More than half of the population experiences significant difficulties with sleep at least on occasion, and as many as one in five persons suffers from chronic sleep problems. Disruption of sleep and waking is the most prevalent health disorder in the United States. Falling asleep while driving, for example, is thought to be responsible for at least 100,000 traffic accidents every year. Lack of sleep was a contributing factor in the disasters at the Three Mile Island and Chernobyl nuclear power plants.
Millions of people struggle through daily life sleepy, and many are irritable or unmotivated owing to disruptions in sleep. As a result, sleep disorders are common in general medical practice. Most sleep problems have mundane causes and may simply require a change in habit. Others involve complicating factors such as shift work, depression, or substance abuse. Some sleep disorders now provide new insights into brain function.
As sleep is organized into several cyclical, roughly 90-minute periods of REM and non-REM sleep, each component can be disrupted. The most common disorders are related to a breakdown in the transition between sleep and waking, such as difficulty falling asleep or early morning wakening. More than half of adults experience insomnia at some point each year. Their sleep is either too short, difficult to obtain, or not refreshing. The lack of adequate or fulfilling sleep often leads to another common complaint: daytime sleepiness.
Other sleep disorders may represent a breakdown in specific neural circuits. For example, sudden activation of the inhibitory descending motor pathways during the waking state can lead to bouts of cataplexy (loss of muscle tone), which is often associated with narcolepsy (described below). The opposite can also happen. In REM behavior disorder the descending inhibitory motor pathways do not function during REM sleep, such that the affected individual may jump up and move about during vivid dreams.
In other sleep disorders circadian rhythmicity may fail, resulting in a phase advance or phase delay in the sleep-wake cycle. Finally, sleep may be associated with inappropriate or unwanted behaviors such as night terrors, sleep walking, tooth grinding, bed wetting, and so on. These unusual behaviors disrupt sleep and are collectively known as parasomnias.
Insomnia Is the Most Common Form of Sleep Disruption
Insomnia, the most common form of sleep disruption, can be prolonged and severe or temporary and mild, as in response to short-term stress. The incidence of insomnia increases with age and is more common in women. Insomnia can manifest as difficulty falling asleep, difficulty staying asleep through the night, or early morning awakening before sufficient sleep is obtained. Insomnia may result from physical or emotional complications or simply from poor sleep habits (eg, consumption of excessive caffeine, alcohol, or food, or exercising vigorously before sleep). Insomnia is often associated with depression where early morning awakening is common.
Benzodiazepines, commonly used as anxiolytics (mild tranquilizers), are also commonly used for short-term treatment of insomnia. Benzodiazepines facilitate the opening of GABAA (γ-aminobutyric acid type A) receptor-channels through a binding site separate from that for GABA. Although these drugs facilitate sleep, they also suppress stage 4 sleep. Chronic use may be habit-forming and lead to a lightening and fragmentation of sleep. A related compound, zolpidem (sold under the trade name Ambien), binds selectively to a subset of benzodiazepine receptors, does not suppress deep sleep, and is considered relatively selective for facilitating sleep. It is therefore safer than general benzodiazepines for treatment of insomnia.
Over-the-counter sleep aids are often antihistamines (H1 histamine receptor antagonists). Antihistamines are sedative in some individuals because they antagonize the activation of H1 receptors, which normally excite thalamic and other central neurons. Muscarinic ACh receptor antagonists also have sedative effects, although these vary between individuals. Anticholinergic actions are common to many psychoactive drugs, such as tricyclic antidepressants, and therefore these drugs are used for insomnia. As discussed earlier, activation of muscarinic ACh receptors in the brain has a general arousal effect by exciting the principal neurons and, in some parts of the brain, by inhibiting GABAergic inhibitory interneurons.
Excessive Daytime Sleepiness Is Indicative of Disrupted Sleep
Sleepiness during the day is the primary complaint of individuals seeking help at hospital sleep centers. The invention of electric lights has allowed people to stay active well into the night. The increasing demands of work, family, and social life along with ever increasing opportunities for entertainment have led to a dramatic shortening in the time spent asleep, from an average of 10 to approximately 7 hours.
This trend has led to a chronic sleep deficit in the average adult that affects not only mood and general feelings of well being, but also work or school performance. Sleep deficit can be dangerous, as when driving or operating machinery. Telltale signs of insufficient sleep include unusually short sleep-onset latencies (less than 15 minutes), the need to sleep in on weekends, overuse of stimulants such as caffeine, and dependence on an alarm clock to wake up in the morning.
