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CC BY-NC-ND 4.0 · Asian J Neurosurg
DOI: 10.1055/s-0045-1806802
Original Article

Spontaneous Intracerebral Hemorrhage Occurring During Sleep: Clinical Characteristics and Risk Factors

Joji Inamasu 
1   Department of Neurosurgery, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan
,
Sota Wakahara
1   Department of Neurosurgery, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan
,
Takeo Oshima
2   Department of Neurology, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan
› Author Affiliations

Funding None.
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Abstract

Background

Ischemic stroke occurring during sleep has been known as wake-up stroke, and many studies have been conducted on the subject. On the other hand, there have only been a few studies on spontaneous intracerebral hemorrhage (ICH) occurring during sleep. To clarify their clinical characteristics and possible risk factors, a single-center retrospective study was conducted on nontraumatic ICH patients admitted to our institution between 2012 and 2017.

Materials and Methods

Demographics and outcomes were compared between 119 patients with ICH occurring during sleep (sleep group) and 401 patients with ICH occurring during the awake period (awake group). Multivariate regression analysis was conducted to identify risk factors. Furthermore, clinical presentation in those 119 patients was further classified into three categories (deficits, sudden headache, and failure to wake up), and their association to the outcomes was evaluated.

Results

Compared with the awake group, the frequency of chronic kidney disease (CKD) and diabetes mellitus were significantly higher in the sleep group. Multivariate regression analysis identified CKD as a risk factor for ICH occurring during sleep. The in-hospital mortality rate was significantly higher in the sleep group. Among the three classifications, failure to wake up was indicative of high mortality rate.

>Conclusion

The current results that ICH occurring during sleep was indicative of worse outcomes is compatible with prior studies. Poorly controlled nocturnal hypertension in patients with CKD and diabetes mellitus may be responsible for the higher incidence of ICH occurring sleep in those populations. The three classifications according to clinical presentation may be useful as a prognosticator.


 

Keywords

intracerebral hemorrhage - sleep - risk factor - chronic kidney disease - diabetes

Introduction

There have been numerous studies on the frequency and risk factors of ischemic stroke that occur during sleep, commonly referred to as wake-up stroke.[1] Moreover, in recent years, mechanical thrombectomy has been actively performed in eligible cases with wake-up stroke.[2] In contrast, studies on hemorrhagic stroke occurring during sleep remain exceedingly scarce.[3] [4] We conducted a study to identify the clinical characteristics and risk factors of patients with spontaneous intracerebral hemorrhage (sICH) occurring during sleep.


 

Materials and Methods

Patient Selection

This was a single-center, retrospective study with a study period between January 2012 and December 2017. For all the sICH patients admitted via our emergency department (ED), stroke types and presenting symptoms as well as detailed data on when, where, and how their symptoms developed were registered on the database by ED residents. Based on behaviors at the time of onset, sICH patients were classified into two groups: those with onset during sleep (sleep group) and those with onset while awake (awake group). For comparison, the proportion of the awake group was also searched for patients with cerebral infarction (CI) and aneurysmal subarachnoid hemorrhage (SAH) treated at our institution during the same period. Patients with ICH secondary to trauma, vascular malformations (such as cerebral aneurysms and arteriovenous malformations), abnormal vasculature (such as moyamoya disease), or infections (such as bacterial endocarditis) were excluded.


 

Two-Group Comparison

Between the sleep group and the awake group, demographic variables including age, sex, systolic blood pressure (BP) measured at ED, comorbidities (hypertension, history of ischemic heart disease, history of stroke, diabetes mellitus, hyperlipidemia, chronic kidney disease, smoking history, use of oral antiplatelet agents, and use of oral anticoagulants), the Glasgow Coma Scale (GCS) score at admission, and the anatomical location of the sICH (basal ganglia/subcortical/posterior fossa) were compared. The GCS scores of 15, ≤8, and 3 were defined as indicators of alertness (GCS 15), coma (GCS ≤8), and deep coma (GCS 3). Additionally, the outcomes at hospital discharge evaluated with the modified Rankin scale (mRS) were compared: those with mRS scores ≤ were defined as having favorable outcomes. The National Institutes of Health Stroke Scale (NIHSS) score was not analyzed in this study due to insufficient data collection during the study period.


 

Multivariate Logistic Regression Analysis

A multivariate logistic regression analysis was conducted using the aforementioned 11 demographic variables (age, sex, hypertension, history of ischemic heart disease, history of stroke, diabetes, hyperlipidemia, chronic kidney disease, smoking history, use of oral antiplatelet agents, and use of oral anticoagulants) to identify potential risk factors associated with sICH occurring during sleep.


