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1995 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation Patients suffering from cerebral infarction often complain of diffuse cerebral symptoms such as impaired memory, inability to concentrate, emotional instability, increased need of sleep, and tiredness. 1 These symptoms have been attributed, in large part, to structural damage to brain tissue. However, many of these symptoms are also noted in patients with sleep disturbances. 2 Indeed, stroke has a profound effect on sleep continuity and architecture because most of the anatomic structures that control sleep are located in the central nervous system. 34 Because the control centers for breathing and upper airway patency are located in the central nervous system as well, it is conceivable that lesions in this area may cause altered breathing pattern and impaired upper airway function during respiration. 6'7 It is not uncommon to encounter a variety of neurological disorders that affect sleep and breathing. It is important to understand not only that the neurological illnesses may affect sleep and breathing, but also that alterations of sleep and breathing may adversely affect the natural history of a neurological disorder. Because centers that control breathing and upper airway function are in the brainstem, lesions in this area have been associated with breathing disorders. 8'9 Lesions in the cerebral hemispheres have been shown to cause periodic breathing. 7'1
From the Pulmonary and Critical Care Section, Yale University School of Medicine, New Haven, CT; and Gaylord Hospital, Wallingford, CT. Submitted for publication May 31, 1994. Accepted in revised form September 8, 1994. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Vahid Mohsenin, MD, Pulmonary and Critical Care Section, Yale University School of Medicine, PO Box 208057, 333 Cedar Street, New Haven, CT 06520-8057. 1995 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003-9993/95/7601-309653.00/0
More recently, Kapen and colleagues reported a high incidence of obstructive sleep apnea in a group of patients with hemispheric stroke, tt However, because of lack of control for confounding factors such as obesity and presence of hypertension, a definite causal relationship between obstructive sleep apnea and stroke cannot be claimed. Because the implication of these findings in the care and management of patients with cerebral stroke could be extremely important, we sought to study patients with hemispheric stroke to define the effect of stroke on breathing pattern, oxygenation, and sleep architecture. We found a significant number of obstructive sleep apneas with marked arterial desaturations and sleep fragmentation compared with controls.
METHODS
Seventeen patients admitted to a rehabilitation unit with stroke were screened. They were evaluated on the basis of medical history, thorough neurological examination, and brain imaging using computed tomography scan, magnetic resonance imaging or cerebral arteriography. Patients with the prior history of habitual snoring, excessive daytime sleepiness, sleep apnea, obesity (greater than 30kg/m 2 body mass index [BMI]), brainstem stroke or other neurological disorders were excluded. Ten patients out of 17 fulfilled the inclusion criteria and hence were included in the study. We studied 10 additional patients without stroke who were matched for age, gender, and BMI and for the presence of hypertension and smoking as controls. Patients, bed-partners, and caregivers were interviewed for detailed sleep history and symptoms especially about snoring, possible pauses during sleep, daytime sleepiness, memory loss, cognitive function, and affective disorders before the stroke, t2 Polysomnography was performed between 9:00 PM and
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7:00 AM. Sleep state was recorded with one channel electroencephalogram (C3/A2 or C4/A1), two channels of electrooculogram, and one channel submental electromyogram (EMG). Breathing was assessed by monitoring chest wall and abdominal movements using bellow pneumographs, and nasal and oral flows using thermisters, a Arterial oxygen saturation was measured using a Biox oximeter, b Leg movements were monitored with two channels of EMG. An electrocardiogram was recorded continuously. All variables were recorded simultaneously and continuously on a 16-channel polygraph. Sleep recordings were scored in 30-second epochs and staged according to standard criteria. ~3 Calculated sleep variables were sleep stages as percentage of total sleep period time (SPT), arousal index, and sleep efficiency (total sleep time/SPT). Nocturnal sleep latency was calculated from "lights out" to the first three consecutive epochs of nonrapid eye movement (NREM) sleep or one epoch of rapid eye movement (REM) sleep. Calculated respiratory variables included respiratory disturbance index (respiratory disturbance index [RDI], the number of apneas and hypopneas per hour of sleep) and number find degree of arterial o2 desaturations. The respiratory events were defined according to the Diagnostic and Coding Manual of The International Classification of Sleep Disorders. 14 An apnea was defined as cessation of airflow for at least 10 seconds. An obstructive apnea was defined when cessation of airflow, for a minimum of 10 sec0nds, was associated with thoracoabdominal wall movements. Central apneas were defined as those without accompanying thoracoabdominal wall movements. Mixed apneas had both central and obstructive components and were included in the results as obstructive apneas. Hypopnea was defined as a reduction in amplitude of airflow or thoracoabdominal wall movement of greater than 50% of the baseline measurement for more than 10 seconds and accompanied by greater than 4% arterial o2 desaturation (no time limit).
