Sleep Medicine

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke and may also, infrequently, be a consequence of stroke. It is significantly underdiagnosed in the general population and is highly prevalent in patients who have had a stroke. Many patients likely had their stroke because of this chronic untreated condition.

This review focuses on OSA and its prevalence, consequences, and treatment in patients after a stroke.

DEFINING AND QUANTIFYING OSA

OSA is the most common type of sleep-disordered breathing.^1,2 It involves repeated narrowing or complete collapse of the upper airway despite ongoing respiratory effort.^3,4 Apneic episodes are terminated by arousals from hypoxemia or efforts to breathe.⁵ In contrast, central sleep apnea is characterized by a patent airway but lack of airflow due to absent respiratory effort.⁵

In OSA, the number of episodes of apnea (absent airflow) and hypopnea (reduced airflow) are added together and divided by hours of sleep to calculate the apnea-hypopnea index (AHI). OSA is diagnosed by either of the following^3,4:

• AHI of 5 or higher, with clinical symptoms related to OSA (described below)
• AHI of 15 or higher, regardless of symptoms.

The AHI also defines OSA severity, as follows³:

• Mild: AHI 5 to 15
• Moderate: AHI 15 to 30
• Severe: AHI greater than 30.

Diagnostic criteria (eg, definition of hypopnea, testing methods, and AHI thresholds) have varied over time, an important consideration when reviewing the literature.

OSA IS MORE COMMON THAN EXPECTED AFTER STROKE

In the most methodologically sound and generalizable study of this topic to date, the Wisconsin Sleep Cohort Study⁶ reported in 2013 that about 14% of men and 5% of women ages 30 to 70 have an AHI greater than 5 (using 4% desaturation to score hypopneic episodes) with daytime sleepiness. Other studies suggest that 80% to 90% of people with OSA are undiagnosed and untreated.^1,7

The prevalence of OSA in patients who have had a stroke is much higher, ranging from 30% to 96% depending on the study methods and population.^1,8–12 A 2010 meta-analysis¹¹ of 29 studies reported that 72% of patients who had a stroke had an AHI greater than 5, and 29% had severe OSA. In this analysis, 7% of those with sleep-disordered breathing had central sleep apnea; still, these data indicate that the prevalence of OSA in these patients is about 5 times higher than in the general population.

RISK FACTORS MAY DIFFER IN STROKE POPULATION

Several risk factors for OSA have been identified.

Obesity is one of the strongest risk factors, with increasing body mass index (BMI) associated with increased OSA prevalence.^4,6,13 However, obesity appears to be a less significant risk factor in patients who have had a stroke than in the general population. In the 2010 meta-analysis¹¹ of OSA after stroke, the average BMI was only 26.4 kg/m² (with obesity defined as a BMI > 30.0 kg/m²), and increasing BMI was not associated with increasing AHI.

Male sex and advanced age are also OSA risk factors.^4,5 They remain significant in patients after a stroke; about 65% of poststroke patients who have OSA are men, and the older the patient, the more likely the AHI is greater than 10.¹¹

Ethnicity and genetics may also play important roles in OSA risk, with roughly 25% of OSA prevalence estimated to have a genetic basis.^14,15 Some risk factors for OSA such as craniofacial shape, upper airway anatomy, upper airway muscle dysfunction, increased respiratory chemosensitivity, and poor arousal threshold during sleep are likely determined by genetics and ethnicity.^14,15 Compared with people of European origin, Asians have a similar prevalence of OSA, but at a much lower average BMI, suggesting that other factors are significant.¹⁴ Possible genetically determined anatomic risk factors have not been specifically studied in the poststroke population, but it can be assumed they remain relevant.

Several studies have tried to find an association between OSA and type, location, etiology, or pattern of stroke.^{10,11,16–19} Although some suggest links between cardioembolic stroke and OSA,^16,20 or thrombolysis and OSA,¹⁰ most have found no association between OSA and stroke features.^11,12,21,22

HOW DOES OSA INCREASE STROKE RISK?

Untreated severe OSA is associated with increased cardiovascular mortality,^21,22 and OSA is an independent risk factor for incident stroke.²³ A number of mechanisms may explain these relationships.

Intermittent hypoxemia and recurrent sympathetic arousals resulting from OSA are thought to lead to many of the comorbid conditions with which it is associated: hypertension, coronary artery disease, heart failure, arrhythmias, pulmonary hypertension, and stroke. Repetitive decreases in ventilation lead to oxygen desaturations that result in cycles of increased sympathetic outflow and eventual sustained nocturnal hypertension and daytime chronic hypertension.^1,5,9,13 Also implicated are various changes in vasodilator and vasoconstrictor substances due to endothelial dysfunction and inflammation, which are thought to play a role in the atherogenic and prothrombotic states induced by OSA.^1,5,13

Cerebral circulation is altered primarily by the changes in partial pressure of carbon dioxide (Pco₂). During apnea, the Pco₂ rises, causing vasodilation and increased blood flow. After the apnea resolves, there is hyperpnea with resultant decreased Pco₂, and vasoconstriction. In a patient who already has vascular disease, the enhanced vasoconstriction could lead to ischemia.^1,5

Changes in intrathoracic pressure result in distortion of cardiac architecture. When the patient tries to breathe against an occluded airway, the intrathoracic pressure becomes more and more negative, increasing preload and afterload. When this happens repeatedly every night for years, it leads to remodeling of the heart such as left and right ventricular hypertrophy, with reduced stroke volume, myocardial ischemia, and increased risk of arrhythmia.^1,5,13

Untreated OSA is believed to predispose patients to develop atrial fibrillation through sympathetic overactivity, vascular inflammation, heart rate variability, and cardiac remodeling.²⁴ As atrial fibrillation is a major risk factor for stroke, particularly cardioembolic stroke, it may be another pathway of increased stroke risk in OSA.^16,20,25

 

 

CLINICAL MANIFESTATIONS OF OSA NOT OBVIOUS AFTER STROKE

OSA typically causes both daytime symptoms (excessive sleepiness, poor concentration, morning headache, depressive symptoms) and nighttime signs and symptoms (snoring, choking, gasping, night sweats, insomnia, nocturia, witnessed episodes of apnea).^3,4,26 Unfortunately, because these are nonspecific, OSA is often underdiagnosed.^4,26

Identifying OSA after a stroke may be a particular challenge, as patients often do not report classic symptoms, and the typical picture of OSA may have less predictive validity in these patients.^1,27,28 Within the first 24 hours after a stroke, hypersomnia, snoring history, and age are not predictive of OSA.¹ Patients found to have OSA after a stroke frequently do not have the traditional symptoms (sleepiness, snoring) seen in usual OSA patients. And they have higher rates of OSA at a younger age than the usual OSA patients, so age is not a predictive risk factor. In addition, daytime sleepiness and obesity are often absent or less prominent.^1,9,27,28  Finally, typical OSA signs and symptoms may be attributed to the stroke itself or to comorbidities affecting the patient, lowering suspicion for OSA.

OSA MAY HINDER STROKE RECOVERY, WORSEN OUTCOMES

OSA, particularly when moderate to severe, is linked to pathophysiologic changes that can hinder recovery from a stroke.

Intermittent hypoxemia during sleep can worsen vascular damage of at-risk tissue: nocturnal hypoxemia correlates with white matter hyperintensities on magnetic resonance imaging, a marker of ischemic demyelination.²⁹ Oxidative stress and release of inflammatory mediators associated with intermittent hypoxemia may impair vascular blood flow to brain tissue attempting to repair itself.³⁰ In addition, sympathetic overactivity and Pco₂ fluctuations associated with OSA may impede cerebral circulation.

Taken together, such ongoing nocturnal insults can lead to clinical consequences during this vulnerable period.

A 1996 study³¹ of patients recovering from a stroke found that an oxygen desaturation index (number of times that the blood oxygen level drops below a certain threshold, as measured by overnight oximetry) of more than 10 per hour was associated with worse functional recovery at discharge and at 3 and 12 months after discharge. This study also noted an association between time spent with oxygen saturations below 90% and the rate of death at 1 year.

A 2003 study³² reported that patients with an AHI greater than 10 by polysomnography spent an average of 13 days longer on the rehabilitation service and had worse functional and cognitive status on discharge, even after controlling for multiple confounders. Several subsequent studies have confirmed these and similar findings.^8,33,34

OSA has also been linked to depression,³⁵ which is common after stroke and may worsen outcomes.³⁶ The interaction between OSA, depression, and poststroke outcomes warrants further study.

In the general population, OSA has been independently associated with increased risk of stroke or death from any cause.^21,22,37 These associations have also been reported in the poststroke population: a 2014 meta-analysis found that OSA increased the risk of a repeat stroke (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2–2.6) and all-cause mortality (RR 1.69, 95% CI 1.4–2.1).³⁸

TESTING FOR OSA AFTER STROKE

Because of the high prevalence of OSA in patients who have had a stroke and the potential for worse outcomes associated with untreated OSA, there should be a low threshold for evaluating for OSA soon after stroke. Objective testing is required to qualify for therapy,  and the gold standard for diagnosis of OSA is formal polysomnography conducted in a sleep laboratory.^2–4 Unfortunately, polysomnography may be unacceptable to some patients, is costly, and is resource-intensive, particularly in an inpatient or rehabilitation setting.²⁸ Ideally, to optimize testing efficiency, patients should be screened for the likelihood of OSA before polysomnography is ordered.

Questionnaires can help determine the need for further testing

Questionnaires developed to assess OSA risk³⁹ include the following:

The Berlin questionnaire, developed in 1999, has 10 questions assessing daytime and nighttime signs and symptoms and presence of hypertension.

The STOP questionnaire, developed in 2008, assesses snoring, tiredness, observed apneic episodes, and elevated blood pressure.

The STOP-BANG questionnaire, published in 2010, includes the STOP questions plus BMI over 35 kg/m², age over 50, neck circumference over 41 cm, and male gender.

A 2017 meta-analysis³⁹ of 108 studies with nearly 50,000 people found that the STOP-BANG questionnaire performed best with regard to sensitivity and diagnostic odds ratio, but with poor specificity.

These screening tools and modified versions of them have also been evaluated in patients who have had a stroke.

In 2015, Boulos et al²⁸ found that the STOP-BAG (a version of STOP-BANG that excludes neck circumference) and the 4-variable (4V) questionnaire (sex, BMI, blood pressure, snoring) had moderate predictive value for OSA within 6 months after sroke.

In 2016, Katzan et al⁴⁰ found that the STOP-BAG2 (STOP-BAG criteria plus continuous variables for BMI and age) had a high sensitivity for polysomnographically diagnosed OSA within the first year after a stroke. The specificity was significantly better than the STOP-BANG or the STOP-BAG questionnaire, although it remained suboptimal at 60.5%.

In 2017, Sico et al⁴¹ developed and assessed the SLEEP Inventory (sex, left heart failure, Epworth Sleepiness Scale, enlarged neck, weight in pounds, insulin resistance or diabetes, and National Institutes of Health Stroke Scale) and found that it outperformed the Berlin and STOP-BANG questionnaires in the poststroke setting. The SLEEP Inventory had the best specificity and negative predictive value, and a slightly better ability to correctly classify patients as having OSA or not, classifying 80% of patients correctly.

These newer screening tools (eg, STOP-BAG, STOP-BAG2, SLEEP) can be used to identify with reasonable accuracy which patients need definitive testing after stroke.

Pulse oximetry is another possible screening tool          

Overnight pulse oximetry may also help screen for sleep apnea and stratify risk after a stroke. A 2012 study⁴² of overnight oximetry to screen patients before surgery found that the oxygen desaturation index was significantly associated with the AHI measured by polysomnography. However, oximetry testing cannot distinguish between OSA and central sleep apnea, so it is insufficient to diagnose OSA or qualify patients for therapy. Further study is needed to examine the ability of overnight pulse oximetry to screen or to stratify risk for OSA after stroke.

Polysomnography vs home testing

Polysomnography is the gold standard for diagnosing OSA. Benefits include technical support and trouble-shooting, determining relationships between OSA, body position, and sleep stage, and the ability to intervene with treatment.² However, polysomnography can be cumbersome, costly, and resource-intensive.

A home sleep apnea test, ie, an unattended, limited-channel sleep study, may be an acceptable alternative.^2–4,43,44 Home testing does not require a sleep technologist to be present during testing, uses fewer sensors, and is less expensive than overnight polysomnography, but its utility can be limited: it fails to accurately discriminate between episodes of OSA and central sleep apnea, there is potential for false-negative results, and it can underestimate sleep apnea burden because it does not measure sleep.²

Institutional resources and logistics may influence the choice of diagnostic modality. No data exist on outcomes from different diagnostic testing methods in poststroke patients. Further research is needed.

 

 

POSITIVE AIRWAY PRESSURE THERAPY: BENEFITS, CHALLENGES, ALTERNATIVES

The first-line treatment for OSA is positive airway pressure (PAP).³ For most patients, this is continuous PAP (CPAP) or autoadjusting PAP (APAP). In some instances, particularly for those who cannot tolerate CPAP or who have comorbid hypoventilation, bilevel PAP (BPAP) may be indicated. More advanced PAP therapies are unlikely to be used after stroke.

PAP therapy is associated with reduced daytime sleepiness, improved mood, normalization of sleep architecture, improved systemic and pulmonary artery blood pressure, reduced rates of atrial fibrillation after ablation, and improved insulin sensitivity.^45–49 Whether it reduces the risk of cardiovascular events, including stroke, remains controversial; most data suggest that it does not.^50,51 However, when adherence to PAP therapy is considered rather than intention to treat, treatment has been found to lead to improved cardiovascular outcomes.⁵²

Mixed evidence of benefits after stroke

Observational studies provide evidence that CPAP may help patients with OSA after stroke, although results are mixed.^53–58 The studies ranged in size from 14 to 105 patients, enrolled patients with mostly moderate to severe OSA, and followed patients from 10 days to 7 years. Adherence to therapy was generally good in the short term (50%–70%), but only  15% to 30% of patients remained adherent at 5 to 7 years. Variable outcomes were reported, with some studies finding improved symptoms in the near term and mixed evidence of cardiovascular benefit in the longer ones. However, as these studies lacked randomization, drawing definitive conclusions on CPAP efficacy is difficult.

Patients were enrolled in the index admission or when starting a rehabilitation service—generally 2 to 3 weeks after their stroke. No clear association was found between the timing of initiating PAP therapy and outcomes. All patients had ischemic strokes, but few details were provided regarding stroke location, size, and severity. Exclusion criteria included severe underlying cardiopulmonary disease, confusion, severe stroke with marked impairment, and inability to cooperate. Almost all patients had moderate to severe OSA, and patients with central sleep apnea were excluded.

The major outcomes examined were drop-out rates, PAP adherence, and neurologic improvement based on neurologic functional scales (National Institutes of Health Stroke Scale and Canadian Neurologic Scale). As expected, dropout rates were higher in patients randomized to CPAP (OR 1.83, 95% CI 1.05–3.21, P = .03), although overall adherence was better than anticipated, with mean CPAP use across trials of 4.5 hours per night (95% CI 3.97–5.08) and with about 50% to 60% of patients adhering to therapy for at least 4 hours nightly.

Improvement in neurologic outcomes favored CPAP (standard mean difference 0.54, 95% CI 0.026–1.05), although considerable heterogeneity was seen. Improved sleepiness outcomes were inconsistent. Major cardiovascular outcomes were reported in only 2 studies (using the same data set) and showed delayed time to the next cardiovascular event for those treated with CPAP but no difference in cardiovascular event-free survival.

