Sudden unexpected death in a mouse model of Dravet syndrome
Franck Kalume, … , Todd Scheuer, William A. Catterall
Franck Kalume, … , Todd Scheuer, William A. Catterall
Published March 25, 2013
Citation Information: J Clin Invest. 2013;123(4):1798-1808. https://doi.org/10.1172/JCI66220.
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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 1

Spontaneous seizures and sudden unexpected deaths in DS mice.

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Spontaneous seizures and sudden unexpected deaths in DS mice. (A) Incide...
(A) Incidence and duration of spontaneous generalized tonic-clonic convulsions 24 hours prior to death. Continuous short-term videos of DS mice in home cages were collected from P25 to P28. Times of death and convulsions in the 24 hours prior to each death were identified during off-line visual inspection of records. Incidence and duration of convulsions were calculated. Left bar graph illustrates higher incidence of seizures observed in mice that died (9.5 ± 3 seizures) than in those that survived (3 ± 2 seizures, P < 0.05). Right graph shows seizure durations (31.2 ± 9 s in mice that died vs. 29.9 ± 9 s in mice that survived, P > 0.05). *P < 0.05. Data are mean ± SD. (B) Survival plot (black line, left axis) and bar graph of daily convulsion incidence (right axis) in DS mice illustrating higher mortality and convulsion incidence in the fourth postnatal week of the mice. Continuous long-term videos of DS mice in home cages were collected from P20 to P34. Deaths and convulsions were identified during off-line inspections of records. Daily number of fatalities and seizure incidence were counted. (C) Graph of cumulative numbers of convulsions in mice studied in B showing a history of elevated number of convulsions experienced by mice that died sporadically during the monitoring period (P20–P34) than by those that survived.