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Postgraduate Education Corner: CONTEMPORARY REVIEWS IN SLEEP MEDICINE |

Obstructive Sleep Apnea and Stroke FREE TO VIEW

Mark Eric Dyken, MD; Kyoung Bin Im, MD
Author and Funding Information

Affiliations: From the Sleep Disorders Center, the Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.

Correspondence to: Mark Eric Dyken, MD, Associate Professor of Neurology, Director, Sleep Disorders Center and Clinical Neurophysiology and Sleep Medicine Fellowship Programs, University of Iowa Hospitals and Clinics, Department of Neurology, 200 Hawkins Dr, Iowa City, IA 52242; e-mail: mark-dyken@uiowa.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(6):1668-1677. doi:10.1378/chest.08-1512
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Obstructive sleep apnea (OSA) and stroke are frequent, multifactorial entities that share risk factors, and for which case-control and cross-sectional studies have shown a strong association. Stroke of respiratory centers can lead to apnea. Snoring preceding stroke, documentation of apneas immediately prior to transient ischemic attacks, the results of autonomic studies, and the circadian pattern of stroke, suggest that untreated OSA can contribute to stroke. Although cohort studies indicate that OSA is a stroke risk factor, controversy surrounds the cost-effectiveness of the screening for and treatment of OSA once stroke has occurred.

Figures in this Article

Obstructive sleep apnea (OSA) has an estimated prevalence of 9% in women and 24% in men.1 In the United States, stroke has an incidence of >700,000, and is the third major cause of death (>160,000 per year).2,3 OSA and stroke share many risk factors including hypertension and cardiovascular disease (CVD).2 Case reports, case-control and cohort studies, and laboratory experiments have led many investigators4 to suspect a cause-and-effect relationship between OSA and stroke.

Snoring

Epidemiologic studies have suggested that snoring is a risk factor for ischemic stroke.5 In 1989, Palomake et al6 evaluated 167 men with stroke. Thirty-six percent of patients experienced stroke during sleep. Snoring was found to be the only potential risk factor significantly related to stroke in sleep. Snoring was a much greater risk factor for stroke when obesity and sleepiness (classic signs and symptoms for OSA) were present.7 It is suspected that these studies, which were performed without polysomnography, may have included a significant number of apneic patients. Consequently, full-formal polysomnography has been encouraged during subsequent research that involves stroke and sleep.

Polysomnography Studies
Case Reports:

Polysomnography allows a precise definition of OSA based on the apnea-hypopnea index (AHI), which is the average number of apneas plus hypopneas per hour of sleep.8 In 1985, Tikare et al9 evaluated an obese, 34-year-old man with a history of snoring, sleepiness, hypertension, and an acute right hemiplegia. His polysomnography revealed an AHI of 78.0 with low value for arterial oxygen saturation (Sao2) of 70%.

In 1991, a 34-year-old obese man, with snoring and sleepiness, awoke with left hemiparesis.10 Subsequent polysomnography revealed an AHI of 36.0 with an Sao2 low value of 60%. A head CT scan showed a hemorrhagic stroke in the right internal capsule. The authors hypothesized that in this case apnea might have induced stroke through hypoxia and cardiac arrhythmia (which are commonly observed in OSA patients), or from hypertensive hemorrhage, because the authors of previous studies reported11 elevated BPs following apneas. Great science often begins with a simple observation, and the speculation generated by case reports such as these rationalized the performance of larger studies.

Case Series:

In 1991, Kapen et al12 selected 31 subjects with ischemic hemispheric stroke for polysomnography. When added to 16 case studies that utilized modified polysomnography techniques, 72% of the patients were found to have OSA (mean AHI, 37.9; S. Kapen, MD; personal communication; May 1997). Good et al13 used oximetry screening to select 19 of 47 patients with stroke for polysomnography. Eighteen subjects had OSA (mean AHI, 36.0). Although case series often used highly selected populations and variable methodologies, their findings justified performing future case-control studies.

Case-Control Studies:

In 1992, a prospective polysomnography analysis14,15 of 24 consecutively encountered, nonselected inpatients with stroke and 27 healthy gender- and age-matched control subjects without stroke showed OSA in 71% of stroke subjects and in 19% of control subjects. Sixty-nine percent of men with stroke and 82% of women with stroke had hypertension, whereas cardiac disease was reported in 31% of men with stroke and in 55% of the women with stroke.

In 1993, Hudgel et al16 studied eight subjects with polysomnography, ≥1 month after stroke, after conducting finger pulse oximetry assessments that suggested the presence of OSA. The mean AHI and lowest Sao2 in the stroke group were 44.0 and 82%, respectively; for control subjects, they were 12.0 and 90%, respectively.

In 1996, Bassetti et al17 studied 23 consecutively encountered subjects with acute stroke. Seventy percent had OSA, with a mean AHI and Sao2 low value of 32.0 and 82%, respectively. Sixteen percent of 19 healthy control subjects had OSA, with a respective mean AHI and Sao2 low values of 6.0 and 89%, respectively.

These case-control studies documented a strong association between stroke and OSA. Some investigators also have suggested14,15,18 mechanisms for cause and effect, and allowed speculation that OSA-induced hypoxemia and elevated autonomic activity might have short-term and long-term effects on cardiac rhythm, BP, intracranial pressure, and blood flow that could predispose patients to stroke.

Mohsenin and Valor19 studied 10 selected subjects who had experienced stroke but did not have histories of significant snoring, sleepiness, or obesity. Stroke subjects and control subjects had respective mean AHIs of 52.0 and 3.0. In this study, the paucity of signs and symptoms suggesting OSA prior to stroke suggested that stroke might have caused OSA.

