205 Sleep Disorders CHAPTER 31

disorders (see below) also cause sleep fragmentation, it is

important that the patient have sufficient sleep opportunity

(at least 8 h per night) for several nights prior to a diagnostic

polysomnogram.

There is growing evidence that inadequate sleep in

humans is associated with glucose intolerance that may

contribute to the development of diabetes, obesity, and the

metabolic syndrome, as well as impaired immune responses,

accelerated atherosclerosis, and increased risk of cardiac

disease, cognitive impairment, Alzheimer’s disease, and

stroke. For these reasons, the National Academy of Medicine

declared sleep deficiency and sleep disorders “an unmet

public health problem.”

■ WAKE AND SLEEP ARE REGULATED BY

BRAIN CIRCUITS

Two principal neural systems govern the expression of

sleep and wakefulness. The ascending arousal system, illustrated in green in Fig. 31-2, consists of clusters of nerve

cells extending from the upper pons to the hypothalamus

and basal forebrain that activate the cerebral cortex, thalamus (which is necessary to relay sensory information to the cortex),

and other forebrain regions. The ascending arousal neurons use

monoamines (norepinephrine, dopamine, serotonin, and histamine),

glutamate, or acetylcholine as neurotransmitters to activate their target neurons. Some basal forebrain neurons use γ-aminobutyric acid

(GABA) to inhibit cortical inhibitory interneurons, thus promoting

arousal. Additional wake-promoting neurons in the hypothalamus use

the peptide neurotransmitter orexin (also known as hypocretin, shown

in Fig. 31-2 in blue) to reinforce activity in the other arousal cell groups.

Damage to the arousal system at the level of the rostral pons and

lower midbrain causes coma, indicating that the ascending arousal

influence from this level is critical in maintaining wakefulness. Injury

to the hypothalamic branch of the arousal system causes profound

sleepiness but usually not coma. Specific loss of the orexin neurons

produces the sleep disorder narcolepsy (see below). Isolated damage

to the thalamus causes loss of the content of wakefulness, known as a

persistent vegetative state, but wake-sleep cycles are largely preserved.

The arousal system is turned off during sleep by inhibitory inputs

from cell groups in the sleep-promoting system, shown in Fig. 31-2 in

red. These neurons in the preoptic area and pons use GABA to inhibit

the arousal system. Additional neurons in the lateral hypothalamus

containing the peptide melanin-concentrating hormone promote

REM sleep. Many sleep-promoting neurons are themselves inhibited

by inputs from the arousal system. This mutual inhibition between

the arousal- and sleep-promoting systems forms a neural circuit akin

to what electrical engineers call a “flip-flop switch.” A switch of this

type tends to promote rapid transitions between the on (wake) and off

(sleep) states, while avoiding intermediate states. The relatively rapid

transitions between waking and sleeping states, as seen in the EEG of

humans and animals, is consistent with this model.

Neurons in the ventrolateral preoptic nucleus, one of the key

sleep-promoting sites, are lost during normal human aging, correlating with reduced ability to maintain sleep (sleep fragmentation).

The ventrolateral preoptic neurons are also injured in Alzheimer’s

disease, which may in part account for the poor sleep quality in those

patients.

Transitions between NREM and REM sleep appear to be governed

by a similar switch in the brainstem. GABAergic REM-Off neurons

have been identified in the lower midbrain that inhibit REM-On neurons in the upper pons. The REM-On group contains both GABAergic

neurons that inhibit the REM-Off group (thus satisfying the conditions

for a REM sleep flip-flop switch) as well as glutamatergic neurons that

project widely in the central nervous system (CNS) to cause the key

phenomena associated with REM sleep. REM-On neurons that project

to the medulla and spinal cord activate inhibitory (GABA and glycinecontaining) interneurons, which in turn hyperpolarize the motor

neurons, producing the paralysis of REM sleep. REM-On neurons that

project to the forebrain may be important in producing dreams.

Clock time

00.00

N3

N2

N1

REM

Awake

N3

Age 23

Age 68

N2

N1

REM

Awake

02.00 04.00 06.00 08.00

FIGURE 31-1 Wake-sleep architecture. Alternating stages of wakefulness, the three stages

of non–rapid eye movement sleep (N1–N3), and rapid eye movement (REM) sleep (solid bars)

occur over the course of the night for representative young and older adult men. Characteristic

features of sleep in older people include reduction of N3 slow-wave sleep, frequent spontaneous

awakenings, early sleep onset, and early morning awakening.

sleep. NREM sleep is further subdivided into three stages: N1, N2, and

N3, characterized by an increasing threshold for arousal and slowing

of the cortical EEG. REM sleep is characterized by a low-amplitude,

mixed-frequency EEG, similar to NREM stage N1 sleep, and an EOG

pattern of REMs that tend to occur in flurries or bursts. EMG activity

is absent in nearly all skeletal muscles except those involved in respiration, reflecting the brainstem-mediated muscle paralysis that is

characteristic of REM sleep.

■ ORGANIZATION OF HUMAN SLEEP

Normal nocturnal sleep in adults displays a consistent organization

from night to night (Fig. 31-1). After sleep onset, sleep usually progresses through NREM stages N1–N3 sleep within 45–60 min. NREM

stage N3 sleep (also known as slow-wave sleep) predominates in the

first third of the night and comprises 15–25% of total nocturnal sleep

time in young adults. Sleep deprivation increases the rapidity of sleep

onset and both the intensity and amount of slow-wave sleep.

The first REM sleep episode usually occurs in the second hour of

sleep. NREM and REM sleep alternate through the night with an average period of 90–110 min (the “ultradian” sleep cycle). Overall, in a

healthy young adult, REM sleep constitutes 20–25% of total sleep, and

NREM stages N1 and N2 constitute 50–60%.

Age has a profound impact on sleep state organization (Fig. 31-1).

