Sleep Disorders

Sheldon Benjamin

I. Background

Sleep, the collection of brain mechanisms that leads to feeling rested and refreshed in the normal state, becomes a source of complaint in patients with primary sleep disorders and sleep disorders secondary to a number of medical, neurologic, and psychiatric conditions. Clinicians who treat patients with neuropsychiatric conditions should become facile at diagnosis and treatment of sleep disorders.

II. Classification

The most frequently used classification systems for sleep disorders in the United States are the International Classification of Sleep Disorders, 2nd edition (ICSD-2),¹ and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR). The ICSD-2 classifies sleep disorders as insomnias, sleep-related breathing disorders, hypersomnias, circadian rhythm disorders, parasomnias, sleep-related movement disorders, and other sleep disorders (see Table 13.1). The DSM-IV-TR classifies sleep disorders as primary and secondary (caused by other psychiatric or medical condition, or substance use) types and lists fewer specific subtypes than does the ICSD-2. This chapter will follow the DSM-IV-TR classification (see Table 13.2).²

A. Definitions

Dyssomnias are characterized by insomnia, hypersomnia, or abnormal sleep–wake cycles. The dyssomnias are subdivided into intrinsic, extrinsic, and circadian rhythm–related disorders.
Parasomnias are abnormal sleep behaviors or physiologic events associated with full or partial arousal that may occur in rapid eye movement (REM) sleep, non-REM sleep, or in transition to or from sleep.

Fatigue must be distinguished from sleepiness. Fatigue is an imprecise term that may include anergia, easy fatigability, muscle tiredness, exhaustion, decreased endurance, decreased motivation, or even excessive daytime sleepiness (EDS). Table 13.3 lists

disorders frequently associated with fatigue. Fatigue may be a complaint in up to 20% of all patients seeking medical care.

TABLE 13.1 International Classification of Sleep Disorders, 2nd Edition¹

Insomnias	Adjustment insomnia Psychophysiologic insomnia Paradoxical insomnia Idiopathic insomnia Insomnia due to mental disorder Inadequate sleep hygiene Behavioral insomnia of childhood Insomnia due to drug or substance Insomnia due to medical condition Insomnia not due to substance or known physiologic condition Physiologic insomnia, unspecified
Sleep-related breathing disorders	Primary central sleep apnea Central sleep apnea due to Cheyne-Stokes breathing pattern Central sleep apnea due to high-altitude periodic breathing Central sleep apnea due to a medical condition, not Cheyne-Stokes breathing pattern Central sleep apnea due to drug or substance Primary sleep apnea of infancy Obstructive sleep apnea Sleep-related nonobstructive alveolar hypoventilation, idiopathic Congenital central alveolar hypoventilation syndrome Sleep-related hypoventilation/hypoxemia due to lower airways obstruction, neuromuscular, and chest wall disorders, pulmonary parenchymal or vascular pathology Sleep apnea/sleep-related breathing disorder, unspecified
Hypersomnias	Narcolepsy with or without cataplexy Narcolepsy with or without cataplexy due to medical condition Narcolepsy unspecified Kleine-Levin syndrome Menstrual-related hypersomnia Idiopathic hypersomnia with or without long sleep time Behaviorally induced insufficient sleep syndrome Hypersomnia due to medical condition Hypersomnia due to drug or substance Hypersomnia not due to substance or known physiologic condition Physiologic hypersomnia, unspecified
Circadian rhythm sleep disorders	Delayed sleep phase type Advanced sleep phase type Irregular sleep–wake cycle Nonentrained type (free-running) Jet lag type Shift work type Due to medical condition Other Due to drug or substance
Parasomnias	Confusional arousals Sleepwalking Sleep terrors Rapid eye movement sleep behavior disorder Recurrent isolated sleep paralysis Nightmare disorder Sleep-related dissociative disorders Sleep enuresis Sleep-related groaning Exploding head syndrome Sleep-related hallucinations Sleep-related eating disorder Parasomnia, unspecified Parasomnias due to drug or substance Parasomnias due to medical condition
Sleep-related movement disorders	Restless legs syndrome Periodic limb movement disorder Sleep-related leg cramps Sleep-related bruxism Sleep-related rhythmic movement disorder Sleep-related movement disorder, unspecified Sleep-related movement disorder due to drug or substance Sleep-related movement disorder due to medical condition
Other sleep disorders	Physiologic sleep disorder, unspecified Environmental sleep disorder Fatal familial insomnia

Sleepiness refers to a need for sleep or a tendency to fall asleep.

