Hemophilia and other coagulation disorders: neurologic aspects
Jun. 20, 2022
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The understanding of sleep has received revitalized attention in recent years due to increasing recognition of the involvement of sleep disorders in numerous medical conditions. The authors discuss advances in this rapidly growing field and summarize the interactions between sleep disorders and medical illnesses, focusing on the impact of medical illness on sleep. The bidirectional relationship between medical illnesses and sleep disorders is also discussed.
• Sleep disturbances are common in medical disorders.
• Numerous medical disorders cause or are associated with sleep disorders such as poor sleep quality, insomnia, hypersomnia, obstructive sleep apnea, and restless legs syndrome.
• Moreover, sleep disorders such as sleep apnea can worsen a medical disorder, such as arterial hypertension or diabetes mellitus.
• The management of sleep disorders associated with medical conditions requires a multimodal approach with a tailored treatment plan addressing sleep hygiene, medication usage, and management of comorbidities.
The interaction between sleep disorders and medical disease has long been recognized. In ancient Greece, Democritus (c. 460 – c. 370 BC) believed that physical illness was the cause of daytime sleepiness, and that poor nutrition was the primary cause of insomnia (35). In 1896, acromegaly was the first endocrine disorder recognized to be associated with heavy snoring and excessive daytime sleepiness (160). Burwell and colleagues published their classic description of obesity hypoventilation (Pickwickian) syndrome in 1956. The misconception that respiratory failure was the cause of excessive daytime sleepiness was not corrected until 1966 when Gastaut and associates polysomnographically monitored the sleep of these patients and documented repetitive episodes of upper-airway obstruction, leading to the discovery of obstructive sleep apnea (169). In the 1970s, Lugaresi and colleagues reported the corollary of obstructive sleep apnea in nonobese patients as sole cause of hypersomnia and identification of the importance of snoring and hypersomnolence as diagnostic indicators (116). Thus, medical and sleep disorders are commonly comorbid, and oftentimes exhibit reciprocal effects.
A wide range of medical conditions is associated with sleep disorders. Sleep disorders may contribute to manifestations of medical conditions, and medical disorders may worsen sleep disorders.
Sleep disorders associated with kidney disease. Poor sleep quality, insomnia, sleep apnea, and restless legs syndrome/Willis-Ekbom disease (RLS/WED) are the main sleep disorders associated with renal illnesses. Sleep disturbance in patients with renal disease is very common, and poor sleep quality predicts disease progression (202; 95). Sleep disorders, such as sleep apnea, insomnia, RLS/WED, and daytime sleepiness occur in 65% of patients with chronic kidney disease on dialysis (130). The most reported issue is insomnia, occurring in 49% of patients with end-stage renal disease, followed by sleep apnea and RLS/WED (130). The sleep disruption appears to be related to uremia and periodic limb movements in sleep. Sleep duration can also be altered, either short (≤ 5 hours) or long (≥ 8 hours), in chronic kidney disease patients. Short and long sleep duration is associated with kidney disease and progression to end-stage renal disease (115; 180). Furthermore, low vitamin D levels may predict poorer sleep quality (75; 90).
Obstructive sleep apnea is also common in chronic kidney disease, occurring in about 56% of nondialysis chronic kidney disease patients. About 40% have moderate to severe obstructive sleep apnea (82; 24). Even mild chronic kidney disease is associated with severe obstructive sleep apnea and arousals (04). However, not all studies have seen this association after controlling for coronary artery disease (56). Objective measures are needed to diagnose obstructive sleep apnea as survey-based measures do not adequately predict obstructive sleep apnea in the chronic kidney disease population (82; 24). Obstructive sleep apnea contributes to daytime sleepiness and cognitive impairment (97). Obstructive sleep apnea also increases mortality, and although treatment improves mortality in this population, the benefit depends on adherence to therapy (151; 154).
Sleep apnea and chronic kidney disease have bidirectional relationships. Chronic kidney disease leads to fluid retention, uremia, chronic metabolic acidosis, and altered peripheral and central chemosensitivity that worsen airway obstruction. Sympathetic surges from sleep apnea affect the renin-angiotensin system and, therefore, renal function (03). The hypoxic burden from sleep apnea also predicts moderate to severe chronic kidney disease (90). Dialysis is helpful for sleep apnea in end-stage renal disease (182). Furthermore, renal transplantation may improve sleep apnea in some patients, but the long-term benefits are mediated by body mass index (159; 118).
Central sleep apnea is also seen in patients with chronic kidney disease, though less commonly than obstructive sleep apnea. Central sleep apnea likely occurs due to fluid overload, interstitial pulmonary edema, and activation of pulmonary mechanoreceptors, resulting in unstable ventilatory control and loop-gain pattern of breathing. Furthermore, metabolic acidosis, which alters the ventilatory response, and changes in chemoreceptor sensitivity contribute to instability of ventilation. However, this association between central sleep apnea and chronic kidney disease is confounded by coexisting cardiovascular disease, including congestive heart failure (137).
RLS/WED is another common disorder in renal disease. RLS/WED is a disorder that involves discomfort in the legs with an urge to move that is worse at rest, better with movement, and is nighttime-predominant. It is reported in 20% of patients with chronic kidney disease and in 40% of those with end-stage renal disease (13; 206). The risk of RLS/WED is associated with the duration of hemodialysis, inflammation, hyperparathyroidism, glycosylated serum protein, erythropoietin treatment (206), and iron deficiency anemia (47). In patients on hemodialysis, RLS/WED is associated with poorer sleep quality, daytime sleepiness, and depression (206). Such patients are at rest for long periods of time, which can worsen the symptoms. RLS/WED increases the odds for insomnia and impaired quality of life in patients on maintenance dialysis (129). RLS/WED in uremic patients appears to worsen faster and responds less to dopaminergic therapy than in those with idiopathic RLS/WED (49). End-stage renal disease patients have a higher frequency of periodic limb movements, a common finding in patients with RLS/WED, and related arousals suggesting that treatment of periodic limb movements may be required to improve sleep quality in this patient population (113).