N3 sleep is most intense and prominent during childhood, decreasing

with puberty and across the second and third decades of life. In older

adults, N3 sleep may be completely absent, and the remaining NREM

sleep typically becomes more fragmented, with frequent awakenings from NREM sleep. It is the increased frequency of awakenings,

rather than a decreased ability to fall back asleep, that accounts for

the increased wakefulness during the sleep episode in older people.

While REM sleep may account for 50% of total sleep time in infancy,

the percentage falls off sharply over the first postnatal year as a mature

REM-NREM cycle develops; thereafter, REM sleep occupies about 25%

of total sleep time.

Sleep deprivation degrades cognitive performance, particularly on

tests that require continual vigilance. Paradoxically, older people are

less vulnerable than young adults to the neurobehavioral performance

impairment induced by acute sleep deprivation, maintaining their

reaction time and sustaining vigilance with fewer lapses of attention.

However, it is more difficult for older adults to obtain recovery sleep

after staying awake all night, as the ability to sleep during the daytime

declines with age.

After sleep deprivation, NREM sleep generally recovers first, followed by REM sleep. However, because REM sleep tends to be most

prominent in the second half of the night, sleep truncation (e.g., by

an alarm clock) results in selective REM sleep deprivation. This may

increase REM sleep pressure to the point where the first REM sleep

may occur much earlier in the nightly sleep episode. Because several

206 PART 2 Cardinal Manifestations and Presentation of Diseases

The REM sleep switch receives cholinergic input, which favors

transitions to REM sleep, and monoaminergic (norepinephrine and

serotonin) input that prevents REM sleep. As a result, drugs that

increase monoamine tone (e.g., serotonin or norepinephrine reuptake

inhibitors) tend to reduce the amount of REM sleep. Damage to the

neurons that promote REM sleep paralysis can produce REM sleep

behavior disorder, a condition in which patients act out their dreams

(see below).

■ SLEEP-WAKE CYCLES ARE DRIVEN BY

HOMEOSTATIC, ALLOSTATIC, AND CIRCADIAN

INPUTS

The gradual increase in sleep drive with prolonged wakefulness,

followed by deeper slow-wave sleep and prolonged sleep episodes,

demonstrates that there is a homeostatic mechanism that regulates

sleep. The neurochemistry of sleep homeostasis is only partially

understood, but with prolonged wakefulness, adenosine levels rise in

parts of the brain. Adenosine may act through A1 receptors to directly

inhibit many arousal-promoting brain regions. In addition, adenosine

promotes sleep through A2a receptors; blockade of these receptors by

caffeine is one of the chief ways in which people fight sleepiness. Other

humoral factors, such as prostaglandin D2

, have also been implicated

in this process. Both adenosine and prostaglandin D2

 activate the

sleep-promoting neurons in the ventrolateral preoptic nucleus.

Allostasis is the physiologic response to a challenge such as physical

danger or psychological threat that cannot be managed by homeostatic

mechanisms. These stress responses can severely impact the need for

and ability to sleep. For example, insomnia is very common in patients

with anxiety and other psychiatric disorders. Stress-induced insomnia

is even more common, affecting most people at some time in their

lives. Positron emission tomography (PET) studies in patients with

chronic insomnia show hyperactivation of components of the ascending arousal system, as well as their limbic system targets in the forebrain

(e.g., cingulate cortex and amygdala). The limbic areas are not only targets for the arousal system, but they also send excitatory outputs back

to the arousal system, which contributes to a vicious cycle of anxiety

about insomnia that makes it more difficult to sleep. Approaches to

treating insomnia may employ drugs that either inhibit the output of

the ascending arousal system (green and blue in Fig. 31-2) or potentiate the output of the sleep-promoting system (red in Fig. 31-2).

However, behavioral approaches (cognitive behavioral therapy [CBT]

and sleep hygiene) that may reduce forebrain limbic activity at bedtime

are often the best long-term treatment.

Sleep is also regulated by a strong circadian timing signal, driven by

the suprachiasmatic nuclei (SCN) of the hypothalamus, as described

below. The SCN sends outputs to key sites in the hypothalamus, which

impose 24-h rhythms on a wide range of behaviors and body systems,

including the wake-sleep cycle.

■ PHYSIOLOGY OF CIRCADIAN RHYTHMICITY

The wake-sleep cycle is the most evident of many 24-h rhythms in

humans. Prominent daily variations also occur in endocrine, thermoregulatory, cardiac, pulmonary, renal, immune, gastrointestinal,

and neurobehavioral functions. In evaluating daily rhythms in humans,

Hypothalamus

Orexin antagonists

Thalamus

Ascending arousal system

GABAergic arousal inhibiting system

Orexin (hypocretin) system

Potentiators of

GABA inhibition:

Benzodiazepines

Barbiturates

Ethanol

Chloral hydrate

Inhibitors of

arousal systems:

H1 antagonists

Alpha-2 agonists

Muscarinic

antagonists

FIGURE 31-2 Relationship of drugs for insomnia with wake-sleep systems. The arousal system in the brain (green) includes monoaminergic, glutamatergic, and cholinergic

neurons in the brainstem that activate neurons in the hypothalamus, thalamus, basal forebrain, and cerebral cortex. Orexin neurons (blue) in the hypothalamus, which are

lost in narcolepsy, reinforce and stabilize arousal by activating other components of the arousal system. The sleep-promoting system (red) consists of GABAergic neurons

in the preoptic area and brainstem that inhibit the components of the arousal system, thus allowing sleep to occur. Drugs used to treat insomnia include those that block

the effects of arousal system neurotransmitters (green and blue) and those that enhance the effects of γ-aminobutyric acid (GABA) produced by the sleep system (red).

