Utilizing Multimodal Imaging to Visualize Potential Mechanism for Sudden Death in Epilepsy

Sudden death in epilepsy, or SUDEP, is a fatal condition that accounts for more than 4000 deaths each year. Limited clinical and preclinical data on sudden death suggests critical contributions from autonomic, cardiac, and respiratory pathways. Recent animal (rat) studies on kainic acid induced seizure models explored a potential mechanism for such sudden and severe cardiorespiratory dysregulation being linked to acid reflux induced laryngospasm. Here, we expand on those previous investigations and utilize a multimodal approach to provide visual evidence of acid reflux-initiated laryngospasm and subsequent fatal cardiorespiratory distress in seizing rats. We used systemic kainic acid to acutely induce seizure activity in Long Evans rats, under urethane anesthesia. We recorded electroencephalography (EEG), electrocardiography (ECG), chest plethysmography and esophageal pH signals during simultaneous fast MRI scans of the rat stomach and esophagus. MRI images, in conjunction with electrophysiology data were used to identify seizure progression, stomach acid movement up the esophagus, cardiorespiratory changes, and sudden death. In all cases of sudden death, esophageal pH recordings alongside MRI images visualized stomach acid movement up the esophagus. Severe cardiac (ST segment elevation), respiratory (intermittent apnea) and brain activity (EEG narrowing due to hypoxia) changes were observed only after acid reached the larynx, which strongly suggests onset of laryngospasm following acid reflux. Additionally, absence of stomach acid in the esophagus of animals that survived acute seizure, provided evidence of a causal relationship between acid reflux and sudden death. The complimentary information coming from electrophysiology and fast MRI scans provided insight into the mechanism of esophageal reflux, laryngospasm, obstructive apnea, and subsequent sudden death in seizing animals. The results carry clinical significance as they outline a potential mechanism that may be relevant to SUDEP in humans.