Characteristics of Wake-up Stroke Aki Tanimoto, BA,* Prachi Mehndiratta, MBBS, MD,† and Brian B. Koo, MD†
Background: Wake-up stroke (WUS) accounts for up to 29.6% of ischemic strokes, but its mechanisms are poorly understood. The purpose of this study is to identify risk factors and characteristics of WUS. Methods: Seven-two ischemic strokes were classified as WUS or non-WUS. Collected were demographic information, medical history, cholesterol profile, and stroke characteristics including severity (National Institutes of Health Stroke Scale [NIHSS]) and mechanism (Trial of Org 10172 in Acute Stroke Treatment criteria). Subjects completed questionnaires screening for sleep apnea (Berlin questionnaire) and assessing sleep characteristics. Results: There were 72 ischemic strokes, of which 28 WUS (38.9%). WUS and non-WUS patients were similar in regard to stroke risk factors. WUS patients tended to be African American and were significantly younger. WUS was significantly more likely to result from small-vessel disease mechanism (42.9% versus 14.0%; P 5 .006) and tended to be less severe WUS (NIHSS score 3 [1, 4] versus 4 [2, 11]; P 5 .13) than non-WUS. Groups did not differ in regard to scoring positively on the Berlin questionnaire, but WUS sufferers were more likely to snore frequently (90.5% versus 70.0%, P 5 .08). The lipid profile was significantly worse in WUS compared with non-WUS (low-density lipoprotein 124.6 6 38.4 versus 103.7 6 36.8; P 5 .03; cholesterol to high-density lipoprotein ratio 5.2 6 1.6 versus 4.3 6 1.6; P 5.02). Conclusions: WUS is more likely to result from small-vessel disease mechanism. Poorer cholesterol profile and frequent snoring may contribute to WUS. Key Words: Wake-up stroke—small vessel—cholesterol—sleep apnea. Ó 2013 by National Stroke Association
Introduction Ischemic stroke displays a circadian pattern of occurrence with morning hours being the most likely time of onset.1,2 Stroke occurring during sleep or wake-up stroke (WUS) accounts for a significant portion of these morning strokes and 14%-29.6% of all ischemic strokes.2,3 Because the exact time of stroke onset is obscured in WUS, the use of time-sensitive intravenous thrombolytic therapy is precluded. Given this disconnect, it is of utmost importance From the *Case Western Reserve University School of Medicine, Cleveland, Ohio; and †Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio. Received September 4, 2013; revision received October 7, 2013; accepted October 24, 2013. The authors have no conflicts of interest to disclose. Address correspondence to Brian B. Koo, MD, Department Neurology, West Haven Veterans Affairs, 950 Campbell Avenue, West Haven, CT 06516. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.10.021
to maximize understanding of WUS, including its underlying pathophysiologic mechanisms and clinical features to increase the chances of timely therapy and ultimately a good outcome. Data regarding the clinical features of WUS are conflicting. Prior studies have reached differing conclusions regarding severity of WUS versus non-WUS, some finding that WUS is more severe and others finding no difference.2-5 Similarly, there is no consensus on WUS mechanism. Several studies have not found a significant difference in stroke mechanism,2,6 whereas others have associated lacunar syndromes and small-vessel mechanism with WUS.4,5,7 Analysis of International Stroke Trial data, including 17,398 ischemic strokes and over 5000 WUS, found that WUS was less likely to include severe anterior circulation syndromes, less severe on presentation but deteriorated to similarly low functional status as non-WUS at 6 months.3 Although severity and mechanism of WUS have been investigated, pathophysiologic risk factors that predispose to WUS have not been well studied. Because WUS
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occurs during sleep, it seems likely that disordered sleep could play a mechanistic role in producing WUS. Obstructive sleep apnea (OSA) seems a conspicuous candidate for involvement in WUS as it has consistently proven an independent stroke risk factor.8 As prior data have suggested that small-vessel disease underlies WUS, diabetes control and cholesterol profile may be other factors that increase risk for WUS. Thus, the aim of the present study is to investigate ischemic WUS occurrence and its potential relationship to sleep disordered breathing while determining clinical features of WUS. We hypothesize that persons with stroke occurring in the sleeping period are more likely to have high risk for OSA and that WUS compared with non-WUS is less severe, more likely of small rather than large-vessel mechanism and associated with measurements of hyperlipidemia and poor blood glucose control.
