2.1 Sleep-disordered breathing (SDB) as a risk factor for ischemic stroke
The first controlled study of sleep related breathing disorders in cerebrovascular diseases were carried out in the 80s. They concerned the snoring as a risk factor for ischemic stroke. The first studies were published by a group of Palomaki (Partinen et al, 1985). They compared the incidence of snoring in 50 men with ischemic stroke with a control group. The study was retrospective with use of a standardized questionnaire. Patients were divided into groups of regularly snoring (every night), often and seldom. Polysomnographic studies were not performed. It was shown that the relative risk of ischemic stroke is 10.8 times higher in regular snorers as compared with not snoring patients. Further results of these investigators have shown that snoring is independent of other risk factor for ischemic stroke (Palomaki 1989, 1991). Results of other studies on snoring as a risk factor of ischemic stroke, show an increased relative risk of stroke in snoring people (Koskenvuo, 1987). The largest cohort study of over 70 thousands women (Nurses Health Study), showed an increased risk of ischemic stroke in regularly snoring women (risk ratio - RR 1.88) and irregularly snoring women (RR 1.60) (Hu, 2000). It should be emphasized that the cited studies were done with the use of different questionnaires. Both the design of different survey questions, the lack of clear criteria for classification of patients as regularly, often and rarely snorers in different studies, and the self- assessment of patients (some snoring patients are not aware of it) can cause false results. The interpretation of these results should be cautious (Harbison, 2000). More recent studies (Davies, 2003) did not show an increased risk of ischemic stroke among snoring men but excessive daytime sleepiness which is associated with an increased risk of ischemic stroke with a relative RR = 3.07 (Davies, 2003).
In recent years a well-designed studies, with large number of participants, were published on the impact of snoring in other vascular diseases. It has been found, that snoring has negative effect on the incidence, clinical course and mortality of myocardial infarction (Janszky, 2008). In women with type II diabetes snoring increases the risk of hyperlipidemia and increases levels of triglycerides (Williams, 2007). Snoring also increases the risk of diabetes (Al-Delaimy, 2002). Snoring, regardless of other risk factors, increases the incidence of carotid atherosclerosis (Lee, 2008). Recent studies (Davies, 2003), however, do not prove that snoring is a direct risk factor for ischemic stroke. A series of new reports indicate the importance of snoring in the development of risk factors for cerebrovascular diseases (Williams, 2007; Lee, 2008). Snoring, especially loud and habitual, can indirectly contribute to the development of ischemic stroke.
The first studies concerning the sleep-disordered breathing in patients with ischemic stroke, with a quantitative assessment of respiratory dysfunction, were conducted in the 90s. It was shown that among 47 patients with ischemic stroke 72% have breathing problems during sleep (defined as AHI> 10), 53% of patients in this group have had AHI> 30, and 30%
of patients have had AHI > 40 (Good 1996). Mohsenin and Valor (1995) showed that, among patients with ischemic stroke SDB (AHI> 10) occur in 80% of patients. Another studies (Bassetti, 1996, 1997, 1999), conducted on 128 patients with ischemic stroke and 28 in the control group, showed the incidence of SDB (AHI> 10) in 62% of patients with ischemic stroke, compared with 12,5% in the control group. It has been also shown that the incidence of apneas is similar and significantly higher in patients with ischemic stroke and TIA than in the control group (Bassetti, 1996). These results suggest that sleep-disordered breathing is a risk factor for ischemic stroke, rather than its consequence.
