiring additional research.