Methods Subjects Acute ischemic stroke patients presenting to University Hospitals Case Medical Center in March and April 2012 and from January to March 2013 were prospectively enrolled. Ischemic stroke was confirmed radiographically by restricted diffusion on brain magnetic resonance imaging, and stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Transient ischemic attacks, hemorrhagic stroke, and venous infarct were not included in this analysis. Subjects were also excluded if there were other medical issues that were likely related to stroke mechanism including malignancy, gastrointestinal bleeding, drug use, rheumatologic exacerbation, and central nervous system infection. Participants were carefully asked about whether symptoms of stroke were present on waking up or began during wakefulness. Lack of confirmation of symptoms arising in either sleep or wakefulness constituted exclusion. Participants provided written informed consent, and the study was approved by the Institutional Review Board of University Hospitals Case Medical Center.
present if 2 of 3 categories are scored.9 Snoring frequency was also used as a surrogate for sleep apnea risk. Strokes were classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria as small vessel, large vessel, cardioembolic, or cryptogenic.10 Localization was further classified as arising from anterior or posterior circulation based on magnetic resonance imaging scanning. Stroke volume (volume) was measured using ABC/2 criteria in which diffusion-weighted imaging, the longest lesion axis (A), its perpendicular (B), and the product of slice number and slice thickness (C) are measured. The product of these measures is then divided by 2 (ABC/2).11
Statistical Analysis Descriptive statistics included frequency for categorical variables, mean and standard deviation for continuous variables, and medians with interquartile range for ordinal variables. Characteristics of WUS were compared with non-WUS using c2, Student t, and Mann–Whitney testing for categorical, continuous, and ordinal variables, respectively. Logistic and multivariate regression analyses were carried out to model the likelihood of smallvessel disease or low-density lipoprotein, respectively, given parameters of age, sex, BMI, diabetes status, and WUS. All significance levels reported were 2 sided. Analyses were conducted using the R statistical package version 2.15.2 (Auckland, New Zealand).
Results Demographic Data There were 72 ischemic stroke patients, 46 men (63.9%), 28 WUS (38.9%), and 44 non-WUS. In the overall sample, age (mean 6 SD) was 66.3 6 14.3 (range 25-97), BMI was 30.8 6 9.0, and admission NIHSS score (median, IQ range) was 4 (2, 7). WUS patients tended to be African American (53.6% versus 34.1%; P 5 .10) and were significantly younger (61.8 6 15.4 versus 69.1 6 13.0; P 5 .04) than non-WUS sufferers. There was no significant difference between the BMI and gender makeup of the groups.
Participant Clinical Characteristics Patient and Stroke Characteristics Data collected included age, sex, race, body mass index (BMI, kg/m2), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), hemoglobin A1c, and blood pressure on admission. Comorbidities noted were hypertension, diabetes, hyperlipidemia, atrial fibrillation, and patent foramen ovale. Stroke onset was noted and recorded as WUS if neurologic deficits were present on waking. Participants or participant next of kin completed the Berlin sleep apnea questionnaire, which consists of 10 questions in 3 categories: snoring/apnea, sleepiness, and blood pressure. High sleep apnea risk is
