Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

YuJaung Kim; Eduardo Bravo; Caitlin K Thirnbeck; Lori A Smith-Mellecker; Se Hee Kim; Brian K Gehlbach; Linda C Laux; Xiuqiong Zhou; Douglas R Nordli; George B Richerson

doi:10.1172/JCI94999

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Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

Journal article

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Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

YuJaung Kim, Eduardo Bravo, Caitlin K Thirnbeck, Lori A Smith-Mellecker, Se Hee Kim, Brian K Gehlbach, Linda C Laux, Xiuqiong Zhou, Douglas R Nordli and George B Richerson

The Journal of clinical investigation, Vol.128(3), pp.1141-1153

03/01/2018

DOI: 10.1172/JCI94999

PMCID: PMC5824857

PMID: 29329111

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Abstract

Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A . Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1a R1407X/+ loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death. We conclude that SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia, presumably via a direct effect of hypoxemia on cardiac muscle.

Neuroscience

Epilepsy

Respiration

Details

Title: Subtitle: Severe peri-ictal respiratory dysfunction is common in Dravet syndrome
Creators: YuJaung Kim - Department of Neurology and
Eduardo Bravo - Department of Neurology and
Caitlin K Thirnbeck - Department of Neurology and
Lori A Smith-Mellecker - Department of Neurology and
Se Hee Kim - Division of Pediatric Neurology, Northwestern University, Chicago, Illinois, USA
Brian K Gehlbach - Department of Internal Medicine and
Linda C Laux - Division of Pediatric Neurology, Northwestern University, Chicago, Illinois, USA
Xiuqiong Zhou - Department of Neurology and
Douglas R Nordli - Division of Pediatric Neurology, Northwestern University, Chicago, Illinois, USA
George B Richerson - Department of Neurology and
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.128(3), pp.1141-1153
Publisher: American Society for Clinical Investigation
DOI: 10.1172/JCI94999
PMID: 29329111
PMCID: PMC5824857
ISSN: 0021-9738
eISSN: 1558-8238
Grant note: U01 NS 090414 / NIH N/A / Beth L. Tross Epilepsy research fund
Language: English
Date published: 03/01/2018
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Iowa Neuroscience Institute; Neurosurgery; Internal Medicine
Record Identifier: 9984013110702771

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