David N. Neubauer
Philip L. Smith III
Christopher J. Earley
Epidemiology and Overview
Increasingly, disorders of sleep and wakefulness are being recognized as pervasive throughout our society. The magnitude of the public health implications was emphasized in a report of the National Commission on Sleep Disorders Research (1). It noted that about 40 million Americans have chronic sleep–wake disorders, and that many of those people are undiagnosed and untreated. The report also emphasized the vital role of primary care physicians in recognizing, treating, and helping to educate the vast majority of those patients experiencing symptoms related to their sleep–wake cycles. Even though sleep-related complaints are common in general medical practice, a Gallup survey (2) showed that only a small minority of sleep-disturbed people bring their concerns to the attention of their physicians.
The sleep disorders represent a wide spectrum of symptoms. The inability to sleep at the desired time and the inability to remain awake during appropriate hours make up the majority of patient concerns. Abnormal behaviors and movements also may be associated with sleep. The International Classification of Sleep Disorders, 2nd edition (ICSD-2) (3), developed by the American Academy of Sleep Medicine in collaboration with other international sleep associations, reflects 7 major categories of sleep disorders and nearly 70 individual diagnoses. The major categories are insomnia, sleep-related breathing disorder, hypersomnia of central origin, circadian rhythm sleep disorder, parasomnias, sleep-related movement disorders, isolated symptoms, apparently normal variants, and unresolved issues, and other sleep disorder.
Appropriate diagnosis and effective treatment of sleep disorders can result in significant improvement in quality of life for patients. In addition, it may allow a reduction in the morbidity and mortality associated with excessive sleepiness, and help avert consequences of persistent insufficient sleep. An exploration of sleep–wake patterns and possible sleep disorders is an important component of any general review of systems. Sleep disturbances can exacerbate other medical conditions, and, conversely, many medical illnesses and medications can affect sleep patterns.
Basic Sleep Physiology
Daytime alertness and nighttime sleepiness are natural drives for most people leading normal lives. The fundamental sleep–wake cycle is maintained by at least two physiologically distinct control processes:
The homeostatic mechanism represents the balance between wake and sleep time over several days. This time balance varies greatly with species, but for adult humans is set at about one third sleep and two thirds waking. Sleep deprivation leads to increased sleepiness; however, the relationship is not exactly linear. Many people have had the experience of getting a second wind of alertness the morning after a night without sleep. This phenomenon is caused by the prominent circadian rhythm driving sleepiness and alertness.
The circadian oscillator establishes a sleep propensity variation over the normal 24-hour day. This oscillator also
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modulates core temperature and the activity levels of a large number of physiologic functions (e.g., certain neurotransmitters and hormone levels). Without time cues, especially the day–night, light–dark cycle, this circadian mechanism has a periodicity slightly greater than 24 hours and therefore must be reset daily. Light exposure during the daytime and darkness at night synchronize the rhythm. Neural pathways including the retina, suprachiasmatic nucleus, and pineal gland are well established, and these mechanisms promote the cycle of sleepiness and alertness and usually are in stable harmony. Although homeostatic sleepiness increases throughout the day, circadian alertness peaks in the evening. Under normal circumstances these rhythms allow one to remain alert for 16 hours and then fall asleep rapidly at one's habitual bedtime.
Normal sleep includes two major physiologically distinct states: rapid eye movement (REM) sleep and nonrapid eye movement (NREM) sleep. Initially, sleep may consist of the four successively deeper stages of NREM sleep. During each of these four stages, there is decreased fluctuation in heart rate, blood pressure, and respiration. This contrasts with REM sleep, where greater lability is noted. The presleep wake stage and the NREM sleep stages have additional distinctive clinical and electroencephalographic (EEG) characteristics.
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FIGURE 7.1. Normal sleep cycles in healthy young and elderly subjects. |
On a typical night, a subject passes through three to five cycles of NREM and REM sleep. Figure 7.1 shows characteristic sleep patterns for healthy young adults and elderly people. With aging, there generally is a decrease in slow-wave sleep (stages 3 and 4), with an earlier sleep onset and waking time and more frequent awakenings during the night. The apparently decreased arousal threshold in older people is the most prominent difference between sleep at age 50 years and that at age 80 years. During the day, young adults require 10 to 15 minutes to fall asleep for a nap; older adults fall asleep more easily. As discussed later in the next section, Table 7.1, and subsequent sections on specific disorders, the recognition and deviations from the normal sleep cycles are helpful at times in establishing the correct diagnosis for a sleep disorder.
Clinical Presentations of Sleep Disorders
The full evaluation of sleep complaints requires a general consideration of the patient's sleep–wake cycle, as well as specific questions that focus on the presenting symptoms. Table 7.1 lists questions that may yield information to support a diagnostic hypothesis.
Insomnia
Insomnia is the perception of not sleeping well, and it is the most common sleep complaint. It is estimated that 10% to 15% of the U.S. adult population have frequent
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or chronic difficulty with insomnia. Almost everyone experiences some degree of insomnia during his or her lifetime. Moreover, people of all ages may experience disrupted sleep; there is a general increase in frequency with age. Men and women are affected equally until middle age. From their mid-forties on, women are much more likely to complain of difficulty sleeping (2).
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TABLE 7.1 Sleep History |
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Insomnia may involve difficulty falling asleep, awakening too early, or experiencing disrupted sleep throughout the night. The presentation also may include the report of unrefreshing sleep. Often, the patient complains of fatigue, poor concentration, and low productivity. In properly diagnosing complaints of poor sleep, it is important to realize that insomnia is a symptom that may result from a wide variety of processes. An essential initial consideration is the duration of the disturbance.
Episodes of insomnia may be acute or chronic. They may be described in terms of the timing of the sleep disturbance (e.g., initiating and maintaining sleep), duration, severity, and pattern over time. For some patients insomnia is a nightly problem. For others, disrupted sleep may be seemingly random or predictable, as with premenstrual insomnia, travel, or with anxiety on Sunday nights in anticipation of the work week. The ICSD-2 includes an Adjustment Insomnia diagnosis to represent the acute response to an identifiable stressor. Several different diagnoses may be associated with chronic insomnia, which generally is considered to be at least 1 month in duration. An initial precipitant often is recognizable in the history, but other perpetuating factors may promote the persistent symptoms (4). Complaints of marked sleep difficulty that have continued for several years are not uncommon. Although the cause of chronic insomnia is often multifactorial, it is useful to consider the individual factors that may be associated with long-standing symptoms (Table 7.2).
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TABLE 7.2 Causes of Chronic Insomnia |
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Most psychiatric disorders can cause disturbed sleep. Symptoms of depression and anxiety often are associated with insomnia and may be precipitating and perpetuating causes. Early morning awakening is a characteristic of major depressive disorder; however, difficulties falling and staying asleep commonly are present as well. Difficulty sleeping is typical of patients with generalized anxiety disorder, posttraumatic stress disorder, panic disorder, schizophrenia, personality disorders, and dementia. Acute sleep changes often are seen with adjustment disorders. Each of these psychiatric disorders is described in detail in Section 3 of this book.
A broad range of physical conditions can cause difficulty sleeping. Pain and discomfort are common factors; however, other pathophysiologic processes may play important contributory roles. The more common medical problems associated with chronic insomnia are arthritic disorders; peptic ulcer disease and gastroesophageal reflux; asthma and chronic obstructive pulmonary disease; cardiovascular disease; hyperthyroidism; and renal failure. Orthopnea and nocturia cause fragmented sleep. Patients with fibromyalgia (see Chapter 74) often complain of unrefreshing sleep. Insomnia is common during normal physiologic stress such as pregnancy, especially during the first and third trimesters.
Among the neurologic disorders more commonly associated with insomnia are Parkinson disease and other movement disorders, stroke, epilepsy, and cerebral degenerative processes. Head trauma can cause long-standing sleep disturbance.
Several hundred medications can cause insomnia. Stimulants, ranging from caffeine to amphetamines, predictably decrease the ability to sleep. Correspondingly, withdrawal from sedating medications, including hypnotics, can be associated with a temporary sleep disruption. Bronchodilators, corticosteroids, and some antihypertensives, antiarrhythmics, calcium channel blockers, antiparkinson agents, anticonvulsants, antidepressants, and nonsteroidal anti-inflammatory drugs can cause insomnia. It is important to consider over-the-counter
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preparations as causes of disrupted sleep, particularly diet and cold and allergy products, because they may contain stimulating compounds such as caffeine.