B. Sleep architecture

Evaluation of sleep disorders requires awareness of normal sleep architecture. A normal night’s sleep typically consists of three to five sleep cycles of approximately 90 minutes length. A normal sleep cycle consists of progression from wakefulness through a few minutes of stage 1 sleep, from which people may be easily aroused, to stage 2, which constitutes approximately half of normal sleep. The normal individual then passes into stages 3 and 4 slow wave sleep, which together account for 20% to 25% of sleep time. After a latency of approximately 90 minutes following sleep onset (the REM latency) the individual passes into REM sleep, during which muscles are paralyzed and individuals report dream activity, if aroused. REM is terminated either by brief arousal or by passage into stage 2 sleep to begin another cycle. The stages of sleep are distinguished by electroencephalogram (EEG) patterns and physiologic changes,
which are listed in Table 13.4. The amount of time spent in each sleep stage varies through the night such that more time is spent in slow wave sleep in the first part of the night and more time is spent in REM sleep during the last part of the night. Infants spend 50% of sleep time in REM. The sleep pattern of the elderly is typically characterized by fragmentation with decreased slow wave sleep. Total sleep time decreases with age.

TABLE 13.2 Diagnostic and Statistical Manual of Mental Disorders (text revision) Classification of Sleep Disorders²

Primary sleep disorders	Dyssomnias	Primary insomnia Primary hypersomnia Narcolepsy Breathing-related sleep disorder Circadian rhythm sleep disorders Delayed sleep phase type Jet lag type Shift work type Unspecified type Dyssomnia NOS
Primary sleep disorders	Parasomnias	Nightmare disorder Sleep terror disorder Sleepwalking disorder Parasomnia NOS
Sleep disorder related to another mental disorder	Insomnia related to another mental disorder	Related disorders Major depression Dysthymic disorder
Sleep disorder related to another mental disorder	Hypersomnia related to another mental disorder	Bipolar disorder Generalized anxiety disorder Panic disorder Adjustment disorder Schizophrenia Somatoform disorder Personality disorder
Sleep disorder related to a general medical condition	Insomnia type Hypersomnia type Parasomnia type Mixed type
Substance-induced sleep disorder (alcohol, amphetamine, caffeine, cocaine, opioid, sedative, hypnotic, anxiolytic, or other substance)	Insomnia type Hypersomnia type Parasomnia type Mixed type	With onset during intoxication With onset during withdrawal
NOS, not otherwise specified.

Neurotransmitter function varies with the sleep cycle.³ Arousal, maintained by the ascending reticular activating system (ARAS),
is an acetylcholine-dependent process. ARAS cholinergic activity decreases to initiate sleep. Slow wave sleep involves increased raphé and basal forebrain activity, with activation of serotonergic and γ-aminobutyric-acid-secreting (GABAergic) neurons, and contributions from opiates, α-melanocyte-stimulating hormone (α-MSH), and somatostatin. Serotonergic, adrenergic, and histaminergic activities are high during wakefulness and suppressed during REM
sleep. REM sleep is initiated by cholinergic neurons in the pontine tegmentum. Cholinergic neurons are most active during wakefulness and REM sleep. Serotonin, which tends to help dampen sensory input and facilitate motor activity, would need to be suppressed during REM sleep to facilitate muscle atonia and dreaming. Monoaminergic activity terminates REM.