WUS were similar to non-WUS patients for rates of diabetes, hypertension, hyperlipidemia, and patent foramen ovale (data not shown); atrial fibrillation was significantly more frequent in non-WUS (Table 1). Although there was no difference in sleep apnea risk by Berlin questionnaire, WUS sufferers were more likely to snore frequently (90.5% versus 70.0%, P 5 .08). Hemoglobin A1c and blood pressure were similar. The lipid profile was consistently and significantly worse in persons suffering WUS. In WUS versus non-WUS, total cholesterol was 193.3 6 37.9 versus 173.6 6 43.4; P 5 .049; LDL was 124.6 6 38.4 versus 103.7 6 36.8; P 5 .03; HDL was 39.7 6 12.1 versus 44.2 6 14.8; P 5 .17; and cholesterol to HDL ratio was
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Table 1. Baseline clinical characteristics of WUS versus non-WUS
Diabetes mellitus, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Atrial fibrillation, n (%) OSA, n (%) Prior stroke, n (%) PFO, n (%) SBP on admission DBP on admission Positive Berlin, n (%) Snoring frequently, n (%) HbA1c Cholesterol LDL HDL Cholesterol:HDL
Overall
WUS
Non-WUS
P value
25 (34.7) 64 (88.9) 48 (70.6) 14 (20.6) 15 (20.8) 31 (44.3) 7 (11.7) 166.3 6 27.1 93.3 6 18.2 48 (67.6) 40 (64.5) 6.8 6 2.2 181.1 6 42.2 111.6 6 38.5 42.5 6 13.9 4.7 6 1.7
11 (37.9) 24 (85.7) 18 (72.0) 2 (7.4) 6 (21.4) 13 (46.4) 4 (18.2%) 168.7 6 28.9 95.2 6 21.3 19 (67.9) 19 (79.2) 7.3 6 2.7 193.3 6 37.9 124.6 6 38.4 39.7 6 12.1 5.2 6 1.6
14 (31.1) 40 (90.9) 30 (69.8) 12 (26.8) 9 (20.5) 18 (42.9) 3 (7.9%) 164.7 6 26.2 92.1 6 16.0 29 (67.4) 21 (55.3) 6.5 6 1.8 173.6 6 43.4 103.7 6 36.8 44.2 6 14.8 4.3 6 1.6
.52 .49 .85 .046 .92 .77 .23 .55 .52 .97 .055 .23 .049 .03 .17 .02
Abbreviations: DBP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OSA, obstructive sleep apnea; PFO, patent foramen ovale; SBP, systolic blood pressure; WUS, wake-up stroke.
5.2 6 1.6 versus 4.3 6 1.6; P 5 .02. In predicting the value of LDL in multivariate regression, WUS status was significantly and positively associated with LDL after controlling for age, sex, race, BMI, and diabetes. WUS compared with non-WUS status accounted for 21.2 6 18.6 LDL units after adjusting for the above confounders (P 5 .02).
Stroke Characteristics WUS was significantly more likely to result from smallvessel disease mechanism (42.9% versus 14.0%; P 5 .006) and significantly less likely to result from large-vessel disease mechanism (28.6% versus 59.5%; P 5 .01). The likelihood of having a small-vessel disease stroke was higher for those with WUS compared with those without WUS. After controlling for age, sex, BMI, race, and diabetes, the odds of having small-vessel disease stroke was 3.41 (95% confidence interval 1.1, 10.6) for those with WUS compared with non-WUS (P 5 .04). Cardioembolism
was marginally less frequent in WUS compared with non-WUS (7.1% versus 21.4%; P 5 .11). There was no difference in regard to involvement of anterior versus posterior circulation, but WUS was more likely to involve the brain stem (25.0% versus 9.1%; P 5 .07). WUS was marginally less severe than non-WUS (P 5 .13) with a lower percentage of WUS having moderate severity, NIHSS of 5 or more (25.0% versus 46.5%; P 5 .07). WUS was also marginally smaller in size than non-WUS (12.4 6 26.8 cm3 versus 25.0 6 44.9 cm3, P 5 .18; Table 2).
Discussion In this study, WUS accounted for 38.9% of 72 ischemic strokes. Compared with stroke occurring during wakefulness, WUS was more likely of small-vessel disease. Patients who had WUS compared with those who had stroke with a known onset were significantly younger and tended to be African American. Although the WUS
Table 2. Stroke characteristics
Admission NIHSS NIHSS $ 5, n (%) Anterior circ, n (%) Posterior circ, n (%) Brainstem, n (%) Large vessel Small vessel, n (%) Cardioembolism Volume infarct (cm3)
Overall
WUS
Non-WUS
P value
4 (2, 6) 27 (38.0) 48 (66.7) 24 (33.3) 11 (15.3) 33 (47.1) 18 (25.4) 11 (15.7) 19.9 6 38.7
3 (1, 4) 7 (25.0) 16 (57.1) 11 (39.3) 7 (25.0) 8 (28.6) 12 (42.9) 2 (7.1) 12.4 6 26.8
4 (2, 7) 20 (46.5) 32 (72.7) 13 (29.5) 4 (9.1) 25 (59.5) 6 (14.0) 9 (21.4) 25.0 6 44.9
.13 .07 .17 .39 .07 .01 .006 .11 .18
Abbreviations: circ, circulation; NIHSS, National Institutes of Health Stroke Scale; WUS, wake-up stroke.
