Sleep and Stroke

HomeStrokeVol. 50, No. 6Sleep and Stroke Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBSleep and Stroke Sandeep P. Khot, MD and Lewis B. Morgenstern, MD Sandeep P. KhotSandeep P. Khot Correspondence to Sandeep P. Khot, MD, Department of Neurology, University of Washington School of Medicine, Box 359775, 325 Ninth Ave, Seattle, WA 98104. Email E-mail Address: [email protected] From the Department of Neurology, University of Washington School of Medicine, Seattle (S.P.K.) Search for more papers by this author and Lewis B. MorgensternLewis B. Morgenstern Stroke Program, Medical School, and the Center for Social Epidemiology and Population Health, School of Public Health, University of Michigan, Ann Arbor (L.B.M.). Search for more papers by this author Originally published2 May 2019https://doi.org/10.1161/STROKEAHA.118.023553Stroke. 2019;50:1612–1617Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 2, 2019: Ahead of Print Stroke is the leading cause of serious long-term disability in the United States, leaving less than half of survivors able to return directly home.1 Stroke recurrence, estimated as high as 17% over 5 years, also remains unacceptably high.1 The use of lytic drugs and endovascular devices has revolutionized the care of select stroke patients in the acute setting. However, enormous challenges remain in changing the trajectory of stroke recovery for the vast majority of patients who do not qualify or remain disabled after these treatments, and also in preventing the accumulating disability associated with stroke recurrence.The role of sleep disorders in stroke outcome and recurrence has become a pressing question. Despite estimates of greater than 50% prevalence of sleep disorders after stroke, only about 6% of stroke survivors are offered formal sleep testing and an estimated 2% complete such testing in the 3-month poststroke period.2 The reasons for the low rate of screening are at least partly related to the lack of awareness about sleep disorders among stroke providers (Figure). This review evaluates the role of sleep disorders, including sleep-disordered breathing (SDB) and sleep-wake cycle disorders, in stroke risk and examines the impact of their treatment on stroke outcome.Download figureDownload PowerPointFigure. Potential causes and consequences of untreated sleep disorders after stroke with proposed mechanisms leading to increased risk of stroke and poor stroke outcome.Physiology and Anatomy of Breathing During SleepDuring sleep, ventilation is reduced compared with wake, in parallel with the restorative and toning down changes that occur to heart rate, temperature, and blood pressure. Volitional or behavioral input on breathing is absent during sleep; only brain stem neurons, peripheral chemoreceptors, and respiratory muscle afferents regulate breathing.3 Groups of chemoreceptive neurons in the brain stem, including those of the dorsolateral pons, nucleus solitarius, and ventral medullary respiratory column, respond to changes in the partial pressure of carbon dioxide and oxygen and thereby serve as a pacemaker regulating the breathing rhythm.4 Along with effects on the breathing pattern, these brain stem neurons cause a reduction in the upper airway tone at sleep onset through reduced activity of airway dilator muscles, especially the genioglossus, which forms the bulk of the tongue.3 Alternatively, the chemoreceptive neurons of the brain stem can detect increased carbon dioxide by peripheral chemoreceptors and initiate increased activity of the dilator muscles in response to airway resistance or collapse.3The stability of sleep can be affected by brief (3–15 second) arousals that occur in response to changes in airflow. Respiratory events include 10 seconds or longer breathing cessation (apneas) and 30% or greater airflow reduction with associated oxygen desaturation or arousals (hypopneas). These are summed in a sleep study to generate an apnea-hypopnea index (AHI)—the number of respiratory events per hour of sleep. The AHI in obstructive sleep apnea (OSA) is typically classified as mild (5–14 per hour), moderate (15–29 per hour), or severe (≥30 per hour). Respiratory provoked arousals during sleep when breathing is otherwise reliant on respiratory and chemical control feedback mechanisms serve to terminate the apnea or hypopnea by opening the airway in response to collapse and to increase the rate of ventilation in response to hypercapnia.3 Although the arousals during sleep may play an important compensatory role in people with SDB, they may also have deleterious effects on sleep stability and other physiological parameters before and after stroke.Central and Obstructive Sleep ApneaTwo types of SDB, central sleep apnea (CSA) and OSA, vary considerably in their cause, prevalence, relative improvement after stroke, and effects on stroke outcome. Central apneas occur most commonly in