Characteristics of Sleep-Disordered Breathing in Etiologic Subtypes of Minor-to-Moderate Acute Ischemic Stroke Pavel Siarnik, MD, Branislav Koll ar, MD, PhD, Zuzana Carnick a, MD, Stanislav Sutovsk y, MD, PhD, Katarına Klobucnıkova, MD, PhD, and Peter Turcani, MD, PhD
Background: Sleep-disordered breathing (SDB) is frequent in stroke patients. A strong association has been suggested between SDB and atrial fibrillation (AF). In this study, we evaluated the characteristics of SDB in etiologic subtypes of acute ischemic stroke. We also investigated the relationship between SDB and AF in acute ischemic stroke. Methods: We prospectively enrolled 72 patients with minorto-moderate acute ischemic stroke. Clinical and laboratory characteristics of population were recorded on admission. SDB was assessed using standard polysomnography within 7 days after stroke onset. Results: Apnea–hypopnea index (AHI) in small-vessel strokes was significantly lower than that in large-artery atherosclerosis strokes (P 5 .031), cardioembolic strokes (P 5 .011), and strokes of other or unknown etiology (.008). Desaturation index (DI) in small-vessel strokes was significantly lower than that in cardioembolic strokes and in large-artery strokes (P 5.008, P 5 .035). Arousal index (AI) in large-artery strokes was significantly higher than that in small-vessel strokes (P 5 .013), cardioembolic strokes (P 5 .007), and strokes of other or unknown etiology (.027). In a multivariate regression model were age (odds ratio [OR], 1.083; 95% confidence interval [CI], 1.022-1.148; P 5 .007) and DI (OR, 1.037; 95% CI, 1.004-1.071; P 5 .026) the only significant variables independently associated with AF. Conclusions: We observed higher AHI, DI, and AI in large-artery strokes that may relate to more severe neurologic deficit in this subgroup. Age and DI were the only independent variables significantly associated with AF in acute ischemic stroke. Higher AHI and DI in cardioembolic strokes may thus mirror more frequent premorbid presence of SDB in patients with AF. Key Words: Sleep-disordered breathing—ischemic stroke—etiologic stroke subtypes—atrial fibrillation—polysomnography. Ó 2015 by National Stroke Association
Stroke is the second most common cause of death worldwide and one of the leading causes of disability.1 Sleep-disordered breathing (SDB) is frequent in stroke patients. Meta-analyses found the presence of SDB in up
to 72% of stroke patients.2 SDB belongs to independent risk factors for stroke.3 On the other hand, stroke may contribute to SDB onset or aggravate premorbid SDB.4 Multiple mechanisms might be responsible for the
From the 1st Department of Neurology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. Received November 16, 2014; revision received January 9, 2015; accepted January 22, 2015. This work was supported by the Grant of The Ministry of Health of the Slovak Republic (2012/56-SAV-6) and by the Framework Programme for Research and Technology Development, Project: Building of Centre of Excellency for Sudden Cerebral Vascular Events, Comenius University Faculty of Medicine in Bratislava
(ITMS:26240120023), cofinanced by European Regional Development Fund. The authors declare no conflict of interest. Address correspondence to Branislav Koll ar, MD, PhD, 1st Department of Neurology, Faculty of Medicine, Comenius University, Mickiewiczova 13, 81369 Bratislava, Slovakia. E-mail: branislavkollarmd@ gmail.com. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.01.023
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 5 (May), 2015: pp 1087-1093
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development of stroke in patients with SDB, including endothelial damage, atherosclerosis, hypercoagulability, inflammatory and hemodynamic changes, paradoxical embolization, and the development of cardiac arrhythmias.5,6 Atrial fibrillation (AF) is the most common cardiac arrhythmia responsible for about 25% of all ischemic strokes.7 Although the association of SDB with AF is well known, the relationship between AF and SDB in acute ischemic stroke is unclear.8 Although SDB is a possible therapeutic target in acute stroke, compliance rates of continuous positive airway pressure (CPAP) therapy in the acute stroke are low (47%) and even decrease in chronic phase (11%).9 Severity of motor disability and aphasia are important predictors of poor CPAP compliance.10 In our study, we focused on the prevalence and characteristics of SDB in population with minor-tomoderate strokes with possibility of better compliance to CPAP. The aim of study was to evaluate characteristics of SDB in etiologic subtypes of acute ischemic stroke and to investigate the relationship between SDB and AF in acute ischemic stroke.
Methods The study subjects were recruited from patients hospitalized in the stroke unit of the 1st Department of Neurology, Comenius University Bratislava with the diagnosis of acute ischemic stroke from January 2011 to December 2013. Patients were excluded in a case of severe neurologic deficit– National Institutes of Health Stroke Scale (NIHSS) more than 15, impairment of consciousness, agitated confusion, acute chest infection, chronic lung disease, or if they refused to participate. The study was approved by the institutional ethics committee. All patients provided informed consent. The diagnosis was confirmed clinically and by computed tomography or magnetic resonance imaging (MRI). NIHSS and modified Rankin Scale score were used to assess baseline stroke severity.11,12 The etiology of stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria.13 Electrocardiography (ECG), carotid and transcranial ultrasonography, computed tomography/magnetic resonance imaging angiography, and echocardiography were used to determine the etiology of ischemia. Medical records of all patients were reviewed to determine the premorbid presence of AF. Native 12-lead ECG, continuous ECG monitoring in stroke unit, ECG monitoring during polysomnography, and 24-hour Holter ECG monitoring were used to detect the AF. Clinical characteristics including age, gender, current smoking habit, blood pressure, neck circumference, and body mass index (BMI) were assessed on admission. Standard biochemical blood tests were performed in the morning of the following day. Samples were processed in local hospital laboratory.
The sleep analysis was performed within 7 days after stroke onset. Subjects underwent standard overnight polysomnography in the sleep laboratory using Alice 5 device (Philips-Respironics, Netherlands). Channels for electroencephalogram, electrooculogram, chin electromyogram, tibialis electromyogram, body position, finger arterial oximetry, and ECG were included. Chest belt, abdominal belt, and nasal cannula were used to monitor the breathing effort and airflow. Recordings were scored manually. Sleep parameters and respiratory events were scored according to standardized criteria.14 Epworth Sleepiness Scale was used to assess the excessive daytime sleepiness.15 Scores were blinded to the stroke subtypes. The statistical analyses were performed using SPSS version 18 (SPSS Inc., Chicago, IL). Categorical variables were expressed as numbers and proportions (%), continuous variables as means 6 standard deviation or median, interquartile range (IQR), minimal and maximal values. Kruskal–Wallis test was used for intergroup comparison. To compare groups, chi-squared test, Student t test, and Mann–Whitney test were used for particular variables. Binary logistic regression analysis was used to identify factors that contributed to the presence of AF. P values less than .05 were considered statistically significant.