Substance abuse can promote acute and chronic disturbances of sleep. Cocaine and other stimulants inhibit or fragment sleep. Paradoxically, narcotics such as heroin and morphine can have arousing effects that disturb sleep. The acute sedating effect of alcohol is well known; however, although sleep onset may be enhanced, the withdrawal-related catecholamine release often causes sleep disruption. This may occur after a single episode of moderate drinking. Heavier drinking can impair sleep markedly. Symptoms may persist during months to years of abstinence.
The influence of circadian rhythms on the sleep–wake cycle becomes apparent (usually transiently) with acute changes in the sleep schedule. Rapid transmeridian travel causes symptoms of jet lag, and changes in shift-work schedules may promote acutely disturbed sleep. Constantly changing work shifts or permanent night work schedules often inhibit effective entrainment and thereby cause chronic insomnia.
Delayed sleep phase syndrome is a disorder of circadian rhythms characterized by difficulty attaining sleep until about 3 to 6 a.m. Affected individuals tend to sleep until late morning or into the afternoon. Occupational or educational requirements may demand a more socially acceptable wake-up time that effectively truncates the sleep period and causes chronic sleep insufficiency. These people feel out of synchronization with the rest of society and usually come to the physician because of their inability to fall asleep at a more conventional hour. At the opposite end of the spectrum are people with advanced sleep phase syndrome who may experience sleepiness from 6 p.m. until 2 a.m., then complain of an inability to remain asleep throughout the night. Generally, the delayed pattern is more common among young people, whereas the advanced pattern occurs more often in the elderly. A rare circadian rhythm disturbance occurs in certain completely sightless people who are not entrained to a 24-hour cycle. They move in and out of phase with the day–night cycle and therefore have periodic symptoms of insomnia every few weeks.
Symptoms of insomnia may be associated with other sleep disorders in which the primary problems are breathing irregularity or excessive body muscle movements during sleep (see later discussions).
Consideration of the sleeping environment is an important component of the evaluation of patients with insomnia. Excessive light or disruptive noise can be arousing. Living near an airport or another source of loud noise may be detrimental to sleep in vulnerable patients. Temperature extremes can disrupt sleep continuity. Discomfort in bed may result from a poor mattress or a snoring bed partner. Household and neighborhood characteristics (e.g., loud televisions, city noises) also may be significant. A sense of insecurity or fear may promote sleeplessness.
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TABLE 7.3 Sleep Hygiene Measures |
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Issues related to sleep hygiene (Table 7.3) are important for all patients with insomnia complaints. Even when there is another reason that sleep is disturbed, behavioral patterns that affect sleep commonly play a role in perpetuating the disorder. Irregularity of bedtime and wake time may undermine the underlying circadian drive for sleepiness and alertness at the appropriate hours. Patients may have unrealistic expectations of their ability to change their sleep schedule markedly and then sleep effectively. Some patients nap in the daytime to make up for lost nighttime sleep and thereby further diminish their propensity to fall asleep at the desired hour.
Chronic insomniacs may spend excessive amounts of time in bed in the hope of maximizing their total sleep time, thereby further fragmenting their sleep. Remaining in bed during extended sleepless periods may reinforce the association between being in bed and being awake. Often, frustration and anxiety are integral to this repeated experience and further prolong wakefulness. Subsequently, sleep becomes less attainable.
In psychophysiologic insomnia, perpetuating factors predominate after the initial stimulating precipitants have subsided. A conditioned pattern of anxiety and tension has become established. The patient may report increasing tiredness during the evening but tortured wakefulness on getting in bed. Alternatively, what might have been a minor nighttime awakening becomes an exaggerated emotional response that further inhibits a rapid return to sleep.
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TABLE 7.4 Complaints Associated with Excessive Daytime Sleepiness |
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In summary, the history may identify one or more precipitating or perpetuating conditions that promote chronic insomnia. Practical approaches to the management of these conditions are described later in this chapter (see Management of Sleep Disorders).
Excessive Daytime Sleepiness
Clinical Features
Up to 5% of the population has problems with excessive daytime sleepiness (EDS) or related symptoms (Table 7.4). The younger and older age groups tend to experience more EDS than the middle-age group. Also, shift workers complain more of being tired and of various other problems associated with EDS than do nonshift workers. Some people do not perceive that their problems are sleep-related and therefore may not mention being sleepy during the day. The degree or severity of reported sleepiness can be judged by identifying which situations are most likely to produce sleep, by determining how often and how pervasively sleepiness occurs throughout the day, and by learning how disruptive this situation is to family, job, and personal well-being.
In determining the severity of sleepiness, one needs to ask patients under what conditions they are most likely to fall asleep. Table 7.5classifies sleepiness severity according to the situations in which sleep may occur. If the situations listed are not associated with falling asleep, it is unlikely that EDS is the problem. If patients awaken from sleep feeling tired, they should be questioned further about their nighttime sleep habits. Patients’ perceptions of sleepiness vary and depend on the environment, level of activity, and degree of motivation. Sitting in a dark room or listening to an uninteresting lecture may unmask sleepiness. Some individuals may be so busy and active all day that they have no sense of tiredness despite the fact they have not slept in more than 36 hours. As noted in Table 7.4, such people may not complain of being tired but may have problems with concentration or stamina. They may be fatigable or forgetful or have decreased motivation. They may have accidents either on the job or on the highway. Their job performance may suffer. Increased irritability or depression may be noted by family or friends.
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TABLE 7.5 Sleepiness Severity |
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Animal and human studies show that with insufficient sleep, the EEG identifies brief but frequent disturbances in the ongoing wakeful state. If frequent, these brief intrusions may lead to inattention and poor concentration before sleepiness is perceived. The problems of EDS often are insidious. However, EDS can be identified by appropriately questioning the patient.
Differential Diagnosis
Once it is established that the patient has EDS, the cause must be identified. One first needs to determine whether drugs (e.g., alcohol, benzodiazepines, antidepressants, antipsychotics, antihistamines, some antihypertensive drugs) or medical conditions (e.g., chronic renal failure, cirrhosis, hypothyroidism) might be the cause of the EDS. After considering these causes, one should attempt to identify patients with disturbed nocturnal sleep. Disorders that are likely to cause sleep disruption and therefore EDS were discussed earlier (see Insomnia). Chronic insufficient sleep, chronic fatigue, narcolepsy, and idiopathic hypersomnia are discussed in this section; the sleep apneas are discussed in the next section.
A common cause of transient daytime fatigue is cessation of caffeine consumption (5). The caffeine withdrawal syndrome may occur after the discontinuation of even relatively low daily amounts of caffeine, such as 100 mg from one cup of coffee or two to three sodas. Withdrawal effects are more likely at higher doses but can occur after short-term use. The average daily caffeine consumption in adults in the United States is about 250 to 300 mg. Because caffeine use is so widespread, it often is not considered as influencing alertness, sleepiness, and fatigue. The caffeine withdrawal syndrome typically evolves over 12 to 24 hours, and it can persist for several days. It is alleviated by resumed caffeine consumption, even at considerably lower levels. The withdrawal effects can be minimized with a gradual reduction in the daily intake. Aside
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from fatigue, caffeine withdrawal most typically is associated with headache. Other effects may include irritability, nausea, and flulike symptoms.
Chronic Insufficient Sleep
The most common cause of EDS is chronic insufficient sleep. The primary problem is that patients do not achieve enough sleep to satisfy their body's requirement. The most common causes are personal lifestyles (e.g., shift workers, medical/surgical residents) and poor sleep habits (e.g., watching television until midnight and then getting up for work at 6 a.m.). Such individuals rarely have problems falling asleep or staying asleep. They may wake up feeling tired and may have symptoms of EDS. A detailed history of the amount of sleep per night over the past several months is important. If someone is getting 7 hours of sleep each night and is still tired, 8 or 9 hours may be needed. Questioning patients about weekend or holiday patterns of sleep, or about how they slept when they were younger or had a different lifestyle, may help to determine what the normal amount of sleep is for them. To establish the diagnosis and treat the problem, an 8-hour sleeping pattern must be established. Patients need to keep a written record of when they go to sleep (not when they go to bed but when they think they fall asleep) and when they awaken. The record should be completed for at least 1 month, after which the patient, with the diary in hand, should return for reassessment. If the patient is feeling better after the forced 8-hour sleep schedule, the diagnosis of chronic insufficient sleep is established. If the patient still complains of EDS and the diary indicates 8 or more hours of sleep per night, a referral to a sleep specialist should be offered.
