Severe peri-ictal respiratory dysfunction is common in Dravet syndrome
YuJaung Kim, … , Douglas R. Nordli Jr., George B. Richerson
YuJaung Kim, … , Douglas R. Nordli Jr., George B. Richerson
Published January 11, 2018
Citation Information: J Clin Invest. 2018;128(3):1141-1153. https://doi.org/10.1172/JCI94999.
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Research Article Neuroscience

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

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 Scn1aR1407X/+ 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.

Authors

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 Jr., George B. Richerson

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Figure 7

Peri-ictal apnea, bradycardia, and death were prevented by N-methylscopolamine administered into the lateral cerebral ventricle at very low dose (0.0003 mg/kg).

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Peri-ictal apnea, bradycardia, and death were prevented by N-methylscopo...
(A) Heart rate and breathing did not change in response to a heat-induced Racine scale 5 seizure in an Scn1aR1407X/+ mouse. A seizure occurred at the time indicated. Insets to the right were obtained at the times indicated with the vertical lines on the left. Respiratory activity and the ECG did not change during the seizure. Note that there was movement artifact seen intermittently on the respiratory trace. Sudden changes in amplitude of the ECG were also an artifact due to movements of the animal. (B) Summary of results from Scn1aR1407X/+ mice with heat-induced Racine scale 5 seizures after N-methylscopolamine (0.3 μg/kg, i.c.v.; n = 5). Breathing and heart rate were not affected in any of the mice. (C) Poincaré plots demonstrated that N-methylscopolamine (0.3 μg/kg, i.c.v.) did not block peripheral muscarinic receptors as seen by the lack of an effect on R-R interval. The Poincaré plots shown here are from a single animal. Summary data for replicate animals for this experiment are shown in Supplemental Figure 7. Number of replicates was 4 animals.