Furthermore, higher risk of cardiovascular disease (206) and even cardiac mortality (105) has been reported in uremic patients with RLS/WED, though a study found lower mortality in this population (13). Uremic patients with RLS/WED can still benefit from pharmacologic therapy such as dopamine agonists and α2δ ligands (eg, gabapentin), with dose adjustment in renally excreted medications, and nonpharmacologic treatments such as warm/cold baths, massages, and aerobic exercises (194; 96). Renal transplantation can significantly improve RLS/WED, though the symptoms can be even worse in those with failed transplant compared to those who did not have transplant (206).
Sleep disorders associated with cardiovascular disease. Sleep disruption, either sleep-disordered breathing or short and long sleep duration, is strongly associated with cardiovascular diseases. Observation studies have noted association of sleep-disordered breathing and high risk of several different cardiovascular diseases, including coronary artery disease, atrial fibrillation, and congestive heart failure (12). Mechanisms by which sleep-disordered breathing affects cardiovascular function include sympathetic nervous activation (eg, elevated heart rate, elevated blood pressure), metabolic dysregulation (eg, insulin resistance, elevated triglycerides, decreased high-density lipoproteins), systemic inflammation, oxidative stress, vascular endothelial dysfunction, and hypercoagulation (93; 18). Short sleep duration has also been associated with the development of multiple cardiometabolic risk factors over an 18-year follow-up period, including central obesity, elevated fasting glucose, hypertension, low high-density lipoprotein, cholesterol, hypertriglyceridemia, and metabolic syndrome (42). Long sleep duration is closely associated with coronary artery disease, stroke, and increased risk for all-cause mortality, likely related to increased arterial stiffness (121).
In patients with insomnia and circadian sleep-wake phase disorder (eg, shift workers), there is supporting evidence that cardiometabolic risk rises from cardiac autonomic dysfunction (138).
Sleep-disordered breathing raises the risk of developing cardiovascular disease. A previous study estimated that patients with mild obstructive sleep apnea had twice the risk of new-onset systemic hypertension compared with those without obstructive sleep apnea, whereas subjects with moderate to severe obstructive sleep apnea had nearly 3 times the risk (149), and the Wisconsin Sleep Cohort Study showed an association between REM sleep-related obstructive sleep apnea with incident hypertension (124). Obstructive sleep apnea and nocturnal hypoxemia are associated with increased high-sensitivity troponin-I, suggesting that obstructive sleep apnea results in low-grade myocardial injury. Subclinical markers of atherosclerosis such as coronary artery calcification, a predictor of major adverse cardiovascular events, have also been associated with increasing obstructive sleep apnea severity (48), confirming the previous association of 3-fold increase in fatal cardiovascular disease, including stroke, myocardial infarction, coronary artery bypass surgery, and percutaneous transluminal coronary angiography, compared to patients without sleep-disordered breathing.
A strong association (up to 4-fold higher odds) between obstructive sleep apnea and atrial fibrillation, independent of obesity and other confounding influences, has been described in multiple studies. During apneic events, there is absence of ventilation, and hypoxic stimulation of the carotid body is vagotonic, which results in bradycardia. After the respiratory event, sympathetic activation occurs due to synergistic influences of hypoxia, hypercapnia, and increasing thoracoabdominal effort, resulting in tachycardia. Arrhythmogenesis is also enhanced in obstructive sleep apnea due to intermittent hypoxia, which may result in delayed depolarization, respiratory acidosis resulting in triggered automaticity, and reentrant mechanisms likely due to autonomic nervous system fluctuations. Treatment of underlying obstructive sleep apnea, however, appears to reduce the recurrence of atrial fibrillation after cardioversion or ablation and reduces the risk of conversion from paroxysmal to persistent atrial fibrillation (69).
Central sleep apnea and Cheyne-Stokes respirations are commonly observed breathing patterns during sleep in patients with congestive heart failure. Proposed mechanisms include augmented peripheral and central chemoreceptor sensitivity that increase ventilator instability during both wakefulness and sleep, and decreased CO2 reserve, predisposing to sleep apnea. In addition, diminished cerebrovascular reactivity and increased circulation time impair the normal buffering of PaCO2 and hydrogen ions, and delay the detection of changes in PaCO2 during sleep, leading to improper ventilatory compensation. Moreover, there is an increase of left ventricular transmural pressures in response to increasingly negative intrathoracic pressure. This results in reduction of left ventricular preload and increased afterload. Neurohumoral effects involve pulmonary congestion, which stimulates pulmonary vagal irritant receptors and results in hyperventilation and elicitation of central apnea. Adaptive servoventilation or continuous positive airway pressure treatment for Cheyne-Stokes respirations in patients with heart failure with preserved ejection fraction can be beneficial (166). However, adaptive servoventilation is currently contraindicated in heart failure patients with ejection fraction of 45% or less as it was shown to have higher mortality compared to medical treatment alone. There is an ongoing study [Adaptive Servo Ventilation (ASV) on Survival and Hospital Admissions in Heart Failure ADVENT-HF] to help elucidate the appropriate therapy for patients with central sleep apnea (85).
Sleep-disordered breathing is important to recognize because its presence is a negative prognostic factor. Obstructive sleep apnea may be underdiagnosed in people with heart failure due to the overlapping symptoms of nocturnal dyspnea and nocturia. However, there has been inconsistent data regarding the benefit of continuous positive airway pressure. A few studies and a randomized trial showed that continuous positive airway pressure use can decrease cardiac deaths, recurrent myocardial infarction, mean arterial blood pressure, and inflammatory biomarkers, such as C-reactive protein (58; 68). However, the SAVE (Sleep Apnea Cardiovascular Endpoints) trial, which examined the effects of continuous positive airway pressure therapy on secondary prevention of incident cardiovascular events, failed to find a favorable effect (122). In a meta-analysis that included several randomized trials, continuous positive airway pressure therapy was associated with a mean net lowering in systolic blood pressure of 2.6 mmHg (55). Even a 1 to 2 mmHg decrease in blood pressure is associated with a reduction in major cardiovascular events, stroke, and heart failure. Alternative therapies such as oral appliances or upper airway surgery are associated with a significant reduction in systolic and diastolic blood pressure (19).
