- Email: [email protected]
Cerebral circulation and sleep
Sleep Medicine Reviews, Vol. 6, No. 6, pp 425±427, 2002 doi:10.1053/smrv.2002.0259, available online at http://www.idealibrary.com on
GUEST EDITORIAL
Cerebral circulation and sleep Dirk M. Hermann and Claudio L. Bassetti Department of Neurology, University Hospital, Zurich-Switzerland
Already Aristoteles discussed on restorative functions of sleep (cf. [1]). BorbeÂly [2] was the ®rst to show that the restorative function of sleep correlates to a reduction of homeostatic pressure built up during the day that can be assessed by the slow wave activity of the sleep electroencephalogram (EEG). The observation of a fronto-occipital power gradient in the EEG slow wave activity [3] points towards the existence of topographical differences in homeostatic functions of sleep. In accord with these electrophysiological data, recent studies with various techniques including positron emission tomography (PET) [4±6], functional magnetic resonance imaging (MRI) [8, 9] and laser Doppler ¯owmetry (LDF) [10, 11] have demonstrated profound changes of cerebral blood ¯ow (CBF) in various brain structures throughout the sleep-wake cycle. Based on the assumption that CBF is closely coupled with cerebral metabolism in the healthy brain these perfusion changes are thought to re¯ect modi®cations in the tissue metabolic state. Three review articles in this journal summarize our present state of knowledge about cerebral hemodynamics during sleep in healthy humans [12] as well as in patients with sleep disordered breathing [13] and cerebrovascular diseases [14]. In their review, Zaccoli et al. [12] ®rst summarize several studies (mainly with PET) demonstrating absolute and region-speci®c CBF changes during wakefulness, NREM and REM sleep as well as throughout the night [4±6]. While recognizing divergences in the results of these studies, the authors stress the Correspondence should be addressed to: Prof. Claudio L. Bassetti, Department of Neurology, University Hospital of Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland. Tel.: (41) 1 255 5526; Fax: (41) 1 255 4649; E-mail: [email protected]
consistent observations that CBF is lower (1) in NREM sleep (versus REM sleep), (2) at the end of the night (versus at the beginning of the night), (3) in the post-sleep wakefulness (versus pre-sleep wakefulness). Zoccoli et al. conclude that these observations are in line with the hypothesis of a restorative function of sleep and particularly of NREM sleep. Along this line, a link between slow wave activity, reduced metabolic demand and diminished CBF is suggested. Since the basic assumption that reduced CBF corresponds to inhibitory neuronal activity has recently been questioned by a functional MRI study [7], the conclusions of the reviewed PET data should, however, be considered with some caution. A better de®nition of the resting state against which PET data in sleep are compared to as well as new functional neuroimaging studies analysing not only CBF but also brain metabolism correlates are needed to clarify this important issue. After the presentation of additional data obtained with functional MRI, LDF, radioactive microspheres and spectro-photometry, Zaccoli et al. [12] focus the second part of their review on how cerebral circulation changes may be induced during sleep. The authors mention that principal regulators of blood ¯ow, i.e., PaO2 and PaCO2, are only mildly altered during sleep and that these variables are therefore unlikely to be responsible for sleep-wake changes in brain perfusion. Subsequently, the authors discuss aspects of ¯owmetabolism coupling with respect to diffusion limitations of glucose and oxygen as primary neuronal energy substrates. Their hypothesis that localized hypoxic microregions at mid-distance between capillaries might trigger perfusion changes is certainly tempting, it does however not explain how the postulated hypoxic signals might reach back to the vasculature. The authors recognize that this question remains unanswered and stress the need of a more
1087±0792/02/$ ± see front matter & 2002 Elsevier Science Ltd. All rights reserved.
