Pathophysiological frameworks and emerging preventative strategies in SUDEP

Abstract

Sudden Unexpected Death in Epilepsy (SUDEP) represents a leading cause of epilepsy-related mortality, reflecting a severe disruption of systemic physiology that remains challenging to address using standard clinical protocols. Although generalized tonic–clonic seizures (GTCS) and pharmacoresistance are established risk indicators, current clinical risk stratification frequently lacks the predictive granularity required to anticipate individual cardiorespiratory collapse. This review provides a comprehensive synthesis of the SUDEP pathophysiological framework, aiming to bridge the gap between retrospective clinical observation and proactive precision medicine. We delineate a translational framework focused on the intrinsic biological susceptibility of the neuro-cardiac axis, particularly the genetic “dual pathology” of channelopathies and structural cardiac remodeling. Furthermore, we evaluate the transition from reactive risk identification toward multimodal “digital phenotyping” leveraging artificial intelligence. Finally, we assess the developmental trajectory of “secondary prevention” strategies, such as automated neurostimulation, designed to interrupt the terminal cascade. By integrating genomic vulnerability with emerging preventative technologies, this review outlines a multidisciplinary approach to transforming SUDEP into a more predictable and preventable clinical entity.