Excessive daytime sleepiness is a symptom of several underlying sleep disorders including sleep apnea, narcolepsy, and restless leg syndrome. Sleep apnea and restless leg syndrome are two of the most prevalent disorders that lead to daytime sleepiness, largely through a reduction in the quantity and quality of sleep. Narcolepsy is present in only a small fraction of the population but is devastating in its negative effects.
The Disruption of Breathing During Sleep Apnea Results in Fragmentation of Sleep
Reduction of muscle tone can result in either an annoying disturbance of sleep, as in snoring, or in greatly disturbed sleep, as in sleep apnea (cessation of breathing). Approximately 4% of middle-aged men (2% of middle-aged women) have sleep apnea. At older than age 65 years these percentages increase to more than 28% of men and 24% of women.
Sleep apnea is a serious condition, for it not only disrupts sleep but also can cause excessive sleepiness during the day, early morning headaches, depression, irritability, sexual dysfunction, and learning and memory difficulties. In severe cases sleep apnea can lead to cardiac dysfunction and be life-threatening.
The most common form of sleep apnea, obstructive sleep apnea, results from a physical obstruction of the pharynx. Breathing ceases for 10 or more seconds. A pathological condition involves at least 5 to 10 of these interruptions per hour. In central sleep apnea the disruption of breathing has a neurological origin. In either type of sleep apnea the decrease in blood oxygen tension and increase in CO2 leads to an arousal response (but not complete awakening). The period of apnea ends with a deep breath, and the sufferer then falls back into a deeper sleep, only to repeat the cycle once again (Figure 51–8).
An episode of sleep apnea is captured in this polysomnogram, a simultaneous record of various bodily functions.
Sleep apnea disrupts normal sleep patterns. The episode shown here includes cessation of breathing. Decreases in respiratory effort and airflow result in the cessation of snoring and a decrease in oxygen saturation. The slowing of the heart rate and appearance of sleep spindles during the apnea episode indicate that the individual is asleep. The period of apnea is preceded and terminated by arousal and leg movements. (EEG, electroencephalogram; EKG, electrocardiogram; EMG, electromyogram.)
These frequent disruptions cause fragmentation of sleep, a general decrease in quality of sleep, and therefore daytime sleepiness. Because the affected individual usually does not become fully awake with each apneic period, he may be completely unaware of the problem except for the resultant daytime sleepiness or the concern of a friend or spouse who observes an apneic spell. This pattern is usually easy to diagnose in a sleep laboratory.
REM sleep is especially conducive to sleep apnea owing to the characteristic reduction in muscle tone, which facilitates collapse of the airway. During REM sleep responses to hypoxia are reduced, and the response to increases in carbon dioxide levels (hypercapnia) is completely lost. In addition, the brain stem mechanisms responsible for regulation of blood O2 and CO2 levels are weakened, allowing these levels to drop well below those that would be tolerated in the waking state. Obesity can be a precipitating factor for obstructive sleep apnea because airflow through the pharynx is typically reduced.
Obstructive sleep apnea is treated by keeping the pharynx open with positive pressure through a face mask. This treatment can lead to an almost immediate reversal of the symptoms, a more restful sleep, and a reduction in daytime sleepiness. However, most patients eventually reject use of the mask because they find it too uncomfortable or claustrophobic to use consistently.
Narcolepsy Is Characterized by Abnormal Activation of Sleep Mechanisms
Narcolepsy occurs in approximately 0.04% of the population or approximately 120,000 people in the United States. It is characterized by a breakdown in the transition between waking and sleep. Sleep and sleep mechanisms invade daytime periods, often at inappropriate times, and sleep at night is fragmented and disrupted by multiple awakenings. Narcolepsy is characteristically manifested in five symptoms, some or all of which may be seen in any one individual.
The most prevalent symptom is excessive daytime sleepiness and irresistible "sleep attacks" during the waking hours. These sleep attacks (usually less than 20 minutes) can come at any moment and sometimes are a source of embarrassment. For example, falling asleep during conversation or at work may lead to the incorrect assumption that the narcoleptic is uninterested in the conversation or in doing a full day's work. Sleep attacks are precipitated by any behavior that is relatively passive and boring such as watching television, driving a car, or studying for finals. Unfortunately, sleeping does not completely alleviate the tendency to have sleep attacks.