426
detailed analysis on the role of oxygen in metabolic coupling, on quanti®cation of aerobic and anaerobic glycolysis, and on blood-brain barrier disturbances. In a second article, Franklin [13] reviews studies on cerebral and cardiovascular changes associated with sleep-disordered breathing. The author ®rst points to the almost unanymous observation of an increased CBF during apneas and a decreased CFB following the resumption of breathing. It follows a discussion on the mechanisms possibly involved in these changes. The author refers to a large number of transcranial LDF studies, including those by KlingelhoÈfer et al. [15] and Balfors and Franklin [16], supporting the hypothesis that sharp swings in blood pressure may be the main reason for the overruling of cerebral autoregulation observed during obstructive respiratory events. Franklin subsequently suggests that a compromised vasomotor activity ± that is detectable also during wakefulness by means of transcranial LDF, SPECT and magnetic resonance spectroscopy ± could also contribute to changes of cerebral perfusion in OSA [17, 18]. He makes use of the latter point to explain the elevated risk of stroke in the early morning hours, although even in patients with OSA most cerebrovascular accidents appear not to occur during sleep [19]. In the second part of his review, Franklin [13] discusses the course of CBF± decrease during respiratory events, increase thereafter± associated with sleep disordered breathing of central type including CheyneStokes respiration (CSR). As opposed to sleep disordered breathing of obstructive type, changes of cerebral activity (arousal level) rather than blood pressure swings are thought to explain these CBF modi®cations. Although the author is probably right in concluding that obstructive respiratory events are associated with more pronounced and hazardous cardiovascular effects, one should keep in mind that (1) the CBF data reviewed are limited and somewhat contradictory [20], (2) the pathophysiology of central sleep apnea syndromes and particularly CSR is heterogeneous, and (3) central and obstructive respiratory events can coexist in single patients [21]. In the last review paper, Neau et al. [14] address the question about the nature of the link between stroke and sleep disordered breathing, which has been found in a signi®cant proportion of patients with cerebrovascular diseases. The authors ®rst summarize the data suggesting that sleep disordered breathing may be both a risk factor for stroke but also a direct consequence of acute brain damage (e.g. central sleep apnea syndromes following brainstem stroke). In the second part of the review, data supporting the hypothesis of a
D. M. HERMANN AND C. L. BASSETTI
cause-effect relationship between OSA and arterial hypertension [22, 23], cardiac arrhythmias [24] and atherosclerosis [25] are presented. The authors mention overactivity of the sympathetic nervous system, impairment of vascular endothelial function (e.g., due to impairment of the nitric oxide synthetase pathway), prothrombotic coagulation changes, and modi®cation of CBF as principal mediators of the adverse cardiovascular effects of OSA. As referred to also by Neau et al., important issues regarding the relationship between sleep disordered breathing and cerebrovascular diseases remain however to be clari®ed. First, do patients with polysomnographically proven OSA have an elevated cerebrovascular morbidity and mortality that is independent from the associated vascular risk pro®le? So-far only studies based on history of snoring support the hypothesis of sleep disordered breathing as independent and signi®cant vascular risk factor. Second, does the presence of sleep disordered breathing have a negative impact on stroke outcome? A recent study [26] brought ®rst arguments along this line. Third, does a continuous positive airway pressure (CPAP) treatment affect risk of recurrence and/or clinical outcome in stroke patients with OSA? In conclusion, the reader of these three review articles can realize the considerable progress made during the last few years in our understanding about hemodynamic changes throughout the sleep-wake cycle as well as in association with sleep disordered breathing. More studies and probably also methodological improvements are however needed to better elucidate some of the physio- and pathophysio-logical mechanisms described and to understand the ``true'' clinical relevance that sleep disordered breathing has as both a risk factor and a consequence of cardio- and cerebro-vascular diseases.
REFERENCES 1. Wittern R. Sleep theories in the antiquity and the renaissance. In: Horne J (ed.) Sleep 88, Stuttgart: Fischer Verlag; 1989 11±22. 2. BorbeÂly AA. A two process model of sleep regulation. Hum Neurobiol 1982; 1(3): 195±204. 3. Werth E, Achermann P, Borbely AA. Fronto-occipital EEG power gradients in human sleep. J Sleep Res 1997; 6(2): 102±112. 4. Maquet P, Peters JM, Aerts J, Del®ore G, Degueldre C, Luxen A, Franck G. Functional neuroanatomy of human rapid-eye-movement sleep and dreaming. Nature 1996; 383(6596): 163±166.
