Sleep disordered breathing and the outcome of stroke
http://www.100md.com
《胸》
Correspondence to:
Professor G J Gibson
Department of Respiratory Medicine, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK; g.j.gibson@ncl.ac.uk
Patients with OSA not only have an increased risk of stroke, but also a higher mortality and greater disability after stroke
Keywords: sleep disordered breathing; obstructive sleep apnoea; stroke; outcome
Abbreviations: AHI, apnoea-hypopnoea index; OSA, obstructive sleep apnoea; SDB, sleep disordered breathing; TIA, transient ischaemic attack
Interest in abnormal breathing after stroke has a long history dating back at least to the observations of John Cheyne in 1818.1 In recent years this interest has been reawakened by a number of publications on the relations between sleep disordered breathing (SDB) and stroke. These studies have been of two main types—those investigating the possible increased risk of stroke in individuals with obstructive sleep apnoea (OSA) and those reporting a high prevalence of SDB after stroke and its possible effects on residual disability and mortality. Unravelling the direction of causality—that is, whether OSA causes stroke or stroke causes OSA—has proved challenging.2–5
OSA AND RISK OF STROKE
Most of the evidence on the risk of stroke associated with OSA is circumstantial and is based on case-control studies in which a history of snoring, with or without other features suggestive of OSA, is compared in patients with stroke and matched controls.6–11 Such studies lack objective confirmation of pre-stroke OSA, are critically dependent on the validity of the control population, and are subject to recall bias. Moreover, most studies have included subjects who had previously had a stroke where, inevitably, the direction of causality is uncertain. In studies where account has been taken of potential confounding factors such as obesity, smoking and hypertension, the estimated risk of stroke is reduced. Of the possible "confounders", hypertension is of particular relevance as the contribution of OSA to systemic hypertension has been demonstrated beyond reasonable doubt and clearly it offers a potential causal link with stroke. Even after statistical adjustment for hypertension, however, several studies still support an association between OSA and stroke. Various alternative mechanisms related to demonstrated abnormalities in patients with OSA have been suggested. These include abnormal cerebral haemodynamics,12 increased platelet aggregability,13 increased fibrinogen concentration,14 increased blood viscosity,15 and abnormal vascular endothelial function.16 On the other hand, snoring alone, without other features of OSA, appears to carry little if any excess risk.17
Although the weight of evidence favouring OSA as an independent risk factor for stroke is suggestive, cross sectional studies can never give a definitive result. Confirmation awaits the full publication of large prospective studies which are currently in progress. Preliminary data from one such study, published so far only as an abstract,18 support the conclusion that OSA is a risk factor for the development of stroke or transient ischaemic attack (TIA), independently of sex, body mass index, diabetes, and hypertension.
SDB AFTER STROKE
Complementing these studies of the risk of stroke associated with OSA, several others have shown a high prevalence of SDB after stroke.19–26 Most have been observational with no control group, an important omission in light of the high frequency of apnoeas and hypopnoeas in apparently healthy elderly subjects.27 However, three studies which included small age matched control groups20,21,28 each showed a significantly higher apnoea-hypopnoea index (AHI) in the stroke patients. On the other hand, a recent study29 comparing patients with TIA and individually matched controls showed no difference in AHI, although the frequency of nocturnal desaturation >4% was greater in the patient group. Two reports of sequential sleep studies after stroke showed a significant reduction in AHI 2–3 months later,23,24 although in a third study,30 based on oximetry only, there was no change in the desaturation index in stroke survivors restudied 3 months after the event.
Are these observations merely of curiosity value or might SDB adversely affect the outcome of stroke? In the current issue of Thorax Turkington et al31 add further evidence that this may indeed be the case. In an earlier study of a small number of patients Good et al19 showed that a higher nocturnal desaturation index was associated with greater mortality and more severe disability in survivors 12 months after the event. More recently, Iranzo et al32 studied patients during the first night after a stroke and found that a high AHI was associated with early neurological deterioration, although this did not correlate with disability 6 months later. The study by Turkington et al has the advantage of including a larger and less selected population, which is broadly typical of patients with stroke admitted to hospital in the UK; they were generally older and more disabled than those included in many of the previous studies performed in neurological or rehabilitation units. Turkington et al showed clear relations between SDB in the first 24 hours after stroke and length of hospital stay, mortality, and greater dependency of survivors 6 months later. Another recent study26 of younger patients in a rehabilitation unit also reported that SDB 6 weeks after a stroke was independently associated with longer hospital stay and greater long term functional impairment.