Similar results for sleep-disordered breathing in patients with ischemic stroke and TIA were obtained in the group of 161 patients (Parra, 2000). The incidence of sleep-disordered breathing in the group with ischemic stroke was 74.5%, while in the TIA group, 61.5%. Another study (Wessendorf, 2001) have shown the incidence of apnea during sleep in 44% of patients with ischemic stroke, obstructive apneas were the most prominent type of SDB -94%, central apneas occurred in 6% of patients. Turkington (2002) observed presence of SDB (AHI> 10) in 61% of patients with ischemic stroke. In other studies (Harbison, 2002), the incidence of sleep-disordered breathing in patients with acute stroke was 94% and decreased during hospitalization to 72% within 6 weeks after stroke. Results presented by Iranzo (2002) show that SDB (AHI> 10) in the first night after the stroke occurred in 62% of patients. Another study (Kaneko, 2003) showed sleep-disordered breathing in 72% of patients with ischemic stroke. A prospective study of 120 patients with excessive day sleepiness have shown the relationship between the severity of obstructive apneas and hypopneas in patients in the first day of stroke and the clinical course and functional capacities, measured using the Barthel scale (Turkington, 2002). Obstructive apneas and hypopneas were also associated with increased probability of death and disability after stroke (Turkington, 2004). Another study assessed the occurrence of sleep-disordered breathing in 139 patients with ischemic stroke within the first three days of stroke, comparing characteristics of the strokes that occur at night and during the day. It was found that strokes occurring at night were associated with higher risk of SDB prevalence (RR = 2.62) compared with strokes occurring during the day. The authors suggest pathophysiological association between apneas during sleep and nocturnal strokes (Martinez-Garcia, 2004). Another studies evaluated the relationship between arterial blood pressure values after stroke and sleep-disordered breathing and prognosis after stroke. It was found that sleep-disordered breathing is associated with elevated nocturnal arterial blood pressure and the lack of nocturnal arterial blood pressure decrease (non dippers). There was little correlation between the severity of neurological symptoms, clinical course (degree of disability assessed with Barthel scale) and the severity of apnea (Selic, 2005). A much larger relationship occurred between nocturnal blood pressure abnormalities and the severity of the clinical course of stroke (Selic, 2005). The lack of nocturnal arterial blood pressure decrease (non dippers), however, is associated with sleep-disordered breathing and increased activity of sympathetic nervous system. Prospective study of 102 patients with ischemic stroke and sleep-disordered breathing showed significantly higher risk of ischemic stroke in patients with AHI> 10 (RR = 3.5), regardless of other risk factors (Dziewas, 2005). Prospective, cohort study ( follow-up of 3.4 years ; 1022 patients diagnosed with obstructive apneas and hypopneas - 68% of the total population), showed a significantly higher risk of stroke or death (RR = 1.97, p = 0.01) in patients with sleep-disordered breathing (AHI> 5) compared with the control group regardless of other risk factors (age, sex, BMI, arterial hypertension, atrial fibrillation and lipid disorders) (Yaggi, 2005). Correlation studies show a trend related to the higher risk of ischemic stroke and death in patients with more advanced sleep-disordered breathing (Yaggi, 2005). Patients with AHI <35 and AHI> 35 had a relative risk ratios respectively 1.74 and 3.3. Another prospective study of stroke risk in patients with sleep-disordered breathing based on a cohort of Wisconsin (Wisconsin Sleep Cohort Study, 1121 patients without SDB and 1475 patients with SDB (AHI> 5), showed significantly higher incidence of ischemic stroke in patients with advanced apneas (AHI> 20) compared with control group matched demographically and by other risk factors, (Arzt, 2005). The relative risk of ischemic stroke in patients with AHI> 20 in a four-year follow-up was RR = 4.33 (Arzt, 2005). Most studies conducted so far focused mainly on obstructive sleep-breathing disorders in stroke. Most of the observational studies of patients with ischemic stroke indicate a small proportion of the central type apneas (20%) (Bassetti, 1996; Parra, 2000; Yaggi, 2003; Kaneko, 2003; Selice, 2005). Respiratory disturbances of the central type (Cheyne-Stokes breathing pattern) are observed mainly in patients with ischemic stroke with concomitant heart failure (Nopmaneejumruslers, 2005). Another prospective study of elderly people (394 pts aged 70 to 100 years) during 6 year follow-up showed significantly higher incidence of ischemic stroke in patients with severe obstructive apneas and hypopneas (AHI> 30) with a relative risk ratio RR: 2.52 (Munoz, 2006). Further prospective studies assessing the mortality of patients with stroke and sleep-disordered breathing in 10-year follow-up showed a significantly higher risk of death in patients with obstructive apneas and hypopneas RR = 1.76, compared with the control group. Mortality of patients with central sleep apneas was comparable with the control group (Sahlin, 2008). Patients with ischemic heart disease and SDB (AHI> 5) were at increased risk of ischemic stroke RR = 2.69 in ten-years perspective (Valham, 2008). Accordingly, with increasing severity of sleep- disordered breathing (AHI <15 and AHI> 15), the risk of stroke was higher (RR = 2.44 and RR = 3.56).
