Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA.
Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Epilepsia. 2018 Jan;59(1):92-105. doi: 10.1111/epi.13953. Epub 2017 Nov 28.
Chronic sleep deficiency is associated with early mortality. In the epileptic population, there is a higher prevalence of sleep disorders, and individuals with severe refractory epilepsy are at greater risk of premature mortality than the general population. Sudden unexpected death in epilepsy affects 1:1000 cases of epilepsy each year. Ketogenic diet (KD) treatment is one of the few effective options for refractory seizures. Despite KD reducing seizures and increasing longevity in Kv1.1 knockout (KO) mice, they still succumb to sudden death. This study aims to determine whether (1) the rest profiles of KO and KD-treated KO (KOKD) mice resemble each other as a function of either age or proximity to death and (2) the timing of death correlates with acute or chronic changes in rest.
Noninvasive actimetry was used to monitor rest throughout the lives of KO and wild-type (WT) littermates administered standard diet or KD.
As KO mice age, rest is reduced (P < .0001). Rest is significantly improved in KDKO mice (P < .0001), resembling WT values at several ages. When age is removed as a variable and data are realigned to the day of death, the rest profiles of KO and KOKD groups worsen to similar degrees as a function of proximity to death. The amount of rest acutely is not sensitive to the timing of death, whereas chronic rest deficiency profiles (10-15 days prior to death) of both groups were indistinguishable. Chronic accumulation of rest deficiency over the final 15 days was associated with 75% of deaths.
Our data suggest that the accumulated rest deficiency is associated with sudden death in Kv1.1 KO mice. These data (1) support the proposed clinical hypothesis that chronic sleep deficiency may be associated with early mortality in epileptic patients and (2) warrant future preclinical and clinical studies on sleep monitoring in epileptic patients.
慢性睡眠不足与早逝有关。在癫痫患者中，睡眠障碍更为普遍，而严重难治性癫痫患者的早逝风险高于普通人群。癫痫猝死影响每年每 1000 例癫痫患者。生酮饮食（KD）治疗是难治性癫痫发作的少数有效选择之一。尽管 KD 可减少 Kv1.1 敲除（KO）小鼠的癫痫发作并延长寿命，但它们仍会死于猝死。本研究旨在确定：（1）KO 和 KD 治疗的 KO（KOKD）小鼠的休息特征是否因年龄或接近死亡而相似；（2）死亡时间是否与休息时的急性或慢性变化相关。
非侵入性活动记录仪用于监测 KO 和 WT 同窝仔鼠在接受标准饮食或 KD 治疗期间的整个生命中的休息情况。
随着 KO 小鼠年龄的增长，休息时间减少（P<.0001）。KDKO 小鼠的休息时间明显改善（P<.0001），在几个年龄时与 WT 值相似。当年龄作为变量被去除并且数据重新调整到死亡当天时，KO 和 KOKD 组的休息特征随着接近死亡的程度而恶化到相似程度。急性休息量对死亡时间不敏感，而两组的慢性休息不足（死亡前 10-15 天）特征则无法区分。在最后 15 天内慢性休息不足的累积与 75%的死亡相关。
我们的数据表明，累积的休息不足与 Kv1.1 KO 小鼠的猝死有关。这些数据（1）支持提出的临床假说，即慢性睡眠不足可能与癫痫患者的早逝有关；（2）需要对癫痫患者的睡眠监测进行未来的临床前和临床研究。
