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 Jr., George B. Richerson
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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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 2

Prolonged postictal hypoventilation in a patient with DS.

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Prolonged postictal hypoventilation in a patient with DS. (A) Schematic ...
(A) Schematic of events while recording cardiorespiratory activity during and after a seizure in a 9-year-old girl with DS. The numbers above the upper line in A are measured values of tcCO2. The upper line shows the approximate time course of the changes in tcCO2. Arrows labeled “b-e” denote the time of recordings shown in parts B–E, respectively. Arrows also denote when supplemental O2 was administered or discontinued, and when the patient was stimulated to cause arousal. Red shading denotes convulsive seizures and orange shading denotes periods of decreased responsiveness and EEG slowing. (B–E) Respiratory impedance plethysmography (Pleth) and ECG during normal breathing when tcCO2 was 43 mmHg (B), between convulsive seizures (C), after the seizures when tcCO2 had risen to 53 mmHg (D), and 44 minutes after the seizures when tcCO2 had risen to 68 mmHg (E). At 2 hours, tcCO2 decreased when the patient was stimulated to arouse, but did not return to baseline until 4 hours.