Results Thirty-two women and 40 men with acute ischemic stroke were enrolled. Mean age was 66.4 years and median NIHSS was 4. Ten strokes (13.9%) were caused by large-artery atherosclerosis, 21 strokes (29.2%) by small-vessel occlusion, and 33 strokes (45.8%) by cardioembolism. Other or unknown etiology was present in 8 patients (11.1%). Sleep apnea syndrome, defined as apnea–hypopnea index (AHI) of 5 or greater, was present in 59.7% of patients. In all, 60.5% of them experienced obstructive sleep apnea (OSA), and central sleep apnea was present in 39.5%. No Cheyne–Stokes respiration was observed. Baseline characteristics are shown in Table 1. SDB-specific indices, including AHI, desaturation index (DI), arousal index (AI), saturation of blood with oxygen, % of total sleep time in supine position, Epworth Sleepiness Scale, BMI, and neck circumference, were compared in etiologic stroke subtypes, see Table 2. Significant intergroup differences were found in values of AHI (P 5 .022), DI (P 5.032), and AI (.038). Populations of subtypes did not significantly differ in age, BMI, and neck circumference. NIHSS was significantly higher in largeartery strokes (median, 6.00; range, 5.00-12.00; IQR, 2.00) than that in all other subtypes: P less than .001 when compared with small-vessel strokes (median, 4.00; range, 1.00-10.00; IQR 1.50), P 5 .017 when compared with cardioembolic strokes (median, 5.00; range, 1.00-11.00; IQR, 3.00) and P 5 .027 when compared with strokes of other or unknown etiology (median, 3.50; range, 2.00-12.00; IQR 3.50). AHI in small-vessel strokes (median, 3.9; range,
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Table 1. Baseline characteristics Variable
N 5 72
Male sex Age (y) NIHSS mRS Etiology Small vessel Large-artery atherosclerosis Cardioembolic Other Unknown Location Supratentorial Cerebellar Brainstem Supra and infratentorial Atrial fibrillation BMI (kg/m2) Smoking habit Neck circumference (cm) Glycemia (mmol/L) Leucocyte count (3109/L) TAG (mmol/L) Total cholesterol (mmol/L) LDL (mmol/L) HDL (mmol/L) Systolic BP (mm Hg) Diastolic BP (mm Hg) Sleep apnea syndrome OSA CSA AHI (n/h) DI (n/h) AI (n/h) Average sat (%) Minimal sat (%) ESS
40 (55.6) 66.4 6 12.5 4.0, 1.0-12.0, 3.0 2.0, 1.0-5.0, 1.8 21 (29.2) 10 (13.9) 33 (45.8) 3 (4.2) 5 (6.9) 54 (75) 5 (6.9) 9 (12.5) 4 (5.6) 24 (33.3) 27.7 6 4.8 17 (23.6) 39.3 6 4.9 5.8 6 1.7 8.0 6 3.2 1.2, .1-11.8, .7 5.1 6 1.4 3.4 6 1.2 1.2 6 .3 156.2 6 22.6 84.3 6 11.3 43 (59.7) 26 (60.5) 17 (39.5) 8.1, .0-87.4, 20.9 8.8, .0-98.4, 19.9 17.4, 1.9-453.0, 22.5 92.4 6 2.2 85.6 6 7.5 4.0, 0-13.0, 5.0
Abbreviations: AHI, apnea–hypopnea index; AI, arousal index; BMI, body mass index; BP, blood pressure; CSA, central sleep apnea; DI, desaturation index; ESS, Epworth Sleepiness Scale; HDL, high-density lipoprotein; LDL, low-density lipoprotein; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; OSA, obstructive sleep apnea; sat, saturation of blood with oxygen; TAG, triglyceride. Categorical variables expressed as numbers and proportions (%). Continuous variables expressed as means 6 standard deviation or median, range, interquartile range.
.0-40.2; IQR 5.4) was significantly lower than that in largeartery strokes (median, 10.2; range, 1.8-62.8; IQR, 24.6; P 5 .031), cardioembolic strokes (median, 14.1; range, .1-87.4; IQR, 32.4; P 5 .011), and strokes of other or unknown etiology (median, 11.0; range, 3.4-35.3; IQR, 19.5; .008). DI in cardioembolic strokes (median, 15.80; range, .00-98.40; IQR, 32.10) and in large-artery strokes (median, 15.25; range, 2.30-44.90; IQR, 21.55) was significantly
higher than that in small-vessel strokes (median, 3.60; range .30-43.80; IQR, 8.50; P 5 .008; P 5 .035). AI in large-artery strokes (median, 29.15; range, 8.30-453.00; IQR, 119.60) was significantly higher than that in smallvessel strokes (median, 7.90; range, 2.40-197.00; IQR, 24.75; P 5 .013), cardioembolic strokes (median, 15.70; range, 2.20-66.30; IQR 21.05; P 5.007), and strokes of other or unknown etiology (median, 16.55; range, 1.90-36.10; IQR, 14.03; P 5 .027). In a study population, we found significant correlation of AF with AHI (r 5 .261, P 5.027) and DI (r 5 .292, P 5 .013). We failed to find any significant correlation with the nocturnal saturation of blood with oxygen or BMI. Comparison of baseline characteristics in population with detected AF and in population without detected AF showed significant difference in age (P , .001), current smoking habit (P 5 .031) AHI (P 5 .028), and DI (P 5 .014), see Table 3. Age (odds ratio [OR], 1.083; 95% confidence interval [CI], 1.022-1.148; P 5 .007) and DI (OR, 1.037; 95% CI, 1.004-1.071; P 5 .026) remained the only significant variables associated with AF in a multivariate regression model. Of the 27 patients indicated for CPAP therapy (AHI $15), only 3 of them (11.1%) remained compliant 12 months after the stroke onset.