Chronic Fatigue
Psychiatric disorders, especially depression and certain life events (e.g., death of family member, divorce, job loss, marital discord) often are associated with insomnia. Occasionally there is no clear-cut insomnia but only what appears to be symptoms of EDS. The patient may complain of increased fatigue, lack of motivation, poor concentration, or feeling tired all the time. These patients may sleep in the afternoon, but if they consistently sleep for long periods during the day, they invariably will have disturbed sleep at night and thus experience insomnia. The severity of sleepiness (Table 7.5) is important in differentiating fatigue from sleepiness. Although there may be complaints of tiredness, often there are no clear and consistent episodes of falling asleep. More often, the complaints are more severe than the actual degree of reported sleepiness. Finally, when lack of motivation overshadows all other complaints, one should consider chronic fatigue syndrome (see Chapter 58) or depression (see Chapter 24). There is no defined treatment for chronic fatigue other than treating the underlying problem. If a clear distinction between sleepiness and fatigue cannot be made, referral to a sleep specialist is appropriate.
Narcolepsy
The prevalence of narcolepsy in the United States is approximately 0.05% to 0.09%. The disorder may start in childhood, but the peak incidence is in the second decade. The diagnosis can be made on clinical grounds; however, a daytime sleep laboratory study (the multiple sleep latency test [MSLT], see Patient Experience) may be valuable when the clinical picture is not clear. Objective support for the diagnosis of narcolepsy is established by an average sleep latency on the MSLT of less than 5 minutes and the presence of two or more naps with REM activity (6). Normal results from this testing include an average sleep latency period of longer than 15 minutes and no REM sleep during these brief daytime naps.
Several clinical features constitute the syndrome of narcolepsy (Table 7.6). The most common of these are problems of attention and concentration and episodes of falling asleep. People with narcolepsy often have little difficulty related to sleepiness when they are physically active. It is when they are engaged in sedentary activities and repetitive or boring tasks that they experience great problems with attention and concentration and uncontrolled bouts of sleepiness. The degree of inattention may be so severe that the individual carries out complex tasks (e.g., driving) but has no recollection of the behaviors. This phenomenon, referred to as an automatic behavior, is rarely associated with other disorders. In contrast to individuals who have chronic sleep insufficiency, those with narcolepsy usually benefit greatly from brief naps.
Cataplexy and sleep paralysis are present in some patients with narcolepsy. Both of these conditions are
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associated with paralysis in the context of full consciousness. Cataplexy occurs only with narcolepsy. Accordingly, a history of cataplexy and excessive daytime sleepiness leads to the diagnosis of narcolepsy. Cataplexy occurs when the patient is awake and is characterized by a sudden onset of paralysis precipitated by an acute emotional response. Although fear, anger, and excitement can cause a cataplexy, the most reliable historical indicator is its occurrence during laughter. Cataplexy can affect any muscle group in the face, trunk, or limbs but is symmetric in its effect. The simplest type of cataplexy is a drop of the jaw, which can affect speech, and cataplexy may make it difficult to hold one's head up for several minutes. However, the most dramatic are the episodes associated with loss of tone throughout the postural musculature. As the episode evolves, those experiencing cataplexy usually are able to lower themselves to a chair or to the floor, but injury may occur. There is full alertness during these episodes, but occasionally a patient falls asleep during the cataplexy. In general, cataplexy resolves spontaneously within a few minutes.
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TABLE 7.6 Clinical Features of Narcolepsy |
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Sleep paralysis occurs just before falling asleep or just after awakening. The patient cannot move and usually cannot speak, but breathing is undisturbed. There may be a high degree of anxiety or terrifying hallucinations. The paralysis lasts seconds or minutes and resolves spontaneously. Because sleep paralysis can occur alone as an idiopathic condition, it does not confirm the presence of narcolepsy. In fact, sleep paralysis is more likely to be seen in patients who are chronically deprived of sleep.
Another cardinal feature of narcolepsy is hallucinations. These are vivid and sometimes very realistic sensory experiences that occur before one falls asleep (hypnagogic) or on awakening (hypnopompic). The experiences may be in any sensory modality (e.g., visual, auditory, tactile) and may range from simple to complex in presentation. For example, there may be a sense of something crawling on the legs, a well-formed visual hallucination, or an out-of-body experience. The phenomenon is comparable to dreaming with one's eyes open and being fully alert. Some patients have hypnagogic hallucinations and no other components of the narcolepsy syndrome.
Disturbed nocturnal sleep often is seen with narcolepsy. The most common complaint is that after sleeping for 3 to 4 hours, the patient awakens fully alert. After about 45 to 60 minutes, the patient again becomes tired and falls back to sleep. Sometimes there are multiple awakenings throughout the night. Patients may experience vivid dreams or hallucinations with these awakenings. The vivid dreams can be terrifying and nightmarish in content. The patient starts the day tired and unrested, which only worsens the underlying daytime problems. The management of narcolepsy is described later (see Management of Sleep Disorders).
Idiopathic Hypersomnia
This syndrome manifests as excessive daytime sleepiness; however, the REM-related clinical features seen with narcolepsy (Table 7.6) are absent. The symptoms are similar to those experienced by anyone who has chronic sleep insufficiency; however, these individuals sleep much more. They wake up tired and remain tired. Often they are very difficult to arouse and, when awake, may stumble around in a semistuporous state, which is referred to as sleep drunkenness. In contrast to narcolepsy, naps are long and unrefreshing. Daytime sleep studies (see discussion of the MSLT under Patient Experience) demonstrate very short sleep latencies, similar to narcolepsy, without REM episodes. The management of idiopathic hypersomnia is described later (see Management of Sleep Disorders).
Sleep-Disordered Breathing (Sleep Apnea)
The sleep apneas are relatively common disorders that involve physiologic and psychological functioning with profound potential consequences. They are characterized by breathing abnormalities that vary from reduction (hypopnea) to complete cessation (apnea) of airflow associated with either an arousal or desaturation in blood oxyhemoglobin, or both. The sleep apneas include central apnea that is associated with cessation of respiratory effort, and obstructive apnea that is associated with occlusion of the upper airway and continued respiratory effort. The number of apneas and hypopneas are collated as the number of events per hour of sleep and are reported in various forms, such as the apnea–hypopnea index (AHI), the sleep-disordered breathing (SDB) index, or the respiratory disturbance index (RDI). The assessment of patients with nonapneic snoring is described in Chapter 111.
Epidemiology
A 1 study of working men and women 30 to 60 years old reported a prevalence of clinically significant SDB of 9% among women and 24% among men (7). The authors estimated that approximately 2% of the women and 4% of the men met criteria for the sleep apnea syndrome. The prevalence may even be higher among obese people. Because of increased public awareness and the availability of diagnostic facilities, breathing problems during sleep are now being recognized in the very young and very old.
The typical patient who presents with obstructive sleep apnea is a middle-aged, mild to moderately obese man. However, it is important to recognize that severe obstructive sleep apnea may be diagnosed in individuals of all ages and body types. Obstructive apneas occasionally are associated with specific abnormalities of the upper airway
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or with various medical conditions (Table 7.7). In general, patients with medical disorders that contribute to the development of obstructive SDB demonstrate overt symptoms and signs of their underlying medical problem. For example, patients with cardiomyopathy present with typical signs of severe congestive heart failure and a reduced ejection fraction on echocardiogram. Patients with renal failure and SDB are usually on dialysis. There are exceptions to this general rule. Patients with hypothyroidism often go undetected because their complaints of fatigue and sleepiness are ignored. Importantly, obesity (body mass index [BMI] ≥30), and even mild obesity (BMI of 26 to 30), continues to be recognized as the major contributor to the development of sleep apnea. This is especially true with adiposity of the visceral (truncal) distribution that is frequently seen in patients taking steroids or on highly active antiretroviral therapy.
