Abstract
Cerebrovascular disease encompassing both ischemic and hemorrhagic strokes are among the leading causes of disability and mortality globally. The current evidence strongly suggests that identifying and addressing sleep disorders should be a part of both primary and secondary stroke prevention. Stroke and sleep are ‘bedfellows’ since sleep disorders, including sleep-disordered breathing, parasomnias, sleep-related movement disorders, insomnia, and hypersomnia are intimately intertwined with co-morbid cardiovascular conditions and increase stroke risk. Post-stroke sleep disorders also impact stroke rehabilitation, quality of life, and if left untreated can contribute to stroke recurrence.
Introduction
Vascular disease is a leading cause of mortality worldwide. In the United States, cerebrovascular disease (CVD) represents a large proportion of vascular events and approximately 795,000 persons/year have a new or recurrent stroke. The direct and indirect costs of cardiovascular disease and stroke are estimated to total more than 316 billion dollars including health care costs and lost productivity due to the morbidity of CVD.1 The impact of CVD on quality of life and life expectancy underscores the importance of primary prevention with the identification and treatment of modifiable risk factors.
The traditional risk factors for CVD include atrial fibrillation, age > 65 years, hypertension, heart disease, carotid artery stenosis, tobacco use, diabetes mellitus, and dyslipidemias. However, there is increasing evidence that sleep disorders including sleep-disordered breathing (SDB), insomnia, hypersomnia, parasomnias, and sleep-related movement disorders are intimately intertwined with the cardiovascular conditions and increase the risk of cerebrovascular events.2 Therefore, the identification and treatment of sleep disorders is an important step in risk factor modification and primary prevention of stroke.
Circadian Rhythmicity of Stroke
Observational studies have recognized that a temporal pattern of stroke events occurs in humans. Both ischemic and hemorrhagic strokes have a bimodal pattern with the major peak of events in the morning and a minor peak in the evening; with 20–40% of ischemic strokes occurring at night; especially at the onset of sleep.3 This circadian pattern is independently linked to ischemic stroke even when other cardiovascular risk factors are adjusted.4 This periodicity falls in the same lines of fatality of the strokes, with one study showing morning strokes to be more likely to be fatal compared to afternoon strokes, even when variables of age, stroke severity, and gender were adjusted.5 Although external factors such as seasonal variation; for example a higher frequency of stroke due to embolism and intracerebral hemorrhage (ICH) during the winter months, have been observed, more research suggests that endogenous factors are the main contributors to the temporal variation of stroke. These endogenous factors include diurnal variability of blood pressure, autonomic nervous system fluctuations, and hypercoagulability.
Blood pressure typically decreases in the evening by approximately 10% and has a surge in the morning at the time of awakening.6 The autonomic nervous system also has a typical circadian pattern with a surge of sympathetic activity in the early morning, which correlates with the morning rise in blood pressure.7 Additionally, our hemostatic balance is also affected by circadian rhythm with increased hematocrit and platelet aggregation and hypercoagulability occurring in the morning.8 These endogenous factors may be the reason for the increased susceptibility to strokes in the morning..
A fair proportion of early morning or so-called, wakeup strokes have been observed to be embolic in nature. There seems to be a higher frequency of paroxysmal atrial fibrillation during the night and early morning hours.9 The pathophysiology underscoring sleep and arrhythmia may be related to surges in autonomic activity which occur during sleep and trigger instability of cardiac electrical activity, such as REM induced surges of the autonomic nervous system. These changes in the vascular tone can lead to brief reduction of cardiac output and increase the risk of thrombus formation, which then may embolize during the periods of paroxysmal atrial fibrillation.10
Impact of Sleep Disorders on Stroke Risk
Elucidating the etiology of an acute stroke can affect outcomes and help to reduce recurrence of further events. The Trial of Acute Stroke Treatment (TOAST) categorized ischemic strokes based on etiology into five subtypes: Strokes due to large artery atherosclerosis, cardioembolic strokes, strokes due to small vessel occlusion, stroke of other determined etiology and cryptogenic strokes.11
The category of cryptogenic stroke is defined as ischemic cerebrovascular events in which the cause remains undetermined. The most frequent etiologies seen in this setting are paradoxical embolism via a patent foramen ovale or paroxysmal atrial fibrillation. Also, many of these cryptogenic strokes are found to be associated with sleep-disordered breathing (SDB). SDB is an umbrella term used to describe patterns of nocturnal breathing disturbances leading to ventilatory abnormalities such as hypoxemia and hypercapnia, and includes obstructive sleep apnea (OSA), central sleep apnea (CSA), sleep-related hypoventilation and Cheyne-Strokes Breathing (CSB). SDB is suspected in approximately 50–70% of acute stroke patients, and patients with recurrent cerebrovascular events are more likely to have SDB than those with a single cerebral ischemic event.12 In this way, sleep and stroke become bedfellows because pre-existing sleep disorders increase the risk for stroke and acute strokes can lead to the development of SDB. After a stroke, the treatment of sleep disorders such as obstructive sleep apnea can augment functional recovery especially regarding ameliorating depression, increasing activities of daily living and improving attention and concentration.
