Approach to the Patient: Sleep Disorders
Patients may seek help from a physician because of one of several symptoms: (1) an acute or chronic inability to initiate or maintain sleep adequately at night (insomnia); (2) chronic fatigue, sleepiness, or tiredness during the day; or (3) a behavioral manifestation associated with sleep itself. The specific approach to an insomnia complaint will depend on the nature of comorbid medical or psychiatric disease, if present. In general, however, the insomnia complaint should be specifically addressed as soon as it is recognized. This more aggressive approach reflects growing evidence that chronic insomnia may contribute to comorbid disease processes. For example, specific management of symptomatic insomnia at the time of diagnosis of major depressive disorder (MDD) has been shown to positively impact the response to antidepressants. Evidence that insomnia and sleep loss affect the perception of pain suggests that a similar approach is warranted in acute and chronic pain management. In general, at least for chronic insomnia, there is little evidence justifying an expectant approach in which specific insomnia therapy is deferred while comorbid disease is first addressed.
Table 27-1 outlines the diagnostic and therapeutic approach to the patient with a complaint of excessive daytime sleepiness.
Table 27-1 Evaluation of the Patient with the Complaint of Excessive Daytime Somnolence |Favorite Table|Download (.pdf)
Table 27-1 Evaluation of the Patient with the Complaint of Excessive Daytime Somnolence
|Findings on History and Physical Examination||Diagnostic Evaluation||Diagnosis||Therapy|
|Obesity, snoring, hypertension||Polysomnography with respiratory monitoring||Obstructive sleep apnea||Continuous positive airway pressure; ENT surgery (e.g., uvulopalatopharyngoplasty); dental appliance; pharmacologic therapy (e.g., protriptyline); weight loss|
|Cataplexy, hypnogogic hallucinations, sleep paralysis, family history||Polysomnography with multiple sleep latency testing||Narcolepsy-cataplexy syndrome||Stimulants (e.g., modafinil, methylphenidate); REM-suppressant antidepressants (e.g., protriptyline); genetic counseling|
|Restless legs, disturbed sleep, predisposing medical condition (e.g., iron deficiency or renal failure)||Assessment for predisposing medical conditions||Restless legs syndrome||Treatment of predisposing condition, if possible; dopamine agonists (e.g., pramipexole, ropinirole)|
|Disturbed sleep, predisposing medical conditions (e.g., asthma), and/or predisposing medical therapies (e.g., theophylline)||Sleep-wake diary recording||Insomnias (see text)||Treatment of predisposing condition and/or change in therapy, if possible; behavioral therapy; short-acting benzodiazepine receptor agonist (e.g., zolpidem)|
A careful history is essential. In particular, the duration, severity, and consistency of the symptoms are important, along with the patient's estimate of the consequences of the sleep disorder on waking function. Information from a friend or family member can be invaluable; some patients may be unaware of, or will underreport, such potentially embarrassing symptoms as heavy snoring or falling asleep while driving.
Patients with excessive sleepiness should be advised to avoid all driving until effective therapy has been achieved.
Completion by the patient of a day-by-day sleep-work-drug log for at least 2 weeks can help the physician better understand the nature of the complaint. Work times and sleep times (including daytime naps and nocturnal awakenings) as well as drug and alcohol use, including caffeine and hypnotics, should be noted each day.
Polysomnography is necessary for the diagnosis of specific disorders such as narcolepsy and sleep apnea and may be of utility in other settings as well.
Insomnia is the complaint of inadequate sleep; it can be classified according to the nature of sleep disruption and the duration of the complaint. Insomnia is subdivided into difficulty falling asleep (sleep onset insomnia), frequent or sustained awakenings (sleep maintenance insomnia), or early morning awakenings (sleep offset insomnia), though most insomnia patients present with two or more of these symptoms. Other insomnia patients present with persistent sleepiness/fatigue despite sleep of adequate duration (nonrestorative sleep). Similarly, the duration of the symptom influences diagnostic and therapeutic considerations. An insomnia complaint lasting one to several nights (within a single episode) is termed transient insomnia and is typically the result of situational stress or a change in sleep schedule or environment (e.g., jet lag disorder). Short-term insomnia lasts from a few days to 3 weeks. Disruption of this duration is usually associated with more protracted stress, such as recovery from surgery or short-term illness. Long-term insomnia, or chronic insomnia, lasts for months or years and, in contrast with short-term insomnia, requires a thorough evaluation of underlying causes (see below). Chronic insomnia is often a waxing and waning disorder, with spontaneous or stressor-induced exacerbations.
