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Difficulty with the regulation of sleep and wake states is present in up to 25% of the general population on a chronic basis and in up to one half of all individuals on occasion. For some, the primary concern is difficulty falling asleep, whereas for others it may be maintaining sleep or awakening feeling unrefreshed, even after a full night’s rest. Other individuals report excess daytime sleepiness, having difficulty maintaining alertness at inopportune or embarrassing times, or interference of sleepiness at times with productivity or even safety. The evaluation and treatment of such patients are the domains of sleep disorders medicine, a field that combines elements of neurology, psychiatry, pulmonary medicine, and otolaryngology.

One of the most important motivations to the development of the field of sleep disorders has been the recognition of the effect of these conditions on multiple aspects of health. For instance, insomnia, the most common sleep disorder, has been hypothesized to account for $10 billion to $15 billion in direct and indirect costs to society, is associated with substantial decrements in quality of life, has been hypothesized to predispose sufferers to a variety of medical disorders, and has been clearly documented to be associated with substantial incident risks of major depression and other psychiatric disorders. Similarly, obstructive sleep apnea is clearly associated with excessive daytime sleepiness and an increase in motor vehicle accidents and is believed to contribute to hypertension and, potentially, premature mortality.

A nosology of sleep disorders, the International Classification of Sleep Disorders, now in its second edition (ICSD-2),1 developed by the American Academy of Sleep Medicine (Table 15-1), has existed for more than 20 years. Its codes are consistent with the existing codes of the International Classification of Disease, 10th edition. The ICSD-2 organizes sleep disorders in eight categories on the basis of their predominant manifesting symptom and/or etiological basis: the insomnias; the sleep-related breathing disorders; hypersomnia not caused by a sleep-related breathing disorder; the circadian rhythm disorders; the parasomnias; the sleep-related movement disorders; and two miscellaneous categories comprising normal variants, isolated symptoms, and other sleep disorders. Readers are referred to Chapters 16 and 37 for detailed descriptions of obstructive sleep apnea and restless legs syndrome (RLS).

TABLE 15-1 International Classification of Sleep Disorders, 2nd Edition

NREM, non–rapid eye movement; REM, rapid eye movement.

Reprinted from American Academy of Sleep Medicine: International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd ed. Rochester, MN: American Academy of Sleep Medicine, 2005.


Insomnia is defined as a difficulty in falling asleep, a difficulty in staying asleep, or nonrestorative sleep (awakening feeling unrefreshed). It is usually classified as transient, short-term, or chronic, according to the duration of symptoms, although many affected individuals describe recurrent episodes of short-term insomnia, which complicates classification. It may also be classified, on the basis of the predominant insomnia complaint, as initial insomnia, sleep maintenance insomnia, or insomnia with premature terminal awakening. This division, however, is also overly simplistic, inasmuch as many patients with chronic or recurrent short-term insomnia have an evolution of symptoms over time: Initial insomnia may develop into frequent or prolonged nocturnal awakenings or a mixture of the two. Thus, etiological inferences based on the type of manifesting symptom are bound to be confounded by these symptomatic fluctuations.

Epidemiology, Consequences, and Diagnosis of Insomnia

Insomnia has also traditionally been characterized as primary or secondary on the basis of its presumed etiology. Insomnia is referred to as secondary when it is believed to be a symptom of an underlying medical, psychiatric, or sleep disorder, or when it follows medication use. This diagnosis is based on a plausible mechanism by which the underlying disorder causes insomnia (e.g., pain, shortness of breath), the occurrence of insomnia after that of the underlying condition, and a course that follows the severity of the underlying condition. According to this schema, treatment of the underlying cause should resolve the insomnia symptom. In contrast, primary insomnia is considered to be caused by physiological and cognitive hyperarousal, both within the sleep environment and during the day. The distinctions between primary and secondary insomnia have more recently been questioned, however, because of the difficulties in making this distinction, the recognition that secondary insomnia may evolve into primary insomnia, and the fact that some insomnia vulnerability factors may predispose persons with medical disorders to develop insomnia.