The greatest prevalence of SDB is found among patients who are male and those with cryptogenic or recurrent strokes.13 SDB has been associated with two to three times higher risk of incident stroke in several population studies. When investigating the link between obstructive sleep apnea and stroke, it has been difficult to determine if OSA and sleep are co-incident due to similar patient demographics namely gender, age, and presence of medical co-morbidities such as obesity, hypertension, hyperlipidemia, diabetes mellitus as opposed to a direct cause and effect of OSA leading to cerebral ischemia or infarction. A large population study, the Sleep Heart Health Study (SHHS) was a prospective cohort study of the cardiovascular effects of OSA. Approximately 5,000 patients were followed from the point of diagnosis of OSA until they either had an ischemic stroke or completed follow up at eight years. The study demonstrated that having OSA increases the risk of ischemic stroke, especially in men with moderate-severe OSA and suggested that having OSA as a co-morbidity increased the likelihood of stroke in this patient subset.14
The impact of disordered sleep breathing has many layers - its presence leads to and augments pre-existing co-morbidities which are typical risk factors for stroke. A cross-sectional analysis of a group of persons with SDB found after adjusting for confounding factors (age, gender, co-existing cardiovascular risk factors including obesity, hypertension, diabetes mellitus, hyperlipidemia) that a significant relationship exists between stroke and SDB. This study also showed that an Apnea Hypopnea Index (AHI) of ≥ 20 is associated with an increased risk of having a stroke within the next four years.15 The presence of SDB portends an overall increased risk of cerebrovascular events.
The hypothesized mechanisms of SDB leading to stroke include fluctuations in the intrathoracic pressure due to apneas, intermittent hypoxemia, sympathetic activation and endothelial dysfunction. Due to sympathetic activation, there is vasoconstriction and hypertension along with direct endothelial damage and cardiac arrhythmias. The result is cerebral ischemia and damage due to the recurrent hypoxemia and variability in cerebral blood flow.16 SDB preceding stroke affects multiple domains including the development of hypertension and early atherosclerosis by increasing platelet adhesion and vascular endothelial dysfunction.
In addition to the association between OSA and refractory hypertension and cardiac arrhythmia, there is also a key association between sleep apnea and systemic atherosclerosis. Overall contributors to plaque development are multifactorial as shown in Figure 1. The repeated hypoxemic events of OSA are implicated in atherosclerosis by increasing oxidative stress, endothelial dysfunction and causing dyslipidemia.
Figure 1.
Overall contributors to plaque development are multifactorial
Impact of Stroke on Sleep
Changes in Sleep Architecture and EEG
Supratentorial strokes have been linked to the reduction in non-REM sleep and total sleep time, and this is more frequently seen with left-sided strokes. There may be an ipsilateral or bilateral reduction in sleep spindles also. A temporary reduction in REM sleep may also be observed in some cases of supratentorial stroke. This is more frequently seen with a right-sided stroke. Saw-tooth waves may be reduced after hemispheric stroke. Reduction in REM sleep can be seen after occipital strokes. Strokes in the ponto-mesencephalic junction and the raphe nucleus may cause a reduced amount of non-REM sleep while lesions in the lower pons can selectively reduce REM sleep.1 Paramedian thalamus and lower pontine strokes can also result in lack of slow-wave sleep with preserved REM sleep.