heart failure and opioid use but can also be observed after stroke because of distinct brain lesions involving autonomic and volitional respiratory centers.4–6 Absent airflow in OSA results from upper airway occlusion or narrowing, which may be related to decreased activity of airway dilator muscles during sleep with the tongue falling backward or anatomic features reducing upper airway diameter, including craniofacial structures, enlarged tonsils, and obesity.4 Obstructive apneas or hypopneas occur despite activity of the thoracic muscles (diaphragm and intercostal muscles).4 Obstructive events can be distinguished from central events during polysomnography by detecting respiratory effort through the activity of chest and abdominal respiratory belts. Both CSA and OSA can disrupt sleep through the frequent arousals and desaturations, leading to fragmentation of sleep architecture and excessive daytime sleepiness.3The development of CSA, which includes both Cheyne-Stokes periodic breathing and ataxic breathing pattern with primarily central apneas, is uncommon after stroke and thought to be related to disruption of respiratory networks involved in the regulation of breathing.5 In a meta-analysis of SDB after ischemic or hemorrhagic stroke or transient ischemic attack (TIA), 72% of patients had an AHI of at least 5 per hour but only 7% of patients had primarily central apneas.7 Further, CSA tends to improve after acute stroke. In a study of 161 patients with first-ever stroke or TIA who underwent portable sleep studies within 48 to 72 hours from admission and again after 3 months, the rate of SDB decreased from 71% to 62% with a significant reduction in central apneas but not obstructive apneas.8 Additionally, the effects of CSA on stroke outcome and the role of early therapy for CSA after stroke are unclear. In a prospective study of stroke rehabilitation patients with a 10-year follow-up period, the risk of death was significantly higher among patients with OSA compared with controls but not among patients with CSA.9 Continuous positive airway pressure (CPAP), the gold standard treatment for OSA, is only effective in about 50% of patients with CSA4 and has unclear benefit in stroke outcome.The estimated prevalence of OSA after stroke or TIA is over 70%.7 The reasons for such high rates remain unclear though are at least partly related to positional sleep apnea, stroke-related upper airway tone changes, and untreated OSA preceding the stroke. Multiple studies suggest that OSA is more often a preexisting condition before stroke rather than the consequence of brain injury. The findings from a prospective study of sleep apnea evaluations both before and after stroke and TIA show a similar frequency of OSA, suggesting it is a common predisposing condition.8 Further, most prior studies have found no link between the prevalence or severity of OSA and stroke subtype, topography or stroke severity.8,10 Also, while SDB may improve over time after stroke, like other stroke-related deficits, over half of patients with stroke have an AHI > 10 per hour even after 3 months.8Effects of OSA on Stroke Occurrence, Recurrence, and RecoveryIf the development of OSA precedes stroke in the majority of patients, what roles does it play in the risk of stroke? Population-based epidemiological studies show that OSA independently predisposes to stroke. In a prospective analysis of 1189 healthy participants in the Wisconsin Sleep Cohort study, an AHI ≥20 per hour was associated with an increased risk of stroke over the next 4 years (unadjusted odds ratio, 4.31; 95% CI, 1.31–14.15; P=0.02), though this relationship was not significant after adjustment for potential confounders.11 In the community-based Sleep Heart Health Study, 5422 healthy participants without stroke were evaluated with polysomnography and followed for a median of 8.7 years.12 An AHI >15 per hour was 30% more common among participants who had an ischemic stroke compared with those who remained stroke-free. Men with moderate or severe OSA had an almost 3-fold increased risk of ischemic stroke compared with those without OSA, with an estimated 6% increased risk of stroke per unit increase in the AHI from 5 to 25 per hour, whereas women had an increased risk of stroke only with an AHI >25 per hour. In an observational cohort study of 1022 clinic patients referred for sleep evaluation, patients with OSA had a nearly 2-fold increase in stroke or death from any cause after a median of 3.4 years independent of known vascular risk factors and with increased risk associated with OSA severity.13 A meta-analysis of 17 population or clinic-based, prospective cohort studies revealed that moderate-to-severe OSA significantly increased cardiovascular risk, in particular, the risk of fatal or nonfatal stroke (relative risk, 2.02; 95% CI, 1.4–2.9).14Along with functioning as an independent risk factor for stroke, OSA