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TABLE 7.7 Disorders Associated with Sleep-Disordered Breathing |
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In contrast with obstructive sleep apnea, central sleep apnea occurs most commonly in infants or patients older than 65 years of age (8). Central apnea may occur as a result of major cerebral disease, brainstem and spinal disorders, or cardiovascular disease (Table 7.7). The Cheyne-Stokes respiratory pattern is one example of central sleep apnea.
Presentation
Characteristically, patients with obstructive SDB present with significant snoring, or daytime hypersomnolence, or both (9). The snoring is loud, intermittent, and often punctuated by respiratory efforts unaccompanied by obvious airflow. A bed partner may observe that the apneas are associated with a struggling effort (obstructive apnea) or a lack of effort (central apnea). Because apnea, or any form of periodic breathing, usually is associated with both oxyhemoglobin desaturation and a brief arousal, sleep becomes fragmented and leads to daytime sleepiness. Initially, the patient may experience a subtle decrease in alertness toward the end of the day or when engaged in sedentary activities. As the apnea progresses in severity because of weight gain or age, more obvious signs of hypersomnolence, such as napping in the daytime, difficulties driving a car, and even severe sleepiness during normal waking activities, may occur (Table 7.5). Because most patients are unaware of their breathing pattern and often underestimate the severity of daytime hypersomnolence, it is essential that a bed partner or other observer be questioned regarding the patient in whom sleep apnea is suspected. Additional clinical features, such as choking or gasping episodes at night, evidence of systemic or pulmonary hypertension, and, in severe cases, cor pulmonale, may also suggest the underlying diagnosis. In general, the presenting symptoms of patients with both obstructive and central apnea are indistinguishable.
The physical examination usually is not diagnostic in patients with obstructive apnea, although patients with narrowing of the upper airway are at significantly higher risk. In particular, sleep-disordered breathing should be suspected in children and adults who demonstrate a compatible history and marked tonsillar hypertrophy or retrognathia. The BMI should be calculated and recorded (see Chapter 83), because visual estimation of whether someone is overweight or obese will lead to significant underestimation of the severity of obesity and the risk of the disorder. In elderly patients with central sleep apnea, the physical examination is normal, whereas patients with neurologic or cardiovascular pathology usually demonstrate obvious localizing neurologic signs (e.g., stroke) or cardiomegaly.
Course
The course of obstructive SDB is chronic and progressive because of the typical weight gain seen in a sedentary, aging population. Some patients develop progressive cardiopulmonary decompensation manifested by worsening hypercarbia and hypoxemia, which can be associated with cor pulmonale and life-threatening arrhythmias (10). Nevertheless, these complications are the exception and tend to occur in the severely obese patients (BMI >40) after many years of disease. By contrast, the course of central apnea is determined by the underlying pathologic process. Thus, if reversible central nervous system or cardiovascular disease exists, central apnea may resolve entirely. In normal elderly patients with central apnea, the course and prognosis are unknown.
Diagnosis
A working diagnosis of SDB can be made by direct observation of the patient during sleep, either at home or in
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a general hospital. However, even with ideal observation, clinically significant apnea may not be appreciated. The occurrence of five or more SDB events per hour constitutes an abnormal number of events. Although an SDB rate of more than five events per hour and daytime sleepiness are the minimal criteria that define the sleep apnea syndrome, there is good evidence that the sleepiness is correlated with the severity of the SDB rate and the degree of hypoxemia (11). Definitive diagnosis requires a sleep study (see Patient Experience) that quantitates the severity of SDB, including the degree of desaturations and the alteration in sleep architecture.
Other screening laboratory studies, such as determination of arterial blood gases and routine pulmonary function studies, provide information about mechanical abnormalities or problems with waking gas exchange that may be useful in therapy but not in diagnosis. Awake flow-volume curves (see Fig. 60.2) may demonstrate fluttering during expiration associated with evidence of variable extrathoracic obstruction in patients with obstructive apnea. However, this test is neither specific nor sensitive; consequently, it is not recommended for screening purposes. Home monitoring of arterial oxygen saturation (SaO2) appears to be specific but not sensitive in the detection of sleep-disordered breathing. Although computed tomography or magnetic resonance imaging may demonstrate narrowing of the upper airway in patients with obstructive sleep apnea, it is presently unclear how this information can best be used in management. The management of SDB is described later (see Management of Sleep Disorders).
Restless Legs Syndrome and Periodic Leg Movements in Sleep
Restless legs syndrome (RLS) is a disorder of sensation of unknown etiology. It occurs in 2% to 5% of the adult population, and in 10% to 15% of individuals 65 years of age or older. The prevalence is increased in conditions of iron deficiency, pregnancy, chronic renal failure, or peripheral neuropathy. It may be induced or aggravated by dopamine antagonists.
RLS is a clinical diagnosis based on the following criteria. First, there is a sensation that usually is characterized as a deep, uncomfortable feeling that occurs in one or both legs, either independently or concomitantly. Occasionally the sensation additionally involves the hands, arms, or trunk. The feeling may be reported as “aching,” as “something moving,” as “little insects,” as “crazy legs,” or in other ways. The description of the feeling is highly variable but is usually not that of pain. If pain is a prominent component, an alternative or coexisting disorder is suggested, such as a neuropathy. Along with the deep, uneasy feeling is a compulsion or urge to move. The urge to move may be so strong that the legs will seemingly jump on their own. Therefore, the patient is constantly moving or rubbing the legs or walking to relieve the sensation. The second feature is that the sensation is brought on with sitting or lying. Third, the uncomfortable sensation is relieved with movement and should be absent during walking. The sensation may return as soon as the individual sits or lies down again. Fourth, the sensation is the worst in the late evening or at bedtime. Typically, it is not present during the early morning. However, as the disorder progresses with time, symptoms appear earlier in the daytime, sometimes to the point that RLS symptoms exist throughout the day. Most commonly, the symptoms appear as soon as the person tries to relax in the late evening or gets into bed at night. Because of this sensory disturbance, the affected person cannot rest comfortably. Travel by any means is not possible if the person's ability to move is limited. Patients commonly cannot relax long enough to sit through a movie or to read without having to shuffle or pace compulsively. At night, the sensation can prevent sleep. Some patients spend several hours at night pacing until exhaustion induces sleep.
An associated component of RLS is the presence of semi-involuntary leg movements while awake or semirhythmic leg movements during sleep. When observing the patient during sleep, brief leg and foot movements occur periodically. The leg movements are called periodic leg movements of sleep (PLMS), and occur in association with many other conditions (Table 7.8). Occasionally, PLMS occur in the absence RLS symptoms and an obvious medical condition. Under these circumstances, the condition is referred to as periodic leg movement disorder (PLMD) and is considered a variant of RLS. The periodic leg movements may cause significant repeated arousals from sleep. The patient usually is unaware of the arousals and complains of awakening feeling tired and of being excessively sleepy during the day. Sometimes the leg kicks cause a complete awakening several times throughout the night, even though patients rarely recognize that the leg movements are the cause.
RLS is diagnosed on the basis of the clinical history, whereas PLMS is identified either by the history given by the bed partner or by polysomnographic recording (see Patient Experience). The polysomnographic recording is
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needed to make the diagnosis of PLMS or PLMD, but not RLS. The deep, uneasy feelings of RLS must be differentiated from arthralgia, myalgia, or sensory neuropathy. The absence of frank pain, the history of relief with movement, the compulsion to move, and normal results on neurologic, muscle, and joint examination help in the differential diagnosis. The presence of an initial sensory component and the voluntary nature of the movements should differentiate the secondary movements of RLS from those of myoclonus or dyskinesia. Nocturnal seizures, sleep-related dystonia, myoclonus, sleep apnea, primary insomnia, and PLMS are part of the differential diagnosis when a patient presents with a history of disturbed sleep associated with movements during sleep. If the clinical history is insufficient to establish the diagnosis, the patient should be referred to a sleep disorder clinic. The management of RLS is described later (see Management of Sleep Disorders).
