Pathophysiology of SUDEP: How far are we from understanding?

Sudden and unexpected death in epilepsy patients (SUDEP) is the leading cause of death in patients suffering from drug-resistant epilepsy. A significant number of studies have been conducted in both patients and animal models to examine the initial cascade of events that directly cause death as well as the factors that contribute to the long-term risk of SUDEP. This review aims to discuss the main pathophysiological hypotheses that are currently considered in both clinical and pre-clinical models of SUDEP. Studies have highlighted that SUDEP is typically triggered by a seizure, with central fatal apnea as the primary cause of death. Findings also suggest that chronic impairments in respiratory regulation may contribute to SUDEP risk, with serotonin dysfunction playing a key role in the associated respiratory abnormalities. These insights on SUDEP pathophysiology contribute to better risk assessment, though gaps remain in understanding the precise mechanisms linking SUDEP and transient peri-ictal respiratory dysfunction.