CNS Injury Studies

Animal studies20 have indicated that stroke can cause apnea, as brainstem lesions caudal to the fifth cranial nerve and rostral to the upper cervical spinal cord can result in failure of automatic respiration. In addition, areas in the mesencephalon, diencephalon, and fronto-orbital, cingulate, insular, anterior temporal, and sensorimotor cortices can have significant modulating effects on brainstem respiratory control.21

Normal involuntary breathing is largely governed by a medullary respiratory center composed of autonomic nuclei located in the reticular formation of the brainstem.22 This center is divided into two neuronal collections designated as the ventral respiratory group (VRG) and the dorsal respiratory group (DRG).

The DRG (in the dorsomedial medulla) is composed of cells from the solitary tract nucleus. It generates inspiration through spinal motor neurons. The VRG (divided into rostral nucleus ambiguus and caudal nucleus retroambiguus components) is located in the ventrolateral medulla, and contains inspiratory and expiratory neurons.

Efferent axons from the DRG descend in the ventrolateral columns of the spinal cord to innervate the diaphragm, intercostal, and accessory respiratory muscles (Fig 1, 2). Central sleep apnea has been documented in humans after stroke of the solitary tract nucleus as a result of diaphragmatic dysfunction.23 Injury to the rostral VRG, an area that provides motor innervation to the larynx and pharynx, has been used to explain OSA following stroke.24

Figure Jump LinkFigure 1 This schematic diagram of the brainstem shows in a parasagittal section the location of the dorsal and VRGs and their projections to the spinal cord and respiratory muscles.Grahic Jump Location
Figure Jump LinkFigure 2 This schematic diagram shows in detail the components and the connectivities of the medullary respiratory center. Modified from Figures 5 to 18 and 5 to 19 of Afifi and Bergman.22 Modified with permission of the McGraw-Hill Companies.Grahic Jump Location

Animal studies and human stroke case reports have long suggested that stroke has the potential to cause OSA in some individuals. Conversely, transient ischemic attack (TIA) and cohort incidence studies imply that OSA can also act as a risk factor for stroke.

TIA Studies

A TIA, often referred to as ministroke, is a focal neurologic deficit that resolves within 24 h.2 As approximately 15% of strokes are preceded by TIA (90-day risk up to 17.3%), some experts2,25,26 have used polysomnography investigations of subjects with TIA as indirect evidence to support a cause-and-effect relationship between OSA and stroke. In one such case,27 a patient with vertebrobasilar stroke began experiencing transient episodes of left hemiplegia, ophthalmoplegia, and Babinski signs on awakening from sleep. Polysomnography showed that each event was preceded by an obstructive apnea.

In another case report,28 an obese, hypersomnolent 64-year-old woman with a history of loud snoring awoke with an aphasia that resolved over 3 h. Polysomnography revealed an AHI of 83.4, with oxygen desaturations of <50%. Continuous positive airway pressure (CPAP) therapy led to a resolution of TIA.

In 1996, Bassetti et al17 studied 13 consecutive subjects with TIA. OSA was diagnosed in 69% of the individuals with TIA, and in only 16% of individuals in a control group. A larger study29 of 86 subjects with TIA revealed no significant difference between the mean (±SD) AHI of the TIA group (21±17.0) and the control group (21±14.4).

Given the conflicting reports, OSA is presently not considered a proven risk factor for TIA.17,29 Nevertheless, these anecdotes have suggested to some27,28 that OSA, through transient hemodynamic impairments, might predispose patients to TIA, and in such cases CPAP might be considered a primary method for stroke prevention.

Cohort Studies

Large population and clinically based cohort studies have been used to address the incidence of stroke in a variety of groups with OSA (Table 1).

Table Graphic Jump Location
Table 1 OSA and Stroke Risk: Incidence Studies

CAD = coronary artery disease.

*Original population providing original cross-sectional prevalence data.

†Population used for longitudinal analysis of incident stroke.

‡In a model adjusted for age and gender.

§In a model adjusted for age, gender, race, smoking, BMI, diabetes, hyperlipidemia, atrial fibrillation, and hypertension.

‖In a model adjusted for gender.

¶In a model adjusted for age, BMI, left ventricular function, diabetes, gender, intervention, hypertension, atrial fibrillation, previous stroke, or TIA.

Population-Based Studies:

In 2005, Arzt et al30 published a report from a 12-year period during which data were gathered from a stratified random sample. A cross-sectional analysis, utilizing logistic regression, of a population of 1,475 adult subjects between the ages of 30 and 60 years showed that a baseline AHI of ≥20 independently increased the odds ratio (OR) for stroke (3.83; 95% CI, 1.17 to 12.56; p = 0.03) when compared with the reference group with an AHI <5, after adjusting for known confounding factors (age, gender, BMI, alcohol consumption, smoking, diabetes, and hypertension).

A longitudinal analysis of 1,189 subjects from the original population tested whether sleep-disordered breathing (SDB) was associated with increased incidence of stroke at 4-year intervals (4, 8, and 12 years). In a model controlled for age and gender, subjects with a baseline AHI of ≥20 also had a significantly higher OR for incident stroke when compared with the reference group (4.48; 95% CI, 1.31 to 15.33; p = 0.02).

In 2001, Shahar et al31 examined the cross-sectional association between SDB and self-reported CVD in 6,424 individuals who underwent unattended home polysomnography. Mild-to-moderate SDB was highly prevalent with a median AHI of 4.4, with an interquartile range of 1.3 to 11.0. A total of 1,023 subjects (16%) reported at least one manifestation of CVD, which was defined as myocardial infarction, angina, coronary revascularization procedure, heart failure, or stroke. The relative odds of prevalent stroke (upper vs lower AHI quartile) was 1.58 (95% CI, 1.02 to 22.46). The authors emphasized that these findings were compatible with modest-to-moderate effects of SDB on heterogeneous manifestations of CVD within a range of AHI values considered normal or only mildly elevated.