Similarly, many changes in surface EEG recording can also be noted in the setting of strokes. Cortical and subcortical strokes can show evidence of neuronal dysfunction in the form of focal slowing. Sometimes, subcortical strokes may display diffuse neuronal dysfunction with intermittent bursts of ipsilateral or bilateral delta wave activity. Thalamic and brainstem infarcts may present with pathological EEG patterns like alpha coma, spindle coma and theta coma. While small infarcts may not produce any discernible EEG changes, massive infarcts may result in attenuation of EEG activity in the involved regions without any associated delta activity.
Insomnia after Stroke
Insomnia is defined as persistent difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep and results in some form of daytime impairment. Daytime symptoms typically include fatigue, mood issues, irritability, malaise, and cognitive impairment. Some patients with insomnia may also experience physical symptoms like muscle tension, palpitations, and headache. Under the international classification of sleep disorders, insomnia associated with stroke falls under the category of “Insomnia due to a Medical condition.”
Insomnia is common in stroke patients and affects 20–56% of them. About 18% of the people reported new-onset insomnia after their stroke. Insomnia typically occurs in the setting of the acute phase of the stroke. The development of insomnia may be related to the stroke location, with an increased prevalence in right hemispheric strokes as well as those within the thalamus or brainstem, including the pontine tegmentum and thalamo-mensencephalic region. Patients with strokes within the paramedian thalamus can also develop insomnia due to an inability to generate sleep spindles due to the involvement of the thalamoreticular system.. Along with stroke location, the development of insomnia in stroke patients may be due to multiple environmental factors such as being hospitalized, unfamiliar environments, loss of uninterrupted sleep and medication side-effects.2 Overall post-stroke insomnia can increase anxiety, impair daytime energy levels, concentration and memory and therefore contribute to a suboptimal performance during rehabilitation.
Hypersomnia after Stroke
Increased sleepiness following stroke was mentioned by MacNish as early as 1830. Carl Wernicke in 1881 reported several patients in home autopsy showing punctate hemorrhages around the third ventricles and called it “Polioencephalitis Hemorrhagica Superioris,” now called “Wernicke-Korsakoff syndrome.” Mauthner in 1890 related to sleepiness and patients with sleeping sickness (encephalitis lethargica) to the presence of inflammatory lesions in the periventricular gray matter of the midbrain. The association between sleep-wake disorders and stroke became increasingly reported by the beginning of the 20th century. Von Economo in 1920 related that sleep might represent an active process of the brain and not just the absence of wakefulness and showed that hypersomnia was associated with lesions of the posterior hypothalamus. Manasseina and Kleitman also remarked on post-stroke hypersomnia in the classic monographs on sleep.3,4 Post-stroke hypersomnia is defined as exacerbated sleep propensity with excessive daytime sleepiness, increased daytime napping or prolonged nighttime sleep following a cerebrovascular accident. The prevalence of hypersomnia in stroke patients ranges from 1.1% to 27%. Poststroke hypersomnia may be found after subcortical (caudate, putamen), upper pontine, medial ponto-medullary and cortical strokes affecting the reticular activating system (RAS). Paramedian or bilateral thalamic strokes present with sudden onset of coma, and when they awake, they can exhibit hypersomnia/sleep like behavior up to 20 hrs/ day with deficits of attention, cognition, and memory.5 Patients with stroke and hypersomnia are more likely to go to a nursing facility compared to those with stroke without hypersomnia, and the presence of hypersomnia may impair optimal stroke rehabilitation.
Stroke and Periodic Leg Movements
Restless leg syndrome (RLS) is an overwhelming urge to move the legs, that is worse with inactivity and at night and relieved by movement. RLS may be associated with sleep disturbance and involuntary movements of the legs during sleep, the periodic leg movements of sleep (PLMS). Overall, this occurs in 5–8% of the population and poststroke PLMS has been associated with lesions of the pons and corona radiata.6 Both RLS and PLMS have been linked to an increased risk of stroke, and this connection may be due to decreased sleep quality leading to an increased risk of cardiovascular disease. The duration of RLS may also be an independent predictor of asymptomatic cerebral small vessel disease, and this factor is associated with a higher rate of symptomatic stroke. Both disorders are associated with sympathetic hyperactivity which can affect the circadian rhythm of blood pressure, leading to more nocturnal hypertension and increased risk of atherosclerotic plaque rupture.7 These factors cumulatively increase the risk of stroke.