CEREBRAL CIRCULATION AND SLEEP 5. Maquet P, Degueldre C, Del®ore G, Aerts J, Peters JM, Luxen A, Franck G. Functional neuroanatomy of human slow wave sleep. J Neurosci 1997; 17(8): 2807±2812. 6. Braun AR, Balkin TJ, Wesensten NJ et al. CBF throughout the sleep-wake cycle ± an (H2O)-O-15 PET study. Brain 1997; 120(Part 7): 1173±1197. 7. Waldvogel D, van Gelderen P, Muellbacher W, Ziemann U, Immisch I, Hallett M. The relative metabolic demand of inhibition and excitation. Nature 2000; 406(6799): 995±998. 8. LoÈvblad KO, Thomas R, Jakob PM et al. Silent functional magnetic resonance imaging demonstrates focal activation in rapid eye movement sleep. Neurology 1999; 53(9): 2193±2195. 9. Portas CM, Krakow K, Allen P, Josephs O, Armony JL, Frith CD. Auditory processing across the sleep-wake cycle: Simultaneous EEG and fMRI monitoring in humans. Neuron 2000; 28(3): 991±999. 10. Droste DW, Berger W, Schuler E, Krauss JK. Middle cerebral artery blood ¯ow velocity in healthy persons during wakefulness and sleep: a transcranial Doppler study. Sleep 1999; 16(7): 603±609. 11. Hajak G, Klingelhofer J, Schulz-Varszegi M, Matzander G, Sander D, Conrad B, Ruther E. Relationship between cerebral blood ¯ow velocities and cerebral electrical activity in sleep. Sleep 1994; 17(1): 11±19. 12. Zoccoli G, Walker AM, Lenzi P, Franzini C. The cerebral circulation during sleep: Regulation mechanisms and functional implications. Sleep Med Rev 2002; 6(6): 442±455. 13. Franklin KA. Cerebral hemodynamics in obstructive sleep apnea and Cheyne-Stokes respiration. Sleep Med Rev 2002; 6(6): 429±441. 14. Neau JP, Paquereau J, Meurice JC, Chavagnat JJ, Gil R. Stroke and sleep apnea. Cause or consequence? Sleep Med Rev 2002; 6(6): 455±468. 15. Klingelhofer J, Hajak G, Sander D, Schulz-Varszegi M, Ruther E, Conrad B. Assessment of intracranial hemodynamics in sleep apnea syndrome. Stroke 1992; 23(10): 1427±1433. 16. Balfors EM, Franklin KA. Impairment of cerebral perfusion during obstructive sleep apneas. Am J Resp Crit Care Med 1994; 150(6 Pt 1): 1587±1591.
427 17. Placidi F, Diomedi M, Cupini LM, Bernardi G, Silvestrini M. Impairment of daytime cerebrovascular reactivity in patients with obstructive sleep apnoea syndrome. J Sleep Res 1998; 7(4): 288±292. 18. Qureshi AI, Christopher Winter W, Bliwise DL. Sleep fragmentation and morning cerebrovasomotor reactivity to hypercapnia. Am J Resp Crit Care Med 1999; 160(4): 1244±1247. 19. Bassetti C, Aldrich M. Night time versus daytime transient ischemic attack and ischemic stroke: A prospective study of 110 patients. J Neurol Neurosurg Psychiatry 1999; 67: 463±467. 20. Netzer N, Werner P, Jochums I, Lehmann M, Strohl KP. Blood ¯ow of the middle cerebral artery with sleepdisordered breathing ± correlation with obstructive hypopneas. Stroke 1998; 29(1): 87±93. 21. Bassetti C, Aldrich MS, Quint D. Sleep-disordered breathing in patients with acute supra- and infratentorial strokesÐa prospective study of 39 patients. Stroke 1997; 28(9): 1765±1772. 22. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. New Engl J Med 2000; 342(19): 1378±1384. 23. Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 2000; 320(7233): 479±482. 24. 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(5): 490±494. 25. Friedlander AH, Friedlander IK, Yueh R, Littner MR. The prevalence of carotid atheromas seen on panoramic radiographs of patients with obstructive sleep apnea and their relation to risk factors for atherosclerosis. J Oral Maxillofac Surg 1999; 57(5): 516±521. 26. Iranzo A, Santamaria J, Berenguer J, Sanchez M, Chamorro A. Prevalence and clinical importance of sleep apnea in the ®rst night after cerebral infarction. Neurology 2000; 58: 911±916.
