Sleep-Related Problems in Common Medical Conditions FREE TO VIEW

Patients with common medical disorders often complain to their physician about sleep problems, and these patients are often referred to sleep specialists for evaluation and diagnosis. Poor quality sleep or insufficient sleep are associated with fatigue, malaise, and sleepiness. Quality of life is impaired, and subjective symptoms due to the underlying disease seem worse to the patient. If the quality of sleep is improved, subjective symptoms related to the disease may improve. Walsh et al¹ showed in a study of patients with rheumatoid arthritis and poor sleep that improving sleep by the use of a benzodiazepine improved subjective symptoms of joint pain even in the absence of objective improvement. Patients with some medical disorders, such as asthma, may have the most severe symptoms during sleep. Sleep disorders such as obstructive sleep apnea (OSA) have many adverse effects on health and may occur more frequently in certain medical disorders. In this review, the objective will be to review literature on sleep-associated problems observed in common medical conditions. Extensive research on the association of sleep-disordered breathing and cardiovascular disease has been reviewed and is not discussed here.²

Patients with COPD often have disrupted and fragmented sleep. Patients with COPD have prolonged sleep latency, decreased sleep efficiency, decreased total sleep time, increased wake after sleep onset, decrease in rapid eye movement (REM) sleep (Stage R), and decreased stage N3 sleep (non-REM stage 3 and 4 sleep). Additionally, coughing or dyspnea can be associated with sleep-related arousals.³ Sleep in patients with COPD is often complicated by hypoxemia. Oxyhemoglobin desaturation frequently occurs during non-REM sleep and worsens significantly during Stage R.^4,5 Hypoxemia may be due to several factors: ventilation-perfusion mismatching, increase in upper airway resistance, unfavorable mechanical position of intercostal muscles and diaphragm due to hyperinflation, relative decrease in oxygen stores, and the position of the baseline arterial oxyhemoglobin saturation (Sao₂) on the oxyhemoglobin dissociation curve (Fig 1).³

The degree of nocturnal hypoxemia in COPD is determined primarily by the daytime Sao₂ and daytime Paco₂. Because of the physiology of oxyhemoglobin dissociation, the lower the daytime resting Sao₂, the more likely severe nocturnal desaturations will occur.⁶ Reduced hypercapniec ventilatory response and respiratory muscle dysfunction further contribute to desaturation.⁷ The coexistence of OSA, termed the overlap syndrome, results in more severe oxygen desaturations.⁸ Sanders et al⁹ analyzed data from nearly 6,000 patients from the Sleep Heart Health Study and observed there was no association between mild COPD and OSA, but that that more severe COPD is associated with more severe desaturations during sleep, and that desaturation is greater in individuals with both COPD and OSA. In contrast, patients with mild airways obstruction in the absence of OSA had minimal alterations in sleep.⁹

A characteristic symptom of asthma is nocturnal awakening with dyspnea, cough, or wheeze.¹⁰ Patients with asthma commonly have their lowest peak flow during the night hours.¹¹ The pathophysiology of nocturnal asthma is complex but is associated with increased parasympathetic activity at night, increased airway inflammation, alteration in glucocorticoid receptors binding, and increased levels of proinflammatory leukotrienes. Evidence shows that a genetic mutation on the β₂-adrenergic receptor, Gly16, is significantly associated with nocturnal asthma.¹² Gastroesophageal reflux is an important contributing cause in many patients. Nocturnal asthma is therefore a complex phenomenon that is related to circadian alterations in airway physiology and inflammation. Treatment with inhaled corticosteriods and long-acting β-agonists is often effective at relieving symptoms in these patients and improving sleep.^13,14

Common interstitial lung diseases are interstitial pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, and drug-related lung disease. Restrictive lung disease is characterized by a decreased total lung capacity, pulmonary compliance, and diffusing capacity of the lung for carbon monoxide. The ventilatory response to these abnormalities in physiology is rapid, shallow breathing due to vagal stimulation from pulmonary mechanical receptors producing a sensation of dyspnea.

