Sleep Disorders
Phyllis C. Zee
Alon Y. Avidan
Sleep disturbances are prevalent in the general population, but certain groups such as older adults, women, and patients with chronic comorbid medical, neurologic, and psychiatric disorders are at particular risk. Indeed, the most recent evidence points to a bidirectional relationship between health and sleep. Sleep problems influence health-related quality of life and may contribute to the development of, or exacerbate, medical and neurologic conditions. Patients who report disturbed sleep generally describe one or more of three types of problems—insomnia, excessive daytime sleepiness (EDS), and abnormal motor activities, complex behaviors, or disturbed sensations during sleep.
The 2005 revised International Classification of Sleep Disorders (ICSD-2) lists five major categories of sleep disorders: insomnias—that is, disorders of initiating and maintaining sleep; sleep-related breathing disorders; hypersomnias—that is, disorders of excessive sleepiness; movement disorders; and circadian rhythm sleep disorders (CRSDs). To assist the clinician, in diagnosing and treating sleep disorders, a differential diagnosis-based classification adapted from the ICSD-2 is used in this chapter.
I. INSOMNIA
Insomnia is a disorder characterized by symptoms of inability to fall asleep, maintain sleep, perception of inadequate sleep, and/or nonrestorative sleep. These symptoms result in distress or impairment of daytime functioning. The three main categories of insomnia are psychophysiologic insomnia, idiopathic insomnia, and paradoxical insomnia (state misperception).
A. Psychophysiologic and idiopathic insomnias.
1. Course.
For the diagnosis of psychophysiologic insomnia to be made, a patient has to have sleep difficulties that substantially affect daytime functioning and have a learning or conditioning component that typically involves one or more of the following: daily worries about not being able to fall asleep or stay asleep accompanied by intense efforts to fall asleep each night; paradoxical improvement away from the usual sleep environment (e.g., in another room of the house or away from home); and somatized tension and anxiety associated with bedtime and the subject of sleep. The most difficult differential diagnosis is with generalized anxiety disorders in which anxiety is pervasive and involves most aspects of daily life rather than exclusively the inability to sleep. Differentiation from affective disorders, such as depression, is also important. Idiopathic or primary insomnia is a lifelong inability to sleep, presumably associated with a predisposition for insomnia resulting from abnormality of the sleep-wake cycle or autonomic activity. Patients with this condition are a heterogeneous group. Most have been poor sleepers since childhood, and the insomnia, although it persists over the entire life span, can be aggravated by stress and tension. Patients with idiopathic insomnia may have atypical reactions to stimulants and sedatives. Idiopathic insomnia often is accompanied by other factors such as poor sleep hygiene or psychiatric disorders. Therefore, there tends to be some overlap between primary insomnia with insomnia that is comorbid with psychiatric disorders.
2. Treatment and outcome.
A multimodal individualized approach is indicated for most patients. Optimizing the treatment of comorbid medical, neurologic, and psychiatric conditions, as well as identifying medications or behaviors that promote insomnia are essential first steps. A combined treatment approach involving good sleep hygiene, cognitive behavioral therapy (CBT), and medications is most often employed. A 4- to 8-week program of sleep hygiene counseling, cognitive/behavioral modifications, and judicious
use of hypnotics is recommended. If insomnia does not improve after this period of treatment, referral to a sleep specialist should be considered for further evaluation.
use of hypnotics is recommended. If insomnia does not improve after this period of treatment, referral to a sleep specialist should be considered for further evaluation.
Cognitive behavioral therapy. The most widely used behavioral therapy program in the management of insomnia includes a combined program of sleep hygiene education, relaxation techniques, stimulus-control therapy, and sleep restriction therapy. Relaxation techniques may include progressive muscle relaxation, biofeedback, deep breathing, meditation, guided imagery, and other techniques to control cognitive arousal. These techniques are first taught during training sessions and then practiced daily for 20 to 30 minutes by the patient at home, usually around bedtime. Stimulus-control therapy is useful in the management of conditioned insomnia. This technique is an attempt to break the conditioning by teaching the patient to associate the bedroom with sleep behavior. The instructions for sleep hygiene and stimulus-control behavioral therapy are listed in Tables 55.1 and 55.2. Sleep restriction therapy involves curtailment of time in bed, so that sleep efficiency (time asleep divided by time in bed) is 85% or greater. As sleep efficiency increases, time in bed is gradually lengthened. Shorter duration behavioral interventions and internet-based CBT are also available.
