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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem 3 Extent and Health Consequences of Chronic Sleep Loss and Sleep Disorders CHAPTER SUMMARY It is estimated that 50 to 70 million Americans chronically suffer from a disorder of sleep and wakefulness, hindering daily functioning and adversely affecting health and longevity. There around 90 distinct sleep disorders; most are marked by one of these symptoms: excessive daytime sleepiness, difficulty initiating or maintaining sleep, and abnormal events occurring during sleep. The cumulative long-term effects of sleep loss and sleep disorders have been associated with a wide range of deleterious health consequences including an increased risk of hypertension, diabetes, obesity, depression, heart attack, and stroke. After decades of research, the case can be confidently made that sleep loss and sleep disorders have profound and widespread effects on human health. This chapter focuses on manifestations and prevalence, etiology and risk factors, and comorbidities of the most common sleep conditions, including sleep loss, sleep-disordered breathing, insomnia, narcolepsy, restless legs syndrome, parasomnias, sleep-related psychiatric disorders, sleep-related neurological disorders, sleep-related medical disorders, and circadian rhythm sleep disorders.
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem Sleep loss and sleep disorders are among the most common yet frequently overlooked and readily treatable health problems. It is estimated that 50 to 70 million Americans chronically suffer from a disorder of sleep and wakefulness, hindering daily functioning and adversely affecting health and longevity (NHLBI, 2003). Questions about sleep are seldom asked by physicians (Namen et al., 1999, 2001). For example, about 80 to 90 percent of adults with clinically significant sleep-disordered breathing remain undiagnosed (Young et al., 1997b). Failure to recognize sleep problems not only precludes diagnosis and treatment—it also precludes the possibility of preventing their grave public health consequences. The public health consequences of sleep loss and sleep-related disorders are far from benign. The most visible consequences are errors in judgment contributing to disastrous events such as the space shuttle Challenger (Walsh et al., 2005). Less visible consequences of sleep conditions are far more prevalent, and they take a toll on nearly every key indicator of public health: mortality, morbidity, performance, accidents and injuries, functioning and quality of life, family well-being, and health care utilization. Some of these consequences, such as automobile crashes, occur acutely within hours (or minutes) of the sleep disorder, and thus are relatively easy to link to sleep problems. Others—for example, obesity and hypertension—develop more insidiously over months and years of chronic sleep problems. After decades of research, the case can be confidently made that sleep loss and sleep disorders have profound and widespread effects on human health. Although there are around 90 distinct sleep disorders, according to the International Classification of Sleep Disorders (AASM, 2005), most are marked by one of these symptoms: excessive daytime sleepiness, difficulty initiating or maintaining sleep, or abnormal movements, behaviors, and sensations occurring during sleep. The cumulative effects of sleep loss and sleep disorders have been associated with a wide range of deleterious health consequences including an increased risk of hypertension, diabetes, obesity, depression, heart attack, and stroke. This chapter focuses on the most common sleep conditions, including sleep loss, sleep-disordered breathing, insomnia, narcolepsy, restless legs syndrome (RLS), parasomnias, sleep-related psychiatric disorders, sleep-related neurological disorders, sleep-related medical disorders, and circadian rhythm sleep disorders. The manifestations and prevalence, etiology and risk factors, and comorbidities for each condition are briefly described. There is a large body of data on these disorders, in part because they encompass the most frequently cited sleep disorders or they carry the greatest public health burden. As such, the committee chose to focus primarily on these disorders.