Clinic-Based Studies:

In 2005, an observational cohort study by Yaggi et al32 utilized 1,022 subjects who were specifically referred with suspected SDB, and compared the combined risk of the development of composite stroke, TIA, or death from any cause in a group of 697 individuals with OSA (AHI ≥5), with that of subjects with an AHI of <5. Many patients with OSA were treated during the study by using weight reduction, positive airway pressure therapy, or upper-airway surgery.

Follow-up data from 842 subjects revealed a total of 22 incident strokes and/or TIAs and 50 deaths in the OSA group, with only two total incident strokes and/or TIAs, and 14 deaths in the comparison group. After adjusting for age, gender, race, smoking, BMI, diabetes, hyperlipidemia, atrial fibrillation, and hypertension, OSA was associated with a significant risk of composite stroke, TIA, or death (hazard ratio [HR], 1.97; 95% CI, 1.12 to 3.48; p = 0.01). In a trend analysis, increased severity of OSA was associated with an increased risk of stroke, TIA, or death from any cause (p = 0.005).

In 2006, Munoz et al33 studied a noninstitutionalized population of elderly individuals, with an age range from 70 to 100 years (median age, 77.28 years), who had been drawn from a random one-stage cluster sampling stratified by census areas, age, and gender. Over a 6-year period, after adjusting for gender, a baseline AHI of ≥30 was found to be a risk factor for incident TIA or ischemic stroke with an HR of 2.52 (95% CI, 1.04 to 6.1; p = 0.04).

In 2008, Valham et al34 studied a population of patients who were ≤70 years of age, and had symptomatic angina pectoris and coronary artery disease (verified by coronary angiography and left ventriculography). A total of 392 patients were randomly selected for modified polysomnography recordings that did not monitor EEG, and used a pressure-sensitive bed to detect respiratory movements.

Initially, 54% of the subjects had sleep apnea (AHI, ≥5). All individuals were followed in a prospective manner over 10 years (only nine received treatment for OSA); stroke subsequently occurred in 47 individuals (12%). Sleep apnea associated with an increased risk of stroke with an HR of 2.89 (95% CI, 1.37 to 6.09; p = 0.005), independent of age, gender, BMI, smoking, left ventricular function, diabetes, hypertension, atrial fibrillation, previous stroke or TIA, or treatment intervention for OSA. Subjects with an AHI >5 and <15, and those with an AHI ≥15, respectively, had 2.44 times (95% CI, 1.08 to 5.52; p = 0.011) and 3.56 times (95% CI, 1.56 to 8.16; p = 0.011) the increased risk of stroke compared with those without apnea, independent of confounders.

Cohort studies to date have addressed a variety of populations by using variable polysomnography methodologies and OSA definition standards, and frequently have addressed the risk of stroke in a combined fashion with other factors. Nevertheless, the data suggest that in the general adult population, untreated OSA with an AHI ≥20 is a risk factor for stroke.30

Treatment vs Nontreatment Studies:

Scientifically, cause and effect is often proven utilizing prospective, treatment vs nontreatment studies. In 1988 and 1990, Partinen and colleagues35,36 published the results of a 7-year study in which 198 patients with OSA were treated with tracheostomy (71 subjects) or weight loss only (127 individuals). At follow-up, 1.2% of patients in the tracheostomy group had experienced a new stroke (2.8% died), whereas 5.2% of patients in the weight-loss group had experienced a new stroke (17.3% of patients died, 11% from vascular causes). These results suggested that undertreated OSA may lead to higher morbidity and mortality from stroke.

The Metabolic Syndrome

OSA, obesity, and hypertension have been independently associated with multiple risk factors for stroke that are nicely (granted, oversimplistically) summarized in the metabolic syndrome. A strong association had been documented between the metabolic syndrome and OSA.3742 Up to 53% of consecutively encountered patients who had recently been given a diagnosis of OSA have been reported to have the metabolic syndrome.37 One cross-sectional controlled study38 revealed the metabolic syndrome to be significantly more common in OSA (men, 49.5% vs 22.0%, respectively [p<0.01]; women, 32.0% vs 6.7% for women, respectively [p<0.01]). OSA has variably been reported39,40 to increase the odds of having the metabolic syndrome anywhere from fivefold to ninefold. Although controversy surrounds whether OSA predisposes patients to or can result from the metabolic syndrome, the strong association between OSA and the metabolic syndrome is well documented.41,42

OSA is independently associated with obesity and hypertension (stroke risk factors of the metabolic syndrome).2,43 An increase in BMI (weight in kilograms divided by the square of the height in meters) by 1 SD increases the OR for SDB (defined as an AHI ≥5) by 4.17.1 A prospective, population-based study44 showed that over a 4-year period the OR of an individual with an AHI either between 5.0 and 14.9 or ≥15.0 for the development of hypertension were respectively two and three times greater than for someone without significant apnea.