PAP poses more challenges after stroke

The primary limitation to PAP therapy is poor acceptance and adherence to therapy.⁵⁹ High rates of refusal of therapy and difficulty complying with treatment have been noted in the poststroke population, although recent studies have reported better adherence rates. How rates of adherence play out in real-world settings, outside of the controlled environment of a research study, has yet to be determined.

In general, CPAP adherence is affected by claustrophobia, difficulty tolerating a mask, problems with pressure intolerance, irritating air leaks, nasal congestion, and naso-oral dryness. Many such barriers can be overcome with use of a properly fitted mask, an appropriate pressure setting, heated humidification, nasal sprays (eg, saline, inhaled steroids), and education, encouragement, and reassurance.

After a stroke, additional obstacles may impede the ability to use PAP therapy.⁶⁸ Facial paresis (hemi- or bifacial) may make fitting of the mask problematic. Paralysis or weakness of the extremities may limit the ability to adjust or remove a mask. Aphasia can impair communication and understanding of the need to use PAP therapy, and upper-airway problems related to stroke, including dysphagia, may lead to pressure intolerance or risk of aspiration. Finally, a lack of perceived benefit, particularly if the patient does not have daytime sleepiness, may limit motivation.

Consider alternatives

For patients unlikely to succeed with PAP therapy, there are alternatives. Surgery and oral appliances are not usually realistic options in the setting of recent stroke, but positional therapy, including the use of body positioners to prevent supine sleep, as well as elevating the head of the bed, may be of some benefit.^69,70 A nasopharyngeal airway stenting device (nasal trumpet) may also be tolerated by some patients.

A proposed algorithm for screening, diagnosing, and treating OSA in patients after stroke is presented in Figure 1.

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke and may also, infrequently, be a consequence of stroke. It is significantly underdiagnosed in the general population and is highly prevalent in patients who have had a stroke. Many patients likely had their stroke because of this chronic untreated condition.

This review focuses on OSA and its prevalence, consequences, and treatment in patients after a stroke.

DEFINING AND QUANTIFYING OSA

OSA is the most common type of sleep-disordered breathing.^1,2 It involves repeated narrowing or complete collapse of the upper airway despite ongoing respiratory effort.^3,4 Apneic episodes are terminated by arousals from hypoxemia or efforts to breathe.⁵ In contrast, central sleep apnea is characterized by a patent airway but lack of airflow due to absent respiratory effort.⁵

In OSA, the number of episodes of apnea (absent airflow) and hypopnea (reduced airflow) are added together and divided by hours of sleep to calculate the apnea-hypopnea index (AHI). OSA is diagnosed by either of the following^3,4:

• AHI of 5 or higher, with clinical symptoms related to OSA (described below)
• AHI of 15 or higher, regardless of symptoms.

The AHI also defines OSA severity, as follows³:

• Mild: AHI 5 to 15
• Moderate: AHI 15 to 30
• Severe: AHI greater than 30.

Diagnostic criteria (eg, definition of hypopnea, testing methods, and AHI thresholds) have varied over time, an important consideration when reviewing the literature.

OSA IS MORE COMMON THAN EXPECTED AFTER STROKE

In the most methodologically sound and generalizable study of this topic to date, the Wisconsin Sleep Cohort Study⁶ reported in 2013 that about 14% of men and 5% of women ages 30 to 70 have an AHI greater than 5 (using 4% desaturation to score hypopneic episodes) with daytime sleepiness. Other studies suggest that 80% to 90% of people with OSA are undiagnosed and untreated.^1,7

The prevalence of OSA in patients who have had a stroke is much higher, ranging from 30% to 96% depending on the study methods and population.^1,8–12 A 2010 meta-analysis¹¹ of 29 studies reported that 72% of patients who had a stroke had an AHI greater than 5, and 29% had severe OSA. In this analysis, 7% of those with sleep-disordered breathing had central sleep apnea; still, these data indicate that the prevalence of OSA in these patients is about 5 times higher than in the general population.

RISK FACTORS MAY DIFFER IN STROKE POPULATION

Several risk factors for OSA have been identified.

Obesity is one of the strongest risk factors, with increasing body mass index (BMI) associated with increased OSA prevalence.^4,6,13 However, obesity appears to be a less significant risk factor in patients who have had a stroke than in the general population. In the 2010 meta-analysis¹¹ of OSA after stroke, the average BMI was only 26.4 kg/m² (with obesity defined as a BMI > 30.0 kg/m²), and increasing BMI was not associated with increasing AHI.

Male sex and advanced age are also OSA risk factors.^4,5 They remain significant in patients after a stroke; about 65% of poststroke patients who have OSA are men, and the older the patient, the more likely the AHI is greater than 10.¹¹

Ethnicity and genetics may also play important roles in OSA risk, with roughly 25% of OSA prevalence estimated to have a genetic basis.^14,15 Some risk factors for OSA such as craniofacial shape, upper airway anatomy, upper airway muscle dysfunction, increased respiratory chemosensitivity, and poor arousal threshold during sleep are likely determined by genetics and ethnicity.^14,15 Compared with people of European origin, Asians have a similar prevalence of OSA, but at a much lower average BMI, suggesting that other factors are significant.¹⁴ Possible genetically determined anatomic risk factors have not been specifically studied in the poststroke population, but it can be assumed they remain relevant.

Several studies have tried to find an association between OSA and type, location, etiology, or pattern of stroke.^{10,11,16–19} Although some suggest links between cardioembolic stroke and OSA,^16,20 or thrombolysis and OSA,¹⁰ most have found no association between OSA and stroke features.^11,12,21,22

HOW DOES OSA INCREASE STROKE RISK?

Untreated severe OSA is associated with increased cardiovascular mortality,^21,22 and OSA is an independent risk factor for incident stroke.²³ A number of mechanisms may explain these relationships.

Intermittent hypoxemia and recurrent sympathetic arousals resulting from OSA are thought to lead to many of the comorbid conditions with which it is associated: hypertension, coronary artery disease, heart failure, arrhythmias, pulmonary hypertension, and stroke. Repetitive decreases in ventilation lead to oxygen desaturations that result in cycles of increased sympathetic outflow and eventual sustained nocturnal hypertension and daytime chronic hypertension.^1,5,9,13 Also implicated are various changes in vasodilator and vasoconstrictor substances due to endothelial dysfunction and inflammation, which are thought to play a role in the atherogenic and prothrombotic states induced by OSA.^1,5,13

Cerebral circulation is altered primarily by the changes in partial pressure of carbon dioxide (Pco₂). During apnea, the Pco₂ rises, causing vasodilation and increased blood flow. After the apnea resolves, there is hyperpnea with resultant decreased Pco₂, and vasoconstriction. In a patient who already has vascular disease, the enhanced vasoconstriction could lead to ischemia.^1,5

Changes in intrathoracic pressure result in distortion of cardiac architecture. When the patient tries to breathe against an occluded airway, the intrathoracic pressure becomes more and more negative, increasing preload and afterload. When this happens repeatedly every night for years, it leads to remodeling of the heart such as left and right ventricular hypertrophy, with reduced stroke volume, myocardial ischemia, and increased risk of arrhythmia.^1,5,13

Untreated OSA is believed to predispose patients to develop atrial fibrillation through sympathetic overactivity, vascular inflammation, heart rate variability, and cardiac remodeling.²⁴ As atrial fibrillation is a major risk factor for stroke, particularly cardioembolic stroke, it may be another pathway of increased stroke risk in OSA.^16,20,25

 

 

CLINICAL MANIFESTATIONS OF OSA NOT OBVIOUS AFTER STROKE

OSA typically causes both daytime symptoms (excessive sleepiness, poor concentration, morning headache, depressive symptoms) and nighttime signs and symptoms (snoring, choking, gasping, night sweats, insomnia, nocturia, witnessed episodes of apnea).^3,4,26 Unfortunately, because these are nonspecific, OSA is often underdiagnosed.^4,26

Identifying OSA after a stroke may be a particular challenge, as patients often do not report classic symptoms, and the typical picture of OSA may have less predictive validity in these patients.^1,27,28 Within the first 24 hours after a stroke, hypersomnia, snoring history, and age are not predictive of OSA.¹ Patients found to have OSA after a stroke frequently do not have the traditional symptoms (sleepiness, snoring) seen in usual OSA patients. And they have higher rates of OSA at a younger age than the usual OSA patients, so age is not a predictive risk factor. In addition, daytime sleepiness and obesity are often absent or less prominent.^1,9,27,28  Finally, typical OSA signs and symptoms may be attributed to the stroke itself or to comorbidities affecting the patient, lowering suspicion for OSA.

OSA MAY HINDER STROKE RECOVERY, WORSEN OUTCOMES

OSA, particularly when moderate to severe, is linked to pathophysiologic changes that can hinder recovery from a stroke.

Intermittent hypoxemia during sleep can worsen vascular damage of at-risk tissue: nocturnal hypoxemia correlates with white matter hyperintensities on magnetic resonance imaging, a marker of ischemic demyelination.²⁹ Oxidative stress and release of inflammatory mediators associated with intermittent hypoxemia may impair vascular blood flow to brain tissue attempting to repair itself.³⁰ In addition, sympathetic overactivity and Pco₂ fluctuations associated with OSA may impede cerebral circulation.

Taken together, such ongoing nocturnal insults can lead to clinical consequences during this vulnerable period.

A 1996 study³¹ of patients recovering from a stroke found that an oxygen desaturation index (number of times that the blood oxygen level drops below a certain threshold, as measured by overnight oximetry) of more than 10 per hour was associated with worse functional recovery at discharge and at 3 and 12 months after discharge. This study also noted an association between time spent with oxygen saturations below 90% and the rate of death at 1 year.

A 2003 study³² reported that patients with an AHI greater than 10 by polysomnography spent an average of 13 days longer on the rehabilitation service and had worse functional and cognitive status on discharge, even after controlling for multiple confounders. Several subsequent studies have confirmed these and similar findings.^8,33,34

OSA has also been linked to depression,³⁵ which is common after stroke and may worsen outcomes.³⁶ The interaction between OSA, depression, and poststroke outcomes warrants further study.

In the general population, OSA has been independently associated with increased risk of stroke or death from any cause.^21,22,37 These associations have also been reported in the poststroke population: a 2014 meta-analysis found that OSA increased the risk of a repeat stroke (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2–2.6) and all-cause mortality (RR 1.69, 95% CI 1.4–2.1).³⁸

TESTING FOR OSA AFTER STROKE

Because of the high prevalence of OSA in patients who have had a stroke and the potential for worse outcomes associated with untreated OSA, there should be a low threshold for evaluating for OSA soon after stroke. Objective testing is required to qualify for therapy,  and the gold standard for diagnosis of OSA is formal polysomnography conducted in a sleep laboratory.^2–4 Unfortunately, polysomnography may be unacceptable to some patients, is costly, and is resource-intensive, particularly in an inpatient or rehabilitation setting.²⁸ Ideally, to optimize testing efficiency, patients should be screened for the likelihood of OSA before polysomnography is ordered.

Questionnaires can help determine the need for further testing

Questionnaires developed to assess OSA risk³⁹ include the following:

The Berlin questionnaire, developed in 1999, has 10 questions assessing daytime and nighttime signs and symptoms and presence of hypertension.

The STOP questionnaire, developed in 2008, assesses snoring, tiredness, observed apneic episodes, and elevated blood pressure.

The STOP-BANG questionnaire, published in 2010, includes the STOP questions plus BMI over 35 kg/m², age over 50, neck circumference over 41 cm, and male gender.

A 2017 meta-analysis³⁹ of 108 studies with nearly 50,000 people found that the STOP-BANG questionnaire performed best with regard to sensitivity and diagnostic odds ratio, but with poor specificity.

These screening tools and modified versions of them have also been evaluated in patients who have had a stroke.

In 2015, Boulos et al²⁸ found that the STOP-BAG (a version of STOP-BANG that excludes neck circumference) and the 4-variable (4V) questionnaire (sex, BMI, blood pressure, snoring) had moderate predictive value for OSA within 6 months after sroke.

In 2016, Katzan et al⁴⁰ found that the STOP-BAG2 (STOP-BAG criteria plus continuous variables for BMI and age) had a high sensitivity for polysomnographically diagnosed OSA within the first year after a stroke. The specificity was significantly better than the STOP-BANG or the STOP-BAG questionnaire, although it remained suboptimal at 60.5%.

In 2017, Sico et al⁴¹ developed and assessed the SLEEP Inventory (sex, left heart failure, Epworth Sleepiness Scale, enlarged neck, weight in pounds, insulin resistance or diabetes, and National Institutes of Health Stroke Scale) and found that it outperformed the Berlin and STOP-BANG questionnaires in the poststroke setting. The SLEEP Inventory had the best specificity and negative predictive value, and a slightly better ability to correctly classify patients as having OSA or not, classifying 80% of patients correctly.

These newer screening tools (eg, STOP-BAG, STOP-BAG2, SLEEP) can be used to identify with reasonable accuracy which patients need definitive testing after stroke.

Pulse oximetry is another possible screening tool          

Overnight pulse oximetry may also help screen for sleep apnea and stratify risk after a stroke. A 2012 study⁴² of overnight oximetry to screen patients before surgery found that the oxygen desaturation index was significantly associated with the AHI measured by polysomnography. However, oximetry testing cannot distinguish between OSA and central sleep apnea, so it is insufficient to diagnose OSA or qualify patients for therapy. Further study is needed to examine the ability of overnight pulse oximetry to screen or to stratify risk for OSA after stroke.

Polysomnography vs home testing

Polysomnography is the gold standard for diagnosing OSA. Benefits include technical support and trouble-shooting, determining relationships between OSA, body position, and sleep stage, and the ability to intervene with treatment.² However, polysomnography can be cumbersome, costly, and resource-intensive.

A home sleep apnea test, ie, an unattended, limited-channel sleep study, may be an acceptable alternative.^2–4,43,44 Home testing does not require a sleep technologist to be present during testing, uses fewer sensors, and is less expensive than overnight polysomnography, but its utility can be limited: it fails to accurately discriminate between episodes of OSA and central sleep apnea, there is potential for false-negative results, and it can underestimate sleep apnea burden because it does not measure sleep.²

Institutional resources and logistics may influence the choice of diagnostic modality. No data exist on outcomes from different diagnostic testing methods in poststroke patients. Further research is needed.

 

 

POSITIVE AIRWAY PRESSURE THERAPY: BENEFITS, CHALLENGES, ALTERNATIVES

The first-line treatment for OSA is positive airway pressure (PAP).³ For most patients, this is continuous PAP (CPAP) or autoadjusting PAP (APAP). In some instances, particularly for those who cannot tolerate CPAP or who have comorbid hypoventilation, bilevel PAP (BPAP) may be indicated. More advanced PAP therapies are unlikely to be used after stroke.

PAP therapy is associated with reduced daytime sleepiness, improved mood, normalization of sleep architecture, improved systemic and pulmonary artery blood pressure, reduced rates of atrial fibrillation after ablation, and improved insulin sensitivity.^45–49 Whether it reduces the risk of cardiovascular events, including stroke, remains controversial; most data suggest that it does not.^50,51 However, when adherence to PAP therapy is considered rather than intention to treat, treatment has been found to lead to improved cardiovascular outcomes.⁵²

Mixed evidence of benefits after stroke

Observational studies provide evidence that CPAP may help patients with OSA after stroke, although results are mixed.^53–58 The studies ranged in size from 14 to 105 patients, enrolled patients with mostly moderate to severe OSA, and followed patients from 10 days to 7 years. Adherence to therapy was generally good in the short term (50%–70%), but only  15% to 30% of patients remained adherent at 5 to 7 years. Variable outcomes were reported, with some studies finding improved symptoms in the near term and mixed evidence of cardiovascular benefit in the longer ones. However, as these studies lacked randomization, drawing definitive conclusions on CPAP efficacy is difficult.

