Sleep Medicine

Click here to download the PDF.

Click here to download the PDF.

Click here to download the PDF.

PORTLAND, OR—In patients with idiopathic REM sleep behavior disorder, microglial activation is increased in the substantia nigra, compared with controls, and microglial activation correlates with putamenal dopaminergic dysfunction, according to research presented at the Fourth World Parkinson Congress. These findings suggest that “anti-inflammatory agents could possibly delay progression to a manifest synucleinopathy in subjects with idiopathic REM sleep behavior disorder,” researchers said.

Longitudinal studies have found that patients with idiopathic REM sleep behavior disorder have an increased risk of Parkinson’s disease and related Lewy body disorders. “This implies that, in idiopathic REM sleep behavior disorder, the underlying pathology of developing neurodegenerative disorders can be investigated years prior to the development of manifest symptoms,” said Morten Gersel Stokholm, MD, a researcher in the Department of Clinical Medicine at Aarhus University and the Department of Nuclear Medicine & PET-Centre at Aarhus University Hospital, Denmark, and his research colleagues.

To investigate the in vivo occurrence of neuroinflammation in the brains of patients with idiopathic REM sleep behavior disorder and neuroinflammation’s temporal relationship with striatal dopamine dysfunction, Dr. Stokholm and colleagues conducted a multitracer PET study of patients with idiopathic REM sleep behavior disorder.

The investigators enrolled 15 patients with polysomnography-confirmed idiopathic REM sleep behavior disorder at Aarhus University Hospital and Hospital Clínic de Barcelona. They also enrolled 19 matched controls. Participants underwent two PET scans with 18F-DOPA and 11C-PK11195 and a structural T1 MRI scan. Parametric images of specific tracer uptake (ie, F-dopa Ki-values and PK11195 binding potential) were constructed at voxel level using Patlak graphical analysis and a supervised cluster-analysis with compartmental modeling, respectively. A region of interest analysis was performed on a priori defined regions.

Compared with controls, patients with idiopathic REM sleep behavior disorder showed significantly reduced 18F-DOPA tracer uptake in the substantia nigra. Patients with higher substantia nigra11C-PK11195 binding also had increased binding in the ipsilateral putamen. Patients with more severe reductions in putamenal 18F-DOPA uptake had significantly higher 11C-PK11195 binding in the putamen and substantia nigra.

—Jake Remaly

PORTLAND, OR—In patients with idiopathic REM sleep behavior disorder, microglial activation is increased in the substantia nigra, compared with controls, and microglial activation correlates with putamenal dopaminergic dysfunction, according to research presented at the Fourth World Parkinson Congress. These findings suggest that “anti-inflammatory agents could possibly delay progression to a manifest synucleinopathy in subjects with idiopathic REM sleep behavior disorder,” researchers said.

Longitudinal studies have found that patients with idiopathic REM sleep behavior disorder have an increased risk of Parkinson’s disease and related Lewy body disorders. “This implies that, in idiopathic REM sleep behavior disorder, the underlying pathology of developing neurodegenerative disorders can be investigated years prior to the development of manifest symptoms,” said Morten Gersel Stokholm, MD, a researcher in the Department of Clinical Medicine at Aarhus University and the Department of Nuclear Medicine & PET-Centre at Aarhus University Hospital, Denmark, and his research colleagues.

To investigate the in vivo occurrence of neuroinflammation in the brains of patients with idiopathic REM sleep behavior disorder and neuroinflammation’s temporal relationship with striatal dopamine dysfunction, Dr. Stokholm and colleagues conducted a multitracer PET study of patients with idiopathic REM sleep behavior disorder.

The investigators enrolled 15 patients with polysomnography-confirmed idiopathic REM sleep behavior disorder at Aarhus University Hospital and Hospital Clínic de Barcelona. They also enrolled 19 matched controls. Participants underwent two PET scans with 18F-DOPA and 11C-PK11195 and a structural T1 MRI scan. Parametric images of specific tracer uptake (ie, F-dopa Ki-values and PK11195 binding potential) were constructed at voxel level using Patlak graphical analysis and a supervised cluster-analysis with compartmental modeling, respectively. A region of interest analysis was performed on a priori defined regions.

Compared with controls, patients with idiopathic REM sleep behavior disorder showed significantly reduced 18F-DOPA tracer uptake in the substantia nigra. Patients with higher substantia nigra11C-PK11195 binding also had increased binding in the ipsilateral putamen. Patients with more severe reductions in putamenal 18F-DOPA uptake had significantly higher 11C-PK11195 binding in the putamen and substantia nigra.

—Jake Remaly

PORTLAND, OR—In patients with idiopathic REM sleep behavior disorder, microglial activation is increased in the substantia nigra, compared with controls, and microglial activation correlates with putamenal dopaminergic dysfunction, according to research presented at the Fourth World Parkinson Congress. These findings suggest that “anti-inflammatory agents could possibly delay progression to a manifest synucleinopathy in subjects with idiopathic REM sleep behavior disorder,” researchers said.

Longitudinal studies have found that patients with idiopathic REM sleep behavior disorder have an increased risk of Parkinson’s disease and related Lewy body disorders. “This implies that, in idiopathic REM sleep behavior disorder, the underlying pathology of developing neurodegenerative disorders can be investigated years prior to the development of manifest symptoms,” said Morten Gersel Stokholm, MD, a researcher in the Department of Clinical Medicine at Aarhus University and the Department of Nuclear Medicine & PET-Centre at Aarhus University Hospital, Denmark, and his research colleagues.

To investigate the in vivo occurrence of neuroinflammation in the brains of patients with idiopathic REM sleep behavior disorder and neuroinflammation’s temporal relationship with striatal dopamine dysfunction, Dr. Stokholm and colleagues conducted a multitracer PET study of patients with idiopathic REM sleep behavior disorder.

The investigators enrolled 15 patients with polysomnography-confirmed idiopathic REM sleep behavior disorder at Aarhus University Hospital and Hospital Clínic de Barcelona. They also enrolled 19 matched controls. Participants underwent two PET scans with 18F-DOPA and 11C-PK11195 and a structural T1 MRI scan. Parametric images of specific tracer uptake (ie, F-dopa Ki-values and PK11195 binding potential) were constructed at voxel level using Patlak graphical analysis and a supervised cluster-analysis with compartmental modeling, respectively. A region of interest analysis was performed on a priori defined regions.

Compared with controls, patients with idiopathic REM sleep behavior disorder showed significantly reduced 18F-DOPA tracer uptake in the substantia nigra. Patients with higher substantia nigra11C-PK11195 binding also had increased binding in the ipsilateral putamen. Patients with more severe reductions in putamenal 18F-DOPA uptake had significantly higher 11C-PK11195 binding in the putamen and substantia nigra.

—Jake Remaly

To the Editor: Thanks for the concise review of obstructive sleep apnea (OSA) in the January 2016 issue.¹ I offer the following comments and questions:

1. Risk factors for OSA include large neck circumference, which in Table 1 is defined as larger than 40 cm (15.75 inches), which would include shirt collar sizes 16 and above. In the second paragraph of the text, large neck circumference is defined as greater than 17 inches in men, which would include collar sizes above 17. The definition of a large neck as larger than 40 cm must obviously be more sensitive for predicting OSA, and the definition of greater than 17 inches more specific. Which do the authors use in clinical practice?

2. The American Academy of Sleep Medicine is quoted as recommending home OSA screening “if direct monitoring of the response to non-[continuous positive airway pressure] treatments for sleep apnea is needed.”² However, the need for direct monitoring would seem to be a contraindication to home testing rather than an indication. If this statement is correct as written, would the authors explain why and how specific non-CPAP treatments for OSA are more amenable to monitoring at home than in the sleep lab?

3. Patients with Parkinson disease are at risk for both OSA and hypotension, making them generally an exception to the association of OSA with hypertension.³

4. The home overnight OSA test often consists of a pulse oximeter worn for 8 hours at night, taped to a finger.⁴ This simple, inexpensive test for OSA detects episodes of apnea or hypopnea that result in arterial desaturation. Is it beneficial to also document episodes of apnea or hypopnea that do not result in arterial desaturation? These episodes are included in the 17% false-negative rate for home OSA testing mentioned in the text. Are these episodes important clinically, other than for prognosis in patients who may go on to develop apneic episodes severe enough to cause desaturation?

5. Lastly, the authors may wish to comment on the importance of diagnosing and treating OSA in patients who plan to have elective surgery under general anesthesia, which can lead to profound sleep apnea in the recovery room, with associated morbidity and death.⁵

To the Editor: Thanks for the concise review of obstructive sleep apnea (OSA) in the January 2016 issue.¹ I offer the following comments and questions:

1. Risk factors for OSA include large neck circumference, which in Table 1 is defined as larger than 40 cm (15.75 inches), which would include shirt collar sizes 16 and above. In the second paragraph of the text, large neck circumference is defined as greater than 17 inches in men, which would include collar sizes above 17. The definition of a large neck as larger than 40 cm must obviously be more sensitive for predicting OSA, and the definition of greater than 17 inches more specific. Which do the authors use in clinical practice?

2. The American Academy of Sleep Medicine is quoted as recommending home OSA screening “if direct monitoring of the response to non-[continuous positive airway pressure] treatments for sleep apnea is needed.”² However, the need for direct monitoring would seem to be a contraindication to home testing rather than an indication. If this statement is correct as written, would the authors explain why and how specific non-CPAP treatments for OSA are more amenable to monitoring at home than in the sleep lab?

3. Patients with Parkinson disease are at risk for both OSA and hypotension, making them generally an exception to the association of OSA with hypertension.³

4. The home overnight OSA test often consists of a pulse oximeter worn for 8 hours at night, taped to a finger.⁴ This simple, inexpensive test for OSA detects episodes of apnea or hypopnea that result in arterial desaturation. Is it beneficial to also document episodes of apnea or hypopnea that do not result in arterial desaturation? These episodes are included in the 17% false-negative rate for home OSA testing mentioned in the text. Are these episodes important clinically, other than for prognosis in patients who may go on to develop apneic episodes severe enough to cause desaturation?

5. Lastly, the authors may wish to comment on the importance of diagnosing and treating OSA in patients who plan to have elective surgery under general anesthesia, which can lead to profound sleep apnea in the recovery room, with associated morbidity and death.⁵

To the Editor: Thanks for the concise review of obstructive sleep apnea (OSA) in the January 2016 issue.¹ I offer the following comments and questions:

1. Risk factors for OSA include large neck circumference, which in Table 1 is defined as larger than 40 cm (15.75 inches), which would include shirt collar sizes 16 and above. In the second paragraph of the text, large neck circumference is defined as greater than 17 inches in men, which would include collar sizes above 17. The definition of a large neck as larger than 40 cm must obviously be more sensitive for predicting OSA, and the definition of greater than 17 inches more specific. Which do the authors use in clinical practice?

2. The American Academy of Sleep Medicine is quoted as recommending home OSA screening “if direct monitoring of the response to non-[continuous positive airway pressure] treatments for sleep apnea is needed.”² However, the need for direct monitoring would seem to be a contraindication to home testing rather than an indication. If this statement is correct as written, would the authors explain why and how specific non-CPAP treatments for OSA are more amenable to monitoring at home than in the sleep lab?

3. Patients with Parkinson disease are at risk for both OSA and hypotension, making them generally an exception to the association of OSA with hypertension.³

4. The home overnight OSA test often consists of a pulse oximeter worn for 8 hours at night, taped to a finger.⁴ This simple, inexpensive test for OSA detects episodes of apnea or hypopnea that result in arterial desaturation. Is it beneficial to also document episodes of apnea or hypopnea that do not result in arterial desaturation? These episodes are included in the 17% false-negative rate for home OSA testing mentioned in the text. Are these episodes important clinically, other than for prognosis in patients who may go on to develop apneic episodes severe enough to cause desaturation?

5. Lastly, the authors may wish to comment on the importance of diagnosing and treating OSA in patients who plan to have elective surgery under general anesthesia, which can lead to profound sleep apnea in the recovery room, with associated morbidity and death.⁵

In Reply: We thank Dr. Keller for his thorough reading of our article.¹

Regarding the predictive value of neck circumference for obstructive sleep apnea, (OSA), neck circumference is one of many tools to screen for OSA. If neck circumference greater than 38 cm is applied without other predictors (such as the presence of snoring, daytime sleepiness, or elevated body mass index), it provides only a 58% sensitivity and 79% specificity.² It is less an issue of inches vs collar size vs centimeters than of combining circumference with other parameters (as in the STOP-BANG questionnaire) before proceeding with a sleep study. The senior author of our article (G.R.) uses 38 cm.

With respect to home vs sleep lab monitoring, the question was beyond the scope of the paper and outside our expertise, as we are both general internists. The home venue recommendations in this instance were taken directly from the American Academy of Sleep Medicine.³ We would rely on consultation with a sleep specialist before ordering home monitoring to determine the potential success of non-CPAP interventions for OSA.

As for Parkinson disease as an exception to OSA and hypertension, we wrote in the paper, “Untreated OSA is associated with a number of conditions.”¹ Yes, resistant hypertension is prominent in today’s epidemic of obesity, diabetes, and OSA, but not everyone with coronary artery disease, atrial fibrillation, or heart failure—as in persons with Parkinson disease—has hypertension. The associated conditions in our paper are more typical of a general medical practice, but we agree that Parkinson disease is associated with OSA. Patients with hypertension and OSA are more prevalent because the clinical risk factors for OSA and hypertension are common to both conditions.⁴

In adults, apnea is considered present when the airflow drops by 90% or more from the pre-event baseline. Hypopnea in adults is present when the airflow drops by 30% or more of the pre-event baseline for 10 or more seconds in association with either 3% or greater arterial oxygen desaturation or an electroencephalographic arousal.⁵ Studies have shown that episodes of hypopnea with 2% oxygen desaturation are associated with an increased prevalence of metabolic impairment.⁶ A higher degree of desaturation, ie, more than 4%, was associated with increased prevalence of self-reported cardiovascular disease.⁷ But the significance of episodes of hypopnea without arterial desaturation is not well known to us and was beyond the scope of our article.

Our article was primarily focused on screening for OSA in ambulatory clinical practice and was not intended as a comprehensive review of screening in different settings of patient care. As to the importance of recognizing OSA in patients undergoing elective surgery under general anesthesia, we agree that screening is important to reduce the risk of postoperative adverse respiratory events in patients with a high pretest probability of OSA. In a recent study by Seet et al,⁸ patients with high STOP-BANG questionnaire scores (≥ 3) had higher rates of intraoperative and early postoperative adverse events than those with low scores (< 3). The risk of adverse events correlated with higher scores, and  patients with a STOP-BANG score of 5 or more had a five times greater risk of unexpected intraoperative and early postoperative adverse events, whereas those with a STOP-BANG score of 3 or more had a one in four chance of an adverse event. We recommend polysomnography for patients with a STOP-BANG score of 5 or more before elective surgery.

In Reply: We thank Dr. Keller for his thorough reading of our article.¹

Regarding the predictive value of neck circumference for obstructive sleep apnea, (OSA), neck circumference is one of many tools to screen for OSA. If neck circumference greater than 38 cm is applied without other predictors (such as the presence of snoring, daytime sleepiness, or elevated body mass index), it provides only a 58% sensitivity and 79% specificity.² It is less an issue of inches vs collar size vs centimeters than of combining circumference with other parameters (as in the STOP-BANG questionnaire) before proceeding with a sleep study. The senior author of our article (G.R.) uses 38 cm.

