Association of ischemic stroke onset time with presenting severity, acute progression, and long-term outcome: A cohort study

Abstract

Background

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.

Methods and findings

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.

Conclusions

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.

Abstract

Wi-Sun Ryu and colleagues investigate the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in ischemic stroke.

Author summary

Why was this study done?

• The diurnal pattern in the distribution of ischemic stroke suggests an influence of circadian rhythms on stroke incidence, but it is unclear whether circadian rhythms may also affect the clinical severity of stroke, and whether time-of-day of stroke occurrence may affect acute clinical worsening after stroke onset.

What did the researchers do and find?

• We performed a multicenter study of 17,461 consecutive patients with ischemic stroke to investigate whether time-of-day of stroke occurrence affected initial clinical severity and progressive clinical worsening within the first 72 hours after onset.

• Night-onset stroke patients were found to have greater clinical severity, and a higher likelihood of experiencing early neurologic worsening during the first 72 hours following symptom onset.

• These patients were also found to have a lower likelihood of favorable 3-month global disability outcome than day-onset stroke patients.

What do these findings mean?

• Our large-scale clinical data suggest that there is a circadian variation in ischemic stroke progression and severity.

• These findings indicate that circadian time of stroke-onset may be an important factor to consider in future epidemiological studies and treatment trials for acute ischemic stroke.

• Further basic science and clinical investigation probing the chronobiologic mechanism of acute brain ischemia may help to identify new pharmacologic targets.