can also increase the risk of stroke through effects on traditional stroke risk factors, especially hypertension. In the Wisconsin Sleep Cohort Study, a dose-response association was noted between the AHI at baseline and the development of hypertension, where participants with moderate OSA compared with those with an AHI of 0 had ≈3× the odds of having hypertension at a 4-year follow-up.15 The presumed mechanism through which OSA may lead to hypertension is through high levels of sympathetic activity during apneas and the associated blood pressure surges during sleep, which is enhanced further by arousals and sleep fragmentation.12 In a study comparing blood pressure and sympathetic nerve activity among patients with OSA to age- and sex-matched subjects without OSA, sympathetic nerve activity was significantly higher in those with OSA during both wakefulness and sleep.16 In this study, apnea-induced nocturnal hypoxemia resulted in progressive increases in sympathetic nerve activity with subsequent surges in blood pressure as high as 240/130 mm Hg on the cessation of apneas.16 Along with direct increases in oxidative stress, the effects of the OSA-related sympathetic activity likely contribute to sustained daytime hypertension and a blunted response to nocturnal dipping, the normal toning down pattern of sleep where blood pressure typically decreases by at least 10% of awake values.17 Such a nondipping blood pressure pattern has been noted in 48% to 84% of patients with OSA, with the increased frequency associated with OSA severity.18Once a stroke has occurred, observational studies suggest that OSA has a negative effect on outcome by predisposing to recurrent stroke, increasing the risk of mortality and worsening functional recovery. In a prospective cohort study of 166 patients with ischemic stroke who underwent a sleep study about 2 months after the acute hospitalization, CPAP was offered to 96 patients (58%) with an AHI of at least 20 per hour.19 After a period of 7 years, patients with moderately severe OSA who could not tolerate CPAP had a nearly 3-fold increased risk of nonfatal cardiovascular events, particularly recurrent stroke, compared with those who were adherent to CPAP, those without OSA, or those with mild disease combined (hazard ratio, 2.87; 95% CI, 1.1–7.7; P=0.03). The number needed to treat to prevent one nonfatal vascular event with CPAP was 5 patients (95% CI, 2–19). In another prospective cohort study of 132 patients undergoing stroke rehabilitation and followed over 10 years, the presence of moderately severe OSA in patients after stroke was associated with a 75% increase in the risk of early death compared with patients without OSA independent of disability and traditional stroke risk factors.9 Several observational studies suggest that OSA may also be a predictor of poor functional outcome after stroke, increasing the risk of short-term neurological worsening and of long-term dependency. In a study evaluating blood pressure and OSA severity among 41 patients with acute ischemic stroke, sleep apnea severity was associated with worsened stroke severity on day 1 and modified Rankin scale scores at hospital discharge.20 In this study, the nondipping blood pressure pattern was more common among patients with OSA and was strongly associated with severe strokes and poor outcomes. In another study of 61 patients with ischemic and hemorrhagic stroke admitted to a rehabilitation unit, OSA was found in 60% of patients and was significantly and independently associated with worse functional impairment and a 40% longer rehabilitation stay.21 The mechanism by which OSA may lead to worse stroke recovery is unknown though thought to possibly be related to the deleterious effects on the injured brain, including fragmented sleep in the setting of impaired cognitive function and the effects of intermittent hypoxemia on the ischemic penumbra and on neuronal plasticity.22Treatment of OSAPrevention of StrokeThe gold standard treatment for OSA is CPAP. Alternative treatments, including oral mandibular advancement appliances and upper airway surgery, have not been studied after stroke and are not practical in the acute stroke setting. Along with issues related to tolerance with high rates of patients discontinuing CPAP entirely and reduced adherence, barriers for CPAP use after stroke also include logistic difficulties and access to sleep apnea testing for patients with severe disability or immobility. Nonetheless, if proven effective in stroke prevention and recovery, CPAP could be a noninvasive and relatively inexpensive intervention that could improve stroke outcome and help prevent the second stroke.Only a few randomized controlled trials have evaluated the use of CPAP in secondary prevention. In one small, secondary prevention trial evaluating cardiovascular survival, 140 ischemic stroke patients were randomized within 3 to 6 