An occasional night of poor sleep, typically in the setting of stress or excitement about external events, is both common and without lasting consequences. However, persistent insomnia can lead to impaired daytime function, injury due to accidents, and the development of major depression. In addition, there is emerging evidence that individuals with chronic insomnia have increased utilization of health care resources, even after controlling for comorbid medical and psychiatric disorders.
All insomnias can be exacerbated and perpetuated by behaviors that are not conducive to initiating or maintaining sleep. Inadequate sleep hygiene is characterized by a behavior pattern prior to sleep or a bedroom environment that is not conducive to sleep, or irregularity in the timing or duration of the nightly sleep episode. Noise, light, or technology (e.g., television, radio, cell phone, mobile email device or computer) in the bedroom can interfere with sleep, as can a bed partner with periodic limb movements during sleep or one who snores loudly. Clocks can heighten the anxiety about the time it has taken to fall asleep. Drugs that act on the central nervous system, large meals, vigorous exercise, or hot showers just before sleep may all interfere with sleep onset. Many individuals participate in stressful work-related activities in the evening, producing a state incompatible with sleep onset. In preference to hypnotic medications, patients should be counseled to avoid stressful activities before bed, develop a soporific bedtime ritual, and prepare and reserve the bedroom environment for sleeping. Consistent, regular bedtimes and rising times should be maintained daily, including weekends.
Many patients with chronic insomnia have no clear, single identifiable underlying cause for their difficulties with sleep. Rather, such patients often have multiple etiologies for their insomnia, which may evolve over the years. In addition, the chief sleep complaint may change over time, with initial insomnia predominating at one point, and multiple awakenings or nonrestorative sleep occurring at other times. Subsyndromal psychiatric disorders (e.g., anxiety and mood complaints), negative conditioning to the sleep environment (psychophysiologic insomnia, see below), amplification of the time spent awake (paradoxical insomnia), physiologic hyperarousal, and poor sleep hygiene (see above) may all be present. As these processes may be both causes and consequences of chronic insomnia, many individuals will have a progressive course to their symptoms in which the severity is proportional to the chronicity, and much of the complaint may persist even after effective treatment of the initial inciting etiology. Treatment of insomnia is often directed to each of the putative contributing factors: behavior therapies for anxiety and negative conditioning (see below), pharmacotherapy and/or psychotherapy for mood/anxiety disorders, and an emphasis on maintenance of good sleep hygiene.
If insomnia persists after treatment of these contributing factors, empirical pharmacotherapy is often used on a nightly or intermittent basis. A variety of sedative compounds are used for this purpose. Alcohol and antihistamines are the most commonly used nonprescription sleep aids. The former may help with sleep onset but is associated with sleep disruption during the night and can escalate into abuse, dependence, and withdrawal in the predisposed individual. Antihistamines, which are the primary active ingredient in most over-the-counter sleep aids, may be of benefit when used intermittently but often produce rapid tolerance and may have multiple side effects (especially anticholinergic), which limit their use, particularly in the elderly. Benzodiazepine-receptor agonists are the most effective and well-tolerated class of medications for insomnia. The broad range of half-lives allows flexibility in the duration of sedative action. The most commonly prescribed agents in this family are zaleplon (5–20 mg), with a half-life of 1–2 h; zolpidem (5–10 mg) and triazolam (0.125–0.25 mg), with half-lives of 2–3 h; eszopiclone (1–3 mg), with a half-life of 5.5–8 h; and temazepam (15–30 mg) and lorazepam (0.5–2 mg), with half-lives of 6–12 h. Generally, side effects are minimal when the dose is kept low and the serum concentration is minimized during the waking hours (by using the shortest-acting effective agent). At least one benzodiazepine receptor agonist (eszopiclone) continues to be effective for 6 months of nightly use. However, longer durations of use have not been evaluated, and it is unclear whether this is true of other agents in this class. Moreover, with even brief continuous use of benzodiazepine-receptor agonists, rebound insomnia can occur upon discontinuation. The likelihood of rebound insomnia and tolerance can be minimized by short durations of treatment, intermittent use, or gradual tapering of the dose. For acute insomnia, nightly use of a benzodiazepine receptor agonist for a maximum of 2–4 weeks is advisable. For chronic insomnia, intermittent use is recommended, unless the consequences of untreated insomnia outweigh concerns regarding chronic use. Benzodiazepine receptor agonists should be avoided, or used very judiciously, in patients with a history of substance or alcohol abuse. The heterocyclic antidepressants (trazodone, amitriptyline, and doxepin) are the most commonly prescribed alternatives to benzodiazepine-receptor agonists due to their lack of abuse potential and lower cost. Trazodone (25–100 mg) is used more commonly than the tricyclic antidepressants as it has a much shorter half-life (5–9 h), has much less anticholinergic activity (sparing patients, particularly the elderly, constipation, urinary retention, and tachycardia), is associated with less weight gain, and is much safer in overdose. The risk of priapism is small (~1 in 10,000).