Statistics
Comparisons between groups were performed using Wilcoxon's signed-ranks test. ~5 Data are reported as mean + SE. A p value of <.05 was considered significant.
RESULTS
The anthropometric characteristics and clinical features of patients with stroke and the control group are shown in table 1. Comparison of age, gender, BMI, smoking history, and the presence of hypertension between patients with stroke and controls showed no significant difference. None of the patients had prior history of habitual snoring, excessive daytime sleepiness, nocturnal sleep disruption, or sleep apnea, but both groups had a history of mild and nonhabitual snoring. Nine of the patients had thromboembolic stroke and one had fight basal ganglia bleed. Eight of the strokes were in the middle cerebral artery (MCA) distribution, one MCA and anterior cerebral artery (ACA), and one ACA. Six of the strokes were on the left side and four on the fight side. All patients had intact brainstem function and no evidence of lesion in this area on brain imaging. The risk factors for
stroke included hypertension in five, atrial fibrillation in one, and cigarette smoking in four. Table 2 and figure 1 show the effect of stroke on sleep architecture and arousals. The quality of sleep was generally poor with awake time accounting for 42% of SPT in stroke patients. The slow wave sleep (SWS) and REM sleep were significantly shorter in stroke patients than controls. The sleep latency, a measure of hypersonmolence, was within the normal range but shorter than the control group. The arousal index of stroke patients was significantly higher than the controls. Eight of the 10 patients with stroke were found to have significant sleep apnea (fig 2). The majority of patients had predominantly obstructive sleep apnea. Mixed apneas that were counted as obstructive apneas comprised a small fraction of apneas. Hypopneas and central apneas were infrequent except for patient AB who had predominantly central apneas. This patient had clinical features similar to other patients with a thrombotic stroke involving left frontoparietal region with right hemiparesis. The control subjects had few hypopneas and apneas with a normal respiratory disturbance index (RDI). There was no evidence for polysomnographic features of increased upper airway resistance ~6 in either group. The latter is a milder form of partial obstructive apnea where arousal is the predominant polysomnographic feature. Figure 3 shows the respiratory events expressed per hour sleep as RDI. The overall RDI in stroke patients was 52 _+ 10 events per hour sleep and was significantly higher than the control group of 3 _+ 1 per hour, p -- .007. To determine the effect of REM and NREM sleep on the respiratory disturbances, RDI was calculated for both sleep phases. The frequency of the respiratory events was higher in REM sleep than NREM sleep in both control and stroke patients indicating the worsening of sleep-disordered breathing in REM. The respiratory disturbances were associated with arterial oxygen desaturations as shown in figure 4. As a group, patients with stroke had 99 _+ 25 episodes of oxygen desaturations (greater than 4%) during the course of the night. There were 36 _+ 16 episodes between SaOz 85% to 89% and 6 + 3 episodes between SaO2 80% to 84%. Six percent of the oxygen desaturations were below SaO2 79%. The control patients who were either normal or had a mild chronic obstructive pulmonary disease or hypertension, had very few episodes of oxygen desaturation. DISCUSSION The results of this study show that patients with hemispheric stroke may develop sleep-disordered breathing. There are a few scattered reports of sleep complaints after stroke and several anecdotal and uncontrolled reports of sleep-related breathing disorders after cerebral infarction. Plum and coworkers noted that the major effect of cerebral hemispheric disease on respiration in sleep was in the form of Cheyne-Stokes respiration or long-cycle Cheyne-Stokes breathing associated with hypocapnia. 7'1'17'~8 The breathing pattern was attributed to heightened central responsiveness to c02. 7 On the other hand, Lee and coworkers found a Cheyne-Stokes pattern of breathing in patients with extensive bilateral pontine lesions. 19 Central apnea was noted as
