Sleep and medical disorders
A number of different medical disorders and diseases, from a common cold to cancer, frequently alter an individual’s sleep-wake cycle. These sleep problems often result from pain or infection associated with the primary condition. Although these are both known to cause problems with sleep-wake cycles, as will be shown below, very little is still known about the etiology.
Pain is described as an acute or chronic unpleasant sensory and emotional experience that varies from dull discomfort to unbearable agony that is associated with actual or potential tissue damage.
It commonly causes sleep fragmentation and changes in an individual’s sleep architecture. The symptoms depend on the type and severity of the pain. They include day-time fatigue and sleepiness, poor sleep quality, delay in sleep onset, and decreased cognitive and motor performance (Bonnet and Arand, 2003).
Chronic pain affects at least 10 percent of the general adult population (Harstall, 2003), of whom 50 percent complain of poor sleep (Atkinson et al., 1988; Dao et al., 1994; Morin et al., 1998; Roizenblatt et al., 2001; Riley et al., 2001; Dauvilliers and Touchon, 2001; McCracken and Iverson, 2002; Perlis et al., 2005), and 44 percent complain of insomnia (Moldofsky, 2001). There are a number of clinical pain conditions that individuals report affect their sleep quality—RLS, irritable bowel, gastric ulcer, cancer, musculoskeletal disorders, dental and orofacial pain, spinal cord damage, burns, and other trauma (Lavigne et al., 2005).
Although progress has been made, there are still many unanswered questions about how pain affects regions of the brain responsible for regulating the sleep-wake cycle. Neurons that carry pain information to the brain do communicate with regions of the brain that are responsible for arousal— raphe magnus “off” cells (Foo and Mason, 2003). However, it is not known if hypocretin and other genes that regulate the circadian rhythms are affected by acute or chronic pain. Further, it is not known whether the hypothalamus, which is involved in sleep homeostasis, is affected by chronic pain (Kshatri et al., 1998; Mignot et al., 2002b). Because little is known about the interaction between pain and the circuitry in the brain that is responsible for regulating the sleep-wake cycle, much of the management of sleep problems focuses on managing and alleviating the pain or sleep quality.
Selected Sleep-Related Symptoms and Findings in the Presence of Pain
• Delay in sleep onset
• Anxiety, rumination
• Intense fatigue and more intense pain
Sleep time findings
• Lower sleep efficacy (less than 90%)
• Longer percentage sleep time in stage 1, with less in stages 3 and 4
• Numerous sleep stage shifts (stages 3 and 4 toward stages 2 or 1)
• Fragmentation of sleep continuity (increase in number of microarousals, awakenings,
sleep stage shifts, respiratory events, movement intrusions)
• Alpha electroencephalographic intrusions in stages 3 and 4 with or without elevated
phasic arousals (cyclic alternating pattern)
• Absence of reduction in heart rate variability in sleep (cardiac sympathetic
• Nightmares, periodic leg movements, apnea, sweating, heart palpitations
• Wake time in sleep with pain (e.g., neck, lower back, visceral, tooth)
Wake time symptoms
• Unrefreshing sleep sensation, fatigue, headache, etc.
• Sleepiness if driving
• Anxiety and anger over fulfilling daytime requirements at home or work
Infections caused by bacterial strains, viruses, and parasites may result in changes to sleep patterns. Although it is accepted that the activity of the immune system affects an individual’s sleep-wake cycle, very little is known about how these two systems interact. This is complicated by the unique effects that specific infections have on sleep patterns and the absence of a large body of clinical research.
Bacterial Infections and Sleep
Bacterial infections typically cause an increase in the total time spent in SWS and a decreased duration of REM sleep (Toth, 1999; Toth and Opp, 2002). Alterations of sleep patterns can be affected by the type of bacterial infection (Opp and Toth, 2003). For example, gram-negative bacteria induce enhanced sleep more rapidly than do gram-positive bacteria. Differences in the process and progression of the disease also affect the sleep-wake cycle.
Viral Infections and Sleep
Viral infections also have effects on the sleep-wake cycle. Individuals inoculated with rhinovirus or influenza virus report less sleep during the incubation period, while during the symptomatic period they slept longer (Smith, 1992). However, compared to healthy individuals there were no reported difference in sleep quality and number of awakenings.
The human immunodeficiency virus (HIV) also has been shown to alter sleep patterns. Individuals spend increased time in SWS during the second half of night (Darko et al., 1995) and suffer from frequent arousals and decreased time in REM sleep (Norman et al., 1990). As the infection progresses to AIDS, individuals develop increased sleep fragmentation, significant reductions in SWS, and disruption to the entire sleep architecture (Norman et al., 1990; Darko et al., 1995).