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and non-WUS groups did not differ in known cardiovascular comorbidity profile, those suffering from WUS had significantly higher LDL cholesterol and higher ratio of total to HDL cholesterol. The 2 groups did not differ in OSA risk by Berlin questionnaire, but high snoring frequency was more common in WUS. The finding that WUS associates with small-vessel disease mechanism is consistent with conclusions from the International Stroke Trial and Canadian Stroke Registry.2-7,12 This latter study found that WUS was composed disproportionately of lacunar strokes.5 Lacunar infarcts are caused by lipohyalinosis of small perforating vessels or microatheroma embolization from large vessels. Lacunar stroke is associated with poor diabetes control and an unfavorable cholesterol profile.13 In the present study, WUS patients had significantly higher LDL cholesterol and higher cholesterol to HDL ratio, both known to increase stroke risk. Although WUS participants had higher hemoglobin A1c, this difference was not statistically significant. The demographic profile, young and African American, of our WUS patients was consistent with prior studies of lacunar stroke. African Americans are more likely than White Americans to have all stroke subtypes, but disparity is greatest for the lacunar subtype of stroke.14 Although WUS participants did not differ in OSA risk by the Berlin questionnaire, they were more likely to snore frequently (P 5 .08). The frequency of snoring at least 3-4 times per week was used to balance problems of specificity which the Berlin is prone to in stroke populations, where hypertension is highly prevalent.15 Several pathogenic mechanisms have been implicated in OSA as a precipitant of stroke. OSA is associated with incident hypertension, intermittent hypoxia, and increased cerebral blood flow velocity. Whether OSA adds risk to the occurrence of WUS over stroke is not known. One study using polysomnography found that WUS compared with non-WUS sufferers were more likely to have OSA, but small sample size limits generalizability.6 Although this study was not designed to answer questions pertaining to treatment, the issue of thrombolytic therapy and WUS is so important that it deserves mention. In WUS, an exact time of onset is unknown and according to conventional thought in acute stroke care, this is a relative contraindication for the use of thrombolytic therapy which can only be given in a specific time window. Because WUS accounts for approximately one third of all ischemic stroke, this is a huge problem.3 Future studies will need to determine the safety of offering thrombolytic therapy in the setting of WUS and, perhaps, identify features of WUS that predict the most feared side effect, intracerebral hemorrhage. There are some limitations to consider. Objective assessment of sleep disordered breathing was lacking, limiting screening of sleep apnea to clinical history and questionnaire. This study was also based on a relatively small number of subjects. Compared with previous liter-
ature, there was a higher percentage of WUS in our cohort of ischemic stroke sufferers. This discrepancy likely relates to persons with severe stroke being unable to or not having next of kin available to complete questionnaires and, thus, not taking part in the study. Despite these limitations, our study adds to the current knowledge of WUS, showing that these events are more likely lacunar in nature and are associated with poor LDL cholesterol profile. A larger study with objective sleep apnea assessment will be important to clarify mechanisms of this very common stroke phenotype. Acknowledgments: The authors would like to thank Hesham Masoud, Ezequiel Piccione, and Eileen Zhuang for their help in recruiting patients and developing the informed consent.