With respect to home vs sleep lab monitoring, the question was beyond the scope of the paper and outside our expertise, as we are both general internists. The home venue recommendations in this instance were taken directly from the American Academy of Sleep Medicine.³ We would rely on consultation with a sleep specialist before ordering home monitoring to determine the potential success of non-CPAP interventions for OSA.

As for Parkinson disease as an exception to OSA and hypertension, we wrote in the paper, “Untreated OSA is associated with a number of conditions.”¹ Yes, resistant hypertension is prominent in today’s epidemic of obesity, diabetes, and OSA, but not everyone with coronary artery disease, atrial fibrillation, or heart failure—as in persons with Parkinson disease—has hypertension. The associated conditions in our paper are more typical of a general medical practice, but we agree that Parkinson disease is associated with OSA. Patients with hypertension and OSA are more prevalent because the clinical risk factors for OSA and hypertension are common to both conditions.⁴

In adults, apnea is considered present when the airflow drops by 90% or more from the pre-event baseline. Hypopnea in adults is present when the airflow drops by 30% or more of the pre-event baseline for 10 or more seconds in association with either 3% or greater arterial oxygen desaturation or an electroencephalographic arousal.⁵ Studies have shown that episodes of hypopnea with 2% oxygen desaturation are associated with an increased prevalence of metabolic impairment.⁶ A higher degree of desaturation, ie, more than 4%, was associated with increased prevalence of self-reported cardiovascular disease.⁷ But the significance of episodes of hypopnea without arterial desaturation is not well known to us and was beyond the scope of our article.

Our article was primarily focused on screening for OSA in ambulatory clinical practice and was not intended as a comprehensive review of screening in different settings of patient care. As to the importance of recognizing OSA in patients undergoing elective surgery under general anesthesia, we agree that screening is important to reduce the risk of postoperative adverse respiratory events in patients with a high pretest probability of OSA. In a recent study by Seet et al,⁸ patients with high STOP-BANG questionnaire scores (≥ 3) had higher rates of intraoperative and early postoperative adverse events than those with low scores (< 3). The risk of adverse events correlated with higher scores, and  patients with a STOP-BANG score of 5 or more had a five times greater risk of unexpected intraoperative and early postoperative adverse events, whereas those with a STOP-BANG score of 3 or more had a one in four chance of an adverse event. We recommend polysomnography for patients with a STOP-BANG score of 5 or more before elective surgery.

In Reply: We thank Dr. Keller for his thorough reading of our article.¹

Regarding the predictive value of neck circumference for obstructive sleep apnea, (OSA), neck circumference is one of many tools to screen for OSA. If neck circumference greater than 38 cm is applied without other predictors (such as the presence of snoring, daytime sleepiness, or elevated body mass index), it provides only a 58% sensitivity and 79% specificity.² It is less an issue of inches vs collar size vs centimeters than of combining circumference with other parameters (as in the STOP-BANG questionnaire) before proceeding with a sleep study. The senior author of our article (G.R.) uses 38 cm.

With respect to home vs sleep lab monitoring, the question was beyond the scope of the paper and outside our expertise, as we are both general internists. The home venue recommendations in this instance were taken directly from the American Academy of Sleep Medicine.³ We would rely on consultation with a sleep specialist before ordering home monitoring to determine the potential success of non-CPAP interventions for OSA.

As for Parkinson disease as an exception to OSA and hypertension, we wrote in the paper, “Untreated OSA is associated with a number of conditions.”¹ Yes, resistant hypertension is prominent in today’s epidemic of obesity, diabetes, and OSA, but not everyone with coronary artery disease, atrial fibrillation, or heart failure—as in persons with Parkinson disease—has hypertension. The associated conditions in our paper are more typical of a general medical practice, but we agree that Parkinson disease is associated with OSA. Patients with hypertension and OSA are more prevalent because the clinical risk factors for OSA and hypertension are common to both conditions.⁴

In adults, apnea is considered present when the airflow drops by 90% or more from the pre-event baseline. Hypopnea in adults is present when the airflow drops by 30% or more of the pre-event baseline for 10 or more seconds in association with either 3% or greater arterial oxygen desaturation or an electroencephalographic arousal.⁵ Studies have shown that episodes of hypopnea with 2% oxygen desaturation are associated with an increased prevalence of metabolic impairment.⁶ A higher degree of desaturation, ie, more than 4%, was associated with increased prevalence of self-reported cardiovascular disease.⁷ But the significance of episodes of hypopnea without arterial desaturation is not well known to us and was beyond the scope of our article.

Our article was primarily focused on screening for OSA in ambulatory clinical practice and was not intended as a comprehensive review of screening in different settings of patient care. As to the importance of recognizing OSA in patients undergoing elective surgery under general anesthesia, we agree that screening is important to reduce the risk of postoperative adverse respiratory events in patients with a high pretest probability of OSA. In a recent study by Seet et al,⁸ patients with high STOP-BANG questionnaire scores (≥ 3) had higher rates of intraoperative and early postoperative adverse events than those with low scores (< 3). The risk of adverse events correlated with higher scores, and  patients with a STOP-BANG score of 5 or more had a five times greater risk of unexpected intraoperative and early postoperative adverse events, whereas those with a STOP-BANG score of 3 or more had a one in four chance of an adverse event. We recommend polysomnography for patients with a STOP-BANG score of 5 or more before elective surgery.

From the School of Aging Studies, University of South Florida, Tampa, FL (Dr. AA Gamaldo) and the Department of Neurology, Johns Hopkins Medicine, Baltimore, MD (Drs. Sloane, CE Gamaldo and Salas).

Abstract

• Objective: To provide guidance on identifying and treating sleep disturbances commonly encountered in older nursing home residents.
• Methods: Review of the literature in the context of 5 clinical cases.
• Results: Sleep disturbances continue to be a growing global epidemic, and public health initiatives have been aimed at improving sleep health across all ages. In older adults, sleep disturbances are often associated with the development and/or worsening of health conditions. Common sleep disturbances observed in older nursing home residents include obstructive sleep apnea, restless legs syndrome/Willis-Ekbom disease, circadian rhythm sleep-wake disorders, insomnia, and parasomnias. The symptoms and recommended treatment plans vary across the sleep disturbances. For many sleep disturbances, modification of residents’ daily activities and/or nursing home environment can be helpful.
• Conclusion: As the number of people residing in nursing homes increases, it is important for health care providers to be knowledgable about sleep disturbances in this population.

By 2030, almost 20% of the US population (approximately 72.1 million people) will be age 65 and older [1]. As many as 63% of older adults in the general population report sleep disturbances [2]. Specifically, older adults demonstrate difficulty with decreased total sleep duration, an increase in sleep fragmentation (ie, interruptions in nighttime sleep), and reduced total sleep time spent in rapid eye movement (REM) and slow wave sleep [3–5]. Poor sleep, either because of not getting enough sleep or having an undiagnosed and thus untreated sleep disorder, is associated with physical illness, impaired cognition, poor physical function, and mortality risk [6,7]. In fact, over 50% of individuals older than 65 years meet the diagnostic criteria for a sleep disorder, many of which are undiagnosed [6,7].

It is forecasted that we will see substantial increases in the rate of nursing home residence among the elderly [8]. The prevalence and severity of disturbed sleep is reportedly higher in NH residents [6,7]. Generally, NH residents tend to be on several medications for various medical disorders that may negatively impact sleep [7]. Reciprocally, sleep disruption may put NH residents at an increased risk for behavioral issues (eg, agitation) [9,10] as well as developing and/or exacerbating health conditions (eg, mood disorders, dementia, cardiovascular disease) [8]. Furthermore, NH residents exhibiting disturbed sleep, behavioral issues, and/or mood disorders are at an increased risk for being prescribed antipsychotic drugs [11], which are associated with adverse side effects and poorer quality of life [12]. Thus, the identification and management of sleep disturbances in the NH setting has become progressively more vital in efforts to optimize medical management of this population. This review identifies common sleep disturbances frequently underdiagnosed and undertreated among residents of NH facilities.

Case 1

A 73-year-old woman with a history of type 2 diabetes mellitus reports poor sleep quality with frequent awakenings during the night and excessive daytime sleepiness. She states that she can fall asleep within 5 minutes, but often is awoken throughout the night with a sensation of breathlessness. She has snored for many years, but the nursing staff at her NH facility has recently commented that her snoring has gone from intermittent to constant. She cannot remember the last time she has had restful sleep. She consumes 3 to 4 cups of caffeinated beverages daily to counter her sleepiness. She denies smoking or illicit drug or alcohol use. Her review of systems was notable for a 30-lb weight gain over the last year, and she reports increasing fatigue, irritability, and memory and concentration issues. Her current medication list includes metformin and amlodipine. Her examination is remarkable for a BMI of 31, large neck circumference (> 16), tonsillar enlargement, a crowded oropharynx, micrognathia, lungs clear to auscultation bilaterally, heart sounds of normal S1 and S2, and legs with trace pitting edema.

Case 1 Reflection: Sleep-Disordered Breathing

Although previous studies have observed high rates (60%–90%) of SDB in NH settings [16,17], one study observed that only 0.5% of nursing home residents carried a diagnosis with SDB, suggesting that SDB is being grossly underappreciated amongst NH residents over the age of 65 [18]. In order to evaluate for SBD, routine annual physical exams or medical chart reviews can elicit the risk factors for sleep apnea (eg, obesity [per BMI], male sex, postmenopausal women, family history of sleep apnea) as well as common comorbidities (eg, hypertension, coronary artery disease, and diabetes). Formal evaluation consists of a sleep evaluation with a sleep specialist and polysomnography (PSG; sleep study) that can be performed in the sleep center or at home depending on the patient’s history and other medical issues.

Case 1 Outcome

Case 2

An 85-year-old man with history of Alzheimer’s disease, major depression and arthritis, reports insomnia and “tingling in my legs” at bedtime. The patient cannot identify when the symptoms started but reports that his legs often jerk during sleep. He consumes a cup of coffee daily and has a previous 20 pack-year smoking history (he quit 40 years ago). On review of systems, he endorses fatigue. His current medication list includes fluoxetine, donepezil hydrochloride, ibuprofen as needed for arthritic pain, and a multivitamin. His examination was unremarkable, with a BMI of 26, neck circumference < 16, no tonsillar enlargement, normal (noncrowded) oropharynx, lungs clear to auscultation bilaterally, heart sounds demonstrating a normal S1 and S2, and legs without edema.

Case 2 Reflection: Restless Legs Syndrome/Willis-Ekbom Disease

Restless legs syndrome (RLS) also known as Willis-Ekbom disease, affects approximately 10 million adults in the United States alone [22]. RLS is a sensorimotor disorder that must satisfy the following 5 primary diagnostic criteria: (1) urge to move the legs with or without dysesthesias; (2) onset or exacerbation with rest or inactivity; (3) relief with movement; (4) symptoms are worse in the evening or at night (circadian component); (5) symptoms cannot be solely accounted for as consequence of another medical or behavioral condition. Other supporting clinical features can alert a clinician to the likelihood of a RLS diagnosis; these include positive family history, response to dopaminergic therapy, lack of profound daytime sleepiness, and presence of periodic limb movements during sleep (PLMS) [23–26]. In younger individuals, the symptoms present insidiously whereas older adults (> 50 years of age) will usually present with sudden onset [27].

Not only do patients lack the restorative sleep needed to ward off fatigue and restfulness, but patients also demonstrate higher rates of comorbidities (eg, anxiety, hypertension, depression) as well as large economic burden secondary to absenteeism and decreased on-the-job effectiveness [28,29]. As a results, patients with RLS experience significant reductions in quality of life related to this sensorimotor disorder [28].

No confirmatory laboratory test exists to diagnose RLS; however, patients suspected of having RLS should be evaluated with a basic metabolic panel, iron studies, and a thorough neurologic examination, as iron deficiency, kidney failure, uremia and peripheral neuropathy can lead to secondary RLS [30,31]. Evidence shows that RLS is common in NH residents [32] and may account for problematic behaviors, such as late night pacing [7]. Forty-five percent of community dwelling individuals over 65 years old exhibit a PLMS index (leg kicks per hour) of greater than 5 [33]. PLMS, while not a disorder in and of itself, can serve as a marker for potential disease. PLMS are characterized by intermittent episodes of stereotyped leg movements. PLMS typically do not awaken the patient from sleep and therefore do not contribute to insomnia or daytime sleepiness, representing a key clinical difference from RLS. It is important to note that PLMS are nonspecific and may be common in older adults that do not meet the diagnostic criteria for RLS.

Treatment of RLS is based on the frequency of symptoms and the level of functional impairment caused by the syndrome. RLS treatment recommendations should always espouse nonpharmacological interventions that include improving sleep practices, engagement in daily physical activity, targeted placement of sedentary activity in the morning when symptoms are less prominent, and concerted efforts to avoid the use of RLS-exacerbating medications (eg, selective serotonin reuptake inhibitor (SSRIs), neuroleptic agents, antihistamines) [28]. If there is an underlying condition contributing to RLS, such as metabolic disturbance or iron deficiency, then these conditions should be corrected before initiating RLS medications. Several medications are FDA-approved for treatment of RLS, including dopamine agonists (eg, ropinirole, rotigotine, pramipexole), dopamine precursor (eg, levodopa), glutamate-related (eg, gabapentin), benzodiazepines (eg, temazepam, clonazepam). Augmentation, the worsening of RLS symptoms, can occur in patients taking dopamine agonists. If this occurs, dopamine agents should be discontinued or switched to other agents (such as a long-acting dopamine agonist, gabapentin encarbil, as well as non-FDA approved therapies such as opioids). However, it is important to note that weaning off dopamine agents may result in mild but in most cases moderate and/or severe withdrawal from the medication, so counseling and close monitoring should be done.

Case 2 Outcome

Given the patient’s history of dementia, opioids, benzodiazepines and other delirium-inducing medications should be avoided. His antidepressive regimen, fluoxetine, should be re-evaluated as these medications have been associated with RLS exacerbation. In addition to SSRIs, medications associated with RLS are MAO inhibitors (selegeline, phenelzine), antipsychotics (risperdone, olanzapine), tricyclic antidepressants (mirtazapine), antihistamines (diphenhydramine, cimetidine), calcium channel blockers (verapamil, nifedipine, diltiazem), and phenytoin [34,35]. His treatment began with behavioral, nonpharmacological management, and blood testing for iron studies. His low iron level prompted initiation of oral supplementation, and he was asked to follow up in 3 months for reevaluation and possible initiation of low-dose dopamine agonists.

Case 3

A 73-year-old man with dementia is found to have very irregular sleep wake patterns with a variable bedtime and awakening time, often missing breakfast. He is found dozing off often during the day, particularly during times of inactivity. He has frequent awakenings during the night often calling for the staff to guide him back to bed. He has had some falls secondary to walking around his room. He has been prescribed various hypnotics without much benefit and instead, has suffered from some confusion while on these medications. His room is very dark and has no windows.

Case 3 Reflection: Circadian Rhythm Sleep-Wake Disorders

Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by an individual’s natural propensity to want to go to sleep and be awake during a period that is undesirable personally and/or socially [36]. CRSWDs can be a result of the desynchronization of the 2 sleep processes: (1) homeostatic drive (regulates sleep intensity) and (2) circadian rhythm (maintains daytime alertness); [36]. CRSWDs can also be due to an individual’s naturally occurring sleep drives becoming misaligned with their social/personal sleep-wake demands (eg, employment schedule and socializing opportunities with family/friends). With increasing age, the circadian rhythm becomes less adept at functioning in a desynchronized pattern [7], which can result in daytime sleepiness and night time sleep fragmentation [7,37]. CRSWDs are highly prevalent in individuals with dementia [7,36]. As dementia progresses, the ability to maintain a balance of the 2 sleep process becomes more impaired [7]. As a result, individuals with dementia, particularly Alzheimer’s disease, are likely to experience agitation, irritability, and/or confusion during the evening and night, a behavioral problem referred to as “sundowning” [38].