POSSIBLE MECHANISMS
Why then might subjects with OSA fare particularly badly after stroke? Several of the pathophysiological features accompanying OSA have also been associated with an adverse outcome in stroke populations. These include:
Large fluctuations of blood pressure and the consequent effects on cerebral blood flow: in OSA repeated elevation of blood pressure, sometimes to an alarming degree, is seen at the termination of each apnoea.33 In stroke patients a greater variation in blood pressure correlates with both increased mortality and greater dependency.34
Baroceptor dysfunction has been reported in OSA35 and impaired cardiac baroceptor sensitivity is associated with higher mortality after stroke.36
Recurrent hypoxaemia associated with frequent apnoeas is another obvious candidate. This might have a critical effect on the "ischaemic penumbra" surrounding the infarcted brain and might result in extension of the neurological damage.
Alternating hypoxaemia and reoxygenation accompanying OSA is associated with increased release of superoxides from neutrophils37 which might have an adverse effect after stroke in light of evidence from animal stroke models.38
Inflammatory and proinflammatory markers and mediators such as C reactive protein39 and adhesion molecules40 are increased in OSA while, in stroke, inflammatory changes are increasingly recognised as possibly contributing to injury of vulnerable brain tissue.41
Clearly, therefore, there are many similarities between the pathophysiological changes which accompany OSA and factors which influence the outcome of stroke. Further work will be required to tease out which of the above are likely to be most relevant to the associations shown by Turkington et al.31
Most of the features associated with more severe SDB after stroke are consistent with pre-existing OSA. These include a history of snoring22,42 or sleepiness28,30 and greater body mass index21,22,25 and neck circumference.22,25 Also relevant is an earlier case-control study43 which showed a clear dose-response relationship between the reported severity of pre-stroke snoring and mortality 6 months after a stroke. On the other hand, there is little apparent relation between SDB and the characteristics of a recent stroke such as its clinical severity24–26,30 or location,23,26,32 or the extent of acute changes visible on CT scanning.44 SDB is, however, more severe in patients with the lacunar syndrome24,30 which is closely related to hypertension, and in those with CT evidence of chronic cerebrovascular disease.44
Taken together, a unifying hypothesis arising from these various studies would be that patients with pre-existing OSA have an increased risk, not only of developing stroke but also of an adverse outcome in terms of both mortality and disability. Such individuals may be more likely to show exaggerated SDB after a stroke and a consequent poor outcome.
CLINICAL IMPLICATIONS
Are these findings merely of theoretical interest or might they have practical relevance? The most obvious therapeutic implication relates to the potential value of treating OSA after a stroke with continuous positive airway pressure (CPAP). Although one study reported that some younger patients during rehabilitation after stroke will tolerate CPAP,45 our experience, like that of others studying a more representative older population,46,47 has been more pessimistic. If CPAP is to influence the outcome of stroke by limiting ischaemic damage to the vulnerable areas of brain in the "penumbra", it seems likely that its optimal timing would be very soon after the event. However, the practicalities of introducing such unfamiliar treatment to elderly, disabled, and sometimes confused patients in an acute hospital ward or stroke unit are such that the widespread applicability of CPAP after a stroke is unlikely. It may, nonetheless, have a role in selected individuals. Hui et al47 found that the small minority of patients who tolerated CPAP shortly after a stroke had symptoms suggesting pre-existing OSA. This conclusion concurs with studies of patients with OSA in whom compliance with CPAP is better in those with more severe symptoms, particularly daytime sleepiness.48 In practice, of course, stroke patients with features of pre-existing OSA may be the very ones to target for CPAP therapy if, as suggested above, the adverse prognosis associated with SDB following stroke is due mainly to pre-stroke OSA.
ACKNOWLEDGEMENTS
The author thanks Professor G A Ford for helpful discussion.
REFERENCES
Cheyne J. A case of apoplexy in which the fleshy part of the heart was converted into fat. Dublin Hospital Reports 1818;2:216–23.
Harbison JA, Gibson GJ. Snoring, sleep apnoea and stroke: chicken or scrambled egg? Q J Med 2000;93:647–54.