2.2 Sleep-disordered breathing in patients in the acute phase of ischemic stroke
Sleep-disordered breathing occurs in 30 to 90% of patients in the acute phase of ischemic stroke. SDB can be divided into two types - central apneas and obstructive hypopneas and apneas. In the acute phase of ischemic stroke obstructive apneas are predominant - (Parra, 2000; Yaggi, 2003; Kaneko, 2003). Central-type apneas occurring in the acute phase of ischemic stroke are promoted by impaired consciousness, brain edema and location of ischemic lesions in the medulla. Supine position and dysphagia favor obstructive type apneas. Recently, many research groups have sought to determine the relationship between the occurrence, type and severity of apnea in the acute phase of ischemic stroke and its outcome. It was found that a quantity of central apneas since the onset of disease decreases over time (Parra, 2000; Kaneko, 2003) while obstructive apneas remain constant in patients with ischemic stroke (Parra, 2000; Kaneko, 2003; Harbison, 2002). The next stage of the research was to determine the relationship between the number of obstructive type apneas during sleep and clinical improvement in patients with ischemic stroke. It was found that the severity of SDB in the acute phase of ischemic stroke negatively correlates with the clinical improvement of neurological syndrome (Turkington, 2004; Harbison, 2002; Kaneko, 2003). The increased number of obstructive type apneas in the acute phase of ischemic stroke is highly correlated with increased mortality in patients with ischemic stroke, especially if the apneas last longer than 30 seconds (Turkington, 2004). The severity of apneas in the acute phase of ischemic stroke may be regarded as a predictor of poor neurological improvement in patients with similar severity of neurological symptoms on admission (Cherkassky, 2003) and duration of hospitalization (Kaneko, 2003). Improvement of the functional status of patients (assessed with the Barthel scale) after stroke is negatively correlated with the frequency of incidents of sleep-disordered breathing (Turkington, 2004; Kaneko, 2003).
2.3 Treatment of sleep-disordered breathing in patients with ischemic stroke
Treatment of sleep-disordered breathing in patients with ischemic stroke is strongly dependent on the patient's clinical condition (Hui, 2002). It was shown that among patients with profound neurological deficit CPAP treatment results are unsatisfactory and do not bring the improvement of respiratory parameters (Sandberg, 2001; Wessendorf, 2001). These failures are mainly due to poor tolerance of CPAP and poor compliance among patients with stroke (Sandberg, 2001; Wessendorf, 2001; Hui, 2002). Results published in 2005 regarding the introduction of CPAP treatment in patients with first episode of ischemic stroke and severe obstructive sleep apneas (AHI> 20) showed a significantly lower occurrence of subsequent vascular events (cerebral and cardiac) in patients treated with CPAP - 6 , 7% compared with 36% in patients not treated within two months of follow-up (Martinez-Garcia, 2005). Other authors did not observe statistically significant benefit from the introduction of CPAP treatment in stroke patients with severe obstructive sleep apneas (AHI> 30) (Hsu, 2006). Further prospective study on 449 patients with mild and severe OSAS and CPAP treatment, showed significantly lower risk of cardiovascular event, including stroke (Buchner, 2007). Therapy of patients with severe obstructive sleep apneas and arterial hypertension is postulated as a primary prophylaxis of ischemic stroke (Goldstein, 2006). Recent prospective study in 223 in stroke patients with concomitant obstructive sleep apneas treated with CPAP have reported that treated patients have reduced risk of death compared with not treated in 5-years follow-up (Martinez-Garcia, 2009). It should be noted that the failure of CPAP treatment is usually the result of a difficult cooperation and intolerance of treatment in patients after ischemic stroke. Although there are discrepant reports in the literature, the method of CPAP treatment appears to be effective in preventing further stroke incidents and reduces the risk of death if there is good tolerance of this type of treatment. These results should not limit the interest of researchers in the problem of obstructive sleep apnea in stroke patients. There are several recognized methods of prevention and treatment of sleep-disordered breathing, which can be used successfully in patients with a history of ischemic stroke. These methods include weight reduction, improving sleep hygiene - proper sleep position, avoiding the supine position, avoiding use of alcohol before bedtime, and very important issue - limitation of the use of sleeping pills, particularly the group of benzodiazepines, which may lead to depression of central respiratory center and worsen SDB. Surgical treatment has a prominent place in the treatment of SDB. Correction of the anatomical defects of nasopharynx results in many patients in reduction of the number and severity of obstructive sleep apneas. It is important among stroke patients to select a group with sleep-disordered breathing because of a double benefit - diagnostic and therapeutic, as it allows to modify on of the risk factor-SDB in these patients.
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