The point prevalence of insomnia that lasts more than a few weeks is approximately 10% to 15% of the general population.2 However, because of its association with medical and psychiatric illnesses, up to 50% of individuals seen in medical practices report at least mild insomnia.3 Results of studies in individuals older than 65 suggest a 5% incidence and a 5% to 15% yearly rate of remission of insomnia.4,5 Female gender, increasing age, psychiatric and medical illnesses, substance use, low income, unemployment, and being single are all risk factors for having insomnia, although some of these may be consequences of insomnia rather than vulnerability factors.68

There is increasing recognition of the adverse consequences of insomnia. Multiple studies have demonstrated that persistent insomnia is associated with a substantial increased risk of incident depression.9 Insomnia is also associated with globally worsened quality of life, even when psychiatric illness10 or medical comorbidity3 is accounted for. The decrements in physical functioning, general health perception, and vitality are as substantial as, or more so than, those observed with congestive heart failure.3 Furthermore, there are suggestions that insomnia is associated with an increased risk of work-related and motor vehicle accidents, as well as falls by elderly persons.11 Finally, health costs in individuals with insomnia are elevated, even when comorbid medical and psychiatric illnesses are accounted for.12

The concept of hyperarousal is being used to unify the understanding of the pathophysiology of primary insomnia.1315 From a physiological perspective, individuals with insomnia have elevated evening cortisol levels,16 increased 24-hour whole body metabolic rate,17 increases in both waking and sleep-related global cerebral glucose metabolism (Fig. 15-1),18 and high-frequency electroencephalographic (EEG) activity during sleep.19 It is unclear which neural circuits are responsible for these disparate findings. Similarly, cognitive arousal is considered to be central to the generation and maintenance of insomnia. It is hypothesized that cognitive and physiological hyperarousal become paired with the sleep environment, which gradually worsens sleep and increases these arousal processes in that setting, creating a vicious cycle of insomnia.15,20 Maladaptive compensatory strategies, such as spending excess time in bed, daytime napping, and alcohol and caffeine intake can then exacerbate this process.


Figure 15-1 Areas in which metabolism did not decrease from sleep to wakefulness in insomniac patients.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Nofzinger EA, Buysse DJ, Germain A, et al: Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161:2126-2168.)

The evaluation of patients with insomnia involves identifying the scope and duration of the complaint, including its effects on daytime functioning, and searching for potential etiologies. Behaviors and cognitions relevant to sleep during both daytime and evening should be solicited from the patient. In particular, explicit focus on the period in bed both before sleep and at nocturnal awakenings may assist with determining physical or mental events that interfere with sleep. Sleep diaries may help in elucidating predictable changes in sleep quality that are based on day of the week and/or work schedules. Factors that worsen or improve sleep quality longitudinally should also be identified.

Life events that have a temporal relationship to the onset of sleep problems can frequently assist in identifying potential causes of insomnia, particularly in individuals with insomnias of shorter duration. In individuals with chronic insomnia, such events may have occurred many years in the past and may not be clear, or the insomnia may have a more insidious waxing course of severity.

Identification of potential medical, sleep-related, and psychiatric causes of insomnia is essential for optimal treatment, because treatment of such causes may at times eliminate the insomnia complaint. Insomnia in elderly persons, in whom frequent nocturnal awakenings are the most common complaint, is particularly related to medical illness,21 and careful attention to patients’ medical problems may provide guides to the etiology of insomnia in this group. The most common medical disorders associated with insomnia are listed in Table 15-2. In addition, all psychiatric disorders can and frequently do cause insomnia, and assessments for depression and anxiety disorders are an essential feature of the insomnia evaluation. However, it should be made clear that approximately 40% of individuals with insomnia do not have a psychiatric disorder,22 and thus the assumption that insomnia is necessarily caused by psychiatric illness is ill founded.

TABLE 15-2 Medical Disorders or Conditions Commonly Associated with Insomnia

Renal Insufficiency or Failure

Polysomnography can also assist with the assessment of insomnia in some cases. This diagnostic procedure is not recommended for most individuals with insomnia23; however, when the clinician suspects sleep apnea or periodic limb movements of sleep (PLMSs), or when the patient reports frequent brief awakenings, polysomnography is indicated for further evaluation.