SLEEP APNEA IN PATIENTS WITH STROKE, Mohsenin Table 1: Patients Characteristics and Clinical Features
Controls
FB CB SF AG LK WL MQ LB EG EH Mean SE Patients AM DG GB MM JR RP RO JK AB DZ Mean SE
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Age (yr)
55 49 47 56 66 64 35 27 78 62 54 5 58 78 51 33 68 50 61 72 44 41 56 5
Sex
F M M F M M M F F F --F F M M M M M M M M ---
BMI (Kg/m 2)
25.9 26.2 28.7 15.8 22.8 25.7 26.4 23.8 21.1 21.9 23.8 1.2 22.2 30 26.5 26.2 20.0 21.0 25.5 25.0 24.9 26.5 26.3 2.5
Site of Stroke
Clinical Features
Mild COPD Hypertension Normal Mild COPD Mild COPD Hypertension Normal Normal Mild COPD Hypertension --R hemiparesis L hemiparesis R hemlparesis R hemiparesis R hemiparesis L hemiparesis Expressive aphasia L hemiparesis R hemiparesis L hemi ~aresis
Other Problems
Smoking
Smoking None Seizures Smoking None Smoking Smoking --Coronary heart disease Hypertension None Smoking Smoking ARDS, smoking Hypertension Hypertension, smoking Hypertension Hypertension
L R L L L R L R L R
ACA MCA MCA MCA MCA MCA thalamic MCA MCA, A C A MCA
the predominant form of apnea in patients with brainstem lesionsY In contrast to these studies, Kapen and associates reported a high incidence of obstructive sleep apnea in hemispheric stroke patients, though, because of associated risk factors such as obesity and hypertension in most of these patients, a definite causal relationship between obstructive sleep apnea and stroke cannot be claimed, l~ In our casecontrol study, we excluded patients with previous complaints of sleep disorders and obesity and matched for the presence of hypertension. Our results confirm the report by Kapen and coworkers on the presence of obstructive sleep apnea in some patients with cerebral stroke. The fact that the pharyngeal airway is open during wakefulness but occludes during sleep implicates a neural component dependent on the state of vigilance. 2m2 We hypothesize two pathogenic mechanisms in the development of sleepbreathing abnormalities in patients with hemispheric stroke. One is the physiological effect of sleep on upper airway control and the second is the flaccidity of upper airway muscles as a result of stroke. The pharyngeal patency during
Table 2: Sleep Architecture and Arousal in Controls and Stroke Patients
Control
Sleep period time (SPT, min) Total sleep time (min) Sleep latency (min) Awake (% SPT) Stage I (% SPT) Stage II (% SPT) Stage I I I + IV (% SPT) REM (% SPT) Arousal index (/h) * p < .05 when compared with control. 356 271 22 26 8 45 9 14 20 _+ 21 _+ 26 _+ 6 _+ 4 _+ 1 _+ 3 -4- 2 _+ 2 _+ 3
Stroke
370 227 13 42 12 36 4 7 64 _+ 21 _+ 35 _+ 5 +_ 9 _+ 3 _+ 6 +_ 2* _+ 3* _+ 16"
wakefulness is, in large part, attributed to continual neuromuscular input by the higher nervous system, which controls the action of pharyngeal muscles and ensures a patent pharynx. During sleep, when this control of the pharyngeal airways by the higher nervous system is disrupted, the patency of the upper airway becomes compromisedY '23 However, when the activation of pharyngeal dilator muscles occurs, adequate airway lumen is promoted so no airway obstruction occurs in a healthy person. 