Patients with interstitial lung disease often have fragmented sleep interrupted by frequent arousals. Sleep in these patients is characterized by an increase in arousals, increased stage N1 sleep and stage N2 sleep, and a decrease in stage N3 sleep and Stage R. Hypoxemia often occurs during sleep, as it does with obstructive lung disease, and there are often severe desaturations during Stage R (Fig 2).^15,16

Kyphoscoliosis, an abnormal curvature of the spine causing deformity in the thoracic cage, results in a restrictive pulmonary defect with reduced total lung capacity, vital capacity, and functional residual capacity. These patients may have hypoxemia, polycythemia, hypercapnia, pulmonary hypertension, and cor pulmonale. Severe desaturations may occur during Stage R. In these individuals, sleep is often characterized by frequent arousals with hypoxemia and hypercapnia. Stage N3 sleep and Stage R are reduced and stage N1 sleep and stage N2 sleep are increased.^17–19 As the abnormalities and ventilatory function progress, noninvasive positive pressure ventilation provides ventilatory assistance and symptomatic improvement to the patient.²⁰

Approximately 10% of the normal population will have symptoms of reflux during sleep.²¹ Patients with gastroesphageal reflux disease (GERD) frequently have sleep disruption from heartburn that adversely affects the quality of their sleep and the ability to function on the following day.^22,23 Patients with nocturnal reflux often report frequent awakenings with burning or chest discomfort, indigestion, heartburn, acid brash, sour taste in the mouth, coughing, or choking. GERD is associated with difficulty initiating and maintaining sleep, and an increased number of awakenings from sleep. Longer esophageal acid exposure measured by pH monitor was directly correlated with poorer sleep quality in one study.²⁴ Minimally symptomatic GERD may be an unsuspected cause of insomnia. In patients with complaints of poor sleep, but minimal symptoms of GERD, Shaheen, et al²⁵ observed 25% of these patients had significant reflux detected by pH monitor and an improvement in sleep quality following therapy for GERD.

Acid reflux may play a role in some patients with nocturnal asthma. Patients with nocturnal asthma and GERD may aspirate gastric acid into the larynx, which can result in bronchoconstriction.^26,27 Bronchoconstriction in response to reflux may also occur also by acid stimulating afferent vagal nerves in the lower esophagus, provoking a parasympathetic bronchoconstriction response. Treatment of GERD with proton-pump inhibitor agents benefits many but not all patients with nocturnal asthma. However, patients with symptomatic reflux or documentation of reflux should be treated with acid-suppressing medications and other antireflux measures.^28–30

The prevalence of sleep disorders in patients with end-stage renal disease is very high and has been reported as high as 80% in several studies.^31–33 The most frequent complaints were difficulty falling asleep, awakenings in the middle of the night, waking up too early in the morning, restless legs, jerking legs, and daytime sleepiness.³⁴ In one study³⁵ 73% of patients receiving continuous ambulatory peritoneal dialysis complained of insomnia, and 52% reported unintentional napping. Disturbing nightmares are also common in these patients.

A complaint of excessive daytime sleepiness occurs in approximately 50% of patients with end-stage renal disease.³⁶ The causes are multifactorial and include insufficient sleep, disrupted sleep, OSA, restless legs syndrome, and systemic effects of uremia. Elevated levels of parathyroid hormone seem to have a neurotoxic effects associated with increased slow-wave activity in the wake EEG. Additionally, the process of hemodialysis is associated with the release of cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α, which have sleep-inducing properties.^37,38

Restless legs syndrome is common in patients with end-stage renal disease, occurring in approximately 20% of patients receiving dialysis. Restless legs are associated with poor sleep at night and daytime fatigue or sleepiness. Symptoms due to restless legs may also occur during the day and cause marked difficulty sitting or lying still during dialysis.³⁹ Treatment options include iron replacement for patients with iron deficiency, dopaminergic agents, narcotics, and benzodiazepines.^40,41 OSA occurs frequently in patients with renal disease and may have a prevalence of 50% in these patients.^42,43