GUEST EDITORIAL
Cerebral circulation and sleep Dirk M. Hermann and Claudio L. Bassetti Department of Neurology, University Hospital, Zurich-Switzerland
Already Aristoteles discussed on restorative functions of sleep (cf. [1]). BorbeÂly [2] was the ®rst to show that the restorative function of sleep correlates to a reduction of homeostatic pressure built up during the day that can be assessed by the slow wave activity of the sleep electroencephalogram (EEG). The observation of a fronto-occipital power gradient in the EEG slow wave activity [3] points towards the existence of topographical differences in homeostatic functions of sleep. In accord with these electrophysiological data, recent studies with various techniques including positron emission tomography (PET) [4±6], functional magnetic resonance imaging (MRI) [8, 9] and laser Doppler ¯owmetry (LDF) [10, 11] have demonstrated profound changes of cerebral blood ¯ow (CBF) in various brain structures throughout the sleep-wake cycle. Based on the assumption that CBF is closely coupled with cerebral metabolism in the healthy brain these perfusion changes are thought to re¯ect modi®cations in the tissue metabolic state. Three review articles in this journal summarize our present state of knowledge about cerebral hemodynamics during sleep in healthy humans [12] as well as in patients with sleep disordered breathing [13] and cerebrovascular diseases [14]. In their review, Zaccoli et al. [12] ®rst summarize several studies (mainly with PET) demonstrating absolute and region-speci®c CBF changes during wakefulness, NREM and REM sleep as well as throughout the night [4±6]. While recognizing divergences in the results of these studies, the authors stress the Correspondence should be addressed to: Prof. Claudio L. Bassetti, Department of Neurology, University Hospital of Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland. Tel.: (41) 1 255 5526; Fax: (41) 1 255 4649; E-mail: [email protected]
consistent observations that CBF is lower (1) in NREM sleep (versus REM sleep), (2) at the end of the night (versus at the beginning of the night), (3) in the post-sleep wakefulness (versus pre-sleep wakefulness). Zoccoli et al. conclude that these observations are in line with the hypothesis of a restorative function of sleep and particularly of NREM sleep. Along this line, a link between slow wave activity, reduced metabolic demand and diminished CBF is suggested. Since the basic assumption that reduced CBF corresponds to inhibitory neuronal activity has recently been questioned by a functional MRI study [7], the conclusions of the reviewed PET data should, however, be considered with some caution. A better de®nition of the resting state against which PET data in sleep are compared to as well as new functional neuroimaging studies analysing not only CBF but also brain metabolism correlates are needed to clarify this important issue. After the presentation of additional data obtained with functional MRI, LDF, radioactive microspheres and spectro-photometry, Zaccoli et al. [12] focus the second part of their review on how cerebral circulation changes may be induced during sleep. The authors mention that principal regulators of blood ¯ow, i.e., PaO2 and PaCO2, are only mildly altered during sleep and that these variables are therefore unlikely to be responsible for sleep-wake changes in brain perfusion. Subsequently, the authors discuss aspects of ¯owmetabolism coupling with respect to diffusion limitations of glucose and oxygen as primary neuronal energy substrates. Their hypothesis that localized hypoxic microregions at mid-distance between capillaries might trigger perfusion changes is certainly tempting, it does however not explain how the postulated hypoxic signals might reach back to the vasculature. The authors recognize that this question remains unanswered and stress the need of a more
1087±0792/02/$ ± see front matter & 2002 Elsevier Science Ltd. All rights reserved.