Discussion Results of our study confirm high prevalence of SDB in acute ischemic stroke with minor-to-moderate severity (median NIHSS, 4). There was no significant difference in SDB prevalence in etiologic stroke subtypes. Significant intergroup differences were found in values of AHI, DI, and AI. AHI and DI in cardioembolic strokes and in large-artery atherosclerosis strokes were significantly higher than those in small-vessel occlusion strokes indicating more severe SDB in these populations. AI in large-artery strokes was significantly higher than that in all other stroke subtypes. In addition, we found age and DI to be the only significant variables associated with AF in acute ischemic stroke. We failed to find higher compliance rates of CPAP therapy in patients with minor-to-moderate stroke. Meta-analysis of 2343 stroke patients described the frequency of SDB in up to 72%. In most included studies, patients were, similarly to our study, excluded if there was a serious medical condition, dementia, confusion, or if consent could not be obtained. Polysomnography in stroke unit patients was performed in 7 of 29 studies, and many of the patients have not been scored for severity of stroke. Sleep apnea was typically obstructive in nature. SDB was more common in strokes of unknown etiology and less common in cardioembolic strokes.2 Similarly to meta-analysis, our study confirmed high prevalence of SDB in acute ischemic stroke (59.7%). OSA, with frequency of 60.5%, was more frequent than central sleep apnea. We failed to find any significant
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Table 2. Sleep characteristics in etiologic stroke subtypes
Etiology
Small vessel
Large-artery atherosclerosis
Cardioembolic
Other/unknown
P
N SDB prevalence AHI (n/h) DI (n/h) AI (n/h) Average sat (%) Minimal sat (%) ESS % of TST in supine position Age (y) BMI (kg/m2) Neck circumference (cm) NIHSS
21 13 (61.9) 3.9, .0-40.2, 5.4 3.6, .3-43.8, 8.5 7.9, 2.4-197.0, 24.8 92.5 6 1.7 88.4 6 4.6 4.0, .0-9.0, 6.0 52.2, 2.4-100.0, 67.0
10 9 (90.0) 10.2, 1.8-62.8, 24.6 15.3, 2.3-44.9, 21.6 29.2, 8.3-453.0, 119.6 92.3 6 2.7 85.1 6 3.8 3.5, 1.0-12.0, 6.8 81.0, 5.9-100.0, 22.4
33 26 (78.8) 14.1, .1-87.4, 32.4 15.8, .0-98.4, 32.1 15.7, 2.2-66.3, 21.1 92.1 6 2.5 84.0 6 9.7 5.0, .0-13.0, 6.0 86.9, .0-100.0, 75.4
8 7 (87.5) 11.0, 3.4-35.3, 19.5 8.3, 2.6-42.9, 13.75 16.6, 1.9-36.1, 14.0 93.4 6 1.7 85.5 6 4.9 3.0, 2.0-10.0, 5.5 86.2, 23.7-100.0, 14.4
.249 .022* .032* .038* .469 .100 .680 .846
64.5 6 11.4 29.6 6 5.9 38.7 6 4.3
62.7 6 13.3 27.1 6 5.4 39.0 6 2.7
68.8 6 13.1 27.1 6 3.8 39.2 6 5.7
66.4 6 12.1 25.9 6 4.0 41.7 6 5.5
.337 .293 .590
4.0, 1.0-10.0, 1.5
6.0, 5.0-12.0, 2.0
5.0, 1.0-11.0, 3.0
3.5, 2.0-12.0, 3.5
.005**
Abbreviations: AHI, apnea–hypopnea index; AI, arousal index; BMI, body mass index; DI, desaturation index; ESS, Epworth Sleepiness Scale; NIHSS, National Institutes of Health Stroke Scale; sat, saturation of blood with oxygen; SDB, sleep-disordered breathing; TST, total sleep time. *P value below .05; **P value below .01. Categorical variables expressed as numbers and proportions (%). Continuous variables expressed as means 6 standard deviation or median, range, interquartile range.
difference in SDB prevalence among etiologic stroke subtypes, which is inconsistent with previous findings. On the other hand, a recent study found no significant difference in SDB prevalence amongst stroke subtypes.16 Multiple mechanisms might link SDB with the development of stroke including endothelial damage, atherosclerosis, hypercoagulability, inflammatory and hemodynamic changes, paradoxical embolization, and the development of cardiac arrhythmias.5,6 SDB might be therefore associated equally with all stroke subtypes. Several factors may be related to the variability in the rates and severity of SBD in acute stroke, including type of stroke, age, and BMI. Increase in supine positioning is suggested to be one of the most important factors that may increase the frequency of SDB in acute stroke.2,17 Populations of stroke subtypes in our study did not significantly differ in age, BMI, neck circumference, and percent of total sleep time in supine position. NIHSS was found to be significantly higher in large artery strokes than that in all other subtypes. We must admit that our population probably differs from representative populations with acute stroke. Cardioembolic strokes in general are expected to have higher NIHSS scores than larger artery strokes.18 Our study included only strokes with minor-to-moderate severity and many large-artery strokes and cardioembolic strokes are probably missing from this cohort because of selection bias. Population of small-vessel strokes, being generally milder in severity, may be more representative in our cohort.
Our study revealed significantly higher AHI and DI in large-artery strokes than those in small-vessel strokes. AI in large-artery strokes was significantly higher than that in all other subtypes. Higher AHI, DI, and AI in largeartery strokes may relate to significantly more severe neurologic deficit in this subgroup, although there is only little apparent relation between SDB and the clinical severity of stroke described in previous studies.19 More severe SDB after large-artery strokes may also reflect pre-existing SDB. An association between SDB after stroke and macroangiopathy as cause of stroke was also observed in the previous study.20 Another study revealed that nocturnal arousals because of respiratory events to be an independent predictor of carotid atherosclerosis.21 Our study included all causes of arousal including nonrespiratory. We assume observed number of arousals exceeds arousals because of respiratory events. Changes in sleep architecture and movement disorders leading to disruption of sleep in stroke patients were described previously.22,23 The exact cause of increased number of arousals in large-artery strokes is beyond the aim of this study. Another finding of this study was significantly higher AHI and DI in cardioembolic strokes compared with small-vessel strokes. AF was the identified etiology in most of the cardioembolic strokes. Association of SDB with AF is well known.24 Although causal relationship between SDB and AF is not exactly clear, onset of AF as a result of multiple mechanisms underlying SDB is assumed.25 Patients with severe SDB have 2- to 4-fold
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Table 3. Characteristics in population with detected and without detected atrial fibrillation Atrial fibrillation
Detected
Not detected
P
Patients Male sex Age (y) NIHSS mRS Supratentorial location Cerebellar location Brainstem location Supra and infratentorial location BMI (kg/m2) Neck circumference (cm) Smoking habit Glycemia (mmol/L) Leucocyte count (3109/L) TAG (mmol/L) Total cholesterol (mmol/L) LDL (mmol/L) HDL (mmol/L) Systolic BP (mm Hg) Diastolic BP (mm Hg) Sleep apnea syndrome OSA CSA AHI (n/h) DI (n/h) AI (n/h) Average sat (%) Minimal sat (%) ESS
24 (33.3) 10 (41.7) 73.5 6 9.6 4.0, 1.0-10.0, 3.0 2.0, 1.0-4.0, 2.0 18 (75) 3 (12.5) 2 (8.3) 1 (4.2) 27.3 6 4.2 39.7 6 6.5 2 (8.3) 5.7 6 1.4 7.6 6 2.3 1.1, .1-3.0, .6 4.8 6 1.5 3.2 6 1.3 1.2 6 0.3 161.5 6 19.8 85.0 6 8.7 18 (75.0) 11 (61.1) 7 (38.9) 16.1, .2-87.4, 40.5 17.8, .4-98.4, 45.0 16.6, 2.2-66.3, 24.8 92.0 6 2.2 84.7 6 7.1 4.0, .0-13.0, 6.0
48 (66.7) 30 (62.5) 62.9 6 12.4 5.0, 1.0-12.0, 3.0 2.0, 1.0-5.0, 1.0 36 (75) 2 (4.2) 7 (14.6) 3 (6.2) 27.9 6 5.2 39.2 6 4.0 15 (31.3) 5.8 6 1.9 8.2 6 3.6 1.2, .6-11.8, .8 5.2 6 1.4 3.6 6 1.2 1.2 6 0.3 153.5 6 23.7 84.0 6 12.5 25 (52.1) 15 (60.0) 10 (40.0) 5.4, .0-62.8, 18.3 7.2, .0-44.9, 15.3 17.4, 1.9-453.0, 21.3 92.6 6 2.2 86.0 6 7.7 4.5, .0-12.0, 5.3
.094 #.001*** .443 .207 1.00 .190 .450 .716 .614 .705 .031* .838 .424 .205 .293 .313 .639 .161 .715 .062 .941 .941 .028* .014* .872 .312 .465 .713
Abbreviations: AHI, apnea–hypopnea index; AI, arousal index; BMI, body mass index; BP, blood pressure; CSA, central sleep apnea; DI, desaturation index; ESS, Epworth Sleepiness Scale; HDL, high-density lipoprotein; LDL, low-density lipoprotein; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; OSA, obstructive sleep apnea; sat, saturation of blood with oxygen; TAG, triglyceride. Categorical variables expressed as numbers and proportions (%). Continuous variables expressed as means 6 standard deviation or median, range, interquartile range. *P value below .05; **P value below .01; ***P value below .001.
