Sudden unexpected death in epilepsy: Fatal post-ictal respiratory and arousal mechanisms

•SUDEP is the leading cause of death in epileptic patients.•Multiple mechanisms are thought to be involved, including respiratory dysfunction.•Serotonin is critical for control of breathing, chemoreception and arousal.•Defects in the serotonin system could be a contributing factor to SUDEP.

Sudden unexplained death in epilepsy (SUDEP) is the cause of premature death of up to 17% of all patients with epilepsy and as many as 50% with chronic refractory epilepsy. However, SUDEP is not widely recognized to exist. The etiology of SUDEP remains unclear, but growing evidence points to peri-ictal respiratory, cardiac, or autonomic nervous system dysfunction. How seizures affect these systems remains uncertain. Here we focus on respiratory mechanisms believed to underlie SUDEP. We highlight clinical evidence that indicates peri-ictal hypoxemia occurs in a large percentage of patients due to central apnea, and identify the proposed anatomical regions of the brain governing these responses. In addition, we discuss animal models used to study peri-ictal respiratory depression. We highlight the role 5-HT neurons play in respiratory control, chemoreception, and arousal. Finally, we discuss the evidence that 5-HT deficits contribute to SUDEP and sudden infant death syndrome and the striking similarities between the two.