Autonomic Activity

OSA elevates sympathetic nerve activity (SNA) as a result of the reflex effects of hypoxia, hypercapnia, and decreased input from thoracic stretch receptors (Figs 3 and 4).45 The hypothesis that OSA-induced hypertension can cause stroke is supported by the authors of microneurographic studies who directly measured efferent SNA.10,46 In a study of 10 subjects with OSA,47 SNA increased by 246% during the last 10 s of apneic events, in association with a mean increase in the mean BP from 92 mm Hg in the waking state to 127 mm Hg in rapid eye movement (REM) sleep. In addition, the documentation of persistently elevated waking sympathetic tone suggests that OSA can induce long-term changes that might also predispose patients to stroke.46,47

Figure Jump LinkFigure 3 A polysomnography tracing (paper speed, 10 mm/s) has been reduced to correspond to a temporally related microneurographic tracing (Fig 4; paper speed 5 mm/s). Arrows indicate a prolonged mixed apnea with a duration of approximately 26 s that occurred during REM sleep and was associated with severe oxygen desaturation. C = central; EMG = electromyogram; ET = ears tied; LOC = left outer canthus; NA = nasal airflow; O = occipital; OA = oral airflow; ROC = right outer canthus; T = temporal; TM = thoracic movement. Reprinted with permission of Marcel Dekker Inc.46Grahic Jump Location
Figure Jump LinkFigure 4 The arrows in this microneurographic tracing recorded from the peroneal nerve indicate a gradual elevation of efferent nerve activity during a mixed apnea. The activity peak is immediately followed by the cessation of the apnea, with a subsequent marked elevation of arterial BP to 215/130 mm Hg from a baseline of 135/80 mm Hg. Finapress = fingertip BP; MSNA = muscle SNA; Pneu = chest excursion. Reprinted with permission of Marcel Dekker Inc.46Grahic Jump Location

Autonomic effects may also explain the high prevalence of cardiac arrhythmias reported in up to 48% of apneic individuals.4850 Obstructive apneas can lead to excessive parasympathetic responses that are associated with inspiration against a closed glottis.48,51 In one study,51 obstructions led to recurrent prolonged episodes of sinus arrest and dramatic reductions in BP from 180/100 mm Hg (prior to obstructions) to systolic BPs <50 mm Hg during obstructions.

In patients with atrial fibrillation, the risk of OSA has been estimated to be 49%, and noncompliance with CPAP has been associated with a greater recurrence rate of atrial fibrillation after cardioversion.52,53 Atrial fibrillation is a strong risk factor for stroke, and it might also contribute to stroke in some patients with OSA.2

Circadian Rhythms

If stroke has an equal probability of occurring at any time during a 24-h time frame, 33% of strokes should occur during an 8-h period of sleep. Nevertheless, ischemic stroke occurs with a relatively high frequency during sleep and in the early morning hours.54 In one prospective prevalence study15 of stroke, a higher than expected percentage of subjects with OSA experienced their strokes during sleep (54%; p = 0.0304).

REM Sleep

The most prolonged period of REM sleep occurs in early morning, coinciding with the greatest circadian risk for stroke. The natural paresis of REM sleep generally worsens OSA and may potentiate the risk for stroke during this longer time frame.

REM sleep is normally associated with elevated SNA and BPs that reach waking levels, and pressure surges with REM-related muscle twitches.55,56 A negative amplification of these autonomic phenomena has been documented47 in OSA patients.

Cerebral blood flow normally increases in REM sleep, whereas obstructive apneas can increase intracranial pressure and reduce cerebral perfusion pressure.57,58 In OSA, these elements, when combined with an REM-related increase in SNA (and its concomitant BP instability) might synergistically predispose a patient to stroke.

The early morning hours are associated with low fibrinolytic activity and high levels of catecholamines, blood viscosity, and platelet activity and aggregability, at a time when REM-related sympathetic nervous system activation and hemodynamic instability might potentiate platelet aggregation and plaque development.59 In this normal hematologic milieu, the elevation of catecholamines and platelet activation associated with OSA may further increase thrombus and embolus formation, and stroke risk.60,61

Increased levels of two platelet activation proteins (soluble CD40 ligand and soluble P-selectin) are linked to silent brain infarctions. Minoguchi et al62 utilized brain MRIs to show silent brain infarctions in 25% of subjects with moderate-to-severe OSA and in only 6.7% of control subjects. The serum levels of soluble CD40 ligand and soluble P-selectin were significantly higher in apneic patients, and CPAP therapy led to their significant reduction.

Twenty percent of stroke survivors require institutional care after 3 months, and up to 30% are permanently disabled.2,63 After stroke, OSA appears to further increase morbidity and mortality. Good et al13 determined the functional abilities for 19 patients with recent stroke, of whom 95% were given a diagnosis of OSA. Hemispheric stroke with snoring and abnormal oximetry readings were predictive of worse functional outcome.

In a study of 61 stroke patients,64 apnea significantly and independently related to lower functional independence measure scores at hospital admission and discharge, and to length of hospitalization. In a 4-year follow-up of 24 consecutively encountered patients with stroke,15 of the five patients with concomitant OSA who subsequently died, four had experienced their original strokes during sleep. In 2008, Sahlin et al65 diagnosed OSA (AHI, ≥15) in 23 of 132 patients admitted to the hospital for stroke rehabilitation. Using patients with central and/or obstructive AHIs of ≤15 as control subjects, individuals with OSA had a higher 10-year risk for death, with an adjusted HR of 1.76 (95% CI, 1.05 to 2.95; p = 0.03). Nevertheless, only six apneic patients received CPAP therapy.

In some reports,66 the effects of CPAP on patients with stroke have been limited due to adherence to therapy as low as 15%. In 2009, a study67 utilizing CPAP determined the 5-year mortality rate of patients with moderate-to-severe OSA (AHI, ≥20), who were given a diagnosis at least 2 months after experiencing an ischemic stroke. Portable polygraphy without EEG was used to document apneas and hypopneas that were defined by using modified standards. Portable CPAP autotitration studies were then offered to those with an AHI ≥20 (with an overall average reduction in AHI from 26.0 to 4.1).