There are several types of CRSWDs, including delayed sleep-phase syndrome, advanced sleep-phase syndrome, irregular sleep-wake disorder, non–24-hour sleep-wake disorder, shift work sleep disorder, and jet lag sleep disorder. However, the most common type of CRSWDs observed in older adults is advanced sleep-phase syndrome [39]. Due to excessive sleepiness in the early evening, affected individuals may report a need to shift to earlier and earlier bedtimes (~6 to 7 pm) and wake times (~3 to 4 am) [36]. For older affected adults, this can cause distress and frustration, particularly if their sleep phase prevents them from participating in evening activities (eg, socializing with family/friends) [36].

In the assessment of patients with suspected CRSWDs, sleep diaries (self-reported or caregiver) daily account of sleep and wake times over at least 1 week) and actigraphy (wrist-worn accelerometer designed to measure activity and inactivity at night) can be used, particularly in older adults with dementia [40,41].

CRSWD treatment may include behavioral modifications and/or pharmacological intervention. Behavioral modifications can consist of chronotherapy, relaxation training, and/or bright light therapy. Chronotherapy involves making gradual shifts in an individual’s sleep time to meet his/her desired sleep schedule. Relaxation training involves implementing behaviors/activities that reduce tension and enhance the smooth transition into sleep. Bright light therapy involves exposure to an appropriate intensity and duration of light, which is an important environmental cue to help the synchrony of the sleep-wake cycle [7]. Previous studies have observed that NH residents are exposed to a restricted amount of bright light during the daytime [42,43], but higher levels of artificial light at night (eg, hallway lighting) [7]. NH residents’ exposure to artificial bright light during the daytime has not only improved the residents’ sleep [44–46], but also has improved their cognitive functioning and reduced their depressive symptoms [47]. Thus, steps towards targeted light exposure in sync with the typical sleep-wake cycle (eg, mandated time in well-lit rooms during the day and during meals) for NH residents, particularly those with CRSWDs, could prove to be beneficial across several social, behavioral and neurocognitive domains. Lastly, NH residents exposed to at least 30 minutes of outdoor daylight and at least 3 occasions of low intensity physical activities for 10 to 15 minutes daily can potentially improve sleep-wake patterns [48]. Thus, it may be beneficial to have an intervention that couples bright light exposure and physical activity in the NH setting.

Pharmacological interventions can also be implemented to improve older residents’ symptoms. However, the medications prescribed should be used with caution and should not be used as part of a long-term treatment plan. Melatonin is a commonly used herbal supplement that can assist advancing the timing of the circadian rhythms in the evening but can delay the circadian rhythms in the morning [49]. Several brands of this herbal supplement can be purchased over-the-counter and are not regulated by the FDA. Since the amount of melatonin used in the herbal supplement varies by brand, caution should be used when selecting a brand [50]. Two FDA-approved drugs (modafinil and armodafinil) are currently being used to reduce daytime sleepiness and improve vigilance amongst adults, but limited research has explored the effectiveness of these medication for older adults specifically suffering with CRSWDS [36,51,52]. Other stimulants (eg, caffeine, amphetamines, and nonamphetamine-derived medications) are also currently being used to reduce daytime sleepiness in patients with CRSWDS. Stimulant use, particularly caffeine consumption, has also been associated with better cognitive functioning in older adults [53]. However, stimulants should be taken with caution, particularly in older adults, because stimulant use has been associated with potentially serious and fatal health sequalae (eg, tachycardia, heart failure, irreversible heart damage and hypertension) [36,54].

Case 3 Outcome

The patient was moved to a room with a window. An alarm clock was set for 7:30 in the morning and he was taken to breakfast, where he sat at a table near a window. Any time he appeared to be sleepy, he was encouraged to go for a walk or engage in other activities so daytime napping opportunities were limited. His environment was assessed for safety and bedrails were utilized to prevent falls.

Case 4

A 75-year-old woman with a history of anxiety and depression moved into the NH 4 months ago after suffering a stroke. She now reports difficulty falling asleep for many years, which has significantly worsened since moving to the NH. Currently, she has been getting only 3 to 4 hour of sleep per night. She reports mild but increasing daytime sleepiness and does not fall asleep until 1:00 am despite getting into bed at 10:30 pm. She occasionally reports arthritic pain that interferes with her sleep. The NH staff has mentioned that she will occasionally cry for her family when she appears to be asleep.

Case 4 Reflection: Insomnia

According to the International Classification of Sleep Disorders (ICSD-3) [39], insomnia is characterized as “a repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment.” Among the sleep disorders, insomnia is one of the most common sleep issues observed in sleep clinics [34]. Older adults with insomnia often have comorbid physical (eg, pulmonary disease, arthritis, chronic pain, cancer diabetes, Parkinson’s disease) and mental illness (eg, depression, panic disorder) [55]. Medications (eg, stimulants, respiratory medications, chemotherapy, decongestants, hormones, or psychotropics) may cause and exacerbate insomnia symptoms [55].

Since insomnia is a clinical diagnosis, there is no specific diagnostic tool or gold standard test to identify individuals suffering with insomnia. Insomnia screening usually involves a clinical interview, in which a health provider, preferably trained in sleep, conducts a physical examination and collects an in-depth history of a patients’ sleep problems [56]. Insomnia screening tools may also include having a patient complete a sleep diary or questionnaire, such as the insomnia severity index (ISI) [57] or Pittsburgh Sleep Quality Index (PSQI) [58].

Cognitive behavioral therapy for insomnia (CBT-I) and/or pharmacological intervention are typically used to treat insomnia in older adults. CBT-I is a combination of cognitive (eg, changing dysfunctional sleep attitudes/beliefs) and behavioral treatment (eg, adhering to a regular sleep schedule) [59]. CBT-I or a combination of CBT-I and pharmacological intervention is recommended as more effective long-term approach to insomnia treatment compared to pharmacological intervention alone [55]. CBT-I involves altering older adults’ misconceptions of their sleep and implementing behavioral techniques to their everyday life (eg, routine sleep-wake schedule, relaxation therapy). Several FDA-approved medications are available to treat insomnia; however, many commonly used medications to treat insomnia in older adults (ie, antihistamines, antidepressants, anticonvulsants, and anti-psychotics) pose more risks than benefits to their health and well-being [35,60–62]. Some of the more recent hypnotics (egm zolpidem, exzopiclone, and ramelteon) on the market have been shown to be safer and more effective pharmacological options [55]. In 2014, the FDA approved the first in class orexin receptor antagonist medication (suvorexant) to treat insomnia [63]. Unlike other medications to treat insomnia, suvorexant, via the blockade of the orexin neurotransmitter, effectively inhibits orexin (one of neurotransmitters involved in the activation pathways of the arousal system), so sleep can easily be induced and maintained [64, 65]. Furthermore, preliminary studies suggest that this medication may be associated with less severe side effects (ie, habituation) than the other approved medications on the market [64, 65]. In fact, in a recent clinical series that included both young and older insomnia patients, the most common adverse reaction to suvorexant was drowsiness [66].

Case 4 Outcome

The patient was initiated on basic CBT-I therapy strategies which included stimulus control therapy [67]; implementation of a consistent bedtime and awakening routine; reducing the use of TV, smart phone, or other electronic leisure devices 1 hour before bedtime; refraining from caffeine after lunchtime; improving the sleep environment; and relaxation techniques.

Case 5

The patient is a 65-year-old man diagnosed with Parkinson’s disease several years ago. Recently, he has often has been experiencing what appears to be very violent and terrifying dreams. While asleep, he often screams and shouts for help. In addition, he occasionally will punch, kick, and/or thrash around in bed at night, which the NH staff has noted as a concern for his safety.

Case 5 Reflection: Parasomnias

Parasomnias represent frequent arousals during sleep or in the wake-to-sleep transition due to abnormal motor movements, behaviors (eg, shouting, flailing, and leaping from bed) and/or sensory experiences (eg, “dreamlike” hallucinations) [68]. Motor movements that occur for parasomnia can be disruptive for the individual and potentially dangerous for the individual and/or bed partner. There are 3 primary types of parasomnias based on the stage of sleep that the event occurs: non-REM (NREM), REM, and other parasomnias during transitions of sleep [68]. The most commonly observed parasomnia seen in older adults is the REM-associated parasomnia or REM sleep behavior disorder (RBD), which is characterized by experiencing vivid, sometimes violent, dreams typically involving fighting an intruder or an animal to protect a loved one [69]. For RBD, disruptive behaviors typically occur during REM sleep [69]. RBD has been associated with neurodegenerative disorders (Parkinson’s disease and Lewy body disease), neurologic disorders (eg, brain tumors and stroke), other primary disorders (narcolepsy and periodic limb movement disorder), and well as some medications (eg, antidepressants and β-blockers) [68]. There is limited knowledge on the prevalence of parasomnias in NH settings. One study, however, reported that 31% of older NH residents experience parasomnias [70]. Evaluation for parasomnias generally involve a clinical evaluation by a sleep specialist and overnight sleep study (ie, polysomnography at a sleep center if there is a concern for sleep apnea or RBD [71].

Medications are not typically first-line for parasomnia. Instead education about improving sleep practices, addressing other underlying sleep disorders, and securing a safe sleep environment are first recommended. Pharmacologic treatment, particularly the use of clonazepam, is commonly used to treat RBD [72]. However, this medication should be used with caution for older adults with a dementia diagnosis, gait disorders, and OSA because the common side effects include sedation, confusion, memory dysfunction, and early morning motor incoordination [68]. Several alternative medications have also been used to treat RBD. For example, medications commonly used to Parkinson disease symptoms, such Levodopa and dopamine agonists, have also been used to treat RBD [73]. Zopiclone, a nonbenzodiazepine hypnotic agent, has also been shown to be as effective as clonazepam, but with less potential side effects [74]. Melatonin, a nutritional supplement, has also been used as a treatment and appears to alleviate some of the RBD symptoms and has fewer side effects [68]. Since melatonin is not regulated by the FDA, it has been suggested that this treatment be used with caution in the older population [73].

Case 5 Outcome

The patient was evaluated with video synchronized in lab PSG. It confirmed REM sleep without evidence of the normal atonia that should be apparent during REM. These PSG findings in combination with repeated accounts of dream enactment established the diagnosis of RBD. Patient was treated with low-dose clonazepam and closely monitored for potential side effects of daytime sedation. Bedroom environment was also carefully reconfigured for safety to avoid potential risk of injury during a dream enactment episode.

Conclusion

Sleep disturbances remain an underappreciated and undertreated health issue in NH residents. Nursing homes can help facilitate optimal sleep health and day functioning by providing mandatory natural light outlets, physical exercise opportunities, and minimal allowable time residents can spend in their bed/bedroom outside of their routine sleep period. Educating NH providers and staff on sleep medicine may benefit residents, but workload and restricted resources may hinder this. Education via mobile and internet based educational platforms and resources (Mysleep101) may be helpful in addressing education barriers [75]. Convenient and cost-effective methods to deliver sleep medicine education to NH health care providers should be part of our ongoing efforts to improve the viability, vitality and quality of life of our aging citizens.

Corresponding author: Alyssa Gamaldo, PhD, Univ. of South Florida, 13301 Bruce B. Downs Blvd, MHC 1340, Tampa, FL 33612, agamaldo@usf.edu.

Financial disclosures: None.

From the School of Aging Studies, University of South Florida, Tampa, FL (Dr. AA Gamaldo) and the Department of Neurology, Johns Hopkins Medicine, Baltimore, MD (Drs. Sloane, CE Gamaldo and Salas).

Abstract

• Objective: To provide guidance on identifying and treating sleep disturbances commonly encountered in older nursing home residents.
• Methods: Review of the literature in the context of 5 clinical cases.
• Results: Sleep disturbances continue to be a growing global epidemic, and public health initiatives have been aimed at improving sleep health across all ages. In older adults, sleep disturbances are often associated with the development and/or worsening of health conditions. Common sleep disturbances observed in older nursing home residents include obstructive sleep apnea, restless legs syndrome/Willis-Ekbom disease, circadian rhythm sleep-wake disorders, insomnia, and parasomnias. The symptoms and recommended treatment plans vary across the sleep disturbances. For many sleep disturbances, modification of residents’ daily activities and/or nursing home environment can be helpful.
• Conclusion: As the number of people residing in nursing homes increases, it is important for health care providers to be knowledgable about sleep disturbances in this population.

By 2030, almost 20% of the US population (approximately 72.1 million people) will be age 65 and older [1]. As many as 63% of older adults in the general population report sleep disturbances [2]. Specifically, older adults demonstrate difficulty with decreased total sleep duration, an increase in sleep fragmentation (ie, interruptions in nighttime sleep), and reduced total sleep time spent in rapid eye movement (REM) and slow wave sleep [3–5]. Poor sleep, either because of not getting enough sleep or having an undiagnosed and thus untreated sleep disorder, is associated with physical illness, impaired cognition, poor physical function, and mortality risk [6,7]. In fact, over 50% of individuals older than 65 years meet the diagnostic criteria for a sleep disorder, many of which are undiagnosed [6,7].

It is forecasted that we will see substantial increases in the rate of nursing home residence among the elderly [8]. The prevalence and severity of disturbed sleep is reportedly higher in NH residents [6,7]. Generally, NH residents tend to be on several medications for various medical disorders that may negatively impact sleep [7]. Reciprocally, sleep disruption may put NH residents at an increased risk for behavioral issues (eg, agitation) [9,10] as well as developing and/or exacerbating health conditions (eg, mood disorders, dementia, cardiovascular disease) [8]. Furthermore, NH residents exhibiting disturbed sleep, behavioral issues, and/or mood disorders are at an increased risk for being prescribed antipsychotic drugs [11], which are associated with adverse side effects and poorer quality of life [12]. Thus, the identification and management of sleep disturbances in the NH setting has become progressively more vital in efforts to optimize medical management of this population. This review identifies common sleep disturbances frequently underdiagnosed and undertreated among residents of NH facilities.

Case 1

A 73-year-old woman with a history of type 2 diabetes mellitus reports poor sleep quality with frequent awakenings during the night and excessive daytime sleepiness. She states that she can fall asleep within 5 minutes, but often is awoken throughout the night with a sensation of breathlessness. She has snored for many years, but the nursing staff at her NH facility has recently commented that her snoring has gone from intermittent to constant. She cannot remember the last time she has had restful sleep. She consumes 3 to 4 cups of caffeinated beverages daily to counter her sleepiness. She denies smoking or illicit drug or alcohol use. Her review of systems was notable for a 30-lb weight gain over the last year, and she reports increasing fatigue, irritability, and memory and concentration issues. Her current medication list includes metformin and amlodipine. Her examination is remarkable for a BMI of 31, large neck circumference (> 16), tonsillar enlargement, a crowded oropharynx, micrognathia, lungs clear to auscultation bilaterally, heart sounds of normal S1 and S2, and legs with trace pitting edema.