Mohsenin V. Sleep-related breathing disorders and risk of stroke. Stroke 2001;32:1271–8.
Neau JP, Paquereau J, Meurice JC, et al. Stroke and sleep apnoea: cause or consequence? Sleep Med Rev 2002;6:457–69.
Yaggi H, Mohsenin V. Sleep-disordered breathing and stroke. Clin Chest Med 2003;24:223–37.
Partinen M, Palomaki H. Snoring and cerebral infarction. Lancet 1985;ii:1325–6.
Koskenvuo M, Kaprio J, Telakivi T, et al. Snoring as a risk factor for ischaemic heart disease and stroke in men. BMJ 1987;294:16–9.
Spriggs DA, French JM, Murdy JM, et al. Historical risk factors for stroke: a case control study. Age Ageing 1990;19:280–7.
Palomaki H. Snoring and the risk of ischemic brain infarction. Stroke 1991;22:1021–5.
Smirne S, Palazzi S, Zucconi M, et al. Habitual snoring as a risk factor for acute vascular disease. Eur Respir J 1993;6:1357–61.
Neau JP, Meurice JC, Paquereau J, et al. Habitual snoring as a risk factor for brain infarction. Acta Neurol Scand 1995;92:63–8.
Franklin KA. Cerebral haemodynamics in obstructive sleep apnoea and Cheyne-Stokes respiration. Sleep Med Rev 2002;6:429–41.
Sanner BM, Konermann M, Tepel M, et al. Platelet function in patients with obstructive sleep apnoea syndrome. Eur Respir J 2000;16:648–52.
Wessendorf TE, Thilmann AF, Wang YM, et al. Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med 2000;162:2039–42.
Nobili L, Schiavi G, Bozano E, et al. Morning increase of whole blood viscosity in obstructive sleep apnea syndrome. Clin Hemorheol Microcirc 2000;22:21–7.
Kato M, Roberts-Thompson P, Phillips B, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102:2607–10.
Davies DP, Rodgers H, Walshaw D, et al. Snoring, daytime sleepiness and stroke: a case-control study of first-ever stroke. J Sleep Res 2003;12:313–8.
Yaggi K, Kernan W, Mohsenin V. The association between obstructive sleep apnea and stroke. Am J Respir Crit Care Med 2003;167:A173.
Good DC, Henkle JQ, Gelber D, et al. Sleep-disordered breathing and poor functional outcome after stroke. Stroke 1996;27:252–9.
Dyken ME, Somers VK, Yamada T, et al. Investigating the relationship between stroke and obstructive sleep apnea. Stroke 1996;27:401–7.
Bassetti C, Aldrich MS. Sleep apnea in acute cerebrovascular diseases: final report on 128 patients. Sleep 1999;22:217–23.
Wessendorf TE, Teschler H, Wang YM, et al. Sleep-disordered breathing among patients with first-ever stroke. J Neurol 2000;247:41–7.
Parra O, Arboix A, Bechich S, et al. Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med 2000;161:375–80.
Harbison J, Ford GA, James OFW, et al. Sleep-disordered breathing following acute stroke. Q J Med 2002;95:741–7.
Turkington PM, Bamford J, Wanklyn P, et al. Prevalence and predictors of upper airway obstruction in the first 24 hours after acute stroke. Stroke 2002;33:2037–42.
Kaneko Y, Hajek VE, Zivanovic V, et al. Relationship of sleep apnea to functional capacity and length of hospitalization following stroke. Sleep 2003;26:293–7.
ty-dwelling elderly. Sleep 1991;14:486–95.
Nasr-Wyler A, Bouillanne O, Lalhou A, et al. Syndrome d’apnees du sommeil et accident vasculaire cerebral dans une population agee. Rev Neurol (Paris) 1999;155:1057–62.
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 ischaemic attacks. Stroke 2003;34:2916–21.
Lawrence E, Dundas R, Higgens S, et al. The natural history and associations of sleep disordered breathing in first ever stroke. Int J Clin Pract 2001;55:584–8.
Turkington PM, Allgar V, Bamford J, et al. Effect of upper airway obstruction in acute stroke on functional outcome at 6 months. Thorax 2004;59:367–71.
