Characteristics of Cardiorespiratory Failure Preceding Seizure-Induced Mortality in SSKcnj16−/− Rats

Epilepsy is a common, chronic neurological condition characterized by repeated, uncontrolled seizures. These patients are at high risk for cardiorespiratory failure (CRF) and Sudden Unexpected Death in Epilepsy (SUDEP) — the mechanisms of which remain unknown. Most SUDEP events are unwitnessed at night suggesting a circadian influence on seizure-induced mortality. Here we studied cardiorespiratory (CR) function continuously (24/7) in a rat model of audiogenic seizures (SS Kcnj16−/− rats) in which repeated seizures have been shown to cause progressive respiratory suppression and mortality. We hypothesized repeated seizures in SS Kcnj16−/− rats also lead to 1) progressive dysfunction of post-ictal heart rate (HR) and blood pressure (BP) responses, and 2) cause death via cardiorespiratory failure most frequently when seizures occur after the onset of the inactive period (8am) or prior to the onset of the active phase (4pm). Age matched male and female SS Kcnj16−/− rats were implanted with a carotid pressure telemeter and housed in a chronic monitoring plethysmograph with HD video to continuously measure breathing, BP, and HR. Audiogenic seizures (1/day (d) for up to 10d) were induced at a specific time of day and the physiologic data analyzed. Consistent with previous findings, repeated generalized tonic-clonic seizures (GTCSs) caused acute ictal/post-ictal apnea and transient respiratory rate suppression for ~5 minutes post-ictal which was exacerbated with additional seizures (n=6). In addition, GTCSs induced progressively greater transient post-ictal HR suppression and increased BP (n=3; p<0.05 on days 8-10 compared to days 1-3). When seizures occurred at either 8am or 4pm, female SS Kcnj16−/− rats had a 10% survival probability (18/20 died) and males had a 40% survival probability (12/20 died). These data combined with previous studies in which seizures were induced throughout the light period showed a higher percentage of deaths at specific times of day: <10am (14%; n=81), 10am-2pm (3%; n=225), 2pm-7pm (8%; n=338). On average seizure-related mortality occurred 2-3 hours after seizures (20 of 30 events) and occurred throughout the 10-day protocol resulting from either moderate (score 2; 53%) or severe (score 3-4; 47%) seizures (Modified Racine Scale). Specific characteristics of death events (n=11-19) included transiently increased BP (+20mmHg) and tidal volume (+0.5 mL/100g; V T ) but decreased HR (-50 beats/min), breathing frequency (-50 breaths/min; F B ) and ventilation (-20 mL/min/100g; V E ). These CR measures then returned to baseline until ~60 minutes post-seizure when there was a secondary decline in BP (-80 mmHg), elevated HR (+100 beats/min), and a concomitant progressive decline in V T and V E prior to terminal apnea/asystole. These data show acute progressive CR suppression with repeated seizures and seizure-induced CRF (tidal volume-mediated decreased ventilation and severe hypotension) leading to death, where time of day for seizure induction contributed to higher mortality rates. This model provides useful insight into the effects of seizures on CR function and understanding the mechanisms of SUDEP, with the ultimate goal of reducing the risk of SUDEP in patients with epilepsy. Supported by NIH HL122358 (MRH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.