Diabetes mellitus. Patients with diabetes mellitus have a higher rate of insomnia, excessive somnolence, sleep-disordered breathing, and snoring. The relationship between sleep-disordered breathing and impaired glucose-insulin metabolism appear to be independent of obesity and age (14). Adult patients with longstanding type 1 diabetes mellitus have disturbed subjective sleep quality and a higher risk for obstructive sleep apnea compared with control participants (187). Moreover, obstructive sleep apnea is more prevalent in diabetic patients with autonomic neuropathy than in those without.
An important contributing factor to fragmented night sleep in diabetes mellitus is painful diabetic polyneuropathy and hypoglycemia. It is uncertain if RLS/WED is significantly more common in adult diabetics. One study suggested a significant association between RLS/WED and type 2 diabetes mellitus (123). Moreover, autonomic neuropathy in diabetes mellitus might alter ventilatory control mechanisms, causing sleep-disordered breathing. Periodic breathing, a respiratory abnormality associated with disturbance of central control of ventilation, may result from the deleterious effects of diabetes mellitus on central control of respiration (157).
Decreased sleep duration or quality, including difficulty falling asleep, early morning arousal, and snoring frequently, increases HbA1c, a key marker of glycemic control. It appears slow-wave sleep plays an important role in the maintenance of normal glucose homeostasis. Furthermore, reduced sleep quality with low levels of slow-wave sleep, as occurs in aging and in many obese individuals, may contribute to an increased risk of type 2 diabetes. Obstructive sleep apnea is common in people with diabetes, with a prevalence of 54.5% in a meta-analysis (52). Treating obstructive sleep apnea during REM rather than NREM sleep is associated with better glycemic control (70; 27). Therefore, optimizing sleep duration and quality could improve glucose control in patients with type 2 diabetes mellitus (11).
One complication of diabetes is retinopathy. Obstructive sleep apnea is an independent predictor for the progression to proliferative diabetic retinopathy in patients with type 2 diabetes. Fortunately, continuous positive airway pressure treatment was associated with reduction in its progression (09).
Whether continuous positive airway pressure improves diabetes mellitus management is controversial. One study suggested that 1 week of effective treatment of obstructive sleep apnea over an entire 8-hour night results in a clinically significant improvement in glycemic control via an amelioration of evening fasting glucose metabolism and a reduction in the dawn phenomenon, a late-night glucose increase that is not adequately treated by oral medications (125). Treatment of obstructive sleep apnea with continuous positive airway pressure may improve glycemic control in type 2 diabetes, though results have been mixed (106; 181). In patients with moderate to severe obstructive sleep apnea, compliant continuous positive airway pressure usage may improve insulin secretion capacity and reduce leptin, total cholesterol, and low-density lipoprotein levels (38).
Thyroid and parathyroid dysfunction. Thyroid stimulating hormone appears to be regulated by an interaction of sleep and the circadian rhythm (98). Thyroid stimulating hormone rises in the evening and falls during sleep. During acute sleep deprivation, thyroid stimulating hormone reaches a higher peak, and chronic sleep restriction dampens the rhythm of thyroid stimulating hormone secretion (176; 87). This interaction and the finding of fatigue as a prominent symptom of hypothyroidism spurred interest in the interaction between sleep and thyroid function. Yet, there is still much that is unknown about their relationship. Shift work has been associated with higher thyroid stimulating hormone levels in 2 meta-analyses, but interpretation is difficult due to the heterogeneity in shift work scheduling, amount, duration, type of shift, and timing of thyroid stimulating hormone testing (37; 108). Subclinical hypothyroidism has been associated with worse sleep quality, longer sleep latency, and shorter sleep duration; risk for these changes was increased by younger age, lower body mass index, and female sex (175). Another study, however, found that subclinical hypothyroidism was associated with longer sleep duration (99). That study also noted that patients with subclinical hyperthyroidism tended to have either short or long sleep durations (100). Restless legs syndrome is more common in those with hypothyroidism and vice versa (05).
The relationship between obstructive sleep apnea and thyroid disease is conflicting. Hypothyroidism has been associated with increased risk of sleep apnea in the NHANES study after controlling for several confounders (183). However, among patients with obstructive sleep apnea, thyroid dysfunction was not more prevalent, and thyroid parameters did not correlate with obstructive sleep apnea severity (20; 177). Thyroid eye disease with compressive optic neuropathy may be associated with higher obstructive sleep apnea risk based on surveys (72; 62). Despite the limited data, lack of international guidelines, and no large multicenter studies, one author suggests that thyroid stimulating hormone screening might prove beneficial in the vast majority of obstructive sleep apnea patients (103).
Two-thirds of the patients with primary hyperparathyroidism reported poor sleep quality by Pittsburgh Sleep Quality Index. When treated, one-third of these had significant improvement in their quality of life (104).
Growth hormone dysfunction. Patients with growth hormone deficiency complain of reduced vitality, general fatigue, lack of concentration, irritability, and reduced alertness during daytime (165). It is speculated that growth hormone deficiency causes sleep irregularities, such as nocturnal awakening and abnormality in REM sleep in Smith-Magenis syndrome, a multiple congenital anomaly syndrome caused by an interstitial deletion of chromosome 17p11.2 (89).
Growth hormone deficiency is associated with sleep disorders that may be caused by specific hormonal alterations and with poor subjective sleep quality and daytime sleepiness. Disturbed sleep is likely to be partly responsible for increased fatigue, a major component of quality of life in growth hormone deficiency. Patients with growth hormone deficiency have poor sleep quality. Those with pituitary growth hormone deficiency have more slow-wave sleep, but more sleep fragmentation (36).
Acromegaly, a disorder of growth hormone excess, is associated with obstructive sleep apnea in 29% to 75% of patients (191; 156; 185). Independent predictors of obstructive sleep apnea are increased activity of acromegaly, male sex, older age, and increased neck circumference (191). Craniofacial changes in acromegaly are associated with increased vertical, dolichofacial growth with posterior airway space narrowing (77). Although most authors report peripheral obstruction due to hypertrophy of tongue and pharyngeal tissues as the cause of sleep apnea in acromegaly, some findings argue for a role of growth hormone-induced changes of central respiratory control. Treatment of acromegaly may be curative of obstructive sleep apnea in 69% (195).