Many patients with cancer also suffer pain or depression, which con-tributes to difficulty sleeping. These require treatment as in other patients with pain or depression as causes of insomnia. Excessive sleepiness may be caused by injury to the ascending arousal system due to brain metastases or by leptomeningeal carcinomatosis. These signs often alert physicians to the need to treat the underlying spread of cancer to the central nervous system. Other patients with cancer may develop antitumor antibodies that attack the brain. In particular, anti-Ma-2 antibodies tend to cause hypothalamic lesions and may precipitate daytime sleepiness and even cataplexy (Rosenfeld et al., 2001). Treatment of the underlying cancer may reverse the symptoms in some cases.
Fungal and parasitic infections also can alter the sleep-wake cycle. For example, sleeping sickness, or African trypanosomiasis, commonly occurs in individuals who have been infected with the Trypanosoma brucei (Tb) parasite. It is characterized by episodes of nocturnal insomnia and daytime sleep, but not hypersomnia (Lundkvist et al., 2004). Sleeping sickness is found primarily in sub-Saharan African countries, where Tb is transmitted to humans as a result of bites received from tsetse flies (Lundkvist et al., 2004). The prevalence of this disorder is not known; however, over 60 million people live in areas where the Tb parasite is endemic.
Sleeping sickness is associated with altered sleep architecture. EEG recordings of individuals with sleeping sickness from Gambia demonstrate periods of REM sleep that occur throughout the entire sleep-wake cycle, frequently without normal intermediate NREM periods (Buguet et al., 2001). Circadian fluctuations of hormones—cortisol, prolactin, and growth hormone—are also altered in individuals with sleeping sickness (Radomski et al., 1994). Therefore, it has been hypothesized that sleeping sickness may be a circadian rhythm disease that affects the neural pathways that inter-connect the circadian-timing and sleep-regulating centers (Lundkvist et al., 2004).
Treatment Effects on Sleep
Numerous medical conditions are associated with a wide variety of sleep disorders including insomnia, hypersomnia, parasomnias, and sleep-related movement disorders. Although these disease-related sleep disorders have recently been receiving an increasing amount of attention, including addition to the latest International Classification of Sleep Disorders (AASM, 2005), the contribution that treatments for these medical conditions make to the development of sleep disturbances is less well appreciated. However, many medical therapies have iatrogenic effects on sleep-wake regulatory systems causing disturbed sleep, daytime sleepiness, and other related side effects.
Treatments for Cardiovascular Disease
Cardiovascular diseases, sometimes associated with sleep-related breathing disorders (Peters, 2005), are commonly treated with a wide range of medications including antihypertensives, hypolipidemics, and antiarrhythmics; each class of medication can adversely affect sleep and/or waking. For example, beta-antagonists, the mainstay of treatment for hypertension, are commonly associated with fatigue, insomnia, nightmares, and vivid dreams (McAinsh and Cruickshank, 1990). Sleep disturbances appear to be more severe with lipophilic drugs (e.g., propranolol) than with hydrophilic drugs (e.g., atenolol). However, even atenolol, one of the most hydrophilic beta-blockers, has been shown to increase total wake time (Van Den Heuvel et al., 1997). The mechanism underlying sleep disruption by beta-blocking agents may be their tendency to deplete melatonin, an important sleep-related hormone (Garrick et al., 1983; Dawson and Encel, 1993).
Fatigue and somnolence have also been reported with other antihypertensive medications such as carvedilol, labetalol, clonidine, methyldopa, and reserpine (Paykel et al., 1982; Miyazaki et al., 2004). In contrast, angiotensin-converting enzyme inhibitors generally have very few effects on sleep (Reid, 1996). Hypolipidemic drugs, including atorvastatin and lovastatin, have also been associated with reports of insomnia, but placebo-controlled clinical trials of lovastatin, simvastatin, and pravastatin did not appear to increase sleep disturbance (Bradford et al., 1991; Keech et al., 1996).
Amiodarone, a widely use antiarrhythmic agent (Hilleman et al., 1998), can cause nocturnal sleep disturbance, and digoxin has been associated with both insomnia and daytime fatigue (Weisberg et al., 2002).
Treatments for Cancer
Patients with cancer receive multiple types of treatments designed at controlling the disease process including chemotherapy, biotherapy, radio-therapy, and medications. All can have important adverse effects on regulating the sleep-wake cycle. For example, sleep problems have been reported in patients undergoing chemotherapy (Broeckel et al., 1998; Berger and Higginbotham, 2000; Lee et al., 2004). However, objective measures of sleep in the patients and analyses of clinical correlates are very limited.
Thus, the mechanisms underlying these sleep problems are poorly under-stood. Menopausal symptoms arising from chemotherapy and hormonal therapy, especially those of a vasomotor type (e.g., hot flashes, sweating), may be a contributing factor (Rombaux et al., 2000; Mourits et al., 2001; Carpenter et al., 2002). Nocturnal sleep disturbances and daytime sleepiness have also been reported in patients undergoing radiotherapy (Beszterczey and Lipowski, 1977; Miaskowski and Lee, 1999).