 

Subgroup Analysis Based on the Mode of Clinical Presentations

The sleep group was further subdivided into three categories based on the mode of presentation to the ED: (1) deficits noticed after waking up (deficits), (2) sudden headache waking up patients (sudden headache), and (3) failure to wake up. Their proportions and association with the outcomes were evaluated.


 

Ethical Approval

This study was approved by the institutional review board of the institution (approval number: 17-0013; approval date: October 17, 2017) and conducted in accordance with the Declaration of Helsinki. The need for informed consent from each participant was waived by the institutional review board.


 

 

Statistical Analysis

Statistical analysis was performed using SPSS version 18.0 (SPSS Inc., Chicago, IL, United States). For continuous variables (expressed as mean ± standard deviation), Student's t-test was used, and Fisher's exact test was performed for categorical variables. A p-value of less than 0.05 was considered statistically significant.


 

Results

Frequency

During the study period, a total of 710 ICH patients were brought to our ED. After excluding 41 patients who met the exclusion criteria, 669 sICH patients were identified, among whom 149 patients had unclear behavioral patterns at onset and excluded from analysis. Ultimately, 520 sICH patients with a clear behavioral pattern at onset were included for analysis. Among those, 119 patients (22.9%) had onset during sleep. During the same period, 1,527 patients with CI and 257 patients with aneurysmal SAH were brought to our ED, with sleep-onset CI occurring in 406 (26.7%) patients and sleep-onset SAH occurring in 41 (16.0%) among those two groups. The proportion of the sleep group among the sICH patients was lower than that of CI patients (26.7%) but was higher than that of SAH patients (16.0%). A significant difference was noted between sICH and SAH patients (p = 0.03; [Fig. 1]).

Zoom
Fig. 1 The total number of acute stroke patients treated from 2011 to 2016 was as follows: 1,527 cases of cerebral infarctions, 520 cases of intracerebral hemorrhages (ICHs), and 257 cases of subarachnoid hemorrhages (SAHs). Among these, the number of patients with onset during sleep was 406 (cerebral infarctions), 119 (ICHs), and 41 (SAHs). The proportion of ICHs with onset during sleep was significantly higher than that SAHs (p = 0.03*).

 

Two-Group Comparison

A comparison of demographic variables between the sleep group and the awake group is shown in [Table 1]. No significant differences were observed between the two groups in terms of age and gender ratio. While the sleep group exhibited lower systolic BP at ED arrival, the difference was not statistically significant (179.9 ± 38.8 vs. 187.4 ± 40.0 mm Hg; p = 0.07). Among the comorbidities, significant differences had been found for diabetes (27.7% in the sleep group vs. 18.7% in the awake group; p = 0.04) and chronic kidney disease (24.4% in the sleep group vs. 12.7% in the awake group; p = 0.004; [Table 1]). Regarding the neurological severity, no significant differences had been observed between the two groups in terms of a GCS score of 15 (alert) or a GCS score of ≤8 (coma). However, the frequency of a GCS score of 3 (deep coma) was significantly higher in the sleep group (14.3 vs. 6.7%; p = 0.01). In terms of the anatomical location of the hematoma, the sleep group tended to have a higher frequency of basal ganglia hemorrhage and a lower frequency of subcortical hemorrhage. However, the difference did not reach statistical significance (both p = 0.07).

Table 1

Comparison of demographic variables in sICH occurring during sleep and sICH occurring during awake activities

Sleep (n = 119)

Awake (n = 401)

p-Value

Age (y)

66.7 ± 15.1

66.3 ± 12.7

0.80

Male:female

75:44

236:165

0.47

SBP at emergency department

179.9 ± 38.8

187.4 ± 40.0

0.07

Hypertension

88 (54.4%)

276 (44.2%)

0.31

Ischemic heart diseases

20 (16.8%)

59 (14.7%)

0.47

Prior stroke

34 (28.6%)

82 (20.4%)

0.08

Diabetes mellitus

33 (27.7%)

75 (18.7%)

0.04[a]

Hyperlipidemia

21 (17.6%)

61 (15.2%)

0.67

Chronic kidney diseases

29 (24.4%)

51 (12.7%)

0.004[a]

Smoking

28 (23.5%)

110 (27.4%)

0.48

Antiplatelet

27 (22.7%)

63 (15.7%)

0.10

Anticoagulant (warfarin 33, DOAC 7)

13 (10.9%)

27 (6.7%)

0.17

GCS 15

32 (26.9%)

119 (29.7%)

0.65

GCS ≤ 8

43 (36.1%)

118 (29.4%)

0.18

GCS 3

17 (14.3%)

27 (6.7%)

0.01[a]

Basal ganglia

81 (68.1%)

234 (58.3%)

0.07

Subcortex

14 (11.8%)

76 (19.0%)

0.07

Posterior fossa

25 (21.0%)

88 (21.9%)

0.90

Abbreviations: DOAC, direct oral anti-coagulant; GCS, Glasgow Coma Scale; SBP, systolic blood pressure.


a Statistically significant.