Adrenocorticosteroid excess. The prevalence of sleep apnea in patients with Cushing syndrome may be up to 50%, of which more than 90% of the apneas and hypopneas were of obstructive or mixed type (63). Insomnia, fatigue, and a multitude of psychiatric syndromes, including frank psychosis and major depression, have been recognized features of Cushing syndrome and may be exacerbated by sleep apnea or be caused by steroid induced changes in sleep architecture. Men with obstructive sleep apnea present with increased post-dexamethasone cortisol levels and heart rate, which are recovered by continuous positive airway pressure (26).
A significant correlation between morning plasma aldosterone concentration and obstructive sleep apnea severity is observed in subjects with resistant hypertension but not in control subjects, suggesting that aldosterone excess may contribute to obstructive sleep apnea severity (152). Studies have found mineralocorticoid receptor expression is increased in obese individuals, and mineralocorticoid receptor blocker reduces the severity of obstructive sleep apnea among resistant hypertension patients (186).
Sleep disorders associated with malignancies. Sleep problems are common in cancer outpatients and are strongly associated with pain and emotional distress. Sleep disturbances have been reported in nearly 60% of patients with cancer and can last for years after the diagnosis (179; 65). Sleep disturbance also predicts lower quality of life and more fatigue after cancer treatment (204; 155). A variety of cancers have been linked to excessive fatigue, leg restlessness, insomnia, and excessive sleepiness. Fatigue is a common symptom and is associated with the presence of inflammation, poor quality of sleep, impaired circadian rhythms, depression/anxiety, and poor quality of life (158; 120). Cancer treatment can result in poor sleep hygiene, pain, and treatment side effects such as nausea, diarrhea, and urinary frequency, which may also precipitate sleep problems (107).
Sleep disruption in cancer patients is associated with worse survival (67). However, there are mixed findings on the effect of short and long sleep duration on mortality (31; 109; 170). Posttraumatic experience and quality of life seemed to be the strongest predictors of sleep quality in a sample of advanced cancer patients referred for palliative care. Many dimensions of cancer influence the clinical manifestations of sleep disturbances. Depression, pain, and life stress scores were each associated with different types of negative change in self-reported sleep disturbances among women with metastatic breast cancer (145).
Large anterior skull base lesions in patients can cause obstructive sleep apnea (131). Numerous case reports observed sleep-disordered breathing in association with local head and neck mass lesions such as pseudopheochromocytoma, medullary thyroid cancer, parapharyngeal angiolipoma, pleomorphic adenoma of the soft palate, or carotid body paraganglioma (76; 78). Patients with head and neck tumors should be screened for symptoms of obstructive sleep apnea.
Recognition and treatment of sleep disturbances is important to improve these patients' function and quality of life. Behavioral therapy intervention improves sleep quality and cancer-related fatigue (16). Further studies have shown benefits from cognitive behavioral therapy and brief behavioral therapy (60; 59; 205; 15). Morning bright light treatment may prevent overall fatigue from worsening during chemotherapy in cancer patients (10). Paroxetine had a significant benefit on sleep problems in both depressed and nondepressed cancer patients. However, rates of sleep problems remained high, even among those effectively treated for depression with paroxetine (146).
Interestingly, sleep disruption, insomnia, and poor sleep quality may increase risk of cancer, including breast cancer and high-grade prostate cancer (86; 192; 111; 174). Night shift work, particularly rotating shifts, also appears to be associated with prostate cancer, which may be related to sleep and circadian rhythm disruption (114). Furthermore, obstructive sleep apnea increases the risk of breast cancer and smoking-related cancers, such as lung, bladder, and thyroid cancer, especially in nonsmokers (81; 190). This relationship has been shown with overall cancer diagnosis and colorectal cancer—with higher obstructive sleep apnea severity predicting higher risk and mortality (29; 80; 92; 32).
Several studies have examined treatments, primarily nonpharmacologic, for sleep disturbance and fatigue in cancer patients and survivors. Cognitive behavioral therapy for insomnia is a standard treatment for insomnia generally and appears to help cancer patients (205). Brief versions of this may also be beneficial (144). Bright light therapy can improve fatigue, depression, and sleep difficulties in various cancers (199), but another study showed that dim red light and bright white lights were both effective (178).
Sleep disorders associated with rheumatologic disorders. Complaints of poor sleep quality, insomnia, and fatigue are common in many rheumatologic disorders. The sleep disturbance may be from—and even worsen—joint pain, but can also be independent of joint pain. These findings have been reported in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, and antiphospholipid antibody syndrome (41; 110; 119; 39; 25; 84; 88; 161; 198). The pattern of alpha-delta sleep has been correlated with nonrestorative sleep in rheumatological patients (126). Disease activity correlates with worse sleep quality in rheumatoid arthritis and psoriatic arthritis (25; 84). Long-term steroid use is also linked to poor sleep quality (84). It is recommended that rheumatoid patients be evaluated for sleep disturbances during routine examinations (01). Although one study did not show an association between rheumatologic disease and an increased risk of RLS/WED, another did show higher prevalence of RLS/WED in psoriatic arthritis (140; 163).
Obstructive sleep apnea may be more common in rheumatologic disorders. This risk has been shown in patients with ankylosing spondylitis (184), Sjogren syndrome, Behçet disease, and juvenile idiopathic arthritis (203; 168). Although obstructive sleep apnea is more prevalent in patients with rheumatoid arthritis, it is not associated with rheumatoid arthritis disease activity (189).
Additional conditions contributing to sleep disorders. Sleep may be influenced by many factors such as nocturnal disruption related to night sweats, seasonal allergies, pain, and HIV. Night sweats may be caused by tuberculosis, lymphoma, HIV, gastroesophageal reflux disease, obstructive sleep apnea, hyperthyroidism, medications, and hypoglycemia (188). Allergic rhinitis leads to increased daytime sleepiness, worse sleep quality, and higher risk of obstructive sleep apnea (112; 143).
