3 years ago

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome.

Caitlin K Thirnbeck, Douglas R Nordli Jr, Linda C Laux, Brian K Gehlbach, Se Hee Kim, Eduardo Bravo, YuJaung Kim, Lori A Smith-Mellecker, George B Richerson
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. DS patients have a high risk of sudden unexplained death in epilepsy (SUDEP), believed to be due to cardiac mechanisms. Here we show that DS patients have peri-ictal respiratory dysfunction. One patient who had severe and prolonged postictal hypoventilation later died of SUDEP. Mice with an Scn1aR1407X/+ loss of function mutation died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures 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 was prevented at doses known to be high enough to cross the blood brain barrier. Anoxia causes bradycardia due to a direct effect on the heart. We conclude that SUDEP in DS may result in some cases from primary central apnea, which can cause bradycardia presumably via an effect of hypoxemia on cardiac muscle.

Publisher URL: http://doi.org/10.1172/JCI94999

DOI: 10.1172/JCI94999

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