TABLE 13.3 Disorders Frequently Associated with Complaints of Fatigue

Anemia	Cancer	Chronic fatigue syndrome
Chronic obstructive pulmonary disease	Depression	Epilepsy
Human immunodeficiency virus/acquired immunodeficiency syndrome	Hypothyroidism	Lyme disease
Multiple sclerosis	Myasthenia gravis	Parkinson disease
Postpolio syndrome	Systemic lupus erythematosus	Neuromuscular disease Traumatic brain injury

TABLE 13.4 Physiologic Findings Associated with Sleep Stages

Sleep Stage	Electroencephalogram Findings	Neurotransmitter Changes
Wakefulness	Alpha background at rest eyes closed	Increased ACh, 5-HT, EPI, histamine
1	Low voltage 5–7 Hz theta slowing	Decreased ACh needed for sleep initiation
2	Theta slowing, sleep spindles, K-complexes
3	20%–50% higher voltage<2 Hz delta slowing	Increased 5-HT and GABA, increases in opiates, α-MSH, somatostatin
4	50% higher voltage delta slowing	Same as stage 3
Rapid eye movement	Low voltage faster activity, with decreased skeletal muscle movements, and eye movements	Increased ACh, decreased 5-HT, EPI, histamine
Ach, acetylcholine; 5-HT, serotonin; EPI, epinephrine; GABA, γ-aminobutyric acid; α-MSH, α-melanocyte stimulating hormone.

III. Evaluation of Sleep Disorders

A. Sleep history

A thorough sleep history is essential to determine the most likely cause and treatment of sleep disorders. Elements of the sleep history are listed in Table 13.5. In evaluating chronic insomnia or circadian rhythm disturbances, it is helpful for patients to maintain and complete a sleep diary for 2 weeks in which bedtime, time of sleep onset, time and duration of awakenings, final awakening time, and times of daytime naps are recorded. The Epworth Sleepiness Scale may be used to quantify the patient’s complaints about sleepiness.⁴

B. Use of the sleep laboratory

Nocturnal polysomnography (PSG) is used for insomnia only if the diagnosis is not obvious from the sleep history. The PSG is mainly used in the evaluation of EDS and parasomnias. The PSG is used in combination with the multiple sleep latency test (MSLT) for evaluation of possible narcolepsy or idiopathic hypersomnia. A mean sleep latency of <5 minutes and the presence of at least two sleep onset REM periods (SOREMPs) out of five measured on the MSLT are suggestive of narcolepsy but do not rule out apnea. A short mean sleep latency on the MSLT is one
way of differentiating EDS from fatigue. Guidelines for the use of the sleep laboratory have been published by the American Academy of Sleep Medicine.⁵

TABLE 13.5 Elements of the Sleep History

Sleep Hygiene Bedtime/awakening time Arrangement of bedroom (television, clock position, lighting, noise and light barriers, nighttime ritual) Exercise Sexual activity Use of stimulants/substances Nighttime eating Napping behavior Shift work, circadian demands	Insomnia History Duration of complaint Sleep onset insomnia (time to sleep) Difficulty maintaining sleep Early morning awakening (time) Nonrestorative sleep
Related Issues Medical conditions (including pain, nocturia, dyspnea, seizures, etc.) Medications Psychosocial stressors Mood changes	Hypersomnia History Irresistible daytime naps Daytime drowsiness Situations in which naps occur (sedentary activity vs. driving, talking, eating, etc.)
History from Partner Snoring Irregular breathing Movements in sleep Estimated sleep length and quality Mood changes/performance changes	Narcolepsy Symptoms Excessive daytime sleepiness Cataplexy Hypnagogic/hypnopompic hallucinations Sleep paralysis

TABLE 13.6 Summary of Cognitive Findings in Major Sleep Disorders⁶

	Attention Impairment	Memory Impairment	Common Deficits
Insomnia	22.8%	20%	Attention span, immediate recall (verbal), vigilance
Sleep-related breathing disorders	35.9%	17.1%	Attention span, divided attention, sustained attention; driving performance (92.9%)
Narcolepsy	44.2%	15.6%	Sustained attention, vigilance, driving performance
Percentage showing more impairment than controls based on analysis of 56 studies.