 

Outcomes

A comparison of outcomes at hospital discharge between the two groups is shown in [Table 2]. While no significant difference was observed between the two groups in the proportion of favorable outcomes (13.4 vs. 14.7%; p = 0.88), the in-hospital mortality rate was significantly higher in the sleep group (39.5 vs. 24.2%; p = 0.002).

Table 2

Comparison of outcomes evaluated at hospital discharge between sICH occurring during sleep and sICH occurring during awake activities

Sleep (n = 119)

Awake (n = 401)

p-Value

Surgical intervention

6 (5.0%)

35 (8.7%)

0.25

Hospital stay (d)

25.8 ± 15.6

24.2 ± 14.0

0.59

Favorable outcomes (mRS ≤ 2)

16 (13.4%)

59 (14.7%)

0.88

In-hospital mortality (mRS 6)

47 (39.5%)

97 (24.2%)

0.002[a]

Abbreviations: mRS, modified Rankin scale; sICH, spontaneous intracerebral hemorrhage.


a Statistically significant.



 

Multivariate Logistic Regression Analysis

Among the 11 variables mentioned earlier, chronic kidney disease was identified as a factor significantly associated with sleep-onset sICH (odds ratio: 1.989; 95% confidence interval: 1.149–3.445; p = 0.014; [Table 3]).

Table 3

Multivariate logistic regression analysis to identify variables associated with sICH occurring during sleep

Variables

OR

95% CI

p-Value

Age

0.996

0.979–1.014

0.660

Male gender

1.177

0.979–1.014

0.492

Hypertension

0.889

0.541–1.458

0.640

Ischemic heart diseases

1.324

0.686–2.555

0.402

Prior stroke

1.179

0.686–2.024

0.552

Diabetes mellitus

1.428

0.861–2.368

0.167

Hyperlipidemia

1.011

0.553–1.849

0.971

Chronic kidney diseases

1.989

1.149–3.445

0.014[a]

Smoking

1.193

0.715–1.989

0.499

Antiplatelet

1.319

0.719–2.421

0.371

Anticoagulant

1.887

0.845–4.215

0.121

Abbreviations: CI, confidence interval; OR, odds ratio; sICH, spontaneous intracerebral hemorrhage.


a Statistically significant.



 

Mode of Clinical Presentations and Outcome

The frequencies of onset for patterns (1), (2), and (3) were 43, 16, and 41%, respectively ([Fig. 2A]). When examining the relationship between those patterns and in-hospital mortality, pattern (3) had a mortality rate of 71%, which was significantly higher compared to those of pattern (1) with a mortality rate 12% and pattern (2) with a mortality rate 32% ([Fig. 2B]).

Zoom
Fig. 2 Presentations in intracerebral hemorrhages (ICHs) occurring during sleep were classified into three groups: (1) deficits noticed after waking up, (2) sudden headache, and (3) failure to wake up. (A) The proportions of each pattern were 43, 16, and 41, respectively. (B) Relationship between mortality and each presentation pattern. The mortality in pattern (3) was significantly higher compared to the other two groups.

 

 

Discussion

In hemorrhagic stroke, the events that may trigger bleeding are often common between sICH and SAH: activities such as sexual intercourse, straining during constipation, and intense physical exercise may lead to a sudden increase in BP or abdominal pressure, and those are known triggers for both sICH and SAH.[5] [6] However, the mechanisms of bleeding in sICH and SAH may not entirely be the same. In this study, the proportion of the sleep group in sICH was significantly higher than that in SAH ([Fig. 1]). This finding may reflect the observation that the mechanism of bleeding in ICH may be less dependent on BP fluctuations compared to SAH,[6] under the assumption that BP does not fluctuate much during sleep. However, in reality, BP is not constant during sleep; it fluctuates according to the sleep phases. Notably, in patients with chronic kidney disease and severe diabetes, BP fluctuations during sleep are more pronounced, and nocturnal hypertension occurs more frequently.[7] [8] [9] This may help explain the finding in this study that chronic kidney disease may be a risk factor for sICH during sleep. While a statistically significant difference was not observed in the multivariate regression analysis, a certain degree of association between diabetes and sleep-onset stroke may not be ruled out. The pathophysiology of BP fluctuations during sleep in patients with diabetes and chronic kidney diseases remains unclear: because of lack of BP measurement before onset in our cohort, whether patients with diabetes or chronic kidney diseases actually had greater nocturnal BP in our cohort remains unanswerable. Further investigation is needed in the future to better understand this phenomenon. Systolic BP at ED in the sleep group tended to be lower than the awake group ([Table 2]). According to the study by Martí-Fàbregas et al, the sleep group also had lower systolic BP, while the diastolic BP was higher in that group.[4] Therefore, the presence of large pulse pressure may causally be associated with sICH occurring during sleep.