higher odds of complex arrhythmias than controls, and patients with untreated SBD are known to have a higher recurrence of AF after cardioversion than patients without SDB.26,27 Higher AHI and DI in cardioembolic strokes may thus mirror prestroke presence of more severe SDB in patients with AF. This is the first study so far to search for predictors of AF in an acute ischemic stroke including polysomnographic findings. Previous studies suggest that many of strokes associated with SDB could be avoided by proper risk assessment and more aggressive treatment of SDB and associated AF.28 Two recent studies described the association of AF with SDB in context of ischemic stroke in more detail. A population-based case–control study of 2980 patients with a new diagnosis of OSA who experienced a first-time ischemic stroke during the same period revealed a strong association among AF, stroke, and SDB. Patients with OSA who experienced a firsttime stroke had much higher rates of AF than controls
without history of stroke (5.34-fold odds of having AF).29 Characteristics of prestroke SDB or characteristics of SDB in chronic poststroke period differ from the complex situation in acute phase of ischemic stroke. Design of mentioned study, in contrast to our study, did not allow the evaluation of AF and SDB in the acute phase of stroke. Another prospective study of 150 patients with acute ischemic stroke found AF to be independently associated with severe SDB (OR, 2.4; 95% CI, 1.079-5.836; P 5 .0359).16 In this study, a portable diagnostic device was used for SDB evaluation instead of polysomnography and sleep duration, quality and respiratory effort could have not been assessed. In our study, population with AF and population without AF significantly differed in age, current smoking habit AHI, and DI. Age and DI remained the only significant variables associated with AF in a multivariable regression model. Increase in frequency of AF with age is well known.30 The previous finding of magnitude of nocturnal oxygen desaturation
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as independent risk factor for incident AF is also consistent with our findings.31 Compliance rates of CPAP therapy in the acute stroke are low (47%) and even decrease in chronic phase (11%).9 Our data are consistent with literature. We expected higher compliance rates of CPAP therapy in patients with minor-to-moderate stroke. However, of 27 patients indicated for CPAP therapy (AHI $15), only 3 of them (11.1%) remained compliant 12 months after the stroke onset. The exact causes of noncompliance and possible effect of CPAP therapy on AF were beyond the aim of this study. Selection bias is the main limitation of our study. Our study included only patients with minor (NIHSS, 1-4) to moderate stroke (NIHSS, 5-15). Patients with more severe neurologic deficit were excluded from measurement. This could have underestimated the exact frequency and severity of SDB in the acute stroke. We must admit that our population probably differs from representative populations with acute stroke, and many cardioembolic strokes are probably missing from this cohort because of selection bias. Our population of small-vessel strokes, being generally milder in severity, may be more representative. If more representative severe cases of AF-related stroke were included in the study, even stronger relationships among SDB specific indices and AF could have been detected.
Conclusion SDB is a modifiable risk factor in primary and secondary prevention of vascular diseases and a potential therapeutic target in acute stroke. Our study confirmed high prevalence of SDB in acute ischemic stroke with mildto-moderate severity. Nevertheless, the real frequency of SDB may be even higher. Observed higher values of AHI, DI, and AI in large-artery strokes may relate to significantly more severe neurologic deficit in this subgroup. Higher AHI and DI in cardioembolic strokes may mirror premorbid presence of more severe SDB in patients with AF. Age and DI were established as the only significant variables associated with AF in acute ischemic stroke. Although AF seems to be an important factor linking SDB with ischemic stroke, we are not able to establish a causal relationship between SDB, AF, and ischemic stroke. However, our data highlight the importance and prevalence of SDB even in cohort with minorto-moderate stroke. We failed to find higher compliance rates of CPAP therapy in patients with minor-tomoderate stroke. In conclusion, our data support the fact that polysomnography should be included in recommendations for management of stroke patients and patients with AF. Future studies should focus on exact causes of noncompliance of CPAP therapy in stroke patients and elucidate the effect of CPAP therapy on stroke and AF recurrence in stroke patients.
References 1. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation 2013;127:143-152. 2. Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis. J Clin Sleep Med 2010;6:131. 3. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034-2041. 4. Bassetti C, Aldrich MS. Sleep apnea in acute cerebrovascular diseases: final report on 128 patients. Sleep 1999; 22:217-224. 5. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82-93. 6. Kato M, Adachi T, Koshino Y, et al. Obstructive sleep apnea and cardiovascular disease. Circ J 2009;73:1363-1370. 7. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005;36: 1115-1119. 8. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004;110:364-367. 9. Hui DS, Choy DK, Wong LK, et al. Prevalence of sleepdisordered breathing and continuous positive airway pressure compliance results in Chinese patients with first-ever ischemic stroke. Chest 2002;122:852-860. 10. Wessendorf T, Wang M, Thilmann A, et al. Treatment of obstructive sleep apnoea with nasal continuous positive airway pressure in stroke. Eur Respir J 2001;18:623-629. 11. Brott T, Adams H, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989;20:864-870. 12. Sulter G, Steen C, De Keyser J. Use of the Barthel index and modified Rankin scale in acute stroke trials. Stroke 1999;30:1538-1541. 13. Adams H, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41. 14. Iber CAIS, Chesson A, Quan SF. The AASM Manual for the scoring of sleep and associated events: rules, terminology and technical specification. Westchester, IL: American Academy of Sleep Medicine 2007. 15. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-545. 16. Shibazaki K, Kimura K, Uemura J, et al. Atrial fibrillation is associated with severe sleep-disordered breathing in patients with ischaemic stroke and transient ischaemic attack. Eur J Neurol 2013;20:266-270. 17. Dziewas R, Hopmann B, Humpert M, et al. Positional sleep apnea in patients with ischemic stroke. Neurol Res 2008;30:645-648. 18. Petty GW, Brown RD, Whisnant JP, et al. Ischemic stroke subtypes a population-based study of functional outcome, survival, and recurrence. Stroke 2000;31: 1062-1068. 19. Turkington P, Bamford J, Wanklyn P, et al. Prevalence and predictors of upper airway obstruction in the first 24 hours after acute stroke. Stroke 2002;33:2037-2042. 20. Bassetti CL, Milanova M, Gugger M. Sleep-disordered breathing and acute ischemic stroke diagnosis, risk factors, treatment, evolution, and long-term clinical outcome. Stroke 2006;37:967-972.