References 1. Marler JR, Price TR, Clark GL, et al. Morning increase in onset of ischemic stroke. Stroke 1989;20:473-476. 2. Mackey J, Kleindorfer D, Sucharew H, et al. Populationbased study of wake-up strokes. Neurology 2011;76: 1662-1667. 3. Moradiya Y, Janjua N. Presentation and outcomes of ‘‘wake-up strokes’’ in a large randomized stroke trial: international stroke trial. J Stroke Cerebrovasc Dis 2013; 22:e286-e292. 4. Kim BK, Lee SH, Shin CW, et al. Ischemic stroke during sleep: association with worse early functional outcome. Stroke 2011;42:1901-1906. 5. Nadeau JO, Fang J, Kapral MK, et al. Outcome after stroke upon awakening. Can J Neurol Sci 2005;32:232-236. 6. Hsieh SW, Lai CL, Liu CK, et al. Obstructive sleep apnea linked to wake-up strokes. J Neurol 2012;259:1433-1439. 7. Silva GS, Lima FO, Camargo EC, et al. Wake-up stroke: clinical and neuroimaging characteristics. Cerebrovasc Dis 2010;29:336-342. 8. Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea and incident stroke: sleep heart health study. Am J Respir Crit Care Med 2010;182:269-277. 9. Netzer NC, Stoohs RA, Netzer CM, et al. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Int Med 1999;131:485-491. 10. Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Stroke 1993;24:35-41. 11. Sims JR, Gharai LR, Schaefer PW, et al. ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumes. Neurology 2009;72:2104-2110. 12. Fink JN, Kumar S, Horkan C, et al. The stroke patient who woke up: clinical and radiological features MRI. Stroke 2002;33:988-993. 13. Bezerra DC, Sharrett AR, Matsushita K, et al. Risk factors for lacune subtypes in the atherosclerosis risk in communities (ARIC) study. Neurology 2012;78:102-108. 14. White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and Hispanics: The Northern Manhattan Study. Circulation 2005;111:1327-1331. 15. Srijithesh PR, Shukla G, Srivastav A, et al. Validity of the Berlin Questionnaire in identifying obstructive sleep apnea syndrome in stroke patients. J Clin Neurosci 2011; 18:340-343.
Background: Wake-up stroke (WUS) accounts for up to 29.6% of ischemic strokes, but its mechanisms are poorly understood. The purpose of this study is to identify risk factors and characteristics of WUS. Methods: Seven-two ischemic strokes were classified as WUS or non-WUS. Collected were demographic information, medical history, cholesterol profile, and stroke characteristics including severity (National Institutes of Health Stroke Scale [NIHSS]) and mechanism (Trial of Org 10172 in Acute Stroke Treatment criteria). Subjects completed questionnaires screening for sleep apnea (Berlin questionnaire) and assessing sleep characteristics. Results: There were 72 ischemic strokes, of which 28 WUS (38.9%). WUS and non-WUS patients were similar in regard to stroke risk factors. WUS patients tended to be African American and were significantly younger. WUS was significantly more likely to result from small-vessel disease mechanism (42.9% versus 14.0%; P 5 .006) and tended to be less severe WUS (NIHSS score 3 [1, 4] versus 4 [2, 11]; P 5 .13) than non-WUS. Groups did not differ in regard to scoring positively on the Berlin questionnaire, but WUS sufferers were more likely to snore frequently (90.5% versus 70.0%, P 5 .08). The lipid profile was significantly worse in WUS compared with non-WUS (low-density lipoprotein 124.6 6 38.4 versus 103.7 6 36.8; P 5 .03; cholesterol to high-density lipoprotein ratio 5.2 6 1.6 versus 4.3 6 1.6; P 5.02). Conclusions: WUS is more likely to result from small-vessel disease mechanism. Poorer cholesterol profile and frequent snoring may contribute to WUS. Key Words: Wake-up stroke—small vessel—cholesterol—sleep apnea. Ó 2013 by National Stroke Association
Introduction Ischemic stroke displays a circadian pattern of occurrence with morning hours being the most likely time of onset.1,2 Stroke occurring during sleep or wake-up stroke (WUS) accounts for a significant portion of these morning strokes and 14%-29.6% of all ischemic strokes.2,3 Because the exact time of stroke onset is obscured in WUS, the use of time-sensitive intravenous thrombolytic therapy is precluded. Given this disconnect, it is of utmost importance From the *Case Western Reserve University School of Medicine, Cleveland, Ohio; and †Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio. Received September 4, 2013; revision received October 7, 2013; accepted October 24, 2013. The authors have no conflicts of interest to disclose. Address correspondence to Brian B. Koo, MD, Department Neurology, West Haven Veterans Affairs, 950 Campbell Avenue, West Haven, CT 06516. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.10.021
to maximize understanding of WUS, including its underlying pathophysiologic mechanisms and clinical features to increase the chances of timely therapy and ultimately a good outcome. Data regarding the clinical features of WUS are conflicting. Prior studies have reached differing conclusions regarding severity of WUS versus non-WUS, some finding that WUS is more severe and others finding no difference.2-5 Similarly, there is no consensus on WUS mechanism. Several studies have not found a significant difference in stroke mechanism,2,6 whereas others have associated lacunar syndromes and small-vessel mechanism with WUS.4,5,7 Analysis of International Stroke Trial data, including 17,398 ischemic strokes and over 5000 WUS, found that WUS was less likely to include severe anterior circulation syndromes, less severe on presentation but deteriorated to similarly low functional status as non-WUS at 6 months.3 Although severity and mechanism of WUS have been investigated, pathophysiologic risk factors that predispose to WUS have not been well studied. Because WUS
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occurs during sleep, it seems likely that disordered sleep could play a mechanistic role in producing WUS. Obstructive sleep apnea (OSA) seems a conspicuous candidate for involvement in WUS as it has consistently proven an independent stroke risk factor.8 As prior data have suggested that small-vessel disease underlies WUS, diabetes control and cholesterol profile may be other factors that increase risk for WUS. Thus, the aim of the present study is to investigate ischemic WUS occurrence and its potential relationship to sleep disordered breathing while determining clinical features of WUS. We hypothesize that persons with stroke occurring in the sleeping period are more likely to have high risk for OSA and that WUS compared with non-WUS is less severe, more likely of small rather than large-vessel mechanism and associated with measurements of hyperlipidemia and poor blood glucose control.