Stroke and Parasomnia
Parasomnias are complex movements and behaviors during sleep which include REM sleep behavior disorder (RBD), nightmares, sleep paralysis, and other disorders of arousal including sleepwalking and sleep terrors. RBD consists of dream enactment behavior and vivid or unpleasant dreams and is frequently seen in neurodegenerative disorders such as Parkinson disease and multiple systems atrophy. Studies have established that individuals with RBD have a higher likelihood of also having concomitant stroke risk factors including diabetes mellitus and dyslipidemia. One study demonstrated that adults with RBD were 1.5 times more likely to develop stroke independent of other demographic variables including age, gender, hypertension, and tobacco use.8 The mechanism linking RBD to stroke may be sleep fragmentation leading to increased sympathetic tone and resulting in changes in heart rate variability and blood pressure surges which are cardiovascular events linked to stroke onset.
Sleep-Disordered Breathing After Stroke
Sleep-disordered breathing include a variety of diseases like Obstructive Sleep Apnea (OSA), Central Sleep Apnea (CSA), Sleep Related Hypoventilation, sleep-related hypoxemia and periodic breathing like Cheyne-Strokes Breathing (CSB).
A systematic literature search of PubMed databases published between January 1, 2001, and January 1, 2017, was performed to identify studies involving the treatment of obstructive sleep apnea in patients with acute ischemic stroke with continuous positive pressure ventilation and their functional outcomes including the impact on cognition, cardiovascular events, activities of daily living. Studies included randomized clinical trials and observational studies. Using MESH terms including ‘stroke’ and sleep apnea syndromes’ as keywords, we found 429 articles, and of these, 27 were clinical trials, and 21 of the 27 trials were published within the last ten years. This demonstrates an increasing awareness of the importance of diagnosing and treating obstructive sleep apnea in patients to reduce their risk of stroke and assist in their recovery following a cerebral ischemic event.
The use of continuous positive pressure ventilation (CPAP) to treat patients following acute ischemic stroke has been beneficial in improving stroke severity. Initiating therapy early can have benefit in improving the overall NIHSS. Several trials have shown treatment with CPAP in the first few days after acute stroke trended toward greater NIHSS improvement.9 The mechanism may be due to improved oxygenation and decreased the frequency of blood pressure surges associated with the apneas. Treatment with CPAP improved left ventricular function and allowed a more rapid normalization of cerebral vascular tone leading to the earlier return of normal cerebral autoregulation.10
Several studies have been performed in the rehabilitation setting with an aim to elucidate the benefits treating SDB would have on the overall functional status and cognitive recovery. A randomized trial in OSA patients admitted to a stroke rehabilitation unit with the premise that treating OSA in this group would enhance motor, neurocognitive and functional recovery found the CPAP group achieved improved functional outcomes, especially in stroke-related impairment as assessed by the Canadian Neurological Scale (CNS). They also achieved improved secondary outcomes including less depressive symptoms and less daytime sleepiness and fatigue.11
Another randomized controlled trial hypothesized that untreated OSA in patients was associated with a worse outcome regarding function and cognitive status during inpatient rehabilitation following an acute stroke. The study found that the group treated with continuous positive pressure ventilation (CPAP) had statistically significant improvement in domains of attention and executive function although overall did not demonstrate any more functional improvement compared to the placebo group after four weeks.12 Albeit a small study, this provides some support that treating SDB can lead to improvement in certain cognitive domains.
The deficits related to a stroke are a function of focal injury to the cerebral cortex, and after an acute stroke, the brain reorganizes to improve and compensate for lost functions. Neurorehabilitation is multi-layered, involving physical, occupational and speech therapies as well as neuropsychological training to improve the overall daily living and cognitive functioning and sleep is a function which promotes recovery in all these domains.13 In addition to SDB, disturbances of wakefulness are also associated with acute stroke, and this spectrum extends from hypersomnia, excessive daytime sleepiness, and fatigue. These conditions can also be intrinsically connected to disorders of breathing; for example, untreated sleep apnea can also be linked to fatigue and excessive daytime sleepiness.
Post-stroke CSA and CSB linked to lesions within the insula and thalamus affecting central autonomic networks which co-ordinate respirations.
