sleep and wake fullness 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 sleep.

Progression through the stages, typically followed by a brief interval of REM sleep, occurs cyclically 5 to 6 times a night (see Fig. 1: Sleep and Wakefulness Disorders: Typical sleep pattern in young adults.).

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.

Fig. 1

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 (see Table 1: Sleep and Wakefulness Disorders: Some Causes of Insomnia and Excessive Daytime Sleepiness)
Table 1

Some Causes of Insomnia and Excessive Daytime Sleepiness

Disorder
Insomnia
Excessive Daytime Sleepiness

Inadequate sleep hygiene

Adjustment insomnia

Psychophysiologic insomnia

Physical or mental sleep disorders

Insufficient sleep syndrome

Drug-dependent and drug-induced sleep disorders

Obstructive sleep apnea syndrome

Central sleep apnea syndrome

Circadian rhythm sleep disorders

Narcolepsy

Periodic limb movement disorder

Restless legs syndrome

√ = present.

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 (see Table 2: Sleep and Wakefulness Disorders: Some Drugs That Interfere With Sleep).
Table 2

Some Drugs That Interfere With Sleep

Cause
Example

Drug use
Alcohol

Anticonvulsants (eg, phenytoin

)

Antimetabolite chemotherapy

Certain antidepressants of the SSRI, SNRI, MAOI, and TCA classes

CNS stimulants (eg, amphetamines, caffeine)

Oral contraceptives

Propranolol

Steroids (anabolic steroids, 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

)

MAOI = monoamine oxidase inhibitor; SNRI = serotonin-norepinephrine

reuptake inhibitor; TCA = tricyclic antidepressant.

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 manifests 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.

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

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 (see Table 3: Sleep and Wakefulness Disorders: Epworth Sleepiness Scale) may be used; a cumulative score ≥ 10 represents abnormal daytime sleepiness.
Table 3

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 legs 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 (see Table 2: Sleep and Wakefulness Disorders: Some Drugs That Interfere With Sleep).

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 patients 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 test, 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 (see Table 4: Sleep and Wakefulness Disorders: Sleep Hygiene) is important whatever the cause and is often the only treatment patients with mild problems need.

Table 4

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. Reading or taking a warm bath before bedtime can aid relaxation. Techniques such as visual imagery, progressive muscle relaxation, and breathing exercises can be used. Patients should not watch the clock.

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 (see Table 5: Sleep and Wakefulness Disorders: Guidelines for the Use of Hypnotics) aim at minimizing abuse, misuse, and addiction.
Table 5

Guidelines for the Use of Hypnotics

Define a clear indication and treatment goal.

Prescribe the lowest effective dose.

Except for specific hypnotics, limit duration of use to a few weeks.

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, see Table 6: Sleep and Wakefulness Disorders: Oral Hypnotics in Common Use. 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.

Table 6

Oral Hypnotics in Common Use

Drug
Half Life* (h)
Dose (mg)†
Comments

Benzodiazepine receptor agonists: Benzodiazepines

Estazolam

10–24
0.5–2
Effective for sleep induction and maintenance

Flurazepam

47-100
15–30
High risk of next-day residual sedation; not recommended for the elderly

Quazepam

39-100
7.5–15
High lipophilicity, which may mitigate residual sedation in first 7–10 days of continuous use

Temazepam

9.5-12.4
7.5–15
Longest latency for sleep induction

Triazolam

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

Zaleplon

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

Zolpidem

2.5
5–10
Effective for sleep induction only

Zolpidem

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

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 (see Drug Use and Dependence: Anxiolytics and Sedatives) and because abrupt discontinuation can cause rebound insomnia or even anxiety, tremor, and seizures. These effects are more common with benzodiazepines (particularly triazolam

) 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 (see also Drug Use and Dependence: Withdrawal and detoxification).

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

, diphenhydramine

) 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

25 to 50
mg, paroxetine

5 to 20 mg, trazodone

50 mg, trimipramine

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; when 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.

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