426
detailed analysis on the role of oxygen in metabolic coupling, on quanti®cation of aerobic and anaerobic glycolysis, and on blood-brain barrier disturbances. In a second article, Franklin [13] reviews studies on cerebral and cardiovascular changes associated with sleep-disordered breathing. The author ®rst points to the almost unanymous observation of an increased CBF during apneas and a decreased CFB following the resumption of breathing. It follows a discussion on the mechanisms possibly involved in these changes. The author refers to a large number of transcranial LDF studies, including those by KlingelhoÈfer et al. [15] and Balfors and Franklin [16], supporting the hypothesis that sharp swings in blood pressure may be the main reason for the overruling of cerebral autoregulation observed during obstructive respiratory events. Franklin subsequently suggests that a compromised vasomotor activity ± that is detectable also during wakefulness by means of transcranial LDF, SPECT and magnetic resonance spectroscopy ± could also contribute to changes of cerebral perfusion in OSA [17, 18]. He makes use of the latter point to explain the elevated risk of stroke in the early morning hours, although even in patients with OSA most cerebrovascular accidents appear not to occur during sleep [19]. In the second part of his review, Franklin [13] discusses the course of CBF± decrease during respiratory events, increase thereafter± associated with sleep disordered breathing of central type including CheyneStokes respiration (CSR). As opposed to sleep disordered breathing of obstructive type, changes of cerebral activity (arousal level) rather than blood pressure swings are thought to explain these CBF modi®cations. Although the author is probably right in concluding that obstructive respiratory events are associated with more pronounced and hazardous cardiovascular effects, one should keep in mind that (1) the CBF data reviewed are limited and somewhat contradictory [20], (2) the pathophysiology of central sleep apnea syndromes and particularly CSR is heterogeneous, and (3) central and obstructive respiratory events can coexist in single patients [21]. In the last review paper, Neau et al. [14] address the question about the nature of the link between stroke and sleep disordered breathing, which has been found in a signi®cant proportion of patients with cerebrovascular diseases. The authors ®rst summarize the data suggesting that sleep disordered breathing may be both a risk factor for stroke but also a direct consequence of acute brain damage (e.g. central sleep apnea syndromes following brainstem stroke). In the second part of the review, data supporting the hypothesis of a
D. M. HERMANN AND C. L. BASSETTI
cause-effect relationship between OSA and arterial hypertension [22, 23], cardiac arrhythmias [24] and atherosclerosis [25] are presented. The authors mention overactivity of the sympathetic nervous system, impairment of vascular endothelial function (e.g., due to impairment of the nitric oxide synthetase pathway), prothrombotic coagulation changes, and modi®cation of CBF as principal mediators of the adverse cardiovascular effects of OSA. As referred to also by Neau et al., important issues regarding the relationship between sleep disordered breathing and cerebrovascular diseases remain however to be clari®ed. First, do patients with polysomnographically proven OSA have an elevated cerebrovascular morbidity and mortality that is independent from the associated vascular risk pro®le? So-far only studies based on history of snoring support the hypothesis of sleep disordered breathing as independent and signi®cant vascular risk factor. Second, does the presence of sleep disordered breathing have a negative impact on stroke outcome? A recent study [26] brought ®rst arguments along this line. Third, does a continuous positive airway pressure (CPAP) treatment affect risk of recurrence and/or clinical outcome in stroke patients with OSA? In conclusion, the reader of these three review articles can realize the considerable progress made during the last few years in our understanding about hemodynamic changes throughout the sleep-wake cycle as well as in association with sleep disordered breathing. More studies and probably also methodological improvements are however needed to better elucidate some of the physio- and pathophysio-logical mechanisms described and to understand the ``true'' clinical relevance that sleep disordered breathing has as both a risk factor and a consequence of cardio- and cerebro-vascular diseases.
REFERENCES 1. Wittern R. Sleep theories in the antiquity and the renaissance. In: Horne J (ed.) Sleep 88, Stuttgart: Fischer Verlag; 1989 11±22. 2. BorbeÂly AA. A two process model of sleep regulation. Hum Neurobiol 1982; 1(3): 195±204. 3. Werth E, Achermann P, Borbely AA. Fronto-occipital EEG power gradients in human sleep. J Sleep Res 1997; 6(2): 102±112. 4. Maquet P, Peters JM, Aerts J, Del®ore G, Degueldre C, Luxen A, Franck G. Functional neuroanatomy of human rapid-eye-movement sleep and dreaming. Nature 1996; 383(6596): 163±166.