Patients were enrolled in the index admission or when starting a rehabilitation service—generally 2 to 3 weeks after their stroke. No clear association was found between the timing of initiating PAP therapy and outcomes. All patients had ischemic strokes, but few details were provided regarding stroke location, size, and severity. Exclusion criteria included severe underlying cardiopulmonary disease, confusion, severe stroke with marked impairment, and inability to cooperate. Almost all patients had moderate to severe OSA, and patients with central sleep apnea were excluded.

The major outcomes examined were drop-out rates, PAP adherence, and neurologic improvement based on neurologic functional scales (National Institutes of Health Stroke Scale and Canadian Neurologic Scale). As expected, dropout rates were higher in patients randomized to CPAP (OR 1.83, 95% CI 1.05–3.21, P = .03), although overall adherence was better than anticipated, with mean CPAP use across trials of 4.5 hours per night (95% CI 3.97–5.08) and with about 50% to 60% of patients adhering to therapy for at least 4 hours nightly.

Improvement in neurologic outcomes favored CPAP (standard mean difference 0.54, 95% CI 0.026–1.05), although considerable heterogeneity was seen. Improved sleepiness outcomes were inconsistent. Major cardiovascular outcomes were reported in only 2 studies (using the same data set) and showed delayed time to the next cardiovascular event for those treated with CPAP but no difference in cardiovascular event-free survival.

PAP poses more challenges after stroke

The primary limitation to PAP therapy is poor acceptance and adherence to therapy.⁵⁹ High rates of refusal of therapy and difficulty complying with treatment have been noted in the poststroke population, although recent studies have reported better adherence rates. How rates of adherence play out in real-world settings, outside of the controlled environment of a research study, has yet to be determined.

In general, CPAP adherence is affected by claustrophobia, difficulty tolerating a mask, problems with pressure intolerance, irritating air leaks, nasal congestion, and naso-oral dryness. Many such barriers can be overcome with use of a properly fitted mask, an appropriate pressure setting, heated humidification, nasal sprays (eg, saline, inhaled steroids), and education, encouragement, and reassurance.

After a stroke, additional obstacles may impede the ability to use PAP therapy.⁶⁸ Facial paresis (hemi- or bifacial) may make fitting of the mask problematic. Paralysis or weakness of the extremities may limit the ability to adjust or remove a mask. Aphasia can impair communication and understanding of the need to use PAP therapy, and upper-airway problems related to stroke, including dysphagia, may lead to pressure intolerance or risk of aspiration. Finally, a lack of perceived benefit, particularly if the patient does not have daytime sleepiness, may limit motivation.

Consider alternatives

For patients unlikely to succeed with PAP therapy, there are alternatives. Surgery and oral appliances are not usually realistic options in the setting of recent stroke, but positional therapy, including the use of body positioners to prevent supine sleep, as well as elevating the head of the bed, may be of some benefit.^69,70 A nasopharyngeal airway stenting device (nasal trumpet) may also be tolerated by some patients.

A proposed algorithm for screening, diagnosing, and treating OSA in patients after stroke is presented in Figure 1.

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke and may also, infrequently, be a consequence of stroke. It is significantly underdiagnosed in the general population and is highly prevalent in patients who have had a stroke. Many patients likely had their stroke because of this chronic untreated condition.

This review focuses on OSA and its prevalence, consequences, and treatment in patients after a stroke.

DEFINING AND QUANTIFYING OSA

OSA is the most common type of sleep-disordered breathing.^1,2 It involves repeated narrowing or complete collapse of the upper airway despite ongoing respiratory effort.^3,4 Apneic episodes are terminated by arousals from hypoxemia or efforts to breathe.⁵ In contrast, central sleep apnea is characterized by a patent airway but lack of airflow due to absent respiratory effort.⁵

In OSA, the number of episodes of apnea (absent airflow) and hypopnea (reduced airflow) are added together and divided by hours of sleep to calculate the apnea-hypopnea index (AHI). OSA is diagnosed by either of the following^3,4:

• AHI of 5 or higher, with clinical symptoms related to OSA (described below)
• AHI of 15 or higher, regardless of symptoms.

The AHI also defines OSA severity, as follows³:

• Mild: AHI 5 to 15
• Moderate: AHI 15 to 30
• Severe: AHI greater than 30.

Diagnostic criteria (eg, definition of hypopnea, testing methods, and AHI thresholds) have varied over time, an important consideration when reviewing the literature.

OSA IS MORE COMMON THAN EXPECTED AFTER STROKE

In the most methodologically sound and generalizable study of this topic to date, the Wisconsin Sleep Cohort Study⁶ reported in 2013 that about 14% of men and 5% of women ages 30 to 70 have an AHI greater than 5 (using 4% desaturation to score hypopneic episodes) with daytime sleepiness. Other studies suggest that 80% to 90% of people with OSA are undiagnosed and untreated.^1,7

The prevalence of OSA in patients who have had a stroke is much higher, ranging from 30% to 96% depending on the study methods and population.^1,8–12 A 2010 meta-analysis¹¹ of 29 studies reported that 72% of patients who had a stroke had an AHI greater than 5, and 29% had severe OSA. In this analysis, 7% of those with sleep-disordered breathing had central sleep apnea; still, these data indicate that the prevalence of OSA in these patients is about 5 times higher than in the general population.

RISK FACTORS MAY DIFFER IN STROKE POPULATION

Several risk factors for OSA have been identified.

Obesity is one of the strongest risk factors, with increasing body mass index (BMI) associated with increased OSA prevalence.^4,6,13 However, obesity appears to be a less significant risk factor in patients who have had a stroke than in the general population. In the 2010 meta-analysis¹¹ of OSA after stroke, the average BMI was only 26.4 kg/m² (with obesity defined as a BMI > 30.0 kg/m²), and increasing BMI was not associated with increasing AHI.

Male sex and advanced age are also OSA risk factors.^4,5 They remain significant in patients after a stroke; about 65% of poststroke patients who have OSA are men, and the older the patient, the more likely the AHI is greater than 10.¹¹

Ethnicity and genetics may also play important roles in OSA risk, with roughly 25% of OSA prevalence estimated to have a genetic basis.^14,15 Some risk factors for OSA such as craniofacial shape, upper airway anatomy, upper airway muscle dysfunction, increased respiratory chemosensitivity, and poor arousal threshold during sleep are likely determined by genetics and ethnicity.^14,15 Compared with people of European origin, Asians have a similar prevalence of OSA, but at a much lower average BMI, suggesting that other factors are significant.¹⁴ Possible genetically determined anatomic risk factors have not been specifically studied in the poststroke population, but it can be assumed they remain relevant.

Several studies have tried to find an association between OSA and type, location, etiology, or pattern of stroke.^{10,11,16–19} Although some suggest links between cardioembolic stroke and OSA,^16,20 or thrombolysis and OSA,¹⁰ most have found no association between OSA and stroke features.^11,12,21,22

HOW DOES OSA INCREASE STROKE RISK?

Untreated severe OSA is associated with increased cardiovascular mortality,^21,22 and OSA is an independent risk factor for incident stroke.²³ A number of mechanisms may explain these relationships.

Intermittent hypoxemia and recurrent sympathetic arousals resulting from OSA are thought to lead to many of the comorbid conditions with which it is associated: hypertension, coronary artery disease, heart failure, arrhythmias, pulmonary hypertension, and stroke. Repetitive decreases in ventilation lead to oxygen desaturations that result in cycles of increased sympathetic outflow and eventual sustained nocturnal hypertension and daytime chronic hypertension.^1,5,9,13 Also implicated are various changes in vasodilator and vasoconstrictor substances due to endothelial dysfunction and inflammation, which are thought to play a role in the atherogenic and prothrombotic states induced by OSA.^1,5,13

Cerebral circulation is altered primarily by the changes in partial pressure of carbon dioxide (Pco₂). During apnea, the Pco₂ rises, causing vasodilation and increased blood flow. After the apnea resolves, there is hyperpnea with resultant decreased Pco₂, and vasoconstriction. In a patient who already has vascular disease, the enhanced vasoconstriction could lead to ischemia.^1,5

Changes in intrathoracic pressure result in distortion of cardiac architecture. When the patient tries to breathe against an occluded airway, the intrathoracic pressure becomes more and more negative, increasing preload and afterload. When this happens repeatedly every night for years, it leads to remodeling of the heart such as left and right ventricular hypertrophy, with reduced stroke volume, myocardial ischemia, and increased risk of arrhythmia.^1,5,13

Untreated OSA is believed to predispose patients to develop atrial fibrillation through sympathetic overactivity, vascular inflammation, heart rate variability, and cardiac remodeling.²⁴ As atrial fibrillation is a major risk factor for stroke, particularly cardioembolic stroke, it may be another pathway of increased stroke risk in OSA.^16,20,25

 

 

CLINICAL MANIFESTATIONS OF OSA NOT OBVIOUS AFTER STROKE

OSA typically causes both daytime symptoms (excessive sleepiness, poor concentration, morning headache, depressive symptoms) and nighttime signs and symptoms (snoring, choking, gasping, night sweats, insomnia, nocturia, witnessed episodes of apnea).^3,4,26 Unfortunately, because these are nonspecific, OSA is often underdiagnosed.^4,26

Identifying OSA after a stroke may be a particular challenge, as patients often do not report classic symptoms, and the typical picture of OSA may have less predictive validity in these patients.^1,27,28 Within the first 24 hours after a stroke, hypersomnia, snoring history, and age are not predictive of OSA.¹ Patients found to have OSA after a stroke frequently do not have the traditional symptoms (sleepiness, snoring) seen in usual OSA patients. And they have higher rates of OSA at a younger age than the usual OSA patients, so age is not a predictive risk factor. In addition, daytime sleepiness and obesity are often absent or less prominent.^1,9,27,28  Finally, typical OSA signs and symptoms may be attributed to the stroke itself or to comorbidities affecting the patient, lowering suspicion for OSA.

OSA MAY HINDER STROKE RECOVERY, WORSEN OUTCOMES

OSA, particularly when moderate to severe, is linked to pathophysiologic changes that can hinder recovery from a stroke.

Intermittent hypoxemia during sleep can worsen vascular damage of at-risk tissue: nocturnal hypoxemia correlates with white matter hyperintensities on magnetic resonance imaging, a marker of ischemic demyelination.²⁹ Oxidative stress and release of inflammatory mediators associated with intermittent hypoxemia may impair vascular blood flow to brain tissue attempting to repair itself.³⁰ In addition, sympathetic overactivity and Pco₂ fluctuations associated with OSA may impede cerebral circulation.

Taken together, such ongoing nocturnal insults can lead to clinical consequences during this vulnerable period.

A 1996 study³¹ of patients recovering from a stroke found that an oxygen desaturation index (number of times that the blood oxygen level drops below a certain threshold, as measured by overnight oximetry) of more than 10 per hour was associated with worse functional recovery at discharge and at 3 and 12 months after discharge. This study also noted an association between time spent with oxygen saturations below 90% and the rate of death at 1 year.

A 2003 study³² reported that patients with an AHI greater than 10 by polysomnography spent an average of 13 days longer on the rehabilitation service and had worse functional and cognitive status on discharge, even after controlling for multiple confounders. Several subsequent studies have confirmed these and similar findings.^8,33,34

OSA has also been linked to depression,³⁵ which is common after stroke and may worsen outcomes.³⁶ The interaction between OSA, depression, and poststroke outcomes warrants further study.

In the general population, OSA has been independently associated with increased risk of stroke or death from any cause.^21,22,37 These associations have also been reported in the poststroke population: a 2014 meta-analysis found that OSA increased the risk of a repeat stroke (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2–2.6) and all-cause mortality (RR 1.69, 95% CI 1.4–2.1).³⁸

TESTING FOR OSA AFTER STROKE

Because of the high prevalence of OSA in patients who have had a stroke and the potential for worse outcomes associated with untreated OSA, there should be a low threshold for evaluating for OSA soon after stroke. Objective testing is required to qualify for therapy,  and the gold standard for diagnosis of OSA is formal polysomnography conducted in a sleep laboratory.^2–4 Unfortunately, polysomnography may be unacceptable to some patients, is costly, and is resource-intensive, particularly in an inpatient or rehabilitation setting.²⁸ Ideally, to optimize testing efficiency, patients should be screened for the likelihood of OSA before polysomnography is ordered.

Questionnaires can help determine the need for further testing

Questionnaires developed to assess OSA risk³⁹ include the following:

The Berlin questionnaire, developed in 1999, has 10 questions assessing daytime and nighttime signs and symptoms and presence of hypertension.

The STOP questionnaire, developed in 2008, assesses snoring, tiredness, observed apneic episodes, and elevated blood pressure.

The STOP-BANG questionnaire, published in 2010, includes the STOP questions plus BMI over 35 kg/m², age over 50, neck circumference over 41 cm, and male gender.

A 2017 meta-analysis³⁹ of 108 studies with nearly 50,000 people found that the STOP-BANG questionnaire performed best with regard to sensitivity and diagnostic odds ratio, but with poor specificity.

These screening tools and modified versions of them have also been evaluated in patients who have had a stroke.

In 2015, Boulos et al²⁸ found that the STOP-BAG (a version of STOP-BANG that excludes neck circumference) and the 4-variable (4V) questionnaire (sex, BMI, blood pressure, snoring) had moderate predictive value for OSA within 6 months after sroke.

In 2016, Katzan et al⁴⁰ found that the STOP-BAG2 (STOP-BAG criteria plus continuous variables for BMI and age) had a high sensitivity for polysomnographically diagnosed OSA within the first year after a stroke. The specificity was significantly better than the STOP-BANG or the STOP-BAG questionnaire, although it remained suboptimal at 60.5%.

In 2017, Sico et al⁴¹ developed and assessed the SLEEP Inventory (sex, left heart failure, Epworth Sleepiness Scale, enlarged neck, weight in pounds, insulin resistance or diabetes, and National Institutes of Health Stroke Scale) and found that it outperformed the Berlin and STOP-BANG questionnaires in the poststroke setting. The SLEEP Inventory had the best specificity and negative predictive value, and a slightly better ability to correctly classify patients as having OSA or not, classifying 80% of patients correctly.

These newer screening tools (eg, STOP-BAG, STOP-BAG2, SLEEP) can be used to identify with reasonable accuracy which patients need definitive testing after stroke.

Pulse oximetry is another possible screening tool          

Overnight pulse oximetry may also help screen for sleep apnea and stratify risk after a stroke. A 2012 study⁴² of overnight oximetry to screen patients before surgery found that the oxygen desaturation index was significantly associated with the AHI measured by polysomnography. However, oximetry testing cannot distinguish between OSA and central sleep apnea, so it is insufficient to diagnose OSA or qualify patients for therapy. Further study is needed to examine the ability of overnight pulse oximetry to screen or to stratify risk for OSA after stroke.

Polysomnography vs home testing

Polysomnography is the gold standard for diagnosing OSA. Benefits include technical support and trouble-shooting, determining relationships between OSA, body position, and sleep stage, and the ability to intervene with treatment.² However, polysomnography can be cumbersome, costly, and resource-intensive.