Several studies have shown an association of poor sleep quality with HIV. For example, earlier studies showed that 47% of the patients with HIV have poor self-reported sleep quality (197; 06). Several cross-sectional studies have confirmed these findings in different populations, with one study showing 73% with poor sleep quality (54; 71; 02; 23). Insomnia is also commonly seen, particularly in women with HIV (71), and correlates with worse quality of life (153). Tailored sleep promotion interventions, such as improved sleep hygiene, can improve sleep disturbances in HIV patients (83). Poorer self-reported sleep quality, short or long sleep duration (< 7 hours or > 8 hours vs. 7-8 hours), and greater fatigue were associated with lower self-reported cognitive function scores in HIV patients (21). Another study found that long sleep duration was associated with a CD4 count of less than 500 cells/mm3 (54). Furthermore, medications can cause sleep disruption. Vivid dreams have been reported in patients taking the nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz (127). Severe insomnia was noted with high concentrations of raltegravir (46). Sleep apnea is also more common in people with HIV and correlates with cognitive dysfunction (171; 28).
Sleep disorders and SARS-CoV-2. In 2020 and 2021, the epidemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2, “COVID-19”) wreaked havoc around the world. COVID-19 causes an atypical infiltrative pneumonia with many neurologic complications, one of which is significant sleep disruptions. It has been shown that residual SARS-CoV-2 RNA in central nervous system may result in neuronal loss (08). Also, the systemic inflammation from COVID-19 is thought to cause generalized endothelitis and disruption of blood-brain barrier. The neuroinflammation caused by cytokines, chemokines, acute-phase proteins affecting brain endothelial cells, and blood-brain barrier permeability may lead to disruptions in sleep, with sleep initiation and maintenance difficulties (167).
Conversely, sleep disorders may increase risk or worsen the course of COVID-19 infection (117). A metaanalysis found elevated risk of severe complications of COVID-19 in people with obstructive sleep apnea, with need for ICU admission, mechanical ventilation, and mortality. This finding may be related to comorbid conditions such as hypertension, diabetes, obesity, and other factors such as increased angiotensin-converting enzyme activity and dysregulation of renin-angiotensin receptor, which allow SARS-CoV2 to gain entry into cells, and overall inflammatory activity due to increased interleukin-6, interleukin-17, tumor necrosis factor-alpha, and overall hypoxic respiratory events due to upper airway resistance (73).
Several studies have evaluated the association between sleep duration and mortality, with some conflicting results. Cohort and meta-analyses have showed higher all-cause mortality in long sleepers (≥ 9 hours) (101; 74; 102), though a cohort also noted higher all-cause mortality in long sleepers (≥ 7.5 hours) (99). A large cohort noted that insomnia or poor sleepers who also had short objectively measured sleep duration had higher incident cardiovascular disease but not all-cause mortality (17). Sleep apnea can worsen mortality and incident diabetes, hypertension, heart disease, and myocardial infarction, and long-term continuous positive airway pressure use appears to reduce cardiovascular risk (43). Obstructive sleep apnea also increases the risk of perioperative complications, metabolic syndrome, nonalcoholic fatty liver disease (133), and cognitive decline and dementia (201).
A 53-year-old man presented due to waking up in the night feeling short of breath. He slept on 2 pillows to help him breathe. He reported being told that he snored and that he stopped breathing intermittently during sleep. He also had mild dyspnea on exertion and reported dozing off during the day. He reported waking up frequently at night to urinate. On exam, his body mass index was 33 kg/m2, and he traced edema in the leg. Echocardiogram revealed grade I diastolic dysfunction and a cardiac ejection fraction of 55%. Polysomnography revealed an apnea-hypopnea index of 35 events/hour, consistent with severe sleep apnea. He underwent titration with continuous positive airway pressure, but with resolution of the obstructive events he developed central apneas in a waxing and waning pattern consistent with Cheyne-Stokes respiration. Titration with adaptive servoventilation was effective. Nightly use of adaptive servoventilation resulted in improvement in sleep quality and significant reduction in nocturia, snoring, and daytime sleepiness.
It is rare for sleep disturbance in chronic medical disease to be due to a single entity. Fragmented night sleep can be related to pain, dyspnea, nocturia, reduced mobility, pruritus, leg movement, apnea, or paresthesias causing frequent awakenings. The treatment of underlying conditions, such as with medications, might interfere with sleep, causing nightmares, disrupted sleep, nocturia, or daytime sleepiness. Anxiety and depression accompanying chronic illness may also contribute to sleep disruption.
Sleep disturbances may have an adverse effect on the course of a medical illness. A vicious cycle may result from the effect of sleep disturbances on medical conditions and the effect of the medical condition on the sleep architecture. Sleep may be disturbed by variety of mechanisms, including:
(1) Indirect effects on the sleep-promoting and wake-promoting neurons in the diencephalon and brainstem and respiratory neurons in the brainstem by metabolic disturbances (eg, renal, hepatic, and respiratory failure, electrolyte disturbances, hypoglycemia, hyperglycemia, ketosis, toxic states)
(2) Adverse effects on sleep organization and sleep structure by drugs used to treat medical illness
(3) Disturbances in the circadian rhythm
(4) Effects on the peripheral respiratory mechanisms (including respiratory muscles) causing sleep-related respiratory disturbances
(5) Esophageal reflux, which may be due to prolonged clearance of the lower esophagus, aspiration, and reflux mechanism
(6) Adverse effect on sleep structure after prolonged immobilization resulting from medical illness
(7) Dysfunction of the autonomic nervous system caused by medical disorders (eg, diabetes mellitus, amyloidosis).
Diabetes mellitus and obstructive sleep apnea appear to share a bidirectional relationship. Diabetes can impact the development of obstructive sleep apnea through inflammatory cell infiltration and denervation changes that affect the mucosa and the upper airway muscles. Conversely, obstructive sleep apnea worsens glucose metabolism through sympathetic activation and neurohormonal and inflammatory changes. Experimental sleep fragmentation across all sleep stages alters glucose metabolism, adrenocortical function, and sympathovagal balance in healthy, normal volunteers leading to decreased insulin sensitivity and glucose effectiveness (181).