Cytokines (biotherapy), a diverse group of peptide molecules that regulate cell functions, are sometimes used as adjunct therapy (Dunlop and Campbell, 2000). Interferon, interleukin-2, and tumor necrosis factor are associated with a variety of side effects including daytime sleepiness, disturbed sleep, and depression (Capuron et al., 2000). Although very effective in reducing cancer-related pain, opioids often cause sleep disturbance and are associated with decreased REM and SWS (Cronin et al., 2001).
Treatments for Renal Disease
RLS, periodic limb movement disorder, sleep apnea, and excessive day-time sleepiness affect up to 70 percent of patients with end-stage renal dis-ease receiving treatment with hemodialysis (Parker et al., 2000; Parker, 2003). Hemodialysis may alter biological systems controlling processes that regulate the sleep-wake cycle via several potential mechanisms. The rapid fluid, electrolyte, and acid/base changes that occur are often associated with central nervous system symptoms such as headache, restlessness, changes in arousal, and fatigue during or immediately after treatment. Several studies have reported an increase in cytokine production secondary to blood inter-actions with bioincompatible aspects of hemodialysis (such as blood exposure to membranes, tubing, and cellular mechanical trauma) and backflow of endotoxins through the membrane (Panichi et al., 2000).
Interleukin-1, tumor necrosis factor-α, and interleukin-6 are the major proinflammatory cytokines that may be involved (Pertosa et al., 2000). These substances have both somnogenic and pyrogenic properties and have been linked to a number of postdialytic symptoms (Konsman et al., 2002), including day-time sleepiness and sleep disturbances (Raison and Miller, 2001; Capuron et al., 2002). Dialysis-associated changes in melatonin levels and pattern of secretion and alterations in body temperature rhythm may also play a role in disrupting circadian systems (Vaziri et al., 1993, 1996; Parker et al., 2000; Parker, 2003).
Treatments for Rheumatologic and Immunologic Disorders
Numerous other classes of medications can alter sleep and waking. Corticosteroids are a class of medications that are used to treat a variety of medical conditions including rheumatologic and immunologic disorders, cancer, and asthma. Sleep disturbances, insomnia, daytime hyperactivity, and mild hypomania are common side effects (Wolkowitz et al., 1990); a significant decrease in REM sleep may also occur (Born et al., 1987). Theophylline, a respiratory stimulant and bronchodilator, is in the same class of medications as caffeine and can likewise disturb sleep—even in healthy subjects (Kaplan et al., 1993). Nonsteroidal anti-inflammatory agents may also affect sleep as they decrease the production of sleep-promoting prostaglandins, suppress normal surge of melatonin, and alter the daily rhythm of body temperature (Murphy et al., 1994, 1996). Pseudoephedrine and phenylpropanolamine, which have many of the same pharmacological properties of ephedrine, also cause sleep disruption—and many of these preparation are readily available over the counter (Lake et al., 1990; Bertrand et al., 1996).
Although the medications and treatments listed above are often necessary, it is essential for patients to be aware of potential side effects relating to the sleep-wake-related cycle. Unfortunately, patients often neglect to report such complaints as they think nothing can be done to alleviate the problems. However, numerous behavioral and pharmacological interventions are available to treat these iatrogenically induced problems with the sleep-wake cycle. In addition, administering treatment or medications at appropriate times of day in relationship to the sleep-wake schedule may potentially be beneficial and enhance clinical outcomes (Levi, 1994; Bliwise et al., 2001; Hermida and Smolensky, 2004). Research in this area is greatly needed.
Shift Work Disorder and Jet Lag
Shift Work Disorder
Shift work type circadian rhythm sleep disorder is characterized by complaints of insomnia or excessive sleepiness resulting from work hours that occur during the normal sleep period, including, night shifts, early morning shifts, and rotating shifts. Total sleep time is normally reduced by 1 to 4 hours and sleep quality is disturbed. During work shifts individuals can experience excessive sleepiness, reduced alertness, and reduced performance capacity. Individuals are also commonly more irritable, and the disorder may have negative social consequences. The condition is closely linked to work schedules; consequently, it abates in response to a conventional sleep schedule.
Jet lag type is a temporary circadian rhythm sleep disorder that occurs when there is a transitory mismatch between the timing of the sleep-wake cycle caused by a change in time zone. Individuals with jet lag potentially experience disturbed sleep, decreased subjective alertness, general malaise, somatic symptoms such as gastrointestinal disturbance, and impaired daytime function. The severity and the duration of the symptoms are usually dependent on the number of time zones traveled and the direction of travel—eastern travel and travel through multiple time zones typically result in worse symptoms than western travel.