A home sleep apnea test, ie, an unattended, limited-channel sleep study, may be an acceptable alternative.^2–4,43,44 Home testing does not require a sleep technologist to be present during testing, uses fewer sensors, and is less expensive than overnight polysomnography, but its utility can be limited: it fails to accurately discriminate between episodes of OSA and central sleep apnea, there is potential for false-negative results, and it can underestimate sleep apnea burden because it does not measure sleep.²

Institutional resources and logistics may influence the choice of diagnostic modality. No data exist on outcomes from different diagnostic testing methods in poststroke patients. Further research is needed.

 

 

POSITIVE AIRWAY PRESSURE THERAPY: BENEFITS, CHALLENGES, ALTERNATIVES

The first-line treatment for OSA is positive airway pressure (PAP).³ For most patients, this is continuous PAP (CPAP) or autoadjusting PAP (APAP). In some instances, particularly for those who cannot tolerate CPAP or who have comorbid hypoventilation, bilevel PAP (BPAP) may be indicated. More advanced PAP therapies are unlikely to be used after stroke.

PAP therapy is associated with reduced daytime sleepiness, improved mood, normalization of sleep architecture, improved systemic and pulmonary artery blood pressure, reduced rates of atrial fibrillation after ablation, and improved insulin sensitivity.^45–49 Whether it reduces the risk of cardiovascular events, including stroke, remains controversial; most data suggest that it does not.^50,51 However, when adherence to PAP therapy is considered rather than intention to treat, treatment has been found to lead to improved cardiovascular outcomes.⁵²

Mixed evidence of benefits after stroke

Observational studies provide evidence that CPAP may help patients with OSA after stroke, although results are mixed.^53–58 The studies ranged in size from 14 to 105 patients, enrolled patients with mostly moderate to severe OSA, and followed patients from 10 days to 7 years. Adherence to therapy was generally good in the short term (50%–70%), but only  15% to 30% of patients remained adherent at 5 to 7 years. Variable outcomes were reported, with some studies finding improved symptoms in the near term and mixed evidence of cardiovascular benefit in the longer ones. However, as these studies lacked randomization, drawing definitive conclusions on CPAP efficacy is difficult.

Patients were enrolled in the index admission or when starting a rehabilitation service—generally 2 to 3 weeks after their stroke. No clear association was found between the timing of initiating PAP therapy and outcomes. All patients had ischemic strokes, but few details were provided regarding stroke location, size, and severity. Exclusion criteria included severe underlying cardiopulmonary disease, confusion, severe stroke with marked impairment, and inability to cooperate. Almost all patients had moderate to severe OSA, and patients with central sleep apnea were excluded.

The major outcomes examined were drop-out rates, PAP adherence, and neurologic improvement based on neurologic functional scales (National Institutes of Health Stroke Scale and Canadian Neurologic Scale). As expected, dropout rates were higher in patients randomized to CPAP (OR 1.83, 95% CI 1.05–3.21, P = .03), although overall adherence was better than anticipated, with mean CPAP use across trials of 4.5 hours per night (95% CI 3.97–5.08) and with about 50% to 60% of patients adhering to therapy for at least 4 hours nightly.

Improvement in neurologic outcomes favored CPAP (standard mean difference 0.54, 95% CI 0.026–1.05), although considerable heterogeneity was seen. Improved sleepiness outcomes were inconsistent. Major cardiovascular outcomes were reported in only 2 studies (using the same data set) and showed delayed time to the next cardiovascular event for those treated with CPAP but no difference in cardiovascular event-free survival.

PAP poses more challenges after stroke

The primary limitation to PAP therapy is poor acceptance and adherence to therapy.⁵⁹ High rates of refusal of therapy and difficulty complying with treatment have been noted in the poststroke population, although recent studies have reported better adherence rates. How rates of adherence play out in real-world settings, outside of the controlled environment of a research study, has yet to be determined.

In general, CPAP adherence is affected by claustrophobia, difficulty tolerating a mask, problems with pressure intolerance, irritating air leaks, nasal congestion, and naso-oral dryness. Many such barriers can be overcome with use of a properly fitted mask, an appropriate pressure setting, heated humidification, nasal sprays (eg, saline, inhaled steroids), and education, encouragement, and reassurance.

After a stroke, additional obstacles may impede the ability to use PAP therapy.⁶⁸ Facial paresis (hemi- or bifacial) may make fitting of the mask problematic. Paralysis or weakness of the extremities may limit the ability to adjust or remove a mask. Aphasia can impair communication and understanding of the need to use PAP therapy, and upper-airway problems related to stroke, including dysphagia, may lead to pressure intolerance or risk of aspiration. Finally, a lack of perceived benefit, particularly if the patient does not have daytime sleepiness, may limit motivation.

Consider alternatives

For patients unlikely to succeed with PAP therapy, there are alternatives. Surgery and oral appliances are not usually realistic options in the setting of recent stroke, but positional therapy, including the use of body positioners to prevent supine sleep, as well as elevating the head of the bed, may be of some benefit.^69,70 A nasopharyngeal airway stenting device (nasal trumpet) may also be tolerated by some patients.

A proposed algorithm for screening, diagnosing, and treating OSA in patients after stroke is presented in Figure 1.

To the Editor: The review by May et al¹ of 3 neglected numbers in the complete blood cell count (CBC) was a good reminder to look more closely at the results of the CBCs we often order in primary care. I was surprised to see no mention of the red cell distribution width in relation to another cardiovascular disorder—obstructive sleep apnea.^2,3 I wonder if the authors would comment on this association?

To the Editor: The review by May et al¹ of 3 neglected numbers in the complete blood cell count (CBC) was a good reminder to look more closely at the results of the CBCs we often order in primary care. I was surprised to see no mention of the red cell distribution width in relation to another cardiovascular disorder—obstructive sleep apnea.^2,3 I wonder if the authors would comment on this association?

To the Editor: The review by May et al¹ of 3 neglected numbers in the complete blood cell count (CBC) was a good reminder to look more closely at the results of the CBCs we often order in primary care. I was surprised to see no mention of the red cell distribution width in relation to another cardiovascular disorder—obstructive sleep apnea.^2,3 I wonder if the authors would comment on this association?

In Reply: We thank Dr. Homler for his question and for highlighting another important disease state, obstructive sleep apnea, in which a high red cell distribution width (RDW) has correlated with disease severity.^1,2 The 2 retrospective studies he mentioned indicated that RDW is negatively correlated with metrics such as oxygen saturation, sleep time, and sleep quality. Interestingly, another retrospective study showed that RDW was significantly higher in patients with concurrent obstructive sleep apnea and cardiovascular disease than in patients with obstructive sleep apnea alone, suggesting that the presence of anisocytosis in obstructive sleep apnea may be due to its link to cardiovascular disease.³

Although we focused on cardiovascular disease in our review, RDW has also shown prognostic significance in many other disorders including ischemic stroke,⁴ pneumonia,^5,6 chronic kidney disease,⁷ and gastrointestinal disorders.⁸ Collectively, these studies indicate that RDW may serve as a red flag for clinicians, raising concern for increased disease severity and potential adverse outcomes. However, further research is needed to determine if and how RDW monitoring should be used to prompt interventions to improve patient outcomes.

In Reply: We thank Dr. Homler for his question and for highlighting another important disease state, obstructive sleep apnea, in which a high red cell distribution width (RDW) has correlated with disease severity.^1,2 The 2 retrospective studies he mentioned indicated that RDW is negatively correlated with metrics such as oxygen saturation, sleep time, and sleep quality. Interestingly, another retrospective study showed that RDW was significantly higher in patients with concurrent obstructive sleep apnea and cardiovascular disease than in patients with obstructive sleep apnea alone, suggesting that the presence of anisocytosis in obstructive sleep apnea may be due to its link to cardiovascular disease.³

Although we focused on cardiovascular disease in our review, RDW has also shown prognostic significance in many other disorders including ischemic stroke,⁴ pneumonia,^5,6 chronic kidney disease,⁷ and gastrointestinal disorders.⁸ Collectively, these studies indicate that RDW may serve as a red flag for clinicians, raising concern for increased disease severity and potential adverse outcomes. However, further research is needed to determine if and how RDW monitoring should be used to prompt interventions to improve patient outcomes.

In Reply: We thank Dr. Homler for his question and for highlighting another important disease state, obstructive sleep apnea, in which a high red cell distribution width (RDW) has correlated with disease severity.^1,2 The 2 retrospective studies he mentioned indicated that RDW is negatively correlated with metrics such as oxygen saturation, sleep time, and sleep quality. Interestingly, another retrospective study showed that RDW was significantly higher in patients with concurrent obstructive sleep apnea and cardiovascular disease than in patients with obstructive sleep apnea alone, suggesting that the presence of anisocytosis in obstructive sleep apnea may be due to its link to cardiovascular disease.³

Although we focused on cardiovascular disease in our review, RDW has also shown prognostic significance in many other disorders including ischemic stroke,⁴ pneumonia,^5,6 chronic kidney disease,⁷ and gastrointestinal disorders.⁸ Collectively, these studies indicate that RDW may serve as a red flag for clinicians, raising concern for increased disease severity and potential adverse outcomes. However, further research is needed to determine if and how RDW monitoring should be used to prompt interventions to improve patient outcomes.

DALLAS – Continuous positive airway pressure (CPAP) is an effective, feasible treatment for infants with obstructive sleep apnea (OSA), according to a study.

“Positive airway pressure is a common treatment for OSA in children,” wrote Christopher Cielo, DO, of Children’s Hospital of Philadelphia Sleep Center, and his colleagues. But the authors note that treating infants with CPAP can be more challenging because infants have less consolidated sleep, may have greater medical complexity, and have smaller faces that make mask fit, titration, and adherence difficult.

The researchers therefore compared use of CPAP for OSA on 32 infants who began the therapy before age 6 months and 102 school-age children who began the therapy between ages 5 and 10 years, all treated at a single sleep center between March 2013 and September 2018.

Only one of the infants (mean age 3 months) had obesity, compared with 37.3% of the school-age children (mean age 7.7 years), but more of the infants (50%) had a craniofacial abnormality compared with the older children (8.9%) (P less than .001).

None of the infants had had an adenotonsillectomy, whereas the majority of the older children (80.4%) had (P less than .001). Rates of neurological abnormality and genetic syndromes (including Down syndrome) were similar between the groups.

In baseline polysomnograms, infants had a higher mean obstructive apnea-hypopnea index (AHI) compared with older children (22.6 vs. 12; P less than .001) and a slightly, but significantly, lower oxygen saturation nadir (81% vs. 87%; P = .002).

Only 9.8% of the children and none of the infants used autotitrating. Similar proportions of both groups – 90.6% of infants and 93.1% of children – achieved a mean AHI below 5 with CPAP treatment, and both CPAP pressure and mean oxygen saturation nadir at final pressure were similar in both groups.

Adherence was higher in infants than in children: Infants used CPAP for at least some time for 93.3% of nights compared with children (83.4%) (P = .009), and infants used CPAP for more than 4 hours for 78.4% of nights, compared with 59.5% of nights among children (P = .04).

Barriers to adherence reported by caregivers were similar between both groups. The most common barrier was child behavior, such as crying or refusing the CPAP, which 25% of infant caregivers and 35.3% of child caregivers reported. While a higher proportion of caregivers reported a poor mask fit for infants (15.6%) than for children (10.8%), the difference was not significant (P = .47). Rates of skin irritation also did not significantly differ between the groups.

In addition to the limitations accompanying any retrospective analysis from a single center, another study limitation was the inability to account for differences in total sleep time between infants and school-age children in comparing CPAP usage.

The National Institutes of Health and the Francis Family Foundation funded the research. The authors had no disclosures.

SOURCE: Cielo CM et al. ATS 2019. Abstract A2786.

DALLAS – Continuous positive airway pressure (CPAP) is an effective, feasible treatment for infants with obstructive sleep apnea (OSA), according to a study.

“Positive airway pressure is a common treatment for OSA in children,” wrote Christopher Cielo, DO, of Children’s Hospital of Philadelphia Sleep Center, and his colleagues. But the authors note that treating infants with CPAP can be more challenging because infants have less consolidated sleep, may have greater medical complexity, and have smaller faces that make mask fit, titration, and adherence difficult.

The researchers therefore compared use of CPAP for OSA on 32 infants who began the therapy before age 6 months and 102 school-age children who began the therapy between ages 5 and 10 years, all treated at a single sleep center between March 2013 and September 2018.

Only one of the infants (mean age 3 months) had obesity, compared with 37.3% of the school-age children (mean age 7.7 years), but more of the infants (50%) had a craniofacial abnormality compared with the older children (8.9%) (P less than .001).

None of the infants had had an adenotonsillectomy, whereas the majority of the older children (80.4%) had (P less than .001). Rates of neurological abnormality and genetic syndromes (including Down syndrome) were similar between the groups.

In baseline polysomnograms, infants had a higher mean obstructive apnea-hypopnea index (AHI) compared with older children (22.6 vs. 12; P less than .001) and a slightly, but significantly, lower oxygen saturation nadir (81% vs. 87%; P = .002).

Only 9.8% of the children and none of the infants used autotitrating. Similar proportions of both groups – 90.6% of infants and 93.1% of children – achieved a mean AHI below 5 with CPAP treatment, and both CPAP pressure and mean oxygen saturation nadir at final pressure were similar in both groups.

Adherence was higher in infants than in children: Infants used CPAP for at least some time for 93.3% of nights compared with children (83.4%) (P = .009), and infants used CPAP for more than 4 hours for 78.4% of nights, compared with 59.5% of nights among children (P = .04).

Barriers to adherence reported by caregivers were similar between both groups. The most common barrier was child behavior, such as crying or refusing the CPAP, which 25% of infant caregivers and 35.3% of child caregivers reported. While a higher proportion of caregivers reported a poor mask fit for infants (15.6%) than for children (10.8%), the difference was not significant (P = .47). Rates of skin irritation also did not significantly differ between the groups.

In addition to the limitations accompanying any retrospective analysis from a single center, another study limitation was the inability to account for differences in total sleep time between infants and school-age children in comparing CPAP usage.

The National Institutes of Health and the Francis Family Foundation funded the research. The authors had no disclosures.

SOURCE: Cielo CM et al. ATS 2019. Abstract A2786.

DALLAS – Continuous positive airway pressure (CPAP) is an effective, feasible treatment for infants with obstructive sleep apnea (OSA), according to a study.

“Positive airway pressure is a common treatment for OSA in children,” wrote Christopher Cielo, DO, of Children’s Hospital of Philadelphia Sleep Center, and his colleagues. But the authors note that treating infants with CPAP can be more challenging because infants have less consolidated sleep, may have greater medical complexity, and have smaller faces that make mask fit, titration, and adherence difficult.

The researchers therefore compared use of CPAP for OSA on 32 infants who began the therapy before age 6 months and 102 school-age children who began the therapy between ages 5 and 10 years, all treated at a single sleep center between March 2013 and September 2018.

Only one of the infants (mean age 3 months) had obesity, compared with 37.3% of the school-age children (mean age 7.7 years), but more of the infants (50%) had a craniofacial abnormality compared with the older children (8.9%) (P less than .001).

None of the infants had had an adenotonsillectomy, whereas the majority of the older children (80.4%) had (P less than .001). Rates of neurological abnormality and genetic syndromes (including Down syndrome) were similar between the groups.