Methods Subjects Acute ischemic stroke patients presenting to University Hospitals Case Medical Center in March and April 2012 and from January to March 2013 were prospectively enrolled. Ischemic stroke was confirmed radiographically by restricted diffusion on brain magnetic resonance imaging, and stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Transient ischemic attacks, hemorrhagic stroke, and venous infarct were not included in this analysis. Subjects were also excluded if there were other medical issues that were likely related to stroke mechanism including malignancy, gastrointestinal bleeding, drug use, rheumatologic exacerbation, and central nervous system infection. Participants were carefully asked about whether symptoms of stroke were present on waking up or began during wakefulness. Lack of confirmation of symptoms arising in either sleep or wakefulness constituted exclusion. Participants provided written informed consent, and the study was approved by the Institutional Review Board of University Hospitals Case Medical Center.
present if 2 of 3 categories are scored.9 Snoring frequency was also used as a surrogate for sleep apnea risk. Strokes were classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria as small vessel, large vessel, cardioembolic, or cryptogenic.10 Localization was further classified as arising from anterior or posterior circulation based on magnetic resonance imaging scanning. Stroke volume (volume) was measured using ABC/2 criteria in which diffusion-weighted imaging, the longest lesion axis (A), its perpendicular (B), and the product of slice number and slice thickness (C) are measured. The product of these measures is then divided by 2 (ABC/2).11
Statistical Analysis Descriptive statistics included frequency for categorical variables, mean and standard deviation for continuous variables, and medians with interquartile range for ordinal variables. Characteristics of WUS were compared with non-WUS using c2, Student t, and Mann–Whitney testing for categorical, continuous, and ordinal variables, respectively. Logistic and multivariate regression analyses were carried out to model the likelihood of smallvessel disease or low-density lipoprotein, respectively, given parameters of age, sex, BMI, diabetes status, and WUS. All significance levels reported were 2 sided. Analyses were conducted using the R statistical package version 2.15.2 (Auckland, New Zealand).
Results Demographic Data There were 72 ischemic stroke patients, 46 men (63.9%), 28 WUS (38.9%), and 44 non-WUS. In the overall sample, age (mean 6 SD) was 66.3 6 14.3 (range 25-97), BMI was 30.8 6 9.0, and admission NIHSS score (median, IQ range) was 4 (2, 7). WUS patients tended to be African American (53.6% versus 34.1%; P 5 .10) and were significantly younger (61.8 6 15.4 versus 69.1 6 13.0; P 5 .04) than non-WUS sufferers. There was no significant difference between the BMI and gender makeup of the groups.