A second symptom, cataplexy, occurs in approximately 70% of narcoleptic patients. Cataplexy is a sudden bilateral loss of muscle tone, typically in the knees and face and neck, leading to a sagging of the jaw and falling to the floor. Consciousness is preserved, however, and the sufferer is typically awake but feels either unable or barely able to move. The onset of a cataplexic episode occurs over a couple of seconds; the episode itself lasts for seconds but in rare instances can last minutes. Emotion, most typically laughter, can provoke an attack, perhaps owing to the fact that during laughter there is a general decrease in muscle tone. Cataplexy is thought to result from abnormal activation of the motor inhibition that normally occurs during periods of REM sleep.
Third, vivid dreamlike experiences may occur during the transition between sleep and waking. These events are known as either hypnagogic (sleep onset) or hypnopompic (sleep offset) hallucinations. What differentiates them from dreams is that the narcoleptic person is not fully asleep and is aware that he is not dreaming—the images seem real. The dreamlike experiences are typically bizarre, frightening, and unpleasant; they are predominantly visual, although auditory and tactile experiences are also frequent. As with dreams, sensations of smell or taste are rare. Hallucinations of this type may also occur in normal people at transitions between sleep and waking.
A fourth symptom, sleep paralysis, also typically occurs in the transition between sleep and waking (either going to sleep at night or waking in the morning). Unlike cataplexy it is not triggered by emotion and episodes last longer, sometimes up to 10 minutes. As sufferers are unable to make even the smallest of movements, such as opening their eyelids or lifting a finger, the experience is frightening and unpleasant. As with cataplexy it is assumed that sleep paralysis results from inappropriate activation of the inhibitory descending motor pathways that are normally responsible for inhibiting movement during REM sleep. Sleep paralysis also occurs in non-narcoleptics (up to 30% of the general population).
The final symptom of narcolepsy is disturbed nocturnal sleep. Although narcoleptics may fall asleep quickly and often immediately fall into REM sleep (Figure 51–9), their sleep is interrupted by frequent arousals. For most narcoleptics these awakenings are brief, but some may stay awake for hours at night.
In narcoleptic patients sleep can initiate with REM sleep.
A. Sleep onset in a normal person is associated with slow rolling eye movements and a slow decrease in muscle tone.
B. Sleep onset in a narcoleptic is associated with a sudden decrease in muscle tone and the appearance of rapid eye movements typical of REM sleep. The REM sleep that occurs at the beginning of sleep usually lasts 10 to 20 minutes, after which sleep progresses through stages 1 through 4 of non-REM sleep. (EEG, electroencephalogram; EMG, electromyogram; EOG, electro-oculogram.)
A diagnosis of narcolepsy requires a minimum of either (1) daytime lapses into sleep and cataplexy or (2) a pattern of excessive daytime sleepiness, sleep paralysis, or hypnagogic or hypnopompic hallucinations, and a polysomnogram demonstrating a short latency to sleep and a period of REM sleep either at the beginning of sleep or shortly thereafter.
The different components of narcolepsy are treated with different pharmacological agents. The excessive sleepiness and sleep spells of narcolepsy are typically treated with central nervous stimulants such as amphetamines. These agents enhance the release of catecholamines and inhibit their reuptake. Cataplexy is treated with tricyclic antidepressants, which inhibit the reuptake of norepinephrine and serotonin and are potent inhibitors of REM sleep.
Both genetic and environmental factors contribute to narcolepsy. In only 1% of cases does narcolepsy run in a family and only approximately one-fourth of identical twins are concordant for narcolepsy. Thus narcolepsy genes appear to confer merely a susceptibility to narcolepsy, whereas environmental factors contribute strongly. By studying narcoleptic dogs, Emmanuel Mignot found that these animals have a defect in the gene coding for the hypocretin-2 receptor. Hypocretin-1 and -2 (also called orexin A and B) are neuropeptides produced in a small cluster of neurons within the hypothalamus that project widely throughout the brain, including the brain stem nuclei responsible for REM sleep (eg, locus ceruleus). Activation of hypocretin receptors in locus ceruleus and other neurons has a slow excitatory effect. Through an unknown mechanism, a loss of this or other modulatory actions of hypocretin results in the abnormal differentiation of sleep and waking typical of narcolepsy.
