Abstracts

Rationale: Sudden Unexpected Death in Epilepsy (SUDEP) is defined as the sudden, unexpected and unexplained death of a person with epilepsy and accounts for between 8 and 17% of epilepsy-related deaths. This statistic rises to 50% for patients with refractory epilepsy. Although the mechanisms of SUDEP are unknown, one proposed mechanism is abnormal control of the heart by the autonomic nervous system (ANS). Our objective was to determine whether the broad changes in ictal heart rate experienced by mouse models of SUDEP are 1) due to the ANS and 2) contribute to seizure-induced death.

Methods: Seizures were induced by electrical stimulation of the hippocampus of mice carrying the human SCN8A encephalopathy mutation p.Asn1768Asp (N1768D; “D/+ mice”), recorded video, electroencephalogram (EEG), electrocardiogram (ECG), and breathing via whole body plethysmography. Standard autonomic pharmacology was used to test the relative roles of the parasympathetic and sympathetic nervous systems on heart rate changes associated with seizures. Heart rate and respiratory frequency were determined using threshold analysis (Spike2 software).

Results: Hippocampus-stimulated seizures had pronounced ictal bradycardia and postictal tachycardia (Fig. 1A), just as we have reported for spontaneous previously. Administration of the pharmacological agents had no effect on seizure susceptibility or severity. Administration of Atropine, a muscarinic antagonist, eliminated ictal bradycardia (Fig. 1B), while carbachol, a muscarinic agonist, had no effect on ictal bradycardia, but reduced postictal tachycardia (Fig. 1C). Sotalol, an adrenergic β-receptor antagonist, had no effect on ictal bradycardia, but did suppress postictal tachycardia (Fig. 1D). Isoproterenol, a β-receptor agonist, had no effect on either ictal bradycardia or postictal tachycardia (Fig. 1E). Administration of the a1-receptor antagonist prazosin increased the incidence of seizure-induced death in D+ mice (Fig. 1F). Although postictal heart rate was lower for these fatal seizures in the presence of prazosin (Fig. 1G), rates were not as low as that recorded for carbachol treated mice, which all survived (Fig. 1H).

Conclusions: Both ictal bradycardia and postictal tachycardia are manifestations of the ANS. Bradycardia is mediated by a maximal activation of the parasympathetic arm of the ANS, and tachycardia is mediated by parasympathetic inactivation and sympathetic activation. While the changes in heart rate during seizures are profound, suppression of postictal heart rate did not increase seizure mortality.

Funding: Please list any funding that was received in support of this abstract.: CURE Epilepsy Taking Flight Award.