days to early CPAP or to conventional treatment.23 Although the mean time to the next cardiovascular event was longer in the CPAP group (14.9 versus 7.9 months, P=0.044), the overall cardiovascular event-free survival after 2 years was similar in both groups. Limitations of this study included the per-protocol analysis, small sample size and poor study retention, with a 20% dropout among patients assigned to CPAP. In the multicenter SAVE study (Sleep Apnea Cardiovascular Endpoints) study, 2717 patients with established coronary artery or cerebrovascular disease and a diagnosis of moderate-to-severe OSA were randomized to CPAP or usual care.24 After a mean follow-up of 3.7 years, treatment with CPAP did not prevent recurrent cardiovascular events through the mean CPAP usage time of 3.3 hours per night did not meet the study’s criterion for CPAP adherence, ≥4 hours of use per night over the first 2 years, making it problematic to estimate actual treatment efficacy. In a prespecified, one-to-one propensity score-matched analysis, participants with ≥4 hours of use per night compared with matched participants in the control group had a lower risk of stroke (relative risk, 2.29; 95% CI, 1.05–4.99; P=0.04). This trend was further evaluated in a recent meta-analysis examining both primary and secondary stroke prevention in 7 randomized controlled trials assessing the occurrence of major cardiovascular events and the treatment of moderate-to-severe OSA with CPAP.25 Treatment with CPAP for a mean duration of 3.5 hours per night at a mean follow-up of 37 months did not demonstrate significant reduction in the incidence of major cardiovascular events though serial sensitivity analyses excluding studies with poor CPAP adherence showed an incremental risk reduction in major adverse cardiovascular events. With the exclusion of the SAVE trial, there was a significant 58% risk reduction of major cardiovascular events. A subgroup analysis showed similar results, demonstrating a decreased incidence of major cardiovascular events when CPAP was consistently used for ≥4 hours per night. Thus, the shortage of data from randomized trials demonstrating clear efficacy of CPAP in reducing stroke occurrence or recurrence may be related to not achieving an adequate dose of CPAP treatment.Improving Stroke OutcomeAlthough observational studies have demonstrated worse recovery in stroke survivors with OSA, the benefit gained from treatment with CPAP on functional recovery remains unknown. Some studies have shown an improvement in stroke severity, depressive symptoms, motor and cognitive recovery and sleepiness,22,23,26–29 whereas others have shown no difference in stroke severity, anxiety, depression, sleepiness and fatigue (Table).30,31 In many of these trials, CPAP adherence and study retention may have been insufficient to produce a clear neurological or functional benefit. Also, studies with high CPAP adherence and participant retention which were able to show short-term benefits after stroke were typically confined to the supportive inpatient environment. Despite these mixed results, a pooled analysis of 5 studies including nearly 400 ischemic stroke patients with OSA demonstrated greater short-term neurological improvement with CPAP than without.32 The authors concluded that further investigation with an adequately powered randomized controlled trial was needed, though addressing these twin issues of poor tolerance and adherence will be fundamental to realizing the full benefits, if any, of CPAP on stroke recovery.Table. Randomized Controlled Trials of CPAP and Stroke Recovery Where Treatment Was Initiated on Average Within 1 Month of Stroke and for a Treatment Period of at Least 4 WeeksStudyPatients Treated With CPAPTreatment Duration and LocationAttrition Rate in CPAP GroupAverage Adherence, Hours/NightOutcomesSandberg et al2633 with AHI ≥1528 d within rehabilitation unit2/33 (6%)4.1±3.6 (16/31 with >4 h/night)Improvement in depression but not ADL, cognitive function, or deliriumHsu et al3115 with AHI ≥308 wk within hospital and home4/15 (27%)1.4 (2/15 with >6 h/night)No improvement in ADL, stroke severity, cognitive function, anxiety, depression, sleepiness, or QOLBravata et al2716 with airflow limitation on autotitrating CPAP30 days within hospital and home9/31 (29%)5.1±2.3 (10/16 with ≥4 h/night on ≥75% nights)Improvement in stroke severity (with greater improvement associated with more CPAP use)Brown et al3015 with AHI ≥53 mo within home7/15 (47%)Estimated <1 (median 53 h over median 16 d)No improvement in sleepiness, fatigue, ADL, depression, or stroke severityParra et al2371 with AHI ≥2524 mo within hospital and home20/71 (28%)5.3±1.9Improvement in stroke severity and ADL at 1 mo but not 3, 12, 24 mo, and no difference in QOLRyan et al2225 with AHI ≥154 wk within rehabilitation unit3/25 (12%)4.96±2.25Improvement in stroke severity, sleepiness, motor