Case 1 Reflection: Sleep-Disordered Breathing

Although previous studies have observed high rates (60%–90%) of SDB in NH settings [16,17], one study observed that only 0.5% of nursing home residents carried a diagnosis with SDB, suggesting that SDB is being grossly underappreciated amongst NH residents over the age of 65 [18]. In order to evaluate for SBD, routine annual physical exams or medical chart reviews can elicit the risk factors for sleep apnea (eg, obesity [per BMI], male sex, postmenopausal women, family history of sleep apnea) as well as common comorbidities (eg, hypertension, coronary artery disease, and diabetes). Formal evaluation consists of a sleep evaluation with a sleep specialist and polysomnography (PSG; sleep study) that can be performed in the sleep center or at home depending on the patient’s history and other medical issues.

Case 1 Outcome

Case 2

An 85-year-old man with history of Alzheimer’s disease, major depression and arthritis, reports insomnia and “tingling in my legs” at bedtime. The patient cannot identify when the symptoms started but reports that his legs often jerk during sleep. He consumes a cup of coffee daily and has a previous 20 pack-year smoking history (he quit 40 years ago). On review of systems, he endorses fatigue. His current medication list includes fluoxetine, donepezil hydrochloride, ibuprofen as needed for arthritic pain, and a multivitamin. His examination was unremarkable, with a BMI of 26, neck circumference < 16, no tonsillar enlargement, normal (noncrowded) oropharynx, lungs clear to auscultation bilaterally, heart sounds demonstrating a normal S1 and S2, and legs without edema.

Case 2 Reflection: Restless Legs Syndrome/Willis-Ekbom Disease

Restless legs syndrome (RLS) also known as Willis-Ekbom disease, affects approximately 10 million adults in the United States alone [22]. RLS is a sensorimotor disorder that must satisfy the following 5 primary diagnostic criteria: (1) urge to move the legs with or without dysesthesias; (2) onset or exacerbation with rest or inactivity; (3) relief with movement; (4) symptoms are worse in the evening or at night (circadian component); (5) symptoms cannot be solely accounted for as consequence of another medical or behavioral condition. Other supporting clinical features can alert a clinician to the likelihood of a RLS diagnosis; these include positive family history, response to dopaminergic therapy, lack of profound daytime sleepiness, and presence of periodic limb movements during sleep (PLMS) [23–26]. In younger individuals, the symptoms present insidiously whereas older adults (> 50 years of age) will usually present with sudden onset [27].

Not only do patients lack the restorative sleep needed to ward off fatigue and restfulness, but patients also demonstrate higher rates of comorbidities (eg, anxiety, hypertension, depression) as well as large economic burden secondary to absenteeism and decreased on-the-job effectiveness [28,29]. As a results, patients with RLS experience significant reductions in quality of life related to this sensorimotor disorder [28].

No confirmatory laboratory test exists to diagnose RLS; however, patients suspected of having RLS should be evaluated with a basic metabolic panel, iron studies, and a thorough neurologic examination, as iron deficiency, kidney failure, uremia and peripheral neuropathy can lead to secondary RLS [30,31]. Evidence shows that RLS is common in NH residents [32] and may account for problematic behaviors, such as late night pacing [7]. Forty-five percent of community dwelling individuals over 65 years old exhibit a PLMS index (leg kicks per hour) of greater than 5 [33]. PLMS, while not a disorder in and of itself, can serve as a marker for potential disease. PLMS are characterized by intermittent episodes of stereotyped leg movements. PLMS typically do not awaken the patient from sleep and therefore do not contribute to insomnia or daytime sleepiness, representing a key clinical difference from RLS. It is important to note that PLMS are nonspecific and may be common in older adults that do not meet the diagnostic criteria for RLS.

Treatment of RLS is based on the frequency of symptoms and the level of functional impairment caused by the syndrome. RLS treatment recommendations should always espouse nonpharmacological interventions that include improving sleep practices, engagement in daily physical activity, targeted placement of sedentary activity in the morning when symptoms are less prominent, and concerted efforts to avoid the use of RLS-exacerbating medications (eg, selective serotonin reuptake inhibitor (SSRIs), neuroleptic agents, antihistamines) [28]. If there is an underlying condition contributing to RLS, such as metabolic disturbance or iron deficiency, then these conditions should be corrected before initiating RLS medications. Several medications are FDA-approved for treatment of RLS, including dopamine agonists (eg, ropinirole, rotigotine, pramipexole), dopamine precursor (eg, levodopa), glutamate-related (eg, gabapentin), benzodiazepines (eg, temazepam, clonazepam). Augmentation, the worsening of RLS symptoms, can occur in patients taking dopamine agonists. If this occurs, dopamine agents should be discontinued or switched to other agents (such as a long-acting dopamine agonist, gabapentin encarbil, as well as non-FDA approved therapies such as opioids). However, it is important to note that weaning off dopamine agents may result in mild but in most cases moderate and/or severe withdrawal from the medication, so counseling and close monitoring should be done.

Case 2 Outcome

Given the patient’s history of dementia, opioids, benzodiazepines and other delirium-inducing medications should be avoided. His antidepressive regimen, fluoxetine, should be re-evaluated as these medications have been associated with RLS exacerbation. In addition to SSRIs, medications associated with RLS are MAO inhibitors (selegeline, phenelzine), antipsychotics (risperdone, olanzapine), tricyclic antidepressants (mirtazapine), antihistamines (diphenhydramine, cimetidine), calcium channel blockers (verapamil, nifedipine, diltiazem), and phenytoin [34,35]. His treatment began with behavioral, nonpharmacological management, and blood testing for iron studies. His low iron level prompted initiation of oral supplementation, and he was asked to follow up in 3 months for reevaluation and possible initiation of low-dose dopamine agonists.

Case 3

A 73-year-old man with dementia is found to have very irregular sleep wake patterns with a variable bedtime and awakening time, often missing breakfast. He is found dozing off often during the day, particularly during times of inactivity. He has frequent awakenings during the night often calling for the staff to guide him back to bed. He has had some falls secondary to walking around his room. He has been prescribed various hypnotics without much benefit and instead, has suffered from some confusion while on these medications. His room is very dark and has no windows.

Case 3 Reflection: Circadian Rhythm Sleep-Wake Disorders

Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by an individual’s natural propensity to want to go to sleep and be awake during a period that is undesirable personally and/or socially [36]. CRSWDs can be a result of the desynchronization of the 2 sleep processes: (1) homeostatic drive (regulates sleep intensity) and (2) circadian rhythm (maintains daytime alertness); [36]. CRSWDs can also be due to an individual’s naturally occurring sleep drives becoming misaligned with their social/personal sleep-wake demands (eg, employment schedule and socializing opportunities with family/friends). With increasing age, the circadian rhythm becomes less adept at functioning in a desynchronized pattern [7], which can result in daytime sleepiness and night time sleep fragmentation [7,37]. CRSWDs are highly prevalent in individuals with dementia [7,36]. As dementia progresses, the ability to maintain a balance of the 2 sleep process becomes more impaired [7]. As a result, individuals with dementia, particularly Alzheimer’s disease, are likely to experience agitation, irritability, and/or confusion during the evening and night, a behavioral problem referred to as “sundowning” [38].

There are several types of CRSWDs, including delayed sleep-phase syndrome, advanced sleep-phase syndrome, irregular sleep-wake disorder, non–24-hour sleep-wake disorder, shift work sleep disorder, and jet lag sleep disorder. However, the most common type of CRSWDs observed in older adults is advanced sleep-phase syndrome [39]. Due to excessive sleepiness in the early evening, affected individuals may report a need to shift to earlier and earlier bedtimes (~6 to 7 pm) and wake times (~3 to 4 am) [36]. For older affected adults, this can cause distress and frustration, particularly if their sleep phase prevents them from participating in evening activities (eg, socializing with family/friends) [36].

In the assessment of patients with suspected CRSWDs, sleep diaries (self-reported or caregiver) daily account of sleep and wake times over at least 1 week) and actigraphy (wrist-worn accelerometer designed to measure activity and inactivity at night) can be used, particularly in older adults with dementia [40,41].

CRSWD treatment may include behavioral modifications and/or pharmacological intervention. Behavioral modifications can consist of chronotherapy, relaxation training, and/or bright light therapy. Chronotherapy involves making gradual shifts in an individual’s sleep time to meet his/her desired sleep schedule. Relaxation training involves implementing behaviors/activities that reduce tension and enhance the smooth transition into sleep. Bright light therapy involves exposure to an appropriate intensity and duration of light, which is an important environmental cue to help the synchrony of the sleep-wake cycle [7]. Previous studies have observed that NH residents are exposed to a restricted amount of bright light during the daytime [42,43], but higher levels of artificial light at night (eg, hallway lighting) [7]. NH residents’ exposure to artificial bright light during the daytime has not only improved the residents’ sleep [44–46], but also has improved their cognitive functioning and reduced their depressive symptoms [47]. Thus, steps towards targeted light exposure in sync with the typical sleep-wake cycle (eg, mandated time in well-lit rooms during the day and during meals) for NH residents, particularly those with CRSWDs, could prove to be beneficial across several social, behavioral and neurocognitive domains. Lastly, NH residents exposed to at least 30 minutes of outdoor daylight and at least 3 occasions of low intensity physical activities for 10 to 15 minutes daily can potentially improve sleep-wake patterns [48]. Thus, it may be beneficial to have an intervention that couples bright light exposure and physical activity in the NH setting.

Pharmacological interventions can also be implemented to improve older residents’ symptoms. However, the medications prescribed should be used with caution and should not be used as part of a long-term treatment plan. Melatonin is a commonly used herbal supplement that can assist advancing the timing of the circadian rhythms in the evening but can delay the circadian rhythms in the morning [49]. Several brands of this herbal supplement can be purchased over-the-counter and are not regulated by the FDA. Since the amount of melatonin used in the herbal supplement varies by brand, caution should be used when selecting a brand [50]. Two FDA-approved drugs (modafinil and armodafinil) are currently being used to reduce daytime sleepiness and improve vigilance amongst adults, but limited research has explored the effectiveness of these medication for older adults specifically suffering with CRSWDS [36,51,52]. Other stimulants (eg, caffeine, amphetamines, and nonamphetamine-derived medications) are also currently being used to reduce daytime sleepiness in patients with CRSWDS. Stimulant use, particularly caffeine consumption, has also been associated with better cognitive functioning in older adults [53]. However, stimulants should be taken with caution, particularly in older adults, because stimulant use has been associated with potentially serious and fatal health sequalae (eg, tachycardia, heart failure, irreversible heart damage and hypertension) [36,54].

Case 3 Outcome

The patient was moved to a room with a window. An alarm clock was set for 7:30 in the morning and he was taken to breakfast, where he sat at a table near a window. Any time he appeared to be sleepy, he was encouraged to go for a walk or engage in other activities so daytime napping opportunities were limited. His environment was assessed for safety and bedrails were utilized to prevent falls.

Case 4

A 75-year-old woman with a history of anxiety and depression moved into the NH 4 months ago after suffering a stroke. She now reports difficulty falling asleep for many years, which has significantly worsened since moving to the NH. Currently, she has been getting only 3 to 4 hour of sleep per night. She reports mild but increasing daytime sleepiness and does not fall asleep until 1:00 am despite getting into bed at 10:30 pm. She occasionally reports arthritic pain that interferes with her sleep. The NH staff has mentioned that she will occasionally cry for her family when she appears to be asleep.

Case 4 Reflection: Insomnia

According to the International Classification of Sleep Disorders (ICSD-3) [39], insomnia is characterized as “a repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment.” Among the sleep disorders, insomnia is one of the most common sleep issues observed in sleep clinics [34]. Older adults with insomnia often have comorbid physical (eg, pulmonary disease, arthritis, chronic pain, cancer diabetes, Parkinson’s disease) and mental illness (eg, depression, panic disorder) [55]. Medications (eg, stimulants, respiratory medications, chemotherapy, decongestants, hormones, or psychotropics) may cause and exacerbate insomnia symptoms [55].

Since insomnia is a clinical diagnosis, there is no specific diagnostic tool or gold standard test to identify individuals suffering with insomnia. Insomnia screening usually involves a clinical interview, in which a health provider, preferably trained in sleep, conducts a physical examination and collects an in-depth history of a patients’ sleep problems [56]. Insomnia screening tools may also include having a patient complete a sleep diary or questionnaire, such as the insomnia severity index (ISI) [57] or Pittsburgh Sleep Quality Index (PSQI) [58].

Cognitive behavioral therapy for insomnia (CBT-I) and/or pharmacological intervention are typically used to treat insomnia in older adults. CBT-I is a combination of cognitive (eg, changing dysfunctional sleep attitudes/beliefs) and behavioral treatment (eg, adhering to a regular sleep schedule) [59]. CBT-I or a combination of CBT-I and pharmacological intervention is recommended as more effective long-term approach to insomnia treatment compared to pharmacological intervention alone [55]. CBT-I involves altering older adults’ misconceptions of their sleep and implementing behavioral techniques to their everyday life (eg, routine sleep-wake schedule, relaxation therapy). Several FDA-approved medications are available to treat insomnia; however, many commonly used medications to treat insomnia in older adults (ie, antihistamines, antidepressants, anticonvulsants, and anti-psychotics) pose more risks than benefits to their health and well-being [35,60–62]. Some of the more recent hypnotics (egm zolpidem, exzopiclone, and ramelteon) on the market have been shown to be safer and more effective pharmacological options [55]. In 2014, the FDA approved the first in class orexin receptor antagonist medication (suvorexant) to treat insomnia [63]. Unlike other medications to treat insomnia, suvorexant, via the blockade of the orexin neurotransmitter, effectively inhibits orexin (one of neurotransmitters involved in the activation pathways of the arousal system), so sleep can easily be induced and maintained [64, 65]. Furthermore, preliminary studies suggest that this medication may be associated with less severe side effects (ie, habituation) than the other approved medications on the market [64, 65]. In fact, in a recent clinical series that included both young and older insomnia patients, the most common adverse reaction to suvorexant was drowsiness [66].

Case 4 Outcome

The patient was initiated on basic CBT-I therapy strategies which included stimulus control therapy [67]; implementation of a consistent bedtime and awakening routine; reducing the use of TV, smart phone, or other electronic leisure devices 1 hour before bedtime; refraining from caffeine after lunchtime; improving the sleep environment; and relaxation techniques.

Case 5

The patient is a 65-year-old man diagnosed with Parkinson’s disease several years ago. Recently, he has often has been experiencing what appears to be very violent and terrifying dreams. While asleep, he often screams and shouts for help. In addition, he occasionally will punch, kick, and/or thrash around in bed at night, which the NH staff has noted as a concern for his safety.

Case 5 Reflection: Parasomnias

Parasomnias represent frequent arousals during sleep or in the wake-to-sleep transition due to abnormal motor movements, behaviors (eg, shouting, flailing, and leaping from bed) and/or sensory experiences (eg, “dreamlike” hallucinations) [68]. Motor movements that occur for parasomnia can be disruptive for the individual and potentially dangerous for the individual and/or bed partner. There are 3 primary types of parasomnias based on the stage of sleep that the event occurs: non-REM (NREM), REM, and other parasomnias during transitions of sleep [68]. The most commonly observed parasomnia seen in older adults is the REM-associated parasomnia or REM sleep behavior disorder (RBD), which is characterized by experiencing vivid, sometimes violent, dreams typically involving fighting an intruder or an animal to protect a loved one [69]. For RBD, disruptive behaviors typically occur during REM sleep [69]. RBD has been associated with neurodegenerative disorders (Parkinson’s disease and Lewy body disease), neurologic disorders (eg, brain tumors and stroke), other primary disorders (narcolepsy and periodic limb movement disorder), and well as some medications (eg, antidepressants and β-blockers) [68]. There is limited knowledge on the prevalence of parasomnias in NH settings. One study, however, reported that 31% of older NH residents experience parasomnias [70]. Evaluation for parasomnias generally involve a clinical evaluation by a sleep specialist and overnight sleep study (ie, polysomnography at a sleep center if there is a concern for sleep apnea or RBD [71].