Participant Clinical Characteristics Patient and Stroke Characteristics Data collected included age, sex, race, body mass index (BMI, kg/m2), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), hemoglobin A1c, and blood pressure on admission. Comorbidities noted were hypertension, diabetes, hyperlipidemia, atrial fibrillation, and patent foramen ovale. Stroke onset was noted and recorded as WUS if neurologic deficits were present on waking. Participants or participant next of kin completed the Berlin sleep apnea questionnaire, which consists of 10 questions in 3 categories: snoring/apnea, sleepiness, and blood pressure. High sleep apnea risk is
WUS were similar to non-WUS patients for rates of diabetes, hypertension, hyperlipidemia, and patent foramen ovale (data not shown); atrial fibrillation was significantly more frequent in non-WUS (Table 1). Although there was no difference in sleep apnea risk by Berlin questionnaire, WUS sufferers were more likely to snore frequently (90.5% versus 70.0%, P 5 .08). Hemoglobin A1c and blood pressure were similar. The lipid profile was consistently and significantly worse in persons suffering WUS. In WUS versus non-WUS, total cholesterol was 193.3 6 37.9 versus 173.6 6 43.4; P 5 .049; LDL was 124.6 6 38.4 versus 103.7 6 36.8; P 5 .03; HDL was 39.7 6 12.1 versus 44.2 6 14.8; P 5 .17; and cholesterol to HDL ratio was
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Table 1. Baseline clinical characteristics of WUS versus non-WUS
Diabetes mellitus, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Atrial fibrillation, n (%) OSA, n (%) Prior stroke, n (%) PFO, n (%) SBP on admission DBP on admission Positive Berlin, n (%) Snoring frequently, n (%) HbA1c Cholesterol LDL HDL Cholesterol:HDL
Overall
WUS
Non-WUS
P value
25 (34.7) 64 (88.9) 48 (70.6) 14 (20.6) 15 (20.8) 31 (44.3) 7 (11.7) 166.3 6 27.1 93.3 6 18.2 48 (67.6) 40 (64.5) 6.8 6 2.2 181.1 6 42.2 111.6 6 38.5 42.5 6 13.9 4.7 6 1.7
11 (37.9) 24 (85.7) 18 (72.0) 2 (7.4) 6 (21.4) 13 (46.4) 4 (18.2%) 168.7 6 28.9 95.2 6 21.3 19 (67.9) 19 (79.2) 7.3 6 2.7 193.3 6 37.9 124.6 6 38.4 39.7 6 12.1 5.2 6 1.6
14 (31.1) 40 (90.9) 30 (69.8) 12 (26.8) 9 (20.5) 18 (42.9) 3 (7.9%) 164.7 6 26.2 92.1 6 16.0 29 (67.4) 21 (55.3) 6.5 6 1.8 173.6 6 43.4 103.7 6 36.8 44.2 6 14.8 4.3 6 1.6
.52 .49 .85 .046 .92 .77 .23 .55 .52 .97 .055 .23 .049 .03 .17 .02
Abbreviations: DBP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OSA, obstructive sleep apnea; PFO, patent foramen ovale; SBP, systolic blood pressure; WUS, wake-up stroke.
5.2 6 1.6 versus 4.3 6 1.6; P 5 .02. In predicting the value of LDL in multivariate regression, WUS status was significantly and positively associated with LDL after controlling for age, sex, race, BMI, and diabetes. WUS compared with non-WUS status accounted for 21.2 6 18.6 LDL units after adjusting for the above confounders (P 5 .02).
Stroke Characteristics WUS was significantly more likely to result from smallvessel disease mechanism (42.9% versus 14.0%; P 5 .006) and significantly less likely to result from large-vessel disease mechanism (28.6% versus 59.5%; P 5 .01). The likelihood of having a small-vessel disease stroke was higher for those with WUS compared with those without WUS. After controlling for age, sex, BMI, race, and diabetes, the odds of having small-vessel disease stroke was 3.41 (95% confidence interval 1.1, 10.6) for those with WUS compared with non-WUS (P 5 .04). Cardioembolism
was marginally less frequent in WUS compared with non-WUS (7.1% versus 21.4%; P 5 .11). There was no difference in regard to involvement of anterior versus posterior circulation, but WUS was more likely to involve the brain stem (25.0% versus 9.1%; P 5 .07). WUS was marginally less severe than non-WUS (P 5 .13) with a lower percentage of WUS having moderate severity, NIHSS of 5 or more (25.0% versus 46.5%; P 5 .07). WUS was also marginally smaller in size than non-WUS (12.4 6 26.8 cm3 versus 25.0 6 44.9 cm3, P 5 .18; Table 2).