207 Sleep Disorders CHAPTER 31

it is important to distinguish between diurnal components passively

evoked by periodic environmental or behavioral changes (e.g., the

increase in blood pressure and heart rate that occurs upon assumption

of the upright posture) and circadian rhythms actively driven by an

endogenous oscillatory process (e.g., the circadian variations in adrenal

cortisol and pineal melatonin secretion that persist across a variety of

environmental and behavioral conditions).

At the cellular level, endogenous circadian rhythmicity is driven by

self-sustaining feedback loops. While it is now recognized that most

cells in the body have circadian clocks that regulate diverse physiologic

processes, these clocks in different tissues, or even in different cells in

the same tissue, when placed in isolation in a tissue explant are unable

to maintain the long-term synchronization with each other that is

required to produce useful 24-h rhythms aligned with the external

light-dark cycle. The only tissue that maintains this rhythm in vitro is

the SCN, whose neurons are interconnected with one another in such

a way as to produce a near-24-h synchronous rhythm of neural activity

even in prolonged slice culture. SCN neurons are located just above the

optic chiasm in the hypothalamus, from which they receive visual input

to synchronize them with the external world, and they have outputs to

transmit that signal to the rest of the body. Bilateral destruction of the

SCN results in a loss of most endogenous circadian rhythms including

wake-sleep behavior and rhythms in endocrine and metabolic systems.

The genetically determined period of this endogenous neural oscillator,

which averages ~24.15 h in humans, is normally synchronized to the

24-h period of the environmental light-dark cycle through direct input

from intrinsically photosensitive ganglion cells in the retina to the

SCN. Humans are exquisitely sensitive to the resetting effects of light,

particularly the shorter wavelengths (~460–500 nm) in the blue part of

the visible spectrum. Small differences in circadian period contribute

to variations in diurnal preference. Changes in homeostatic sleep regulation may underlie age-related changes in sleep-wake timing.

The timing and internal architecture of sleep are directly coupled

to the output of the endogenous circadian pacemaker. Paradoxically, the endogenous circadian rhythm for wake propensity peaks

just before the habitual bedtime, whereas that of sleep propensity

peaks near the habitual wake time. These rhythms are thus timed to

oppose the rise of sleep tendency throughout the usual waking day

and the decline of sleep propensity during the habitual sleep episode,

respectively, thus promoting consolidated sleep and wakefulness. Misalignment of the endogenous circadian pacemaker with the desired

wake-sleep cycle can, therefore, induce insomnia, decrease alertness,

and impair performance, posing health problems for night-shift workers and airline travelers.

■ BEHAVIORAL AND PHYSIOLOGIC CORRELATES

OF SLEEP STATES AND STAGES

Polysomnographic staging of sleep correlates with behavioral changes

during specific states and stages. During the transitional state (stage N1)

between wakefulness and deeper sleep, individuals may respond to faint

auditory or visual signals. Formation of short-term memories is inhibited

at the onset of NREM stage N1 sleep, which may explain why individuals

aroused from that transitional sleep stage frequently lack situational

awareness. After sleep deprivation, such transitions may intrude upon

behavioral wakefulness notwithstanding attempts to remain continuously awake (for example, see “Shift-Work Disorder,” below).

Subjects awakened from REM sleep recall vivid dream imagery

>80% of the time, especially later in the night. Less vivid imagery may

also be reported after NREM sleep interruptions. Certain disorders

may occur during specific sleep stages and are described below under

“Parasomnias.” These include sleepwalking, night terrors, and enuresis

(bed wetting), which occur most commonly in children during deep

(N3) NREM sleep, and REM sleep behavior disorder, which occurs

mainly among older men who fail to maintain full paralysis during

REM sleep, and often call out, thrash around, or even act out fragments

of dreams.

All major physiologic systems are influenced by sleep. Blood pressure and heart rate decrease during NREM sleep, particularly during

N3 sleep. During REM sleep, bursts of eye movements are associated

with large variations in both blood pressure and heart rate mediated by

the autonomic nervous system. Cardiac dysrhythmias may occur selectively during REM sleep. Respiratory function also changes. In comparison to relaxed wakefulness, respiratory rate becomes slower but

more regular during NREM sleep (especially N3 sleep) and becomes

irregular during bursts of eye movements in REM sleep. Decreases in

minute ventilation during NREM sleep are out of proportion to the

decrease in metabolic rate, resulting in a slightly higher Pco2

.

Within the brain itself, neurotransmission is supported by ion gradients across the cell membranes of neurons and astrocytes. These ion

flows are accompanied by increases in intracellular volume, so that

during wake, there is very little extracellular space in the brain. During

sleep, intracellular volume is reduced, resulting in increased extracellular space, which has higher calcium and lower potassium concentrations, supporting hyperpolarization and reduced firing of neurons.

This expansion of the extracellular space during sleep increases diffusion of substances that accumulate extracellularly, like β-amyloid

peptide, enhancing their clearance from the brain via cerebrospinal

fluid (CSF) flow. Recent evidence suggests that lack of adequate sleep

may contribute to extracellular accumulation of β-amyloid peptide, a

key step in the pathogenesis of Alzheimer’s disease.

Endocrine function also varies with sleep. N3 sleep is associated

with secretion of growth hormone in men, while sleep in general is

associated with augmented secretion of prolactin in both men and

women. Sleep has a complex effect on the secretion of luteinizing

hormone (LH): during puberty, sleep is associated with increased LH

secretion, whereas sleep in postpubertal women inhibits LH secretion

in the early follicular phase of the menstrual cycle. Sleep onset (and

probably N3 sleep) is associated with inhibition of thyroid-stimulating

hormone and of the adrenocorticotropic hormone–cortisol axis, an

effect that is superimposed on the prominent circadian rhythms in the

two systems.