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TABLE 7.8 Causes of Periodic Limb Movements of Sleep |
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Abnormal Behaviors Emanating from Sleep (Parasomnias)
Restful sleep may be punctuated by behaviors that may or may not awaken the patient. Sleep-related behaviors usually can be divided into the slow-wave sleep and REM-associated symptom complexes. Nocturnal enuresis, discussed below under Enuresis, is not associated with a particular sleep stage. In rare instances, sleep-related behaviors can be shown to be complex partial seizures (see Chapter 88). The parasomnias tend to occur in <10% of the population. These behaviors can range from the benign to the dramatic and may be violent. Several distinct syndromes have been recognized. Factors that can help distinguish the causes include the timing of the behavior, the likelihood of awakening from the episode, the degree of confusion present, and the patient's memory of the events. Sleep laboratory recordings may associate the various types of episodes with different sleep stages.
Arousal Disorders
Three types of sleep-related behaviors are classified as arousal disorders (3): sleepwalking, sleep terrors, and confusional arousals. They share an association with slow-wave sleep and thereby tend to occur during the first third of the night. The prevalence is greatest in childhood, but the disorders may persist in adulthood. A familial association has been noted in some cases. The frequency of episodes may range from several times per night to less than once a year. Commonly there is amnesia for the event. Typically the individual does not awaken spontaneously and is difficult to arouse. The patient may become aware of the events because of residual evidence such as relocated furniture or food left out on a table. Resistance to full awakening is characteristic, and marked confusion may be evident. Behaviors may be inappropriate, such as urinating in a closet or searching for nonexistent intruders.
Sleepwalking most commonly is simple and characterized by the patient walking around the room or house but rarely going outside. Generally sleepwalkers do not put themselves or others in a dangerous situation; however, dramatic exceptions have been reported. In some cases, there is an overlap with sleep terror symptoms, in which the person aggressively attempts to escape from, or protect against, an imagined threat.
By definition, sleep terrors are dramatic events. Evidence of autonomic discharge may be pronounced. Often, the person sits up and screams loudly and commonly is unarousable. The patient may return to sleep after several minutes and have no recollection of the incident the following morning. Patients who do awaken report an intense sense of fear associated with a distinct threat, but generally they do not offer a lengthy, dreamlike narrative. The sleep terror may lead to forceful escape behavior, which can injure the patient or someone else perceived to be an obstacle. Injury may result from leaping out of bed or colliding with furniture. Rarely, people have jumped through windows in an attempt to escape.
Confusional arousals involve persistent disorientation and incomplete awakening after an arousing stimulus that occurs while the person is in slow-wave sleep. Behaviors and speech content may be meaningless or inappropriate. A typical example would be a person responding to a ringing telephone 1 hour after sleep onset. The person may reach for other objects or may make little sense when talking. Amnesia for these episodes is common. Factors promoting deeper sleep increase the likelihood of such incomplete awakening. These may include sleep deprivation and use of sedating substances such as alcohol and central nervous system depressants.
Nightmares
Nightmares usually result in full awakenings and generally are not associated with prolonged confusion or sleep-related behaviors. Typically the patient can recount an extended dream narrative and can describe the frightening aspects of the story. In contrast to arousal disorders, nightmares are most common during REM sleep and tend to occur during the latter part of the night. Nightmares also are more likely to be remembered in the morning.
Dreams may be related to physical activity during sleep in REM behavior disorder (3). This disorder is more common in elderly persons. Normally there is skeletal muscle atonia during REM sleep; however, in this disorder, the active inhibition of motor impulses is incomplete. The dreamer may physically act out dream content, which may include kicking, punching, or leaping from the bed. Violent behaviors causing injury to the patient or to his or her bed partner have been reported. Most cases are
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idiopathic; however, neurologic diseases, toxic and metabolic processes, and medications have been implicated in promoting the symptoms. An association with the future development of Parkinson disease has been reported.
Management of the parasomnias is discussed in the next section.
Management of Sleep Disorders
Insomnia
A comprehensive sleep history from a patient with insomnia establishes the duration of the symptoms and explores possible predisposing, precipitating, and perpetuating factors. Multifactorial causes are common with insomnia. Treatment of the primary cause of the insomnia may be important, but reinforcing factors should also be addressed. Identified medical and psychiatric illnesses must be treated. Attention to sleep hygiene, behavioral programs, relaxation techniques, psychotherapy, environmental manipulations, and the use of hypnotic medications can play important roles in management. The objective of treatment is development by the patient of new behaviors and routines that allow a renewed sense of confidence in the ability to sleep effectively. This is achieved by a therapeutic alliance wherein the patient plays an active role in exploring potential sleep-inhibiting factors. Considerable experimentation may be necessary.
Although the quality of clinical studies has been highly variable, critical reviews of the published literature support the conclusion that both behavioral and pharmacologic approaches reduce the time it takes to fall asleep by 15 to 30 minutes and the number of awakenings by one to three per night (see Kupfer and Reynolds, Management of Insomnia, at http://www.hopkinsbayview.org/PAMreferences).
Sleep Hygiene Measures
Recommendations about sleep hygiene are beneficial to most patients with insomnia, regardless of the duration of their symptoms (Table 7.3). These basic guidelines address factors that directly cause disturbed sleep and inhibit recovery. They take into account fundamental physiologic and psychological understanding of the sleep process.
It is important to take full advantage of the underlying circadian rhythm, described previously, that promotes nighttime sleepiness and daytime alertness. Attempts to sleep at various times throughout the 24-hour cycle may perturb the rhythm. Daytime or evening napping can inhibit the onset of sleep at night. A consistent wake-up time is important because this is when the system is most sensitive to daily reinforcement.
Some people with insomnia spend excessive time in bed (e.g., 9 p.m. to 9 a.m.) in the hope of getting a little more sleep. Generally this is counterproductive. Physiologically there may be less-effective support of the circadian pattern. Because continuous sleep is unlikely, a situation is created in which failure is inevitable. Extended wakeful periods may be self-reinforcing. Sleep restriction (see Sleep Restriction Therapy) is a treatment modality that specifically addresses the problem of excessive time in bed without sleep.
It is useful to consider the extent to which a patient develops negative associations with the bed and bedtime routines. Good general advice includes reserving the bed for sleeping and sexual relations. Anxiety-provoking activities performed in bed may promote residual tension when sleep is attempted. Stressful behaviors may include studying for tests, paying bills, having domestic discussions, or watching violent television drama or news programs. These negatively stimulating activities should be replaced with relaxing behaviors.
Some patients find significantly improved sleep with the elimination of stimulants such as nicotine and caffeine, especially during the hours leading up to bedtime. Late-evening alcohol consumption should be avoided because of the potential for stimulation related to withdrawal later in the night.
A comfortable bedroom environment is important. Temperature extremes, particularly a warm room, can promote sleep disruption. Outside noises may be blocked out by white noise machines or wax ear plugs. Generally, people should not try to fall asleep with the television or radio playing. This tends to inhibit deep sleep and can cause awakenings.
Dietary habits may need to be addressed. Late, heavy meals may produce abdominal discomfort or reflux symptoms. On the other hand, hunger may interfere with sleep onset. A light snack may be an appropriate solution.
Regular exercise (see Chapter 16) is recommended to promote improved sleep at night (12). However, to prevent excessive stimulation, aerobic exercises should be avoided in the hours leading up to bedtime. For this reason, patients should be warned against wearing themselves out at night in the hope of falling asleep quickly.
Behavioral Management
Behavioral approaches are important in the treatment of chronic insomnia.
Relaxation Techniques
Relaxation techniques may have a permissive effect by reducing arousal, thereby allowing sleep onset (4). Relaxation may be achieved through the use of progressive relaxation, meditation, or biofeedback (see Chapter 22). Two other techniques—stimulus control therapy and sleep restriction therapy—involve specific instructions regarding nighttime routines and sleep–wake schedule hours.
