Abstracts

Rationale: Status epilepticus (SE) is a prevalent disorder, which is associated with significant morbidity, including the development of epilepsy and mortality. Studies indicate that lethal cardiac arrhythmias contribute to death following SE as well as sudden unexpected death in epilepsy (SUDEP). A range of potentially lethal cardiac arrhythmias (i.e. tachycardia, bradycardia, and asystole) are observed in epilepsy and are indicative of underlying autonomic nervous system (ANS) dysfunction. Tachycardia is the most commonly reported seizure-related to arrhythmia but asystole and bradycardia have been observed and may occur ictally in people with temporal lobe epilepsy (TLE). Studies have described ANS imbalance during ictal and postictal periods but less is understood about ANS function during interictal periods. We sought to understand ANS changes following SE by monitoring cardiac electrical activity in a chemoconvulsant mouse model of TLE. Methods: Intrahippocampal administration of kainate, a glutamate analog, results in SE, followed by the development of chronic, spontaneous recurring seizures (epilepsy) that are associated with hippocampal neuron loss, mossy fiber sprouting, and closely model what occurs in humans with TLE. To simultaneously investigate alterations in electrocardiography (EKG) and video synchronized electroencephalographic (vEEG) signals following SE, male C57BL6J mice were implanted with six electrodes at 2-4 months of age.A guide cannula was placed into the hippocampus for the administration of kainate in a freely moving and awake animal. Baseline EKG and vEEG activity were recorded. Then, animals received saline or kainate via the intrahippocampal cannula and monitored for two weeks. Results: Recordings showed ictal bradycardia and post-ictal tachycardia, which had been described in other mouse models of SE, as well as humans. Interictally, no changes were seen in heart rate, RR interval, QTc interval, and PR interval between saline and kainate treated animals. However, SE animals exhibited decreased interictal beat-to-beat variability of the QTc and decreased PR intervals for the two weeks of monitoring after SE or until a death event. Sinus pause with a junctional escape beat, premature ventricular contractions, and accelerated ventricular rhythm were observed interictally following SE during sleep. Additionally, death events were captured and showed seizure-related increases in beat-to-beat variability in the RR, QTc, and PR intervals preceding death. Conclusions: Our mouse model recapitulates changes that are observed in human TLE. Although average values for heart rate, R-R interval, QTc interval, and PR interval showed no difference interictally between saline and kainate treated animals, the potentially lethal arrhythmias observed and beat-to-beat variations in RR, QTc, and PR intervals indicate ANS dysfunction ictally and interictally. Interestingly, the arrhythmias were observed commonly during sleep and more than half of all cases of SUDEP are reported to occur during sleep. Further research into the mechanisms of ANS dysfunction following SE may be fruitful in providing greater understanding as well as treatments to prevent future cases of SUDEP. Funding: N/A