The pineal hormone melatonin is secreted predominantly at night

in both day- and night-active species, reflecting the direct modulation

of pineal activity by the SCN via the sympathetic nervous system,

which innervates the pineal gland. Melatonin secretion does not

require sleep, but melatonin secretion is inhibited by ambient light, an

effect mediated by the neural connection from the retina to the pineal

gland via the SCN. In humans, sleep efficiency is highest when sleep

coincides with endogenous melatonin secretion. When endogenous

melatonin levels are low, such as during the biological day or at the

desired bedtime in people with delayed sleep-wake phase disorder

(DSWPD), administration of exogenous melatonin can hasten sleep

onset and increase sleep efficiency, but it does not increase sleep efficiency if administered when endogenous melatonin levels are elevated.

This may explain why melatonin is often ineffective in the treatment

of patients with primary insomnia. On the other hand, patients with

sympathetic denervation of the pineal gland, such as occurs in cervical

spinal cord injury or in patients with Parkinson’s disease, often have

low melatonin levels, and administration of melatonin (3 mg 30 min

before bedtime) may help them sleep.

Sleep is accompanied by alterations of thermoregulatory function.

NREM sleep is associated with an increase in the firing of warmresponsive neurons in the preoptic area and a fall in body temperature;

conversely, skin warming without increasing core body temperature

has been found to increase NREM sleep. REM sleep is associated with

reduced thermoregulatory responsiveness.

DISORDERS OF SLEEP AND WAKEFULNESS

APPROACH TO THE PATIENT

Sleep Disorders

Patients may seek help from a physician because of: (1) sleepiness

or tiredness during the day; (2) difficulty initiating or maintaining

sleep at night (insomnia); or (3) unusual behaviors during sleep

itself (parasomnias).

208 PART 2 Cardinal Manifestations and Presentation of Diseases

Obtaining 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 bed partner or family

member is often helpful because some patients may be unaware of

symptoms such as heavy snoring or may underreport symptoms

such as falling asleep at work or while driving. Physicians should

inquire about when the patient typically goes to bed, when they fall

asleep and wake up, whether they awaken during sleep, whether

they feel rested in the morning, and whether they nap during the

day. Depending on the primary complaint, it may be useful to ask

about snoring, witnessed apneas, restless sensations in the legs,

movements during sleep, depression, anxiety, and behaviors around

the sleep episode. The physical examination may provide evidence

of a small airway, large tonsils, or a neurologic or medical disorder

that contributes to the main complaint.

It is important to remember that, rarely, seizures may occur

exclusively during sleep, mimicking a primary sleep disorder; such

sleep-related seizures typically occur during episodes of NREM

sleep and may take the form of generalized tonic-clonic movements

(sometimes with urinary incontinence or tongue biting) or stereotyped movements in partial complex epilepsy (Chap. 418).

It is often helpful for the patient to complete a daily sleep log

for 1–2 weeks to define the timing and amounts of sleep. When

relevant, the log can also include information on levels of alertness, work times, and drug and alcohol use, including caffeine and

hypnotics.

Polysomnography is necessary for the diagnosis of several disorders such as sleep apnea, narcolepsy, and periodic limb movement

disorder (PLMD). A conventional polysomnogram performed in

a clinical sleep laboratory allows measurement of sleep stages,

respiratory effort and airflow, oxygen saturation, limb movements,

heart rhythm, and additional parameters. A home sleep test usually

focuses on just respiratory measures and is helpful in patients with

a moderate to high likelihood of having obstructive sleep apnea.

The multiple sleep latency test (MSLT) is used to measure a patient’s

propensity to sleep during the day and can provide crucial evidence

for diagnosing narcolepsy and some other causes of sleepiness.

The maintenance of wakefulness test is used to measure a patient’s

ability to sustain wakefulness during the daytime and can provide

important evidence for evaluating the efficacy of therapies for

improving sleepiness in conditions such as narcolepsy and obstructive sleep apnea.

■ EVALUATION OF DAYTIME SLEEPINESS

Up to 25% of the adult population has persistent daytime sleepiness

that impairs an individual’s ability to perform optimally in school, at

work, while driving, and in other conditions that require alertness.

Sleepy students often have trouble staying alert and performing well in

school, and sleepy adults struggle to stay awake and focused on their

work. More than half of Americans have fallen asleep while driving. An

estimated 1.2 million motor vehicle crashes per year are due to drowsy

drivers, causing about 20% of all serious crash injuries and deaths. One

need not fall asleep to have a motor vehicle crash, as the inattention and

slowed responses of drowsy drivers are major contributors. Twentyfour hours of continuous wakefulness impairs reaction time as much

as a blood alcohol concentration of 0.10 g/dL (which is legally drunk

in all 50 states).

Identifying and quantifying sleepiness can be challenging. First,

patients may describe themselves as “sleepy,” “fatigued,” or “tired,” and

the meanings of these words may differ between patients. For clinical

purposes, it is best to use the term “sleepiness” to describe a propensity to fall asleep, whereas “fatigue” is best used to describe a feeling

of low physical or mental energy but without a tendency to actually

sleep. Sleepiness is usually most evident when the patient is sedentary,

whereas fatigue may interfere with more active pursuits. Sleepiness

generally occurs with disorders that reduce the quality or quantity of

sleep or that interfere with the neural mechanisms of arousal, whereas

fatigue is more common in inflammatory disorders such as cancer,

multiple sclerosis (Chap. 444), fibromyalgia (Chap. 373), chronic

fatigue syndrome (Chap. 450), or endocrine deficiencies such as hypothyroidism (Chap. 383) or Addison’s disease (Chap. 386). Second,

sleepiness can affect judgment in a manner analogous to ethanol, such

that patients may have limited insight into the condition and the extent

of their functional impairment. Finally, patients may be reluctant to

admit that sleepiness is a problem because they may have become

unfamiliar with feeling fully alert, and because sleepiness is sometimes

viewed pejoratively as reflecting poor motivation or bad sleep habits.

Table 31-1 outlines the diagnostic and therapeutic approach to the

patient with a complaint of excessive daytime sleepiness.