CEREBRAL CIRCULATION AND SLEEP 5. Maquet P, Degueldre C, Del®ore G, Aerts J, Peters JM, Luxen A, Franck G. Functional neuroanatomy of human slow wave sleep. J Neurosci 1997; 17(8): 2807±2812. 6. Braun AR, Balkin TJ, Wesensten NJ et al. CBF throughout the sleep-wake cycle ± an (H2O)-O-15 PET study. Brain 1997; 120(Part 7): 1173±1197. 7. Waldvogel D, van Gelderen P, Muellbacher W, Ziemann U, Immisch I, Hallett M. The relative metabolic demand of inhibition and excitation. Nature 2000; 406(6799): 995±998. 8. LoÈvblad KO, Thomas R, Jakob PM et al. Silent functional magnetic resonance imaging demonstrates focal activation in rapid eye movement sleep. Neurology 1999; 53(9): 2193±2195. 9. Portas CM, Krakow K, Allen P, Josephs O, Armony JL, Frith CD. Auditory processing across the sleep-wake cycle: Simultaneous EEG and fMRI monitoring in humans. Neuron 2000; 28(3): 991±999. 10. Droste DW, Berger W, Schuler E, Krauss JK. Middle cerebral artery blood ¯ow velocity in healthy persons during wakefulness and sleep: a transcranial Doppler study. Sleep 1999; 16(7): 603±609. 11. Hajak G, Klingelhofer J, Schulz-Varszegi M, Matzander G, Sander D, Conrad B, Ruther E. Relationship between cerebral blood ¯ow velocities and cerebral electrical activity in sleep. Sleep 1994; 17(1): 11±19. 12. Zoccoli G, Walker AM, Lenzi P, Franzini C. The cerebral circulation during sleep: Regulation mechanisms and functional implications. Sleep Med Rev 2002; 6(6): 442±455. 13. Franklin KA. Cerebral hemodynamics in obstructive sleep apnea and Cheyne-Stokes respiration. Sleep Med Rev 2002; 6(6): 429±441. 14. Neau JP, Paquereau J, Meurice JC, Chavagnat JJ, Gil R. Stroke and sleep apnea. Cause or consequence? Sleep Med Rev 2002; 6(6): 455±468. 15. Klingelhofer J, Hajak G, Sander D, Schulz-Varszegi M, Ruther E, Conrad B. Assessment of intracranial hemodynamics in sleep apnea syndrome. Stroke 1992; 23(10): 1427±1433. 16. Balfors EM, Franklin KA. Impairment of cerebral perfusion during obstructive sleep apneas. Am J Resp Crit Care Med 1994; 150(6 Pt 1): 1587±1591.
427 17. Placidi F, Diomedi M, Cupini LM, Bernardi G, Silvestrini M. Impairment of daytime cerebrovascular reactivity in patients with obstructive sleep apnoea syndrome. J Sleep Res 1998; 7(4): 288±292. 18. Qureshi AI, Christopher Winter W, Bliwise DL. Sleep fragmentation and morning cerebrovasomotor reactivity to hypercapnia. Am J Resp Crit Care Med 1999; 160(4): 1244±1247. 19. Bassetti C, Aldrich M. Night time versus daytime transient ischemic attack and ischemic stroke: A prospective study of 110 patients. J Neurol Neurosurg Psychiatry 1999; 67: 463±467. 20. Netzer N, Werner P, Jochums I, Lehmann M, Strohl KP. Blood ¯ow of the middle cerebral artery with sleepdisordered breathing ± correlation with obstructive hypopneas. Stroke 1998; 29(1): 87±93. 21. Bassetti C, Aldrich MS, Quint D. Sleep-disordered breathing in patients with acute supra- and infratentorial strokesÐa prospective study of 39 patients. Stroke 1997; 28(9): 1765±1772. 22. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. New Engl J Med 2000; 342(19): 1378±1384. 23. Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 2000; 320(7233): 479±482. 24. 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(5): 490±494. 25. Friedlander AH, Friedlander IK, Yueh R, Littner MR. The prevalence of carotid atheromas seen on panoramic radiographs of patients with obstructive sleep apnea and their relation to risk factors for atherosclerosis. J Oral Maxillofac Surg 1999; 57(5): 516±521. 26. Iranzo A, Santamaria J, Berenguer J, Sanchez M, Chamorro A. Prevalence and clinical importance of sleep apnea in the ®rst night after cerebral infarction. Neurology 2000; 58: 911±916.