To study the role of the hypocretin system in feeding behavior, Masashi Yanagisawa and collaborators knocked out the genes for both hypocretin-1 and -2 in mice and found that these mice displayed symptoms typical of narcolepsy. In narcoleptic humans the cerebral spinal fluid levels of hypocretin are remarkably reduced even though the hypocretin genes are not mutated. Immunocytochemical examination of the brains of deceased narcoleptics has revealed a striking loss of hypocretinergic neurons (Figure 51–10).
Narcolepsy is associated with a loss of hypothalamic neurons that produce the peptide hypocretin.
A dramatic loss of neurons is evident in the brain of a narcoleptic compared to a normal brain. The inset illustrates the positive identification of a hypocretinergic cell from a normal person. (f, fornix.) (Reproduced, with permission, from Peyron et al. 2000.)
Restless Leg Syndrome and Periodic Leg Movements Disrupt Sleep
Restless leg syndrome occurs in approximately 8% of the population and is characterized by an irresistible urge to move the legs. This symptom occurs during the day but is usually worse at night while resting in bed. The patient may feel relief only by moving the legs either in bed or by walking about.
Approximately 80% of people suffering from restless leg syndrome also experience periodic leg movements in sleep, when the legs move for a few seconds every 10 to 20 seconds. These leg movements result in a lightening of sleep and therefore an increase in daytime sleepiness. The prevalence of restless leg syndrome and periodic leg movements increases greatly with age, becoming more common in the elderly.
Parasomnias Include Sleep Walking, Sleep Talking, and Night Terrors
Parasomnias are repeated disruptions of sleep that are relatively common and usually mild. They include sleep walking, sleep talking, confusional arousals, bed wetting, night terrors, and REM behavior disorder. Although not normally considered a sleep disorder, sudden infant death syndrome (SIDS) is an example of fatal respiratory failure that occurs during sleep (see Chapter 46).
Sleep walking, sleep talking, and confusional arousals are relatively common in children and typically occur during stages 3 and 4 sleep. These events may be precipitated by disturbing or arousing the child from deep sleep. For short events the EEG is a continued pattern of slow waves; for longer events the pattern changes to an "activated" pattern—low-voltage, desynchronized high-frequency activity—characteristic of waking. Usually sleepwalkers or talkers are unaware of an event and have no memory of it. Speech is largely incoherent during an event; remarkably sleep walkers are often able to avoid colliding with objects.
Night terrors also occur in stages 3 and 4 sleep and are common in children (approximately 2–3%). The child cries as if in great fear, perhaps with eyes wide open and heart rate greatly elevated, for several minutes or longer. Even though they may appear awake, they are actually asleep. During the episode they are inconsolable, and attempts to calm or wake the child may only cause the screams and fearful behavior to worsen. The child usually does not remember the night terror, in contrast to remembering nightmares. Thus night terrors are typically much more difficult for the parent than for the child.
During REM sleep descending inhibition of motor neurons in the spinal cord normally prevents people from acting out their vivid dreams. This descending pathway may be damaged in people suffering from REM behavior disorder (usually men and elderly people). During REM sleep the body may become rigid or extremely tense and may exhibit prominent muscle twitching in association with the phasic eye movements of REM sleep. If the dream has intense physical activity, the patient may even get out of bed and injure himself or his bed partner with his vigorous activity. The mechanisms underlying REM behavior disorder are not yet known.
Circadian Rhythm Sleep Disorders Are Characterized by an Activity Cycle That Is Out of Phase with the World
The most frequent circadian rhythm disorder involves problems with entrainment to the day-night cycle. A patient may find it impossible to fall asleep until very late at night, for example 3 a.m. (delayed sleep phase disorder or DSPD) or impossible to stay awake past the early evening hours, for example 7 p.m. (advanced sleep phase disorder or ASPD).
The most prevalent disruption of normal circadian rhythms occurs in those who work either part-time or full-time during the night. In some individuals forcing a lifestyle that is out of phase with the natural day-night cycle can lead to several medical problems, including unstable mood, vigilance impairments, colds, high blood pressure, stomach problems, and weight gain. In general, shift workers also experience a higher incidence of workplace and automobile accidents because of increased sleepiness.
In rare cases patients may lack an endogenous circadian rhythm or may not be able to synchronize their rhythm with that of the environment. As one can imagine, these disorders cause great difficulties for those afflicted.