Persistent psychophysiologic insomnia is a behavioral disorder in which patients are preoccupied with a perceived inability to sleep adequately at night. This sleep disorder begins like any other acute insomnia; however, the poor sleep habits and sleep-related anxiety ("insomnia phobia") persist long after the initial incident. Such patients become hyperaroused by their own efforts to sleep or by the sleep environment, and the insomnia becomes a conditioned or learned response. Patients may be able to fall asleep more easily at unscheduled times (when not trying) or outside the home environment. Polysomnographic recording in patients with psychophysiologic insomnia reveals an objective sleep disturbance, often with an abnormally long sleep latency; frequent nocturnal awakenings; and an increased amount of stage N1 transitional sleep. Rigorous attention should be paid to improving sleep hygiene, correction of counterproductive, arousing behaviors before bedtime, and minimizing exaggerated beliefs regarding the negative consequences of insomnia. Behavioral therapies are the treatment modality of choice, with intermittent use of medications. When patients are awake for >20 min, they should read or perform other relaxing activities to distract themselves from insomnia-related anxiety. In addition, bedtime and wake time should be scheduled to restrict time in bed to be equal to their perceived total sleep time. This will generally produce sleep deprivation, greater sleep drive, and, eventually, better sleep. Time in bed can then be gradually expanded. In addition, methods directed toward producing relaxation in the sleep setting (e.g., meditation, muscle relaxation) are encouraged.
Adjustment Insomnia (Acute Insomnia)
This typically develops after a change in the sleeping environment (e.g., in an unfamiliar hotel or hospital bed) or before or after a significant life event, such as a change of occupation, loss of a loved one, illness, or anxiety over a deadline or examination. Increased sleep latency, frequent awakenings from sleep, and early morning awakening can all occur. Recovery is generally rapid, usually within a few weeks. Treatment is symptomatic, with intermittent use of hypnotics and resolution of the underlying stress. Altitude insomnia describes a sleep disturbance that is a common consequence of exposure to high altitude. Periodic breathing of the Cheyne-Stokes type occurs during NREM sleep about half the time at high altitude, with restoration of a regular breathing pattern during REM sleep. Both hypoxia and hypocapnia are thought to be involved in the development of periodic breathing. Frequent awakenings and poor quality sleep characterize altitude insomnia, which is generally worse on the first few nights at high altitude but may persist. Treatment with acetazolamide can decrease time spent in periodic breathing and substantially reduce hypoxia during sleep.
Insomnia Associated with Mental Disorders
Approximately 80% of patients with psychiatric disorders describe sleep complaints. There is considerable heterogeneity, however, in the nature of the sleep disturbance both between conditions and among patients with the same condition. Depression can be associated with sleep onset insomnia, sleep maintenance insomnia, or early morning wakefulness. However, hypersomnia occurs in some depressed patients, especially adolescents and those with either bipolar or seasonal (fall/winter) depression (Chap. 391). Indeed, sleep disturbance is an important vegetative sign of depression and may commence before any mood changes are perceived by the patient. Consistent polysomnographic findings in depression include decreased REM sleep latency, lengthened first REM sleep episode, and shortened first NREM sleep episode; however, these findings are not specific for depression, and the extent of these changes varies with age and symptomatology. Depressed patients also show decreased slow-wave sleep and reduced sleep continuity.
In mania and hypomania, sleep latency is increased and total sleep time can be reduced. Patients with anxiety disorders tend not to show the changes in REM sleep and slow-wave sleep seen in endogenously depressed patients. Chronic alcoholics lack slow-wave sleep, have decreased amounts of REM sleep (as an acute response to alcohol), and have frequent arousals throughout the night. This is associated with impaired daytime alertness. The sleep of chronic alcoholics may remain disturbed for years after discontinuance of alcohol usage. Sleep architecture and physiology are disturbed in schizophrenia, with a decreased amount of slow-wave sleep (NREM stage N3 sleep) and a lack of augmentation of REM sleep following REM sleep deprivation; chronic schizophrenics often show day-night reversal, sleep fragmentation, and insomnia.
