Unique features of seizure-induced cardiorespiratory failure in SSKcnj16−/− rats: Implications for sudden unexpected death in epilepsy

Abstract

Objective

Patients with uncontrolled epilepsy are at high risk for sudden unexpected death in epilepsy (SUDEP), which likely results from a pathological, seizure-induced disruption of vital physiological systems. The objective of this study was to characterize seizure-induced physiological dysfunction leading to death in SS^{Kcnj16−/−} rats and determine the importance of time of day of seizures regarding mortality rates.

Methods

Male and female SS^{Kcnj16−/−} rats were surgically implanted with an arterial pressure telemeter and chronically housed in a custom plethysmograph. This setup allowed for continuous measurement of breathing, blood pressure, heart rate, body temperature, and behavior before and during a 10-day seizure protocol. Audiogenic seizure inductions were time-restricted to the early (8–10 a.m.) or late (4–6 p.m.) inactive periods. We assessed acute and chronic physiological functions before, during, and after repeated seizures in both survival and death events.

Results

Time-restricted audiogenic seizures in SS^{Kcnj16−/−} rats induced transient disruptions in breathing, blood pressure, heart rate, and temperature, which eventually normalized in both survival and death events. However, after returning to physiological normalization, death was preceded by subsequent spontaneous physiological decompensation, characterized by altered breathing patterns, hypotension, and hypothermia. Finally, seizure-induced mortality was highest during the early and late inactive periods compared to historical data without time restriction and was greater in females than in males but did not correlate with prior seizure severity or number.

Significance

Understanding the causes of SUDEP in patients with epilepsy is limited due to unpredictable and heterogeneous circumstances and incomplete physiological data. This study provides insights into seizure-induced and delayed physiological decompensation leading to SUDEP-like events, demonstrating a need for additional prospective, integrated physiological measures for a more complete picture of SUDEP.