Medications are not typically first-line for parasomnia. Instead education about improving sleep practices, addressing other underlying sleep disorders, and securing a safe sleep environment are first recommended. Pharmacologic treatment, particularly the use of clonazepam, is commonly used to treat RBD [72]. However, this medication should be used with caution for older adults with a dementia diagnosis, gait disorders, and OSA because the common side effects include sedation, confusion, memory dysfunction, and early morning motor incoordination [68]. Several alternative medications have also been used to treat RBD. For example, medications commonly used to Parkinson disease symptoms, such Levodopa and dopamine agonists, have also been used to treat RBD [73]. Zopiclone, a nonbenzodiazepine hypnotic agent, has also been shown to be as effective as clonazepam, but with less potential side effects [74]. Melatonin, a nutritional supplement, has also been used as a treatment and appears to alleviate some of the RBD symptoms and has fewer side effects [68]. Since melatonin is not regulated by the FDA, it has been suggested that this treatment be used with caution in the older population [73].

Case 5 Outcome

The patient was evaluated with video synchronized in lab PSG. It confirmed REM sleep without evidence of the normal atonia that should be apparent during REM. These PSG findings in combination with repeated accounts of dream enactment established the diagnosis of RBD. Patient was treated with low-dose clonazepam and closely monitored for potential side effects of daytime sedation. Bedroom environment was also carefully reconfigured for safety to avoid potential risk of injury during a dream enactment episode.

Conclusion

Sleep disturbances remain an underappreciated and undertreated health issue in NH residents. Nursing homes can help facilitate optimal sleep health and day functioning by providing mandatory natural light outlets, physical exercise opportunities, and minimal allowable time residents can spend in their bed/bedroom outside of their routine sleep period. Educating NH providers and staff on sleep medicine may benefit residents, but workload and restricted resources may hinder this. Education via mobile and internet based educational platforms and resources (Mysleep101) may be helpful in addressing education barriers [75]. Convenient and cost-effective methods to deliver sleep medicine education to NH health care providers should be part of our ongoing efforts to improve the viability, vitality and quality of life of our aging citizens.

Corresponding author: Alyssa Gamaldo, PhD, Univ. of South Florida, 13301 Bruce B. Downs Blvd, MHC 1340, Tampa, FL 33612, agamaldo@usf.edu.

Financial disclosures: None.

From the School of Aging Studies, University of South Florida, Tampa, FL (Dr. AA Gamaldo) and the Department of Neurology, Johns Hopkins Medicine, Baltimore, MD (Drs. Sloane, CE Gamaldo and Salas).

Abstract

• Objective: To provide guidance on identifying and treating sleep disturbances commonly encountered in older nursing home residents.
• Methods: Review of the literature in the context of 5 clinical cases.
• Results: Sleep disturbances continue to be a growing global epidemic, and public health initiatives have been aimed at improving sleep health across all ages. In older adults, sleep disturbances are often associated with the development and/or worsening of health conditions. Common sleep disturbances observed in older nursing home residents include obstructive sleep apnea, restless legs syndrome/Willis-Ekbom disease, circadian rhythm sleep-wake disorders, insomnia, and parasomnias. The symptoms and recommended treatment plans vary across the sleep disturbances. For many sleep disturbances, modification of residents’ daily activities and/or nursing home environment can be helpful.
• Conclusion: As the number of people residing in nursing homes increases, it is important for health care providers to be knowledgable about sleep disturbances in this population.

By 2030, almost 20% of the US population (approximately 72.1 million people) will be age 65 and older [1]. As many as 63% of older adults in the general population report sleep disturbances [2]. Specifically, older adults demonstrate difficulty with decreased total sleep duration, an increase in sleep fragmentation (ie, interruptions in nighttime sleep), and reduced total sleep time spent in rapid eye movement (REM) and slow wave sleep [3–5]. Poor sleep, either because of not getting enough sleep or having an undiagnosed and thus untreated sleep disorder, is associated with physical illness, impaired cognition, poor physical function, and mortality risk [6,7]. In fact, over 50% of individuals older than 65 years meet the diagnostic criteria for a sleep disorder, many of which are undiagnosed [6,7].

It is forecasted that we will see substantial increases in the rate of nursing home residence among the elderly [8]. The prevalence and severity of disturbed sleep is reportedly higher in NH residents [6,7]. Generally, NH residents tend to be on several medications for various medical disorders that may negatively impact sleep [7]. Reciprocally, sleep disruption may put NH residents at an increased risk for behavioral issues (eg, agitation) [9,10] as well as developing and/or exacerbating health conditions (eg, mood disorders, dementia, cardiovascular disease) [8]. Furthermore, NH residents exhibiting disturbed sleep, behavioral issues, and/or mood disorders are at an increased risk for being prescribed antipsychotic drugs [11], which are associated with adverse side effects and poorer quality of life [12]. Thus, the identification and management of sleep disturbances in the NH setting has become progressively more vital in efforts to optimize medical management of this population. This review identifies common sleep disturbances frequently underdiagnosed and undertreated among residents of NH facilities.

Case 1

A 73-year-old woman with a history of type 2 diabetes mellitus reports poor sleep quality with frequent awakenings during the night and excessive daytime sleepiness. She states that she can fall asleep within 5 minutes, but often is awoken throughout the night with a sensation of breathlessness. She has snored for many years, but the nursing staff at her NH facility has recently commented that her snoring has gone from intermittent to constant. She cannot remember the last time she has had restful sleep. She consumes 3 to 4 cups of caffeinated beverages daily to counter her sleepiness. She denies smoking or illicit drug or alcohol use. Her review of systems was notable for a 30-lb weight gain over the last year, and she reports increasing fatigue, irritability, and memory and concentration issues. Her current medication list includes metformin and amlodipine. Her examination is remarkable for a BMI of 31, large neck circumference (> 16), tonsillar enlargement, a crowded oropharynx, micrognathia, lungs clear to auscultation bilaterally, heart sounds of normal S1 and S2, and legs with trace pitting edema.

Case 1 Reflection: Sleep-Disordered Breathing

Although previous studies have observed high rates (60%–90%) of SDB in NH settings [16,17], one study observed that only 0.5% of nursing home residents carried a diagnosis with SDB, suggesting that SDB is being grossly underappreciated amongst NH residents over the age of 65 [18]. In order to evaluate for SBD, routine annual physical exams or medical chart reviews can elicit the risk factors for sleep apnea (eg, obesity [per BMI], male sex, postmenopausal women, family history of sleep apnea) as well as common comorbidities (eg, hypertension, coronary artery disease, and diabetes). Formal evaluation consists of a sleep evaluation with a sleep specialist and polysomnography (PSG; sleep study) that can be performed in the sleep center or at home depending on the patient’s history and other medical issues.

Case 1 Outcome

Case 2

An 85-year-old man with history of Alzheimer’s disease, major depression and arthritis, reports insomnia and “tingling in my legs” at bedtime. The patient cannot identify when the symptoms started but reports that his legs often jerk during sleep. He consumes a cup of coffee daily and has a previous 20 pack-year smoking history (he quit 40 years ago). On review of systems, he endorses fatigue. His current medication list includes fluoxetine, donepezil hydrochloride, ibuprofen as needed for arthritic pain, and a multivitamin. His examination was unremarkable, with a BMI of 26, neck circumference < 16, no tonsillar enlargement, normal (noncrowded) oropharynx, lungs clear to auscultation bilaterally, heart sounds demonstrating a normal S1 and S2, and legs without edema.

Case 2 Reflection: Restless Legs Syndrome/Willis-Ekbom Disease

Restless legs syndrome (RLS) also known as Willis-Ekbom disease, affects approximately 10 million adults in the United States alone [22]. RLS is a sensorimotor disorder that must satisfy the following 5 primary diagnostic criteria: (1) urge to move the legs with or without dysesthesias; (2) onset or exacerbation with rest or inactivity; (3) relief with movement; (4) symptoms are worse in the evening or at night (circadian component); (5) symptoms cannot be solely accounted for as consequence of another medical or behavioral condition. Other supporting clinical features can alert a clinician to the likelihood of a RLS diagnosis; these include positive family history, response to dopaminergic therapy, lack of profound daytime sleepiness, and presence of periodic limb movements during sleep (PLMS) [23–26]. In younger individuals, the symptoms present insidiously whereas older adults (> 50 years of age) will usually present with sudden onset [27].

Not only do patients lack the restorative sleep needed to ward off fatigue and restfulness, but patients also demonstrate higher rates of comorbidities (eg, anxiety, hypertension, depression) as well as large economic burden secondary to absenteeism and decreased on-the-job effectiveness [28,29]. As a results, patients with RLS experience significant reductions in quality of life related to this sensorimotor disorder [28].

No confirmatory laboratory test exists to diagnose RLS; however, patients suspected of having RLS should be evaluated with a basic metabolic panel, iron studies, and a thorough neurologic examination, as iron deficiency, kidney failure, uremia and peripheral neuropathy can lead to secondary RLS [30,31]. Evidence shows that RLS is common in NH residents [32] and may account for problematic behaviors, such as late night pacing [7]. Forty-five percent of community dwelling individuals over 65 years old exhibit a PLMS index (leg kicks per hour) of greater than 5 [33]. PLMS, while not a disorder in and of itself, can serve as a marker for potential disease. PLMS are characterized by intermittent episodes of stereotyped leg movements. PLMS typically do not awaken the patient from sleep and therefore do not contribute to insomnia or daytime sleepiness, representing a key clinical difference from RLS. It is important to note that PLMS are nonspecific and may be common in older adults that do not meet the diagnostic criteria for RLS.

Treatment of RLS is based on the frequency of symptoms and the level of functional impairment caused by the syndrome. RLS treatment recommendations should always espouse nonpharmacological interventions that include improving sleep practices, engagement in daily physical activity, targeted placement of sedentary activity in the morning when symptoms are less prominent, and concerted efforts to avoid the use of RLS-exacerbating medications (eg, selective serotonin reuptake inhibitor (SSRIs), neuroleptic agents, antihistamines) [28]. If there is an underlying condition contributing to RLS, such as metabolic disturbance or iron deficiency, then these conditions should be corrected before initiating RLS medications. Several medications are FDA-approved for treatment of RLS, including dopamine agonists (eg, ropinirole, rotigotine, pramipexole), dopamine precursor (eg, levodopa), glutamate-related (eg, gabapentin), benzodiazepines (eg, temazepam, clonazepam). Augmentation, the worsening of RLS symptoms, can occur in patients taking dopamine agonists. If this occurs, dopamine agents should be discontinued or switched to other agents (such as a long-acting dopamine agonist, gabapentin encarbil, as well as non-FDA approved therapies such as opioids). However, it is important to note that weaning off dopamine agents may result in mild but in most cases moderate and/or severe withdrawal from the medication, so counseling and close monitoring should be done.

Case 2 Outcome

Given the patient’s history of dementia, opioids, benzodiazepines and other delirium-inducing medications should be avoided. His antidepressive regimen, fluoxetine, should be re-evaluated as these medications have been associated with RLS exacerbation. In addition to SSRIs, medications associated with RLS are MAO inhibitors (selegeline, phenelzine), antipsychotics (risperdone, olanzapine), tricyclic antidepressants (mirtazapine), antihistamines (diphenhydramine, cimetidine), calcium channel blockers (verapamil, nifedipine, diltiazem), and phenytoin [34,35]. His treatment began with behavioral, nonpharmacological management, and blood testing for iron studies. His low iron level prompted initiation of oral supplementation, and he was asked to follow up in 3 months for reevaluation and possible initiation of low-dose dopamine agonists.

Case 3

A 73-year-old man with dementia is found to have very irregular sleep wake patterns with a variable bedtime and awakening time, often missing breakfast. He is found dozing off often during the day, particularly during times of inactivity. He has frequent awakenings during the night often calling for the staff to guide him back to bed. He has had some falls secondary to walking around his room. He has been prescribed various hypnotics without much benefit and instead, has suffered from some confusion while on these medications. His room is very dark and has no windows.

Case 3 Reflection: Circadian Rhythm Sleep-Wake Disorders

Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by an individual’s natural propensity to want to go to sleep and be awake during a period that is undesirable personally and/or socially [36]. CRSWDs can be a result of the desynchronization of the 2 sleep processes: (1) homeostatic drive (regulates sleep intensity) and (2) circadian rhythm (maintains daytime alertness); [36]. CRSWDs can also be due to an individual’s naturally occurring sleep drives becoming misaligned with their social/personal sleep-wake demands (eg, employment schedule and socializing opportunities with family/friends). With increasing age, the circadian rhythm becomes less adept at functioning in a desynchronized pattern [7], which can result in daytime sleepiness and night time sleep fragmentation [7,37]. CRSWDs are highly prevalent in individuals with dementia [7,36]. As dementia progresses, the ability to maintain a balance of the 2 sleep process becomes more impaired [7]. As a result, individuals with dementia, particularly Alzheimer’s disease, are likely to experience agitation, irritability, and/or confusion during the evening and night, a behavioral problem referred to as “sundowning” [38].

There are several types of CRSWDs, including delayed sleep-phase syndrome, advanced sleep-phase syndrome, irregular sleep-wake disorder, non–24-hour sleep-wake disorder, shift work sleep disorder, and jet lag sleep disorder. However, the most common type of CRSWDs observed in older adults is advanced sleep-phase syndrome [39]. Due to excessive sleepiness in the early evening, affected individuals may report a need to shift to earlier and earlier bedtimes (~6 to 7 pm) and wake times (~3 to 4 am) [36]. For older affected adults, this can cause distress and frustration, particularly if their sleep phase prevents them from participating in evening activities (eg, socializing with family/friends) [36].

In the assessment of patients with suspected CRSWDs, sleep diaries (self-reported or caregiver) daily account of sleep and wake times over at least 1 week) and actigraphy (wrist-worn accelerometer designed to measure activity and inactivity at night) can be used, particularly in older adults with dementia [40,41].

CRSWD treatment may include behavioral modifications and/or pharmacological intervention. Behavioral modifications can consist of chronotherapy, relaxation training, and/or bright light therapy. Chronotherapy involves making gradual shifts in an individual’s sleep time to meet his/her desired sleep schedule. Relaxation training involves implementing behaviors/activities that reduce tension and enhance the smooth transition into sleep. Bright light therapy involves exposure to an appropriate intensity and duration of light, which is an important environmental cue to help the synchrony of the sleep-wake cycle [7]. Previous studies have observed that NH residents are exposed to a restricted amount of bright light during the daytime [42,43], but higher levels of artificial light at night (eg, hallway lighting) [7]. NH residents’ exposure to artificial bright light during the daytime has not only improved the residents’ sleep [44–46], but also has improved their cognitive functioning and reduced their depressive symptoms [47]. Thus, steps towards targeted light exposure in sync with the typical sleep-wake cycle (eg, mandated time in well-lit rooms during the day and during meals) for NH residents, particularly those with CRSWDs, could prove to be beneficial across several social, behavioral and neurocognitive domains. Lastly, NH residents exposed to at least 30 minutes of outdoor daylight and at least 3 occasions of low intensity physical activities for 10 to 15 minutes daily can potentially improve sleep-wake patterns [48]. Thus, it may be beneficial to have an intervention that couples bright light exposure and physical activity in the NH setting.