Hypnotic drugs. The most widely used prescription hypnotics are the benzodiazepine receptor agonists, which include benzodiazepines and the non-benzodiazepine receptor agonist (BZRA) hypnotics, such as eszopiclone, zaleplon, and zolpidem. Traditionally, this class of medications was indicated for short-term use. More recently, with the recognition that insomnia is often chronic and with the availability of longer term studies for up to a year, the short-term indication has been removed from the newly The U.S. Food and Drug Administration (FDA)-approved BZRA
hypnotics such as eszopiclone and zolpidem MR. Ramelteon, a melatonin receptor agonist and low-dose doxepin, represent different classes of hypnotics that in the nonscheduled category.
TABLE 55.1 Sleep Hygiene Instructions | |||||||||||||||||||||||||
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TABLE 55.2 Stimulus-Control Behavioral Therapy | ||||||
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TABLE 55.3 FDA Approved Hypnotics for the Management of Insomnia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The choice of hypnotic may depend on the type of insomnia. For example, if the predominant problem is falling asleep, a fast-acting, short-half-life hypnotic may be preferable. If the problem is frequent awakenings and sleep maintenance insomnia, a longer acting hypnotic may be more effective. Most hypnotics approved by the FDA are indicated for the treatment of sleep onset insomnia, whereas eszopiclone, zolpidem-CR and low-dose doxepin are also indicated for the treatment of sleep maintenance insomnia. In practice, sedating antidepressants, such as the tricyclic antidepressants and heterocyclics (trazodone), are often used off label for the treatment of insomnia. However, there is limited data regarding their efficacy or long-term safety for the treatment of insomnia that is not comorbid with depression. The exception is low-dose doxepin (3 to 6 mg), which is FDA approved for insomnia.
The most widely used prescription hypnotics and their properties are listed in Table 55.3. Although patients with chronic insomnia rarely become “great” sleepers
after treatment, most can manage the predisposition to insomnia by using sleep hygiene, cognitive behavioral treatment, and when indicated hypnotics.
after treatment, most can manage the predisposition to insomnia by using sleep hygiene, cognitive behavioral treatment, and when indicated hypnotics.
B. Paradoxical insomnia.
1. Course.
It is not uncommon for patients to overestimate sleep latency and underestimate total sleep time. In paradoxical insomnia, this tendency is extreme.
2. Diagnosis.
The disorder is characterized by reports of persistent difficulty falling, staying asleep or disturbed sleep, although sleep duration and quality are objectively normal.
3. Treatment and outcome.
Reassuring patients with the fact that their sleep is normal and that they sleep longer than they think they do and cognitive behavioral treatments are effective.
C. Insomnia associated with psychiatric disorders.
1. Course.
Insomnia is often comorbid with psychiatric conditions. Results of epidemiologic studies suggest that as many as 57% of persons with insomnia have a psychiatric condition or will have one within 1 year. The comorbid condition usually is a mood disorder, anxiety disorder, somatoform disorder, personality disorder, schizophrenia, or substance abuse. Sleep in major depression is characterized by early morning awakening (2 to 4 hours after sleep onset) and frequent nocturnal awakening with inability to reinitiate sleep. Insomnia often precedes the diagnosis of depression. The incidence of insomnia among patients with anxiety disorders is high. The typical symptoms are difficulty with sleep initiation and, to a lesser degree, nocturnal awakenings. Fatigue is common, but napping is unusual. Patients with anxiety disorders are susceptible to conditioning factors that produce psychophysiologic insomnia.
2. Treatment and outcome.
Treatment should address the comorbid psychiatric disorder as well as insomnia. For major depressive and anxiety disorders, this involves use of antidepressants or anxiolytics such as the selective serotonin reuptake inhibitors (SSRIs). An antidepressant with sedative properties is favored over a less-sedating one for patients with insomnia. Administration 30 minutes before bedtime also aids in promoting sleep. Amitriptyline, trimipramine, doxepin, trazodone, and mirtazapine are the most sedating, whereas protriptyline and SSRIs such as fluoxetine have stimulating effects that may worsen insomnia. Antidepressants with anxiolytic properties are useful in the treatment of anxious, depressed patients and facilitate psychotherapeutic or pharmacologic treatment. Anticholinergic side effects of tricyclic antidepressants (cardiotoxicity, urinary retention, erectile dysfunction, and dry mouth) limit the usefulness of these agents, particularly in the elderly.