Changes in Circadian Rhythm After Stroke
After an acute stroke, changes occur in the physiological circadian profile of blood pressure. As compared to normotensive persons, patients with both ischemic stroke and hemorrhagic strokes demonstrated a loss of the biphasic circadian variation. Normally nocturnal blood pressure drops approximately 10% or more, and after a stroke, this nocturnal dipping profile is eliminated.14 Additionally, following a stroke, there are other alterations in the circadian rhythm, especially the sleep/wake cycle leading to sleep fragmentation and decreased sleep efficiency. This alteration in sleep/wake cycle also correlates to the development of post-stroke apathy, which is defined as a syndrome of decreased goal-directed behavior including a lack of motivation, emotion or interest.15 The disturbance of sleep architecture and the development of apathy following a stroke has consequences on rehabilitation performance and can negatively impact functional recovery.
Conclusion
There is a body of evidence which demonstrates that sleep disorders are intrinsically bound to both ischemic and hemorrhagic cerebrovascular events by increasing a patient’s risk profile and as a sequela of an acute stroke. This underscores the importance of screening patients for sleep disorders especially SDB and appropriately manage them to help in the primary or secondary prevention of stroke which in the long run will decrease the morbidity and mortality of this potentially devastating disease.
Footnotes
From top left, clockwise: Madihah Hepburn, MD, Pradeep C. Bollu, MD, Pradeep Sahota, MD, MSMA member since 2003, and Brandi French, MD, are in the Department of Neurology, University of Missouri - Columbia.
Contact: BolluP@health.missouri.edu
Disclosure
None reported.
References
- 1.Benjamin EJ, et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation. 2017;135(10):e146–e603. doi: 10.1161/CIR.0000000000000485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Ferre A, et al. Strokes and their relationship with sleep and sleep disorders. Neurologia. 2013;28(2):103–18. doi: 10.1016/j.nrl.2010.09.016. [DOI] [PubMed] [Google Scholar]
- 3.Ferre A, et al. Strokes and their relationship with sleep and sleep disorders. Neurologia. 2013;28(2):103–18. doi: 10.1016/j.nrl.2010.09.016. [DOI] [PubMed] [Google Scholar]
- 4.Ferre A, et al. Strokes and their relationship with sleep and sleep disorders. Neurologia. 2013;28(2):103–18. doi: 10.1016/j.nrl.2010.09.016. [DOI] [PubMed] [Google Scholar]
- 5.Turin TC, et al. Is there any circadian variation consequence on acute case fatality of stroke? Takashima Stroke Registry, Japan (1990–2003) Acta Neurol Scand. 2012;125(3):206–12. doi: 10.1111/j.1600-0404.2011.01522.x. [DOI] [PubMed] [Google Scholar]
- 6.Schallner N, LeBlanc R, III, Otterbein LE, Hanafy KA. Circadian rhythm in stroke: The influence of our internal cellular clock on cerebrovascular Events. J Clin Exp Pathol. 2014;4(163) [Google Scholar]
- 7.Fodor DM, Babiciu I, Perju-Dumbrava L. Circadian Variation of Stroke Onset: A Hospital-Based Study. Clujul Medical. 2014;87(4):242–249. doi: 10.15386/cjmed-328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Fodor DM, Babiciu I, Perju-Dumbrava L. Circadian Variation of Stroke Onset: A Hospital-Based Study. Clujul Medical. 2014;87(4):242–249. doi: 10.15386/cjmed-328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Riccio PM, et al. Newly diagnosed atrial fibrillation linked to wake-up stroke and TIA: hypothetical implications. Neurology. 2013;80(20):1834–40. doi: 10.1212/WNL.0b013e318292a330. [DOI] [PubMed] [Google Scholar]
- 10.Riccio PM, et al. Newly diagnosed atrial fibrillation linked to wake-up stroke and TIA: hypothetical implications. Neurology. 2013;80(20):1834–40. doi: 10.1212/WNL.0b013e318292a330. [DOI] [PubMed] [Google Scholar]
- 11.Adams HP, Jr, 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(1):35–41. doi: 10.1161/01.str.24.1.35. [DOI] [PubMed] [Google Scholar]