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Stimulus Control Therapy
Conditioned arousal is an important perpetuating factor in many people with chronic insomnia (13). The goal of stimulus control therapy is to re-establish the connection between the bedroom and sleeping. The fundamental strategy is to eliminate the nightly reinforcement of the anxiety and arousal that have become associated with the act of going to bed or awakening during the night. Basic sleep hygiene measures (Table 7.3) are pointed out as the necessary elements in a stimulus control plan. The purpose of these measures is to minimize the time that the patient is sleepless in bed. Chronic insomniacs often overvalue their time in bed and find the prospect of being out of bed abhorrent. They do not want to miss the opportunity for any potential sleep. The prescription of this technique should be framed positively so that the patient can view the time out of bed as an investment in better future sleep. Considerable discipline in following the guidelines is required for a positive result, but many patients respond very well to this approach.
Sleep Restriction Therapy
The excessive time some chronic insomniacs spend in bed can undermine their recovery. Sleep may occur intermittently over a long period. Maximal reinforcement of the circadian influence is reduced. Sleep-restriction therapy (14) attempts to consolidate sleep by limiting time in bed to specific hours. The schedule depends on the patient's perception of total sleep time. For example, patients who report only 5 hours of sleep at night are told that they may be in bed only from 3 a.m. until 8 a.m. As sleep efficiency increases during this restricted time, the bedtime hour gradually is advanced. The wake-up time remains constant to promote regularity in the circadian pattern. The efficacy of this method has been confirmed in at least one clinical trial (15).
Circadian Manipulations
Successful treatment of insomnia may require paying attention to fundamental circadian principles. Transient insomnia secondary to jet lagcan be minimized with the appropriate timing of activity and bedtime before and after the travel. Generally it is advisable to begin following the day–night pattern of the new time zone as quickly as possible. This allows more rapid entrainment as advantage is taken of external reinforcing stimuli, particularly sunlight. In some cases, problems associated with shift work also can be decreased to a limited extent with strategic manipulation of sleeping hours and light exposure (16).
Basic recommendations include regularity in timing of the sleep–wake cycle to maximize circadian reinforcement. Specific guidelines about bedtime, wake-up time, and bright light exposure are advisable in selected cases. Delayed sleep phase syndrome (discussed earlier) may be treated with varying degrees of success by a program of gradually advancing the wake-up time. Exposure to bright light (sunlight or therapeutic light boxes) soon after the wake-up time should help in resetting the underlying circadian clock. Bright light late in the day should be avoided. Advanced sleep phase syndrome may be treated with evening bright light exposure and the avoidance of bright light around dawn.
Hypnotic Medications
Hypnotic medications may play a valuable role in the treatment of selected patients. The use of hypnotics should always be part of an integrated approach that includes measures to promote sleep hygiene and psychotherapeutic support. The hypnotics may be used to help the patient during a stressful period and thereby hasten a return to a normal sleep–wake pattern. Hypnotics also may be beneficial in re-establishing a regular sleep cycle after time zone and work schedule shifts. A meta-analysis of clinical trials confirmed the efficacy of the benzodiazepine receptor agonist hypnotics for the short-term treatment of insomnia in adults younger than 65 years of age (17).
Until 2005, all prescription hypnotics shared the class-labeling indication “for short-term use” (e.g., no more than 3 or 4 weeks), although it was evident that selected patients continued to benefit from longer-term use. The prescription sleep-promoting medications approved since 2005 no longer have a short-term indication, and therefore where clinically indicated, longer-term use is supported in the U.S. Food and Drug Administration (FDA)-approved label. Generally, the lowest effective dosage should be prescribed for the shortest possible duration. These medications may be used nightly; however, intermittent use (e.g., 2 to 4 nights per week) should be encouraged for many patients. Rarely is it necessary to recommend a dosage higher than that specified in the prescribing information.
Medications from several classes are used for their hypnotic effects. The predominant ones are the barbiturates (secobarbital, amobarbital, and pentobarbital) and related compounds (chloral hydrate, ethchlorvynol, and methyprylon); the benzodiazepines and related compounds (Table 7.9); sedating antidepressant medications (see Chapter 24); and over-the-counter antihistaminic preparations (18).
The barbiturates were the mainstay of prescription hypnotic use until the introduction of the benzodiazepines in the 1960s and 1970s. Thebenzodiazepines are much safer (decreased toxicity and potential for lethal overdose, fewer and less-severe withdrawal effects, and reduced potential for abuse and dependence). There is no reason to use barbiturates in the routine management of insomnia. Of the older prescription nonbarbiturate hypnotic agents, chloral
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hydrate (500-mg tablet) has the best safety profile, but tolerance and toxicity limit its use.
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TABLE 7.9 Benzodiazepine and Related Hypnotic Medications |
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Sedating antidepressants with minimal anticholinergic action, such as trazodone, have been used successfully in promoting sleep. They are especially helpful for depressed patients who have disturbed sleep. Although some nondepressed patients with insomnia respond well to low dosages of these medications, there is little evidence to support this recommendation (19). Characteristics of the antidepressants are described in Chapter 24.
There is a confusing array of products now available in the nonprescription sleep aid market. Although some include antihistaminic agents(diphenhydramine, hydroxyzine, doxylamine, and pyrilamine), others contain no ingredients with demonstrated sedative or sleep-promoting characteristics. Among the antihistamine preparations, diphenhydramine is the most common and is present in various pill forms with doses of 25, 38, and 50 mg. Their hypnotic efficacy is limited compared with that of the benzodiazepines. The antihistamines may promote anticholinergic side effects, including urinary retention and delirium, so they should be used cautiously in elderly individuals and in people taking other medications with anticholinergic activity (e.g., some antidepressants). The relatively long elimination half-lives of antihistamines commonly promote residual sedation the morning after bedtime use.
Benzodiazepine hypnotics, zolpidem, zaleplon, and eszopiclone (positive allosteric modulators of the γ-aminobutyric acid A receptor complex) are widely prescribed for insomnia. Zolpidem now is available in a controlled-release formulation. The approval of indiplon in immediate- and modified-release formulations is anticipated. All are classified as schedule IV drugs under the federal Controlled Substance Act. Their proper use requires knowledge of their onset and duration of action. All benzodiazepines marketed as hypnotics are rapidly absorbed and therefore have an acceptable onset of action. The duration of action depends on several factors, including volume of distribution, solubility in fat, elimination half-life, and presence of active metabolites. The age of the patient also may be a factor; elderly patients generally have extended elimination periods, as may patients with liver impairment.
The benzodiazepines and related hypnotics can be categorized according to their duration of action (Table 7.9). The advantages and disadvantages of the shorter- and longer-acting medications should be considered in selection of a hypnotic.
Shorter-acting hypnotics (i.e., those of short and intermediate duration) have the advantage of producing minimal residual daytime sedation. Excessive daytime sleepiness can be a major problem with longer-acting agents, particularly flurazepam. In addition, impairment of daytime performance and an increased propensity for falls in elderly patients may be associated with the longer-duration hypnotics. On the other hand, the longer-acting medications may be useful when a daytime anxiolytic or sedative effect is desired.
Less-common side effects of benzodiazepines include dizziness, headache, and disinhibited or bizarre behaviors. Ataxia, slurred speech, or confusion may be seen at higher dosages. Interdose anxiety and anterograde amnesia have been reported with triazolam in rare cases. Caution is advised in using benzodiazepines for patients with hepatic, renal, or respiratory impairment. Additionally, they should be avoided during pregnancy and lactation. Cumulative effects with other central nervous system depressants always must be considered.
A gradually tapered dosage often is useful when discontinuing a benzodiazepine hypnotic to minimize withdrawal or rebound insomnia symptoms. This helps reduce patient discomfort after extended use of hypnotic agent. Patients may confuse physiologically predictable symptoms of discontinuation insomnia with the belief that they inherently are unable to sleep without the sleeping pill. Patient education is vital to successful treatment. The longer-acting hypnotics tend to be associated with less pronounced withdrawal symptoms than are the shorter-duration compounds. An exception may be the reported minimal withdrawal symptoms associated with the short-acting nonbenzodiazepine agents. When discontinuation insomnia is present, it tends to occur earlier with the shorter-acting agents. Withdrawal from longer-acting hypnotics may be delayed for several days after discontinuation. A rebound insomnia syndrome has been reported with sudden discontinuation of triazolam, which has an especially short half-life.