function, depression but not cognitive function, walking, sustained attention, or executive functionAaronson et al2920 with AHI ≥154 wk within rehabilitation unit6/20 (30%)2.5±2.8 (7/20 with >4 h/night for ≥5 d/wk)Improvement in attention and executive function (with greater improvement associated with more CPAP use) but not other domains of cognitive function, stroke severity, ADL, sleep quality, sleepiness, fatigue, depression, or anxietyADL indicates activities of daily living; AHI, apnea-hypopnea index; CPAP, continuous positive airway pressure; and QOL, quality of life.To date, no randomized trials of CPAP after stroke have been sufficiently powered and demonstrated adequate treatment adherence. The upcoming, phase 3 Sleep for SMART (Stroke Management And Recovery Trial; URL: https://www.clinicaltrials.gov. Unique identifier: NCT03812653) will evaluate in over 3000 participants the treatment of OSA with CPAP on both secondary stroke prevention and acute stroke recovery within the National Institutes of Health StrokeNet, a network of >200 stroke trial sites across the United States. To address issues related to adherence, Sleep SMART will randomize to either CPAP or control only patients with at least 4 hours of CPAP use on a single-night run-in. As such, Sleep SMART may be able to define, for the first time, the role of adequate CPAP therapy within a sufficiently powered study.Adherence to Treatment With CPAPLong-term adherence to CPAP among patients with stroke is lower than in individuals without stroke, with estimates ranging between 12% and 25% when CPAP is initiated soon after a stroke. A dose-response relationship between CPAP use and stroke outcome likely exists,24 and the optimum cutoff for CPAP use necessary to improve stroke outcome may need to be higher than for other symptomatic benefits. Yet treatment with CPAP during the early period after stroke is a challenge for stroke survivors, and the burden of CPAP therapy can be overwhelming.Compared with the general OSA population, stroke patients with OSA have less daytime sleepiness, making altering patient perceptions of symptomatic benefit from CPAP particularly challenging. Recent trials, however, have shed some light on potential ways to improve CPAP tolerance and adherence. Early CPAP adherence has been shown to be strongly predictive of long-term CPAP use. Among 275 patients with established cardiovascular disease who were randomized into the active CPAP arm of the multicenter SAVE trial, adherence to CPAP declined from 4.4±2 hours per night at 1 month to 3.3±2.4 hours per night at 12 months and the only predictors of CPAP adherence at 1 year were early CPAP use and initial side effects from CPAP.33 In an effort to improve early tolerance, many studies have focused on interventions to optimize CPAP use and minimize side effects, including closer monitoring, increased encouragement and education, and continual CPAP adjustments to troubleshoot potential side effects with treatment.22,23,27 Improvement in CPAP adherence in patients with stroke has also been linked to intensive support by nursing staff and other providers. In a randomized trial during stroke rehabilitation where the average daily use of CPAP was 4.96 hours over a 1 month treatment period, nurses were trained to administer CPAP to study patients with increased inpatient monitoring and support, which likely influenced environmental and social factors for adherence.22 Psychological variables, including coping strategies, may also influence CPAP adherence, and behavioral interventions to increase patient motivation to use CPAP have shown some success in the general population. However, in one recent randomized controlled trial, SLEEP TIGHT (Sleep Apnea in Transient Ischemic Attack and Stroke), patients with recent stroke or TIA who were assigned to an enhanced intervention with behavioral therapy showed similar CPAP use after 12 months compared with patients with the standard intervention.34Sleep-Wake Cycle Disturbance and StrokeThe association of sleep and stroke extends beyond SDB to disorders of the sleep-wake cycle, including long and short sleep duration, circadian rhythm disorders, and insomnia. Approximately half of stroke survivors have insomnia.35 In a study using polysomnography and multiple sleep latency tests 12 months after stroke, sleep latencies were longer, and sleep efficiency was worse among motor-impaired, right hemisphere stroke patients compared with age- and sex-matched controls.36 These findings were not related to SDB or periodic limb movements, which did not differ between the groups. Insomnia has also been associated with higher rates of incident stroke and worse poststroke outcome. A Taiwan administrative data study examined 21 438 people with insomnia and 64 314 without who were age and sex-matched.37 Those with insomnia had a 54% increased risk of stroke in the ensuing 4 years. In a study