Treatment of Insomnia

The treatment of insomnia is best achieved by addressing all possible underlying contributing factors, whether they are related to medical or psychiatric causes, poor sleep habits, or counterproductive sleep-related cognitions. A combination of approaches is generally recommended. For individuals with insomnia of recent onset, an identifiable precipitant (a physical or emotional stressor) is usually present, and the duration of the complaint is often short. If, in such individuals, the insomnia is associated with substantial concern or daytime dysfunction, short-term use of a hypnotic agent is recommended so as to minimize the immediate effect of the insomnia and to prevent the development of a more chronic conditioned insomnia.

In individuals with chronic primary insomnia, and in some individuals with secondary insomnia, first-line treatments are modification of sleep-related behaviors and attitudes, called cognitive-behavioral therapy. Cognitive-behavioral therapy has a number of components: (1) limitation of time in bed (sleep restriction and stimulus control), which produces mild sleep deprivation, thus allowing shorter sleep onset and reduction in the number and duration of awakenings, and reduces the duration of time awake in bed, limiting negative associations to the sleep environment; (2) relaxation techniques, which reduce physiological and cognitive arousal in the sleep setting by use of yoga, meditation, and/or biofeedback; (3) cognitive restructuring, which addresses catastrophic beliefs and attitudes regarding sleeplessness, replacing them with more rational expectations of sleep and effects of insomnia; and (4) sleep hygiene, which refers to a variety of habits that promote good sleep such as regular bedtimes and waking times, daily exercise, avoidance of napping, careful use of alcohol and caffeine, and reduction in behaviors that promote nocturnal emotional and physical arousal (e.g., work, emotional stimulation, nighttime exercise). Cognitive-behavioral therapy has been shown to produce consistent reduction in sleep onset latency and wake time during the night, as well as smaller increases in total sleep time.24,25 These gains have generally been maintained over periods of up to 24 months.

Pharmacological therapies for insomnia have evolved since the 1950s from barbiturates to long-acting benzodiazepines, then to shorter acting benzodiazepines, and, since the mid-1990s, to nonbenzodiazepine receptor agonists (BzRAs). In addition, there has been a trend away from these approved medications for insomnia and toward the use of sedating medications with original indications for other disorders (e.g., antidepressants, anticonvulsants, antipsychotics), to the point at which antidepressants constitute more than 50% of all prescription medications for insomnia.26 Recommendations as to the appropriate use of hypnotics in the treatment of insomnia are evolving, and this and other treatment issues in insomnia were reviewed in a state-of-the-science National Institute of Mental Health consensus statement.27

Benzodiazepines and BzRAs bind at an allosteric site on the γ-amino butyric acid A (GABAA) receptor complex, influencing GABA binding and chloride flux. The BzRAs demonstrate relatively selective binding for GABAA receptors that contain α1 subunits. The α1 subunits mediate the sedative, amnestic, and anticonvulsant properties of these agents but few of the muscle relaxant and anxiolytic aspects (Fig. 15-2).28 However, it is unclear whether the relative receptor selectivity of the BzRAs have clinical significance in terms of efficacy or short- or long-term tolerability.

More important than the receptor-binding characteristics of these agents are the major differences between the half-lives of these agents, which, when combined with dosage, determine the duration of the medication’s effects. Half-lives of hypnotics in this class vary from 1 to more than 100 hours (Table 15-3). Because of the variability of sleep complaints, medication choices in this class are usually based on matching the patient’s sleep complaint with an appropriate half-life agent, so as to maximize the opportunity for sleep but minimize waking hangover effects.

TABLE 15-3 Benzodiazepine Receptor Agonists Commonly Used for the Treatment of Insomnia

Agent (Brand Name) Dosage Range Half-Life
Flurazepam (Dalmane)* 15-30 mg 50-100 hours
Estazolam (Prosom)* 1.0-2.0 mg 10-20 hours
Temazepam (Restoril)* 7.5-30 mg 4-18 hours
Triazolam (Halcion)* 0.125-0.25 mg 2-3 hours
Eszopiclone (Lunesta) 1-3 mg 5.5-8 hours
Zolpidem (Ambien) 5-10 mg 2-3 hours
Zaleplon (Sonata) 5-10 mg 1-2 hours