Sleep loss is associated with disease, but the mechanisms and functions of sleep and sleep loss on health remain speculative. Despite these critical attributes, the mechanisms and functions by which sleep and sleep loss impact health remain speculative. One study suggests that sleep loss induces phagocyte migration and cellular stress in liver, lung, and intestine (50). Cytokine may contribute to sleep disturbance and fatigue. Clevenger and colleagues found a direct association of IL-6 with sleep disturbances in patients with ovarian cancer, whereas the relationship between IL-6 and fatigue prior to surgery may be mediated by poor sleep (34).
Iron deficiency anemia is an observed phenomenon in patients with a renal condition, especially those on dialysis. Iron-deficiency is a common contributing factor in patients with RLS/WED. Iron deficiency peripherally and in the brain is a common feature in the pathophysiology of RLS/WED (66). Therefore, the iron depletion common among dialysis patients is a likely contributor to their leg restlessness. However, the sources of the sleep disturbance in renal disease are often multifactorial, including electrolyte and other metabolite abnormalities. In addition, a link between sleep-related breathing disorders and renal illness have emerged in the past several years. Hypocapnia from metabolic acidosis and acidemia may change the apnea-PCO2 or hydrogen ion threshold, predisposing the patients with chronic kidney disease to unstable breathing patterns. Accumulation of uremic toxins may affect the CNS and result in a reduction of airway muscle tone during sleep or instability of respiratory control.
Multisynaptic neural and endocrine pathways from the suprachiasmatic nucleus of the hypothalamus have been hypothesized to communicate circadian and photic information to the adrenal glands. In humans, bright light exposure in the morning increases cortisol levels compared to dim light (150). After sleep restriction, light exposure restores the decrease in morning cortisol (53).
Sleep disturbances are common in medical disorders. Eighty percent of dialysis patients complain of subjective sleep disturbances, including RLS/WED, sleep-onset insomnia, and sleep maintenance insomnia. Obstructive sleep apnea occurs in up to 75% of acromegaly patients and in 50% of patients with Cushing disease (191; 63). Risk of obstructive sleep apnea is 2 to 3 times greater in those with compared to those without cardiovascular disease (173). Seven percent of the general population has insomnia associated with general medical disorders (139). Several malignancies are associated with excessive fatigue (44% of patients), leg restlessness (41%), insomnia (31%), and excessive sleepiness (28%) (40). Poor sleep quality was observed in up to 47% to 73% of patients with HIV (197; 06; 71).
Specific risk factors for sleep disorders in medical conditions are like those factors for patients without medical illnesses. Improving the treatment of the underlying medical condition, such as diabetes mellitus or renal disease, might avoid the progression or development of a sleep disorder. Advising patients as to proper sleep hygiene may be beneficial. Regular daytime exercise, evening relaxation, and elimination of stimulants and alcohol, and limiting napping are important. Patients should be discouraged from self-medication and seek professional opinion in a timely manner. Patients should be instructed that the bedroom is reserved for sleep and that waking activities, except for sexual activity, should be excluded from the bedroom. Obtaining patient and sleep observer information may help decide if completion of polysomnography is necessary to better define the treatment strategy. Additionally, in patients who are advised of a specific treatment like continuous positive airway pressure or medication treatment, compliance should be emphasized and monitored by either downloading data in the case of continuous positive airway pressure or by thorough clinical history taking from the patient and/or family.
A broad range of differential diagnoses should be considered in a patient presenting with sleep disturbances. Differential diagnoses include:
(1) Intrinsic sleep disorders, such as narcolepsy, RLS/WED, and sleep apnea.
(2) Extrinsic sleep disorders, such as environmental sleep disorder, inadequate sleep hygiene, medication-related sleep disorder, and alcohol abuse.
(3) Circadian rhythm sleep disorders, such as delayed sleep-wake phase disorder.
(4) Sleep disturbance due to mental disorders such as depression, schizophrenia, and anxiety disorders.
(5) Sleep disturbance due to neurologic disorders such as dementia, encephalopathy, mental retardation, epilepsy, multiple sclerosis, neuromuscular disorders, post traumatic disorders, spinal cord disorders, parkinsonism, and stroke.
The differential diagnosis should include medical conditions mimicking a sleep disorder, including but not limited to congestive heart failure, airway narrowing associated with fluid overload, and seizures.
A thorough sleep history and examination is a primary approach. The history should be complemented by reviewing the comorbidities and analyzing the current prescription and over-the-counter medications. The history should also review sleep hygiene, smoking, and alcohol or stimulant use such as coffee or tea. The physical examination will reveal findings associated with medical disorders that possibly contribute to sleep disorders such as macroglossia, micrognathia, mandibular abnormalities, neck circumference, finger clubbing, absent tendon reflexes, or lymph node swelling.
Sleep architecture and sleep organization may be affected in a variety of medical conditions. Patients may present with either insomnia or hypersomnia or both. Patients with insomnia may complain of difficulty initiating sleep or maintaining sleep, with repeated arousals at night or early morning awakening. Daytime symptoms include fatigue, lack of concentration, irritability, anxiety, or depression related to the sleep deprivation. Patients with hypersomnia may also present with fatigue, headache, depression, or cognitive complaints.
Addressing sleep-related symptoms by using screening sleep questionnaires such as the Epworth Sleepiness Scale or STOP-BANG is an additional step in the diagnostic approach. Sleep diaries over at least 1 to 2 weeks are helpful to examine sleep patterns of insomnia or circadian rhythm sleep-wake disorder for diagnosis and to monitor response to treatment.
Specific sleep disorders may require different diagnostic approaches. The diagnosis of sleep-disordered breathing is best substantiated by polysomnography with either in-laboratory or home sleep apnea testing. To assess functional daytime impairment of wakefulness, particularly in cases of professional drivers or pilots, a maintenance of wakefulness test may be useful and provide a benchmark for the effectiveness of treatment. Multiple sleep latency tests are useful for measuring excessive daytime sleepiness and diagnosing narcolepsy. For RLS/WED, diagnostic criteria may be fulfilled by history alone.