SDB IN SUBTYPES OF STROKE 21. Saletu M, Sauter C, Lalouschek W, et al. Is excessive daytime sleepiness a predictor of carotid atherosclerosis in sleep apnea? Atherosclerosis 2008;196:810-816. 22. Mehanna R, Jankovic J. Movement disorders in cerebrovascular disease. Lancet Neurol 2013;12:597-608. 23. Terzoudi A, Vorvolakos T, Heliopoulos I, et al. Sleep architecture in stroke and relation to outcome. Eur Neurol 2008;61:16-22. 24. Braga B, Poyares D, Cintra F, et al. Sleep-disordered breathing and chronic atrial fibrillation. Sleep Med 2009; 10:212-216. 25. Caples SM, Somers VK. Sleep disordered breathing and atrial fibrillation. Prog Cardiovasc Dis 2009;51: 411-415. 26. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173:910.
1093 27. Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107:2589-2594. 28. Wilson D, Frontera A, Thomas G, et al. Screening for atrial fibrillation in patients with obstructive sleep apnoea to reduce ischaemic strokes. Int J Cardiol 2014; 172:297-298. 29. Mansukhani MP, Calvin AD, Kolla BP, et al. The association between atrial fibrillation and stroke in patients with obstructive sleep apnea: a population-based case-control study. Sleep Med 2013;14:243-246. 30. Piccini JP, Hammill BG, Sinner MF, et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries: 1993–2007. Circ Cardiovasc Qual Outcomes 2012;5:85-93. 31. Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007;49:565-571.
Background: Sleep-disordered breathing (SDB) is frequent in stroke patients. A strong association has been suggested between SDB and atrial fibrillation (AF). In this study, we evaluated the characteristics of SDB in etiologic subtypes of acute ischemic stroke. We also investigated the relationship between SDB and AF in acute ischemic stroke. Methods: We prospectively enrolled 72 patients with minorto-moderate acute ischemic stroke. Clinical and laboratory characteristics of population were recorded on admission. SDB was assessed using standard polysomnography within 7 days after stroke onset. Results: Apnea–hypopnea index (AHI) in small-vessel strokes was significantly lower than that in large-artery atherosclerosis strokes (P 5 .031), cardioembolic strokes (P 5 .011), and strokes of other or unknown etiology (.008). Desaturation index (DI) in small-vessel strokes was significantly lower than that in cardioembolic strokes and in large-artery strokes (P 5.008, P 5 .035). Arousal index (AI) in large-artery strokes was significantly higher than that in small-vessel strokes (P 5 .013), cardioembolic strokes (P 5 .007), and strokes of other or unknown etiology (.027). In a multivariate regression model were age (odds ratio [OR], 1.083; 95% confidence interval [CI], 1.022-1.148; P 5 .007) and DI (OR, 1.037; 95% CI, 1.004-1.071; P 5 .026) the only significant variables independently associated with AF. Conclusions: We observed higher AHI, DI, and AI in large-artery strokes that may relate to more severe neurologic deficit in this subgroup. Age and DI were the only independent variables significantly associated with AF in acute ischemic stroke. Higher AHI and DI in cardioembolic strokes may thus mirror more frequent premorbid presence of SDB in patients with AF. Key Words: Sleep-disordered breathing—ischemic stroke—etiologic stroke subtypes—atrial fibrillation—polysomnography. Ó 2015 by National Stroke Association
Stroke is the second most common cause of death worldwide and one of the leading causes of disability.1 Sleep-disordered breathing (SDB) is frequent in stroke patients. Meta-analyses found the presence of SDB in up
to 72% of stroke patients.2 SDB belongs to independent risk factors for stroke.3 On the other hand, stroke may contribute to SDB onset or aggravate premorbid SDB.4 Multiple mechanisms might be responsible for the
From the 1st Department of Neurology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. Received November 16, 2014; revision received January 9, 2015; accepted January 22, 2015. This work was supported by the Grant of The Ministry of Health of the Slovak Republic (2012/56-SAV-6) and by the Framework Programme for Research and Technology Development, Project: Building of Centre of Excellency for Sudden Cerebral Vascular Events, Comenius University Faculty of Medicine in Bratislava
(ITMS:26240120023), cofinanced by European Regional Development Fund. The authors declare no conflict of interest. Address correspondence to Branislav Koll ar, MD, PhD, 1st Department of Neurology, Faculty of Medicine, Comenius University, Mickiewiczova 13, 81369 Bratislava, Slovakia. E-mail: branislavkollarmd@ gmail.com. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.01.023
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 5 (May), 2015: pp 1087-1093
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development of stroke in patients with SDB, including endothelial damage, atherosclerosis, hypercoagulability, inflammatory and hemodynamic changes, paradoxical embolization, and the development of cardiac arrhythmias.5,6 Atrial fibrillation (AF) is the most common cardiac arrhythmia responsible for about 25% of all ischemic strokes.7 Although the association of SDB with AF is well known, the relationship between AF and SDB in acute ischemic stroke is unclear.8 Although SDB is a possible therapeutic target in acute stroke, compliance rates of continuous positive airway pressure (CPAP) therapy in the acute stroke are low (47%) and even decrease in chronic phase (11%).9 Severity of motor disability and aphasia are important predictors of poor CPAP compliance.10 In our study, we focused on the prevalence and characteristics of SDB in population with minor-tomoderate strokes with possibility of better compliance to CPAP. The aim of study was to evaluate characteristics of SDB in etiologic subtypes of acute ischemic stroke and to investigate the relationship between SDB and AF in acute ischemic stroke.
Methods The study subjects were recruited from patients hospitalized in the stroke unit of the 1st Department of Neurology, Comenius University Bratislava with the diagnosis of acute ischemic stroke from January 2011 to December 2013. Patients were excluded in a case of severe neurologic deficit– National Institutes of Health Stroke Scale (NIHSS) more than 15, impairment of consciousness, agitated confusion, acute chest infection, chronic lung disease, or if they refused to participate. The study was approved by the institutional ethics committee. All patients provided informed consent. The diagnosis was confirmed clinically and by computed tomography or magnetic resonance imaging (MRI). NIHSS and modified Rankin Scale score were used to assess baseline stroke severity.11,12 The etiology of stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria.13 Electrocardiography (ECG), carotid and transcranial ultrasonography, computed tomography/magnetic resonance imaging angiography, and echocardiography were used to determine the etiology of ischemia. Medical records of all patients were reviewed to determine the premorbid presence of AF. Native 12-lead ECG, continuous ECG monitoring in stroke unit, ECG monitoring during polysomnography, and 24-hour Holter ECG monitoring were used to detect the AF. Clinical characteristics including age, gender, current smoking habit, blood pressure, neck circumference, and body mass index (BMI) were assessed on admission. Standard biochemical blood tests were performed in the morning of the following day. Samples were processed in local hospital laboratory.