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem SLEEP LOSS Manifestations and Prevalence Sleep loss generally, in adults, refers to sleep of shorter duration than the average basal need of 7 to 8 hours per night. The main symptom of sleep loss is excessive daytime sleepiness, but other symptoms include depressed mood and poor memory or concentration (Dinges et al., 2005). Chronic sleep loss, while neither a formal syndrome nor a disorder, has serious consequences for health, performance, and safety, as described in Chapter 4. Sleep loss is a highly prevalent problem that continues to worsen in frequency as individuals grow older. Recent studies find that at least 18 percent of adults report receiving insufficient sleep (Liu et al., 2000; Kapur et al., 2002; Strine and Chapman, 2005). Historically, there have been a limited number of nationally representative surveys that provide reliable data on sleep patterns in the population. The National Health Interview Survey (NHIS), run by the Centers for Disease Control and Prevention (CDC) (see Chapter 5), included the following question in the 1977, 1985, 1990 cycles: “On average how many hours of sleep do you get a night (24-hour period)?” The same question was added to the core NHIS questionnaire in 2004. Based on these data, it has been estimated that the percentage of men and women who sleep less than 6 hours has increased significantly over the last 20 years (Figure 3-1) (CDC, 2005). More than 35 years ago, adults reported sleeping 7.7 hours per night (Tune, 1968). Adolescents also frequently report receiving insufficient sleep. Contrary to public perceptions, adolescents need as much sleep as preteens. A large survey of over 3,000 adolescents in Rhode Island found that only 15 percent reported sleeping 8.5 or more hours on school nights, and 26 percent reported sleeping 6.5 hours or less (Wolfson and Carskadon, 1998). The optimal sleep duration for adolescents, about 9 hours per night, is based on research about alertness, sleep-wake cycles, hormones, and circadian rhythms (Carskadon et al., 2004). Among adolescents, extensive television viewing and growing social, recreational, and academic demands contribute to sleep loss or sleep problems (Wolfson and Carskadon, 1998; Johnson et al., 2004). Etiology and Risk Factors The causes of sleep loss are multifactoral. They fall under two major, somewhat overlapping categories: lifestyle/occupational (e.g., shift work,1 1 The term “shift work” is defined by regular employment outside of the normal day work hours of 7:00 a.m. to 6:00 p.m.
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem FIGURE 3-1 Percent of adults in the United States who usually slept 6 hours or less a night. SOURCE: CDC (2005). prolonged working hours, jet lag, irregular sleep schedules2), and sleep disorders (e.g., insomnia, sleep-disordered breathing, RLS, narcolepsy, and circadian rhythm disorders). Unfortunately, available epidemiological data are not sufficient to determine the extent to which sleep loss is caused by pathology versus behavioral components. The increase in sleep loss is driven largely by broad societal changes, including greater reliance on longer work hours, shift work, and greater access to television and the Internet. About 20 percent of workers are engaged in some kind of shift work (Monk, 2005), of whom there is a growing number of night shift workers suffering chronic sleep loss and disruption of circadian rhythms (Harma et al., 1998; Drake et al., 2004). One indication of the growing trend is the number of adults departing for work between midnight and 5:30 a.m.; that number has grown, over a 10-year period, by 24 percent (United States Census Bureau, 1990). A greater prevalence of insomnia also may contribute to the rise in sleep loss, but probably to a lesser extent than do occupational or lifestyle 2 Irregular sleep schedules frequently include significant disparities between sleep on week-days and weekends, which contribute to shifts in sleep phase and sleep problems.
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem changes. Adults are sleeping less to get more work accomplished and are staying up later to watch television or use the Internet (NSF, 2005b). Sleep Loss Affects Health In the past 10 or more years, research has overturned the dogma that sleep loss has no health effects, apart from daytime sleepiness. The studies discussed in this section suggest that sleep loss (less than 7 hours per night) may have wide-ranging effects on the cardiovascular, endocrine, immune, and nervous systems, including the following: Obesity in adults and children Diabetes and impaired glucose tolerance Cardiovascular disease and hypertension Anxiety symptoms Depressed mood Alcohol use Many of the studies find graded associations, insofar as the greater the degree of sleep deprivation, the greater the apparent adverse effect (although the difference may not reach statistical significance). Another common finding is the relationship that adverse effects