Sudden unexpected death in a mouse model of Dravet syndrome
Franck Kalume, Ruth E. Westenbroek, Christine S. Cheah, Frank H. Yu, John C. Oakley, Todd Scheuer, William A. Catterall
Franck Kalume, Ruth E. Westenbroek, Christine S. Cheah, Frank H. Yu, John C. Oakley, Todd Scheuer, William A. Catterall
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Research Article

Sudden unexpected death in a mouse model of Dravet syndrome

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsies, but physiological mechanisms that lead to SUDEP are unknown. Dravet syndrome (DS) is an infantile-onset intractable epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes brain type-I voltage-gated sodium channel NaV1.1. We studied the mechanism of premature death in Scn1a heterozygous KO mice and conditional brain- and cardiac-specific KOs. Video monitoring demonstrated that SUDEP occurred immediately following generalized tonic-clonic seizures. A history of multiple seizures was a strong risk factor for SUDEP. Combined video-electroencephalography-electrocardiography revealed suppressed interictal resting heart-rate variability and episodes of ictal bradycardia associated with the tonic phases of generalized tonic-clonic seizures. Prolonged atropine-sensitive ictal bradycardia preceded SUDEP. Similar studies in conditional KO mice demonstrated that brain, but not cardiac, KO of Scn1a produced cardiac and SUDEP phenotypes similar to those found in DS mice. Atropine or N-methyl scopolamine treatment reduced the incidence of ictal bradycardia and SUDEP in DS mice. These findings suggest that SUDEP is caused by apparent parasympathetic hyperactivity immediately following tonic-clonic seizures in DS mice, which leads to lethal bradycardia and electrical dysfunction of the ventricle. These results have important implications for prevention of SUDEP in DS patients.

Authors

Franck Kalume, Ruth E. Westenbroek, Christine S. Cheah, Frank H. Yu, John C. Oakley, Todd Scheuer, William A. Catterall

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Figure 5

Ictal bradycardia and premature death.

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Ictal bradycardia and premature death. (A) Representative traces of EEG-...
(A) Representative traces of EEG-ECG records (black, blue), instantaneous heart rate, and instantaneous EEG power before death, illustrating the seizure and bradycardia preceding death. Time of death was defined as the moment when the power of the EEG fell to zero value, which coincided with cessation of ambulatory and respiration movements. Inset shows magnification of power trace below. (B) Left shows seizure durations in 4 DS (black) and 4 F/+:Dlx-Cre+ mice (gray) that died. In DS mice, the duration of seizures was 32.9 ± 5.5 ms for fatal seizures vs. 27.1 ± 5.6 ms for nonfatal seizures (P > 0.05). In F/+:Dlx-Cre+ mice, duration was 13.2 ± 3.0 for fatal seizures vs. 13.2 ± 4.0 ms for nonfatal (P > 0.05). Right shows bradycardia duration. DS mice, 22.8 ± 2.0 ms in fatal seizures vs. 5.1 ± 1.0 ms in nonfatal ones; F/+:Dlx-Cre+ mice, no nonfatal seizures; bradycardia duration for fatal seizures, 6.4 ± 2.0 ms. (C) Fractional changes in ECG parameters during nonfatal bradycardia in DS mice (n = 4), calculated as the ratio ictal bradycardia/baseline. (D) Fractional changes in ECG parameters in fatal bradycardia. Left shows DS mice (n = 4). Right shows F/+:Dlx-Cre+ mice (n = 4). *P < 0.05.