The sleep analysis was performed within 7 days after stroke onset. Subjects underwent standard overnight polysomnography in the sleep laboratory using Alice 5 device (Philips-Respironics, Netherlands). Channels for electroencephalogram, electrooculogram, chin electromyogram, tibialis electromyogram, body position, finger arterial oximetry, and ECG were included. Chest belt, abdominal belt, and nasal cannula were used to monitor the breathing effort and airflow. Recordings were scored manually. Sleep parameters and respiratory events were scored according to standardized criteria.14 Epworth Sleepiness Scale was used to assess the excessive daytime sleepiness.15 Scores were blinded to the stroke subtypes. The statistical analyses were performed using SPSS version 18 (SPSS Inc., Chicago, IL). Categorical variables were expressed as numbers and proportions (%), continuous variables as means 6 standard deviation or median, interquartile range (IQR), minimal and maximal values. Kruskal–Wallis test was used for intergroup comparison. To compare groups, chi-squared test, Student t test, and Mann–Whitney test were used for particular variables. Binary logistic regression analysis was used to identify factors that contributed to the presence of AF. P values less than .05 were considered statistically significant.
Results Thirty-two women and 40 men with acute ischemic stroke were enrolled. Mean age was 66.4 years and median NIHSS was 4. Ten strokes (13.9%) were caused by large-artery atherosclerosis, 21 strokes (29.2%) by small-vessel occlusion, and 33 strokes (45.8%) by cardioembolism. Other or unknown etiology was present in 8 patients (11.1%). Sleep apnea syndrome, defined as apnea–hypopnea index (AHI) of 5 or greater, was present in 59.7% of patients. In all, 60.5% of them experienced obstructive sleep apnea (OSA), and central sleep apnea was present in 39.5%. No Cheyne–Stokes respiration was observed. Baseline characteristics are shown in Table 1. SDB-specific indices, including AHI, desaturation index (DI), arousal index (AI), saturation of blood with oxygen, % of total sleep time in supine position, Epworth Sleepiness Scale, BMI, and neck circumference, were compared in etiologic stroke subtypes, see Table 2. Significant intergroup differences were found in values of AHI (P 5 .022), DI (P 5.032), and AI (.038). Populations of subtypes did not significantly differ in age, BMI, and neck circumference. NIHSS was significantly higher in largeartery strokes (median, 6.00; range, 5.00-12.00; IQR, 2.00) than that in all other subtypes: P less than .001 when compared with small-vessel strokes (median, 4.00; range, 1.00-10.00; IQR 1.50), P 5 .017 when compared with cardioembolic strokes (median, 5.00; range, 1.00-11.00; IQR, 3.00) and P 5 .027 when compared with strokes of other or unknown etiology (median, 3.50; range, 2.00-12.00; IQR 3.50). AHI in small-vessel strokes (median, 3.9; range,
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Table 1. Baseline characteristics Variable
N 5 72
Male sex Age (y) NIHSS mRS Etiology Small vessel Large-artery atherosclerosis Cardioembolic Other Unknown Location Supratentorial Cerebellar Brainstem Supra and infratentorial Atrial fibrillation BMI (kg/m2) Smoking habit Neck circumference (cm) Glycemia (mmol/L) Leucocyte count (3109/L) TAG (mmol/L) Total cholesterol (mmol/L) LDL (mmol/L) HDL (mmol/L) Systolic BP (mm Hg) Diastolic BP (mm Hg) Sleep apnea syndrome OSA CSA AHI (n/h) DI (n/h) AI (n/h) Average sat (%) Minimal sat (%) ESS
40 (55.6) 66.4 6 12.5 4.0, 1.0-12.0, 3.0 2.0, 1.0-5.0, 1.8 21 (29.2) 10 (13.9) 33 (45.8) 3 (4.2) 5 (6.9) 54 (75) 5 (6.9) 9 (12.5) 4 (5.6) 24 (33.3) 27.7 6 4.8 17 (23.6) 39.3 6 4.9 5.8 6 1.7 8.0 6 3.2 1.2, .1-11.8, .7 5.1 6 1.4 3.4 6 1.2 1.2 6 .3 156.2 6 22.6 84.3 6 11.3 43 (59.7) 26 (60.5) 17 (39.5) 8.1, .0-87.4, 20.9 8.8, .0-98.4, 19.9 17.4, 1.9-453.0, 22.5 92.4 6 2.2 85.6 6 7.5 4.0, 0-13.0, 5.0
Abbreviations: AHI, apnea–hypopnea index; AI, arousal index; BMI, body mass index; BP, blood pressure; CSA, central sleep apnea; DI, desaturation index; ESS, Epworth Sleepiness Scale; HDL, high-density lipoprotein; LDL, low-density lipoprotein; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; OSA, obstructive sleep apnea; sat, saturation of blood with oxygen; TAG, triglyceride. Categorical variables expressed as numbers and proportions (%). Continuous variables expressed as means 6 standard deviation or median, range, interquartile range.
.0-40.2; IQR 5.4) was significantly lower than that in largeartery strokes (median, 10.2; range, 1.8-62.8; IQR, 24.6; P 5 .031), cardioembolic strokes (median, 14.1; range, .1-87.4; IQR, 32.4; P 5 .011), and strokes of other or unknown etiology (median, 11.0; range, 3.4-35.3; IQR, 19.5; .008). DI in cardioembolic strokes (median, 15.80; range, .00-98.40; IQR, 32.10) and in large-artery strokes (median, 15.25; range, 2.30-44.90; IQR, 21.55) was significantly
higher than that in small-vessel strokes (median, 3.60; range .30-43.80; IQR, 8.50; P 5 .008; P 5 .035). AI in large-artery strokes (median, 29.15; range, 8.30-453.00; IQR, 119.60) was significantly higher than that in smallvessel strokes (median, 7.90; range, 2.40-197.00; IQR, 24.75; P 5 .013), cardioembolic strokes (median, 15.70; range, 2.20-66.30; IQR 21.05; P 5.007), and strokes of other or unknown etiology (median, 16.55; range, 1.90-36.10; IQR, 14.03; P 5 .027). In a study population, we found significant correlation of AF with AHI (r 5 .261, P 5.027) and DI (r 5 .292, P 5 .013). We failed to find any significant correlation with the nocturnal saturation of blood with oxygen or BMI. Comparison of baseline characteristics in population with detected AF and in population without detected AF showed significant difference in age (P , .001), current smoking habit (P 5 .031) AHI (P 5 .028), and DI (P 5 .014), see Table 3. Age (odds ratio [OR], 1.083; 95% confidence interval [CI], 1.022-1.148; P 5 .007) and DI (OR, 1.037; 95% CI, 1.004-1.071; P 5 .026) remained the only significant variables associated with AF in a multivariate regression model. Of the 27 patients indicated for CPAP therapy (AHI $15), only 3 of them (11.1%) remained compliant 12 months after the stroke onset.