Meta-analyses have demonstrated the efficacy of benzodiazepines and BzRAs in reducing sleep onset latency, decreasing the amount of wakefulness after sleep onset, and in increasing total sleep time in patients with primary insomnia.29 However, when a meta-analysis of benzodiazepines alone was performed, the absolute size of this effect for sleep onset latency was not dramatic: a reduction of 4.2 minutes when assessed by polysomnography and of 14.3 minutes by self-report. On the other hand, total sleep time was increased by a mean of 61.8 minutes.30

The majority of these efficacy data come from short-duration studies. For instance, the median duration of the studies in the benzodiazepine and BzRA meta-analysis was 7 days; the common duration of insomnia complaints, in contrast, is often months to years. Studies addressing the longer term efficacy of these medications in continuous and intermittent use have been performed. Eszopiclone, the S-isomer of the commonly prescribed hypnotic zopiclone, has been shown to produce persistent benefits for sleep onset latency, wakefulness after sleep onset, total sleep time, and daytime functioning for 6 months of nightly use in comparison with placebo in patients with primary insomnia.31


PLMSs are commonly recorded movements during sleep consisting of repetitive dorsiflexion of the foot and/or lower leg. Movements are generally subtle and may not be recognized by a bed partner, although in more severe forms, they are more obvious. PLMS may or may not be associated with arousals from sleep, and indices of the number of movements with and without arousal per hour of sleep are derived. The term periodic limb movement of sleep is derived from the strict periodicity of movements, which occur at 15- to 30-second intervals during sleep. Movements are roughly 2 seconds in duration (Fig. 15-3). When a sleep complaint occurs in the presence of PLMS, in the absence of other known causes of sleep disruption, a diagnosis of periodic limb movement disorder is given.

PLMSs are commonly recorded on overnight polysomnography, and population estimates of the prevalence of PLMSs exceeding five per hour range from 11% to 58%.32 PLMSs are more commonly recorded in elderly persons, in patients taking antidepressants, and in a number of medical conditions (end-stage renal disease, congestive heart failure, diabetes) and neurological or sleep disorders (obstructive sleep apnea, narcolepsy, Parkinson’s disease, multiple sclerosis). Although approximately 80% of individuals with RLS demonstrate PLMS, only a small proportion of those with PLMS describe symptoms of RLS. Controversy exists regarding the clinical importance of PLMS for sleep quality or daytime alertness; some studies show a lack of correlation between PLMS index and subjective or objective sleep quality or daytime sleepiness, and others show some mild associations.33

There is substantial evidence that PLMSs are associated with dopaminergic dysregulation at either spinal or higher central nervous system levels. Dopaminergic antagonists can produce PLMS,34 whereas dopaminergic agonists are extremely effective in reducing PLMS.35 Disorders characterized by dopaminergic deficiency (e.g., narcolepsy, rapid eye movement [REM] sleep behavior disorder [RBD]) are accompanied by high rates of PLMS. Functional imaging of the brain has demonstrated small but consistent reductions in dopaminergic function in PLMS. Finally, dopaminergic metabolites have been observed to be correlated with the number of PLMSs.36 The presence of PLMS in quadriplegic patients suggests that the motor programs for these movements exist in the spinal cord and are somehow disinhibited in patients with excessive movements during sleep.

Clinically, periodic limb movement disorder should be suspected when an individual (or his or her bed partner) reports kicking or jerking of his or her legs during sleep and has a complaint of sleep disruption or excess daytime sleepiness that cannot be accounted for by another cause. Polysomnography is necessary to make the diagnosis of periodic limb movement disorder, both to document the PLMS but also to exclude other causes of repetitive leg movements—most prominently, obstructive sleep apnea. The differential diagnosis of nocturnal leg movements in the sleep period includes RLS (in which leg restlessness is reported before sleep onset), anxiety (in which leg movements are observed during wakefulness, not sleep), nocturnal seizures (which produce abnormal EEG changes), obstructive sleep apnea (in which characteristic respiratory abnormalities are observed), or RBD (in which movements are dream enactments, occur during REM sleep, and are not periodic).

