© 2007 American Thoracic Society doi: 10.1164/rccm.200701-015ED
Brain Death by a Thousand Hypoxic Cuts in SleepSunnybrook Health Sciences Centre, Toronto, Canada and University of Toronto, Toronto, Canada Evidence supporting the role of obstructive sleep apnea in the pathogenesis of ischemic stroke continues to emerge. Obstructive sleep apnea is a risk factor for the development of hypertension (1), and hypertension is known to be a significant stroke risk factor. Further recent evidence has identified obstructive sleep apnea as a risk factor for stroke (2), even independent of its association with hypertension and other comorbid conditions (3). Several mechanisms may contribute to the development of ischemic stroke in patients with sleep apnea. For example, a recent study demonstrated that apnea-related hypoxia was associated with systemic inflammation and the progression of carotid atherosclerosis as measured by ultrasound (4). In this issue of the Journal (pp. 612–617), Minoguchi and colleagues provide further important observations on the association between stroke and obstructive sleep apnea, with significant public health implications (5). The authors, using brain magnetic resonance imaging, demonstrate that patients with obstructive sleep apnea have a higher incidence of so-called silent brain infarctions (i.e., those devoid of obvious clinical symptoms leading to self-detection or identification by physician examination). This well-designed and executed study excluded patients with known risk factor comorbidities, thereby establishing the relationship between brain infarcts and obstructive sleep apnea itself. The significance of this finding pertains not only to stroke pathophysiology but to dementia as well. Clinically identified stroke represents the tip of the iceberg in terms of cerebral vascular disease by at least an order of magnitude (6). Small, but strategically placed, lesions in the brain can produce a clinically obvious stroke. For example, a lesion of only a few millimeters in diameter that is located in the posterior limb of the internal capsule may leave a patient with devastating hemiplegia that would be obvious clinically. The need to prevent these types of strokes from developing is obvious. Silent infarctions identified on routine neuroimaging studies, on the other hand, may occur in areas of the brain that can only be detected clinically by detailed neuropsychological assessment—or perhaps not at all with currently available tests. It is hard to believe, however, that loss of brain tissue should go without consequences. The brain may reorganize functional networks to adapt to lesions and recover function, but with each subsequent stroke, the capacity to do so is diminished. This may at least partially account for the finding that patients with stroke and obstructive sleep apnea tend to have a longer rehabilitation stay and worse functional recovery than those patients without obstructive sleep apnea (7).
The question is then raised as to how often obstructive sleep apnea may be contributing to subtle cognitive impairment, or even overt dementia. "Silent" brain infarcts are known to contribute to dementia (8), and even a small strategic infarction of the anterior thalamus may be associated with clinically overt dementia (9). Vascular disease is the second most common cause of dementia (10), and is often seen as a contributor in mixed states with Alzheimer's disease. Recurrent hypoxic stress from apnea may be triggering small strokes, whose effects eventually accumulate, with dementia as a consequence. Some groups of patients may be more susceptible to this injury than others. A study of patients with the apolipoprotein E White matter changes of varying degrees are common incidental findings in neuroimaging studies, and the significance in an individual patient is not always clear; the cause is often even less evident. Intermittent hypoxia has been hypothesized as a potential factor (13) among many that may contribute to white matter abnormalities. The study by Minoguchi and colleagues provides evidence that at least some of these white matter lesions are related to apnea. These findings should now trigger a clinician to consider the possibility that sleep apnea may be contributing to the development of white matter lesions, and lead the physician to seek appropriate investigations. This may be important as treatment of obstructive sleep apnea may help reduce the burden of the clinical condition that leads to neuroimaging in the first place. For example, silent infarcts and even diffuse white matter changes are a risk factor for stroke (14), so the treatment of obstructive sleep apnea is of particular importance for secondary stroke prevention. Treating obstructive sleep apnea with continuous positive airway pressure appears to reduce the incidence of clinically obvious stroke (15). The study by Minoguchi and colleagues provides a novel potential mechanism for this finding. In particular, those patients with silent infarcts and sleep apnea had elevated markers of platelet activation, such as soluble CD40 ligand and soluble P-selectin. Furthermore, continuous positive airway pressure therapy for 3 months can lower such markers in this population, thereby providing a link between the white matter lesions and their pathogenesis. Treatment with continuous positive airway pressure may therefore lead to a reduced incidence of subsequent ischemic brain lesions. The high prevalence of obstructive sleep apnea has significant implications for stroke and dementia in our aging population, particularly as obesity becomes more common. Finding ways to reduce brain ischemia is indeed important to the individual and to our society, as stroke and dementia provide tremendous economic and personal burdens (16). FOOTNOTES Conflict of Interest Statement: B.J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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4 allele, who are at greater genetic risk for sleep apnea (