Of 96 patients, only 28 (29.2%) had good CPAP adherence over the course of the 5-year study, with an overall mean number of usage hours per night of 5.9±2.2. Patients who were not tolerant to CPAP (n = 68) had an increase in adjusted risk mortality (HR, 1.58; 95% CI, 1.10 to 2.49; p = 0.04) compared with those who tolerated CPAP. Nevertheless, in this study, the mortality risk in those patients who tolerated CPAP of 48% (12 deaths) was higher than the overall mortality rate of 40% that has been reported68 in the general population of patients with a first-ever stroke.

In addition, the authors were concerned for the potential for selection bias, despite using a multivariate analysis to address potentially confounding factors. They postulated that patients intolerant to CPAP may also have been intolerant to other therapies that might otherwise explain the increased mortality risk observed in the group of patients who were not tolerant to CPAP.

Strollo et al69 summarized a variety of issues that could promote CPAP intolerance in any patient group, as follows: claustrophobia, rhinorrhea, sinus and chest discomfort, difficulty exhaling, contact dermatitis from mask materials, aerophagia, and insomnia (additional potential problems unique to the stroke population are listed in Table 2). Nevertheless, one study70 showed that in a supportive hospital environment five subjects with stroke and OSA were able to tolerate CPAP well (>4 h per night) with normalization of oxygen saturation levels despite moderately severe disability on mean motor and cognitive functional independence measure scores.

Table Graphic Jump Location
Table 2 Potential Unique Sources/Problems Leading to Poor CPAP Adherence in the Stroke Population

Positional sleep apnea (OSA that is worse in the supine position secondary to gravitational effects on the oropharynx) appears to be a prominent feature in acute stroke. In a study71 of 43 subjects with acute stroke or TIA, the mean AHI determined with patients in the supine position of 17.7±20 was significantly higher than the mean AHI of 8.4±14.6 determined with patients in other than the supine position (p<0.001). In 2008, 55 subjects were assessed within 72 h of stroke, and after 6 months, by using cardiorespiratory polygraphy.72 Initially, 78% of patients had OSA (AHI ≥10), with 65% demonstrating positional apnea. After 6 months, the prevalence of OSA was only 49% (33% with positional apnea).

There is speculation that the recognized loss of normal physiologic nocturnal BP dipping the first few days after severe stroke might exacerbate the reported hypoxemic and autonomic concomitants documented in OSA, leading to worsened morbidity and mortality.7377 Nevertheless, many experts have suggested that by aggressively addressing issues, such as CPAP adherence and body position, the successful treatment of OSA is possible in stroke patients.

OSA is associated with a variety of stroke risk factors that may independently contribute to stroke risk. Although the successful treatment of sleep apnea can reduce BP in some cases, there are no prospective randomized studies showing that the treatment of OSA reduces the overall stroke risk.2

In addition, the attempts to prove overwhelming benefit from the treatment of OSA after stroke, have met limited success. If future clinical trials can show that effective therapy of OSA directly leads to a significant reduction in long-term morbidity and mortality in the stroke population, then routine screening for OSA after stroke might become a future consideration.78

AHI

apnea-hypopnea index

CPAP

continuous positive airway pressure

CVD

cardiovascular disease

DRG

dorsal respiratory group

HR

hazard ratio

OR

odds ratio

OSA

obstructive sleep apnea

REM

rapid eye movement

Sao2

arterial oxygen saturation

SDB

sleep-disordered breathing

SNA

sympathetic nerve activity

TIA

transient ischemic attack

VRG

ventral respiratory group

Financial/nonfinancial disclosures: Dr. Dyken has been a primary investigator, and Dr. Im has been a coinvestigator, on studies for which they have recently received research grants from Cephalon and Merck. Dr. Dyken was until recently, but is no longer, on the speaker's bureaus for Boehringer Ingelheim and Cephalon.

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Kleinddorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis of transient ischemic attack in a population based study. Stroke. 2005;36:720-723. [PubMed]
 
Rivest J, Reiher J. Transient ischemic attacks triggered by symptomatic sleep apneas [abstract]. Stroke. 1987;18:293
 
Pressman MR, Schetman WR, Figueroa WG, et al. Transient ischemic attacks and minor stroke during sleep. Stroke. 1995;26:2361-2365. [PubMed]
 
McArdle N, Riha RL, Vennelle M, et al. Sleep-disordered breathing as a risk factor for cerebrovascular disease; a case-control study in patients with transient ischemic attacks. Stroke. 2003;34:2916-2921. [PubMed]
 
Arzt M, Young T, Finn L, et al. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med. 2005;172:1147-1151
 
Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the sleep heart health study. Am J Respir Crit Care Med. 2001;163:19-25. [PubMed]
 
Yaggi KH, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;19:2034-2041
 
Munoz R, Duran-Cantolla J, Martinez-Vila E, et al. Severe sleep apnea and risk of ischemic stroke in the elderly. Stroke. 2006;37:2317-2321. [PubMed]
 
Valham F, Mooe T, Rabben T, et al. Increased risk of stroke in patients with coronary artery disease and sleep apnea: a 10-year follow-up. Circulation. 2008;118:955-960. [PubMed]
 
Partinen M, Jamieson A, Guilleminault C. Long-term outcome for obstructive sleep apnea syndrome patients: mortality. Chest. 1988;94:1200-1204. [PubMed]
 
Partinen M, Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest. 1990;97:27-32. [PubMed]
 
Ambrosetti M, Lucioni AM, Conti S, et al. Metabolic syndrome in obstructive sleep apnea and related cardiovascular risk. J Cardiovasc Med. 2006;7:826-829
 
Sasanabe R, Banno K, Otake K, et al. Metabolic syndrome in Japanese patients with obstructive sleep apnea syndrome. Hypertens Res. 2006;29:315-322. [PubMed]
 
Lam JC, Lam B, Lam CL, et al. Obstructive sleep apnea and the metabolic syndrome in community-based Chinese adults in Hong Kong. Respir Med. 2006;100:980-987. [PubMed]
 