24 The second and potentially important factor is the dimension of the upper airway itself. Narrowing of the upper airway by obesity, hypertrophy, of lymphatic tissue (tonsils and adenoids), and/or mucosal swelling reduces airway patencyY Because of bilateral upper motor neuron innervation of pharyngeal and laryngeal muscles from the corticobulbar pathways, a unilateral upper motor neuron lesion, such as in hemispheric cerebral stroke, should not cause any significant weakness of the muscle, however it has been shown that it may cause a transient contralateral loss of tone or weakness in these muscles. 26'27 In support of this, Robbins and coworkers showed that patients with hemispheric infarctions were more likely to exhibit pharyngeal muscle dysfunction with impaired swallowing. 28 The impaired upper airway control as a result of upper motor neuron dysfunction may be caused by a required and highly complex neuronal control of a nasopharyngeal and pharyngolaryngeal muscles. We speculate that the maintenance of upper airway tone and function requires a dual upper motor neuron control. The lack of optimal tone of the muscles may lead to a highly compliant upper airway with a propensity to narrowing and collapse. In hemispheric stroke with hemiplegia and, depending on the site and extent of the stroke, the patient may have dysarthria, dysphagia, tongue weakness, and palatal muscle weakness contralateral
74
60
i
(/3
I!
_._J
F ] Control CVA
x "~ ~D
8070-
[]
[]
=o 605o-
=g
i:~
40-
30e-~ rr 20-
13-
Awake
Stage 1
Stage 2
SWS
REM
Control
CVA
Fig 1 - - S l e e p architecture in patients with stroke and controls. Patients with stroke (CVA) had a significantly shorter SWS and REM sleep than the controls. *P < .05.
Fig 3 - - T h e RDI in controls and patients with stroke (CVA). The RDI was significantly higher in stroke patients than controis. P = .007 control versus CVA for all categories.
to the side of the upper motor neuron lesion. These abnormalities are more profound in patients with bilateral upper motor neuron lesions; however, they may occur, as in our patients with unilateral involvement. 29'3 The pseudobulbar and bulbar palsies predispose patients to obstructive apneas during sleep. When the physiological change, decreased upper airway muscle tone, occurs superimposed on a background of a narrowed pharyngeal lumen, severe narrowing or closure of the pharyngeal airway may occur during sleep. Because the activities of pharyngeal dilator muscles are virtually absent in REM sleep, this phenomenon would become more pronounced during REM sleep, as was shown in this study. Significant increases in systemic arterial pressure occur cyclically with episodes of apnea, and maximal elevation follows arousals and after the resumption of ventilation.
DZ AB- m JKF~3RP- E JRMMGB- 1--I DGAM0 , , , 5~0 100 150 Number of Respiratory Events 200 250
With apneas occurring in very close clusters continuously throughout the night, often in association with very severe oxygen desaturations, elevations may be extreme. 3~ Further, cerebral blood flow during sleep is more decreased in patients with apnea than controls. 32'33 Further, the global and regional cerebral perfusion is decreased in sleep apnea patients during even wakefulness, 33'34 suggesting altered cerebral blood flow autoregulatory mechanisms. Thus patients with stroke and sleep apnea with oxygen desaturations are at greater potential risk of repeated stroke or incomplete neurological recovery. Repeated episodes of apneas and oxygen desaturation can also cause multiple awakenings and arousals. Arousals to the fully awake state or stage shifts from a deeper to a lighter stage of sleep disrupt the sleep architecture, leading
120 ~
[]
Control CVA
._o lOO-
"////~
[] [] Obstructiveapnea Centralapnea Hypopnea
80-
a
~, X
"
-
4020
"5
.~
E ~ Z
Total
89-85%
84-80% 79-70%
<70%
Fig 2 - - T h e number and type of sleep-disordered breathing during the course of the night in patients with stroke. All but two patients had higher than 32 events, predominantly obstructive apneas, during the night.
