Abstract
People with epilepsy have a markedly increased risk of premature mortality, with sudden unexpected death in epilepsy (SUDEP) accounting for approximately half of epilepsy-related deaths. Although rarely witnessed, converging evidence indicates that SUDEP arises from seizure-triggered cardiorespiratory failure mediated by central and peripheral mechanisms. In this article, we explore mechanisms of SUDEP related to respiratory, cardiac, and autonomic control of vital functions. Specifically, we examine how seizure propagation to a discrete amygdala subregion can induce profound ictal and postictal apnea; how complementary genetic and animal studies reveal that ion channelopathies affecting genes expressed in both brain and heart produce intrinsic neuronal and cardiac electrical dysfunction; and how emerging evidence implicates stress physiology and hypothalamic-pituitary-adrenal axis dysfunction as underrecognized contributors to SUDEP risk. Together, these findings support a multifactorial model in which respiratory suppression, cardiac vulnerability, autonomic dysregulation, and stress-responsive mechanisms converge to produce fatal outcomes.