Treatment of periodic limb movement disorder begins with an accurate diagnosis and proceeds to consideration of eliminating potential precipitating or exacerbating agents (e.g., antidepressants). PLMS can be dramatically reduced with the addition of dopaminergic agents, at least within the context of RLS. However, there is some suggestion that EEG arousals may persist even with elimination of the manifest motor activity. For this reason, coadministration of substitution of a benzodiazepine has also been advocated. Although studies of triazolam in patients with PLMS did not reveal a reduction in the periodic limb movement index, improvements in leg movements associated with arousal, sleep architecture, and daytime alertness were all demonstrated,37 even after 12 weeks of nightly use.38 Use of clonazepam in small numbers of patients was effective in reducing the number of PLMs, as well as improving scores on sleep continuity measures.39


Excess daytime sleepiness has numerous causes. Clinical diagnostic algorithms proceed from a determination of sleep quantity to an evaluation of sleep quality and then to assessment of potential contributors to an intrinsic excess sleep drive. Insufficient sleep is the most common cause of excess daytime sleepiness among both adults and children. Because of its pervasiveness, careful attention to sleep times is required in individuals with a description of excess daytime sleepiness. Sleep quantity is determined by history, sleep logs, and if necessary, polysomnography.

Any cause of poor sleep quality can produce excess daytime sleepiness, although the most common are sleep apnea, neurological, pulmonary and cardiac diseases, and environmental sleep disruption. The underlying cause of sleep disruption is commonly discernible from the history and/or physical examination, although polysomnography may be required for some disorders (e.g., sleep apnea). Finally, if excessive daytime sleepiness is present, and if sleep quantity and quality appear to be sufficient, a primary disorder of sleepiness or a medication effect should be suspected. These are discussed as follows.

Excess Daytime Sleepiness as a Result of Medical and Neurological Diseases

Multiple neurological diseases can cause sleepiness: either by disrupting the mechanisms involved in sleep homeostasis or by simply disrupting nighttime sleep. For example, cerebral traumatic injury or thalamic lesions (such as bilateral medial thalamic infarcts) can impair the central mechanisms of sleep-wake regulation, while pain from diabetic neuropathy of multiple sclerosis can cause sleep fragmentation and thus result in excessive sleepiness. Some specific examples are described as follows.


Common Comorbid Conditions

One common cause of excessive sleepiness in the general population is sleep apnea. This condition is also quite common in patients with stroke.40 Symptoms of sleepiness and snoring may in fact be associated with higher risk of first-ever stroke.41,42 Prevalence after stroke may be even higher: Harbison and associates42 reported that up to 94% of patients had a respiratory disturbance index of 10 or above on polysomnography, performed in the 2 weeks after a stroke. Patients more likely to have more severe sleep apnea were older and more likely to have lacunar infarcts and greater prestroke disability. Sleep-disordered breathing improved over time, but about 72% of the patients had clinically important sleep apnea 6 weeks later.

As good-quality sleep may improve recovery from illness, treatment of sleep apnea can also hasten recovery from stroke. Patients with sleep apnea may have more residual symptoms of stroke after rehabilitation,43 whereas treatment of sleep apnea, when present in a patient with stroke, may hasten the rehabilitation process.44

Multiple Sclerosis

Patients with multiple sclerosis frequently complain of sleepiness, fatigue, and cognitive problems, as well as sleep disruption. Common causes for impairment of sleep and resulting sleepiness are described as follows.

Associated Psychiatric Disorders

Many patients with multiple sclerosis have associated depressive or other psychiatric symptoms.5456 These symptoms may vary in intensity, depending on the short-term risk of disability or wheelchair dependence.56 Because both depression and anxiety are associated with sleep disturbance, they can contribute to sleep impairments in patients with multiple sclerosis.

Immunological Factors

Immunological factors, which are involved in the pathogenesis of multiple sclerosis, may also have somnogenic effects. These include interleukin-1,57 which is known to be associated with sleepiness. Fatigue may be more prominent in patients who have markers of immune activation, including inductors of lymphocyte B cells, increase in helper T cells, interleukin-2 receptor cells, or other markers.54

Impaired Sleep-Wake Regulation as a Result of Plaques

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