In baseline polysomnograms, infants had a higher mean obstructive apnea-hypopnea index (AHI) compared with older children (22.6 vs. 12; P less than .001) and a slightly, but significantly, lower oxygen saturation nadir (81% vs. 87%; P = .002).

Only 9.8% of the children and none of the infants used autotitrating. Similar proportions of both groups – 90.6% of infants and 93.1% of children – achieved a mean AHI below 5 with CPAP treatment, and both CPAP pressure and mean oxygen saturation nadir at final pressure were similar in both groups.

Adherence was higher in infants than in children: Infants used CPAP for at least some time for 93.3% of nights compared with children (83.4%) (P = .009), and infants used CPAP for more than 4 hours for 78.4% of nights, compared with 59.5% of nights among children (P = .04).

Barriers to adherence reported by caregivers were similar between both groups. The most common barrier was child behavior, such as crying or refusing the CPAP, which 25% of infant caregivers and 35.3% of child caregivers reported. While a higher proportion of caregivers reported a poor mask fit for infants (15.6%) than for children (10.8%), the difference was not significant (P = .47). Rates of skin irritation also did not significantly differ between the groups.

In addition to the limitations accompanying any retrospective analysis from a single center, another study limitation was the inability to account for differences in total sleep time between infants and school-age children in comparing CPAP usage.

The National Institutes of Health and the Francis Family Foundation funded the research. The authors had no disclosures.

SOURCE: Cielo CM et al. ATS 2019. Abstract A2786.

DALLAS – Children with cystic fibrosis or asthma report sleep interruptions 1 or 2 nights a week caused by their symptoms, but nighttime use of technology may contribute more to sleep problems, according to a new study.

“Routinely addressing sleep concerns, sleep hygiene, and mental health is important in the care of pediatric patients with chronic illness,” concluded Lauren Greenawald, DO, and colleagues at the Alfred I. duPont Hospital for Children in Wilmington, Del. The researchers presented their findings on sleep quality and mental health of children with asthma or cystic fibrosis (CF) at the American Thoracic Society’s international conference.

Dr. Greenawald’s team screened 31 children (aged 7-17 years) with CF and 34 children with asthma for anxiety, depression, and ADHD. The researchers also assessed the children’s sleep hygiene, sleep quality, and physical and emotional symptoms. Instruments included the validated Pediatric Daytime Sleepiness Scale (PDSS), Pediatric Quality of Life Inventory, and Patient-Reported Outcomes Measurement Information System Pediatric Anxiety Survey, plus an investigator-designed survey about sleep habits.

Just over half the children with CF (52%) and 14% of children with asthma had mental health diagnoses (P less than .01). The same proportion of patients with CF (52%) and nearly a third of patients with asthma (30%) reported they often or always felt they needed more sleep based on the PDSS. Further, 42% of children with CF and 55% of children with asthma said their symptoms kept them awake 1-2 nights a week. Only 6% of asthma patients and no CF patients said their symptoms keep them awake often, 3-4 nights a week. Just over a third of children with CF (36%) and 46% of those with asthma thought they would sleep better if they didn’t have a medical condition.

Yet, for the vast majority of children, the sleeping problems did not appear to result from worry about their illness: 85% of those with CF and nearly all of those with asthma (97%) did not have trouble sleeping as a result of anxiety about their medical condition.

The researchers identified nighttime use of technology that may affect the children’s sleep in ways similar to that of the general population. Many of the participants – 68% of those with CF and 47% of those with asthma – reported texting or using social media or other technology an hour before going to bed. In addition, 55% of those with CF and 25% of those with asthma said they use their phone after the lights are out at least 5 nights a week. One in five of those with CF (20%) said they go to bed later than they planned at least 5 days a week because of social media or texting, though only 6% of those with asthma said the same.

Despite the children’s reports of inadequate sleep, very few – 3.2% of children with CF and 5.9% of children with asthma – reported feeling low daytime energy.

The use of child self-reporting in the presence of family members is a study limitation, including potentially introducing social desirability bias.

The research was funded by the Nemours Summer Undergraduate Research Program. The authors reported no disclosures.

SOURCE: Greenawald L et al. ATS 2019, Abstract A2788.

DALLAS – Children with cystic fibrosis or asthma report sleep interruptions 1 or 2 nights a week caused by their symptoms, but nighttime use of technology may contribute more to sleep problems, according to a new study.

“Routinely addressing sleep concerns, sleep hygiene, and mental health is important in the care of pediatric patients with chronic illness,” concluded Lauren Greenawald, DO, and colleagues at the Alfred I. duPont Hospital for Children in Wilmington, Del. The researchers presented their findings on sleep quality and mental health of children with asthma or cystic fibrosis (CF) at the American Thoracic Society’s international conference.

Dr. Greenawald’s team screened 31 children (aged 7-17 years) with CF and 34 children with asthma for anxiety, depression, and ADHD. The researchers also assessed the children’s sleep hygiene, sleep quality, and physical and emotional symptoms. Instruments included the validated Pediatric Daytime Sleepiness Scale (PDSS), Pediatric Quality of Life Inventory, and Patient-Reported Outcomes Measurement Information System Pediatric Anxiety Survey, plus an investigator-designed survey about sleep habits.

Just over half the children with CF (52%) and 14% of children with asthma had mental health diagnoses (P less than .01). The same proportion of patients with CF (52%) and nearly a third of patients with asthma (30%) reported they often or always felt they needed more sleep based on the PDSS. Further, 42% of children with CF and 55% of children with asthma said their symptoms kept them awake 1-2 nights a week. Only 6% of asthma patients and no CF patients said their symptoms keep them awake often, 3-4 nights a week. Just over a third of children with CF (36%) and 46% of those with asthma thought they would sleep better if they didn’t have a medical condition.

Yet, for the vast majority of children, the sleeping problems did not appear to result from worry about their illness: 85% of those with CF and nearly all of those with asthma (97%) did not have trouble sleeping as a result of anxiety about their medical condition.

The researchers identified nighttime use of technology that may affect the children’s sleep in ways similar to that of the general population. Many of the participants – 68% of those with CF and 47% of those with asthma – reported texting or using social media or other technology an hour before going to bed. In addition, 55% of those with CF and 25% of those with asthma said they use their phone after the lights are out at least 5 nights a week. One in five of those with CF (20%) said they go to bed later than they planned at least 5 days a week because of social media or texting, though only 6% of those with asthma said the same.

Despite the children’s reports of inadequate sleep, very few – 3.2% of children with CF and 5.9% of children with asthma – reported feeling low daytime energy.

The use of child self-reporting in the presence of family members is a study limitation, including potentially introducing social desirability bias.

The research was funded by the Nemours Summer Undergraduate Research Program. The authors reported no disclosures.

SOURCE: Greenawald L et al. ATS 2019, Abstract A2788.

DALLAS – Children with cystic fibrosis or asthma report sleep interruptions 1 or 2 nights a week caused by their symptoms, but nighttime use of technology may contribute more to sleep problems, according to a new study.

“Routinely addressing sleep concerns, sleep hygiene, and mental health is important in the care of pediatric patients with chronic illness,” concluded Lauren Greenawald, DO, and colleagues at the Alfred I. duPont Hospital for Children in Wilmington, Del. The researchers presented their findings on sleep quality and mental health of children with asthma or cystic fibrosis (CF) at the American Thoracic Society’s international conference.

Dr. Greenawald’s team screened 31 children (aged 7-17 years) with CF and 34 children with asthma for anxiety, depression, and ADHD. The researchers also assessed the children’s sleep hygiene, sleep quality, and physical and emotional symptoms. Instruments included the validated Pediatric Daytime Sleepiness Scale (PDSS), Pediatric Quality of Life Inventory, and Patient-Reported Outcomes Measurement Information System Pediatric Anxiety Survey, plus an investigator-designed survey about sleep habits.

Just over half the children with CF (52%) and 14% of children with asthma had mental health diagnoses (P less than .01). The same proportion of patients with CF (52%) and nearly a third of patients with asthma (30%) reported they often or always felt they needed more sleep based on the PDSS. Further, 42% of children with CF and 55% of children with asthma said their symptoms kept them awake 1-2 nights a week. Only 6% of asthma patients and no CF patients said their symptoms keep them awake often, 3-4 nights a week. Just over a third of children with CF (36%) and 46% of those with asthma thought they would sleep better if they didn’t have a medical condition.

Yet, for the vast majority of children, the sleeping problems did not appear to result from worry about their illness: 85% of those with CF and nearly all of those with asthma (97%) did not have trouble sleeping as a result of anxiety about their medical condition.

The researchers identified nighttime use of technology that may affect the children’s sleep in ways similar to that of the general population. Many of the participants – 68% of those with CF and 47% of those with asthma – reported texting or using social media or other technology an hour before going to bed. In addition, 55% of those with CF and 25% of those with asthma said they use their phone after the lights are out at least 5 nights a week. One in five of those with CF (20%) said they go to bed later than they planned at least 5 days a week because of social media or texting, though only 6% of those with asthma said the same.

Despite the children’s reports of inadequate sleep, very few – 3.2% of children with CF and 5.9% of children with asthma – reported feeling low daytime energy.

The use of child self-reporting in the presence of family members is a study limitation, including potentially introducing social desirability bias.

The research was funded by the Nemours Summer Undergraduate Research Program. The authors reported no disclosures.

SOURCE: Greenawald L et al. ATS 2019, Abstract A2788.

Seattle – Periodic limb movements during sleep (PLMS) are common in patients with multiple sclerosis (MS) who report fatigue, according to a retrospective analysis described at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“PLMS may contribute to daytime sleepiness and should be recognized and potentially treated. The etiology of fatigue related to sleep problems in people with MS is multifactorial and not just due to obstructive sleep apnea,” said lead author Jared Srinivasan, clinical research coordinator at South Shore Neurologic Associates in East Northport, New York, and colleagues.

Fatigue is common in patients with MS and can be disabling. For many patients with MS, sleep apnea is the underlying cause of fatigue. PLMS – leg movements that usually occur at 20- to 40-second intervals during sleep – are not commonly reported in MS. These movements cause sleep fragmentation, increase the energy cost of sleep, and contribute to daytime somnolence. Patients with PLMS often are unaware that they have them and do not report related symptoms unless they are specifically questioned about them. Polysomnography (PSG) is an effective, objective method of evaluating a patient for PLMS, but previous studies of PLMS in patients with MS have been small.

Mr. Srinivasan and colleagues performed a retrospective analysis to investigate the incidence and degree of PLMS in people with MS who had reported fatigue, had not previously been diagnosed as having sleep apnea or PLMS, and agreed to undergo overnight PSG.

The investigators included 292 participants in their study. The population’s average age was 47.3 years. Approximately 81% of patients were female. About 41% of the population had a PLMS index (PLMS per hour) greater than 0. Of participants with PSG-identified PLMS, 10% had a PLMS index of 5-10, 5% had a PLMS index of 11-21, and 12% had a PLMS index greater than 21. About 38% of the population experienced arousal because of PLMS. Of patients with arousal, 34% had a PLMS arousal index (number of arousals per hour) between 0 and 5, 31% had PLMS arousal index of 5-20, 14% had a PLMS arousal index of 20-50, and 21% had a PLMS arousal index greater than 50.

The investigators did not receive financial support for this study and did not report disclosures.
 

egreb@mdedge.com

SOURCE: Srinivasan J et al. CMSC 2019. Abstract QOL29.

Seattle – Periodic limb movements during sleep (PLMS) are common in patients with multiple sclerosis (MS) who report fatigue, according to a retrospective analysis described at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“PLMS may contribute to daytime sleepiness and should be recognized and potentially treated. The etiology of fatigue related to sleep problems in people with MS is multifactorial and not just due to obstructive sleep apnea,” said lead author Jared Srinivasan, clinical research coordinator at South Shore Neurologic Associates in East Northport, New York, and colleagues.

Fatigue is common in patients with MS and can be disabling. For many patients with MS, sleep apnea is the underlying cause of fatigue. PLMS – leg movements that usually occur at 20- to 40-second intervals during sleep – are not commonly reported in MS. These movements cause sleep fragmentation, increase the energy cost of sleep, and contribute to daytime somnolence. Patients with PLMS often are unaware that they have them and do not report related symptoms unless they are specifically questioned about them. Polysomnography (PSG) is an effective, objective method of evaluating a patient for PLMS, but previous studies of PLMS in patients with MS have been small.

Mr. Srinivasan and colleagues performed a retrospective analysis to investigate the incidence and degree of PLMS in people with MS who had reported fatigue, had not previously been diagnosed as having sleep apnea or PLMS, and agreed to undergo overnight PSG.

The investigators included 292 participants in their study. The population’s average age was 47.3 years. Approximately 81% of patients were female. About 41% of the population had a PLMS index (PLMS per hour) greater than 0. Of participants with PSG-identified PLMS, 10% had a PLMS index of 5-10, 5% had a PLMS index of 11-21, and 12% had a PLMS index greater than 21. About 38% of the population experienced arousal because of PLMS. Of patients with arousal, 34% had a PLMS arousal index (number of arousals per hour) between 0 and 5, 31% had PLMS arousal index of 5-20, 14% had a PLMS arousal index of 20-50, and 21% had a PLMS arousal index greater than 50.

The investigators did not receive financial support for this study and did not report disclosures.
 

egreb@mdedge.com

SOURCE: Srinivasan J et al. CMSC 2019. Abstract QOL29.

Seattle – Periodic limb movements during sleep (PLMS) are common in patients with multiple sclerosis (MS) who report fatigue, according to a retrospective analysis described at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“PLMS may contribute to daytime sleepiness and should be recognized and potentially treated. The etiology of fatigue related to sleep problems in people with MS is multifactorial and not just due to obstructive sleep apnea,” said lead author Jared Srinivasan, clinical research coordinator at South Shore Neurologic Associates in East Northport, New York, and colleagues.

Fatigue is common in patients with MS and can be disabling. For many patients with MS, sleep apnea is the underlying cause of fatigue. PLMS – leg movements that usually occur at 20- to 40-second intervals during sleep – are not commonly reported in MS. These movements cause sleep fragmentation, increase the energy cost of sleep, and contribute to daytime somnolence. Patients with PLMS often are unaware that they have them and do not report related symptoms unless they are specifically questioned about them. Polysomnography (PSG) is an effective, objective method of evaluating a patient for PLMS, but previous studies of PLMS in patients with MS have been small.

Mr. Srinivasan and colleagues performed a retrospective analysis to investigate the incidence and degree of PLMS in people with MS who had reported fatigue, had not previously been diagnosed as having sleep apnea or PLMS, and agreed to undergo overnight PSG.

The investigators included 292 participants in their study. The population’s average age was 47.3 years. Approximately 81% of patients were female. About 41% of the population had a PLMS index (PLMS per hour) greater than 0. Of participants with PSG-identified PLMS, 10% had a PLMS index of 5-10, 5% had a PLMS index of 11-21, and 12% had a PLMS index greater than 21. About 38% of the population experienced arousal because of PLMS. Of patients with arousal, 34% had a PLMS arousal index (number of arousals per hour) between 0 and 5, 31% had PLMS arousal index of 5-20, 14% had a PLMS arousal index of 20-50, and 21% had a PLMS arousal index greater than 50.

The investigators did not receive financial support for this study and did not report disclosures.
 

egreb@mdedge.com

SOURCE: Srinivasan J et al. CMSC 2019. Abstract QOL29.