Coughlin SR, Mawdsley L, Mugarza JA, et al. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J. 2004;25:735-741. [PubMed]
 
Kono M, Tatsumi K, Saibara T, et al. Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome. Chest. 2007;131:1387-1392. [PubMed]
 
Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev. 2005;9:211-224. [PubMed]
 
Tishler PV, Larkin EK, Schluchter MD, et al. Incidence of sleep-disordered breathing in an urban adult population. JAMA. 2003;289:2230-2237. [PubMed]
 
Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342:1378-1384. [PubMed]
 
Somers VK, Mark AL, Abboud FM. Sympathetic activation by hypoxia and hypercapnia: implications for sleep apnea [abstract]. Clin Exp Hypertens. 1988;A10suppl:413-422
 
Dyken ME.Bradley DT, Floras JS. Cerebrovascular disease and sleep apnea. Sleep disorders and cardiovascular and cerebrovascular disease. 2000; New York, NY Marcel Dekker:285-306
 
Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995;96:1897-1904. [PubMed]
 
Somers VK, Dyken ME, Skinner JL. Autonomic and hemodynamic responses and interactions during the Mueller maneuver in humans. J Auton Nerv Syst. 1993;44:253-259. [PubMed]
 
Wolk R, Somers VK. Obesity-related cardiovascular disease: implications of obstructive sleep apnea. Diabetes Obes Metab. 2006;8:250-260. [PubMed]
 
Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol. 1983;52:490-494. [PubMed]
 
Somers VK, Dyken ME, Mark AL, et al. Parasympathetic hyperresponsiveness and bradyarrhythmias during apnea in hypertension. Clin Auton Res. 1992;2:171-176. [PubMed]
 
Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation. 2004;110:364-367. [PubMed]
 
Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107:2589-2594. [PubMed]
 
Marsh E, Biller J, Adams H, et al. Circadian variation in onset of acute ischemic stroke. Arch Neurol. 1990;47:1178-1180. [PubMed]
 
Hornyak M, Cejnar M, Elam M, et al. Sympathetic muscle nerve activity during sleep in man. Brain. 1991;114:1281-1295. [PubMed]
 
Somers VK, Dyken ME, Mark AL, et al. Sympathetic nerve activity during sleep in normal humans. N Engl J Med. 1993;328:303-307. [PubMed]
 
Klingelhofer J, Hajak G, Sander D, et al. Assessment of intracranial hemodynamics in sleep apnea syndrome. Stroke. 1992;23:1427-1433. [PubMed]
 
Jennum P, Borgesen SE. Intracranial pressure and obstructive sleep apnea. Chest. 1989;95:279-283. [PubMed]
 
Tofler GH, Brezinski D, Schafer AI, et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514-1518. [PubMed]
 
Fletcher EC, Miller J, Schaaf JW, et al. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep. 1987;10:35-44. [PubMed]
 
Geiser T, Buck F, Meyer BJ, et al. In vivoplatelet activation is increased during sleep in patients with obstructive sleep apnea syndrome. Respiration. 2002;69:229-234. [PubMed]
 
Minoguchi K, Yokoe T, Tazaki T, et al. Silent brain infarction and platelet activation in obstructive sleep apnea. Am J Respir Crit Care Med. 2007;175:612-617. [PubMed]
 
American Heart Association Heart disease and stroke statistics: 2004 update. 2003; Dallas, TX American Heart Association
 
Kaneko Y, Hajek VE, Zivanovic V, et al. Relationship of sleep apnea to functional capacity and length of hospitalization following stroke. Sleep. 2003;26:293-297. [PubMed]
 
Sahlin C, Sandberg O, Gustafson Y, et al. Obstructive sleep apnea is a risk factor for death in patients with stroke. Arch Intern Med. 2008;168:297-301. [PubMed]
 
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. [PubMed]
 
Martinez-Garcia MA, Soler-Cataluna JJ, Ejarque-Martinex L, et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: a 5-year follow-up study. Am J Respir Crit Care Med. 2009;180:36-41. [PubMed]
 
Hunkey GJ, Jamrozik D, Broadhurst RJ, et al. Five-year survival after first-ever stroke and related prognostic factors in the Perth Community Stroke Study. Stroke. 2005;31:2080-2086
 
Strollo PJ, Sanders MH, Atwood CW. Positive pressure therapy. Clin Chest Med Sleep Disorders. 1998;19:55-68
 
Disler P, Hansford A, Skelton J, et al. Diagnosis and treatment of obstructive sleep apnea in a stroke rehabilitation unit: a feasibility study. Am J Phys Med Rehabil. 2002;81:622-625. [PubMed]
 
Wierzbicka A, Rola R, Wichniak A, et al. The incidence of sleep apnea in patients with stroke or transient ischemic attack. J Physiol Pharmacol. 2006;57:385-390. [PubMed]
 
Dziewas R, Hopmann B, Humpert M, et al. Positional sleep apnea in patients with ischemic stroke. Neurol Res. 2008;30:645-648. [PubMed]
 
Lip GY, Zarifis J, Farooqi IS, et al. Ambulatory blood pressure monitoring in acute stroke: the West Birmingham Stroke Project. Stroke. 1997;28:31-35. [PubMed]
 
Bhalla A, Wolfe CDA, Rudd AG. The effect of 24 h blood pressure levels on early neurological recovery after stroke. J Intern Med. 2001;250:121-130. [PubMed]
 
Morfis L, Schwartz RS, Poulos R, et al. Blood pressure changes in acute cerebral infarction and hemorrhage. Stroke. 1997;28:1401-1405. [PubMed]
 