To determine the extent and impact of sleepiness on daytime function,

it is helpful to ask patients about the occurrence of sleep episodes during

normal waking hours, both intentional and unintentional. 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 its impact on performance), and the effect of sleepiness on

social and family life. Standardized questionnaires such as the Epworth

Sleepiness Scale are often used clinically to measure sleepiness.

TABLE 31-1 Evaluation of the Patient with Excessive Daytime Sleepiness

FINDINGS ON HISTORY AND PHYSICAL

EXAMINATION DIAGNOSTIC EVALUATION DIAGNOSIS THERAPY

Difficulty waking in the morning,

rebound sleep on weekends and

vacations with improvement in

sleepiness

Sleep log Insufficient sleep Sleep education and behavioral modification to

increase amount of sleep

Obesity, snoring, hypertension Polysomnogram or home sleep test Obstructive sleep apnea

(Chap. 297)

Continuous positive airway pressure; upper

airway surgery (e.g., uvulopalatopharyngoplasty);

dental appliance; weight loss

Cataplexy, hypnagogic hallucinations,

sleep paralysis

Polysomnogram and multiple sleep

latency test

Narcolepsy Stimulants (e.g., modafinil, methylphenidate);

REM sleep-suppressing antidepressants (e.g.,

venlafaxine); pitolisant; solriamfetol; sodium

oxybate

Restless legs, kicking movements during

sleep

Assessment for predisposing medical

conditions (e.g., iron deficiency or renal

failure)

Restless legs syndrome with

or without periodic limb

movements

Treatment of predisposing condition; dopamine

agonists (e.g., pramipexole, ropinirole);

gabapentin; pregabalin; opiates

Sedating medications, stimulant

withdrawal, head trauma, systemic

inflammation, Parkinson’s disease and

other neurodegenerative disorders,

hypothyroidism, encephalopathy

Thorough medical history and

examination including detailed

neurologic examination

Sleepiness due to a drug or

medical condition

Change medications, treat underlying condition,

consider stimulants

209 Sleep Disorders CHAPTER 31

Eliciting a history of daytime sleepiness is usually adequate, but

objective quantification is sometimes necessary. The MSLT measures a

patient’s propensity to sleep under quiet conditions. An overnight polysomnogram should precede the MSLT to establish that the patient has

had an adequate amount of good-quality nighttime sleep. The MSLT

consists of five 20-min nap opportunities every 2 h across the day. The

patient is instructed to try to fall asleep, and the major endpoints are

the average latency to sleep and the occurrence of REM sleep during

the naps. An average sleep latency across the naps of <8 min is considered objective evidence of excessive daytime sleepiness. REM sleep

normally occurs only during nighttime sleep, and the occurrence of

REM sleep in two or more of the MSLT daytime naps provides support

for the diagnosis of narcolepsy.

For the safety of the individual and the general public, physicians

have a responsibility to help manage issues around driving in patients

with sleepiness. Legal reporting requirements vary between states

and countries, but at a minimum, physicians should inform sleepy

patients about their increased risk of having an accident and advise

such patients not to drive a motor vehicle until the sleepiness has been

treated effectively. This discussion is especially important for commercial drivers, and it should be documented in the patient’s medical

record.

■ INSUFFICIENT SLEEP

Insufficient sleep is probably the most common cause of excessive

daytime sleepiness. The average adult needs 7.5–8 h of sleep, but on

weeknights the average U.S. adult gets only 6.75 h of sleep. Only 30%

of the U.S. adult population reports consistently obtaining sufficient

sleep. Insufficient sleep is especially common among shift workers,

individuals working multiple jobs, and people in lower socioeconomic

groups. Most teenagers need ≥9 h of sleep, but many fail to get enough

sleep because of circadian phase delay, plus social pressures to stay up

late coupled with early school start times. Late evening light exposure,

television viewing, video-gaming, social media, texting, and smartphone use often delay bedtimes, despite the fixed early wake times

required for work or school. As is typical with any disorder that causes

sleepiness, individuals with chronically insufficient sleep may feel inattentive, irritable, unmotivated, and depressed, and have difficulty with

school, work, and driving. Individuals differ in their optimal amount of

sleep, and it can be helpful to ask how much sleep the patient obtains

on a quiet vacation when he or she can sleep without restrictions. Some

patients may think that a short amount of sleep is normal or advantageous, and they may not appreciate their biological need for more

sleep, especially if coffee and other stimulants mask the sleepiness.

A 2-week sleep log documenting the timing of sleep and daily level

of alertness is diagnostically useful and provides helpful feedback for

the patient. Extending sleep to the optimal amount on a regular basis

can resolve the sleepiness and other symptoms. As with any lifestyle

change, extending sleep requires commitment and adjustments, but

the improvements in daytime alertness

make this change worthwhile.

■ SLEEP APNEA SYNDROMES

Respiratory dysfunction during sleep

is a common, serious cause of excessive daytime sleepiness as well as of

disturbed nocturnal sleep. At least 24%

of middle-aged men and 9% of middleaged women in the United States have

a reduction or cessation of breathing

dozens or more times each night during sleep, with 9% of men and 4% of

women doing so more than a hundred

times per night. These episodes may

be due to an occlusion of the airway

(obstructive sleep apnea), absence of

respiratory effort (central sleep apnea),

or a combination of these factors.

Failure to recognize and treat these

conditions appropriately may reduce daytime alertness and increase

the risk of sleep-related motor vehicle crashes, depression, hypertension, myocardial infarction, diabetes, stroke, and mortality. Sleep apnea

is particularly prevalent in overweight men and in the elderly, yet it

is estimated to go undiagnosed in most affected individuals. This is

unfortunate because several effective treatments are available. Readers

are referred to Chap. 297 for a comprehensive review of the diagnosis and treatment of patients with sleep apnea.