Pharmacological interventions can also be implemented to improve older residents’ symptoms. However, the medications prescribed should be used with caution and should not be used as part of a long-term treatment plan. Melatonin is a commonly used herbal supplement that can assist advancing the timing of the circadian rhythms in the evening but can delay the circadian rhythms in the morning [49]. Several brands of this herbal supplement can be purchased over-the-counter and are not regulated by the FDA. Since the amount of melatonin used in the herbal supplement varies by brand, caution should be used when selecting a brand [50]. Two FDA-approved drugs (modafinil and armodafinil) are currently being used to reduce daytime sleepiness and improve vigilance amongst adults, but limited research has explored the effectiveness of these medication for older adults specifically suffering with CRSWDS [36,51,52]. Other stimulants (eg, caffeine, amphetamines, and nonamphetamine-derived medications) are also currently being used to reduce daytime sleepiness in patients with CRSWDS. Stimulant use, particularly caffeine consumption, has also been associated with better cognitive functioning in older adults [53]. However, stimulants should be taken with caution, particularly in older adults, because stimulant use has been associated with potentially serious and fatal health sequalae (eg, tachycardia, heart failure, irreversible heart damage and hypertension) [36,54].

Case 3 Outcome

The patient was moved to a room with a window. An alarm clock was set for 7:30 in the morning and he was taken to breakfast, where he sat at a table near a window. Any time he appeared to be sleepy, he was encouraged to go for a walk or engage in other activities so daytime napping opportunities were limited. His environment was assessed for safety and bedrails were utilized to prevent falls.

Case 4

A 75-year-old woman with a history of anxiety and depression moved into the NH 4 months ago after suffering a stroke. She now reports difficulty falling asleep for many years, which has significantly worsened since moving to the NH. Currently, she has been getting only 3 to 4 hour of sleep per night. She reports mild but increasing daytime sleepiness and does not fall asleep until 1:00 am despite getting into bed at 10:30 pm. She occasionally reports arthritic pain that interferes with her sleep. The NH staff has mentioned that she will occasionally cry for her family when she appears to be asleep.

Case 4 Reflection: Insomnia

According to the International Classification of Sleep Disorders (ICSD-3) [39], insomnia is characterized as “a repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment.” Among the sleep disorders, insomnia is one of the most common sleep issues observed in sleep clinics [34]. Older adults with insomnia often have comorbid physical (eg, pulmonary disease, arthritis, chronic pain, cancer diabetes, Parkinson’s disease) and mental illness (eg, depression, panic disorder) [55]. Medications (eg, stimulants, respiratory medications, chemotherapy, decongestants, hormones, or psychotropics) may cause and exacerbate insomnia symptoms [55].

Since insomnia is a clinical diagnosis, there is no specific diagnostic tool or gold standard test to identify individuals suffering with insomnia. Insomnia screening usually involves a clinical interview, in which a health provider, preferably trained in sleep, conducts a physical examination and collects an in-depth history of a patients’ sleep problems [56]. Insomnia screening tools may also include having a patient complete a sleep diary or questionnaire, such as the insomnia severity index (ISI) [57] or Pittsburgh Sleep Quality Index (PSQI) [58].

Cognitive behavioral therapy for insomnia (CBT-I) and/or pharmacological intervention are typically used to treat insomnia in older adults. CBT-I is a combination of cognitive (eg, changing dysfunctional sleep attitudes/beliefs) and behavioral treatment (eg, adhering to a regular sleep schedule) [59]. CBT-I or a combination of CBT-I and pharmacological intervention is recommended as more effective long-term approach to insomnia treatment compared to pharmacological intervention alone [55]. CBT-I involves altering older adults’ misconceptions of their sleep and implementing behavioral techniques to their everyday life (eg, routine sleep-wake schedule, relaxation therapy). Several FDA-approved medications are available to treat insomnia; however, many commonly used medications to treat insomnia in older adults (ie, antihistamines, antidepressants, anticonvulsants, and anti-psychotics) pose more risks than benefits to their health and well-being [35,60–62]. Some of the more recent hypnotics (egm zolpidem, exzopiclone, and ramelteon) on the market have been shown to be safer and more effective pharmacological options [55]. In 2014, the FDA approved the first in class orexin receptor antagonist medication (suvorexant) to treat insomnia [63]. Unlike other medications to treat insomnia, suvorexant, via the blockade of the orexin neurotransmitter, effectively inhibits orexin (one of neurotransmitters involved in the activation pathways of the arousal system), so sleep can easily be induced and maintained [64, 65]. Furthermore, preliminary studies suggest that this medication may be associated with less severe side effects (ie, habituation) than the other approved medications on the market [64, 65]. In fact, in a recent clinical series that included both young and older insomnia patients, the most common adverse reaction to suvorexant was drowsiness [66].

Case 4 Outcome

The patient was initiated on basic CBT-I therapy strategies which included stimulus control therapy [67]; implementation of a consistent bedtime and awakening routine; reducing the use of TV, smart phone, or other electronic leisure devices 1 hour before bedtime; refraining from caffeine after lunchtime; improving the sleep environment; and relaxation techniques.

Case 5

The patient is a 65-year-old man diagnosed with Parkinson’s disease several years ago. Recently, he has often has been experiencing what appears to be very violent and terrifying dreams. While asleep, he often screams and shouts for help. In addition, he occasionally will punch, kick, and/or thrash around in bed at night, which the NH staff has noted as a concern for his safety.

Case 5 Reflection: Parasomnias

Parasomnias represent frequent arousals during sleep or in the wake-to-sleep transition due to abnormal motor movements, behaviors (eg, shouting, flailing, and leaping from bed) and/or sensory experiences (eg, “dreamlike” hallucinations) [68]. Motor movements that occur for parasomnia can be disruptive for the individual and potentially dangerous for the individual and/or bed partner. There are 3 primary types of parasomnias based on the stage of sleep that the event occurs: non-REM (NREM), REM, and other parasomnias during transitions of sleep [68]. The most commonly observed parasomnia seen in older adults is the REM-associated parasomnia or REM sleep behavior disorder (RBD), which is characterized by experiencing vivid, sometimes violent, dreams typically involving fighting an intruder or an animal to protect a loved one [69]. For RBD, disruptive behaviors typically occur during REM sleep [69]. RBD has been associated with neurodegenerative disorders (Parkinson’s disease and Lewy body disease), neurologic disorders (eg, brain tumors and stroke), other primary disorders (narcolepsy and periodic limb movement disorder), and well as some medications (eg, antidepressants and β-blockers) [68]. There is limited knowledge on the prevalence of parasomnias in NH settings. One study, however, reported that 31% of older NH residents experience parasomnias [70]. Evaluation for parasomnias generally involve a clinical evaluation by a sleep specialist and overnight sleep study (ie, polysomnography at a sleep center if there is a concern for sleep apnea or RBD [71].

Medications are not typically first-line for parasomnia. Instead education about improving sleep practices, addressing other underlying sleep disorders, and securing a safe sleep environment are first recommended. Pharmacologic treatment, particularly the use of clonazepam, is commonly used to treat RBD [72]. However, this medication should be used with caution for older adults with a dementia diagnosis, gait disorders, and OSA because the common side effects include sedation, confusion, memory dysfunction, and early morning motor incoordination [68]. Several alternative medications have also been used to treat RBD. For example, medications commonly used to Parkinson disease symptoms, such Levodopa and dopamine agonists, have also been used to treat RBD [73]. Zopiclone, a nonbenzodiazepine hypnotic agent, has also been shown to be as effective as clonazepam, but with less potential side effects [74]. Melatonin, a nutritional supplement, has also been used as a treatment and appears to alleviate some of the RBD symptoms and has fewer side effects [68]. Since melatonin is not regulated by the FDA, it has been suggested that this treatment be used with caution in the older population [73].

Case 5 Outcome

The patient was evaluated with video synchronized in lab PSG. It confirmed REM sleep without evidence of the normal atonia that should be apparent during REM. These PSG findings in combination with repeated accounts of dream enactment established the diagnosis of RBD. Patient was treated with low-dose clonazepam and closely monitored for potential side effects of daytime sedation. Bedroom environment was also carefully reconfigured for safety to avoid potential risk of injury during a dream enactment episode.

Conclusion

Sleep disturbances remain an underappreciated and undertreated health issue in NH residents. Nursing homes can help facilitate optimal sleep health and day functioning by providing mandatory natural light outlets, physical exercise opportunities, and minimal allowable time residents can spend in their bed/bedroom outside of their routine sleep period. Educating NH providers and staff on sleep medicine may benefit residents, but workload and restricted resources may hinder this. Education via mobile and internet based educational platforms and resources (Mysleep101) may be helpful in addressing education barriers [75]. Convenient and cost-effective methods to deliver sleep medicine education to NH health care providers should be part of our ongoing efforts to improve the viability, vitality and quality of life of our aging citizens.

Corresponding author: Alyssa Gamaldo, PhD, Univ. of South Florida, 13301 Bruce B. Downs Blvd, MHC 1340, Tampa, FL 33612, agamaldo@usf.edu.

Financial disclosures: None.

Hot flashes and sleep disruption contribute independently to the development of depression in menopause, judging from the findings of a recent study.

In that study, 29 premenopausal women, aged 18-45 years, received a single dose of the GnRH agonist leuprolide in order to induce hypoestrogenism and ovarian suppression for the study period. The women in the study had no history of primary sleep disturbances, low estrogen levels, or depression, according to Hadine Joffe, MD, director of the Women’s Hormone and Aging Research Program at Harvard Medical School, in Boston, and her associates.

All the study participants underwent baseline mood evaluation using both the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI). Existing sleep disturbances were ruled out at baseline with sleep diaries, questionnaires, and two ambulatory screening polysomnography (PSG) studies.

After 4 weeks of administration of leuprolide, depressive symptoms had developed among most of the women in the study. The mean MADRS score was 4.1, and overall, it was 3.1 points higher than it had been at baseline. One woman had a 15-point increase in her score, suggesting significant depression. The MADRS score increased by at least 5 points in 24% of the women and remained unchanged in 38%, reflecting variability among the women on the impact of leuprolide on depressive symptoms, the investigators reported (J Clin Endocrinol Metab. 2016 Sep 20. doi: 10.1210/jc.2016-2348).

Leuprolide universally suppressed estradiol to postmenopausal levels in the women within 2 weeks. Hot flashes developed in 20 (69%) women, with a median of 3.6 hot flashes during the day and 3.8 at night. The median number of objectively measured nighttime hot flashes per night was 3.

Changes to sleep patterns varied widely for each woman; for example, wake time after sleep onset ranged from an additional 140 minutes to 23 fewer minutes for one woman. There was a correlation between the number of subjectively reported nighttime hot flashes with increased sleep fragmentation as measured by PSG. The number of reported nighttime hot flashes was associated with an increase in depressive symptoms that was disproportionate to the number of nighttime hot flashes reported, according to the findings of a univariate analysis. The number of daytime hot flashes had no such effect.

In light of these findings, Dr. Joffe and her associates urged clinicians to screen women who report nighttime hot flashes and sleep interruption for mood disturbance. “Treatment of those with menopause-related depressive symptoms should encompass therapies that improve sleep interruption as well as nocturnal [hot flashes],” they wrote.

The study was sponsored by the National Institute of Mental Health. Dr. Joffe has received grant support from Merck and has served as a consultant/adviser for Merck, Mitsubishi Tanabe, NeRRe Therapeutics, and Noven.

skubetin@frontlinemedcom.com

Hot flashes and sleep disruption contribute independently to the development of depression in menopause, judging from the findings of a recent study.

In that study, 29 premenopausal women, aged 18-45 years, received a single dose of the GnRH agonist leuprolide in order to induce hypoestrogenism and ovarian suppression for the study period. The women in the study had no history of primary sleep disturbances, low estrogen levels, or depression, according to Hadine Joffe, MD, director of the Women’s Hormone and Aging Research Program at Harvard Medical School, in Boston, and her associates.

All the study participants underwent baseline mood evaluation using both the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI). Existing sleep disturbances were ruled out at baseline with sleep diaries, questionnaires, and two ambulatory screening polysomnography (PSG) studies.

After 4 weeks of administration of leuprolide, depressive symptoms had developed among most of the women in the study. The mean MADRS score was 4.1, and overall, it was 3.1 points higher than it had been at baseline. One woman had a 15-point increase in her score, suggesting significant depression. The MADRS score increased by at least 5 points in 24% of the women and remained unchanged in 38%, reflecting variability among the women on the impact of leuprolide on depressive symptoms, the investigators reported (J Clin Endocrinol Metab. 2016 Sep 20. doi: 10.1210/jc.2016-2348).

Leuprolide universally suppressed estradiol to postmenopausal levels in the women within 2 weeks. Hot flashes developed in 20 (69%) women, with a median of 3.6 hot flashes during the day and 3.8 at night. The median number of objectively measured nighttime hot flashes per night was 3.

Changes to sleep patterns varied widely for each woman; for example, wake time after sleep onset ranged from an additional 140 minutes to 23 fewer minutes for one woman. There was a correlation between the number of subjectively reported nighttime hot flashes with increased sleep fragmentation as measured by PSG. The number of reported nighttime hot flashes was associated with an increase in depressive symptoms that was disproportionate to the number of nighttime hot flashes reported, according to the findings of a univariate analysis. The number of daytime hot flashes had no such effect.

In light of these findings, Dr. Joffe and her associates urged clinicians to screen women who report nighttime hot flashes and sleep interruption for mood disturbance. “Treatment of those with menopause-related depressive symptoms should encompass therapies that improve sleep interruption as well as nocturnal [hot flashes],” they wrote.

The study was sponsored by the National Institute of Mental Health. Dr. Joffe has received grant support from Merck and has served as a consultant/adviser for Merck, Mitsubishi Tanabe, NeRRe Therapeutics, and Noven.

skubetin@frontlinemedcom.com

Hot flashes and sleep disruption contribute independently to the development of depression in menopause, judging from the findings of a recent study.

In that study, 29 premenopausal women, aged 18-45 years, received a single dose of the GnRH agonist leuprolide in order to induce hypoestrogenism and ovarian suppression for the study period. The women in the study had no history of primary sleep disturbances, low estrogen levels, or depression, according to Hadine Joffe, MD, director of the Women’s Hormone and Aging Research Program at Harvard Medical School, in Boston, and her associates.

All the study participants underwent baseline mood evaluation using both the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI). Existing sleep disturbances were ruled out at baseline with sleep diaries, questionnaires, and two ambulatory screening polysomnography (PSG) studies.

After 4 weeks of administration of leuprolide, depressive symptoms had developed among most of the women in the study. The mean MADRS score was 4.1, and overall, it was 3.1 points higher than it had been at baseline. One woman had a 15-point increase in her score, suggesting significant depression. The MADRS score increased by at least 5 points in 24% of the women and remained unchanged in 38%, reflecting variability among the women on the impact of leuprolide on depressive symptoms, the investigators reported (J Clin Endocrinol Metab. 2016 Sep 20. doi: 10.1210/jc.2016-2348).

Leuprolide universally suppressed estradiol to postmenopausal levels in the women within 2 weeks. Hot flashes developed in 20 (69%) women, with a median of 3.6 hot flashes during the day and 3.8 at night. The median number of objectively measured nighttime hot flashes per night was 3.

Changes to sleep patterns varied widely for each woman; for example, wake time after sleep onset ranged from an additional 140 minutes to 23 fewer minutes for one woman. There was a correlation between the number of subjectively reported nighttime hot flashes with increased sleep fragmentation as measured by PSG. The number of reported nighttime hot flashes was associated with an increase in depressive symptoms that was disproportionate to the number of nighttime hot flashes reported, according to the findings of a univariate analysis. The number of daytime hot flashes had no such effect.