OSA can be a consequence of hypothyroidism. The symptoms of hypothyroidism overlap with those of OSA and are difficult to distinguish with certainty. Obesity is a common factor. Pelttari et al⁴⁴ found that 50% of hypothyroid patients had some degree of sleep-disordered breathing compared with 29% of a euthyroid control group. Whether thyroid function tests should be ordered in all patients with suspected OSA is controversial. Three studies^45–47 show the prevalence of undiagnosed hypothyroidism in patients suspected of sleep apnea to be relatively low, 1.4 to 2.9%, suggesting routine screening is not cost-effective. It seems reasonable, however, to perform thyroid function testing in patients who have other reasons to consider hypothyroidism, such as in postmenopausal women or patients with dyslipidemia. The results of thyroid replacement in improving OSA and hypothyroidism have been conflicting. In hypothyroid patients with OSA, thyroid replacement as been shown to improve sleep-disordered breathing in some studies.^47,48 However, Grunstein and Sullivan⁴⁹ reported that six of eight patients did not have complete resolution of OSA with thyroid replacement alone. They observed two patients who had angina and arrhythmias with initiation of low-dose thyroxine doses that resolved with initiation of continuous positive airway pressure (CPAP). Based on these observations, hypothyroid patients should be treated with CPAP until thyroid replacement has been achieved and follow-up polysomnography completed.

Acromegaly is the consequence of excessive growth hormone; OSA is commonly associated with acromegaly. Several of the morphologic abnormalities secondary to acromegaly predispose to sleep apnea. Acromegaly is often complicated by macroglossia, elongation and thickening of the soft palate, swelling and thickening of the pharyngeal walls, and thickening of the true and false vocal cords. Additionally, there is overgrowth of the mandible and maxilla. Each of these abnormalities in the soft tissue and bone structure of the pharyngeal airway result in narrowing and an increased tendency of the airway to collapse, resulting in sleep-disordered breathing.⁵⁰ Sixty percent of patients with acromegaly had sleep apnea in one study.⁵¹ Central sleep apnea also occurs in up to one third of patients with acromegaly, and is likely due to an increased hypercapneic ventilatory response compared to control subjects.⁵² OSA associated with acromegaly is treated with CPAP; central sleep apnea is treated with CPAP, bilevel positive airway pressure, or supplemental oxygen. Two studies^53,54 have found that treatment of acromegaly has been disappointing in resolving the sleep-disordered breathing. Only one in five patients reported in one study⁵³ demonstrated reversal of obstructive apneas following pituitary surgery. In another study,⁵⁴ in which acromegaly was treated with adenomectomy with or without radiation therapy, central apnea persisted in 10 of 11 cases.

Diabetes has been associated with complaints related to sleep. In a study of 3,201 Swedish men, the presence of diabetes was associated with subjective complaints of sleep disturbance. Difficulty initiating sleep was observed in 21.1%, difficulty maintaining sleep was reported by 21.9%, and 12.2% reported excessive daytime sleepiness.⁵⁵ Significant complaints of difficulty sleeping were observed in 33.7% of patients with diabetes compared with 8.2% of control subjects in another study.⁵⁶ Both short sleep or long sleep have been found to be associated with the development of diabetes. In a cohort of 70,026 women enrolled in the Nurses Health Study,⁵⁷ the development of diabetes correlated with both self-described short sleepers (≤ 5 h of sleep) and long sleepers (≥ 9 h of sleep). Furthermore, in a study⁵⁸ of 2,663 Swedish subjects who responded to a health questionnaire 12 years apart, the relative risk for development of diabetes was higher in men with short sleep duration or difficulties maintaining sleep, after adjusting for age and other relevant risk factors. However, in women, neither short or long sleep duration or sleep complaints influenced the risk of new-onset diabetes in this study.⁵⁸ Yaggi et al⁵⁹ reported that men with short sleep duration (≤ 5 h of sleep per night) were two times more likely to have diabetes develop, and men reporting long sleep duration (> 8 h of sleep per night) were more than three times as likely to have diabetes develop when adjusted for other confounding variables. In a study of 8,992 subjects as part of the First National Health and Nutrition Examination Survey,⁶⁰ subjects with both short sleep (≤ 5 h of sleep) and long sleep (≥ 9 h of sleep) were significantly more likely to have diabetes develop over the follow-up period after controlling for other relevant variables. Diabetes may be an independent risk factor for OSA, even when adjusted for obesity.⁶¹

