Sleep Disorders and Acute Stroke: Profile and Research Opportunities

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Sleep Disorders and Acute Stroke: Profile and Research Opportunities

Stroke remains a leading cause of disability and mortality worldwide, with more than half of stroke patients experiencing sleep disorders. These disorders include sleep breathing disorders, non-apnea sleep disturbances, and circadian rhythm disruptions. Among these, obstructive sleep apnea (OSA) has been particularly highlighted as a potential preventive and therapeutic target for stroke. However, the specific roles of these sleep disorders in stroke outcomes and the efficacy of OSA treatment with continuous positive airway pressure (CPAP) therapy in preventing cerebrovascular events remain uncertain. This review addresses the current understanding of the relationship between sleep disorders and stroke, identifies research gaps, and outlines opportunities for future clinical research.

Sleep-Disordered Breathing and Stroke

Sleep-disordered breathing (SDB) is broadly categorized into obstructive and central types. The majority of research has focused on OSA, with studies consistently demonstrating a correlation between OSA and ischemic stroke. The prevalence of post-stroke OSA is estimated to exceed 70%, which may be attributed to positional sleep apnea, stroke-related upper airway tone changes, and untreated OSA preceding the stroke. A prospective study evaluating sleep apnea before and after stroke found a similar frequency of OSA, suggesting that OSA is often a pre-existing condition rather than a consequence of stroke. Population-based cohort studies have further confirmed that OSA independently increases the risk of ischemic stroke. The underlying mechanisms may involve hypoxia-reoxygenation cycles, sleep fragmentation, increased expression of proinflammatory markers, oxidative stress, endothelial damage, and sympathetic hyperactivity. Additionally, OSA exacerbates vascular risk factors such as hypertension, further elevating stroke risk.

In terms of stroke recovery and recurrence, several cohort studies indicate that post-stroke OSA patients are more likely to experience recurrent strokes, higher mortality rates, and worse functional recovery compared to non-OSA patients. While the evidence supporting the impact of OSA on stroke is robust, research on central sleep apnea (CSA) is limited. Isolated retrospective studies suggest that CSA is common after stroke, particularly in cases involving brainstem or interbrain infarctions that affect respiratory regulation.

Non-Apnea Sleep Disorders and Stroke

Non-apnea sleep disorders, such as rapid eye movement sleep behavior disorder (RBD) and restless leg syndrome (RLS), have been less extensively studied in relation to stroke. RBD is characterized by vivid dreams accompanied by vigorous motor activity, while RLS involves uncomfortable leg sensations that worsen during rest. Both disorders are rarely associated with sleep apnea in terms of etiology. Small cohort studies have suggested that non-apnea sleep disturbances may increase the risk of stroke, potentially through mechanisms involving excessive sympathetic activation and dopaminergic neurotransmitter deficiencies. However, these studies are limited by small sample sizes, short follow-up periods, and methodological weaknesses, necessitating cautious interpretation of their findings.

Sleep Duration and Stroke Risk

The relationship between sleep duration and stroke risk has been explored in several meta-analyses and cohort studies. One meta-analysis of 11 studies found that the risk of stroke increased by 17% per hour of sleep increment in individuals sleeping more than 7 hours per day compared to those sleeping within 7 hours. Conversely, another meta-analysis reported that short sleep duration was associated with a higher stroke risk. A recent cohort study in China with an 8-year follow-up period suggested a U-shaped association, where both short and long sleep durations increased stroke risk. Potential explanations for this relationship include proinflammatory markers, atrial fibrillation, and arterial atherosclerosis. However, these studies face limitations such as inconsistent definitions of long sleep duration, lack of adjustment for psychiatric comorbidities like depression and anxiety, and reliance on self-assessment questionnaires rather than objective measures like polysomnography (PSG).