In light of these findings, Dr. Joffe and her associates urged clinicians to screen women who report nighttime hot flashes and sleep interruption for mood disturbance. “Treatment of those with menopause-related depressive symptoms should encompass therapies that improve sleep interruption as well as nocturnal [hot flashes],” they wrote.

The study was sponsored by the National Institute of Mental Health. Dr. Joffe has received grant support from Merck and has served as a consultant/adviser for Merck, Mitsubishi Tanabe, NeRRe Therapeutics, and Noven.

skubetin@frontlinemedcom.com

The phenomenon of preconditioning reflects complex adaptive responses by living organisms to stimuli such as ischemia, hypoxia, hypothermia, or starvation. Acute ischemic preconditioning, initially described by Murry in 1986 (Circulation. 1986;74[5]:1124), occurs when multiple brief episodes of ischemia followed by reperfusion elicit a protective effect on the heart from a subsequent prolonged period of ischemia, such as a heart attack. This protective effect from ischemic preconditioning can be in the form of a smaller heart attack, lower chance of cardiac arrhythmias, less myocardial cell death, and lower risk of heart muscle failure. The cardioprotective effect of ischemic preconditioning is dependent on the duration and strength of the preconditioning stimulus. If the preconditioning stimulus is too strong or prolonged, detrimental effects on the heart may be observed.

Like ischemic preconditioning, hypoxic preconditioning represents a complex adaptive response that organisms have developed to offset damage inflicted by oxygen deprivation. The concept of hypoxic preconditioning is familiar to humans; for years, athletes have been using hypoxic training (high altitude and other newer technologies) to boost their performance in sporting events. Additionally, there is evidence dating back to before the breakthrough findings of Murry and colleagues who confirm the cardioprotective effects of hypoxia. In 1973, Meerson and colleagues (Am J Cardiol. 1973;31[1]:30) reported that mice exposed to high-altitude hypoxia have reduced mortality and smaller areas of necrotic myocardium after coronary artery occlusion.

Both of the ischemic and hypoxic preconditioning animal experiments mentioned above involve acute exposure to the preconditioning stimuli, resulting in a cardioprotective response for a limited time period. In order to afford a sustained period of cardioprotection, recurrent hypoxic exposure may be necessary. Indeed, recent studies have concentrated on just that; repeated exposure to intermittent hypoxia over a few weeks (Manukhina et al. Exp Biol Med. 2013;238[12]:1413) results in robust cardioprotection after coronary artery occlusion and reperfusion.

Despite the convincing cardioprotective discoveries from ischemic and hypoxic preconditioning, translation into clinical practice as a therapeutic modality is absent. This is partly because human beings are more complex than animals. They have comorbidities and are affected by aging, both of which may alter the milieu for preconditioning stimuli. Furthermore, the therapeutic range for any given preconditioning stimulus is unknown.

Sleep apnea (SA) is exceedingly prevalent in the United States. In SA, an individual stops breathing either completely (apnea) or partially (hypopnea) during sleep resulting in intermittent hypoxia, with arousal from sleep and resumption of breathing leading to reoxygenation. Hence, SA is characterized by intermittent hypoxia followed by reoxygenation. So, one can speculate that SA could exert cardioprotective effects as seen in hypoxic preconditioning and ischemic preconditioning. It is important to note, however, that SA is associated with hypercapnic intermittent hypoxia, whereas most of the investigations on ischemic preconditioning and intermittent hypoxia are with eucapnia or hypocapnia.

The potentially cardioprotective role of SA is supported by a growing body of complementary research that indicates that coronary collateral flow is higher in patients with SA vs. control subjects (Steiner. Chest. 2010;137[3]:516) and that there is an increased mobilization, proliferation, and angiogenic capacity of endothelial progenitor cells from patients with myocardial infarction and SA as compared with cells from controls subjects without SA (Berger. Am J Respir Crit Care Med. 2013;187[1]:90). Some epidemiologic data support a weaker relationship between SA and coronary ischemic events compared with other cardiovascular events (Gottlieb. Circulation. 2010;122[4]:352). Hypoxic preconditioning may explain the relatively decreased pro-thrombotic influence of SA in the coronary vascular bed. Nevertheless, more research is needed to determine if SA is cardioprotective. If, however, cardioprotection from SA is confirmed, it may contribute to a paradigm shift in how SA is considered in relationship to coronary heart disease. Furthermore, future investigations would need to focus on what dose and duration of SA is needed for cardioprotection to occur. Prospective studies may also provide an opportunity for investigating interindividual variability in the susceptibility of the myocardium to the hypoxic preconditioning stimulus from SA.

This article highlights how complex the relationship between hypoxia and myocardial response is. This is further supported by results from a recent clinical trial, AVOID (Air Versus Oxygen In ST-elevation MyocarDial Infarction) (Stub. Circulation. 2015;131[24]:2143). Results from the AVOID trial report that routine oxygen use in normoxic patients hospitalized with a heart attack was not beneficial and, in fact, was harmful. Patients who received oxygen had more myocardial injury than those who did not. Therefore, even though for decades we thought that oxygen therapy helps hospitalized heart attack patients, results from the AVOID trial have initiated a paradigm shift. It remains to be determined whether such a paradigm shift will follow for sleep apnea.

Dr. Shah is with the department of epidemiology and population health, Albert Einstein College of Medicine, N.Y.

The phenomenon of preconditioning reflects complex adaptive responses by living organisms to stimuli such as ischemia, hypoxia, hypothermia, or starvation. Acute ischemic preconditioning, initially described by Murry in 1986 (Circulation. 1986;74[5]:1124), occurs when multiple brief episodes of ischemia followed by reperfusion elicit a protective effect on the heart from a subsequent prolonged period of ischemia, such as a heart attack. This protective effect from ischemic preconditioning can be in the form of a smaller heart attack, lower chance of cardiac arrhythmias, less myocardial cell death, and lower risk of heart muscle failure. The cardioprotective effect of ischemic preconditioning is dependent on the duration and strength of the preconditioning stimulus. If the preconditioning stimulus is too strong or prolonged, detrimental effects on the heart may be observed.

Like ischemic preconditioning, hypoxic preconditioning represents a complex adaptive response that organisms have developed to offset damage inflicted by oxygen deprivation. The concept of hypoxic preconditioning is familiar to humans; for years, athletes have been using hypoxic training (high altitude and other newer technologies) to boost their performance in sporting events. Additionally, there is evidence dating back to before the breakthrough findings of Murry and colleagues who confirm the cardioprotective effects of hypoxia. In 1973, Meerson and colleagues (Am J Cardiol. 1973;31[1]:30) reported that mice exposed to high-altitude hypoxia have reduced mortality and smaller areas of necrotic myocardium after coronary artery occlusion.

Both of the ischemic and hypoxic preconditioning animal experiments mentioned above involve acute exposure to the preconditioning stimuli, resulting in a cardioprotective response for a limited time period. In order to afford a sustained period of cardioprotection, recurrent hypoxic exposure may be necessary. Indeed, recent studies have concentrated on just that; repeated exposure to intermittent hypoxia over a few weeks (Manukhina et al. Exp Biol Med. 2013;238[12]:1413) results in robust cardioprotection after coronary artery occlusion and reperfusion.

Despite the convincing cardioprotective discoveries from ischemic and hypoxic preconditioning, translation into clinical practice as a therapeutic modality is absent. This is partly because human beings are more complex than animals. They have comorbidities and are affected by aging, both of which may alter the milieu for preconditioning stimuli. Furthermore, the therapeutic range for any given preconditioning stimulus is unknown.

Sleep apnea (SA) is exceedingly prevalent in the United States. In SA, an individual stops breathing either completely (apnea) or partially (hypopnea) during sleep resulting in intermittent hypoxia, with arousal from sleep and resumption of breathing leading to reoxygenation. Hence, SA is characterized by intermittent hypoxia followed by reoxygenation. So, one can speculate that SA could exert cardioprotective effects as seen in hypoxic preconditioning and ischemic preconditioning. It is important to note, however, that SA is associated with hypercapnic intermittent hypoxia, whereas most of the investigations on ischemic preconditioning and intermittent hypoxia are with eucapnia or hypocapnia.

The potentially cardioprotective role of SA is supported by a growing body of complementary research that indicates that coronary collateral flow is higher in patients with SA vs. control subjects (Steiner. Chest. 2010;137[3]:516) and that there is an increased mobilization, proliferation, and angiogenic capacity of endothelial progenitor cells from patients with myocardial infarction and SA as compared with cells from controls subjects without SA (Berger. Am J Respir Crit Care Med. 2013;187[1]:90). Some epidemiologic data support a weaker relationship between SA and coronary ischemic events compared with other cardiovascular events (Gottlieb. Circulation. 2010;122[4]:352). Hypoxic preconditioning may explain the relatively decreased pro-thrombotic influence of SA in the coronary vascular bed. Nevertheless, more research is needed to determine if SA is cardioprotective. If, however, cardioprotection from SA is confirmed, it may contribute to a paradigm shift in how SA is considered in relationship to coronary heart disease. Furthermore, future investigations would need to focus on what dose and duration of SA is needed for cardioprotection to occur. Prospective studies may also provide an opportunity for investigating interindividual variability in the susceptibility of the myocardium to the hypoxic preconditioning stimulus from SA.

This article highlights how complex the relationship between hypoxia and myocardial response is. This is further supported by results from a recent clinical trial, AVOID (Air Versus Oxygen In ST-elevation MyocarDial Infarction) (Stub. Circulation. 2015;131[24]:2143). Results from the AVOID trial report that routine oxygen use in normoxic patients hospitalized with a heart attack was not beneficial and, in fact, was harmful. Patients who received oxygen had more myocardial injury than those who did not. Therefore, even though for decades we thought that oxygen therapy helps hospitalized heart attack patients, results from the AVOID trial have initiated a paradigm shift. It remains to be determined whether such a paradigm shift will follow for sleep apnea.

Dr. Shah is with the department of epidemiology and population health, Albert Einstein College of Medicine, N.Y.

The phenomenon of preconditioning reflects complex adaptive responses by living organisms to stimuli such as ischemia, hypoxia, hypothermia, or starvation. Acute ischemic preconditioning, initially described by Murry in 1986 (Circulation. 1986;74[5]:1124), occurs when multiple brief episodes of ischemia followed by reperfusion elicit a protective effect on the heart from a subsequent prolonged period of ischemia, such as a heart attack. This protective effect from ischemic preconditioning can be in the form of a smaller heart attack, lower chance of cardiac arrhythmias, less myocardial cell death, and lower risk of heart muscle failure. The cardioprotective effect of ischemic preconditioning is dependent on the duration and strength of the preconditioning stimulus. If the preconditioning stimulus is too strong or prolonged, detrimental effects on the heart may be observed.

Like ischemic preconditioning, hypoxic preconditioning represents a complex adaptive response that organisms have developed to offset damage inflicted by oxygen deprivation. The concept of hypoxic preconditioning is familiar to humans; for years, athletes have been using hypoxic training (high altitude and other newer technologies) to boost their performance in sporting events. Additionally, there is evidence dating back to before the breakthrough findings of Murry and colleagues who confirm the cardioprotective effects of hypoxia. In 1973, Meerson and colleagues (Am J Cardiol. 1973;31[1]:30) reported that mice exposed to high-altitude hypoxia have reduced mortality and smaller areas of necrotic myocardium after coronary artery occlusion.

Both of the ischemic and hypoxic preconditioning animal experiments mentioned above involve acute exposure to the preconditioning stimuli, resulting in a cardioprotective response for a limited time period. In order to afford a sustained period of cardioprotection, recurrent hypoxic exposure may be necessary. Indeed, recent studies have concentrated on just that; repeated exposure to intermittent hypoxia over a few weeks (Manukhina et al. Exp Biol Med. 2013;238[12]:1413) results in robust cardioprotection after coronary artery occlusion and reperfusion.

Despite the convincing cardioprotective discoveries from ischemic and hypoxic preconditioning, translation into clinical practice as a therapeutic modality is absent. This is partly because human beings are more complex than animals. They have comorbidities and are affected by aging, both of which may alter the milieu for preconditioning stimuli. Furthermore, the therapeutic range for any given preconditioning stimulus is unknown.

Sleep apnea (SA) is exceedingly prevalent in the United States. In SA, an individual stops breathing either completely (apnea) or partially (hypopnea) during sleep resulting in intermittent hypoxia, with arousal from sleep and resumption of breathing leading to reoxygenation. Hence, SA is characterized by intermittent hypoxia followed by reoxygenation. So, one can speculate that SA could exert cardioprotective effects as seen in hypoxic preconditioning and ischemic preconditioning. It is important to note, however, that SA is associated with hypercapnic intermittent hypoxia, whereas most of the investigations on ischemic preconditioning and intermittent hypoxia are with eucapnia or hypocapnia.

The potentially cardioprotective role of SA is supported by a growing body of complementary research that indicates that coronary collateral flow is higher in patients with SA vs. control subjects (Steiner. Chest. 2010;137[3]:516) and that there is an increased mobilization, proliferation, and angiogenic capacity of endothelial progenitor cells from patients with myocardial infarction and SA as compared with cells from controls subjects without SA (Berger. Am J Respir Crit Care Med. 2013;187[1]:90). Some epidemiologic data support a weaker relationship between SA and coronary ischemic events compared with other cardiovascular events (Gottlieb. Circulation. 2010;122[4]:352). Hypoxic preconditioning may explain the relatively decreased pro-thrombotic influence of SA in the coronary vascular bed. Nevertheless, more research is needed to determine if SA is cardioprotective. If, however, cardioprotection from SA is confirmed, it may contribute to a paradigm shift in how SA is considered in relationship to coronary heart disease. Furthermore, future investigations would need to focus on what dose and duration of SA is needed for cardioprotection to occur. Prospective studies may also provide an opportunity for investigating interindividual variability in the susceptibility of the myocardium to the hypoxic preconditioning stimulus from SA.

This article highlights how complex the relationship between hypoxia and myocardial response is. This is further supported by results from a recent clinical trial, AVOID (Air Versus Oxygen In ST-elevation MyocarDial Infarction) (Stub. Circulation. 2015;131[24]:2143). Results from the AVOID trial report that routine oxygen use in normoxic patients hospitalized with a heart attack was not beneficial and, in fact, was harmful. Patients who received oxygen had more myocardial injury than those who did not. Therefore, even though for decades we thought that oxygen therapy helps hospitalized heart attack patients, results from the AVOID trial have initiated a paradigm shift. It remains to be determined whether such a paradigm shift will follow for sleep apnea.

Dr. Shah is with the department of epidemiology and population health, Albert Einstein College of Medicine, N.Y.

Many patients are sleep deprived but are either unaware of, or unwilling to acknowledge, their problem. Sleep deprivation occurs because of inadequate sleep duration (often caused by insomnia or simply not allowing enough time for sleep), or poor sleep quality (often caused by sleep-disordered breathing). These conditions can be diagnosed by obtaining a thorough sleep history that consists of 5 groups of questions. The specific questions that should be asked in order to make a more accurate diagnosis are included in this article from Current Psychiatry, available at http://www.currentpsychiatry.com/the-publication/issue-single-view/disordered-sleep-ask-the-right-questions-to-reveal-this-hidden-confounder/913369ef53768717303c9cd35a58e790.html.