occur with either short or long sleep duration, as compared to a sleep time of 7 to 8 hours. This type of association is often described as a U-shaped relationship. It should be noted, however, that the majority of these studies are observational in nature, and thus definite causal inferences cannot be made. The associations observed in some studies might be subject to different types of biases, such as temporal (or “reverse causality”) bias, whereby sleep loss might be a manifestation or a symptom of the disease in question. The latter is most likely in cross-sectional studies but could also affect associations observed in cohort studies, particularly when they are relatively short term and/or when the disease under investigation has a long preclinical phase. In the discussion that follows, and wherever possible, potential physiological mechanisms behind epidemiological associations and that support the plausibility of a true causal relationship are noted. Sleep Loss Is Associated with Obesity When a person sleeps less than 7 hours a night there is a dose-response relationship between sleep loss and obesity: the shorter the sleep, the greater the obesity, as typically measured by body mass index (BMI)—weight in kilograms divided by height in meters squared. Although most studies were cross-sectional, one prospective study was a 13-year cohort study of nearly
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem 500 adults. By age 27, individuals with short sleep duration (less than 6 hours) were 7.5 times more likely to have a higher body mass index, after controlling for confounding factors such as family history, levels of physical activity, and demographic factors (Hasler et al., 2004). Another study, a large population-based study of more than 1,000 adults, found a U-shaped relationship between sleep duration, measured by polysomnography, and BMI (Figure 3-2). Adults who slept 7.7 hours had the lowest BMI; those with shorter and longer sleep duration had progressively higher BMI. The U-shaped association also applies to other health outcomes, such as heart attacks. The impact of sleep loss diminishes with age. The study also sought to investigate physiological mechanisms behind the relationship between sleep duration and BMI. Measuring two appetite-related hormones, the study found that sleep insufficiency increased appetite. Sleep insufficiency was associated with lower levels of leptin, a hormone produced by an adipose tissue hormone that suppresses appetite, and higher levels of ghrelin, a peptide that stimulates appetite (Taheri et al., 2004). Another study—a small randomized, cross-over clinical trial—also found that sleep restriction was associated with lower leptin and higher ghrelin levels (Spiegel et al., 2004). The findings suggest that a hormonally mediated increase in appetite may help to explain why short sleep is related to obesity. Several mediating mechanisms have been proposed, including effects of sleep deprivation on FIGURE 3-2 Curvilinear relationship between BMI and average nightly sleep. SOURCE: Taheri et al. (2004).
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem the sympathetic nervous system and/or hypothalamic hormones (Spiegel et al., 2004), which also influence appetite. Obesity also contributes to obstructive sleep apnea (OSA). This most likely occurs through fat deposition in airways, causing them to narrow. This point is inferred from studies finding that large neck size is a better predictor of OSA than is BMI (Katz et al., 1990) and the finding that central obesity (obesity around the waist) is a better predictor of OSA than total obesity (Grunstein, 2005b). The relationship has been found in well-designed epidemiological studies of young children (Locard et al., 1992; Sekine et al., 2002; von Kries et al., 2002) and adults (Vioque et al., 2000; Kripke et al., 2002; Gupta et al., 2002; Taheri et al., 2004; Hasler et al., 2004). Taken as a whole, the body of evidence suggests that the serious public health problem of obesity may continue to grow as sleep loss trends continue to worsen. It also suggests that addressing obesity will likely benefit sleep disorders, and treating sleep deprivation and sleep disorders may benefit individuals with obesity (Taheri et al., 2004). Sleep Loss Is Associated with Diabetes and Impaired Glucose Tolerance Two large epidemiological studies and one experimental study found an association between sleep loss and diabetes, or impaired glucose tolerance. Impaired glucose tolerance, which is a precursor to diabetes, is manifested by glucose levels rising higher than normal and for a longer period after an intravenous dose of glucose. In the Sleep Heart Health Study, which is a community-based cohort, adults (middle-aged and older) who reported 5 hours of sleep or less were 2.5 times more likely to have diabetes, compared with those who slept 7 to 8 hours per night (Figure 3-3, [Gottlieb et al., 2005]). Those reporting 6 hours per night were about 1.7 times more likely to have