Iranzo A, Santamaria J, Berenguer J, et al. Prevalence and clinical importance of sleep apnea in the first night after cerebral infarction. Neurology 2002;58:911–6.
Shepard JW. Gas exchange and hemodynamics during sleep. Med Clin North Am 1985;69:1234–64.
Dawson SL, Manktelow BN, Robinson TG, et al. Which parameters of beat-to-beat blood pressure and variability best predict early outcome after acute ischemic stroke? Stroke 2000;31:463–8.
Belozeroff V, Berry RB, Khoo MC. Model-based assessment of autonomic control in obstructive sleep apnea syndrome. Sleep 2003;26:65–73.
Robinson TG, Dawson SL, Eames PJ, et al. Cardiac baroreceptor sensitivity predicts long-term outcome after acute ischemic stroke. Stroke 2003;34:705–12.
Schulz R, Mahmoudi S, Hattar K, et al. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Am J Respir Crit Care Med 2000;162:566–70.
Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 2001;21:2–14.
Shamsuzzaman ASM, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105:2462–4.
Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002;165:934–9.
del Zoppo G, Ginis I, Hallenbeck JM, et al. Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 2000;10:95–112.
Cherkassky T, Oksenberg A, Froom P, et al. Sleep-related breathing disorders and rehabilitation outcome of stroke patients. A prospective study. Am J Phys Med Rehabil 2003;82:452–5.
Spriggs DA, French JM, Murdy JM, et al. Snoring increases the risk of stroke and adversely affects prognosis. Q J Med 1992;83:555–62.
Harbison J, Gibson GJ, Birchall D, et al. White matter disease and sleep-disordered breathing after acute stroke. Neurology 2003;61:959–63.
Wessendorf TE, Wang YM, Thilmann AF, et al. Treatment of obstructive sleep apnoea with nasal continuous positive airway pressure in stroke. Eur Respir J 2001;18:623–9.
Sandberg O, Franklin KA, Bucht G, et al. Nasal continuous positive airway pressure in stroke patients with sleep apnoea: a randomised treatment study. Eur Respir J 2001;18:630–4.
Hui DSC, Choy DKL, Wong LKS, et al. Prevalence of sleep-disordered breathing and continuous positive airway pressure compliance. Results in Chinese patients with first-ever ischemic stroke. Chest 2002;122:852–60.
McArdle N, Devereux G, Heidarnejad H, et al. Long-term use of CPAP therapy for sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999;159:1108–14.(G J Gibson)
Professor G J Gibson
Department of Respiratory Medicine, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK; g.j.gibson@ncl.ac.uk
Patients with OSA not only have an increased risk of stroke, but also a higher mortality and greater disability after stroke
Keywords: sleep disordered breathing; obstructive sleep apnoea; stroke; outcome
Abbreviations: AHI, apnoea-hypopnoea index; OSA, obstructive sleep apnoea; SDB, sleep disordered breathing; TIA, transient ischaemic attack
Interest in abnormal breathing after stroke has a long history dating back at least to the observations of John Cheyne in 1818.1 In recent years this interest has been reawakened by a number of publications on the relations between sleep disordered breathing (SDB) and stroke. These studies have been of two main types—those investigating the possible increased risk of stroke in individuals with obstructive sleep apnoea (OSA) and those reporting a high prevalence of SDB after stroke and its possible effects on residual disability and mortality. Unravelling the direction of causality—that is, whether OSA causes stroke or stroke causes OSA—has proved challenging.2–5
OSA AND RISK OF STROKE
Most of the evidence on the risk of stroke associated with OSA is circumstantial and is based on case-control studies in which a history of snoring, with or without other features suggestive of OSA, is compared in patients with stroke and matched controls.6–11 Such studies lack objective confirmation of pre-stroke OSA, are critically dependent on the validity of the control population, and are subject to recall bias. Moreover, most studies have included subjects who had previously had a stroke where, inevitably, the direction of causality is uncertain. In studies where account has been taken of potential confounding factors such as obesity, smoking and hypertension, the estimated risk of stroke is reduced. Of the possible "confounders", hypertension is of particular relevance as the contribution of OSA to systemic hypertension has been demonstrated beyond reasonable doubt and clearly it offers a potential causal link with stroke. Even after statistical adjustment for hypertension, however, several studies still support an association between OSA and stroke. Various alternative mechanisms related to demonstrated abnormalities in patients with OSA have been suggested. These include abnormal cerebral haemodynamics,12 increased platelet aggregability,13 increased fibrinogen concentration,14 increased blood viscosity,15 and abnormal vascular endothelial function.16 On the other hand, snoring alone, without other features of OSA, appears to carry little if any excess risk.17
Although the weight of evidence favouring OSA as an independent risk factor for stroke is suggestive, cross sectional studies can never give a definitive result. Confirmation awaits the full publication of large prospective studies which are currently in progress. Preliminary data from one such study, published so far only as an abstract,18 support the conclusion that OSA is a risk factor for the development of stroke or transient ischaemic attack (TIA), independently of sex, body mass index, diabetes, and hypertension.