Discussion Results of our study confirm high prevalence of SDB in acute ischemic stroke with minor-to-moderate severity (median NIHSS, 4). There was no significant difference in SDB prevalence in etiologic stroke subtypes. Significant intergroup differences were found in values of AHI, DI, and AI. AHI and DI in cardioembolic strokes and in large-artery atherosclerosis strokes were significantly higher than those in small-vessel occlusion strokes indicating more severe SDB in these populations. AI in large-artery strokes was significantly higher than that in all other stroke subtypes. In addition, we found age and DI to be the only significant variables associated with AF in acute ischemic stroke. We failed to find higher compliance rates of CPAP therapy in patients with minor-to-moderate stroke. Meta-analysis of 2343 stroke patients described the frequency of SDB in up to 72%. In most included studies, patients were, similarly to our study, excluded if there was a serious medical condition, dementia, confusion, or if consent could not be obtained. Polysomnography in stroke unit patients was performed in 7 of 29 studies, and many of the patients have not been scored for severity of stroke. Sleep apnea was typically obstructive in nature. SDB was more common in strokes of unknown etiology and less common in cardioembolic strokes.2 Similarly to meta-analysis, our study confirmed high prevalence of SDB in acute ischemic stroke (59.7%). OSA, with frequency of 60.5%, was more frequent than central sleep apnea. We failed to find any significant
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Table 2. Sleep characteristics in etiologic stroke subtypes
Etiology
Small vessel
Large-artery atherosclerosis
Cardioembolic
Other/unknown
P
N SDB prevalence AHI (n/h) DI (n/h) AI (n/h) Average sat (%) Minimal sat (%) ESS % of TST in supine position Age (y) BMI (kg/m2) Neck circumference (cm) NIHSS
21 13 (61.9) 3.9, .0-40.2, 5.4 3.6, .3-43.8, 8.5 7.9, 2.4-197.0, 24.8 92.5 6 1.7 88.4 6 4.6 4.0, .0-9.0, 6.0 52.2, 2.4-100.0, 67.0
10 9 (90.0) 10.2, 1.8-62.8, 24.6 15.3, 2.3-44.9, 21.6 29.2, 8.3-453.0, 119.6 92.3 6 2.7 85.1 6 3.8 3.5, 1.0-12.0, 6.8 81.0, 5.9-100.0, 22.4
33 26 (78.8) 14.1, .1-87.4, 32.4 15.8, .0-98.4, 32.1 15.7, 2.2-66.3, 21.1 92.1 6 2.5 84.0 6 9.7 5.0, .0-13.0, 6.0 86.9, .0-100.0, 75.4
8 7 (87.5) 11.0, 3.4-35.3, 19.5 8.3, 2.6-42.9, 13.75 16.6, 1.9-36.1, 14.0 93.4 6 1.7 85.5 6 4.9 3.0, 2.0-10.0, 5.5 86.2, 23.7-100.0, 14.4
.249 .022* .032* .038* .469 .100 .680 .846
64.5 6 11.4 29.6 6 5.9 38.7 6 4.3
62.7 6 13.3 27.1 6 5.4 39.0 6 2.7
68.8 6 13.1 27.1 6 3.8 39.2 6 5.7
66.4 6 12.1 25.9 6 4.0 41.7 6 5.5
.337 .293 .590
4.0, 1.0-10.0, 1.5
6.0, 5.0-12.0, 2.0
5.0, 1.0-11.0, 3.0
3.5, 2.0-12.0, 3.5
.005**
Abbreviations: AHI, apnea–hypopnea index; AI, arousal index; BMI, body mass index; DI, desaturation index; ESS, Epworth Sleepiness Scale; NIHSS, National Institutes of Health Stroke Scale; sat, saturation of blood with oxygen; SDB, sleep-disordered breathing; TST, total sleep time. *P value below .05; **P value below .01. Categorical variables expressed as numbers and proportions (%). Continuous variables expressed as means 6 standard deviation or median, range, interquartile range.
difference in SDB prevalence among etiologic stroke subtypes, which is inconsistent with previous findings. On the other hand, a recent study found no significant difference in SDB prevalence amongst stroke subtypes.16 Multiple mechanisms might link SDB with the development of stroke including endothelial damage, atherosclerosis, hypercoagulability, inflammatory and hemodynamic changes, paradoxical embolization, and the development of cardiac arrhythmias.5,6 SDB might be therefore associated equally with all stroke subtypes. Several factors may be related to the variability in the rates and severity of SBD in acute stroke, including type of stroke, age, and BMI. Increase in supine positioning is suggested to be one of the most important factors that may increase the frequency of SDB in acute stroke.2,17 Populations of stroke subtypes in our study did not significantly differ in age, BMI, neck circumference, and percent of total sleep time in supine position. NIHSS was found to be significantly higher in large artery strokes than that in all other subtypes. We must admit that our population probably differs from representative populations with acute stroke. Cardioembolic strokes in general are expected to have higher NIHSS scores than larger artery strokes.18 Our study included only strokes with minor-to-moderate severity and many large-artery strokes and cardioembolic strokes are probably missing from this cohort because of selection bias. Population of small-vessel strokes, being generally milder in severity, may be more representative in our cohort.
