Severe peri-ictal respiratory dysfunction is common in Dravet syndrome
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.
Jose Eduardo Peixoto-Santos, Luciana Estefani Drumond de Carvalho, Ludmyla Kandratavicius, Paula Rejane Beserra Diniz, Renata Caldo Scandiuzzi, Roland Coras, Ingmar Bl ümcke, Joao Alberto Assirati, Carlos Gilberto Carlotti, Caio Cesar Marconato Simoes Matias, Carlos Ernesto Garrido Salmon, Antonio Carlos dos Santos, Tonicarlo R. Velasco, Marcio Flavio D. Moraes, Joao Pereira Leite
Condition: Epilepsy Intervention: Other: An App for reminding patients to take their medication Sponsor: Tahel Ilan Ber Not yet recruiting
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