Jain S, Namboodri KK, Kumari S, et al. Loss of circadian rhythm of blood pressure following acute stroke. BMC Neurol. 2004;4:1. [PubMed]
 
Selic C, Siccoli MM, Hermann DM, et al. Blood pressure evolution after acute ischemic stroke in patients with and without sleep apnea. Stroke. 2005;36:2614-2618. [PubMed]
 
Brown DL, Chervin RD, Hickenbottom SL, et al. Screening for obstructive sleep apnea in stroke patients: a cost-effectiveness analysis. Stroke. 2005;36:1291-1294. [PubMed]
 

Figures

Figure Jump LinkFigure 1 This schematic diagram of the brainstem shows in a parasagittal section the location of the dorsal and VRGs and their projections to the spinal cord and respiratory muscles.Grahic Jump Location
Figure Jump LinkFigure 2 This schematic diagram shows in detail the components and the connectivities of the medullary respiratory center. Modified from Figures 5 to 18 and 5 to 19 of Afifi and Bergman.22 Modified with permission of the McGraw-Hill Companies.Grahic Jump Location
Figure Jump LinkFigure 3 A polysomnography tracing (paper speed, 10 mm/s) has been reduced to correspond to a temporally related microneurographic tracing (Fig 4; paper speed 5 mm/s). Arrows indicate a prolonged mixed apnea with a duration of approximately 26 s that occurred during REM sleep and was associated with severe oxygen desaturation. C = central; EMG = electromyogram; ET = ears tied; LOC = left outer canthus; NA = nasal airflow; O = occipital; OA = oral airflow; ROC = right outer canthus; T = temporal; TM = thoracic movement. Reprinted with permission of Marcel Dekker Inc.46Grahic Jump Location
Figure Jump LinkFigure 4 The arrows in this microneurographic tracing recorded from the peroneal nerve indicate a gradual elevation of efferent nerve activity during a mixed apnea. The activity peak is immediately followed by the cessation of the apnea, with a subsequent marked elevation of arterial BP to 215/130 mm Hg from a baseline of 135/80 mm Hg. Finapress = fingertip BP; MSNA = muscle SNA; Pneu = chest excursion. Reprinted with permission of Marcel Dekker Inc.46Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 OSA and Stroke Risk: Incidence Studies

CAD = coronary artery disease.

*Original population providing original cross-sectional prevalence data.

†Population used for longitudinal analysis of incident stroke.

‡In a model adjusted for age and gender.

§In a model adjusted for age, gender, race, smoking, BMI, diabetes, hyperlipidemia, atrial fibrillation, and hypertension.

‖In a model adjusted for gender.

¶In a model adjusted for age, BMI, left ventricular function, diabetes, gender, intervention, hypertension, atrial fibrillation, previous stroke, or TIA.

Table Graphic Jump Location
Table 2 Potential Unique Sources/Problems Leading to Poor CPAP Adherence in the Stroke Population

References

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Ovbiagele B, Kidwell CS, Saver JL. Epidemiological impact in the United States of a tissue-based definition of transient ischemic attack. Stroke. 2003;34:919-924. [PubMed]
 
Kleinddorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis of transient ischemic attack in a population based study. Stroke. 2005;36:720-723. [PubMed]
 
Rivest J, Reiher J. Transient ischemic attacks triggered by symptomatic sleep apneas [abstract]. Stroke. 1987;18:293
 
Pressman MR, Schetman WR, Figueroa WG, et al. Transient ischemic attacks and minor stroke during sleep. Stroke. 1995;26:2361-2365. [PubMed]
 
McArdle N, Riha RL, Vennelle M, et al. Sleep-disordered breathing as a risk factor for cerebrovascular disease; a case-control study in patients with transient ischemic attacks. Stroke. 2003;34:2916-2921. [PubMed]
 
Arzt M, Young T, Finn L, et al. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med. 2005;172:1147-1151
 
Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the sleep heart health study. Am J Respir Crit Care Med. 2001;163:19-25. [PubMed]
 
Yaggi KH, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;19:2034-2041
 
Munoz R, Duran-Cantolla J, Martinez-Vila E, et al. Severe sleep apnea and risk of ischemic stroke in the elderly. Stroke. 2006;37:2317-2321. [PubMed]
 
Valham F, Mooe T, Rabben T, et al. Increased risk of stroke in patients with coronary artery disease and sleep apnea: a 10-year follow-up. Circulation. 2008;118:955-960. [PubMed]
 
Partinen M, Jamieson A, Guilleminault C. Long-term outcome for obstructive sleep apnea syndrome patients: mortality. Chest. 1988;94:1200-1204. [PubMed]
 
Partinen M, Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest. 1990;97:27-32. [PubMed]
 
Ambrosetti M, Lucioni AM, Conti S, et al. Metabolic syndrome in obstructive sleep apnea and related cardiovascular risk. J Cardiovasc Med. 2006;7:826-829
 
Sasanabe R, Banno K, Otake K, et al. Metabolic syndrome in Japanese patients with obstructive sleep apnea syndrome. Hypertens Res. 2006;29:315-322. [PubMed]
 
Lam JC, Lam B, Lam CL, et al. Obstructive sleep apnea and the metabolic syndrome in community-based Chinese adults in Hong Kong. Respir Med. 2006;100:980-987. [PubMed]
 
Coughlin SR, Mawdsley L, Mugarza JA, et al. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J. 2004;25:735-741. [PubMed]
 
Kono M, Tatsumi K, Saibara T, et al. Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome. Chest. 2007;131:1387-1392. [PubMed]
 
Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev. 2005;9:211-224. [PubMed]
 
Tishler PV, Larkin EK, Schluchter MD, et al. Incidence of sleep-disordered breathing in an urban adult population. JAMA. 2003;289:2230-2237. [PubMed]
 
Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342:1378-1384. [PubMed]
 
Somers VK, Mark AL, Abboud FM. Sympathetic activation by hypoxia and hypercapnia: implications for sleep apnea [abstract]. Clin Exp Hypertens. 1988;A10suppl:413-422
 
Dyken ME.Bradley DT, Floras JS. Cerebrovascular disease and sleep apnea. Sleep disorders and cardiovascular and cerebrovascular disease. 2000; New York, NY Marcel Dekker:285-306
 
Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995;96:1897-1904. [PubMed]
 
Somers VK, Dyken ME, Skinner JL. Autonomic and hemodynamic responses and interactions during the Mueller maneuver in humans. J Auton Nerv Syst. 1993;44:253-259. [PubMed]
 
Wolk R, Somers VK. Obesity-related cardiovascular disease: implications of obstructive sleep apnea. Diabetes Obes Metab. 2006;8:250-260. [PubMed]
 
Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol. 1983;52:490-494. [PubMed]
 
Somers VK, Dyken ME, Mark AL, et al. Parasympathetic hyperresponsiveness and bradyarrhythmias during apnea in hypertension. Clin Auton Res. 1992;2:171-176. [PubMed]
 
Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation. 2004;110:364-367. [PubMed]
 
Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107:2589-2594. [PubMed]
 
Marsh E, Biller J, Adams H, et al. Circadian variation in onset of acute ischemic stroke. Arch Neurol. 1990;47:1178-1180. [PubMed]
 
Hornyak M, Cejnar M, Elam M, et al. Sympathetic muscle nerve activity during sleep in man. Brain. 1991;114:1281-1295. [PubMed]
 
Somers VK, Dyken ME, Mark AL, et al. Sympathetic nerve activity during sleep in normal humans. N Engl J Med. 1993;328:303-307. [PubMed]
 
Klingelhofer J, Hajak G, Sander D, et al. Assessment of intracranial hemodynamics in sleep apnea syndrome. Stroke. 1992;23:1427-1433. [PubMed]
 
Jennum P, Borgesen SE. Intracranial pressure and obstructive sleep apnea. Chest. 1989;95:279-283. [PubMed]
 
Tofler GH, Brezinski D, Schafer AI, et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514-1518. [PubMed]
 
Fletcher EC, Miller J, Schaaf JW, et al. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep. 1987;10:35-44. [PubMed]
 
Geiser T, Buck F, Meyer BJ, et al. In vivoplatelet activation is increased during sleep in patients with obstructive sleep apnea syndrome. Respiration. 2002;69:229-234. [PubMed]
 
Minoguchi K, Yokoe T, Tazaki T, et al. Silent brain infarction and platelet activation in obstructive sleep apnea. Am J Respir Crit Care Med. 2007;175:612-617. [PubMed]
 
American Heart Association Heart disease and stroke statistics: 2004 update. 2003; Dallas, TX American Heart Association
 
Kaneko Y, Hajek VE, Zivanovic V, et al. Relationship of sleep apnea to functional capacity and length of hospitalization following stroke. Sleep. 2003;26:293-297. [PubMed]
 
Sahlin C, Sandberg O, Gustafson Y, et al. Obstructive sleep apnea is a risk factor for death in patients with stroke. Arch Intern Med. 2008;168:297-301. [PubMed]
 
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. [PubMed]
 
Martinez-Garcia MA, Soler-Cataluna JJ, Ejarque-Martinex L, et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: a 5-year follow-up study. Am J Respir Crit Care Med. 2009;180:36-41. [PubMed]
 
Hunkey GJ, Jamrozik D, Broadhurst RJ, et al. Five-year survival after first-ever stroke and related prognostic factors in the Perth Community Stroke Study. Stroke. 2005;31:2080-2086
 
Strollo PJ, Sanders MH, Atwood CW. Positive pressure therapy. Clin Chest Med Sleep Disorders. 1998;19:55-68
 
Disler P, Hansford A, Skelton J, et al. Diagnosis and treatment of obstructive sleep apnea in a stroke rehabilitation unit: a feasibility study. Am J Phys Med Rehabil. 2002;81:622-625. [PubMed]
 
Wierzbicka A, Rola R, Wichniak A, et al. The incidence of sleep apnea in patients with stroke or transient ischemic attack. J Physiol Pharmacol. 2006;57:385-390. [PubMed]
 
Dziewas R, Hopmann B, Humpert M, et al. Positional sleep apnea in patients with ischemic stroke. Neurol Res. 2008;30:645-648. [PubMed]
 
Lip GY, Zarifis J, Farooqi IS, et al. Ambulatory blood pressure monitoring in acute stroke: the West Birmingham Stroke Project. Stroke. 1997;28:31-35. [PubMed]
 
Bhalla A, Wolfe CDA, Rudd AG. The effect of 24 h blood pressure levels on early neurological recovery after stroke. J Intern Med. 2001;250:121-130. [PubMed]
 
Morfis L, Schwartz RS, Poulos R, et al. Blood pressure changes in acute cerebral infarction and hemorrhage. Stroke. 1997;28:1401-1405. [PubMed]
 
Jain S, Namboodri KK, Kumari S, et al. Loss of circadian rhythm of blood pressure following acute stroke. BMC Neurol. 2004;4:1. [PubMed]
 
Selic C, Siccoli MM, Hermann DM, et al. Blood pressure evolution after acute ischemic stroke in patients with and without sleep apnea. Stroke. 2005;36:2614-2618. [PubMed]
 
Brown DL, Chervin RD, Hickenbottom SL, et al. Screening for obstructive sleep apnea in stroke patients: a cost-effectiveness analysis. Stroke. 2005;36:1291-1294. [PubMed]
 
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