The question of abuse often influences the decision to initiate hypnotic treatment. This issue was examined in a task force report by the American Psychiatric Association
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(20). It was concluded that most patients who take benzodiazepines do so for limited periods and according to the prescription guidelines. It was noted that benzodiazepine abuse occurs most commonly in patients who are concurrently abusing alcohol and/or other substances (seeChapters 28 and 29). Accordingly, particular caution is recommended with such patients.
In summary, benzodiazepines and related hypnotics can be used effectively in selected patients when they are prescribed as part of an overall treatment plan. The pattern of the patient's sleep disturbance helps guide selection of a hypnotic agent. Sleep-onset insomnia may respond well to a short-acting agent. A sleep-continuity problem may be helped more by a medication of short or intermediate duration.
Ramelteon (Rozerem) was recently approved by the FDA for the treatment of insomnia characterized by difficulty with sleep onset. This medication has a novel mechanism of action that does not promote sedation, but rather targets the sleep-promoting and circadian rhythm reinforcement activity in the suprachiasmic nucleus. It is a selective agonist for the MT1 and MT2 melatonin receptor subtypes. Because studies suggest an absence of abuse liability, it has been approved as the first nonscheduled sleep-promoting medication. The recommended dose of ramelteon is 8 mg approximately 30 minutes prior to bedtime.
Narcolepsy and Idiopathic Hypersomnolence
The management of narcolepsy includes pharmacologic and nonpharmacologic approaches to excessive daytime sleepiness (6). Nonpharmacologic treatments (Table 7.10) should be used by all narcoleptic patients whenever possible. The first of these approaches isactivity. As long as narcoleptic patients continue some level of physical activity, a reasonable degree of alertness usually can be maintained. Adding exercise to the daily schedule further enhances the alertness. Brief naps (10 to 30 minutes), preferably taken on a scheduled basis (e.g., work breaks, lunchtime), are a valuable strategy for maintaining alertness throughout the day. Caffeinated beverages may be used for a short and quick pick-me-up, whereas food may attenuate alertness. These various approaches may be used alone or in combination for the best effect. For example, at lunchtime a light meal may be taken or avoided altogether. This may be followed by a brief nap and 30 minutes of mild to moderate activity. A brief nap followed by consumption of a caffeinated beverage may be used just before a conference or just before driving to or from work. In fact, narcoleptic patients should be instructed about the dangers of driving. If they feel tired while driving, they should not push themselves but should pull off the road as soon as possible, take a brief nap or get out of the car and walk, or drink a cup of coffee. The final concern is nocturnal sleep. Extra nighttime sleep has no effect on daytime alertness and sleepiness. However, disturbed sleep at night produces greater problems during the day. Patients need to maintain normal sleep habits when possible. Staying out late at night, working two jobs, performing shift work, or living on 4 or 5 hours of sleep compounds the underlying sleepiness in patients with narcolepsy.
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TABLE 7.10 Nonpharmacologic Treatment of Narcolepsy |
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The pharmacologic treatment of daytime sleepiness and diminished alertness involves the use of stimulant medication (Table 7.11). Attempts to completely normalize a patient with narcolepsy are problematic and often lead to marked frustration and frequent failure. It is important to identify specific difficulties for targeted use of stimulants (e.g., falling asleep while driving or during meetings, inability to concentrate while at work or during the afternoon). The patient should understand that the ideal of full alertness throughout a 16-hour waking period should not be the ultimate goal of the medication management. Specific times and activities for maximum alertness should be planned. Both pharmacologic and nonpharmacologic treatment must be structured to suit the problems that have been identified. Moreover, patients should be aware that the same amount of medication need not be given every day or at the same time each day. Drug holidays and weekends off stimulants should be established as often as possible. A persistent increase in heart rate and blood pressure is not uncommon with these medications. Addiction to amphetamine or methylphenidate may occur in rare cases. Weight loss, agitated behavior, tachycardia, hypertension, diaphoresis, end-of-dose depression, and high expectation or strong social pressure to be normal are characteristics of psychophysiologic dependence. In patients who exhibit these characteristics, efforts should be made to withdraw the medication under optimal conditions. This might include support from a chemical dependence service and a specialist in narcolepsy.
The cataplexy of narcolepsy may improve when either pharmacologic or nonpharmacologic therapies are used in the management of excessive daytime somnolence. Many patients with cataplexy make adaptive changes in their personal and social lifestyles. These changes may reduce or eliminate emotional precipitants in the environment. However, even with the therapies previously described
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and lifestyle adaptations, cataplexy may remain a significant problem. Frequent and severe cataplexy usually warrants a pharmacologic approach. Previously, tricyclic antidepressants were the primary medication used for this problem. Now, the selective serotonin reuptake inhibitors (SSRIs) should be the first choice for treatment of cataplexy. The standard antidepressant doses often are sufficient (see Chapter 24). If several SSRIs have been tried and have not proved to be completely effective, then a trial on venlafaxine (Effexor) should be considered. The use of a tricyclic antidepressant may be necessary if these initial approaches are unsuccessful. The FDA has approved sodium oxybate (Xyrem) for the treatment of cataplexy in patients with narcolepsy. Evidence also suggests that this medication benefits nighttime sleep quality and daytime alertness for those with narcolepsy.
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TABLE 7.11 Stimulant Medicationa,b |
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The tricyclic antidepressants can be used to treat sleep paralysis and hypnagogic hallucinations. Protriptyline 5 mg can be given about 1 hour before bedtime if the paralysis or hallucinations occur near sleep onset. Otherwise, the medication can be given at bedtime.
The management of idiopathic hypersomnia is less clear-cut than that for narcolepsy. The stimulant medications outlined in Table 7.11 are used, but with less-predictable benefits. The use of nonpharmacologic methods, as outlined for narcolepsy, is even less beneficial in this condition. These patients have moderate to severe disabilities related to their excessive daytime tiredness.
Sleep-Disordered Breathing
The treatment of obstructive sleep apnea continues to evolve. Usually patients are referred for management of abnormal breathing events that are associated with daytime sleepiness or fatigue. Although SDB may occur in the absence of sleepiness, there is increasing evidence that even 5 to 10 SDB events per hour may predispose to increased cardiovascular risk (10,21,22) and thus warrant some form of treatment. Patients with comorbid conditions such as diabetes, cardiopulmonary disease, or underlying neurologic disease should be considered a high priority for treatment to reduce further exacerbations of their underlying disease.
The most recent epidemiologic studies (21,22) offer strong support to the hypothesized association between SDB and hypertension. Both the Sleep Heart Health Study and Wisconsin Sleep Cohort evaluated more than 6000 and 700 individuals, respectively, for multiple factors, including sleep characteristics and hypertension. These cross-sectional, community-based, multicenter studies have demonstrated an independent relationship between increasing SDB measures and hypertension.
Management options for an individual patient often are recommended by the consultant who has evaluated the patient with a formal sleep study (see Management of Sleep Disorders). Initial management should emphasize correction of associated medical conditions such as hypothyroidism (23), severe tonsillar hypertrophy, and obesity. Central nervous system depressants, if prescribed, should be discontinued. Although the mechanism is still unknown, it is clear that loss of as little as 10% to 15% of body weight may markedly improve the severity of the sleep apnea (24). Because most patients are 30% to 40% above ideal body weight, the minimal amount of weight reduction expected does not represent an unrealistic goal (see Chapter 83).
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Continuous positive airway pressure (CPAP) remains the mainstay of therapy for symptomatic patients with moderate to severe disease (25,26, 27). The patient is fitted with a cuplike mask that forces air, usually from a small stationary unit in the bedroom, into the nasal airway. The pressure from the continuous airflow prevents upper airway collapse during sleep. Careful adjustment of pressure is important because patient compliance depends on elimination of apnea and symptom improvement. Patients experience a pressure sensation in the upper airway and the ears when first using the mask. Drying of the mucosal membranes and rhinorrhea can be reduced by adding a humidifier to the inspired air, and nasal congestion is improved by the addition of decongestants. Most patients experience immediate and dramatic improvement in their daytime sleepiness. If fact, there often is a significant impact on the patient's mood and quality of life. If this does not occur, compliance may be inadequate; otherwise, inadequate sleep or another concomitant sleep disorder should be suspected (28). It is expected that successful treatment of SDB with CPAP will decrease associated risks, such as cardiovascular morbidity.