■ NARCOLEPSY

Narcolepsy is characterized by difficulty sustaining wakefulness, poor

regulation of REM sleep, and disturbed nocturnal sleep. All patients

with narcolepsy have excessive daytime sleepiness. This sleepiness is

usually moderate to severe, and in contrast to patients with disrupted

sleep (e.g., sleep apnea), people with narcolepsy usually feel well rested

upon awakening and then feel tired throughout much of the day. They

may fall asleep at inappropriate times, but then feel refreshed again

after a nap. In addition, they often experience symptoms related to an

intrusion of REM sleep characteristics into wakefulness. REM sleep

is characterized by dreaming and muscle paralysis, and people with

narcolepsy can have: (1) sudden muscle weakness without a loss of consciousness, which is usually triggered by strong emotions (cataplexy;

Video 31-1); (2) dream-like hallucinations at sleep onset (hypnagogic

hallucinations) or upon awakening (hypnopompic hallucinations); and

(3) muscle paralysis upon awakening (sleep paralysis). With severe

cataplexy, an individual may be laughing at a joke and then suddenly

collapse to the ground, immobile but awake for 1–2 min. With milder

episodes, patients may have partial weakness of the face or neck. Narcolepsy is one of the more common causes of chronic sleepiness and

affects about 1 in 2000 people in the United States. Narcolepsy typically

begins between age 10 and 20; once established, the disease persists

for life.

Narcolepsy is caused by loss of the hypothalamic neurons that produce the orexin neuropeptides (also known as hypocretins). Research

in mice and dogs first demonstrated that a loss of orexin signaling

due to null mutations of either the orexin neuropeptides or one of the

orexin receptors causes sleepiness and cataplexy nearly identical to

that seen in people with narcolepsy. Although genetic mutations rarely

cause human narcolepsy, researchers soon discovered that patients

with narcolepsy with cataplexy (now called type 1 narcolepsy) have

very low or undetectable levels of orexins in their CSF, and autopsy

studies showed a nearly complete loss of the orexin-producing neurons

in the hypothalamus. The orexins normally promote long episodes of

wakefulness and suppress REM sleep, and thus loss of orexin signaling

results in frequent intrusions of sleep during the usual waking episode, with REM sleep and fragments of REM sleep at any time of day

(Fig. 31-3). Patients with narcolepsy but no cataplexy (type 2 narcolepsy) usually have normal orexin levels and may have other yet

uncharacterized causes of their excessive daytime sleepiness.

Clock time

20:00

Narcolepsy

N3

N2

N1

REM

Awake

00:00 04:00 08:00 12:00 16:00

Healthy

N3

N2

N1

REM

Awake

FIGURE 31-3 Polysomnographic recordings of a healthy individual and a patient with narcolepsy. The healthy individual

has a long period or NREM sleep before entering REM sleep, but the individual with narcolepsy enters rapid eye

movement (REM) sleep quickly at night and has moderately fragmented sleep. During the day, the healthy subject stays

awake from 8:00 a.m. until midnight, but the patient with narcolepsy dozes off frequently, with many daytime naps that

include REM sleep.

210 PART 2 Cardinal Manifestations and Presentation of Diseases

Extensive evidence suggests that an autoimmune process likely

causes this selective loss of the orexin-producing neurons. Certain

human leukocyte antigens (HLAs) can increase the risk of autoimmune

disorders (Chap. 350), and narcolepsy has the strongest known HLA

association. HLA DQB1*06:02 is found in >90% of people with type 1

narcolepsy, whereas it occurs in only 12–25% of the general population. Researchers now hypothesize that in people with DQB1*06:02, an

immune response against influenza, Streptococcus, or other infections

may also damage the orexin-producing neurons through a process of

molecular mimicry. This mechanism may account for the eight- to

twelvefold increase in new cases of narcolepsy among children in

Europe who received a particular brand of H1N1 influenza A vaccine

(Pandemrix). In support of this hypothesis, people with type 1 narcolepsy have heightened T cell responses against orexin peptides.

On rare occasions, narcolepsy can occur with neurologic disorders

such as tumors or strokes that directly damage the orexin-producing

neurons in the hypothalamus or their projections.

Diagnosis Narcolepsy is most commonly diagnosed by the history

of chronic sleepiness plus cataplexy or other symptoms. Many disorders can cause feelings of weakness, but with true cataplexy patients

will describe definite functional weakness (e.g., slurred speech, dropping a cup, slumping into a chair) that has consistent emotional triggers

such as laughing at a joke, happy surprise at unexpectedly seeing a

friend, or intense anger. Cataplexy occurs in about half of all narcolepsy

patients and is diagnostically very helpful because it occurs in almost

no other disorder. In contrast, occasional hypnagogic hallucinations

and sleep paralysis occur in about 20% of the general population, and

these symptoms are not as diagnostically specific.

When narcolepsy is suspected, the diagnosis should be firmly

established with a polysomnogram followed the next day by an

MSLT. The polysomnogram helps rule out other possible causes

of sleepiness such as sleep apnea and establishes that the patient

had adequate sleep the night before, and the MSLT provides essential, objective evidence of sleepiness plus REM sleep dysregulation.

Across the five naps of the MSLT, most patients with narcolepsy

will fall asleep in <8 min on average, and they will have episodes of

REM sleep in at least two of the naps. Abnormal regulation of REM

sleep is also manifested by the appearance of REM sleep within

15 min of sleep onset at night, which is rare in healthy individuals

sleeping at their habitual bedtime. Stimulants should be stopped

1 week before the MSLT and antidepressants should be stopped

3 weeks prior, because these medications can affect the MSLT. In addition, patients should be encouraged to obtain a fully adequate amount

of sleep each night for the week prior to the test to eliminate any effects

of insufficient sleep.

TREATMENT

Narcolepsy

The treatment of narcolepsy is symptomatic. Most patients with

narcolepsy feel more alert after sleep, and they should be encouraged to get adequate sleep each night and to take a 15- to 20-min

nap in the afternoon. This nap may be sufficient for some patients

with mild narcolepsy, but most also require treatment with wakepromoting medications. Modafinil is often used because it has

fewer side effects than amphetamines and a relatively long halflife; for most patients, 200–400 mg each morning is very effective.

Methylphenidate (10–20 mg bid) or dextroamphetamine (10 mg

bid) are also effective, but sympathomimetic side effects, anxiety,

and the potential for abuse can be concerns. These medications are

available in slow-release formulations, extending their duration of

action and allowing easier dosing. Solriamfetol, a norepinephrine–

dopamine reuptake inhibitor (75–150 mg daily), and pitolisant, a

selective histamine 3 (H3

) receptor antagonist (8.9–35.6 mg daily),

also improve sleepiness and have relatively few side effects. Sodium

oxybate (gamma hydroxybutyrate), given at bedtime and 3–4 h

later, is often very valuable in improving alertness, but it can produce excessive sedation, nausea, and confusion.

Cataplexy is usually much improved with antidepressants that

increase noradrenergic or serotonergic tone because these neurotransmitters strongly suppress REM sleep and cataplexy. Venlafaxine (37.5–150 mg each morning) and fluoxetine (10–40 mg each

morning) are often quite effective. The tricyclic antidepressants,

such as protriptyline (10–40 mg/d) or clomipramine (25–50 mg/d)

are potent suppressors of cataplexy, but their anticholinergic effects,

including sedation and dry mouth, make them less attractive.1

Sodium oxybate, twice each night, is also very helpful in reducing

cataplexy.

1

No antidepressant has been approved by the US Food and Drug Administration

(FDA) for treating narcolepsy.

■ EVALUATION OF INSOMNIA

Insomnia is the complaint of poor sleep and usually presents as difficulty initiating or maintaining sleep. People with insomnia are dissatisfied with their sleep and feel that it impairs their ability to function

well in work, school, and social situations. Affected individuals often

experience fatigue, decreased mood, irritability, malaise, and cognitive

impairment.

Chronic insomnia, lasting >3 months, occurs in about 10% of adults

and is more common in women, older adults, people of lower socioeconomic status, and individuals with medical, psychiatric, and substance

abuse disorders. Acute or short-term insomnia affects over 30% of

adults and is often precipitated by stressful life events such as a major

illness or loss, change of occupation, medications, and substance abuse.

If the acute insomnia triggers maladaptive behaviors such as increased

nocturnal light exposure, frequently checking the clock, or attempting

to sleep more by napping, it can lead to chronic insomnia.

Most insomnia begins in adulthood, but many patients may be

predisposed and report easily disturbed sleep predating the insomnia,

suggesting that their sleep is lighter than usual. Clinical studies and

animal models indicate that insomnia is associated with activation

during sleep of brain areas normally active only during wakefulness.

The polysomnogram is rarely used in the evaluation of insomnia, as

it typically confirms the patient’s subjective report of long latency to

sleep and numerous awakenings but usually adds little new information. Many patients with insomnia have increased fast (beta) activity in

the EEG during sleep; this fast activity is normally present only during

wakefulness, which may explain why some patients report feeling

awake for much of the night. The MSLT is rarely used in the evaluation of insomnia because, despite their feelings of low energy, most

people with insomnia do not easily fall asleep during the day, and on

the MSLT, their average sleep latencies are usually longer than normal.

Many factors can contribute to insomnia, and obtaining a careful

history is essential so one can select therapies targeting the underlying

factors. The assessment should focus on identifying predisposing, precipitating, and perpetuating factors.

Psychophysiological Factors Many patients with insomnia have

negative expectations and conditioned arousal that interfere with sleep.

These individuals may worry about their insomnia during the day and

have increasing anxiety as bedtime approaches if they anticipate a poor

night of sleep. While attempting to sleep, they may frequently check the

clock, which only heightens anxiety and frustration. They may find it

easier to sleep in a new environment rather than their bedroom, as it

lacks the negative associations.

Inadequate Sleep Hygiene Patients with insomnia sometimes

develop counterproductive behaviors that contribute to their insomnia.

These can include daytime napping that reduces sleep drive at night;

an irregular sleep-wake schedule that disrupts their circadian rhythms;

use of wake-promoting substances (e.g., caffeine, tobacco) too close to

bedtime; engaging in alerting or stressful activities close to bedtime

(e.g., arguing with a partner, work-related emailing and texting while in

bed, sleeping with a smartphone or tablet at the bedside); and routinely

using the bedroom for activities other than sleep or sex (e.g., email,

211 Sleep Disorders CHAPTER 31

television, work), so the bedroom becomes associated with arousing

or stressful feelings.

Psychiatric Conditions About 80% of patients with psychiatric

disorders have sleep complaints, and about half of all chronic insomnia

occurs in association with a psychiatric disorder. Depression is classically associated with early morning awakening, but it can also interfere

with the onset and maintenance of sleep. Mania and hypomania can

disrupt sleep and often are associated with substantial reductions in

the total amount of sleep. Anxiety disorders can lead to racing thoughts

and rumination that interfere with sleep and can be very problematic

if the patient’s mind becomes active midway through the night. Panic

attacks can arise from sleep and need to be distinguished from other

parasomnias. Insomnia is common in schizophrenia and other psychoses, often resulting in fragmented sleep, less deep NREM sleep, and

sometimes reversal of the day-night sleep pattern.