Recent studies demonstrate that insomnia may persist despite adequate treatment of depression and that insomnia predicts future relapse of depression. Therefore, oftentimes, a parallel approach that combines treatment for both depression and insomnia is recommended. If the patient is refractory to treatment, referral to a sleep specialist or psychiatrist is recommended for further evaluation of comorbid psychiatric or other sleep disorders.
II. CIRCADIAN RHYTHM SLEEP DISORDERS
Circadian rhythms are generated by a neural clock located in the suprachiasmatic nucleus of the hypothalamus. Disruption of biologic timing results in circadian rhythm disorders that are most often associated with patients’ reports of insomnia and excessive sleepiness. CRSDs are characterized by essentially normal total sleep time that is not synchronized with conventional environmental light-dark cycles and periods of sleep. Diagnosis requires specialized assessment, including use of a sleep diary for 7 days alone, or in combination with actigraphy, physiologic markers of circadian timing such as core body temperature or melatonin onset. A careful history interview to elicit the appropriate major diagnostic criteria is a key. CRSDs include delayed sleep phase disorder (DSPD), advanced sleep phase disorder (ASPD), non-24-hour sleep-wake disorder, irregular sleep-wake rhythm disorder, (ISWR) shift work sleep disorder (SWSD), and jet lag disorder. Effective treatment for CRSDs typically require a multifaceted approach to realign circadian rhythms with the use of timed bright light exposure and low-dose melatonin, together with cognitive behavioral treatments
that promote healthy sleep habits. Melatonin is not approved by the FDA for the treatment of CRSDs, and one should also be aware of potential side effects such as headaches, vivid dreams, nausea, and cardiovascular effects.
that promote healthy sleep habits. Melatonin is not approved by the FDA for the treatment of CRSDs, and one should also be aware of potential side effects such as headaches, vivid dreams, nausea, and cardiovascular effects.
A. DSPD and ASPD.
1. Course. DSPD
is characterized by a persistent inability to fall asleep until the early morning hours (1 to 3 a.m., and sometimes later) and difficulty waking up in the morning. If allowed, the patient would sleep until the late morning or early afternoon (10 a.m. to 2 p.m.). When the patient is forced to rise at 7 or 8 a.m., sleep is curtailed, and daytime sleepiness develops. Despite the daytime sleepiness, patients find that in the evening they become more alert and remain unable to fall asleep until the early morning hours. The prevalence rate is estimated to be between 1.7% in the general population to 7% of those with insomnia complaints. Onset of this disorder typically occurs during adolescence or early adulthood. ASPD is characterized by early evening sleep onset (7 to 9 p.m.) and early morning awakening (3 to 5 a.m.). Although DSPD predominates at younger ages and ASPD at older ages, both disorders can result in sleep problems throughout life. Because many features of the sleep of patients with depression resemble those of either DSPD or ASPD, depression and other psychiatric disorders must be considered in the differential diagnosis.
2. Treatment and outcome.
Chronotherapy is a behavioral technique in which bedtime is systematically delayed (for DSPD) or advanced (for ASPD) in 3-hour increments each day until the desired sleep phase is achieved. The patient is then instructed to maintain the newly established bedtime rigidly. Although this approach works, it is an arduous procedure, and maintenance of the effect has been difficult.
Bright light therapy. Light intensity >2,500 lux is considered bright. Appropriately timed bright light (white or blue/green enriched) exposure can reset the timing of circadian rhythms, and normalize circadian phase in DSPD and ASPD. Exposure to bright light in the early morning results in an advancement of circadian phase, whereas exposure to light in the evening delays circadian rhythms. For management of DSPD, exposure to light usually is scheduled for 1 to 2 hours in the morning (close to the time of habitual awakening). For ASPD, light exposure is recommended in the evening, approximately 2 to 4 hours before scheduled bedtime. Avoidance of bright light in the evening in DSPD should also be encouraged. Despite high rates of success in achieving the desired sleep phase under immediate treatment, many patients do not continue the light regimen and have a relapse. Some patients are able to maintain a normalized phase without maintenance of light exposure for as long as several months, whereas others drift back toward the pretreatment phase within a few days.
Melatonin has been shown to shift the phase of circadian rhythms in humans. Although not approved by the FDA, melatonin of 1 to 5 mg has been shown to be effective when taken in the early evening for patients with DSPD.
