The Kv1.1 null mouse, a model of sudden unexpected death in epilepsy (SUDEP)

Abstract

Objective: Kv1.1 potassium channel null mouse (NULL) exhibits spontaneous seizure-related bradycardia, dies following seizure, and has been proposed as a model for vagus-mediated SUDEP. We characterized the cardiac events surrounding sudden unexpected death in epilepsy (SUDEP) in NULL during terminal asystole for comparison to patients with epilepsy who exhibit bradycardia and terminal or nonterminal asystole during/following seizure and explored the contribution of vagal-mediated bradycardia to SUDEP.

Methods: Electrocardiography (ECG) studies of 27 freely moving telemetered NULL mice was evaluated surrounding seizure-associated death. Chronic unilateral vagal section and, in a separate set of experiments, electrical stimulation of the cervical vagi in NULL and wild-type (WT) littermates assessed the role of the vagus nerve in seizure-related death. Seizure activity indicated by intense myogenic activity on the ECG recording correlated with visual and video recording.

Results: All NULL died following seizures, which were preceded by normal rhythm. Bradycardia followed seizure and led to slow ventricular escape rhythm (70-150 bpm) and asystole. The sequence from seizure to asystole was complete within approximately 3 min and was similar to that reported in individuals exhibiting ictal and postictal bradycardia/asystole. To address the singular role of vagus nerves in seizure-related asystole, cervical vagus nerves were stimulated in the absence of seizure. Heart rate was reduced 3 min to values similar to that following seizure but never produced asystole, suggesting activation of the vagi alone is insufficient for SUDEP. Nevertheless, unilateral chronic section of the vagus nerve increased survival time compared to nonsectioned NULL animals, supporting a role for the vagus nerve in seizure-associated death.

Significance: The Kv1.1 null mouse is a potential model for SUDEP in patients who experience ictal and postictal bradycardia. It offers the opportunity for evaluation of the combination of factors, in addition to vagal activation, necessary to produce a terminal asystole following seizure. It is notable that long-term studies that evaluate electroencephalography (EEG) and cardiorespiratory events surrounding nonfatal seizures may provide indices predictive of terminal seizure.

Keywords: Kcna1; Parasympathetic; Vagus.