SDB AFTER STROKE
Complementing these studies of the risk of stroke associated with OSA, several others have shown a high prevalence of SDB after stroke.19–26 Most have been observational with no control group, an important omission in light of the high frequency of apnoeas and hypopnoeas in apparently healthy elderly subjects.27 However, three studies which included small age matched control groups20,21,28 each showed a significantly higher apnoea-hypopnoea index (AHI) in the stroke patients. On the other hand, a recent study29 comparing patients with TIA and individually matched controls showed no difference in AHI, although the frequency of nocturnal desaturation >4% was greater in the patient group. Two reports of sequential sleep studies after stroke showed a significant reduction in AHI 2–3 months later,23,24 although in a third study,30 based on oximetry only, there was no change in the desaturation index in stroke survivors restudied 3 months after the event.
Are these observations merely of curiosity value or might SDB adversely affect the outcome of stroke? In the current issue of Thorax Turkington et al31 add further evidence that this may indeed be the case. In an earlier study of a small number of patients Good et al19 showed that a higher nocturnal desaturation index was associated with greater mortality and more severe disability in survivors 12 months after the event. More recently, Iranzo et al32 studied patients during the first night after a stroke and found that a high AHI was associated with early neurological deterioration, although this did not correlate with disability 6 months later. The study by Turkington et al has the advantage of including a larger and less selected population, which is broadly typical of patients with stroke admitted to hospital in the UK; they were generally older and more disabled than those included in many of the previous studies performed in neurological or rehabilitation units. Turkington et al showed clear relations between SDB in the first 24 hours after stroke and length of hospital stay, mortality, and greater dependency of survivors 6 months later. Another recent study26 of younger patients in a rehabilitation unit also reported that SDB 6 weeks after a stroke was independently associated with longer hospital stay and greater long term functional impairment.
POSSIBLE MECHANISMS
Why then might subjects with OSA fare particularly badly after stroke? Several of the pathophysiological features accompanying OSA have also been associated with an adverse outcome in stroke populations. These include:
Large fluctuations of blood pressure and the consequent effects on cerebral blood flow: in OSA repeated elevation of blood pressure, sometimes to an alarming degree, is seen at the termination of each apnoea.33 In stroke patients a greater variation in blood pressure correlates with both increased mortality and greater dependency.34
Baroceptor dysfunction has been reported in OSA35 and impaired cardiac baroceptor sensitivity is associated with higher mortality after stroke.36
Recurrent hypoxaemia associated with frequent apnoeas is another obvious candidate. This might have a critical effect on the "ischaemic penumbra" surrounding the infarcted brain and might result in extension of the neurological damage.
Alternating hypoxaemia and reoxygenation accompanying OSA is associated with increased release of superoxides from neutrophils37 which might have an adverse effect after stroke in light of evidence from animal stroke models.38
Inflammatory and proinflammatory markers and mediators such as C reactive protein39 and adhesion molecules40 are increased in OSA while, in stroke, inflammatory changes are increasingly recognised as possibly contributing to injury of vulnerable brain tissue.41
Clearly, therefore, there are many similarities between the pathophysiological changes which accompany OSA and factors which influence the outcome of stroke. Further work will be required to tease out which of the above are likely to be most relevant to the associations shown by Turkington et al.31
Most of the features associated with more severe SDB after stroke are consistent with pre-existing OSA. These include a history of snoring22,42 or sleepiness28,30 and greater body mass index21,22,25 and neck circumference.22,25 Also relevant is an earlier case-control study43 which showed a clear dose-response relationship between the reported severity of pre-stroke snoring and mortality 6 months after a stroke. On the other hand, there is little apparent relation between SDB and the characteristics of a recent stroke such as its clinical severity24–26,30 or location,23,26,32 or the extent of acute changes visible on CT scanning.44 SDB is, however, more severe in patients with the lacunar syndrome24,30 which is closely related to hypertension, and in those with CT evidence of chronic cerebrovascular disease.44
Taken together, a unifying hypothesis arising from these various studies would be that patients with pre-existing OSA have an increased risk, not only of developing stroke but also of an adverse outcome in terms of both mortality and disability. Such individuals may be more likely to show exaggerated SDB after a stroke and a consequent poor outcome.