B. Free-running disorder (FRD).
1. Course.
Individuals with FRD typically have a longer than 24-hour circadian rhythm, similar to those living in temporal isolation. Because these patients are unable to entrain to the external 24-hour physical, social or activity cycles, sleep and wake periods progressively drift later each day. Diagnosis of FRD includes complaints of insomnia or excessive sleepiness associated with the misalignment between the endogenous circadian rhythm and the light-dark cycle. FRD is most common in blind people, but can occur in sighted persons.
2. Treatment and outcomes.
Both behavioral and pharmacologic options are available for the treatment of FRD, depending on whether the patient is sighted or blind. For blind and sighted patients, planned sleep schedules and/or low-dose melatonin (0.5 to 3 mg) approximately 1 to 2 hours before habitual bedtime are recommended. In sighted persons, the addition of timed exposure to bright light is also recommended.
C. Irregular sleep wake rhythm disorder.
1. Course.
ISWR differs from the phase disorders in that there is loss of circadian rhythmicity, which results in the lack of a long, consolidated sleep period. Sleep usually is broken into three or more short sleep periods or naps during the course of 24 hours.
Irregular sleep-wake patterns occur among patients with Alzheimer’s disease and among other elderly persons in nursing homes.
Irregular sleep-wake patterns occur among patients with Alzheimer’s disease and among other elderly persons in nursing homes.
2. Treatment and outcomes.
Management of irregular sleep-wake patterns and associated behavioral problems in this group of elderly and often cognitively impaired patients is a challenge. Treatment with sedative-hypnotics is prevalent in nursing homes. These medications have side effects that may not be well-tolerated by older patients. Some promising studies have indicated that structured activity programs, increasing exposure to bright light and evening melatonin may alleviate these sleep-wake and behavioral disorders. The effects of melatonin have been mixed, and a recent placebo-controlled multicenter study in Alzheimer’s disease failed to demonstrate its effectiveness. Light therapy units are commercially available.
E. SWSD.
1. Course.
SWSD is characterized by chronic symptoms of insomnia and excessive sleepiness that are due to unconventional work schedules, resulting in circadian misalignment. Typically, sleep is curtailed by 1 to 4 hours in patients with SWSD, with most complaints associated with night and early morning work. Excessive sleepiness at work and commute poses important safety concerns.
2. Treatment and outcomes.
Clinical management of SWSD is aimed at realigning circadian rhythms with the sleep and work schedules, as well as improving sleep, alertness, and safety. Nonpharmacologic treatments are basic to the management of SWSD. Optimizing the sleep environment, adherence to healthy sleep habits, and planned naps, when possible, should be encouraged for all patients.
Bright light therapy. Timed bright light therapy and avoidance of light at the wrong time of the day can help accelerate and maintain entrainment to the shift schedule. For night workers, circadian rhythms need to be delayed, so that the highest sleep propensity occurs during the day, rather than at night. Intermittent bright light exposure (approximately 20 minutes per hour blocks) and avoidance of bright light exposure in the morning during the commute home (using driving safe sunglasses) has being shown to accelerate circadian adaptation to night shift.
Melatonin. Studies on the effectiveness of melatonin for the treatment of SWSD have been mixed. When taken at bedtime after the night shift, melatonin can improve daytime sleep; it may have limited effects on alertness at work. Other pharmaceuticals often used for the treatment of sleep disturbance and excessive sleepiness in shift workers includes: hypnotics for sleep and stimulants for maintaining alertness. However, these approaches do not specifically address the issue of circadian misalignment, and thus should be used in concert with behavioral strategies as discussed above.
III. DISORDERS OF EXCESSIVE DAYTIME SLEEPINESS
Sleepiness severe enough to affect activities of daily living is estimated to be present among 30% of the population and is most commonly caused by self-imposed restriction of sleep. However, approximately 4% to 5% of the population has EDS as a result of a sleep disorder. Sleepiness is excessive and an indication of a sleep disorder when it occurs at undesirable times, such as while driving and during social activities. EDS can be divided into two types: extrinsic and intrinsic. Some extrinsic causes include environmental factors, drug dependency, sleep-disordered breathing, and movement disorders during sleep. The more common types of intrinsic hypersomnia usually associated with primary CNS includes disorders such as narcolepsy and idiopathic hypersomnia.
A. Narcolepsy.
1. Course.
Narcolepsy is a manifestation of dissociation between wakefulness and sleep, particularly rapid eye movement (REM) sleep. The onset usually occurs in adolescence or young adulthood, and men are affected more often than are women. Studies have shown a strong genetic association between narcolepsy and the human leukocyte antigen (HLA) type DR2 and DQ1. A more sensitive marker for narcolepsy is the DQB1*0602 genotype, which appears to be correlated with both the frequency and severity of cataplexy (loss of muscle tone elicited by a strong emotional response).