SEATTLE – Future behavioral interventions for improving sleep in patients with multiple sclerosis (MS) should focus on sedentary behavior and light physical activity, according to a study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Reducing sedentary behavior among young adults with MS could improve sleep efficiency, and increasing the time spent in light physical activity could improve sleep latency for older adults with MS, said the researchers.

Sleep quality generally decreases with age. Among patients with MS, the prevalence of sleep problems increases threefold with age. Although data indicate that physical activity has many benefits for patients with MS, little research has examined the relationships between physical activity, sedentary behavior, and sleep quality across the lifespan in this population.

Katie L.J. Cederberg, a doctoral student at the University of Alabama at Birmingham, and colleagues recruited 127 adults with MS representing three age groups into a study. In all, 42 participants were younger (aged 20-39 years), 44 were middle-aged (40-59 years), and 41 were older (60-79 years). Participants completed the Pittsburgh Sleep Quality Index (PSQI) and the Patient-Determined Disease Steps (PDDS) scale. Each participant also wore an accelerometer for 7 days. Ms. Cederberg and colleagues analyzed the accelerometer data to determine the time per day that participants spent in light physical activity, moderate-to-vigorous physical activity, and sedentary behavior using MS-specific cutpoints.

Compared with younger adults, older adults had significantly lower PSQI global scores and reported more frequent use of sleeping medications. Compared with middle-aged adults, older adults had significantly higher disability levels and spent significantly less time in moderate-to-vigorous physical activity. In addition, among older adults, sleep latency was negatively associated with time spent in light physical activity, and clinical disability was inversely associated with time spent in moderate-to-vigorous physical activity.

In younger adults, habitual sleep efficiency was inversely associated with time spent in sedentary behavior. The researchers found no significant associations between these variables in middle-aged adults.
 

egreb@mdedge.com

SOURCE: Cederberg KLJ et al. CMSC 2019. Abstract DXA05.

SEATTLE – Future behavioral interventions for improving sleep in patients with multiple sclerosis (MS) should focus on sedentary behavior and light physical activity, according to a study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Reducing sedentary behavior among young adults with MS could improve sleep efficiency, and increasing the time spent in light physical activity could improve sleep latency for older adults with MS, said the researchers.

Sleep quality generally decreases with age. Among patients with MS, the prevalence of sleep problems increases threefold with age. Although data indicate that physical activity has many benefits for patients with MS, little research has examined the relationships between physical activity, sedentary behavior, and sleep quality across the lifespan in this population.

Katie L.J. Cederberg, a doctoral student at the University of Alabama at Birmingham, and colleagues recruited 127 adults with MS representing three age groups into a study. In all, 42 participants were younger (aged 20-39 years), 44 were middle-aged (40-59 years), and 41 were older (60-79 years). Participants completed the Pittsburgh Sleep Quality Index (PSQI) and the Patient-Determined Disease Steps (PDDS) scale. Each participant also wore an accelerometer for 7 days. Ms. Cederberg and colleagues analyzed the accelerometer data to determine the time per day that participants spent in light physical activity, moderate-to-vigorous physical activity, and sedentary behavior using MS-specific cutpoints.

Compared with younger adults, older adults had significantly lower PSQI global scores and reported more frequent use of sleeping medications. Compared with middle-aged adults, older adults had significantly higher disability levels and spent significantly less time in moderate-to-vigorous physical activity. In addition, among older adults, sleep latency was negatively associated with time spent in light physical activity, and clinical disability was inversely associated with time spent in moderate-to-vigorous physical activity.

In younger adults, habitual sleep efficiency was inversely associated with time spent in sedentary behavior. The researchers found no significant associations between these variables in middle-aged adults.
 

egreb@mdedge.com

SOURCE: Cederberg KLJ et al. CMSC 2019. Abstract DXA05.

SEATTLE – Future behavioral interventions for improving sleep in patients with multiple sclerosis (MS) should focus on sedentary behavior and light physical activity, according to a study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Reducing sedentary behavior among young adults with MS could improve sleep efficiency, and increasing the time spent in light physical activity could improve sleep latency for older adults with MS, said the researchers.

Sleep quality generally decreases with age. Among patients with MS, the prevalence of sleep problems increases threefold with age. Although data indicate that physical activity has many benefits for patients with MS, little research has examined the relationships between physical activity, sedentary behavior, and sleep quality across the lifespan in this population.

Katie L.J. Cederberg, a doctoral student at the University of Alabama at Birmingham, and colleagues recruited 127 adults with MS representing three age groups into a study. In all, 42 participants were younger (aged 20-39 years), 44 were middle-aged (40-59 years), and 41 were older (60-79 years). Participants completed the Pittsburgh Sleep Quality Index (PSQI) and the Patient-Determined Disease Steps (PDDS) scale. Each participant also wore an accelerometer for 7 days. Ms. Cederberg and colleagues analyzed the accelerometer data to determine the time per day that participants spent in light physical activity, moderate-to-vigorous physical activity, and sedentary behavior using MS-specific cutpoints.

Compared with younger adults, older adults had significantly lower PSQI global scores and reported more frequent use of sleeping medications. Compared with middle-aged adults, older adults had significantly higher disability levels and spent significantly less time in moderate-to-vigorous physical activity. In addition, among older adults, sleep latency was negatively associated with time spent in light physical activity, and clinical disability was inversely associated with time spent in moderate-to-vigorous physical activity.

In younger adults, habitual sleep efficiency was inversely associated with time spent in sedentary behavior. The researchers found no significant associations between these variables in middle-aged adults.
 

egreb@mdedge.com

SOURCE: Cederberg KLJ et al. CMSC 2019. Abstract DXA05.

Unrecognized severe obstructive sleep apnea is a risk factor for cardiovascular complications after major noncardiac surgery, according to a study published in JAMA.

The researchers state that perioperative mismanagement of obstructive sleep apnea can lead to serious medical consequences. “General anesthetics, sedatives, and postoperative analgesics are potent respiratory depressants that relax the upper airway dilator muscles and impair ventilatory response to hypoxemia and hypercapnia. Each of these events exacerbates [obstructive sleep apnea] and may predispose patients to postoperative cardiovascular complications,” said researchers who conducted the The Postoperative vascular complications in unrecognised Obstructive Sleep apnoea (POSA) study (NCT01494181).

They undertook a prospective observational cohort study involving 1,218 patients undergoing major noncardiac surgery, who were already considered at high risk of postoperative cardiovascular events – having, for example, a history of coronary artery disease, stroke, diabetes, or renal impairment. However, none had a prior diagnosis of obstructive sleep apnea.

Preoperative sleep monitoring revealed that two-thirds of the cohort had unrecognized and untreated obstructive sleep apnea, including 11.2% with severe obstructive sleep apnea.

At 30 days after surgery, patients with obstructive sleep apnea had a 49% higher risk of the primary outcome of myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation, or stroke, compared with those without obstructive sleep apnea.

However, this association was largely due to a significant 2.23-fold higher risk among patients with severe obstructive sleep apnea, while those with only moderate or mild sleep apnea did not show a significant increased risk of cardiovascular complications.

Patients in this study with severe obstructive sleep apnea had a 13-fold higher risk of cardiac death, 80% higher risk of myocardial injury, more than sixfold higher risk of heart failure, and nearly fourfold higher risk of atrial fibrillation.

Researchers also saw an association between obstructive sleep apnea and increased risk of infective outcomes, unplanned tracheal intubation, postoperative lung ventilation, and readmission to the ICU.

The majority of patients received nocturnal oximetry monitoring during their first 3 nights after surgery. This revealed that patients without obstructive sleep apnea had significant increases in oxygen desaturation index during their first night after surgery, while those with sleep apnea did not return to their baseline oxygen desaturation index until the third night after surgery.

“Despite a substantial decrease in ODI [oxygen desaturation index] with oxygen therapy in patients with OSA during the first 3 postoperative nights, supplemental oxygen did not modify the association between OSA and postoperative cardiovascular event,” wrote Matthew T.V. Chan, MD, of Chinese University of Hong Kong, Prince of Wales Hospital, and coauthors.

Given that the events were associated with longer durations of severe oxyhemoglobin desaturation, more aggressive interventions such as positive airway pressure or oral appliances may be required, they noted.

“However, high-level evidence demonstrating the effect of these measures on perioperative outcomes is lacking [and] further clinical trials are now required to test if additional monitoring or alternative interventions would reduce the risk,” they wrote.

The study was supported by the Health and Medical Research Fund (Hong Kong), National Healthcare Group–Khoo Teck Puat Hospital, University Health Network Foundation, University of Malaya, Malaysian Society of Anaesthesiologists, Auckland Medical Research Foundation, and ResMed. One author declared grants from private industry and a patent pending on an obstructive sleep apnea risk questionnaire used in the study.

SOURCE: Chan M et al. JAMA 2019;321[18]:1788-98. doi: 10.1001/jama.2019.4783.

Unrecognized severe obstructive sleep apnea is a risk factor for cardiovascular complications after major noncardiac surgery, according to a study published in JAMA.

The researchers state that perioperative mismanagement of obstructive sleep apnea can lead to serious medical consequences. “General anesthetics, sedatives, and postoperative analgesics are potent respiratory depressants that relax the upper airway dilator muscles and impair ventilatory response to hypoxemia and hypercapnia. Each of these events exacerbates [obstructive sleep apnea] and may predispose patients to postoperative cardiovascular complications,” said researchers who conducted the The Postoperative vascular complications in unrecognised Obstructive Sleep apnoea (POSA) study (NCT01494181).

They undertook a prospective observational cohort study involving 1,218 patients undergoing major noncardiac surgery, who were already considered at high risk of postoperative cardiovascular events – having, for example, a history of coronary artery disease, stroke, diabetes, or renal impairment. However, none had a prior diagnosis of obstructive sleep apnea.

Preoperative sleep monitoring revealed that two-thirds of the cohort had unrecognized and untreated obstructive sleep apnea, including 11.2% with severe obstructive sleep apnea.

At 30 days after surgery, patients with obstructive sleep apnea had a 49% higher risk of the primary outcome of myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation, or stroke, compared with those without obstructive sleep apnea.

However, this association was largely due to a significant 2.23-fold higher risk among patients with severe obstructive sleep apnea, while those with only moderate or mild sleep apnea did not show a significant increased risk of cardiovascular complications.

Patients in this study with severe obstructive sleep apnea had a 13-fold higher risk of cardiac death, 80% higher risk of myocardial injury, more than sixfold higher risk of heart failure, and nearly fourfold higher risk of atrial fibrillation.

Researchers also saw an association between obstructive sleep apnea and increased risk of infective outcomes, unplanned tracheal intubation, postoperative lung ventilation, and readmission to the ICU.

The majority of patients received nocturnal oximetry monitoring during their first 3 nights after surgery. This revealed that patients without obstructive sleep apnea had significant increases in oxygen desaturation index during their first night after surgery, while those with sleep apnea did not return to their baseline oxygen desaturation index until the third night after surgery.

“Despite a substantial decrease in ODI [oxygen desaturation index] with oxygen therapy in patients with OSA during the first 3 postoperative nights, supplemental oxygen did not modify the association between OSA and postoperative cardiovascular event,” wrote Matthew T.V. Chan, MD, of Chinese University of Hong Kong, Prince of Wales Hospital, and coauthors.

Given that the events were associated with longer durations of severe oxyhemoglobin desaturation, more aggressive interventions such as positive airway pressure or oral appliances may be required, they noted.

“However, high-level evidence demonstrating the effect of these measures on perioperative outcomes is lacking [and] further clinical trials are now required to test if additional monitoring or alternative interventions would reduce the risk,” they wrote.

The study was supported by the Health and Medical Research Fund (Hong Kong), National Healthcare Group–Khoo Teck Puat Hospital, University Health Network Foundation, University of Malaya, Malaysian Society of Anaesthesiologists, Auckland Medical Research Foundation, and ResMed. One author declared grants from private industry and a patent pending on an obstructive sleep apnea risk questionnaire used in the study.

SOURCE: Chan M et al. JAMA 2019;321[18]:1788-98. doi: 10.1001/jama.2019.4783.

Unrecognized severe obstructive sleep apnea is a risk factor for cardiovascular complications after major noncardiac surgery, according to a study published in JAMA.

The researchers state that perioperative mismanagement of obstructive sleep apnea can lead to serious medical consequences. “General anesthetics, sedatives, and postoperative analgesics are potent respiratory depressants that relax the upper airway dilator muscles and impair ventilatory response to hypoxemia and hypercapnia. Each of these events exacerbates [obstructive sleep apnea] and may predispose patients to postoperative cardiovascular complications,” said researchers who conducted the The Postoperative vascular complications in unrecognised Obstructive Sleep apnoea (POSA) study (NCT01494181).

They undertook a prospective observational cohort study involving 1,218 patients undergoing major noncardiac surgery, who were already considered at high risk of postoperative cardiovascular events – having, for example, a history of coronary artery disease, stroke, diabetes, or renal impairment. However, none had a prior diagnosis of obstructive sleep apnea.

Preoperative sleep monitoring revealed that two-thirds of the cohort had unrecognized and untreated obstructive sleep apnea, including 11.2% with severe obstructive sleep apnea.

At 30 days after surgery, patients with obstructive sleep apnea had a 49% higher risk of the primary outcome of myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation, or stroke, compared with those without obstructive sleep apnea.

However, this association was largely due to a significant 2.23-fold higher risk among patients with severe obstructive sleep apnea, while those with only moderate or mild sleep apnea did not show a significant increased risk of cardiovascular complications.

Patients in this study with severe obstructive sleep apnea had a 13-fold higher risk of cardiac death, 80% higher risk of myocardial injury, more than sixfold higher risk of heart failure, and nearly fourfold higher risk of atrial fibrillation.

Researchers also saw an association between obstructive sleep apnea and increased risk of infective outcomes, unplanned tracheal intubation, postoperative lung ventilation, and readmission to the ICU.

The majority of patients received nocturnal oximetry monitoring during their first 3 nights after surgery. This revealed that patients without obstructive sleep apnea had significant increases in oxygen desaturation index during their first night after surgery, while those with sleep apnea did not return to their baseline oxygen desaturation index until the third night after surgery.

“Despite a substantial decrease in ODI [oxygen desaturation index] with oxygen therapy in patients with OSA during the first 3 postoperative nights, supplemental oxygen did not modify the association between OSA and postoperative cardiovascular event,” wrote Matthew T.V. Chan, MD, of Chinese University of Hong Kong, Prince of Wales Hospital, and coauthors.

Given that the events were associated with longer durations of severe oxyhemoglobin desaturation, more aggressive interventions such as positive airway pressure or oral appliances may be required, they noted.

“However, high-level evidence demonstrating the effect of these measures on perioperative outcomes is lacking [and] further clinical trials are now required to test if additional monitoring or alternative interventions would reduce the risk,” they wrote.

The study was supported by the Health and Medical Research Fund (Hong Kong), National Healthcare Group–Khoo Teck Puat Hospital, University Health Network Foundation, University of Malaya, Malaysian Society of Anaesthesiologists, Auckland Medical Research Foundation, and ResMed. One author declared grants from private industry and a patent pending on an obstructive sleep apnea risk questionnaire used in the study.

SOURCE: Chan M et al. JAMA 2019;321[18]:1788-98. doi: 10.1001/jama.2019.4783.