CLINICAL IMPLICATIONS
Are these findings merely of theoretical interest or might they have practical relevance? The most obvious therapeutic implication relates to the potential value of treating OSA after a stroke with continuous positive airway pressure (CPAP). Although one study reported that some younger patients during rehabilitation after stroke will tolerate CPAP,45 our experience, like that of others studying a more representative older population,46,47 has been more pessimistic. If CPAP is to influence the outcome of stroke by limiting ischaemic damage to the vulnerable areas of brain in the "penumbra", it seems likely that its optimal timing would be very soon after the event. However, the practicalities of introducing such unfamiliar treatment to elderly, disabled, and sometimes confused patients in an acute hospital ward or stroke unit are such that the widespread applicability of CPAP after a stroke is unlikely. It may, nonetheless, have a role in selected individuals. Hui et al47 found that the small minority of patients who tolerated CPAP shortly after a stroke had symptoms suggesting pre-existing OSA. This conclusion concurs with studies of patients with OSA in whom compliance with CPAP is better in those with more severe symptoms, particularly daytime sleepiness.48 In practice, of course, stroke patients with features of pre-existing OSA may be the very ones to target for CPAP therapy if, as suggested above, the adverse prognosis associated with SDB following stroke is due mainly to pre-stroke OSA.
ACKNOWLEDGEMENTS
The author thanks Professor G A Ford for helpful discussion.
REFERENCES
Cheyne J. A case of apoplexy in which the fleshy part of the heart was converted into fat. Dublin Hospital Reports 1818;2:216–23.
Harbison JA, Gibson GJ. Snoring, sleep apnoea and stroke: chicken or scrambled egg? Q J Med 2000;93:647–54.
Mohsenin V. Sleep-related breathing disorders and risk of stroke. Stroke 2001;32:1271–8.
Neau JP, Paquereau J, Meurice JC, et al. Stroke and sleep apnoea: cause or consequence? Sleep Med Rev 2002;6:457–69.
Yaggi H, Mohsenin V. Sleep-disordered breathing and stroke. Clin Chest Med 2003;24:223–37.
Partinen M, Palomaki H. Snoring and cerebral infarction. Lancet 1985;ii:1325–6.
Koskenvuo M, Kaprio J, Telakivi T, et al. Snoring as a risk factor for ischaemic heart disease and stroke in men. BMJ 1987;294:16–9.
Spriggs DA, French JM, Murdy JM, et al. Historical risk factors for stroke: a case control study. Age Ageing 1990;19:280–7.
Palomaki H. Snoring and the risk of ischemic brain infarction. Stroke 1991;22:1021–5.
Smirne S, Palazzi S, Zucconi M, et al. Habitual snoring as a risk factor for acute vascular disease. Eur Respir J 1993;6:1357–61.
Neau JP, Meurice JC, Paquereau J, et al. Habitual snoring as a risk factor for brain infarction. Acta Neurol Scand 1995;92:63–8.
Franklin KA. Cerebral haemodynamics in obstructive sleep apnoea and Cheyne-Stokes respiration. Sleep Med Rev 2002;6:429–41.
Sanner BM, Konermann M, Tepel M, et al. Platelet function in patients with obstructive sleep apnoea syndrome. Eur Respir J 2000;16:648–52.
Wessendorf TE, Thilmann AF, Wang YM, et al. Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med 2000;162:2039–42.
Nobili L, Schiavi G, Bozano E, et al. Morning increase of whole blood viscosity in obstructive sleep apnea syndrome. Clin Hemorheol Microcirc 2000;22:21–7.
Kato M, Roberts-Thompson P, Phillips B, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102:2607–10.