The role of hypocretin in narcolepsy is supported by the finding that hypocretin levels are abnormally low or undetectable in the CSF of most narcoleptic patients. Values below 110 pg per ml are highly diagnostic for narcolepsy in the absence of severe brain pathology. The most consistent abnormalities were observed in the amygdala, where increased dopamine and metabolite levels were found.
2. Clinical features.
Narcolepsy is a syndrome characterized by a pentad of severe unremitting EDS manifesting as sleep attacks, cataplexy, sleep paralysis, and hypnagogic/ hypnopompic hallucinations and disturbed nocturnal sleep. Some patients will also have other comorbid primary sleep disorders such as restless legs and REM sleep behavior disorder (RBD; see next section). All patients must have pathologic levels of daytime sleepiness, and the presence of unequivocal cataplexy, a feature pathognomonic for narcolepsy. Cataplexy is associated with a drop in H-reflex and loss of skeletal muscle and is induced by strong emotional stimuli. Decreased quality and quantity of nocturnal sleep exacerbate the EDS even further.
B. Classification of narcolepsy.
1. Narcolepsy with cataplexy.
Characterized by EDS and bona fide cataplexy. Sleepiness is maximal during monotonous activities and may appear as irresistible sleep attacks.
2. Narcolepsy without cataplexy.
Narcolepsy without cataplexy is similar to narcolepsy with cataplexy in most clinical respects except for the lack of definite cataplexy.
3. Narcolepsy caused by a medical condition.
Narcolepsy with and without cataplexy is found in a number of key medical and neurologic conditions including genetic disorders associated such as type Prader-Willi’s syndrome, structural lesions in the hypothalamic region, and inflammatory lesions such as multiple sclerosis and acute disseminated encephalomyelitis.
4. Diagnosis.
In addition to the clinical history, nocturnal polysomnography (PSG) and multiple sleep latency testing (MSLT) are performed to establish a diagnosis of narcolepsy.
Sleep studies.
PSG. A baseline sleep study is generally required for an accurate diagnosis of narcolepsy because of the spectrum of conditions that can cause excessive sleepiness. Most typically, the nocturnal PSG is required, followed by the MSLT. PSG features of narcolepsy include sleep disruption, repetitive awakenings, and decreased REM sleep latency. A sleep-onset REM period (SOREMP) at night is highly predictive of narcolepsy.
The MSLT. The MSLT during the day following the PSG and is designed to determine a patient’s propensity to fall asleep. Current criteria for narcolepsy include a mean sleep latency (MSL) ≤8 minutes and ≥2 SOREMPs. Up to onethird of the general population may have an MSL of ≤8 minutes so the finding of a short MSL alone, without any SOREMP, should be interpreted cautiously together with the clinical picture.
If the results of sleep studies are inconclusive, results of HLA typing and CSF hypocretin (below 110 pg per ml) may provide additional aid in establishing the diagnosis.
5. Treatment and outcome.
Treatment approaches to narcolepsy emphasize control of narcoleptic symptoms to allow optimal social and professional productivity by maintaining the patient’s alertness throughout the day. Choice of treatment must take into account that narcolepsy is a lifelong disorder and that patients will have to take medications for many years. Clinicians are not unanimous in their approach to management of narcolepsy.
The drugs commonly used to manage EDS and sleep attacks are the nonamphetamine stimulants such as armodafinil and modafinil and CNS stimulants including, methylphenidate, and dextroamphetamine. Because of frequent side effects of sympathomimetic stimulants, such as irritability, tachycardia, elevated blood pressure, and nocturnal sleep disturbance, methylphenidate and amphetamines are probably less preferred first-line treatment. Armodafinil and modafinil has several advantages over other stimulants in that it has fewer cardiovascular side effects, has longer halflife, and can be taken one daily in the morning, and the prescription can be refilled. Sodium oxybate has been recently approved for the management of symptoms of hypersomnia and cataplexy in narcolepsy. Medications used in the management of
EDS and the dosages are listed in Table 55.4. Drugs with norepinephrine-releasing properties have the greatest impact on sleepiness. However, evidence shows that even at the highest recommended doses, no drug is capable of returning a person with narcolepsy to a normal baseline level of alertness.Related posts:
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