Sleep Structure and Stroke

The impact of sleep structure on acute ischemic stroke has not been thoroughly investigated. Only one study has examined brain lesions at autopsy in individuals who underwent PSG before death, finding that greater slow-wave sleep is associated with less brain atrophy, a feature of cerebral small vessel disease. While this evidence is preliminary, multiple studies have explored the effects of ischemic stroke on sleep structure, though no consistent associations have been established. Compared to controls, ischemic stroke patients often exhibit reduced sleep efficiency, total sleep time, and stages of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. These changes may result from ischemic injury affecting thalamocortical projections that regulate the sleep-wake cycle. The heterogeneity in stroke etiology, location, volume, and timing across studies likely contributes to the variability in findings.

Circadian Rhythm Disruption and Stroke

The role of circadian rhythm disruption in ischemic stroke is an emerging area of research. A few studies have reported decreased melatonin levels after ischemic stroke, but these studies are limited by the absence of pre-stroke melatonin measurements, making it difficult to establish causality. Additionally, it remains unclear whether circadian rhythm disruptions are directly caused by stroke or influenced by environmental factors such as light exposure. The heterogeneity among stroke patients in terms of etiology, topography, and severity further complicates the interpretation of these findings. Future research should measure daytime light exposure and pre-stroke melatonin levels, and perform stratified analyses based on stroke characteristics.

CPAP Therapy and Stroke Prevention

Among sleep disorders, OSA is the most closely associated with stroke, and CPAP therapy is the gold standard for treating moderate to severe OSA. The potential of CPAP to reduce stroke risk has been a topic of significant discussion. The Sleep Apnea Cardiovascular Endpoints (SAVE) trial, a pivotal study in this field, found that CPAP therapy with low compliance (3.3 hours per night) did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. A systematic review of eight randomized controlled trials involving 5,817 participants also found no evidence that CPAP therapy improves stroke outcomes. However, subgroup analyses based on CPAP adherence and OSA severity revealed significant stroke risk reduction in patients with good CPAP adherence and moderate-to-severe OSA. These findings suggest that CPAP therapy holds promise as a secondary prevention method for stroke, but its effectiveness depends on improving apnea severity detection and CPAP compliance in the post-stroke population. Long-term CPAP adherence in stroke patients is often lower than in non-stroke populations, possibly due to the lack of typical OSA symptoms and awareness of secondary prevention benefits.

Research Recommendations

To advance the understanding of sleep disorders and their relationship with stroke, the following research recommendations are proposed:

  1. Central Sleep Apnea (CSA) and Stroke: Further studies are needed to explore the association between CSA and stroke, as existing research has predominantly focused on OSA.

  2. Non-Apnea Sleep Disorders and Stroke: Future studies on RBD and RLS should employ larger sample sizes and longer follow-up periods to establish their roles in stroke risk.

  3. Sleep Duration and Stroke: Sleep duration should be analyzed as a continuous variable, and studies should adjust for psychiatric comorbidities. Objective sleep duration measurements using PSG are essential to overcome the limitations of self-assessment questionnaires.

  4. Sleep Structure and Stroke: Research on sleep structure should stratify analyses by stroke etiology and location to account for heterogeneity among stroke patients.

  5. Circadian Rhythm Disruption and Stroke: Standardized methods for measuring circadian rhythms in stroke patients are needed. Future studies should measure pre-stroke melatonin levels and daytime light exposure, and perform stratified analyses based on stroke characteristics.

  6. CPAP Adherence in Stroke Patients: Observational studies should investigate the causes of low CPAP adherence in the post-stroke population. Developing strategies to improve CPAP compliance is a critical area for future research.

Conclusion

Sleep disorders, particularly OSA, are prevalent among stroke patients and may significantly impact stroke risk, recovery, and recurrence. While CPAP therapy shows potential as a secondary prevention method, its effectiveness depends on improved detection of apnea severity and enhanced patient compliance. Non-apnea sleep disorders, sleep duration, sleep structure, and circadian rhythm disruptions also warrant further investigation to elucidate their roles in stroke. Addressing these research gaps will provide valuable insights into the interplay between sleep disorders and stroke, ultimately guiding the development of targeted prevention and treatment strategies.

doi.org/10.1097/CM9.0000000000001426

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