Medications and Drugs of Abuse A wide variety of psychoactive

drugs can interfere with sleep. Caffeine, which has a half-life of 6–9 h,

can disrupt sleep for up to 8–14 h, depending on the dose, variations in

metabolism, and an individual’s caffeine sensitivity. Insomnia can also

result from use of prescription medications too close to bedtime (e.g.,

antidepressants, stimulants, glucocorticoids, theophylline). Conversely,

withdrawal of sedating medications such as alcohol, narcotics, or benzodiazepines can cause insomnia. Alcohol taken just before bed can

shorten sleep latency, but it often produces rebound insomnia 2–3 h

later as it wears off. This same problem with sleep maintenance can

occur with short-acting medications such as alprazolam or zolpidem.

Medical Conditions A large number of medical conditions disrupt sleep. Pain from rheumatologic disorders or a painful neuropathy

commonly disrupts sleep. Some patients may sleep poorly because of

respiratory conditions such as asthma, chronic obstructive pulmonary

disease, cystic fibrosis, congestive heart failure, or restrictive lung disease, and some of these disorders are worse at night due to circadian

variations in airway resistance and postural changes in bed that can

result in nocturnal dyspnea. Many women experience poor sleep with

the hormonal changes of menopause. Gastroesophageal reflux is also a

common cause of difficulty sleeping.

Neurologic Disorders Dementia (Chap. 29) is often associated

with poor sleep, probably due to a variety of factors, including napping

during the day, altered circadian rhythms, and perhaps a weakened

output of the brain’s sleep-promoting mechanisms. In fact, insomnia

and nighttime wandering are some of the most common causes for

institutionalization of patients with dementia, because they place a

larger burden on caregivers. Conversely, in cognitively intact elderly

men, fragmented sleep and poor sleep quality are associated with

subsequent cognitive decline. Patients with Parkinson’s disease may

sleep poorly due to rigidity, dementia, and other factors. Fatal familial

insomnia is a very rare neurodegenerative condition caused by mutations in the prion protein gene (Chap. 438), and although insomnia is

a common early symptom, most patients present with other obvious

neurologic signs such as dementia, myoclonus, dysarthria, or autonomic dysfunction.

TREATMENT

Insomnia

Treatment of insomnia improves quality of life and can promote

long-term health. With improved sleep, patients often report less

daytime fatigue, improved cognition, and more energy. Treating the

insomnia can also improve comorbid disease. For example, management of insomnia at the time of diagnosis of major depression

often improves the response to antidepressants and reduces the risk

of relapse. Sleep loss can heighten the perception of pain, so a similar approach is warranted in acute and chronic pain management.

The treatment plan should target all putative contributing factors: establish good sleep hygiene, treat medical disorders, use

behavioral therapies for anxiety and negative conditioning, and use

pharmacotherapy and/or psychotherapy for psychiatric disorders.

Behavioral therapies should be the first-line treatment, followed by

judicious use of sleep-promoting medications if needed.

TREATMENT OF MEDICAL AND PSYCHIATRIC DISEASE

If the history suggests that a medical or psychiatric disease contributes to the insomnia, then it should be addressed by, for example,

treating the pain or depression, improving breathing, and switching

or adjusting the timing of medications.

IMPROVE SLEEP HYGIENE

Attention should be paid to improving sleep hygiene and avoiding

counterproductive, arousing behaviors before bedtime. Patients

should establish a regular bedtime and wake time, even on weekends, to help synchronize their circadian rhythms and sleep patterns. The amount of time allocated for sleep should not be more

than their actual total amount of sleep. In the 30 min before bedtime, patients should establish a relaxing “wind-down” routine that

can include a warm bath, listening to music, meditation, or other

relaxation techniques. The bedroom should be off-limits to computers, televisions, radios, smartphones, videogames, and tablets.

If an e-reader is used, the light should be adjusted for evening use

(dimmer and reduced blue light) if possible, because light itself,

especially in the blue spectrum, suppresses melatonin secretion and

is arousing. Once in bed, patients should try to avoid thinking about

anything stressful or arousing such as problems with relationships

or work. If they cannot fall asleep within 20 min, it often helps to

get out of bed and read or listen to relaxing music in dim light as a

form of distraction from any anxiety, but artificial light, including

light from a television, cell phone, or computer, should be avoided.

Table 31-2 outlines some of the key aspects of good sleep

hygiene to improve insomnia.

COGNITIVE BEHAVIORAL THERAPY

Cognitive behavioral therapy (CBT) uses a combination of the

techniques above plus additional methods to improve insomnia.

A trained therapist may use cognitive psychology techniques to

reduce excessive worrying about sleep and to reframe faulty beliefs

about the insomnia and its daytime consequences. The therapist

may also teach the patient relaxation techniques, such as progressive muscle relaxation or meditation, to reduce autonomic arousal,

intrusive thoughts, and anxiety.

MEDICATIONS FOR INSOMNIA

If insomnia persists after treatment of these contributing factors,

pharmacotherapy is often used on a nightly or intermittent basis. A

variety of sedatives can improve sleep.

Antihistamines, such as diphenhydramine, are the primary active

ingredient in most over-the-counter sleep aids. These may be of

TABLE 31-2 Methods to Improve Sleep Hygiene in Insomnia Patients

HELPFUL BEHAVIORS BEHAVIORS TO AVOID

Use the bed only for sleep and sex

• If you cannot sleep within 20 min,

get out of bed and read or do other

relaxing activities in dim light before

returning to bed

Avoid behaviors that interfere with

sleep physiology, including:

• Napping, especially after 3:00 PM

• Attempting to sleep too early

• Caffeine after lunchtime

Make quality sleep a priority

• Go to bed and get up at the same

time each day

• Ensure a restful environment

(comfortable bed, bedroom quiet

and dark)

In the 2–3 h before bedtime, avoid:

• Heavy eating

• Smoking or alcohol

• Vigorous exercise

Develop a consistent bedtime routine.

For example:

• Prepare for sleep with 20–30 min

of relaxation (e.g., soft music,

meditation, yoga, pleasant reading)

• Take a warm bath

When trying to fall asleep, avoid:

• Solving problems

• Thinking about life issues

• Reviewing events of the day