Davies DP, Rodgers H, Walshaw D, et al. Snoring, daytime sleepiness and stroke: a case-control study of first-ever stroke. J Sleep Res 2003;12:313–8.
Yaggi K, Kernan W, Mohsenin V. The association between obstructive sleep apnea and stroke. Am J Respir Crit Care Med 2003;167:A173.
Good DC, Henkle JQ, Gelber D, et al. Sleep-disordered breathing and poor functional outcome after stroke. Stroke 1996;27:252–9.
Dyken ME, Somers VK, Yamada T, et al. Investigating the relationship between stroke and obstructive sleep apnea. Stroke 1996;27:401–7.
Bassetti C, Aldrich MS. Sleep apnea in acute cerebrovascular diseases: final report on 128 patients. Sleep 1999;22:217–23.
Wessendorf TE, Teschler H, Wang YM, et al. Sleep-disordered breathing among patients with first-ever stroke. J Neurol 2000;247:41–7.
Parra O, Arboix A, Bechich S, et al. Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med 2000;161:375–80.
Harbison J, Ford GA, James OFW, et al. Sleep-disordered breathing following acute stroke. Q J Med 2002;95:741–7.
Turkington PM, Bamford J, Wanklyn P, et al. Prevalence and predictors of upper airway obstruction in the first 24 hours after acute stroke. Stroke 2002;33:2037–42.
Kaneko Y, Hajek VE, Zivanovic V, et al. Relationship of sleep apnea to functional capacity and length of hospitalization following stroke. Sleep 2003;26:293–7.
ty-dwelling elderly. Sleep 1991;14:486–95.
Nasr-Wyler A, Bouillanne O, Lalhou A, et al. Syndrome d’apnees du sommeil et accident vasculaire cerebral dans une population agee. Rev Neurol (Paris) 1999;155:1057–62.
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 ischaemic attacks. Stroke 2003;34:2916–21.
Lawrence E, Dundas R, Higgens S, et al. The natural history and associations of sleep disordered breathing in first ever stroke. Int J Clin Pract 2001;55:584–8.
Turkington PM, Allgar V, Bamford J, et al. Effect of upper airway obstruction in acute stroke on functional outcome at 6 months. Thorax 2004;59:367–71.
Iranzo A, Santamaria J, Berenguer J, et al. Prevalence and clinical importance of sleep apnea in the first night after cerebral infarction. Neurology 2002;58:911–6.
Shepard JW. Gas exchange and hemodynamics during sleep. Med Clin North Am 1985;69:1234–64.
Dawson SL, Manktelow BN, Robinson TG, et al. Which parameters of beat-to-beat blood pressure and variability best predict early outcome after acute ischemic stroke? Stroke 2000;31:463–8.
Belozeroff V, Berry RB, Khoo MC. Model-based assessment of autonomic control in obstructive sleep apnea syndrome. Sleep 2003;26:65–73.
Robinson TG, Dawson SL, Eames PJ, et al. Cardiac baroreceptor sensitivity predicts long-term outcome after acute ischemic stroke. Stroke 2003;34:705–12.
Schulz R, Mahmoudi S, Hattar K, et al. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Am J Respir Crit Care Med 2000;162:566–70.
Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 2001;21:2–14.
Shamsuzzaman ASM, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105:2462–4.
Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002;165:934–9.
del Zoppo G, Ginis I, Hallenbeck JM, et al. Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 2000;10:95–112.
Cherkassky T, Oksenberg A, Froom P, et al. Sleep-related breathing disorders and rehabilitation outcome of stroke patients. A prospective study. Am J Phys Med Rehabil 2003;82:452–5.
Spriggs DA, French JM, Murdy JM, et al. Snoring increases the risk of stroke and adversely affects prognosis. Q J Med 1992;83:555–62.
Harbison J, Gibson GJ, Birchall D, et al. White matter disease and sleep-disordered breathing after acute stroke. Neurology 2003;61:959–63.
Wessendorf TE, Wang YM, Thilmann AF, et al. Treatment of obstructive sleep apnoea with nasal continuous positive airway pressure in stroke. Eur Respir J 2001;18:623–9.
Sandberg O, Franklin KA, Bucht G, et al. Nasal continuous positive airway pressure in stroke patients with sleep apnoea: a randomised treatment study. Eur Respir J 2001;18:630–4.
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