PHILADELPHIA – Nearly a quarter of adults with epilepsy have moderate or severe insomnia, and insomnia symptoms are associated with depression, anxiety, worse seizure control, and poorer quality of life, according to a prospective analysis presented at the annual meeting of the American Academy of Neurology. Insomnia symptoms are not associated with epilepsy type, number of antiepileptic drugs (AEDs), or AED standardized dose, however.

“Given the potential benefits of sleep therapies on epilepsy outcomes, routine screening of insomnia symptoms is warranted,” said lead study author Thapanee Somboon, MD, a researcher at the sleep disorders center at Cleveland Clinic Neurological Institute in Ohio and at Prasat Neurological Institute in Bangkok.

Insomnia is common and associated with depression in patients with epilepsy, but prior studies that looked at the relationship between insomnia and epilepsy-related characteristics yielded limited and conflicting results, according to Dr. Somboon.

To evaluate potential associations between insomnia and epilepsy, Dr. Somboon and colleagues conducted a prospective analysis of data from 270 patients with epilepsy who presented to the Cleveland Clinic Epilepsy Center for an initial evaluation between January and August 2018. The patients completed the Insomnia Severity Index (ISI). An ISI score of 8 or greater indicated clinical insomnia symptoms, and an ISI score of 15 or greater indicated moderate or severe insomnia symptoms.

The researchers used Spearman’s correlation and the Kruskal-Wallis test to evaluate associations among insomnia symptoms and AED standardized dose, monthly seizure frequency, Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Questionnaire (GAD-7), and Quality of Life in Epilepsy-10 (QOLIE10).

Among the 270 patients, the average age was 43.5 years, 58% were female, 74% had focal epilepsy, and 26% had one or more seizures per month. The population’s median ISI score was 7. Nearly half had an ISI score of 8 or greater, and 23% had an ISI score of 15 or greater.

“A positive correlation was found between ISI and PHQ-9 (r = 0.64, P less than .001), GAD-7 (r = 0.68, P less than .001), QOLIE (r = 0.55, P less than .001), and monthly seizure frequency (r = 0.31, P less than .001),” the researchers reported. Insomnia symptoms had a significantly stronger correlation with PHQ-9 and GAD-7 than with seizure frequency.

Dr. Somboon had no disclosures. A coinvestigator has received research support from Jazz Pharmaceuticals.

jremaly@mdedge.com

SOURCE: Somboon T et al. AAN 2019, Abstract P3.6-026.

PHILADELPHIA – Nearly a quarter of adults with epilepsy have moderate or severe insomnia, and insomnia symptoms are associated with depression, anxiety, worse seizure control, and poorer quality of life, according to a prospective analysis presented at the annual meeting of the American Academy of Neurology. Insomnia symptoms are not associated with epilepsy type, number of antiepileptic drugs (AEDs), or AED standardized dose, however.

“Given the potential benefits of sleep therapies on epilepsy outcomes, routine screening of insomnia symptoms is warranted,” said lead study author Thapanee Somboon, MD, a researcher at the sleep disorders center at Cleveland Clinic Neurological Institute in Ohio and at Prasat Neurological Institute in Bangkok.

Insomnia is common and associated with depression in patients with epilepsy, but prior studies that looked at the relationship between insomnia and epilepsy-related characteristics yielded limited and conflicting results, according to Dr. Somboon.

To evaluate potential associations between insomnia and epilepsy, Dr. Somboon and colleagues conducted a prospective analysis of data from 270 patients with epilepsy who presented to the Cleveland Clinic Epilepsy Center for an initial evaluation between January and August 2018. The patients completed the Insomnia Severity Index (ISI). An ISI score of 8 or greater indicated clinical insomnia symptoms, and an ISI score of 15 or greater indicated moderate or severe insomnia symptoms.

The researchers used Spearman’s correlation and the Kruskal-Wallis test to evaluate associations among insomnia symptoms and AED standardized dose, monthly seizure frequency, Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Questionnaire (GAD-7), and Quality of Life in Epilepsy-10 (QOLIE10).

Among the 270 patients, the average age was 43.5 years, 58% were female, 74% had focal epilepsy, and 26% had one or more seizures per month. The population’s median ISI score was 7. Nearly half had an ISI score of 8 or greater, and 23% had an ISI score of 15 or greater.

“A positive correlation was found between ISI and PHQ-9 (r = 0.64, P less than .001), GAD-7 (r = 0.68, P less than .001), QOLIE (r = 0.55, P less than .001), and monthly seizure frequency (r = 0.31, P less than .001),” the researchers reported. Insomnia symptoms had a significantly stronger correlation with PHQ-9 and GAD-7 than with seizure frequency.

Dr. Somboon had no disclosures. A coinvestigator has received research support from Jazz Pharmaceuticals.

jremaly@mdedge.com

SOURCE: Somboon T et al. AAN 2019, Abstract P3.6-026.

PHILADELPHIA – Nearly a quarter of adults with epilepsy have moderate or severe insomnia, and insomnia symptoms are associated with depression, anxiety, worse seizure control, and poorer quality of life, according to a prospective analysis presented at the annual meeting of the American Academy of Neurology. Insomnia symptoms are not associated with epilepsy type, number of antiepileptic drugs (AEDs), or AED standardized dose, however.

“Given the potential benefits of sleep therapies on epilepsy outcomes, routine screening of insomnia symptoms is warranted,” said lead study author Thapanee Somboon, MD, a researcher at the sleep disorders center at Cleveland Clinic Neurological Institute in Ohio and at Prasat Neurological Institute in Bangkok.

Insomnia is common and associated with depression in patients with epilepsy, but prior studies that looked at the relationship between insomnia and epilepsy-related characteristics yielded limited and conflicting results, according to Dr. Somboon.

To evaluate potential associations between insomnia and epilepsy, Dr. Somboon and colleagues conducted a prospective analysis of data from 270 patients with epilepsy who presented to the Cleveland Clinic Epilepsy Center for an initial evaluation between January and August 2018. The patients completed the Insomnia Severity Index (ISI). An ISI score of 8 or greater indicated clinical insomnia symptoms, and an ISI score of 15 or greater indicated moderate or severe insomnia symptoms.

The researchers used Spearman’s correlation and the Kruskal-Wallis test to evaluate associations among insomnia symptoms and AED standardized dose, monthly seizure frequency, Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Questionnaire (GAD-7), and Quality of Life in Epilepsy-10 (QOLIE10).

Among the 270 patients, the average age was 43.5 years, 58% were female, 74% had focal epilepsy, and 26% had one or more seizures per month. The population’s median ISI score was 7. Nearly half had an ISI score of 8 or greater, and 23% had an ISI score of 15 or greater.

“A positive correlation was found between ISI and PHQ-9 (r = 0.64, P less than .001), GAD-7 (r = 0.68, P less than .001), QOLIE (r = 0.55, P less than .001), and monthly seizure frequency (r = 0.31, P less than .001),” the researchers reported. Insomnia symptoms had a significantly stronger correlation with PHQ-9 and GAD-7 than with seizure frequency.

Dr. Somboon had no disclosures. A coinvestigator has received research support from Jazz Pharmaceuticals.

jremaly@mdedge.com

SOURCE: Somboon T et al. AAN 2019, Abstract P3.6-026.

Clinicians are well aware of the acute effects of hypoxemia when encountered in conditions such as pulmonary embolism, pulmonary edema, COPD exacerbation, and others, whereas effects of chronic hypoxemia, such as pulmonary hypertension and polycythemia, are more difficult to recognize. Chronic hypoxemia is frequent in chronic lung diseases, such as COPD, but how it leads to increased mortality in severe COPD is unknown (NHLBI Working Group for LTOT in COPD. Am J Respir Crit Care Med. 2006;174:373). Chronic hypoxemia following high altitude exposure tends to have more unpredictable effects. Chronic hypoxemia, greater than that expected for the altitude of residence, is encountered frequently in high altitude dwellers. Here it has been implicated in the pathophysiology of chronic mountain sickness (Villafeurte and Corante. High Alt Med Biol. 2016;17[2]:61) and low birth weights (Maatta J, et al. Sci Rep. 2018;8[1]:13583), even though high altitude residence has been linked to better cardiovascular outcomes and reduced cancer-related deaths (Burstcher M. Aging Dis. 2013;5[4]:274). Chronic hypoxia effects at high altitude may, therefore, be variegated depending on a number of factors that include organ-system-specific effects, severity of chronic hypoxia, and a propensity to disease determined by genetic background and generations of residence.

Such diverse effects of chronic sleep-related hypoxemia are also being reported with obstructive sleep apnea (OSA). While sleep can result in sustained drops in ventilation and consequent hypoxemia similar to what is seen in COPD, OSA is typified by a form of sleep-related hypoxemia in a pattern termed as chronic intermittent hypoxia (CIH). CIH is characterized by rapid fluctuations in oxygen saturations (Figure 1) that is virtually pathognomonic of sleep apnea either from recurrent upper airway obstructions (as in OSA) or pauses in respiratory generator firing (as in central sleep apnea). OSA-driven CIH has received most attention, given its purported role in in the causation of the wide range of pathologic conditions associated with OSA. Outcomes from cross-sectional and longitudinal studies have correlated time spent below 90% or recurrent oxygen desaturations to a number of OSA-related outcomes such as cardiovascular disease, diabetes, and cognitive dysfunction (Dewan et al. Chest. 2015;147[1]:266). While these effects of OSA-related intermittent hypoxemia occur over long periods of time, as with other forms of chronic hypoxia, some effects, such as hypertension, are demonstrable in animal models after much shorter durations of sleep-related intermittent hypoxia exposure. As seen with other forms of chronic hypoxemia, an opposing beneficial effect has also been demonstrated on the size of myocardial infarct during acute coronary events and from mild OSA-related mortality in elderly subjects (Javaheri et al. J Am Coll Cardiol. 2017;69[7]:841).

Given how common sleep-related hypoxemia and OSA are, it is important to understand the implications of different patterns of sleep-related hypoxemia that a vast segment of the population experiences on a nightly basis. A number of factors may determine chronic outcomes with sleep-related hypoxemia that include the pattern of sleep-related hypoxemia (chronic sustained hypoxemia associated with sleep-related hypoventilation vs chronic intermittent hypoxemia of OSA), degree of hypoxemia, presence of underlying disease, and hitherto undescribed individual factors. While a correlation between hypoxemic burden secondary to sleep-disordered breathing and cardiovascular outcomes has been shown (Azabarzin A, et al. Eur Heart J. 2018 Oct 30), CPAP interventional studies that address OSA-related CIH have shown mixed results for prevention of cardiovascular disease (McEvoy RD, et al. N Engl J Med. 2016;375[10]:919). It has also been difficult to draw upon results of oxygen supplementation in other forms of hypoxemia, such as COPD, when specifically targeted to addressing the hypoxemia seen only at night or with exercise (LOTT Research Group. N Engl J Med. 2016;375:1617 ). To complicate this further, high altitude residence (that may result in similar levels of sleep-related hypoxemia) is not associated with any differences in life-expectancy but may provide a reduction in cardiovascular outcomes (Ezzati, et al. J Epidemiol Community Health. 2012;66[7]:e17).

How do we reconcile such disparate effects of chronic hypoxemia? Part of difference may be in the pattern of chronic intermittent hypoxemia noted with OSA characterized not only by rapid drops in oxygen but also rapid reoxygenation events secondary to arousals terminating an apnea – these reoxygenation events have been attributed to the increased oxidant stress demonstrable in multiple tissues. While chronic hypoxia itself may cause increased oxidant stress, such effects seen with sustained forms of hypoxia, such as sleep-related hypoventilation or high altitude residence, may be more gradual resulting in lesser degrees of tissue effects and regulation of antioxidant defenses with sustained exposure. Herein lies the importance of understanding physiologic and biological effects stemming from chronic hypoxia to explain its variegated effects on different organ systems. In this regard, the role of carotid body, a structure with unique vascular supply and with the ability to respond to minor changes in oxygen saturation as is seen in patients with OSA is key to the causation of hypertension associated with OSA (Shell et al. Curr Hyperten Rep. 2016;18[3]:19). Carotid body activation by intermittent hypoxia and long-term sensory facilitation drives the elevated sympathetic activity and consequent increases in blood pressure that can be improved by supplemental oxygen (Turnbull CD, et al. Am J Respir Crit Care Med. 2019;199[2]:211).

While carotid body responses are key to the pathophysiology of OSA, every organ in the body (in fact, every cell within the body) has the ability to sense and respond to hypoxia. This ability to sense oxygen tensions is ingrained in every cell by virtue of oxygen’s critical role in the genesis of life and evolution. These cellular responses to hypoxia are mediated by hypoxia-inducible factors (HIFs), isoforms of which include the more ubiquitous HIF-1 found in all parenchymal cells and HIF-2 found in specialized erythropoietin-producing cells of the kidney and the pulmonary circulation (the polycythemia and pulmonary vasoconstrictive responses from hypoxia are mediated through HIF-2 ). HIFs mediate the transcription of hundreds of genes, and they have been implicated in the pathobiology of a wide range of phenomena, from cancer to atherosclerotic vascular disease, metabolic syndrome, neurodegenerative disorders, pulmonary hypertension, and nonalcoholic fatty liver disease (Prabhakar and Semenza. Physiol Rev. 2012;92[3]:967). While HIF activation is an attractive target for examining the effects of chronic hypoxia of high altitude and sleep-disordered breathing, HIF activation varies from tissue to tissue and interacts with a number of other cellular systems in leading to differential effects. The short half-life of HIF proteins make them difficult to detect in tissues, so a number of secondary HIF-effects has been measured with mixed results depending on animal model utilized, pattern and degree of hypoxia studied, and the target effect measured. Comparative effects of intermittent vs sustained hypoxemia need to be systematically studied in different organ systems in different species, given the differing oxygen thresholds of individual cells due to unique blood flows and variations in the system of co-factors and prolyl hydroxylases that regulate the activation of HIFs. While the thrust of the work has been centered on HIF-related effects and the role of NF-kB-driven inflammation seen in OSA, there is substantial evidence to the role of oxidant stress that may be directly related to reoxygenation events occurring with CIH (Lavie L. Sleep Med Rev. 2015;20:27).

For life that has been intricately involved with oxygen from its genesis, it is not unreasonable to expect adaptations of cells, organs, and the whole individual to a wide range of oxygen tensions. Attempts to understand the import of sleep-disordered breathing has led to a need to unravel the implications of OSA-related chronic intermittent hypoxia and sleep-hypoventilation. This has led to a resurgence of interest in hypoxia-related research. Whether such chronic sleep-related sustained and intermittent hypoxemia is a harbinger of chronic disease is still not fully clear. A number of challenges exist with the understanding of these chronic hypoxia effects that include the long time needed for disease occurrence, its differential effects on organ systems, the role of hypoxia vs reoxygenation injury, importance of local blood flow, etc. Understanding these pathways will be crucial in prognosticating the role of sleep-related hypoxemia, the recognition of which has become part and parcel of routine management in sleep medicine.

Dr. Sundar is Medical Director, Sleep-Wake Center, Clinical Professor, Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Utah, Salt Lake City, Utah.