of 123 inpatient rehabilitation patients, insomnia but not SDB was associated with worse activities of daily living ability and less rehabilitation improvements after adjusting for confounders.38 As a treatment, cognitive behavior therapy has shown preliminary efficacy as a treatment for insomnia poststroke.39Other disturbances of sleep may also predispose to cerebrovascular disease. People who have rotating shift work may have increased stroke risk, perhaps related to sleep-wake cycle disruption. A report from the Nurses’ Health Study suggested a 4% increased ischemic stroke risk in nurses with rotating night shift work schedules.40 Suboptimal sleep duration has also been linked to increased risk of stroke. In a meta-analysis of 16 prospective studies, a J-shaped association was observed between sleep duration and total stroke with the lowest risk noted in people sleeping for 7 hours.41 Longer sleepers had a higher risk of stroke than short sleepers with a 13% increased risk of total stroke for every 1 hour increment of sleep duration above 7 hours.One of the most intriguing and disturbing hypotheses about the relationship of sleep disturbances and stroke is that it is, in part, responsible for the increased stroke risk among poor and minority populations.42 Different data sources find that populations who reside in inner cities are frequently kept awake at night by loud environmental sounds such as industrial plants, sirens, and public and private transport vehicles. These result in reduced total sleep, insomnia, reduced sleep efficiency, and excessive daytime sleepiness.43 Several studies have suggested increased stroke risk in low socioeconomic status neighborhoods. It is possible that reduced sleep duration and reduced sleep quality are links between neighborhood disadvantage and stroke.44ConclusionsIt is apparent that there is an association between SDB and other sleep impairments with stroke. Sleep disturbances seem to be both a stroke risk factor for and worsened by a stroke. As such, remedies to reduce sleep impairments may have important roles in both primary and secondary stroke prevention. Ongoing clinical trials will determine whether prompt treatment of SDB will improve outcome and reduce the second stroke. Further, increased attention on reducing insomnia through cognitive behavior therapy, and the general recognition of the importance of sleep may improve non-SDB sleep disturbances. Sleep disturbances, while equally prevalent among different race/ethnic populations,45 are more profoundly felt by the poor and minority groups because of these populations’ more prevalent location in cities where noise, light, and other impediments to sleep are more common.The anatomy, physiology, and clinical data paint a coherent picture of sleep disturbance as both a risk for stroke and a link to poor stroke outcome. Researchers and clinicians are poised to bring this often overlooked stroke risk factor into the limelight with new vigor.Sources of FundingThis work was supported by National Institutes of Health R01NS38916 (Dr Morgenstern).DisclosuresDrs Khot and Morgenstern are investigators in the National Institutes of Health funded Sleep SMART (Sleep for Stroke Management and Recovery Trial).FootnotesCorrespondence to Sandeep P. Khot, MD, Department of Neurology, University of Washington School of Medicine, Box 359775, 325 Ninth Ave, Seattle, WA 98104. Email [email protected]eduReferences1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2017 update: a report from the American Heart Association.Circulation. 2017; 135:e146–e603. doi: 10.1161/CIR.0000000000000485LinkGoogle Scholar2. Brown DL, Jiang X, Li C, Case E, Sozener CB, Chervin RD, et al. Sleep apnea screening is uncommon after stroke [published online September 27, 2018].Sleep Med. doi: 10.1016/j.sleep.2018.09.009Google Scholar3. Eckert DJ, Malhotra A, Jordan AS. Mechanisms of apnea.Prog Cardiovasc Dis. 2009; 51:313–323. doi: 10.1016/j.pcad.2008.02.003Google Scholar4. Javaheri S, Barbe F, Campos-Rodriguez F, Dempsey JA, Khayat R, Javaheri S, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences.J Am Coll Cardiol. 2017; 69:841–858. doi: 10.1016/j.jacc.2016.11.069CrossrefMedlineGoogle Scholar5. Hermann DM, Siccoli M, Kirov P, Gugger M, Bassetti CL. Central periodic breathing during sleep in acute ischemic stroke.Stroke. 2007; 38:1082–1084. doi: 10.1161/01.STR.0000258105.58221.9aLinkGoogle Scholar6. Siccoli MM, Valko PO, Hermann DM, Bassetti CL. Central periodic breathing during sleep in 74 patients with acute ischemic stroke - neurogenic and cardiogenic factors.J Neurol. 2008; 255:1687–1692. doi: 10.1007/s00415-008-0981-9CrossrefMedlineGoogle Scholar7. Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis.J Clin Sleep Med. 2010; 6:131–137.CrossrefMedlineGoogle Scholar8. Parra O, Arboix A, Bechich S, García-Eroles L, Montserrat JM, López JA, et al. Time course of sleep-relat