There is substantial evidence that glucose tolerance is impaired in patients with OSA.^62–64 However, there are other studies^65,66 that have not supported an independent association with sleep-disordered breathing but attribute the glucose intolerance to the presence of obesity. The metabolic syndrome is a term used to describe the grouping of several risk factors for cardiovascular disease: obesity, hypertension, insulin resistance, and dyslipidemia. These metabolic abnormalites are often observed in patients with OSA, and some^67,68 have proposed that OSA is probably another manifestation of the metabolic syndrome. However, since obesity and OSA are so closely associated, it is difficult to distinguish the metabolic effects of obesity and OSA. Visceral fat is known to be metabolically active, producing a variety of inflammatory and metabolic substances that have been implicated in the pathogenesis of insulin resistance and atherosclerosis⁶⁹ (Fig 3).

It has been observed for many years that people with acute infections have the need for more sleep or hypersomnolence. Evidence suggests that the basis for this may be that the immunologic response to infection may have coincidental soporific effects. Two important cytokines involved in the immune response to infection, IL-1β and TNF-α, have been found to play an important role in inducing and regulating sleep.⁷⁰ For example, both IL-1β and TNF-α will induce slow-wave sleep in experimental animal models.⁷¹

Volunteers inoculated with rhinovirus or influenza virus sleep less during the incubation phase but longer during the symptomatic phase. Severe fatigue and sleepiness occurs in patients with acute infectious mononucleosis. Infections with cytomegalovirus, brucellosis, and hepatitis B and C may be associated with sleep disturbance. A variety of animal models have shown alterations in sleep time and sleep architecture when infected with bacteria and viruses.⁷¹

Chronic Lyme disease may cause significant changes in sleep. In one study⁷² of patients with Lyme disease, sleep-related complaints, including difficulty initiating sleep, frequent nocturnal awakenings, excessive daytime somnolence, and restless legs/nocturnal leg jerking, were reported. Polysomnography in these patients showed greater sleep latency, decreased sleep efficiency, and a greater arousal index than in normal control subjects.⁷²

Sleep complaints such as insomnia, excessive daytime sleepiness, and multiple awakenings at night have been reported frequently in patients with HIV infection.⁷³ Medications that are used to treat HIV infection may also be associated with sleep disturbance. Zidovudine may cause insomnia. Nevirapine and efavirenz have been associated with vivid dreaming and sleep disruption.⁷⁴

The severity of sleep complaints appears to be related to the stage of the disease.⁷⁵ Mild symptoms of insomnia and sleep disruption may occur in the early stages of HIV infection (CD4 counts > 400/μL). Polysomnography has demonstrated an increase in total N3 and a relative shift of N3 sleep to the latter part of the night. Also, the alpha-delta pattern may be observed in sleep architecture of patients with HIV. Sleep difficulty increases as the severity of HIV infection increases. Patients with CD4 counts between 200 and 400/μL have suppression of stage 3 sleep, sleep fragmentation, and disruption of normal sleep architecture. Finally, severe difficulty with insomnia and daytime fatigue are reported in patients with CD4 counts < 200 μL. Slow-wave sleep is further decreased in these patients.^73,76

Fibromyalgia is a syndrome characterized by diffuse pain that is bilateral, occurs both above and below the waist, has widespread distribution, and consists of tenderness or pain in at least 11 of 18 anatomic sites.⁷⁷ Sleep-related problems are almost universal in fibromyalgia syndrome and are strongly predictive of pain, fatigue, and difficulty with social functioning.⁷⁸ The perception of pain in patients with fibromyalgia is worse in patients who also have poor sleep quality.⁷⁹ Total sleep time, sleep efficiency, and Stage R are all decreased and arousals are increased in patients with fibromyalgia.⁸⁰ Sleep apnea and restless legs syndrome may also occur in these patients. The alpha-delta pattern can be observed in the EEG of patients with fibromyalgia and chronic pain. Initially described by Moldofsky and Lue,⁸¹ this intrusion of alpha activity into delta (now termed stage N3 sleep) was initially thought to occur primarily in fibromyalgia. However, further investigations have shown that alpha-delta sleep can be seen in patients with chronic pain of any cause, and in fact can be seen in normal individuals as well.⁸² Although many pharmacologic agents have been used to treat both the pain and the sleep disorder related to fibromyalgia, no drug or class of drugs have been found to be especially helpful. Only one drug, pregalbin, has received approval by the Food and Drug Administration for use in fibromyalgia.⁸³ A double-blind, randomized study⁸⁴ demonstrated improvement in pain, quality of life, and sleep disturbance in fibromyalgia. Other pharmacologic agents, including antidepressants, have not shown a durable response in treating sleep complaints. Physical therapy, exercise training, and complementary forms of treatment are often advocated but have not been the subjects of high-quality prospective clinical trials.⁸³

