Sudden unexpected death in epilepsy patients (SUDEP) is the leading cause of death in people with drug-resistant epilepsy. The mechanisms underlying SUDEP are not well understood, but evidence from animal and human studies suggest that most SUDEP is due to seizure-induced respiratory dysfunction. The primary purpose of my project was to determine how seizures disrupt breathing, how this increases the risk for SUDEP, and how to use this knowledge to develop a novel dietary therapy that protects against seizure-induced death.

This dissertation shows that generalized convulsive seizures in a mouse model of Dravet Syndrome (DS) inhibit breathing via apparent impairment of serotonin signaling, manifest as defects in CO2 chemoreception and thermoregulation. We also found that a ketogenic diet was protective against seizure-induced respiratory arrest in two mouse models, an effect that was independent of ketone body formation. Finally, we made the novel observation that adding whey to a regular mouse diet greatly reduced the incidence of spontaneous seizures and SUDEP in two mouse models. This rescue effect was associated with increased 5-HT levels in the brain of DS mice. 

Taken together, these data indicate that interictal and postictal abnormalities of respiratory control play a major role in SUDEP and may be a biomarker for those at highest risk. Moreover, this project addresses the critical need to identify therapies that increase longevity of patients at risk for SUDEP and provides preclinical data indicating that whey protects mouse models of epilepsy from seizure-induced death.