- 12.Hermann DM, Bassetti CL. Sleep-related breathing and sleep-wake disturbances in ischemic stroke. Neurology. 2009;73(16):1313–22. doi: 10.1212/WNL.0b013e3181bd137c. [DOI] [PubMed] [Google Scholar]
- 13.Quan SF, et al. The Sleep Heart Health Study: design, rationale, and methods. Sleep. 1997;20(12):1077–85. [PubMed] [Google Scholar]
- 14.Quan SF, et al. The Sleep Heart Health Study: design, rationale, and methods. Sleep. 1997;20(12):1077–85. [PubMed] [Google Scholar]
- 15.Arzt M, et al. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med. 2005;172(11):1447–51. doi: 10.1164/rccm.200505-702OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Birkbak J, Clark AJ, Rod NH. The effect of sleep disordered breathing on the outcome of stroke and transient ischemic attack: a systematic review. J Clin Sleep Med. 2014;10(1):103–8. doi: 10.5664/jcsm.3376. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Ferre A, et al. Strokes and their relationship with sleep and sleep disorders. Neurologia. 2013;28(2):103–18. doi: 10.1016/j.nrl.2010.09.016. [DOI] [PubMed] [Google Scholar]
- 18.Da Rocha PC, et al. Predictive factors of subjective sleep quality and insomnia complaint in patients with stroke: implications for clinical practice. An Acad Bras Cienc. 2013;85(3):1197–206. doi: 10.1590/S0001-37652013005000053. [DOI] [PubMed] [Google Scholar]
- 19.Kleitman N. Sleep and wakefulness. University of Chicago Press; 1963. [Google Scholar]
- 20.Manasseina M. Sleep as one third of human life, or physiology, pathology, hygiene and psychology of sleep. Moscow, D: Gintsburg printing-house; 1892. (In Russian) [Google Scholar]
- 21.Bassetti CL. Sleep and stroke. Semin Neurol. 2005;25(1):19–32. doi: 10.1055/s-2005-867073. [DOI] [PubMed] [Google Scholar]
- 22.Woo HG, et al. Post-stroke restless leg syndrome and periodic limb movements in sleep. Acta Neurologica Scandinavica. 2017;135(2):204–210. doi: 10.1111/ane.12582. [DOI] [PubMed] [Google Scholar]
- 23.Chou CH, et al. The potential impact of sleep-related movement disorders on stroke risk: a population-based longitudinal study. Qjm. 2017 doi: 10.1093/qjmed/hcx097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ma C, et al. Probable REM sleep behavior disorder and risk of stroke: A prospective study. Neurology. 2017;88(19):1849–1855. doi: 10.1212/WNL.0000000000003902. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Minnerup J, et al. Continuous positive airway pressure ventilation for acute ischemic stroke: a randomized feasibility study. Stroke. 2012;43(4):1137–9. doi: 10.1161/STROKEAHA.111.637611. [DOI] [PubMed] [Google Scholar]
- 26.Bravata DM, et al. Continuous positive airway pressure: evaluation of a novel therapy for patients with acute ischemic stroke. Sleep. 2011;34(9):1271–7. doi: 10.5665/SLEEP.1254. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Ryan CM, et al. Influence of continuous positive airway pressure on outcomes of rehabilitation in stroke patients with obstructive sleep apnea. Stroke. 2011;42(4):1062–7. doi: 10.1161/STROKEAHA.110.597468. [DOI] [PubMed] [Google Scholar]
- 28.Aaronson JA, et al. Effects of Continuous Positive Airway Pressure on Cognitive and Functional Outcome of Stroke Patients with Obstructive Sleep Apnea: A Randomized Controlled Trial. J Clin Sleep Med. 2016;12(4):533–41. doi: 10.5664/jcsm.5684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Duss SB, et al. The role of sleep in recovery following ischemic stroke: A review of human and animal data. Neurobiology of Sleep and Circadian Rhythms. 2017;2:94–105. doi: 10.1016/j.nbscr.2016.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Jain S, et al. Loss of circadian rhythm of blood pressure following acute stroke. BMC Neurol. 2004;4:1. doi: 10.1186/1471-2377-4-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Cosin C, et al. Circadian sleep/wake rhythm abnormalities as a risk factor of a poststroke apathy. Int J Stroke. 2015;10(5):710–5. doi: 10.1111/ijs.12433. [DOI] [PubMed] [Google Scholar]