Compared to ischemic stroke, there are very few reports on the prognosis and treatment of hemorrhagic stroke occurring during sleep. In a study by Nagakane et al, the sleep group had a significantly higher 1-month mortality rate compared to the awake group.[3] In our study, the in-hospital mortality rate was also significantly higher in the sleep group, consistent with the previous report. One possible explanation for the higher mortality rate in the sleep group could be that many cases had already been in deep coma (GCS score of 3) at the time of ED arrival. In the aforementioned report by Nagakane et al, there was also a significant difference in hematoma volume between the two groups, with the sleep group having a significantly larger hematoma volume.[3]

A unique feature of this study is that, due to the relatively large sample size, it was possible to further make subdivisions (into 3 groups) based on the mode of presentations. It is intuitively understandable that the pattern (3), that is, failure to wake up, predicts the worse outcomes, considering that patients with large hematoma volume and/or deep-seated hematoma tend to have both disturbed consciousness and poor outcomes. Nevertheless, this is probably the first study to report concrete numerical value—71% in-hospital mortality rate for this presentation pattern—making this study meaningful in predicting outcomes based on clinical symptoms. Of note, however, was that the larger hematoma volume in the sleep group simply may have been a reflection of the longer interval between onset and clinical recognition in that group.

There are a few limitations of this study. First, it is a retrospective study conducted at a single institution, and, particularly, our institution is a tertiary stroke center where patients with disturbed consciousness are often transferred from beyond the medical jurisdiction. As a result, the proportion of severe sICH patients may have increased beyond the population proportion of the medical area, potentially introducing a bias. Second, the study period was from 2011 to 2016, and therefore, the data are not the most recent. Although no significant impact of oral anticoagulant use was observed in this study, the majority of patients who were using anticoagulants were on warfarin ([Table 2]). In recent years, direct oral anticoagulants have been used more frequently than warfarin,[10] and if the study period had been more recent, it is possible that the results could have differed. Additionally, this study did not differentiate between hypertensive hemorrhage and hemorrhagic strokes caused by cerebral amyloid angiopathy. While there are overlapping and distinct risk factors for both conditions,[11] the mixture of those two pathologies may have made it more challenging to distinguish risk factors. Finally, in recent years, reports have increasingly indicated that sleep disorders, such as sleep apnea syndrome, are risk factors for hemorrhagic stroke.[12] However, sleep disorders were not investigated in this study.


 

Conclusion

The outcomes of the sleep group was significantly worse compared to those of the awake group. Chronic kidney disease was identified as a potential risk factor for sleep-onset sICH. Furthermore, the presence of large pulse pressure may also be associated with sICH occurring during sleep. In patients with chronic kidney disease and advanced-stage diabetes, substantial BP fluctuations during sleep may have contributed to the onset of sICH during sleep. The outcomes may differ among clinical presentations, with particularly high mortality rates observed in those who failed to wake up.


 

 

Conflict of Interest

None declared.

Authors' Contributions

J.I. contributed to the conception of the study, writing of the manuscript, and statistical analysis. S.W. and T.O. contributed to data collection.


Ethical Approval

This report was approved by the Ethics Committee of our institution and conducted in accordance with the Declaration of Helsinki.



Address for correspondence

Joji Inamasu, MD, FACS
Department of Neurosurgery, Saiseikai Utsunomiya Hospital
Utsunomiya, Tochigi 321-0974
Japan   

Publication History

Article published online:
21 March 2025

© 2025. Asian Congress of Neurological Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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Zoom
Fig. 1 The total number of acute stroke patients treated from 2011 to 2016 was as follows: 1,527 cases of cerebral infarctions, 520 cases of intracerebral hemorrhages (ICHs), and 257 cases of subarachnoid hemorrhages (SAHs). Among these, the number of patients with onset during sleep was 406 (cerebral infarctions), 119 (ICHs), and 41 (SAHs). The proportion of ICHs with onset during sleep was significantly higher than that SAHs (p = 0.03*).
Zoom
Fig. 2 Presentations in intracerebral hemorrhages (ICHs) occurring during sleep were classified into three groups: (1) deficits noticed after waking up, (2) sudden headache, and (3) failure to wake up. (A) The proportions of each pattern were 43, 16, and 41, respectively. (B) Relationship between mortality and each presentation pattern. The mortality in pattern (3) was significantly higher compared to the other two groups.