Insomnia Associated with Neurologic Disorders
A variety of neurologic diseases result in sleep disruption through both indirect, nonspecific mechanisms (e.g., pain in cervical spondylosis or low back pain) or by impairment of central neural structures involved in the generation and control of sleep itself. For example, dementia from any cause has long been associated with disturbances in the timing of the sleep-wake cycle, often characterized by nocturnal wandering and an exacerbation of symptomatology at night (so-called sundowning).
Epilepsy may rarely present as a sleep complaint (Chap. 369). Often the history is of abnormal behavior, at times with convulsive movements during sleep. The differential diagnosis includes REM sleep behavior disorder, sleep apnea syndrome, and periodic movements of sleep (see above). Diagnosis requires nocturnal polysomnography with a full EEG montage. Other neurologic diseases associated with abnormal movements, such as Parkinson's disease, hemiballismus, Huntington's chorea, and Tourette's syndrome (Chap. 372), are also associated with disrupted sleep, presumably through secondary mechanisms. However, the abnormal movements themselves are greatly reduced during sleep. Headache syndromes (migraine or cluster headache) may show sleep-associated exacerbations (Chap. 14) by unknown mechanisms.
Fatal familial insomnia is a rare hereditary disorder caused by degeneration of anterior and dorsomedial nuclei of the thalamus. Insomnia is a prominent early symptom. Patients develop progressive autonomic dysfunction, followed by dysarthria, myoclonus, coma, and death. The pathogenesis is a mutation in the prion gene (Chap. 383).
Insomnia Associated with Other Medical Disorders
A number of medical conditions are associated with disruptions of sleep. The association is frequently nonspecific, e.g., sleep disruption due to chronic pain from rheumatologic disorders. Attention to this association is important in that sleep-associated symptoms are often the presenting or most bothersome complaint. Treatment of the underlying medical problem is the most useful approach. Sleep disruption can also result from the use of medications such as glucocorticoids (see below).
One prominent association is between sleep disruption and asthma. In many asthmatics there is a prominent daily variation in airway resistance that results in marked increases in asthmatic symptoms at night, especially during sleep. In addition, treatment of asthma with theophylline-based compounds, adrenergic agonists, or glucocorticoids can independently disrupt sleep. When sleep disruption is a side effect of asthma treatment, inhaled glucocorticoids (e.g., beclomethasone) that do not disrupt sleep may provide a useful alternative.
Cardiac ischemia may also be associated with sleep disruption. The ischemia itself may result from increases in sympathetic tone as a result of sleep apnea. Patients may present with complaints of nightmares or vivid, disturbing dreams, with or without awareness of the more classic symptoms of angina or of the sleep-disordered breathing. Treatment of the sleep apnea may substantially improve the angina and the nocturnal sleep quality. Paroxysmal nocturnal dyspnea can also occur as a consequence of sleep-associated cardiac ischemia that causes pulmonary congestion exacerbated by the recumbent posture.
Chronic obstructive pulmonary disease is also associated with sleep disruption, as is cystic fibrosis, menopause, hyperthyroidism, gastroesophageal reflux, chronic renal failure, and liver failure.
Medication-, Drug-, or Alcohol-Dependent Insomnia
Disturbed sleep can result from ingestion of a wide variety of agents. Caffeine is perhaps the most common pharmacologic cause of insomnia. It produces increased latency to sleep onset, more frequent arousals during sleep, and a reduction in total sleep time for up to 8–14 h after ingestion. Even small amounts of coffee can significantly disturb sleep in some patients; therefore, a 1- to 2-month trial without caffeine should be attempted in patients with these symptoms. Similarly, alcohol and nicotine can interfere with sleep, despite the fact that many patients use them to relax and promote sleep. Although alcohol can increase drowsiness and shorten sleep latency, even moderate amounts of alcohol increase awakenings in the second half of the night. In addition, alcohol ingestion prior to sleep is contraindicated in patients with sleep apnea because of the inhibitory effects of alcohol on upper airway muscle tone. Acutely, amphetamines and cocaine suppress both REM sleep and total sleep time, which return to normal with chronic use. Withdrawal leads to an REM sleep rebound. A number of prescribed medications can produce insomnia. Antidepressants, sympathomimetics, and glucocorticoids are common causes. In addition, severe rebound insomnia can result from the acute withdrawal of hypnotics, especially following the use of high doses of benzodiazepines with a short half-life. For this reason, hypnotic doses should be low to moderate, and prolonged drug tapering is encouraged.