Problems with sleep are one of the main symptoms women have with menopause. Complaints related to sleep are multifactorial and are associated with sleep disturbance from hot flashes, sleep apnea, restless legs syndrome, depression, and symptoms of fibromyalgia.⁸⁵ Perhaps the most common symptom related to sleep that occurs during menopause is disturbed sleep related to vasomotor instability, or hot flashes. Perimenopausal women who also have vasomotor symptoms are also more likely to have insomnia and depression. In one study,⁸⁶ the prevalence of chronic insomnia was 36.5% in premenopausal women, 56.6% in menopausal women, and 50.7% in postmenopausal women. Prevalence of insomnia complaints increased with the severity of hot flashes, and occurred in > 80% of perimenopausal and postmenopausal women who had the most severe hot flashes. Vasomotor symptoms were closely associated with disturbed sleep in this study. Multivariate analysis in this study showed a significant correlation of hot flashes with insomnia.⁸⁶ However, hot flashes are not the only cause of disturbed sleep in perimenopausal women. Perimenopausal women are at increased risk for sleep apnea, restless legs syndrome, or both. The incidence of sleep-disordered breathing increases significantly following menopause, possibly due to alterations in upper airway physiology associated with hormonal changes or weight gain. Freedman and Roehrs⁸⁷ found 53% of perimenopausal women had sleep apnea, complaints of restless legs, or both. Sleep quality in these women was related to the presence of apneas, periodic limb movements, subjective complaints of anxiety, and hot flashes. Estrogen improves disturbed sleep associated menopause, although its use is uncertain due to concerns about risk of breast cancer.^85,88 Eszopiclone can also be useful in treating insomnia in perimenopausal and postmenopausal women and improve quality of life and mood.⁸⁹

Patients with cancer who are undergoing cancer therapy are likely to have sleep disturbance. The most common symptoms these patients report are excessive fatigue (44%), leg restlessness (41%), insomnia (31%), and excessiveness sleepiness (28%).⁹⁰ Patients with lung cancer and breast cancer seem more likely to have sleep disturbance, insomnia, and fatigue compared to patients with other types of cancer. Recent or current therapy for cancer are strongly associated with excessive fatigue, multiple awakenings, insomnia, and hypersomnolence. Patients undergoing cancer therapy with insomnia also report that their sleep trouble affects how they feel physically, affects their ability to cope with stress, affects daily emotions, affects their ability to carry out usual daily activities, and affects their ability to concentrate during the day. Poor sleep is also associated with the development of depression.⁹⁰

Sleep disorders occur commonly in patients with common medical conditions (Table 1). Patients with COPD, restrictive lung disease, and asthma have frequently disruptions of sleep due to oxygen desaturations, coughing, and dyspnea. GERD is often associated with disturbed sleep due to symptoms related to acid reflux, and may contribute to nocturnal asthma. Patients with chronic renal disease have a variety of sleep problems. Insomnia and other sleep disturbances are very common in fibromyalgia and in relationship to menopause, and needs to be addressed and managed to optimize quality of life and daytime functioning. HIV-related disease and other infections are commonly associated with sleep problems. Patients receiving therapy for cancer find their quality of life and ability to perform daytime activities are impaired by disorders of sleep. The sleep specialist should be aware of these problems and be able to evaluate and manage them.