Oxygen Saturation
Fig 4 - - T h e number and degree of arterial oxygen desaturations during sleep as a result of apneas and hypopneas in controis as well as patients with stroke.
75
to unrefreshing sleep and a state of chronic sleep deprivation. 35 The sleep architecture in our patients showed significantly shorter SWS and REM sleep when compared with controls. Giubilei and coworkers showed a marked reduction in REM sleep within 3 weeks of stroke. 4 In another study, Korner and colleagues noted marked attenuation of REM as well as SWS sleep in a group of patients with infarction in the territory of the middle cerebral artery. 3 Diffuse cerebral symptoms such as memory impairment, lack of concentration ability, lack of initiatives, depression, irritability, fatigue, and increased need of sleep are present in more than 50% of patients with cerebral infarction. 1 These symptoms are generally attributed to a structural brain damage. These symptoms are also shared by patients with sleep apnea. 2"36'37 The reversibility of intellectual impairment in patients with sleep apnea with continuous positive airway pressure treatment suggests that it has, at least in part, a functional rather than a structural o r i g i n . 3s'39 The present study has several unique and limiting features: (1) Our results are based on a select population presenting to a rehabilitation facility and therefore may not be generalized. Nevertheless, our findings are in agreement with a larger case series reported by Kapen and associates. I~ (2) There is a possibility that stroke patients may have had sleep apnea before their cerebrovascular accident despite a negative history for sleep-disordered breathing. The sensitivity of a clinical evaluation in identifying a person with sleep apnea is in the order of 80%. 4o Short of a longitudinal prospective study of a large cohort with no evidence for sleep-disordered breathing on polysomnography at baseline, the present casecontrolled study provides some evidence that sleep apnea may be a sequel to hemispheric stroke. (3) The prevalence of sleep apnea in stroke is unknown at the present time and requires a large cross-sectional study of patients with polysomnography. In conclusion, this study suggests that sleep-associated breathing disorders may be an additional clinical sequela in patients with hemispheric stroke. This may have an important implication in the rehabilitation potential of patients and future risk for cerebrovascular and cardiovascular events. Hence, we suggest that the symptoms and signs of sleep-disordered breathing should be actively sought in patients with hemispheric stroke and appropriate work-up be initiated. Future work is required to examine the effect of therapy of sleep-disordered breathing in patients with stroke on the rate of neuropsychiatric recovery from stroke.
Acknowledgment: The authors thank Robert Stein, MD, and Michael Collins, MD, for assistance in recruitment of patients and Thomas Whelan, RRT, RPSGT, for his technical assistance. References
1. Leegaard OF. Diffuse cerebral symptoms in convalescents from cerebral infarction and myocardial infarction. Acta Neurol Scand 1983;67:348-55. 2. Kales A, Caldwell AB, Cadieux RJ, Vela-Bueno A, Ruch LG, Mayes SD. Severe obstructive sleep apnea. II Associated psychopathology and psychosocial consequences. J Citron Dis 1985;38:427-34. 3. Korner E, Flooh E, Reinhart B, Wolf R, Ott E, Krenn W, Lechner H. Sleep alteration in ischemic stroke. Eur Neurol 1986; 25:104-10. 4. Giubilei F, Iannilli M, Vitale A, Pierallini A, Sacchetti ML, Antonini