Restless Legs Syndrome (RLS)
Patients with this sensorimotor disorder report an irresistible urge to move the legs, or sometimes the upper extremities, that is often associated with creepy-crawling or aching dysesthesias deep within the affected limbs. For most patients with RLS, the dysesthesias and restlessness are much worse in the evening or night compared to the daytime and frequently interfere with the ability to fall asleep. The symptoms appear with inactivity and are temporarily relieved by movement. In contrast, paresthesias secondary to peripheral neuropathy persist with activity. The severity of this chronic disorder may wax and wane over time and can be exacerbated by sleep deprivation, caffeine, alcohol, serotonergic antidepressants, and pregnancy. The prevalence is 1–5% of young to middle-age adults and 10–20% of those aged >60 years. There appear to be important differences in RLS prevalence among racial groups, with higher prevalence in those of Northern European ancestry. Roughly one-third of patients (particularly those with an early age of onset) will have multiple affected family members. At least three separate chromosomal loci have been identified in familial RLS, though no gene has been identified to date. Iron deficiency and renal failure may cause RLS, which is then considered secondary RLS. The symptoms of RLS are exquisitely sensitive to dopaminergic drugs (e.g., pramipexole 0.25–0.5 mg q8PM or ropinirole 0.5–4 mg q8PM), which are the treatments of choice. Opioids, benzodiazepines, and gabapentin may also be of therapeutic value. Most patients with restless legs also experience periodic limb movements of sleep, although the reverse is not the case.
Periodic Limb Movement Disorder (PLMD)
Periodic limb movements of sleep (PLMS), previously known as nocturnal myoclonus, consists of stereotyped, 0.5- to 5.0-s extensions of the great toe and dorsiflexion of the foot, which recur every 20–40 s during NREM sleep, in episodes lasting from minutes to hours, as documented by bilateral surface EMG recordings of the anterior tibialis on polysomnography. PLMS is the principal objective polysomnographic finding in 17% of patients with insomnia and 11% of those with excessive daytime somnolence (Fig. 27-3). It is often unclear whether it is an incidental finding or the cause of disturbed sleep. When deemed to be the latter, PLMS is called PLMD. PLMS occurs in a wide variety of sleep disorders (including narcolepsy, sleep apnea, REM sleep behavior disorder, and various forms of insomnia) and may be associated with frequent arousals and an increased number of sleep-stage transitions. The pathophysiology is not well understood, though individuals with high spinal transections can exhibit periodic leg movements during sleep, suggesting the existence of a spinal generator. Treatment options include dopaminergic medications or benzodiazepines.
Polysomnographic recordings of (A) obstructive sleep apnea and (B) periodic limb movement of sleep. Note the snoring and reduction in air flow in the presence of continued respiratory effort, associated with the subsequent oxygen desaturation (upper panel). Periodic limb movements occur with a relatively constant intermovement interval and are associated with changes in the EEG and heart rate acceleration (lower panel). RAT, right anterior tibialis; LAT, left anterior tibialis. (From the Division of Sleep Medicine, Brigham and Women's Hospital.)
Evaluation of Daytime Sleepiness
Daytime impairment due to sleep loss may be difficult to quantify for several reasons. First, patients may be unaware of the extent of sleep deprivation. In obstructive sleep apnea, for example, the brief arousals from sleep associated with respiratory recovery after each apneic episode results in daytime sleepiness, despite the fact that the patient may be unaware of the sleep fragmentation. Second, subjective descriptions of waking impairment vary from patient to patient. Patients may describe themselves as "sleepy," "fatigued," or "tired" and may have a clear sense of the meaning of those terms, while others may use the same terms to describe a completely different condition. Third, sleepiness, particularly when profound, may affect judgment in a manner analogous to ethanol, such that subjective awareness of the condition and the consequent cognitive and motor impairment is reduced. Finally, patients may be reluctant to admit that sleepiness is a problem, both because they are generally unaware of what constitutes normal alertness and because sleepiness is generally viewed pejoratively, ascribed more often to a deficit in motivation than to an inadequately addressed physiologic sleep need.
Specific questioning about the occurrence of sleep episodes during normal waking hours, both intentional and unintentional, is necessary to determine the extent of the adverse effects of sleepiness on a patient's daytime function. Specific areas to be addressed include the occurrence of inadvertent sleep episodes while driving or in other safety-related settings, sleepiness while at work or school (and the relationship of sleepiness to work and school performance), and the effect of sleepiness on social and family life. Standardized questionnaires, e.g., the Epworth Sleepiness Scale, are now commonly used in clinical and research settings to quantify daytime sleep tendency and screen for excessive sleepiness.