Our study revealed significantly higher AHI and DI in large-artery strokes than those in small-vessel strokes. AI in large-artery strokes was significantly higher than that in all other subtypes. Higher AHI, DI, and AI in largeartery strokes may relate to significantly more severe neurologic deficit in this subgroup, although there is only little apparent relation between SDB and the clinical severity of stroke described in previous studies.19 More severe SDB after large-artery strokes may also reflect pre-existing SDB. An association between SDB after stroke and macroangiopathy as cause of stroke was also observed in the previous study.20 Another study revealed that nocturnal arousals because of respiratory events to be an independent predictor of carotid atherosclerosis.21 Our study included all causes of arousal including nonrespiratory. We assume observed number of arousals exceeds arousals because of respiratory events. Changes in sleep architecture and movement disorders leading to disruption of sleep in stroke patients were described previously.22,23 The exact cause of increased number of arousals in large-artery strokes is beyond the aim of this study. Another finding of this study was significantly higher AHI and DI in cardioembolic strokes compared with small-vessel strokes. AF was the identified etiology in most of the cardioembolic strokes. Association of SDB with AF is well known.24 Although causal relationship between SDB and AF is not exactly clear, onset of AF as a result of multiple mechanisms underlying SDB is assumed.25 Patients with severe SDB have 2- to 4-fold
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Table 3. Characteristics in population with detected and without detected atrial fibrillation Atrial fibrillation
Detected
Not detected
P
Patients Male sex Age (y) NIHSS mRS Supratentorial location Cerebellar location Brainstem location Supra and infratentorial location BMI (kg/m2) Neck circumference (cm) Smoking habit Glycemia (mmol/L) Leucocyte count (3109/L) TAG (mmol/L) Total cholesterol (mmol/L) LDL (mmol/L) HDL (mmol/L) Systolic BP (mm Hg) Diastolic BP (mm Hg) Sleep apnea syndrome OSA CSA AHI (n/h) DI (n/h) AI (n/h) Average sat (%) Minimal sat (%) ESS
24 (33.3) 10 (41.7) 73.5 6 9.6 4.0, 1.0-10.0, 3.0 2.0, 1.0-4.0, 2.0 18 (75) 3 (12.5) 2 (8.3) 1 (4.2) 27.3 6 4.2 39.7 6 6.5 2 (8.3) 5.7 6 1.4 7.6 6 2.3 1.1, .1-3.0, .6 4.8 6 1.5 3.2 6 1.3 1.2 6 0.3 161.5 6 19.8 85.0 6 8.7 18 (75.0) 11 (61.1) 7 (38.9) 16.1, .2-87.4, 40.5 17.8, .4-98.4, 45.0 16.6, 2.2-66.3, 24.8 92.0 6 2.2 84.7 6 7.1 4.0, .0-13.0, 6.0
48 (66.7) 30 (62.5) 62.9 6 12.4 5.0, 1.0-12.0, 3.0 2.0, 1.0-5.0, 1.0 36 (75) 2 (4.2) 7 (14.6) 3 (6.2) 27.9 6 5.2 39.2 6 4.0 15 (31.3) 5.8 6 1.9 8.2 6 3.6 1.2, .6-11.8, .8 5.2 6 1.4 3.6 6 1.2 1.2 6 0.3 153.5 6 23.7 84.0 6 12.5 25 (52.1) 15 (60.0) 10 (40.0) 5.4, .0-62.8, 18.3 7.2, .0-44.9, 15.3 17.4, 1.9-453.0, 21.3 92.6 6 2.2 86.0 6 7.7 4.5, .0-12.0, 5.3
.094 #.001*** .443 .207 1.00 .190 .450 .716 .614 .705 .031* .838 .424 .205 .293 .313 .639 .161 .715 .062 .941 .941 .028* .014* .872 .312 .465 .713
Abbreviations: AHI, apnea–hypopnea index; AI, arousal index; BMI, body mass index; BP, blood pressure; CSA, central sleep apnea; DI, desaturation index; ESS, Epworth Sleepiness Scale; HDL, high-density lipoprotein; LDL, low-density lipoprotein; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; OSA, obstructive sleep apnea; sat, saturation of blood with oxygen; TAG, triglyceride. Categorical variables expressed as numbers and proportions (%). Continuous variables expressed as means 6 standard deviation or median, range, interquartile range. *P value below .05; **P value below .01; ***P value below .001.
higher odds of complex arrhythmias than controls, and patients with untreated SBD are known to have a higher recurrence of AF after cardioversion than patients without SDB.26,27 Higher AHI and DI in cardioembolic strokes may thus mirror prestroke presence of more severe SDB in patients with AF. This is the first study so far to search for predictors of AF in an acute ischemic stroke including polysomnographic findings. Previous studies suggest that many of strokes associated with SDB could be avoided by proper risk assessment and more aggressive treatment of SDB and associated AF.28 Two recent studies described the association of AF with SDB in context of ischemic stroke in more detail. A population-based case–control study of 2980 patients with a new diagnosis of OSA who experienced a first-time ischemic stroke during the same period revealed a strong association among AF, stroke, and SDB. Patients with OSA who experienced a firsttime stroke had much higher rates of AF than controls
without history of stroke (5.34-fold odds of having AF).29 Characteristics of prestroke SDB or characteristics of SDB in chronic poststroke period differ from the complex situation in acute phase of ischemic stroke. Design of mentioned study, in contrast to our study, did not allow the evaluation of AF and SDB in the acute phase of stroke. Another prospective study of 150 patients with acute ischemic stroke found AF to be independently associated with severe SDB (OR, 2.4; 95% CI, 1.079-5.836; P 5 .0359).16 In this study, a portable diagnostic device was used for SDB evaluation instead of polysomnography and sleep duration, quality and respiratory effort could have not been assessed. In our study, population with AF and population without AF significantly differed in age, current smoking habit AHI, and DI. Age and DI remained the only significant variables associated with AF in a multivariable regression model. Increase in frequency of AF with age is well known.30 The previous finding of magnitude of nocturnal oxygen desaturation
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as independent risk factor for incident AF is also consistent with our findings.31 Compliance rates of CPAP therapy in the acute stroke are low (47%) and even decrease in chronic phase (11%).9 Our data are consistent with literature. We expected higher compliance rates of CPAP therapy in patients with minor-to-moderate stroke. However, of 27 patients indicated for CPAP therapy (AHI $15), only 3 of them (11.1%) remained compliant 12 months after the stroke onset. The exact causes of noncompliance and possible effect of CPAP therapy on AF were beyond the aim of this study. Selection bias is the main limitation of our study. Our study included only patients with minor (NIHSS, 1-4) to moderate stroke (NIHSS, 5-15). Patients with more severe neurologic deficit were excluded from measurement. This could have underestimated the exact frequency and severity of SDB in the acute stroke. We must admit that our population probably differs from representative populations with acute stroke, and many cardioembolic strokes are probably missing from this cohort because of selection bias. Our population of small-vessel strokes, being generally milder in severity, may be more representative. If more representative severe cases of AF-related stroke were included in the study, even stronger relationships among SDB specific indices and AF could have been detected.
Conclusion SDB is a modifiable risk factor in primary and secondary prevention of vascular diseases and a potential therapeutic target in acute stroke. Our study confirmed high prevalence of SDB in acute ischemic stroke with mildto-moderate severity. Nevertheless, the real frequency of SDB may be even higher. Observed higher values of AHI, DI, and AI in large-artery strokes may relate to significantly more severe neurologic deficit in this subgroup. Higher AHI and DI in cardioembolic strokes may mirror premorbid presence of more severe SDB in patients with AF. Age and DI were established as the only significant variables associated with AF in acute ischemic stroke. Although AF seems to be an important factor linking SDB with ischemic stroke, we are not able to establish a causal relationship between SDB, AF, and ischemic stroke. However, our data highlight the importance and prevalence of SDB even in cohort with minorto-moderate stroke. We failed to find higher compliance rates of CPAP therapy in patients with minor-tomoderate stroke. In conclusion, our data support the fact that polysomnography should be included in recommendations for management of stroke patients and patients with AF. Future studies should focus on exact causes of noncompliance of CPAP therapy in stroke patients and elucidate the effect of CPAP therapy on stroke and AF recurrence in stroke patients.
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