Severe peri-ictal respiratory dysfunction is common in Dravet syndrome
Severe peri-ictal respiratory dysfunction is common in Dravet syndrome
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DOI：
10.1172/jci94999
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发表时间：
2018-03-01
影响因子：
15.9
通讯作者：
Richerson, George B.
中科院分区：
文献类型：
--
作者：
Kim, YuJaung;Bravo, Eduardo;Richerson, George B.
Dravet 综合征 (DS) 是一种严重的儿童期发病的癫痫，通常由钠通道基因 SCN1A 突变引起。 DS 患者发生癫痫性猝死 (SUDEP) 的风险很高，人们普遍认为这是由于心脏机制所致。在这里，我们发现 DS 患者通常有发作期呼吸功能障碍。一名患者在视频脑电图监测期间出现严重且长期的发作后通气不足，后来死于 SUDEP。对具有 Scn1a(R1407x/+) 功能丧失突变的小鼠进行监测，并在由于中枢性呼吸暂停和进行性心动过缓导致自发性和热诱发的癫痫发作后死亡。因高热或最大电击诱发癫痫发作后，可以通过机械通气来预防死亡。当以选择性外周副交感神经阻滞的剂量给予毒蕈碱受体拮抗剂时，不能预防心动过缓或死亡，而以足以穿过血脑屏障的剂量给予相同的药物可以预防呼吸暂停、心动过缓和死亡。当通过脑室内输注极低剂量时，毒蕈碱受体拮抗剂可以预防呼吸暂停、心动过缓和死亡。我们得出的结论是，DS 患者的 SUDEP 可能是由原发性中枢性呼吸暂停引起的，这可能是通过低氧血症对心肌的直接影响而导致心动过缓。
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.