Driving is particularly hazardous for patients with increased sleepiness. Reaction time is equally impaired by 24 h of sleep loss as by a blood alcohol level of 0.10 g/dL. More than half of Americans admit to having fallen asleep while driving. An estimated 250,000 motor vehicle crashes per year are due to drowsy drivers, causing about 20% of all serious crash injuries and deaths. Drowsy driving legislation, aimed at improving education of all drivers about the hazards of driving drowsy and establishing sanctions comparable to those for drunk driving, has been enacted in New Jersey and is pending in several other states. Screening for sleep disorders, provision of an adequate number of safe highway rest areas, maintenance of unobstructed shoulder rumble strips, and strict enforcement and compliance monitoring of hours-of-service policies are needed to reduce the risk of sleep-related transportation crashes. Evidence for significant daytime impairment in association either with the diagnosis of a primary sleep disorder, such as narcolepsy or sleep apnea, or with imposed or self-selected sleep-wake schedules (see "Shift-Work Disorder," below) raises the issue of the physician's responsibility to notify motor vehicle licensing authorities of the increased risk of sleepiness-related motor vehicle crashes. As with epilepsy, legal requirements vary from state to state, and existing legal precedents do not provide a consistent interpretation of the balance between the physician's responsibility and the patient's right to privacy. At a minimum, physicians should inform patients who report a history of nodding off or falling asleep at the wheel or who have excessive daytime sleepiness about the increased risk of operating a motor vehicle, advise such patients not to drive a motor vehicle until the cause of the excessive sleepiness has been diagnosed and successful treatment has been implemented, and reevaluate the patient to determine when it is safe for the patient to resume driving. Each of those steps should be documented in the patient's medical record.
The distinction between fatigue and sleepiness can be useful in the differentiation of patients with complaints of fatigue or tiredness in the setting of disorders such as fibromyalgia (Chap. 335), chronic fatigue syndrome (Chap. 389), or endocrine deficiencies such as hypothyroidism (Chap. 341) or Addison's disease (Chap. 342). While patients with these disorders can typically distinguish their daytime symptoms from the sleepiness that occurs with sleep deprivation, substantial overlap can occur. This is particularly true when the primary disorder also results in chronic sleep disruption (e.g., sleep apnea in hypothyroidism) or in abnormal sleep (e.g., fibromyalgia).
While clinical evaluation of the complaint of excessive sleepiness is usually adequate, objective quantification is sometimes necessary. Assessment of daytime functioning as an index of the adequacy of sleep can be made with the multiple sleep latency test (MSLT), which utilizes repeated measurement of sleep latency (time to onset of sleep) under standardized conditions during a day following quantified nocturnal sleep. The average latency across four to six tests (administered every 2 h across the waking day) provides an objective measure of daytime sleep tendency. Disorders of sleep that result in pathologic daytime somnolence can be reliably distinguished with the MSLT. In addition, the multiple measurements of sleep onset may identify direct transitions from wakefulness to REM sleep that are suggestive of specific pathologic conditions (e.g., narcolepsy).
Narcolepsy is both a disorder of the ability to sustain wakefulness voluntarily and a disorder of REM sleep regulation (Table 27-2). The classic "narcolepsy tetrad" consists of excessive daytime somnolence plus three specific symptoms related to an intrusion of REM sleep characteristics (e.g., muscle atonia, vivid dream imagery) into the transition between wakefulness and sleep: (1) sudden weakness or loss of muscle tone without loss of consciousness, often elicited by emotion (cataplexy); (2) hallucinations at sleep onset (hypnagogic hallucinations) or upon awakening (hypnopompic hallucinations); and (3) muscle paralysis upon awakening (sleep paralysis). The severity of cataplexy varies, as patients may have two to three attacks per day or per decade. Some patients with objectively confirmed narcolepsy (see below) may show no evidence of cataplexy. In those with cataplexy, the extent and duration of an attack may also vary, from a transient sagging of the jaw lasting a few seconds to rare cases of flaccid paralysis of the entire voluntary musculature for up to 20–30 min. Symptoms of narcolepsy typically begin in the second decade, although the onset ranges from ages 5–50 years. Once established, the disease is chronic without remissions. Secondary forms of narcolepsy have been described (e.g., after head trauma).
Table 27-2 Prevalence of Symptoms in Narcolepsy |Favorite Table|Download (.pdf)
Table 27-2 Prevalence of Symptoms in Narcolepsy
|Excessive daytime somnolence||100|
Narcolepsy affects about 1 in 4000 people in the United States and appears to have a genetic basis. Recently, several convergent lines of evidence suggest that the hypothalamic neuropeptide hypocretin (orexin) is involved in the pathogenesis of narcolepsy: (1) a mutation in the hypocretin receptor 2 gene has been associated with canine narcolepsy; (2) hypocretin "knockout" mice that are genetically unable to produce this neuropeptide exhibit behavioral and electrophysiologic features resembling human narcolepsy; and (3) cerebrospinal fluid levels of hypocretin are reduced in most patients who have narcolepsy with cataplexy. The inheritance pattern of narcolepsy in humans is more complex than in the canine model. However, almost all narcoleptics with cataplexy are positive for HLA DQB1*0602 (Chap. 315), suggesting that an autoimmune process may be responsible.
The diagnostic criteria continue to be a matter of debate. Certainly, objective verification of excessive daytime somnolence, typically with MSLT mean sleep latencies <8 min, is an essential if nonspecific diagnostic feature. Other conditions that cause excessive sleepiness, such as sleep apnea or chronic sleep deprivation, must be rigorously excluded. The other objective diagnostic feature of narcolepsy is the presence of REM sleep in at least two of the naps during the MSLT. Abnormal regulation of REM sleep is also manifested by the appearance of REM sleep immediately or within minutes after sleep onset in 50% of narcoleptic patients, a rarity in unaffected individuals maintaining a conventional sleep-wake schedule. The REM-related symptoms of the classic narcolepsy tetrad are variably present. There is increasing evidence that narcoleptics with cataplexy (one-half to two-thirds of patients) may represent a more homogeneous group than those without this symptom. However, a history of cataplexy can be difficult to establish reliably. Hypnagogic and hypnopompic hallucinations and sleep paralysis are often found in nonnarcoleptic individuals and may be present in only one-half of narcoleptics. Nocturnal sleep disruption is commonly observed in narcolepsy but is also a nonspecific symptom. Similarly, a history of "automatic behavior" during wakefulness (a trancelike state during which simple motor behaviors persist) is not specific for narcolepsy and serves principally to corroborate the presence of daytime somnolence.
The treatment of narcolepsy is symptomatic. Somnolence is treated with wake-promoting therapeutics. Modafinil is now the drug of choice, principally because it is associated with fewer side effects than older stimulants and has a long half-life; 200–400 mg is given as a single daily dose. Older drugs such as methylphenidate (10 mg bid to 20 mg qid) or dextroamphetamine (10 mg bid) are still used as alternatives, particularly in refractory patients.
These latter medications are now available in slow-release formulations, extending their duration of action and allowing once-daily dosing.
Treatment of the REM-related phenomena of cataplexy, hypnagogic hallucinations, and sleep paralysis requires the potent REM sleep suppression produced by antidepressant medications. The tricyclic antidepressants [e.g., protriptyline (10–40 mg/d) and clomipramine (25–50 mg/d)] and the selective serotonin reuptake inhibitors (SSRIs) [e.g., fluoxetine (10–20 mg/d)] are commonly used for this purpose. Efficacy of the antidepressants is limited largely by anticholinergic side effects (tricyclics) and by sleep disturbance and sexual dysfunction (SSRIs). Alternately, gamma hydroxybutyrate (GHB), given at bedtime, and 4 h later, is effective in reducing daytime cataplectic episodes. Adequate nocturnal sleep time and planned daytime naps (when possible) are important preventive measures.
Respiratory dysfunction during sleep is a common, serious cause of excessive daytime somnolence as well as of disturbed nocturnal sleep. An estimated 2–5 million individuals in the United States have a reduction or cessation of breathing for 10–150 s from thirty to several hundred times every night during sleep. These episodes may be due to either an occlusion of the airway (obstructive sleep apnea), absence of respiratory effort (central sleep apnea), or a combination of these factors (mixed sleep apnea) (Fig. 27-3). Failure to recognize and treat these conditions appropriately may lead to impairment of daytime alertness, increased risk of sleep-related motor vehicle accidents, hypertension and other serious cardiovascular complications, and increased mortality. Sleep apnea is particularly prevalent in overweight men and in the elderly, yet it is estimated to remain undiagnosed in 80–90% of affected individuals. This is unfortunate since effective treatments are available. Readers are referred to Chap. 265 for a comprehensive review of the diagnosis and treatment of patients with these conditions.
The term parasomnia refers to abnormal behaviors or experiences that arise from or occur during sleep. A continuum of parasomnias arise from NREM sleep, from brief confusional arousals to sleepwalking and night terrors. The presenting complaint is usually related to the behavior itself, but the parasomnias can disturb sleep continuity or lead to mild impairments in daytime alertness. Two main parasomnias occur in REM sleep: REM sleep behavior disorder (RBD), which will be described below, and nightmare disorder.
Patients affected by this disorder carry out automatic motor activities that range from simple to complex. Individuals may walk, urinate inappropriately, eat, or exit from the house while remaining only partially aware. Full arousal may be difficult, and individuals may rarely respond to attempted awakening with agitation or even violence. Sleepwalking arises from slow-wave sleep (NREM stage N3 sleep), usually in the first 2 h of the night, and is most common in children and adolescents, when these sleep stages are most robust. Episodes are usually isolated but may be recurrent in 1–6% of patients. The cause is unknown, though it has a familial basis in roughly one-third of cases.
This disorder, also called pavor nocturnus, occurs primarily in young children during the first several hours after sleep onset, in slow-wave sleep (NREM stage N3 sleep). The child suddenly screams, exhibiting autonomic arousal with sweating, tachycardia, and hyperventilation. The individual may be difficult to arouse and rarely recalls the episode on awakening in the morning. Parents are usually reassured to learn that the condition is self-limited and benign and that no specific therapy is indicated. Both sleep terrors and sleepwalking represent abnormalities of arousal. In contrast, nightmares occur during REM sleep and cause full arousal, with intact memory for the unpleasant episode.
Bruxism is an involuntary, forceful grinding of teeth during sleep that affects 10–20% of the population. The patient is usually unaware of the problem. The typical age of onset is 17–20 years, and spontaneous remission usually occurs by age 40. Sex distribution appears to be equal. In many cases, the diagnosis is made during dental examination, damage is minor, and no treatment is indicated. In more severe cases, treatment with a rubber tooth guard is necessary to prevent disfiguring tooth injury. Stress management or, in some cases, biofeedback can be useful when bruxism is a manifestation of psychological stress. There are anecdotal reports of benefit using benzodiazepines.
Bedwetting, like sleepwalking and night terrors, is another parasomnia that occurs during sleep in the young. Before age 5 or 6 years, nocturnal enuresis should probably be considered a normal feature of development. The condition usually improves spontaneously by puberty, has a prevalence in late adolescence of 1–3%, and is rare in adulthood. In older patients with enuresis, a distinction must be made between primary and secondary enuresis, the latter being defined as bedwetting in patients who have previously been fully continent for 6–12 months. Treatment of primary enuresis is reserved for patients of appropriate age (>5 or 6 years) and consists of bladder training exercises and behavioral therapy. Urologic abnormalities are more common in primary enuresis and must be assessed by urologic examination. Important causes of secondary enuresis include emotional disturbances, urinary tract infections or malformations, cauda equina lesions, epilepsy, sleep apnea, and certain medications. Symptomatic pharmacotherapy is usually accomplished with desmopressin (0.2 mg qhs), oxybutynin chloride (5–10 mg qhs), or imipramine (10–50 mg qhs).
Other clinical entities may be characterized as a parasomnia or a sleep-related movement disorder in that they occur selectively during sleep and are associated with some degree of sleep disruption. Examples include jactatio capitis nocturna (nocturnal headbanging, rhythmic movement disorder), confusional arousals, sleep-related eating disorder, and nocturnal leg cramps.
REM Sleep Behavior Disorder (Rbd)
RBD is a rare condition that is distinct from other parasomnias in that it occurs during REM sleep. It primarily afflicts men of middle age or older, many of whom have an existing, or developing, neurologic disease. Approximately one-half of patients with RBD will develop Parkinson's disease (Chap. 372) within 10–20 years. Presenting symptoms consist of agitated or violent behavior during sleep, as reported by a bed partner. In contrast to typical somnambulism, injury to the patient or bed partner is not uncommon, and, upon awakening, the patient reports vivid, often unpleasant, dream imagery. The principal differential diagnosis is nocturnal seizures, which can be excluded with polysomnography. In RBD, seizure activity is absent on the EEG, and disinhibition of the usual motor atonia is observed in the EMG during REM sleep, at times associated with complex motor behaviors. The pathogenesis is unclear, but damage to brainstem areas mediating descending motor inhibition during REM sleep may be responsible. In support of this hypothesis are the remarkable similarities between RBD and the sleep of animals with bilateral lesions of the pontine tegmentum in areas controlling REM sleep motor inhibition. Treatment with clonazepam (0.5–1.0 mg qhs) provides sustained improvement in almost all reported cases.