Selection of surgical measures to alter upper airway anatomy requires consultation with an otolaryngologist. Although tracheostomy was used regularly in the past for the treatment of this syndrome, it is performed now only when other forms of therapy fail. Palatopharyngoplasty usually is considered after medical therapy has been tried; however, at present there is insufficient evidence from controlled trials to support the use of surgery for obstructive sleep apnea (29). Presently there are limited data to support the use of oral appliances. Although sometimes preferred by patients, they appear to be less effective than nasal CPAP (30).
Patients with significant cor pulmonale appear to benefit from oxygen therapy. These patients usually have evidence of hypoxemia both when awake and when asleep; therefore, continuous 24-hour oxygen therapy usually is indicated. When central sleep apnea is recognized, the patient should be evaluated for signs and symptoms of congestive heart failure. As a general rule, use of oxygen reduces, but does not eliminate, episodes of obstructive sleep apnea. The use of oxygen does not have a primary independent role in the treatment of SDB, but it may be beneficial with underlying pathology.
Currently, no therapies for central apnea consistently reduce the frequency of events. However, administration of oxygen may reverse any associated hypoxemia and bradyarrhythmias. CPAP and various respiratory stimulants have produced conflicting results. However, the central sleep apnea associated with Cheyne-Stokes respiration appears to respond to CPAP or theophylline, as well as to treatment of the underlying heart failure that commonly is associated (31,32). The management of nonapneic snoring is described in Chapter 111.
Restless Legs Syndrome
Nonpharmacologic methods to improve the symptoms of RLS have not been consistently effective (33). Exercise and prolonged soaking in a hot bath usually eliminate the symptoms, and there may be attenuation of the symptoms for a brief period after the patient stops exercising or gets out of the hot bath. This reprieve may be sufficient to allow the patient to fall asleep, but it has little effect on subsequent development of nighttime leg movements.
For patients who ask for treatment, a pharmacologic approach to symptom management is the most consistently successful strategy. The medication strategies outlined here may be beneficial for PLMD also. Currently, for the treatment of most RLS cases, the dopamine agonists (Table 7.12) are the first choice, even before levodopa, a dopamine precursor. At best, patients may experience a dramatic improvement or complete disappearance of both the uncomfortable daytime and evening sensations, as well as of the sleep-related limb movements. There may be
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rapid improvement soon after initiation of the dopamine agonist, although maximum effectiveness many not be evident for several weeks. For many patients, experimentation with different medications and doses is necessary for an optimal response.
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TABLE 7.12 Dopamine Agents for Restless Legs Syndrome (RLS)a,b,c |
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The single most common side effect of the dopaminergic agents is an augmentation of the symptoms. RLS augmentation is seen as a temporal redistribution of the underlying symptoms: The late-night symptoms become early evening symptoms. If the dosage is increased further, RLS symptoms may begin in the early afternoon, or, worse, become an all-day-long problem. With RLS augmentation, symptoms may extend well beyond the legs and involve the shoulders, hands, arms, and trunk. Augmentation can be so severe as to cause a condition indistinguishable from neuroleptic-induced akathisia. At this stage, progressive increments in the daily dose lead to a worsening of symptoms between doses and a shortening of the duration of the medication effectiveness. If augmentation occurs, the choice is to make no further increments in the medication or to change to a nondopaminergic agent.
The opiates are probably the next most effective agents for the treatment of RLS. Opiate effectiveness for RLS does not necessarily parallel analgesic potency. Relatively mild analgesics, such as propoxyphene and tramadol, may be more effective than oxycodone. Several different opiates should be tried before considering this medication class ineffective. Patients who have responded well to opiates and who are taking the medication three or more times per day may benefit from changing to a longer-acting preparation, or perhaps to methadone. The management of RLS may be sufficiently complicated that referral to a sleep disorder center is warranted. Practical details regarding all classes of dopaminergic medications are found in Chapter 90.
Benzodiazepines and gabapentin may provide another line of treatment if opiates and dopamine agonists fail. However, at this stage, the patient should be assessed by a sleep disorder specialist. If the patient's symptoms are associated with pain or other painful conditions (e.g., neuropathy, back pain, arthritis), then gabapentin or opiates may be employed as first-line agents.
Sleepwalking, Sleep Terrors, and Confusional States
These arousal disorders are viewed as emanating from slow-wave sleep. Sleep deprivation for any reason enhances slow-wave sleep on recovery nights and increases the likelihood of these events in vulnerable people. Accordingly, appropriate recommendations always include minimizing situations that increase sleep loss. Vulnerable people also are more likely to experience episodes during stressful periods. Stress reduction techniques may be helpful for some patients, and psychotherapy may be indicated in selected cases. In some cases, presleep suggestions are beneficial. In a relaxed state at bedtime, the patient can focus on anticipated sleep-related behavior and can reaffirm that he or she will be safe and will do no harm. The sleepwalker can gradually limit the boundaries of wandering in this manner.
The severity in these disorders may be reflected in the frequency of the events and the dangerousness of the behaviors. Particularly severe cases (e.g., multiple episodes per week or less-frequent incidents resulting in injury) may be appropriate for pharmacologic treatment. In theory, substances that decrease the intensity and duration of slow-wave sleep should decrease the symptoms. This seems to be the case with the benzodiazepines. Successful extended treatment has been accomplished with clonazepam 0.5 mg at bedtime. Some individuals with frequent arousal disorders benefit from nightly zolpidem, although this is not within the scope of FDA approval for this medication. Patients with REM behavior disorder, although it is not associated with slow-wave sleep, often respond well to treatment with clonazepam.
Enuresis
Primary enuresis in the adult, which is not associated with a particular sleep stage, warrants urologic evaluation. The absence of demonstrable organic pathology should not discourage treatment attempts. Several strategies used in children also may be beneficial for adults. Behavioral management is the initial treatment of choice. Conditioning of the urge to urinate and going to the bathroom can be developed with pad and alarm systems (Wet-Stop, Palco Laboratories, Santa Cruz, CA). Standard medication trials have included tricyclic antidepressants. Intranasal desmopressin has been used successfully in many cases (34).
Sleep Center Referral
For a number of the problems discussed in this chapter, referral for expert evaluation and management is recommended. The evaluation of patients with sleep disorders often includes consideration of referral for sleep laboratory evaluation. Because sleep laboratories are now more accessible, it is possible to refer the patient either directly to a laboratory for specific sleep studies or to an expert at a sleep center who may be useful in determining the specific type of sleep test to be conducted. Often, a consultant recommends adjustments in medications or in the sleep–wake cycle before suggesting a sleep study. More importantly, interpretation of the sleep laboratory results and an explanation to the patient must be made by someone familiar with these studies. Currently there are more than 350 sleep disorders centers accredited by the American Academy of Sleep Medicine (AASM). The AASM (One Westbrook Corporate Center, Ste. 920, Westchester,
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IL 60154; or http://www.aasmnet.org) can supply the locations of these centers.
Patient Experience
When patients are evaluated at a sleep center, they undergo a careful historical review of their sleep problem and a general physical examination. An all-night sleep study (polysomnogram) may be scheduled to evaluate sleep objectively. The polysomnogram is performed using noninvasive simultaneous measurements of a number of physiologic activities during sleep: eye movements, brain activity by EEG, submental and anterior tibialis muscle activity, respiratory air flow and effort, cardiac rhythm, and continuous blood oxyhemoglobin saturation.
A MSLT, a day test involving four or five 20-minute naps spaced 2 hours apart, may also be scheduled. For this nap test, patients stay in their usual sleeping clothes and are asked to remain awake between the naps. A full-sleep EEG is recorded as for the polysomnogram; however, respiration and oxygen saturation measurements either are not made or are used in a limited form because the primary question addressed by this test is the degree of excessive sleepiness. The time required for the patient to fall asleep (sleep latency) during these naps provides the measure of the patient's sleepiness. The nap test usually is scheduled for the day after the nighttime polysomnogram. A typical schedule for the patient in the sleep laboratory is 8:30 p.m. to 8 a.m. for the polysomnogram and 8 a.m. to 4:30 p.m. for the nap tests.
Specific References*
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