diabetes. Both groups were also more likely to display impaired glucose tolerance. Adults with sleep times of 9 hours or more also showed these effects, a finding consistent with the Nurses Health Study. Adjustment for waist girth, a measure of obesity, did not alter the significance of the findings, suggesting that the diabetes effect was independent of obesity. The relationship between shorter sleep times and impaired glucose tolerance is also supported by an experimental study in which 11 healthy male volunteers were restricted to 4 hours of sleep for a total of six nights (Spiegel et al., 1999). Even after this relatively short period of time, the study found that sleep loss, compared with a fully rested state, led to impaired glucose tolerance. The effect resolved after restoring sleep to normal. Glucose clearance was 40 percent slower with sleep loss than with sleep recovery. Further, mice that have a mutation in a gene that regulates
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem FIGURE 3-3 Sleep duration impacts prevalence of diabetes. NOTE: Data were adjusted for age, sex, race, waist girth, caffeine, alcohol, smoking, and apnea-hypopnea index. SOURCE: Gottlieb et al. (2005). circadian rhythms have metabolic disorders (Turek et al., 2005). The association between sleep loss and diabetes or impaired glucose tolerance may mediate the relationship between sleep loss and cardiovascular morbidity and mortality, as discussed below. Sleep Loss Is Associated with Cardiovascular Morbidity Sleep loss and sleep complaints are associated with heart attacks (myocardial infarction) and perhaps stroke, according to several large epidemiological studies (Eaker et al., 1992; Qureshi et al., 1997; Schwartz et al., 1998; Newman et al., 2000; Ayas et al., 2003; Yaggi et al., 2005; Bradley et al., 2005; Caples et al., 2005) and one case-control study (Liu et al., 2002). One of these studies, of incident cases of heart attacks in the Nurses Health Study, was discussed earlier because it also found increased incidence of diabetes (Ayas et al., 2003). The cohort had no coronary heart disease at baseline. Ten years later, in 1996, the likelihood of nonfatal and fatal heart attack was modestly increased for both short and long sleep duration. Five hours of sleep or less was associated with a 45 percent increase in risk (odds ratio [OR] = 1.45, 95% confidence interval [CI], 1.10–1.92), after adjusting for age, BMI, smoking, and snoring. Similarly elevated risks were also found for sleeping 9 hours or more. The effects were independent of a history of hypertension or diabetes because additional adjustment for these
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem conditions yielded slightly lower, but still significantly elevated, relative risks. Several potential mechanisms could explain the link between sleep loss and cardiovascular events, including blood pressure increases, sympathetic hyperactivity, or impaired glucose tolerance. Experimental data, showing that acute sleep loss (3.6 hours sleep) for one night results in increased blood pressure in healthy young males, may provide a biological mechanism for the observed associations between sleep loss and cardiovascular disease (Tochikubo et al., 1996; Meier-Ewert et al., 2004). Sleep Loss, Mood, Anxiety, and Alcohol Use Sleep loss is associated with adverse effects on mood and behavior. Adults with chronic sleep loss report excess mental distress, depressive symptoms, anxiety, and alcohol use (Baldwin and Daugherty, 2004; Strine and Chapman, 2005; Hasler et al., 2005). A meta-analysis of 19 original articles found that partial sleep deprivation alters mood to an even greater extent that it does cognitive or motor functions (Pilcher and Huffcutt, 1996). Several studies of adolescents, including one with more than 3,000 high school students, found that inadequate sleep is associated with higher levels of depressed mood, anxiety, behavior problems, alcohol use (Carskadon, 1990; Morrison et al., 1992; Wolfson and Carskadon, 1998), and attempted suicide (Liu, 2004). Nevertheless, it is not clear from cross-sectional studies whether sleep influences mood or anxiety level, or vice versa. On the other hand, a large, 3-year longitudinal study of more than 2,200 middle school students (ages 11 to 14) found that self-reported sleep loss was associated with more depressive symptoms and lower self-esteem over time (Fredriksen et al., 2004). The study measured sleep loss using a single question about sleep duration on school nights and measured depressive symptoms and self-esteem by the Children’s Depressive Inventory and the Self-Esteem Questionnaire, respectively. Therefore, although this study suggests an association, the evidence is still limited. Sleep Loss and Disease Mortality Sleep loss is also associated with increased age-specific mortality, according to three large, population-based, prospective studies (Kripke et al., 2002; Tamakoshi et al., 2004; Patel et al., 2004). The studies were of large cohorts, ranging from 83,000 to 1.1 million people. In three studies, respondents were surveyed about their sleep duration, and then they were followed for periods ranging from 6 to 14 years. Deaths in short or long sleepers were compared with those who slept 7 hours (the reference group), after adjusting for numer-