Patients with insomnia may show prolonged sleep latency on polysomnography, reduction of REM and slow-wave sleep, frequent arousals, frequent stage shifts, early morning awakenings, and increased percentage of wakefulness and stage N1 sleep. Patients with hypersomnia may exhibit polysomnographic findings that include sleep-disordered breathing, repeated arousals with oxygen desaturation at night, sleep fragmentation, sleep stage shifts, reduced slow-wave sleep, REM sleep abnormalities, and shortened sleep onset latency on the multiple sleep latency test.
Specific suspected underlying medical conditions require a tailored workup. Routine blood samples assessing the state of the underlying disorder are indicated in selected patients. These tests may include a basic metabolic panel, complete blood count, serum ferritin and iron studies, chest x-ray, arterial blood gas analysis, echocardiography, and pulmonary or cardiac function tests. A referral to an appropriate specialist to further diagnose and manage the medical or sleep disorder may be necessary.
The management of sleep disorders associated with medical conditions requires a multimodal approach. A priority for all patients with sleep disorders is the improvement of sleep hygiene. Sleep hygiene refers to actions that tend to improve and maintain good sleep. They include:
(1) Obtain the optimal amount of sleep to feel rested (usually 7 to 8 hours for adults, though individuals may require shorter or longer times) and then get out of bed.
(2) Maintain a regular sleep schedule, particularly a regular wake-up time in the morning.
(3) Try not to force sleep.
(4) Avoid caffeinated beverages after lunch.
(5) Avoid alcohol near bedtime (eg, late afternoon and evening).
(6) Avoid smoking or other nicotine intake, particularly during the evening.
(7) Adjust the bedroom environment as needed to decrease stimuli (eg, reduce ambient light, turn off the television or radio).
(8) Avoid prolonged use of light-emitting screens (laptops, tablets, smartphones, e-books) before bedtime.
(9) Resolve concerns or worries before bedtime.
(10) Exercise regularly for at least 20 minutes, preferably more than 4 to 5 hours prior to bedtime.
(11) Avoid daytime naps, especially if they are longer than 20 to 30 minutes or occur late in the day.
(12) Limiting the use of bedroom for activities other than sleep and sex.
For those with chronic insomnia, psychological and behavioral interventions are considered first-line in the standard of care. Strategies may include sleep restriction or sleep compression therapy, mindfulness-based therapies, guided imagery, scheduled worry, progressive muscle relaxation, and others (45).
Pharmacologic treatment should be used as a supplement to this whenever possible and is only recommended for short-term use. Preferably, benzodiazepines should be considered only after other classes of hypnotics unless there are contraindications to these other options or if the benzodiazepine is also managing another disorder such as anxiety or parasomnia.
Medications or classes of medications that are approved to treat insomnia in the short-term include benzodiazepines, nonbenzodiazepine hypnotics, melatonin agonists, doxepin, and orexin antagonists (193; 132; 164).
For patients with sleep-onset insomnia, a short-acting medication (duration of effect ≤ 8 hours) is a reasonable choice, like zaleplon, zolpidem, triazolam, lorazepam, and ramelteon. For patients with sleep-maintenance insomnia, a longer-acting medication is a preferable choice, such as zolpidem extended-release, eszopiclone, temazepam, estazolam, low-dose doxepin, suvorexant, and lemborexant. For patients with awakening in the middle of the night, both zaleplon and a specific sublingual tablet form of zolpidem have been developed for use during the night, with the constraint that there will be at least 4 hours of time in bed remaining after administration.
Another key consideration should be the identification and possible modification of medications causing side effects that contribute to disturbed nocturnal sleep. Many sleep-related issues such as pain control, sleep hygiene, and nocturnal manifestation of the medical disease such as gastric reflux or nocturnal asthma do not necessarily require initial extensive workup and may improve with symptomatic treatment.
Depending on the underlying medical condition, a tailored treatment plan should address, for example, the management of nocturnal pain. It is often observed that cancer patients do not receive adequate analgesics to control their nocturnal symptoms, causing significant sleep fragmentation resulting in daytime sleepiness, reduced concentration, or depression. The main goal in these cancer patients is optimal pain control with medications or adjunctive treatment. In chronic pain patients without malignancy, analgesic medications, antiepileptics, or tricyclic antidepressants may be considered. Medication management can be complemented by non-pharmacological treatments, such as physical therapy, cognitive behavioral therapy, light, or alternative methods such as acupuncture.
Sleep-related breathing disorders often require polysomnography for evaluation of sleep apnea. Treatment for sleep apnea generally focuses on the judicious use of positive airway pressure, surgery, or oral appliances. In patients with obesity, weight loss is critical and can be curative in some patients. In selected patients, hypoglossal nerve stimulation may also be an option. A major difficulty is the reluctance of patients to add a medical technology (continuous positive airway pressure) to their lives. There have been observations that treatment of underlying medical conditions can substantially improve sleep apnea, such as following renal transplantation or treatment of acromegaly.
Pharmacologic therapy is the mainstay treatment for RLS/WED. First-line treatment for restless legs syndrome consists of α2δ ligands, including gabapentin enacarbil, gabapentin, and pregabalin. Although evidence exists for all 3 of these options, only gabapentin enacarbil has been approved for the treatment of restless legs syndrome. Gabapentin enacarbil is generally well tolerated, with self-limited side effects of dizziness and somnolence (57).
Nonergot dopamine agonists like pramipexole, ropinirole, and rotigotine are the next line of treatment and are effective. They are typically well-tolerated, and side effects are self-limited with cessation of drug therapy. Restless legs syndrome patients treated with dopamine agonists may develop dopamine dysregulation syndrome. These patients may exhibit an addictive pattern of dopamine replacement therapy use and/or behavioral disturbances including impulse control disorders such as pathologic gambling, compulsive shopping, compulsive eating, and hypersexuality. Additionally, patients may develop augmentation, particularly on dopaminergic therapy. Augmentation is a worsening of RLS/WED symptoms, with earlier onset of symptoms in the daytime and spread to other parts of the body such as the hands and arms. This complication is dose-dependent and reversible with taper or discontinuation of the offending agent.
Although ergot-derived dopamine agonists like pergolide and cabergoline are considered effective in the treatment of restless legs syndrome/WED, pergolide was withdrawn in the United States because of the risk of cardiac valvulopathy. The risk of valvular heart disease is also present with cabergoline, thus it is only recommended when other agents have been tried first and failed, and close clinical follow-up is provided.