G, Fieschi C. Sleep patterns in acute ischemic stroke. Acta Neurol Scand 1992;86:567-71. 5. Hobson JA, Lydic R, Baghdoyan HA. Evolving concepts of sleep cycle generation: From brain centers to neuronal populations. Behav Brain Sci 1986;9:371-448. 6. Pitts RF. The respiratory center and its descending pathways. J Comp Neurol 1940;72:605-25. 7. Plum F. Neurological integration of behavioral and metabolic control of breathing, In: Porter R, editor. Ciba Foundation Symposium on Breathing. Herine-Breuer Centenary Symposium. London: Churchill, 1970:159-81. 8. Askenasy JJM, Goldhammer I. Sleep apnea as a feature of bulbar stroke. Stroke 1988;19:637-9. 9. Heyman A, Birchfield RI, Sieker HO. Effects of bilateral cerebral infarction on respiratory center sensitivity. Neurology 1958;8:694-700. 10. Plum F, Brown HW. The effect on respiration of central nervous system disease. Ann NY Acad Sci 1963; 109:915-31. 11. Kapen S, Park A, Goldberg J. The incidence and severity of obstructive sleep apnea in ischemic cerebrovascular disease. Neurology 1991;41(suppl 1):125. 12. Folstein MF, Folstein SE, McHughPR. "Mini-mental state" apractical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189-98. 13. Rechschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: UCLA: NIH Publication no. 268, 1986. 14. Diagnostic Classification Steering Committee. Thorpy MJ, Chairman. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. Rochester, MN: American Sleep Disorders Association, 1990. 15. Bailar JC, Mosteller F. Medical uses of statistics. Waltham MA: N Engl J Med Books, 1986:237. 16. Guilleminault C, Stoohs R. Upper airway resistance syndrome. Sleep Res 1991;20:250. 17. Plum F, Brown HW. The effect on respiration of central nervous system disease. Ann NY Acad Sci 1963; 109:915-31. 18. Plum F. Breathlessness in neurologicai disease: The effects of neurological disease on the act of breathing. In: Howell JBL, Campbell EJM, editor. Breathlessness. Oxford: Blackwell Scientific, 1966:203-22. 19. Lee MC, Klassen AC, Heaney LM, Resch JA. Respiratory rate and pattern disturbances in acute brain stem infarction. Stroke 1976;7:3825. 20. North JB, Jennett S. Abnormal breathing patterns associated with acute brain damage. Arch Neurol 1974;31:338-44. 21. Safar P, Escarrga LA, Chang F. Upper airway obstruction in the unconscious patient. J Appl Physiol 1959; 14:760-4. 22. Remmers JE, DeGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978;44(6):9318. 23. Sherrey JH, Megirian D. Respiratory EMG activity of the posterior cricoarytenoid, cricothyroid and diaphragm muscles during sleep. Respir Physiol 1980;39:355-65. 24. Hwang JC, St John WM, Bartlett D Jr. Afferent pathways for hypoglossal and phrenic responses to changes in upper airway pressure. Respir Physiol 1984;55:341-54. 25. Suratt PM, McTier RF, Findley LJ, Pohl SL, Wilhoit SC. Changes in breathing and the pharynx after weight loss in obstructive sleep apnea. Chest 1987;92:631-7. 26. Brain WR, Walton JN. Brain's diseases of the nervous system. (7th ed.) London: Oxford University, 1969:20-4. 27. Holmes G. Introduction to clinical neurology. Edinburgh and London: Churchill Livingston, 1971:25. 28. Robbins JA, Levine RL. Swallowing after unilateral stroke of the cerebral cortex: Preliminary experience. Dysphagia 1988;3:11-7. 29. Warlow C. Handbook of Neurology. London: Blackwell Scientific Publications, 1991. 30. Palmer JB, DuChane AS. Rehabilitation of swallowing disorders due to stroke. Phys Med Rehab Clin North Am 1991;3:529-46. 31. Schroeder JS, Motta J, Gnilleminault C. Hemodynamic studies in sleep apnea. In: Gnilleminanlt C, Dement W, editors. Sleep Apnea Syndromes. New York: Liss, 1978:177-96. 32. Meyers JS, Sakai F, Karacan I, Derman S, Yamamoto M. Sleep apnea,
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