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem ous health and demographic factors. Sleeping 5 hours or less increased mortality risk, from all causes, by roughly 15 percent. The largest American study, depicted in Figure 3-4, graphically illustrates what has been found in all three studies: a U-shaped curve, showing that progressively shorter or longer sleep duration is associated with greater mortality. Other epidemiological studies suggest that sleep-loss-related mortality is largely from acute heart attacks (Ayas et al., 2003). Potential pathophysiological mechanisms accounting for the relationship, while poorly understood, have become the focus of growing interest and are discussed later in this chapter. Management and Treatment Management and treatment of sleep loss are rarely addressed by clinicians, despite the large toll on society (Chapters 4, 5, and 7). There are no formal treatment guidelines in primary or specialty care for dealing with sleep loss (Dinges et al., 1999). The most effective treatment for sleep loss is to sleep longer or take a short nap lasting no more than 2 hours (Veasey et al., 2002), and to have a better understanding of proper sleep habits. Catching up on sleep on the weekends—a popular remedy for sleep loss—does not return individuals to baseline functioning (Szymczak et al., 1993; Dinges et al., 1997; Klerman and Dijk, 2005; Murdey et al., 2005). If extended work hours or shift work cannot be avoided, specific behavioral tips to stay alert are available (NSF, 2005c), as are such wake-promoting FIGURE 3-4 Shorter or longer sleep duration is associated with greater mortality. NOTE: Hazard ratio is an individual’s relative risk of dying compared to the general population, based upon average number of hours of sleep per night. SOURCE: Kripke et al. (2002).
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Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem medications as caffeine, modafinil, and sympathomimetic medications (direct and indirect acting), including pemoline and methylphenidate (Mitler and O’Malley, 2005). In a randomized clinical trial caffeine and modafinil showed similar benefits for performance and alertness (Wesensten et al., 2002). Modafinil is the only FDA-approved drug for shift work sleep disorder, although it is not approved for sleep loss. Behavioral approaches developed for insomnia also may be useful for sleep loss, but no formal studies have been undertaken expressly for sleep loss. Furthermore, there have been no large-scale clinical trials examining the safety and efficacy of modafinil, or other drugs, in children and adolescents. SLEEP-DISORDERED BREATHING Manifestations and Prevalence Sleep-disordered breathing refers to a spectrum of disorders that feature breathing pauses during sleep. The most common disorder is characterized by obstructive apneas and hypopneas (White, 2005), where repeated episodes of collapse (apneas) or partial collapse of the pharyngeal airway occur, usually a result of obstruction by soft tissue in the rear of the throat. Snoring, which is produced by vibrations of the soft tissues, is a good marker for OSA (Netzer, et al., 2003). Apneas or hypopneas (a reduction without cessation in airflow or effort) typically result in abrupt and intermittent reduction in blood oxygen saturation, which leads to sleep arousal, often accompanied by loud snorts or gasps as breathing resumes. Episodic interruptions of breathing also frequently cause cortical and brainstem arousals, interrupting sleep continuity, reducing sleep time, and causing increased sympathetic nervous system activation. These broad systemic effects on gas exchange and nervous system activation may lead to a range of systemic effects that affect vascular tone, levels of inflammatory mediators, and hormonal changes. As discussed in the following sections, these in turn may contribute to the development of hypertension, coronary artery disease, congestive heart failure, arrhythmias, stroke, glucose intolerance, and diabetes. The defining symptom of sleep-disordered breathing is excessive daytime sleepiness. The symptom is likely influenced by sleep fragmentation tied to recurrent arousals that occur in response to breathing pauses. Other symptoms of fragmented sleep include decreased concentration and mood changes. The diagnosis of OSA requires detection, by polysomnography, of at least five or more apneas or hypopneas per hour of sleep (Thorpy, 2005). This rate is expressed as an index, the apnea-hypopnea index (or respiratory disturbance index), which is the average hourly number of apneas plus hypopneas.
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Representative terms from entire chapter: