Almost half of all people in the
Approach to the Patient With a Sleep or Wakefulness Disorder
The most commonly reported sleep-related symptoms are insomnia and excessive daytime sleepiness (EDS).
• Insomnia is difficulty falling or staying asleep or a sensation of unrefreshing sleep.
• EDS is the tendency to fall asleep during normal waking hours.
Insomnia and EDS are not disorders themselves but are symptoms of various sleep-related disorders. Parasomnias are abnormal sleep-related events.
Pathophysiology
There are 2 states of sleep, each marked by characteristic physiologic changes:
• Nonrapid eye movement (NREM): NREM sleep constitutes about 75 to 80% of total sleep time in adults. It consists of 4 stages in increasing depth of sleep. Slow, rolling eye movements, which characterize quiet wakefulness and early stage 1 sleep, disappear in deeper sleep stages. Muscle activity decreases as well. Stages 3 and 4 are referred to as deep sleep because arousal threshold is high; people may perceive these stages as high-quality sleep.
• Rapid eye movement (REM): REM sleep follows each cycle of NREM sleep. It is characterized by low-voltage fast activity on the EEG and postural muscle atonia. Respiration rate and depth fluctuate dramatically. Most dreams occur during REM.
Progression through the stages, typically followed by a brief interval of REM sleep, occurs cyclically 5 to 6 times a night
Individual sleep requirements vary widely, ranging from 6 to 10 h/24 h. Infants sleep a large part of the day; with aging, total sleep time and deep sleep tend to decrease, and sleep becomes more interrupted. In the elderly, stages 3 and 4 may disappear. These changes may account for increasing EDS and fatigue with aging, but their clinical significance is unclear.
Typical sleep pattern in young adults.
Rapid eye movement (REM) sleep occurs cyclically throughout the night every 90–120 min Sleep time is spent as follows:
•Stage 1: 2–5%
•Stage 2: 45–55%
•Stage 3: 3–8%
•Stage 4: 10–15%
•REM: 20–25%
Etiology
Some disorders can cause either insomnia or EDS (sometimes both), and some cause one or the other
Insomnia is most often caused by
•Inadequate sleep hygiene
•Psychiatric disorders, particularly mood, anxiety, and substance use disorders
•Miscellaneous medical disorders such as cardiopulmonary disorders, musculoskeletal conditions, and chronoic pain
•Adjustment sleep disorder and psychophysiologic insomnia
EDS is most often caused by
•Insufficient sleep syndrome
•Obstructive sleep apnea syndrome
•Miscellaneous medical, neurologic, and psychiatric conditions
•Circadian rhythm disorders such as jet lag and shift work sleep disorders
Inadequate sleep hygiene refers to behaviors that are not conducive to sleep. They include consumption of caffeine or sympathomimetic or other stimulant drugs (typically near bedtime, but even in the afternoon for people who are particularly sensitive), exercise or excitement (eg, a thrilling TV show) late in the evening, and an irregular sleep-wake schedule. Patients who compensate for lost sleep by sleeping late or by napping further fragment their nocturnal sleep.
Adjustment insomnia results from acute emotional stressors (eg, job loss, hospitalization) that disrupt sleep.
Psychophysiologic insomnia is insomnia (regardless of cause) that persists well beyond resolution of precipitating factors, usually because patients feel anticipatory anxiety about the prospect of another sleepless night followed by another day of fatigue. Typically, patients spend hours in bed focusing on and brooding about their sleeplessness, and they have greater difficulty falling asleep in their own bedroom than falling asleep away from home.
Physical disorders that cause pain or discomfort (eg, arthritis, cancer, herniated disks), particularly those that worsen with movement, can cause transient awakenings and poor sleep quality. Nocturnal seizures can also interfere with sleep.
Most major mental disorders are associated with EDS and insomnia. About 80% of patients with major depression report EDS and insomnia; conversely, 40% of chronic insomniacs have a major mental disorder, most commonly a mood disorder.
Insufficient sleep syndrome involves not sleeping enough at night despite adequate opportunity to do so, typically because of various social or employment commitments.
Drug-related sleep disorders result from chronic use of or withdrawal from various drugs
Circadian rhythm disorders result in misalignment between endogenous sleep-wake rhythms and environmental light-darkness cycle. The cause may be external (eg, jet lag, shift work) or internal (eg, delayed or advanced sleep phase syndrome).
Central sleep apnea consists of repeated episodes of breathing cessation or shallow breathing during sleep, lasting at least 10 sec, caused by diminished respiratory effort. The disorder typically presents as insomnia or as disturbed and unrefreshing sleep.
Obstructive sleep apnea consists of episodes of partial or complete closure of the upper airway during sleep, leading to cessation of breathing for > 10 sec. Sometimes patients awaken, gasping. These episodes disrupt sleep and result in a feeling of unrefreshing sleep and EDS.
Narcolepsy is characterized by chronic EDS, often with cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations. Cataplexy is momentary muscular weakness or paralysis without loss of consciousness that is evoked by sudden emotional reactions (eg, mirth, anger, fear, joy, surprise). Weakness may be confined to the limbs (eg, patients may drop the rod when a fish strikes their line) or may cause a limp fall during hearty laughter (as in “weak with laughter”) or sudden anger. Sleep paralysis is momentary inability to move when just falling asleep or immediately after awakening. Hypnagogic and hypnopompic phenomena are vivid auditory or visual illusions or hallucinations that occur when just falling asleep (hypnagogic) or, less often, immediately after awakening (hypnopompic).
Periodic limb movement disorder (PLMD) is characterized by repetitive (usually every 20 to 40 sec) twitching or kicking of the lower extremities during sleep. Patients usually complain of interrupted nocturnal sleep or EDS. They are typically unaware of the movements and brief arousals that follow and have no abnormal sensations in the extremities.
Restless legs syndrome is characterized by an irresistible urge to move the legs and, less frequently, the arms, usually accompanied by paresthesias (eg, creeping or crawling sensations) in the limbs when reclining. To relieve symptoms, patients move the affected extremity by stretching, kicking, or walking. As a result, they have difficulty falling asleep, repeated nocturnal awakenings, or both.
Some Drugs That Interfere With Sleep
Cause Example
Drug use Alcohol
Anticonvulsants (eg, phenytoin Some Trade Names
DILANTIN
)
Antimetabolite chemotherapy
Certain antidepressants of the SSRI, SNRI, MAOI, and TCA classes
CNS stimulants (eg, amphetamines, caffeine)
Oral contraceptives
Propranolol Some Trade Names
INDERAL
Steroids (anabolic and corticosteroids)
Thyroid hormone preparations
Drug withdrawal Alcohol
Certain antidepressants of the SSRI, SNRI, MAOI, and TCA classes
CNS depressants (eg, barbiturates, opioids, sedatives)
Illicit drugs (eg, cocaine, heroin, marijuana, phencyclidine Some Trade Names
No US trade name
)
Evaluation
History: History of present illness should include duration and age at onset of symptoms and any events (eg, a life or work change, new drug, new medical disorder) that coincided with onset. Symptoms during sleeping and waking hours should be noted. The quality and quantity of sleep are identified by determining bedtime, latency of sleep (time from bedtime to falling asleep), number and time of awakenings, final morning awakening and arising times, and frequency and duration of naps. Having patients keep a sleep log for several weeks is more accurate than questioning them. Bedtime events (eg, food or alcohol consumption, physical or mental activity) should be evaluated. Intake of and withdrawal from drugs, alcohol, caffeine, and nicotine Some Trade Names
COMMIT
NICORETTE
NICOTROL
as well as level and timing of physical activity should also be included.
If EDS is the problem, severity should be quantified based on the propensity for falling asleep in different situations (eg, resting comfortably vs when driving a car). The Epworth Sleepiness Scale may be used; a cumulative score ≥ 10 represents abnormal daytime sleepiness.
Epworth Sleepiness Scale
Situation
Sitting and reading
Watching TV
Sitting inactive in a public place
Riding as a car passenger for 1 h continuously
Lying down to rest in the afternoon
Sitting and talking to someone
Sitting quietly after lunch (no alcohol)
Sitting in a car stopped for a few minutes in traffic
For each situation, probability of dozing is self-rated as none (0), slight (1), moderate (2), or high (3). A score of ≥ 10 suggests abnormal daytime sleepiness.
Review of systems should check for symptoms of specific sleep disorders, including snoring, interrupted breathing patterns, other nocturnal respiratory disturbances (sleep apnea syndromes); depression, anxiety, mania, and hypomania (mental sleep disorders); restlessness in the legs, an irresistible desire to move them, and jerking leg movements (restless leg syndrome); and cataplexy, sleep paralysis, and hypnagogic phenomena (narcolepsy). Bed partners or other family members can best identify some of these symptoms.
Past medical history should check for known disorders that can interfere with sleep, including COPD, asthma, heart failure, hyperthyroidism, gastroesophageal reflux, neurologic disorders (particularly movement and degenerative disorders), and painful disorders (eg, RA). Risk factors for obstructive sleep apnea include obesity, heart disorders, hypertension, stroke, smoking, snoring, and nasal trauma. Drug history should include questions about use of any drugs associated with sleep disturbance
Physical examination: The physical examination is useful mainly for identifying signs associated with obstructive sleep apnea syndrome. Signs include obesity with fat distributed around the neck or midriff; large neck circumference (≥ 43.2 cm in males, ≥ 40.6 cm in females); mandibular hypoplasia and retrognathia; nasal obstruction; enlarged tonsils, tongue, uvula, or soft palate; decreased pharyngeal patency; increased obstruction of uvula and soft palate by the tongue; and redundant pharyngeal mucosa. The chest should be examined for expiratory wheezes and kyphoscoliosis. Signs of right ventricular failure should be noted. A thorough neurologic examination should be done.
Red flags: The following findings are of particular concern:
•Falling asleep while driving or other potentially dangerous situations
•Repeated sleep attacks (falling asleep without warning)
•Breathing interruptions or awakening with gasping reported by bed partner
•Unstable cardiac or pulmonary status
•Recent stroke
•Status cataplecticus (continuous cataplexy attacks)
•History of violent behaviors or injury to self or others during asleep
•Frequent sleepwalking or other out-of-bed behavior
Interpretation of findings: Inadequate sleep hygiene and situational stressors are usually apparent in the history. EDS that disappears when sleep time is increased (eg, on weekends or vacations) suggests inadequate sleep syndrome. EDS that occurs without insomnia and is accompanied by cataplexy, hypnagogic/hypnopompic hallucinations, or sleep paralysis suggests narcolepsy.
Difficulty falling asleep (initial insomnia) should be distinguished from difficulty maintaining sleep (sleep maintenance insomnia). Initial insomnia suggests delayed sleep phase syndrome, chronic psychophysiologic insomnia, or childhood phobias. Sleep maintenance insomnia suggests advanced sleep phase syndrome, major depression, central or obstructive sleep apnea, periodic limb movement disorder, or aging; in those with significant snoring, frequent awakenings, and other risk factors, obstructive sleep apnea is quite likely.
Testing: Tests are usually done when the clinical diagnosis is in doubt or when response to initial presumptive treatment is inadequate. Patients with obvious problems (eg, poor sleep habits, transient stress, shift work) do not require testing.
Polysomnography is particularly useful when obstructive sleep apnea syndrome, narcolepsy, nocturnal seizures, or periodic limb movement disorder is suspected. It also helps clinicians evaluate violent and potentially injurious sleep-related behaviors. It monitors brain activity (via EEG), eye movements, heart rate, respirations, O2 saturation, and muscle tone and activity during sleep. Video recording may be used to identify abnormal movements during sleep. Polysomnography is typically done in a sleep laboratory; equipment for home use has been devised but is not widely used.
The multiple sleep latency test assesses speed of sleep onset in 5 daytime nap opportunities 2 h apart during the patient's typical daytime. Patients lie in a darkened room and are asked to sleep. Onset and stage of sleep (including REM) are monitored by polysomnography. This test's main use is in the diagnosis of narcolepsy.
For the maintenance of wakefulness, patients are asked to stay awake in a quiet room. This test is probably a more accurate measure of ability to remain awake in everyday situations.
Patients with EDS may require laboratory tests of renal, liver, and thyroid function.
Treatment
Specific conditions are treated. Good sleep hygiene is important whatever the cause and is often the only treatment patients with mild problems need.
Sleep Hygiene
Measure Implementation
Regular sleep schedule Bedtime and particularly wake-up time should be the same each day, including weekends. Patients should not spend excessive time in bed.
Restriction of time in bed Limiting time in bed improves sleep continuity. If unable to fall sleep within 20 min, patients should get out of bed and return when sleepy. The bed should not be used for activities other than sleep or sex (eg, for reading, eating, watching television, or paying bills).
Avoidance of daytime naps, except by shift workers, the elderly, and patients with narcolepsy Daytime naps may aggravate sleeplessness in patients with insomnia. However, naps decrease the need for stimulants in patients with narcolepsy and improve performance in shift workers. Naps should be taken at the same time each day and limited to 30 min.
Regular bedtime routine A pattern of activities—brushing teeth, washing, setting the alarm clock—can set the mood for sleep.
Sleep-conducive environment The bedroom should be dark, quiet, and reasonably cool; it should be used only for sleep and sexual activity. Heavy curtains or a sleep mask can eliminate light, and earplugs, fans, or white-noise devices can help eliminate disturbing noise.
Pillows Pillows between the knees or under the waist can increase comfort. For patients with back problems, lying supine with a large pillow under the knees can help.
Regular exercise Exercise promotes sleep and reduces stress, but if done in the late evening, it can stimulate the nervous system and interfere with falling asleep.
Relaxation Stress and worry interfere with sleep.
Avoidance of stimulants and diuretics Drinking alcoholic or caffeinated beverages, smoking, eating caffeinated foods (eg, chocolate), and taking appetite suppressants, or prescription diuretics—especially near bedtime—should be avoided.
Bright light exposure while awake Light exposure during the day can help rectify circadian rhythms.
Hypnotics: General guidelines for use of hypnotics aim at minimizing abuse, misuse, and addiction.
Guidelines for the Use of Hypnotics
Define a clear indication and treatment goal.
Prescribe the lowest effective dose.
Limit duration of use to a few weeks, except for specific hypnotics do not limit duration of use.
Individualize the dose for each patient.
Use lower doses in patients also taking a CNS depressant, in the elderly, and in patients with hepatic or renal disorders.
Avoid* if patients have sleep apnea syndrome or respiratory disorders or a history of sedative abuse, if they are drinking alcohol, or if they are pregnant.
For patients who need longer-term treatment, consider intermittent therapy.
Avoid abruptly stopping the drug if possible (ie, taper it).
Re-evaluate drug treatment regularly; assess efficacy and adverse events.
*Ramelteon is an exception; it can be given to patients with mild to moderate obstructive sleep apnea syndrome or COPD or a history of sedative abuse.
For commonly used hypnotics, All hypnotics except ramelteon act at the benzodiazepine recognition site on the γ-aminobutyric (GABA) receptor and augment the inhibitory effects of GABA. The drugs differ primarily in elimination half-life and onset of action. Drugs with a short half-life are used for sleep-onset insomnia. Drugs with a longer half-life are useful for both sleep-onset and sleep-maintenance insomnia; they have greater potential for daytime carryover effects, especially after prolonged use or in the elderly. Patients who experience daytime sedation, incoordination, or other daytime effects should avoid activities requiring alertness (eg, driving), and the dose should be reduced, the drug stopped, or, if needed, another drug used. Other adverse effects include amnesia, hallucinations, incoordination, and falls.
Oral Hypnotics in Common Use
Drug Half Life* (h) Dose (mg)† Comments
Benzodiazepine Receptor Agonists: Benzodiazepines
Flurazepam Some Trade Names
DALMANE
47-100 15–30 High risk of next-day residual sedation; not recommended for the elderly
Quazepam Some Trade Names
DORAL
9-100 7.5–15 High lipophilicity, which may mitigate residual sedation in first 7–10 days of continuous use
Estazolam Some Trade Names
PROSOM
10–24 0.5–2 Effective for sleep induction and maintenance
Temazepam Some Trade Names
RESTORIL
9.5-12.4 7.5–15 Longest latency for sleep induction
Triazolam Some Trade Names
HALCION
1.5−5.5 0.25–0.5 May cause anterograde amnesia; high likelihood of tolerance and rebound after repeated use
Benzodiazepine Receptor Agonists: Nonbenzodiazepines
Eszopiclone 6 1-3 Effective for sleep-onset insomnia and sleep maintenance insomnia. No tolerance with up to 6 mo nightly use
Zolpidem Some Trade Names
AMBIEN
ER 2.8 6.25-12.5 Effective for sleep-onset insomnia and sleep maintenance insomnia. No tolerance with up to 6 mo use 3 to 7 nights/wk
Zolpidem Some Trade Names
AMBIEN
2.5 5–10 Effective for sleep induction only
Zaleplon Some Trade Names
SONATA
1 5-20 Ultrashort-acting; can be given for initial insomnia or after nocturnal awakening (minimum of 4 h from arising ); when given at normal bedtime, least likely to have residual effects
Melatonin Receptor Agonists
Ramelteon 1-5 8 Useful only for sleep-onset insomnia. Only hypnotic that is not associated with abuse liability and that can be safely given to patients with mild to moderate obstructive sleep apnea syndrome or COPD. Probably no difficulties with long term use, but no controlled studies of > 5 wk.
*Includes parent and active metabolites. Arranged in order from longest to shortest half-life.
†Dose given at bedtime.
Hypnotics should be used cautiously in patients with pulmonary insufficiency. In the elderly, any hypnotic, even in small doses, can cause restlessness, excitement, or exacerbation of delirium and dementia. Rarely, hypnotics can cause complex sleep-related behaviors, such as sleepwalking and even sleep driving; use of higher-than-recommended doses and concurrent consumption of alcoholic beverages may increase risk of such behaviors. Rarely, severe allergic reactions occur.
Prolonged use is discouraged because tolerance can develop and because abrupt discontinuation can cause rebound insomnia or even anxiety, tremor, and seizures. These effects are more common with benzodiazepines (particularly triazolam Some Trade Names
HALCION
) and less common with the nonbenzodiazepines. Difficulties can be minimized by using the lowest effective dose for brief periods and by tapering the dose before stopping the drug)
Other sedatives: Many drugs not specifically indicated for insomnia are used to induce and maintain sleep.
Many patients use alcohol to help them sleep, but alcohol is a poor choice because after prolonged use and at higher doses, it produces unrefreshing, disturbed sleep with frequent nocturnal awakenings, often increasing daytime sleepiness. Alcohol can further impair respiration during sleep in patients with obstructive sleep apnea syndrome.
OTC antihistamines (eg, doxylamine Some Trade Names
GOOD SENSE SLEEP AID
UNISOM SLEEPTABS
, diphenhydramine Some Trade Names
BENADRYL
NYTOL
) can induce sleep. However, efficacy is unpredictable, and these drugs have adverse effects such as daytime sedation, confusion, and systemic anticholinergic effects, which are particularly worrisome in the elderly.
Low doses of some antidepressants at bedtime may improve sleep, eg, doxepin Some Trade Names
SINEQUAN
ZONALON
25 to 50 mg, paroxetine Some Trade Names
PAXIL
5 to 20 mg, trazodone Some Trade Names
DESYREL
50 mg, trimipramine Some Trade Names
SURMONTIL
75 to 200 mg. However, antidepressants should be used in these low doses mainly when standard hypnotics are not tolerated (rare) or in higher (antidepressant) doses when depression is present.
Melatonin is a hormone that is secreted by the pineal gland (and that occurs naturally in some foods). Darkness stimulates secretion, and light inhibits it. By binding with melatonin receptors in the suprachiasmatic nucleus, melatonin mediates circadian rhythm, especially during physiologic sleep onset. Oral melatonin (typically 0.5 to 5 mg at bedtime) may be effective for sleep problems due to delayed sleep phase syndrome. It must be taken at the appropriate time (when endogenous melatonin is normally secreted, in early evening for most people); taken at the wrong time, it can aggravate sleep problems. Its efficacy is largely unproved, and its safety is in question because it appears to stimulate coronary artery changes in animals. Available preparations of melatonin are unregulated, so content and purity cannot be ensured, and the effects of long-term use are unknown. Its use should be supervised by a physician.
Key Points
•Poor sleep hygiene and situational disruptors (eg, shift work, emotional stressors) cause many cases of insomnia.
•Medical conditions (eg, sleep apnea syndromes, pain disorders) and psychiatric conditions (eg, mood disorders) must be considered.
•Sleep studies (eg, polysomnography) are usually done when sleep apnea syndrome, periodic limb movements, or other sleep disorders are suspected, the clinical diagnosis is in doubt, or when response to initial presumptive treatment is inadequate.
•Hypnotics and sedatives should be used with caution in the elderly.
•Good sleep hygiene may be the only treatment needed by patients with mild insomnia problems.
Circadian Rhythm Sleep Disorders
Circadian rhythm sleep disorders are caused by desynchronization between internal sleep-wake rhythms and the light-dark cycle. Patients typically have insomnia, excessive daytime sleepiness, or both, which typically resolve as the body clock realigns itself. Diagnosis is clinical. Treatment depends on the cause.
In circadian rhythm disorders, endogenous sleep-wake rhythms (body clock) and the external light/dark cycle become misaligned (desynchronized). The cause may be internal (eg, delayed or advanced sleep phase syndrome) or external (eg, jet lag, shift work).
If the cause is external, the timing of other circadian body rhythms, including temperature and hormone secretion, is altered; in addition to insomnia and sleepiness, these alterations may cause nausea, malaise, irritability, and depression. Risk of cardiovascular disorders may also be increased.
Repetitive circadian shifts (eg, due to frequent long-distance travel or rotating shift work), are particularly difficult to adapt to, especially when the shifts change in a counterclockwise direction. Counterclockwise shifts are those that shift awakening and sleeping times earlier (eg, when flying eastward or when rotating shifts from days to nights to evenings). Symptoms resolve over several days or, in some patients (eg, the elderly), over a few weeks or months, as rhythms readjust. Because light is the strongest synchronizer of circadian rhythms, exposure to bright light (sunlight or artificial light of 5,000 to 10,000 lux intensity) after desired awakening time speeds readjustment. Melatonin given in the evening may be tried.
Patients with circadian rhythm disorders often misuse alcohol, hypnotics, and stimulants.
Circadian rhythm disorders include the following.
Circadian rhythm sleep disorder, jet lag type (jeg lag disorder): This syndrome is caused by rapid travel across > 2 time zones. Eastward travel (advancing the sleep cycle) causes more severe symptoms than westward travel (delaying sleep).
If possible, travelers should gradually shift their sleep-wake schedule before travel to approximate that of their destination and maximize exposure to daylight (particularly in the morning) in the new locale. Short-acting hypnotics or wake-promoting drugs (eg, modafinil Some Trade Names
PROVIGIL
) may be used for brief periods after arrival.
Circadian rhythm sleep disorder, shift work type (shift work disorder): Severity of symptoms is proportional to the frequency of shift changes, the magnitude of each change, and the frequency of counterclockwise (sleep advancing) changes. Fixed-shift work (ie, full-time night or evening) is preferable; rotating shifts should go clockwise (ie, day to evening to night). However, even fixed-shift workers have difficulties because daytime noise and light interfere with sleep quality, and workers often shorten sleep times to participate in social or family events.
Shift workers should maximize their exposure to bright light (sunlight or, for night workers, especially constructed bright artificial lightboxes) at times when they should be awake and ensure that the bedroom is as dark and quiet as possible during sleep. Sleep masks and white-noise devices are helpful. When symptoms persist and interfere with functioning, judicious use of hypnotics with a short half-life and wake-promoting drugs is appropriate.
Circadian rhythm sleep disorder, altered sleep phase types: In these syndromes, patients have normal sleep quality and duration with a 24-h circadian rhythm cycle, but the cycle is out of synch with desired or necessary wake times. Less commonly, the cycle is not 24 h, and patients awaken and sleep earlier or later each day. If able to follow their natural cycle, patients have no symptoms.
• Delayed sleep phase syndrome: Patients consistently go to sleep and awaken late (eg, 3 am and 10 am). This pattern is more common during adolescence. If required to awaken earlier for work or school, excessive daytime sleepiness results; patients often present because school performance is poor or they miss morning classes. They can be distinguished from people who stay up late by choice because they cannot fall asleep earlier even if they try. Mild phase delay (<> 24 h, resulting in a delay of sleep and wake times by 1 to 2 h each day. This disorder is more common among blind people.
Insomnia and Excessive Daytime Sleepiness (EDS)
Many sleep disorders manifest with insomnia and usually excessive daytime sleepiness (EDS). Sleep disorders may be caused by factors inside the body (intrinsic) or outside the body (extrinsic).
Inadequate sleep hygiene: Sleep is impaired by certain behaviors. They include consumption of caffeine or sympathomimetic or other stimulant drugs (typically near bedtime, but even in the afternoon for people who are particularly sensitive), exercise or excitement (eg, a thrilling TV show) late in the evening, and an irregular sleep-wake schedule. Patients who compensate for lost sleep by sleeping late or by napping further fragment nocturnal sleep.
Insomniacs should adhere to a regular awakening time and avoid naps regardless of the amount of nocturnal sleep.
Adequate sleep hygiene can improve sleep
Adjustment insomnia: Acute emotional stressors (eg, job loss, hospitalization) can cause insomnia. Symptoms typically remit shortly after the stressors abate; insomnia is usually transient and brief. Nevertheless, if daytime sleepiness and fatigue develop, especially if they interfere with daytime functioning, short-term treatment with hypnotics is warranted. Persistent anxiety may require specific treatment.
Psychophysiologic insomnia: Insomnia, regardless of cause, may persist well beyond resolution of precipitating factors, usually because patients feel anticipatory anxiety about the prospect of another sleepless night followed by another day of fatigue. Typically, patients spend hours in bed focusing on and brooding about their sleeplessness, and they have greater difficulty falling asleep in their own bedroom than falling asleep away from home.
Optimal treatment combines cognitive-behavioral strategies and hypnotics. Although cognitive-behavioral strategies are more difficult to implement and take longer, effects are longer lasting, up to 2 yr after treatment is ended. These strategies include sleep hygiene (particularly restriction of time in bed), education, relaxation training, stimulus control, and cognitive therapy.
Hypnotics are suitable for patients who need rapid relief and whose insomnia has had daytime effects such as EDS and fatigue. These drugs must not be used indefinitely in most cases.
Physical sleep disorders: Physical disorders may interfere with sleep and cause insomnia and EDS. Disorders that cause pain or discomfort (eg, arthritis, cancer, herniated disks), particularly those that worsen with movement, cause transient awakenings and poor sleep quality. Nocturnal seizures can also interfere with sleep.
Treatment is directed at the underlying disorder and symptom relief (eg, with bedtime analgesics).
Mental sleep disorders: Most major mental disorders can cause insomnia and EDS. About 80% of patients with major depression report these symptoms. Conversely, 40% of chronic insomniacs have a major mental disorder, most commonly a mood disorder.
Patients with depression may have initial sleeplessness or sleep maintenance insomnia. Sometimes in the depressed phase of bipolar disorder and in seasonal affective disorder, sleep is uninterrupted, but patients complain of unrelenting daytime fatigue.
If depression is accompanied by sleeplessness, antidepressants that provide more sedation (eg, amitriptyline Some Trade Names
ELAVIL
ENDEP
, doxepin Some Trade Names
SINEQUAN
ZONALON
, mirtazapine Some Trade Names
REMERON
, paroxetine Some Trade Names
PAXIL
, trazodone Some Trade Names
DESYREL
) may be chosen. These drugs are used at regular, not low, doses to ensure correction of the depression. These drugs may cause EDS and other side effects, such as weight gain. Alternatively, any antidepressant may be used with a hypnotic.
If depression is accompanied by EDS, antidepressants with activating qualities (eg, bupropion Some Trade Names
WELLBUTRIN
ZYBAN
, venlafaxine Some Trade Names
EFFEXOR
, certain SSRIs such as fluoxetine Some Trade Names
PROZAC
SARAFEM
and sertraline Some Trade Names
ZOLOFT
) may be chosen.
Insufficient sleep syndrome (sleep deprivation): Patients with this syndrome do not sleep enough at night, despite adequate opportunity to do so, to stay alert when awake. The cause is usually various social or employment commitments. This syndrome is probably the most common cause of EDS, which disappears when sleep time is increased (eg, on weekends or vacations).
Drug-related sleep disorders: Drug-related sleep disorders: Insomnia and EDS can result from chronic use of CNS stimulants (eg, amphetamines, caffeine), hypnotics (eg, benzodiazepines), other sedatives, antimetabolite chemotherapy, anticonvulsants (eg, phenytoin Some Trade Names
DILANTIN
), oral contraceptives, methyldopa Some Trade Names
ALDOMET
, propranolol Some Trade Names
INDERAL
, alcohol, and thyroid hormone preparations Commonly prescribed hypnotics can cause irritability and apathy and reduce mental alertness. Many psychoactive drugs can induce abnormal movements during sleep.
Insomnia can develop during withdrawal of CNS depressants (eg, barbiturates, opioids, sedatives), tricyclic antidepressants, monoamine oxidase inhibitors, or illicit drugs (eg, cocaine, heroin, marijuana, phencyclidine Some Trade Names
No
). Abrupt withdrawal of hypnotics or sedatives can cause nervousness, tremors, and seizures.
Narcolepsy
Narcolepsy is characterized by chronic excessive daytime sleepiness, often with sudden loss of muscle tone (cataplexy). Other symptoms include sleep paralysis and hypnagogic and hypnopompic hallucinations. Diagnosis is by polysomnography and multiple sleep latency testing. Treatment is with modafinil, various stimulants, or Na oxybate for excessive daytime sleepiness and certain antidepressants for associated symptoms.
The cause is unknown. In Europe,
Narcolepsy is strongly associated with specific HLA haplotypes, and children of patients with narcolepsy have a 40-fold increased risk, suggesting a genetic cause. However, concordance in twins is low (25%), suggesting a prominent role for environmental factors, which often trigger the disorder. The neuropeptide hypocretin-1 is deficient in CSF of narcoleptic animals and most human patients, suggesting that the cause may be HLA-associated autoimmune destruction of hypocretin-containing neurons in the lateral hypothalamus.
Narcolepsy features dysregulation of the timing and control of REM sleep. Therefore, REM sleep intrudes into wakefulness and into the transition from wakefulness to sleep. Many symptoms of narcolepsy result from postural muscle paralysis and vivid dreaming, which characterize REM.
Symptoms and Signs
The main symptoms are excessive daytime sleepiness (EDS), cataplexy, hypnagogic and hypnopompic hallucinations, and sleep paralysis; about 10% of patients have all 4. Nocturnal sleep is often also disturbed and some patients develop hypersomnia (prolonged sleep times). Symptoms usually begin in adolescents or young adults without prior illness, although onset can be precipitated by an illness, a stressor, or a period of sleep deprivation. Once established, narcolepsy persists throughout life; life span is unaffected.
EDS: EDS can occur anytime. Sleep episodes vary from few to many per day, and each may last minutes or hours. Patients can resist the desire to sleep only temporarily but can be roused as readily as from normal sleep. Sleep tends to occur during monotonous conditions (eg, reading, watching television, attending meetings) but may also occur during complex tasks (eg, driving, speaking, writing, eating). Patients may also experience sleep attacks—episodes of sleep that strike without warning. Patients may feel refreshed when they awaken yet fall asleep again in a few minutes. Nighttime sleep may be unsatisfying and interrupted by vivid, frightening dreams. Consequences include low productivity, breaches in interpersonal relationships, poor concentration, low motivation, depression, a dramatic reduction in quality of life, and potential for physical injury (particularly due to motor vehicle collisions).
Cataplexy: Momentary muscular weakness or paralysis occurs without loss of consciousness; it is evoked by sudden emotional reactions, such as mirth, anger, fear, joy, or, often, surprise. Weakness may be confined to the limbs (eg, patients may drop the rod when a fish strikes their line) or may cause a limp fall during hearty laughter (as in “weak with laughter”) or sudden anger. These attacks resemble the loss of muscle tone that occurs during REM sleep. Cataplexy occurs in about ¾ of patients.
Sleep paralysis: Patients are momentarily unable to move as they are just falling asleep or immediately after they awaken. These occasional episodes may be very frightening. They resemble the motor inhibition that accompanies REM sleep. Sleep paralysis occurs in about ¼ of patients but also in some healthy children and, less commonly, in healthy adults.
Hypnagogic or hypnopompic hallucinations: Particularly vivid auditory or visual illusions or hallucinations may occur when just falling asleep (hypnagogic) or, less often, immediately after awakening (hypnopompic). They are difficult to distinguish from intense reverie and are somewhat similar to vivid dreams, which are normal in REM sleep. Hypnagogic hallucinations occur in about 1/3 of patients, are common among healthy young children, and occasionally occur in healthy adults.
Diagnosis
• Polysomnography
• Multiple sleep latency testing
A delay of 10 yr from onset to diagnosis is common. A history of cataplexy strongly suggests narcolepsy in patients with EDS.Nocturnal polysomnography, followed by multiple sleep latency testing, is diagnostic. Findings include the following:
• REM episodes during at least 2 of 5 daytime nap opportunities
• Average sleep latency (time to fall asleep) of ≤ 8 min, observed after a minimum of 6 h of nocturnal sleep
• No other diagnostic abnormalities on nocturnal polysomnography
The maintenance of wakefulness test does not help with diagnosis but does help monitor treatment efficacy.
Other disorders that can cause chronic EDS are usually suggested by the history and physical examination; brain imaging and blood and urine tests can confirm the diagnosis. These disorders include space-occupying lesions affecting the hypothalamus or upper brain stem, increased intracranial pressure, and certain forms of encephalitis. Hypothyroidism, hyperglycemia, hypoglycemia, anemia, uremia, hypercapnia, hypercalcemia, hepatic failure, and seizure disorders can also cause EDS with or without hypersomnia. Acute, relatively brief EDS and hypersomnia commonly accompany acute systemic disorders such as influenza.
The Kleine-Levin syndrome, a very rare disorder in adolescent boys, causes episodic hypersomnia and hyperphagia. Etiology is unclear but may be an autoimmune response to an infection.
Treatment
• Modafinil Some Trade Names
PROVIGIL
• Sometimes amphetamine derivatives or Na oxybate
• Certain REM-suppressant antidepressants
Some patients who have occasional episodes of sleep paralysis or hypnagogic and hypnopompic hallucinations, infrequent and partial cataplexy, and mild EDS need no treatment. For others, stimulant drugs and anticataplectic drugs are used. Patients should also get enough sleep at night and take brief naps (<>Idiopathic Hypersomnia
Idiopathic hypersomnia is EDS with or without long sleep time; it is differentiated from narcolepsy by lack of cataplexy, hypnagogic hallucinations, and sleep paralysis.
Idiopathic hypersomnia is not well characterized. Cause is presumed to CNS dysfunction.
In idiopathic hypersomnia with long sleep time, the history or sleep logs reveal noctural sleep > 10 h; in idiopathic hypersomnia without long sleep time it is > 6 h but <>Parasomnias
Parasomnias are undesirable behaviors that occur during entry into sleep, during sleep, or during arousal from sleep. Diagnosis is clinical. Treatment may include drugs and psychotherapy.
For many of these disorders, history and physical examination can confirm the diagnosis.
Somnambulism : : Sitting, walking, or other complex behavior occurs during sleep, usually with the eyes open but without evidence of recognition. Somnambulism is most common during late childhood and adolescence and occurs after and during arousal from nonrapid eye movement (NREM) stage 3 or 4 sleep. Prior sleep deprivation and poor sleep hygiene increase the likelihood of these episodes, and risk is higher for 1st-degree relatives of patients with the disorder. Patients may mumble repetitiously, and some injure themselves on obstacles or stairs. There is no accompanying dream. Usually, patients do not remember the episode.
Treatment is directed at protecting patients from injury. It includes using electronic alarms to awaken patients when they leave the bed, using a low bed, and removing obstacles from the bedroom. Benzodiazepines, particularly clonazepam Some Trade Names
KLONOPIN
0.5 to 2 mg po, at bedtime may help.
Sleep (night) terrors: During the night, patients have episodes of fear, screaming, and flailing, often with sleepwalking. Patients are difficult to awaken. Sleep terrors are more common among children and occur after arousal from NREM stages 3 or 4 sleep; thus, they do not represent nightmares. In adults, sleep terrors can be associated with mental difficulties or alcoholism. If daily activities are affected (eg, if school work deteriorates), intermediate- or long-acting oral benzodiazepines (eg, clonazepam Some Trade Names
KLONOPIN
1 to 2 mg, diazepam Some Trade Names
VALIUM
2 to 5 mg) at bedtime may help.
Nightmares: Children are more likely to have nightmares than adults. Nightmares occur during REM sleep, more commonly when fever is present or after alcohol has been ingested. Treatment is directed at any underlying mental distress.
REM sleep behavior disorder: Verbalization (sometimes profane) and often violent movements (eg, waving the arms, punching, kicking) occur during REM sleep. These behaviors may represent acting out dreams by patients who, for unknown reasons, do not have the atonia normally present during REM sleep.
This disorder is more common among the elderly, particularly those with CNS degenerative disorders (eg, Parkinson's or Alzheimer's disease, vascular dementia, olivopontocerebellar degeneration, multiple system atrophy, progressive supranuclear palsy). It can also occur in patients who have narcolepsy and with use of norepinephrine Some Trade Names
LEVOPHED
reuptake inhibitors (eg, atomoxetine Some Trade Names
STRATTERA
, reboxetine, venlafaxine Some Trade Names
EFFEXOR
). Cause is usually unknown.
Diagnosis may be suspected based on symptoms reported by patients or the bed partner. Polysomnography can usually confirm the diagnosis. It may detect excessive motor activity during REM; audiovisual monitoring may document abnormal body movements and vocalizations. A neurologic examination is done to rule out neurodegenerative disorders. If an abnormality is detected, CT or MRI may be done.
Treatment is with clonazepam Some Trade Names
KLONOPIN 0.5 to 2 mg po at bedtime. Most patients need to take the drug indefinitely to prevent recurrences; potential for tolerance or abuse is low. Bed partners should be warned about the possibility of harm and may wish to sleep in another bed until symptoms resolve. Sharp objects should be removed from the bedside.
Sleep-related leg cramps: Muscles of the calf or foot muscles often cramp during sleep in otherwise healthy middle-aged and elderly patients. Diagnosis is based on the history and lack of physical signs or disability.
Prevention includes stretching the affected muscles for several minutes before sleep. Stretching as soon as cramps occur relieves symptoms promptly and is preferable to drug treatment. Numerous drugs (eg, quinine Some Trade Names
QUALAQUIN , Ca and Mg supplements, diphenhydramine Some Trade Names
BENADRYL
NYTOL , benzodiazepines, mexiletine Some Trade Names
MEXITIL) have been used; none is likely to be effective, and adverse effects may be significant (particularly with quinine Some Trade Names
QUALAQUIN and mexiletine Some Trade Names
MEXITIL). Avoiding caffeine and other sympathetic stimulants may help.
Periodic Limb Movement Disorder and Restless Legs Syndrome
Periodic limb movement disorder and restless legs syndrome are characterized by abnormal motions of and sometimes sensations in the lower or upper extremities, which may interfere with sleep.
Periodic limb movement disorder (PLMD) and restless legs syndrome (RLS) are more common during middle and older age; > 80% of patients with RLS also have PLMD.
The mechanism is unclear but may involve abnormalities in dopamine Some Trade Names
INTROPIN
neurotransmission in the CNS. The disorders can occur in isolation or during drug withdrawal, with use of stimulants or certain antidepressants, during pregnancy, or in patients with chronic renal or hepatic failure, iron deficiency, anemia, and other disorders. In primary restless legs syndrome, heredity may be involved; > 1/3 of patients with primary RLS have a family history of it. Risk factors may include a sedentary lifestyle, smoking, and obesity.
Symptoms
PLMD is characterized by repetitive (usually every 20 to 40 sec) twitching or kicking of the lower or upper extremities during sleep. Patients usually complain of interrupted nocturnal sleep or excessive daytime sleepiness. They are typically unaware of the movements and brief arousals that follow and have no abnormal sensations in the extremities.
RLS is a sensorimotor disorder characterized by an irresistible urge to move the legs, usually accompanied by paresthesias (eg, creeping or crawling sensations) and sometimes pain in the upper or lower extremities, which are more prominent when patients are inactive or recline, and peak in severity around bedtime. To relieve symptoms, patients move the affected extremity by stretching, kicking, or walking. As a result, they have difficulty falling asleep, repeated nocturnal awakenings, or both.
Diagnosis
• History alone for RLS
• History and polysomnography for PLMD
Diagnosis may be suggested by the patient's or bed partner's history. Polysomnography is necessary to confirm the diagnosis of PLMD, which is usually apparent as repetitive bursts of electromyographic activity. Polysomnography may be also done after RLS is diagnosed to determine whether patients also have PLMD, but polysomnography is not necessary for diagnosis of RLS itself.
Patients with either disorder should be evaluated medically for disorders that can contribute (eg, with blood tests for anemia and iron deficiency and with hepatic and renal function tests).
Treatment
• Pramipexole Some Trade Names
MIRAPEX
or ropinirole Some Trade Names
REQUIP
Numerous drugs (eg, dopaminergic drugs, benzodiazepines, anticonvulsants, vitamins and minerals) are used; only dopaminergic drugs are specific for RLS.
Dopaminergic drugs, although often effective, may have adverse effects such as augmentation (symptoms are felt earlier in the day), rebound (symptoms worsen after stopping the drug or after effects of the drug dissipate), nausea, orthostatic hypotension, and insomnia.Two D2 and D3 dopamine Some Trade Names
INTROPIN
agonists, pramipexole Some Trade Names
MIRAPEX
and ropinirole Some Trade Names
REQUIP
, are effective and have few serious adverse effects. Pramipexole Some Trade Names
MIRAPEX
0.125 mg is given 2 h before onset of severe symptoms and increased, as needed, by 0.125 mg q 2 nights until symptoms are relieved (maximum dose 0.5 mg). Ropinirole Some Trade Names
REQUIP
0.25 mg is given 1 to 3 h before symptoms occur and is increased, as needed, by 0.25 mg nightly (maximum dose 4 mg).
Benzodiazepines may improve sleep continuity but do not reduce limb movements; they should be used cautiously to avoid tolerance and daytime sleepiness. Gabapentin Some Trade Names
NEURONTIN
beginning with 300 mg at bedtime can help when RLS is accompanied by pain. Dose is increased by 300 mg weekly (maximum dose 2700 mg). Opioids may also work but are used as a last resort because of tolerance, adverse effects, and abuse potential. Ferritin levels should be obtained and, if low (<>
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