Many patients are sleep deprived but are either unaware of, or unwilling to acknowledge, their problem. Sleep deprivation occurs because of inadequate sleep duration (often caused by insomnia or simply not allowing enough time for sleep), or poor sleep quality (often caused by sleep-disordered breathing). These conditions can be diagnosed by obtaining a thorough sleep history that consists of 5 groups of questions. The specific questions that should be asked in order to make a more accurate diagnosis are included in this article from Current Psychiatry, available at http://www.currentpsychiatry.com/the-publication/issue-single-view/disordered-sleep-ask-the-right-questions-to-reveal-this-hidden-confounder/913369ef53768717303c9cd35a58e790.html.

Many patients are sleep deprived but are either unaware of, or unwilling to acknowledge, their problem. Sleep deprivation occurs because of inadequate sleep duration (often caused by insomnia or simply not allowing enough time for sleep), or poor sleep quality (often caused by sleep-disordered breathing). These conditions can be diagnosed by obtaining a thorough sleep history that consists of 5 groups of questions. The specific questions that should be asked in order to make a more accurate diagnosis are included in this article from Current Psychiatry, available at http://www.currentpsychiatry.com/the-publication/issue-single-view/disordered-sleep-ask-the-right-questions-to-reveal-this-hidden-confounder/913369ef53768717303c9cd35a58e790.html.

Lack of sleep had a significant impact on brain responses to an attention task, and circadian rhythms played a role, according to functional magnetic resonance imaging data from 33 healthy adults. The findings were published online Aug. 11 in Science.

Despite the data showing that acute sleep loss impacts cognition, “human performance remains remarkably well preserved until wakefulness is extended into the biological night,” wrote Vincenzo Muto of the University of Liège, Belgium, and his colleagues (Science 2016;353:687-90. doi: 10.1126/science.aad2993).

Wavebreak Media/Thinkstockphotos.com

Study participants stayed awake for 42 hours, beginning in the morning and covering 2 biological days, 1 biological night, and part of a second night. They periodically performed the psychomotor vigilance task (PVT), a visual reaction time task designed to measure attention; and an auditory n-back task, and the researchers collected functional and structural MRI data across 13 sessions. The average age of the participants (17 men and 16 women) was 21 years.

Overall, PVT performance was stable during the first day, but decreased significantly after sleep deprivation, then recovered during the second day, and returned to baseline after a period of recovery sleep, the researchers said.

Brain responses to the n-back task were “significantly modulated by a circadian oscillation, synchronous to the melatonin rhythm,” they noted. “This finding rules out a global task-independent circadian influence and suggest the influence of a local, region-specific task-dependent circadian signal,” they added.

Although more research is needed on how different cognitive tasks are affected by sleep deprivation, the findings may help in “understanding of the brain mechanisms underlying the maintenance of daytime cognitive performance and its deterioration, as observed in shift work, jet lag, sleep disorders, aging, and neurodegenerative diseases,” the researchers wrote.

They had no financial conflicts to disclose.

Lack of sleep had a significant impact on brain responses to an attention task, and circadian rhythms played a role, according to functional magnetic resonance imaging data from 33 healthy adults. The findings were published online Aug. 11 in Science.

Despite the data showing that acute sleep loss impacts cognition, “human performance remains remarkably well preserved until wakefulness is extended into the biological night,” wrote Vincenzo Muto of the University of Liège, Belgium, and his colleagues (Science 2016;353:687-90. doi: 10.1126/science.aad2993).

Wavebreak Media/Thinkstockphotos.com

Study participants stayed awake for 42 hours, beginning in the morning and covering 2 biological days, 1 biological night, and part of a second night. They periodically performed the psychomotor vigilance task (PVT), a visual reaction time task designed to measure attention; and an auditory n-back task, and the researchers collected functional and structural MRI data across 13 sessions. The average age of the participants (17 men and 16 women) was 21 years.

Overall, PVT performance was stable during the first day, but decreased significantly after sleep deprivation, then recovered during the second day, and returned to baseline after a period of recovery sleep, the researchers said.

Brain responses to the n-back task were “significantly modulated by a circadian oscillation, synchronous to the melatonin rhythm,” they noted. “This finding rules out a global task-independent circadian influence and suggest the influence of a local, region-specific task-dependent circadian signal,” they added.

Although more research is needed on how different cognitive tasks are affected by sleep deprivation, the findings may help in “understanding of the brain mechanisms underlying the maintenance of daytime cognitive performance and its deterioration, as observed in shift work, jet lag, sleep disorders, aging, and neurodegenerative diseases,” the researchers wrote.

They had no financial conflicts to disclose.

Lack of sleep had a significant impact on brain responses to an attention task, and circadian rhythms played a role, according to functional magnetic resonance imaging data from 33 healthy adults. The findings were published online Aug. 11 in Science.

Despite the data showing that acute sleep loss impacts cognition, “human performance remains remarkably well preserved until wakefulness is extended into the biological night,” wrote Vincenzo Muto of the University of Liège, Belgium, and his colleagues (Science 2016;353:687-90. doi: 10.1126/science.aad2993).

Wavebreak Media/Thinkstockphotos.com

Study participants stayed awake for 42 hours, beginning in the morning and covering 2 biological days, 1 biological night, and part of a second night. They periodically performed the psychomotor vigilance task (PVT), a visual reaction time task designed to measure attention; and an auditory n-back task, and the researchers collected functional and structural MRI data across 13 sessions. The average age of the participants (17 men and 16 women) was 21 years.

Overall, PVT performance was stable during the first day, but decreased significantly after sleep deprivation, then recovered during the second day, and returned to baseline after a period of recovery sleep, the researchers said.

Brain responses to the n-back task were “significantly modulated by a circadian oscillation, synchronous to the melatonin rhythm,” they noted. “This finding rules out a global task-independent circadian influence and suggest the influence of a local, region-specific task-dependent circadian signal,” they added.

Although more research is needed on how different cognitive tasks are affected by sleep deprivation, the findings may help in “understanding of the brain mechanisms underlying the maintenance of daytime cognitive performance and its deterioration, as observed in shift work, jet lag, sleep disorders, aging, and neurodegenerative diseases,” the researchers wrote.

They had no financial conflicts to disclose.

Adults with moderate to severe sleep apnea and coronary or cerebrovascular disease had about the same frequency of cardiovascular events whether they received continuous positive airway pressure (CPAP) therapy or usual care alone, according to a large randomized trial.

But CPAP was used for only 3.3 hours per night by these patients and might have been “insufficient to provide the level of effect on cardiovascular outcomes that had been hypothesized,” Dr. Doug McEvoy of the Adelaide Institute for Sleep Health, Flinders University, Adelaide, Australia and his associates reported at the annual congress of the European Society of Cardiology. Their study was simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Aug 28. doi: 10.1056/NEJMoa1606599).

Notably, CPAP did show a trend toward significance in a prespecified subgroup analysis that matched 561 patients who used CPAP for a longer period – more than 4 hours a night – with the same number of controls (hazard ratio, 0.8; 95% CI, 0.6 to 1.1; P = .1). Dr. McEvoy discussed the implications of prolonged CPAP use in a video interview with Bruce Jancin, our reporter at the ESC Congress in Rome.

Obstructive sleep apnea causes episodic hypoxemia, sympathetic nervous system activation; intrathoracic pressure swings strain the heart and great vessels, and increases markers of oxidative stress, hypercoagulation, and inflammation. Randomized trials have linked CPAP therapy to lower systolic blood pressure measures and improved endothelial function and insulin sensitivity. Observational studies suggest that CPAP might help prevent cardiovascular events and death if used consistently, the investigators noted.

Because cardiovascular disease and obstructive sleep apnea often co-occur, the researchers carried out a secondary prevention trial, Sleep Apnea Cardiovascular Endpoints (SAVE), to quantify rates of major cardiovascular events among 2,717 adults aged 45-75 years with obstructive sleep apnea and established coronary or cerebrovascular disease. Patients were randomly assigned to receive CPAP therapy plus usual care, or usual care alone. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization from unstable angina, transient ischemic attack, or heart failure. The researchers also looked at other cardiovascular outcomes, snoring symptoms, mood, daytime sleepiness, and health-related quality of life. They used a 1-week run-in period of sham CPAP (administered at subtherapeutic pressure) to ensure what they considered an adequate level of adherence.

The average apnea-hypopnea index (that is, the average number of apnea or hypopnea events recorded per hour) was 29 at baseline and 3.7 after initiating CPAP, the investigators said. At a mean of 3.7 years of follow-up, 17% of CPAP users (220 patients) and 15.4% of controls had a cardiovascular event, for a hazard ratio of 1.1 (95% confidence interval, 0.9 to 1.3; P = 0.3).

Not only did CPAP fail to meet the composite primary endpoint, but it did not significantly affect any cause-specific cardiovascular outcome, the researchers said. However, CPAP users did improve significantly more than controls on measures of daytime sleepiness (the Epworth Sleepiness Scale), anxiety and depression (Hospital Anxiety and Depression Scale), self-reported physical and mental health (Short-Form Health Survey), and quality of life (European Quality of Life-5 Dimensions questionnaire). They also missed fewer days of work than did controls.

Study funders included the National Health and Medical Research Council of Australia, Respironics Sleep and Respiratory Research Foundation, and Phillips Respironics. Dr. McEvoy reported receiving research equipment for the study from AirLiquide. Several coinvestigators reported other ties to industry.

Adults with moderate to severe sleep apnea and coronary or cerebrovascular disease had about the same frequency of cardiovascular events whether they received continuous positive airway pressure (CPAP) therapy or usual care alone, according to a large randomized trial.

But CPAP was used for only 3.3 hours per night by these patients and might have been “insufficient to provide the level of effect on cardiovascular outcomes that had been hypothesized,” Dr. Doug McEvoy of the Adelaide Institute for Sleep Health, Flinders University, Adelaide, Australia and his associates reported at the annual congress of the European Society of Cardiology. Their study was simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Aug 28. doi: 10.1056/NEJMoa1606599).

Notably, CPAP did show a trend toward significance in a prespecified subgroup analysis that matched 561 patients who used CPAP for a longer period – more than 4 hours a night – with the same number of controls (hazard ratio, 0.8; 95% CI, 0.6 to 1.1; P = .1). Dr. McEvoy discussed the implications of prolonged CPAP use in a video interview with Bruce Jancin, our reporter at the ESC Congress in Rome.

Obstructive sleep apnea causes episodic hypoxemia, sympathetic nervous system activation; intrathoracic pressure swings strain the heart and great vessels, and increases markers of oxidative stress, hypercoagulation, and inflammation. Randomized trials have linked CPAP therapy to lower systolic blood pressure measures and improved endothelial function and insulin sensitivity. Observational studies suggest that CPAP might help prevent cardiovascular events and death if used consistently, the investigators noted.

Because cardiovascular disease and obstructive sleep apnea often co-occur, the researchers carried out a secondary prevention trial, Sleep Apnea Cardiovascular Endpoints (SAVE), to quantify rates of major cardiovascular events among 2,717 adults aged 45-75 years with obstructive sleep apnea and established coronary or cerebrovascular disease. Patients were randomly assigned to receive CPAP therapy plus usual care, or usual care alone. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization from unstable angina, transient ischemic attack, or heart failure. The researchers also looked at other cardiovascular outcomes, snoring symptoms, mood, daytime sleepiness, and health-related quality of life. They used a 1-week run-in period of sham CPAP (administered at subtherapeutic pressure) to ensure what they considered an adequate level of adherence.

The average apnea-hypopnea index (that is, the average number of apnea or hypopnea events recorded per hour) was 29 at baseline and 3.7 after initiating CPAP, the investigators said. At a mean of 3.7 years of follow-up, 17% of CPAP users (220 patients) and 15.4% of controls had a cardiovascular event, for a hazard ratio of 1.1 (95% confidence interval, 0.9 to 1.3; P = 0.3).

Not only did CPAP fail to meet the composite primary endpoint, but it did not significantly affect any cause-specific cardiovascular outcome, the researchers said. However, CPAP users did improve significantly more than controls on measures of daytime sleepiness (the Epworth Sleepiness Scale), anxiety and depression (Hospital Anxiety and Depression Scale), self-reported physical and mental health (Short-Form Health Survey), and quality of life (European Quality of Life-5 Dimensions questionnaire). They also missed fewer days of work than did controls.

Study funders included the National Health and Medical Research Council of Australia, Respironics Sleep and Respiratory Research Foundation, and Phillips Respironics. Dr. McEvoy reported receiving research equipment for the study from AirLiquide. Several coinvestigators reported other ties to industry.

Adults with moderate to severe sleep apnea and coronary or cerebrovascular disease had about the same frequency of cardiovascular events whether they received continuous positive airway pressure (CPAP) therapy or usual care alone, according to a large randomized trial.

But CPAP was used for only 3.3 hours per night by these patients and might have been “insufficient to provide the level of effect on cardiovascular outcomes that had been hypothesized,” Dr. Doug McEvoy of the Adelaide Institute for Sleep Health, Flinders University, Adelaide, Australia and his associates reported at the annual congress of the European Society of Cardiology. Their study was simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Aug 28. doi: 10.1056/NEJMoa1606599).

Notably, CPAP did show a trend toward significance in a prespecified subgroup analysis that matched 561 patients who used CPAP for a longer period – more than 4 hours a night – with the same number of controls (hazard ratio, 0.8; 95% CI, 0.6 to 1.1; P = .1). Dr. McEvoy discussed the implications of prolonged CPAP use in a video interview with Bruce Jancin, our reporter at the ESC Congress in Rome.

Obstructive sleep apnea causes episodic hypoxemia, sympathetic nervous system activation; intrathoracic pressure swings strain the heart and great vessels, and increases markers of oxidative stress, hypercoagulation, and inflammation. Randomized trials have linked CPAP therapy to lower systolic blood pressure measures and improved endothelial function and insulin sensitivity. Observational studies suggest that CPAP might help prevent cardiovascular events and death if used consistently, the investigators noted.

Because cardiovascular disease and obstructive sleep apnea often co-occur, the researchers carried out a secondary prevention trial, Sleep Apnea Cardiovascular Endpoints (SAVE), to quantify rates of major cardiovascular events among 2,717 adults aged 45-75 years with obstructive sleep apnea and established coronary or cerebrovascular disease. Patients were randomly assigned to receive CPAP therapy plus usual care, or usual care alone. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization from unstable angina, transient ischemic attack, or heart failure. The researchers also looked at other cardiovascular outcomes, snoring symptoms, mood, daytime sleepiness, and health-related quality of life. They used a 1-week run-in period of sham CPAP (administered at subtherapeutic pressure) to ensure what they considered an adequate level of adherence.

The average apnea-hypopnea index (that is, the average number of apnea or hypopnea events recorded per hour) was 29 at baseline and 3.7 after initiating CPAP, the investigators said. At a mean of 3.7 years of follow-up, 17% of CPAP users (220 patients) and 15.4% of controls had a cardiovascular event, for a hazard ratio of 1.1 (95% confidence interval, 0.9 to 1.3; P = 0.3).

Not only did CPAP fail to meet the composite primary endpoint, but it did not significantly affect any cause-specific cardiovascular outcome, the researchers said. However, CPAP users did improve significantly more than controls on measures of daytime sleepiness (the Epworth Sleepiness Scale), anxiety and depression (Hospital Anxiety and Depression Scale), self-reported physical and mental health (Short-Form Health Survey), and quality of life (European Quality of Life-5 Dimensions questionnaire). They also missed fewer days of work than did controls.

Study funders included the National Health and Medical Research Council of Australia, Respironics Sleep and Respiratory Research Foundation, and Phillips Respironics. Dr. McEvoy reported receiving research equipment for the study from AirLiquide. Several coinvestigators reported other ties to industry.