Clinicians are well aware of the acute effects of hypoxemia when encountered in conditions such as pulmonary embolism, pulmonary edema, COPD exacerbation, and others, whereas effects of chronic hypoxemia, such as pulmonary hypertension and polycythemia, are more difficult to recognize. Chronic hypoxemia is frequent in chronic lung diseases, such as COPD, but how it leads to increased mortality in severe COPD is unknown (NHLBI Working Group for LTOT in COPD. Am J Respir Crit Care Med. 2006;174:373). Chronic hypoxemia following high altitude exposure tends to have more unpredictable effects. Chronic hypoxemia, greater than that expected for the altitude of residence, is encountered frequently in high altitude dwellers. Here it has been implicated in the pathophysiology of chronic mountain sickness (Villafeurte and Corante. High Alt Med Biol. 2016;17[2]:61) and low birth weights (Maatta J, et al. Sci Rep. 2018;8[1]:13583), even though high altitude residence has been linked to better cardiovascular outcomes and reduced cancer-related deaths (Burstcher M. Aging Dis. 2013;5[4]:274). Chronic hypoxia effects at high altitude may, therefore, be variegated depending on a number of factors that include organ-system-specific effects, severity of chronic hypoxia, and a propensity to disease determined by genetic background and generations of residence.

Such diverse effects of chronic sleep-related hypoxemia are also being reported with obstructive sleep apnea (OSA). While sleep can result in sustained drops in ventilation and consequent hypoxemia similar to what is seen in COPD, OSA is typified by a form of sleep-related hypoxemia in a pattern termed as chronic intermittent hypoxia (CIH). CIH is characterized by rapid fluctuations in oxygen saturations (Figure 1) that is virtually pathognomonic of sleep apnea either from recurrent upper airway obstructions (as in OSA) or pauses in respiratory generator firing (as in central sleep apnea). OSA-driven CIH has received most attention, given its purported role in in the causation of the wide range of pathologic conditions associated with OSA. Outcomes from cross-sectional and longitudinal studies have correlated time spent below 90% or recurrent oxygen desaturations to a number of OSA-related outcomes such as cardiovascular disease, diabetes, and cognitive dysfunction (Dewan et al. Chest. 2015;147[1]:266). While these effects of OSA-related intermittent hypoxemia occur over long periods of time, as with other forms of chronic hypoxia, some effects, such as hypertension, are demonstrable in animal models after much shorter durations of sleep-related intermittent hypoxia exposure. As seen with other forms of chronic hypoxemia, an opposing beneficial effect has also been demonstrated on the size of myocardial infarct during acute coronary events and from mild OSA-related mortality in elderly subjects (Javaheri et al. J Am Coll Cardiol. 2017;69[7]:841).

Given how common sleep-related hypoxemia and OSA are, it is important to understand the implications of different patterns of sleep-related hypoxemia that a vast segment of the population experiences on a nightly basis. A number of factors may determine chronic outcomes with sleep-related hypoxemia that include the pattern of sleep-related hypoxemia (chronic sustained hypoxemia associated with sleep-related hypoventilation vs chronic intermittent hypoxemia of OSA), degree of hypoxemia, presence of underlying disease, and hitherto undescribed individual factors. While a correlation between hypoxemic burden secondary to sleep-disordered breathing and cardiovascular outcomes has been shown (Azabarzin A, et al. Eur Heart J. 2018 Oct 30), CPAP interventional studies that address OSA-related CIH have shown mixed results for prevention of cardiovascular disease (McEvoy RD, et al. N Engl J Med. 2016;375[10]:919). It has also been difficult to draw upon results of oxygen supplementation in other forms of hypoxemia, such as COPD, when specifically targeted to addressing the hypoxemia seen only at night or with exercise (LOTT Research Group. N Engl J Med. 2016;375:1617 ). To complicate this further, high altitude residence (that may result in similar levels of sleep-related hypoxemia) is not associated with any differences in life-expectancy but may provide a reduction in cardiovascular outcomes (Ezzati, et al. J Epidemiol Community Health. 2012;66[7]:e17).

How do we reconcile such disparate effects of chronic hypoxemia? Part of difference may be in the pattern of chronic intermittent hypoxemia noted with OSA characterized not only by rapid drops in oxygen but also rapid reoxygenation events secondary to arousals terminating an apnea – these reoxygenation events have been attributed to the increased oxidant stress demonstrable in multiple tissues. While chronic hypoxia itself may cause increased oxidant stress, such effects seen with sustained forms of hypoxia, such as sleep-related hypoventilation or high altitude residence, may be more gradual resulting in lesser degrees of tissue effects and regulation of antioxidant defenses with sustained exposure. Herein lies the importance of understanding physiologic and biological effects stemming from chronic hypoxia to explain its variegated effects on different organ systems. In this regard, the role of carotid body, a structure with unique vascular supply and with the ability to respond to minor changes in oxygen saturation as is seen in patients with OSA is key to the causation of hypertension associated with OSA (Shell et al. Curr Hyperten Rep. 2016;18[3]:19). Carotid body activation by intermittent hypoxia and long-term sensory facilitation drives the elevated sympathetic activity and consequent increases in blood pressure that can be improved by supplemental oxygen (Turnbull CD, et al. Am J Respir Crit Care Med. 2019;199[2]:211).

While carotid body responses are key to the pathophysiology of OSA, every organ in the body (in fact, every cell within the body) has the ability to sense and respond to hypoxia. This ability to sense oxygen tensions is ingrained in every cell by virtue of oxygen’s critical role in the genesis of life and evolution. These cellular responses to hypoxia are mediated by hypoxia-inducible factors (HIFs), isoforms of which include the more ubiquitous HIF-1 found in all parenchymal cells and HIF-2 found in specialized erythropoietin-producing cells of the kidney and the pulmonary circulation (the polycythemia and pulmonary vasoconstrictive responses from hypoxia are mediated through HIF-2 ). HIFs mediate the transcription of hundreds of genes, and they have been implicated in the pathobiology of a wide range of phenomena, from cancer to atherosclerotic vascular disease, metabolic syndrome, neurodegenerative disorders, pulmonary hypertension, and nonalcoholic fatty liver disease (Prabhakar and Semenza. Physiol Rev. 2012;92[3]:967). While HIF activation is an attractive target for examining the effects of chronic hypoxia of high altitude and sleep-disordered breathing, HIF activation varies from tissue to tissue and interacts with a number of other cellular systems in leading to differential effects. The short half-life of HIF proteins make them difficult to detect in tissues, so a number of secondary HIF-effects has been measured with mixed results depending on animal model utilized, pattern and degree of hypoxia studied, and the target effect measured. Comparative effects of intermittent vs sustained hypoxemia need to be systematically studied in different organ systems in different species, given the differing oxygen thresholds of individual cells due to unique blood flows and variations in the system of co-factors and prolyl hydroxylases that regulate the activation of HIFs. While the thrust of the work has been centered on HIF-related effects and the role of NF-kB-driven inflammation seen in OSA, there is substantial evidence to the role of oxidant stress that may be directly related to reoxygenation events occurring with CIH (Lavie L. Sleep Med Rev. 2015;20:27).

For life that has been intricately involved with oxygen from its genesis, it is not unreasonable to expect adaptations of cells, organs, and the whole individual to a wide range of oxygen tensions. Attempts to understand the import of sleep-disordered breathing has led to a need to unravel the implications of OSA-related chronic intermittent hypoxia and sleep-hypoventilation. This has led to a resurgence of interest in hypoxia-related research. Whether such chronic sleep-related sustained and intermittent hypoxemia is a harbinger of chronic disease is still not fully clear. A number of challenges exist with the understanding of these chronic hypoxia effects that include the long time needed for disease occurrence, its differential effects on organ systems, the role of hypoxia vs reoxygenation injury, importance of local blood flow, etc. Understanding these pathways will be crucial in prognosticating the role of sleep-related hypoxemia, the recognition of which has become part and parcel of routine management in sleep medicine.

Dr. Sundar is Medical Director, Sleep-Wake Center, Clinical Professor, Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Utah, Salt Lake City, Utah.

Clinicians are well aware of the acute effects of hypoxemia when encountered in conditions such as pulmonary embolism, pulmonary edema, COPD exacerbation, and others, whereas effects of chronic hypoxemia, such as pulmonary hypertension and polycythemia, are more difficult to recognize. Chronic hypoxemia is frequent in chronic lung diseases, such as COPD, but how it leads to increased mortality in severe COPD is unknown (NHLBI Working Group for LTOT in COPD. Am J Respir Crit Care Med. 2006;174:373). Chronic hypoxemia following high altitude exposure tends to have more unpredictable effects. Chronic hypoxemia, greater than that expected for the altitude of residence, is encountered frequently in high altitude dwellers. Here it has been implicated in the pathophysiology of chronic mountain sickness (Villafeurte and Corante. High Alt Med Biol. 2016;17[2]:61) and low birth weights (Maatta J, et al. Sci Rep. 2018;8[1]:13583), even though high altitude residence has been linked to better cardiovascular outcomes and reduced cancer-related deaths (Burstcher M. Aging Dis. 2013;5[4]:274). Chronic hypoxia effects at high altitude may, therefore, be variegated depending on a number of factors that include organ-system-specific effects, severity of chronic hypoxia, and a propensity to disease determined by genetic background and generations of residence.

Such diverse effects of chronic sleep-related hypoxemia are also being reported with obstructive sleep apnea (OSA). While sleep can result in sustained drops in ventilation and consequent hypoxemia similar to what is seen in COPD, OSA is typified by a form of sleep-related hypoxemia in a pattern termed as chronic intermittent hypoxia (CIH). CIH is characterized by rapid fluctuations in oxygen saturations (Figure 1) that is virtually pathognomonic of sleep apnea either from recurrent upper airway obstructions (as in OSA) or pauses in respiratory generator firing (as in central sleep apnea). OSA-driven CIH has received most attention, given its purported role in in the causation of the wide range of pathologic conditions associated with OSA. Outcomes from cross-sectional and longitudinal studies have correlated time spent below 90% or recurrent oxygen desaturations to a number of OSA-related outcomes such as cardiovascular disease, diabetes, and cognitive dysfunction (Dewan et al. Chest. 2015;147[1]:266). While these effects of OSA-related intermittent hypoxemia occur over long periods of time, as with other forms of chronic hypoxia, some effects, such as hypertension, are demonstrable in animal models after much shorter durations of sleep-related intermittent hypoxia exposure. As seen with other forms of chronic hypoxemia, an opposing beneficial effect has also been demonstrated on the size of myocardial infarct during acute coronary events and from mild OSA-related mortality in elderly subjects (Javaheri et al. J Am Coll Cardiol. 2017;69[7]:841).

Given how common sleep-related hypoxemia and OSA are, it is important to understand the implications of different patterns of sleep-related hypoxemia that a vast segment of the population experiences on a nightly basis. A number of factors may determine chronic outcomes with sleep-related hypoxemia that include the pattern of sleep-related hypoxemia (chronic sustained hypoxemia associated with sleep-related hypoventilation vs chronic intermittent hypoxemia of OSA), degree of hypoxemia, presence of underlying disease, and hitherto undescribed individual factors. While a correlation between hypoxemic burden secondary to sleep-disordered breathing and cardiovascular outcomes has been shown (Azabarzin A, et al. Eur Heart J. 2018 Oct 30), CPAP interventional studies that address OSA-related CIH have shown mixed results for prevention of cardiovascular disease (McEvoy RD, et al. N Engl J Med. 2016;375[10]:919). It has also been difficult to draw upon results of oxygen supplementation in other forms of hypoxemia, such as COPD, when specifically targeted to addressing the hypoxemia seen only at night or with exercise (LOTT Research Group. N Engl J Med. 2016;375:1617 ). To complicate this further, high altitude residence (that may result in similar levels of sleep-related hypoxemia) is not associated with any differences in life-expectancy but may provide a reduction in cardiovascular outcomes (Ezzati, et al. J Epidemiol Community Health. 2012;66[7]:e17).

How do we reconcile such disparate effects of chronic hypoxemia? Part of difference may be in the pattern of chronic intermittent hypoxemia noted with OSA characterized not only by rapid drops in oxygen but also rapid reoxygenation events secondary to arousals terminating an apnea – these reoxygenation events have been attributed to the increased oxidant stress demonstrable in multiple tissues. While chronic hypoxia itself may cause increased oxidant stress, such effects seen with sustained forms of hypoxia, such as sleep-related hypoventilation or high altitude residence, may be more gradual resulting in lesser degrees of tissue effects and regulation of antioxidant defenses with sustained exposure. Herein lies the importance of understanding physiologic and biological effects stemming from chronic hypoxia to explain its variegated effects on different organ systems. In this regard, the role of carotid body, a structure with unique vascular supply and with the ability to respond to minor changes in oxygen saturation as is seen in patients with OSA is key to the causation of hypertension associated with OSA (Shell et al. Curr Hyperten Rep. 2016;18[3]:19). Carotid body activation by intermittent hypoxia and long-term sensory facilitation drives the elevated sympathetic activity and consequent increases in blood pressure that can be improved by supplemental oxygen (Turnbull CD, et al. Am J Respir Crit Care Med. 2019;199[2]:211).

While carotid body responses are key to the pathophysiology of OSA, every organ in the body (in fact, every cell within the body) has the ability to sense and respond to hypoxia. This ability to sense oxygen tensions is ingrained in every cell by virtue of oxygen’s critical role in the genesis of life and evolution. These cellular responses to hypoxia are mediated by hypoxia-inducible factors (HIFs), isoforms of which include the more ubiquitous HIF-1 found in all parenchymal cells and HIF-2 found in specialized erythropoietin-producing cells of the kidney and the pulmonary circulation (the polycythemia and pulmonary vasoconstrictive responses from hypoxia are mediated through HIF-2 ). HIFs mediate the transcription of hundreds of genes, and they have been implicated in the pathobiology of a wide range of phenomena, from cancer to atherosclerotic vascular disease, metabolic syndrome, neurodegenerative disorders, pulmonary hypertension, and nonalcoholic fatty liver disease (Prabhakar and Semenza. Physiol Rev. 2012;92[3]:967). While HIF activation is an attractive target for examining the effects of chronic hypoxia of high altitude and sleep-disordered breathing, HIF activation varies from tissue to tissue and interacts with a number of other cellular systems in leading to differential effects. The short half-life of HIF proteins make them difficult to detect in tissues, so a number of secondary HIF-effects has been measured with mixed results depending on animal model utilized, pattern and degree of hypoxia studied, and the target effect measured. Comparative effects of intermittent vs sustained hypoxemia need to be systematically studied in different organ systems in different species, given the differing oxygen thresholds of individual cells due to unique blood flows and variations in the system of co-factors and prolyl hydroxylases that regulate the activation of HIFs. While the thrust of the work has been centered on HIF-related effects and the role of NF-kB-driven inflammation seen in OSA, there is substantial evidence to the role of oxidant stress that may be directly related to reoxygenation events occurring with CIH (Lavie L. Sleep Med Rev. 2015;20:27).

For life that has been intricately involved with oxygen from its genesis, it is not unreasonable to expect adaptations of cells, organs, and the whole individual to a wide range of oxygen tensions. Attempts to understand the import of sleep-disordered breathing has led to a need to unravel the implications of OSA-related chronic intermittent hypoxia and sleep-hypoventilation. This has led to a resurgence of interest in hypoxia-related research. Whether such chronic sleep-related sustained and intermittent hypoxemia is a harbinger of chronic disease is still not fully clear. A number of challenges exist with the understanding of these chronic hypoxia effects that include the long time needed for disease occurrence, its differential effects on organ systems, the role of hypoxia vs reoxygenation injury, importance of local blood flow, etc. Understanding these pathways will be crucial in prognosticating the role of sleep-related hypoxemia, the recognition of which has become part and parcel of routine management in sleep medicine.

Dr. Sundar is Medical Director, Sleep-Wake Center, Clinical Professor, Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Utah, Salt Lake City, Utah.