Department of Neurology, Dongguk University Ilsan Hospital, Goyang, Korea.
National Priority Research Center for Stroke, Goyang, Korea.
PLoS Med. 2022 Feb 4;19(2):e1003910. doi: 10.1371/journal.pmed.1003910. eCollection 2022 Feb.
Preclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke.
In a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules.
Night-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.
临床前数据表明，缺血性卒中进展存在昼夜节律变化，与非活动期（白天）相比，在处于活动期（夜间）的啮齿动物模型中，细胞死亡和梗死面积增加更为活跃。我们旨在研究卒中发作时间与发病时严重程度、早期神经功能恶化（END）以及人类缺血性卒中的长期功能结局之间的相关性。
在 2011 年 5 月至 2020 年 7 月期间，我们进行了一项来自韩国全国多中心观察性队列研究，评估了昼夜节律对初始卒中严重程度（入院时国立卫生研究院卒中量表[NIHSS]评分）、END 和有利功能结局（3 个月改良 Rankin 量表[mRS]评分 0 至 2 分与 3 至 6 分）的影响。我们纳入了 17461 例发病 6 小时内的有目击者的缺血性卒中患者。将卒中发作时间分为两组（白天发作[06：00 至 18：00]与夜间发作[18：00 至 06：00]）和六组（每 4 小时一组）。我们使用混合效应有序或逻辑回归模型，同时考虑了医院聚类。平均年龄为 66.9（SD 13.4）岁，其中 6900 例（39.5%）为女性。2219 例（12.7%）患者发生 END。在校正包括年龄、性别、既往卒中、发病前 mRS 评分、入院 NIHSS 评分、高血压、糖尿病、血脂异常、吸烟、房颤、发病前抗血小板治疗、发病前他汀类药物治疗、血管再通、卒中发作季节以及从发病到入院的时间等混杂因素后，夜间发作的卒中更易发生 END（校正发病率 14.4%与 12.8%，p=0.006），且更可能出现不良结局（校正优势比，0.88[95%CI，0.79 至 0.98]；p=0.03）。当按 4 小时间隔分组时，入院 NIHSS 评分呈单调递增梯度，从 06：00 至 10：00 的最低点上升到 02：00 至 06：00 的最高点。18：00 至 22：00 和 22：00 至 02：00 发作的卒中患者比 06：00 至 10：00 发作的卒中患者更易发生 END。3 个月时，有利功能结局的发生率呈单调递增梯度，从 06：00 至 10：00 的峰值下降到 22：00 至 02：00 的最低点。研究的局限性包括缺乏关于睡眠障碍和患者工作/活动时间表的信息。
与日间发作的卒中相比，夜间发作的卒中与更高的发病时神经严重程度、更频繁的 END 和更差的 3 个月功能结局相关。这些发现表明，卒中发作的昼夜节律是纳入卒中流行病学自然史研究和神经保护及再灌注药物治疗急性缺血性卒中临床试验的一个重要附加变量。