Discussion In this study, WUS accounted for 38.9% of 72 ischemic strokes. Compared with stroke occurring during wakefulness, WUS was more likely of small-vessel disease. Patients who had WUS compared with those who had stroke with a known onset were significantly younger and tended to be African American. Although the WUS
Table 2. Stroke characteristics
Admission NIHSS NIHSS $ 5, n (%) Anterior circ, n (%) Posterior circ, n (%) Brainstem, n (%) Large vessel Small vessel, n (%) Cardioembolism Volume infarct (cm3)
Overall
WUS
Non-WUS
P value
4 (2, 6) 27 (38.0) 48 (66.7) 24 (33.3) 11 (15.3) 33 (47.1) 18 (25.4) 11 (15.7) 19.9 6 38.7
3 (1, 4) 7 (25.0) 16 (57.1) 11 (39.3) 7 (25.0) 8 (28.6) 12 (42.9) 2 (7.1) 12.4 6 26.8
4 (2, 7) 20 (46.5) 32 (72.7) 13 (29.5) 4 (9.1) 25 (59.5) 6 (14.0) 9 (21.4) 25.0 6 44.9
.13 .07 .17 .39 .07 .01 .006 .11 .18
Abbreviations: circ, circulation; NIHSS, National Institutes of Health Stroke Scale; WUS, wake-up stroke.
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and non-WUS groups did not differ in known cardiovascular comorbidity profile, those suffering from WUS had significantly higher LDL cholesterol and higher ratio of total to HDL cholesterol. The 2 groups did not differ in OSA risk by Berlin questionnaire, but high snoring frequency was more common in WUS. The finding that WUS associates with small-vessel disease mechanism is consistent with conclusions from the International Stroke Trial and Canadian Stroke Registry.2-7,12 This latter study found that WUS was composed disproportionately of lacunar strokes.5 Lacunar infarcts are caused by lipohyalinosis of small perforating vessels or microatheroma embolization from large vessels. Lacunar stroke is associated with poor diabetes control and an unfavorable cholesterol profile.13 In the present study, WUS patients had significantly higher LDL cholesterol and higher cholesterol to HDL ratio, both known to increase stroke risk. Although WUS participants had higher hemoglobin A1c, this difference was not statistically significant. The demographic profile, young and African American, of our WUS patients was consistent with prior studies of lacunar stroke. African Americans are more likely than White Americans to have all stroke subtypes, but disparity is greatest for the lacunar subtype of stroke.14 Although WUS participants did not differ in OSA risk by the Berlin questionnaire, they were more likely to snore frequently (P 5 .08). The frequency of snoring at least 3-4 times per week was used to balance problems of specificity which the Berlin is prone to in stroke populations, where hypertension is highly prevalent.15 Several pathogenic mechanisms have been implicated in OSA as a precipitant of stroke. OSA is associated with incident hypertension, intermittent hypoxia, and increased cerebral blood flow velocity. Whether OSA adds risk to the occurrence of WUS over stroke is not known. One study using polysomnography found that WUS compared with non-WUS sufferers were more likely to have OSA, but small sample size limits generalizability.6 Although this study was not designed to answer questions pertaining to treatment, the issue of thrombolytic therapy and WUS is so important that it deserves mention. In WUS, an exact time of onset is unknown and according to conventional thought in acute stroke care, this is a relative contraindication for the use of thrombolytic therapy which can only be given in a specific time window. Because WUS accounts for approximately one third of all ischemic stroke, this is a huge problem.3 Future studies will need to determine the safety of offering thrombolytic therapy in the setting of WUS and, perhaps, identify features of WUS that predict the most feared side effect, intracerebral hemorrhage. There are some limitations to consider. Objective assessment of sleep disordered breathing was lacking, limiting screening of sleep apnea to clinical history and questionnaire. This study was also based on a relatively small number of subjects. Compared with previous liter-
ature, there was a higher percentage of WUS in our cohort of ischemic stroke sufferers. This discrepancy likely relates to persons with severe stroke being unable to or not having next of kin available to complete questionnaires and, thus, not taking part in the study. Despite these limitations, our study adds to the current knowledge of WUS, showing that these events are more likely lacunar in nature and are associated with poor LDL cholesterol profile. A larger study with objective sleep apnea assessment will be important to clarify mechanisms of this very common stroke phenotype. Acknowledgments: The authors would like to thank Hesham Masoud, Ezequiel Piccione, and Eileen Zhuang for their help in recruiting patients and developing the informed consent.
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