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.

中文翻译：

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严重的围壁呼吸功能障碍在Dravet综合征中很常见

Dravet综合征（DS）通常是由于钠通道基因SCN1A的突变引起的一种严重的儿童期癫痫病。DS患癫痫病（SUDEP）的原因不明的猝死风险很高，人们普遍认为这是由于心脏机制引起的。在这里，我们显示DS病人通常有周围性呼吸功能不全。一名患者在视频脑电图监测期间出现严重且长时间的通气不足，后来死于SUDEP。带有Scn1a ^{R1407X / +的}小鼠监测功能丧失突变并在中枢性呼吸暂停，进行性心动过缓引起的自发性和热诱发的癫痫发作后死亡。体温过高或最大电击诱发癫痫发作后，可通过机械通气预防死亡。当以对外周副交感神经阻滞有选择性的剂量给予时，毒蕈碱受体拮抗剂不能预防心动过缓或死亡，而以足以穿过血脑屏障的相同剂量给予的相同药物可以预防呼吸暂停，心动过缓和死亡。当以非常低的剂量通过脑室内注入时，毒蕈碱受体拮抗剂可以预防呼吸暂停，心动过缓和死亡。我们得出结论，DS患者的SUDEP可能由原发性中枢性呼吸暂停引起，可引起心动过缓，