Opioids have been used for severe, treatment-resistant cases of RLS/WED. However, opioids carry the risk of abuse potential and exacerbation of sleep apnea.
Given that brain iron deficiency, which can be due to low peripheral iron stores, is a feature of restless legs syndrome pathophysiology, iron supplementation is a recommended treatment in those with low ferritin levels. Oral iron supplementation should be started if the ferritin level is less than 75 μg/L. If oral iron is not tolerated or unable to replete the iron stores, intravenous formations of iron replacement therapy should be considered (07).
Patients with end-stage renal disease may benefit from gabapentin or pregabalin, at lower doses, after each hemodialysis session or intravenous iron dextran during dialysis. Intradialytic exercise and cool dialysate may also be helpful (194; 30).
There is also insufficient evidence for the use of nonpharmacological therapy for RLS/WED. One study on pneumatic compression devices has shown some self-reported benefits (194).
Numerous medical conditions require stays in hospital intensive care units (ICUs), which involve environmental stimuli known to cause fragmented night sleep. Earplugs and eye masks promote sleep and melatonin balance in healthy subjects exposed to simulated ICU noise and light, making their promotion in ICU patients reasonable (79).
When a medical condition is presumed to contribute to disturbed sleep, management of the primary disease may be helpful in ameliorating the sleep disorder, although limited evidence exists for this. Occasionally, sleep apnea syndrome in end-stage renal disease is reversed after kidney transplantation. Clinically, it often appears that quality of life improves with treatment for sleep apnea, but long-term follow-up studies have not systematically addressed these issues. In chronic heart failure patients with sleep disordered breathing, cardiac resynchronization therapy led to a reduction of central sleep apnea and to increased sleep quality (172).
Treatment of a primary sleep disorder may also impact medical conditions. This has most often been studied in obstructive sleep apnea. Several studies have demonstrated that treatment of obstructive sleep apnea with continuous positive airway pressure is associated with improvements in hypertension (162), glycemic control (125), dyslipidemia (134), and possibly mortality (43).
The spectrum of association between pregnancy and sleep and awake disturbances ranges from an increased incidence of insomnia, nocturnal awakenings, sleep-disordered breathing, excessive sleepiness, and especially RLS/WED. Although the timing and occurrence of different sleep disorders varies, they are most prevalent during the third trimester. Pregnancy may also affect an existing sleep disorder. Particular attention may be given to obese pregnant women who would gain more weight during pregnancy or those who develop hypertensive conditions. Care should be taken when addressing insomnia in this population as sedative-hypnotics may increase the risk of fetal malformations if used during the first trimester.
Pregnancy increases the risk of obstructive sleep apnea, occurring in about 15% to 50% of obese pregnant women and is more common later in pregnancy (44; 61; 94). The mother goes through various physiological changes, including increases in blood volume, adipose tissue mass, and edema contributing to upper airway narrowing. In addition, changes in thoracoabdominal compliance elevate the diaphragm, causing reduction in functional residual capacity (128). These changes cause severity of sleep-disordered breathing to increase from the first to third trimester (147). A diagnosis of sleep-disordered breathing may increase the likelihood of pregnancy being labeled as “high-risk,” with increased risk of preeclampsia-eclampsia (91) and potentially other maternal complications such as chorioamnionitis, postpartum hemorrhage, venous thromboembolism, cardiovascular complications, and maternal death (148).
Sleep disruption in pregnancy also increases the risk of gestational diabetes. During pregnancy, Asian women with poor sleep quality or short nocturnal sleep duration exhibited abnormal glucose regulation (22). Short and long sleep duration also appears to be associated with a higher risk of gestational diabetes (200). Obstructive sleep apnea may also increases the risk of gestational diabetes (51; 61; 136). Treatment of obstructive sleep apnea in pregnant patients with gestational diabetes using continuous positive airway pressure did not improve glucose levels but did improve insulin secretion and may improve pregnancy outcomes (33).
Patients with obstructive sleep apnea are vulnerable during anesthesia and sedation as the effects of loss of wakefulness are compounded by drug-induced depression of muscle activity and altered arousal responses. Patients at high risk of obstructive sleep apnea are more likely to require repeated attempts at intubation (142). Patients with obstructive sleep apnea require special attention of the airway maintenance, influencing intra- and postoperative care. Difficulty with airway maintenance during anesthesia may prompt further investigation for the possibility of obstructive sleep apnea. Furthermore, obstructive sleep apnea is associated with a higher risk of perioperative complications (141; 64), though a study did not see a higher rate of postoperative complication after high-risk surgery (196). Patients undergoing elective surgeries should be screened for obstructive sleep apnea, such as with the STOP-BANG, and evaluated and treated accordingly (135). Alternatives could include monitored anesthesia care, peripheral nerve blocks, or neuraxial anesthesia.
Additional strategies to minimize airway problems during monitored anesthesia include:
(1) Consider infusion at the lowest effective doses rather than bolus dosing of sedatives or opioids to decrease episodic respiratory depression.
(2) Use short-acting sedatives/opioids (eg, propofol, remifentanil) to minimize carryover into the postoperative period.
(3) Avoid or minimize muscle relaxants and monitoring or reversing neuromuscular blocking drugs prior to extubation.
(4) Use sedatives without respiratory depression (eg, dexmedetomidine).
(5) Use airway positioning to relieve obstruction, such as sniffing position (lower cervical flexion, upper cervical extension) or jaw thrust.
(6) Use an oral or nasopharyngeal airway.
(7) Consider continuous positive airway pressure for patients who have obstructive sleep apnea.
Roneil Gopal Malkani MD MS
Dr. Malkani of Northwestern University Feinberg School of Medicine has no relevant financial relationships to disclose.See Profile
Alexander J Choi MD MPH
Dr. Choi of McGaw Medical Center of Northwestern University Feinberg School of Medicine has no relevant financial relationships to disclose.See Profile
Federica Provini MD
Dr. Provini of the University of Bologna and IRCCS Institute of Neurological Sciences of Bologna received speakers' fees from Italfarmaco and Pfizer.See Profile
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