C. Neuropsychological testing

Impairment of daytime cognitive function is among the major concerns of individuals with sleep disorders. Neuropsychological evaluation may be used to assess the impact of sleep disorders on arousal, vigilance, attention, concentration, recall, and motor performance in sleep disorders. A subset of testing may be repeated following treatment to determine the degree of cognitive benefit. Table 13.6 describes the common cognitive findings in the three principal sleep disorders on the basis of an analysis of 56 neuropsychological studies.⁶

IV. Dyssomnias

A. Insomnia

1. Phenomenology

Insomnia, according to the ICSD, is characterized by difficulty in initiating or maintaining sleep. A broader definition, according to the National Center on Sleep Disorders Research, is inadequate or poor quality sleep characterized by one or more of the following: Difficulty falling asleep, difficulty maintaining sleep, waking up too early in the morning, or nonrefreshing sleep; and having daytime consequences such as tiredness, lack of energy, difficulty concentrating, or irritability. Insomnia can have many causes, and may be transient (several days), short term, or chronic (more than 3 weeks). Primary insomnia, according to the DSM-IV-TR, refers to insomnia of at least 1 month duration that causes distress and social or occupational dysfunction, and is not due to another sleep disorder, medical disorder, or substances of abuse.

2. Prevalence

Insomnia tends to increase with age, with approximately one third of people older than 65 reporting nearly continuous insomnia. Chronic insomnia tends to occur in approximately 10% of middle-aged adults, is approximately
1.5 times more frequent in women than men, and is a frequent perimenopausal complaint. Sleep onset insomnia is more common in younger individuals. Middle and terminal insomnia is more common in middle-aged and elderly individuals.

3. Etiology/pathophysiology

Secondary insomnia may be caused by a number of primary sleep disorders, or psychiatric, neurologic, and medical conditions, with the pathophysiology varying according to cause.

4. Differential diagnosis

A thorough sleep history will typically resolve the differential diagnosis. Transient/intermittent insomnia is most often stress or excitement related but can be caused by exposure to high altitudes, shifting time zones or work shift changes, and acute medical illness. Short-term insomnia is also typically stress induced and is also common in bereavement.

Primary insomnia has a broad differential diagnosis (see Table 13.7). The most common causes of insomnia seen at sleep centers are psychiatric disorders, psychophysiologic insomnia, substance dependence, restless leg syndrome (RLS)/periodic limb movement disorder (PLMD) (see subsequent text), sleep state misperception, and breathing-related sleep disorders. Certain medications, such as corticosteroids, calcium channel blockers, antidepressants, psychostimulants, bronchodilators, and
decongestants, have a propensity to cause insomnia. Having ruled out medical, psychiatric, and substance-related insomnia; circadian rhythm disorders (see subsequent text); PLMD (see subsequent text); and central apnea (see subsequent text), most of the remaining patients will have sleep state misperception, complaining of insomnia but shown by PSG not to be insomniac; learned or psychophysiologic insomnia; and primary (idiopathic) insomnia.

TABLE 13.7 Differential Diagnosis of Primary Insomnia

Medical Disorders GERD COPD, asthma Fibromyalgia, rheumatologic diseases	Psychiatric Disorders Substance dependence Mood disorders Anxiety disorders Psychotic disorders Adjustment disorders
Primary Sleep Disorders Idiopathic insomnia Breathing-related sleep disorders Restless leg syndrome and periodic limb movements of sleep Parasomnias Sleep state misperception	Neurologic Disorders Dementia Stroke Parkinson and other extrapyramidal diseases Epilepsy Headache and other pain syndromes Myotonic dystrophy Fatal familial insomnia
Circadian Rhythm Disturbances Irregular sleep pattern Time zone shift Delayed or advanced sleep phase Shift work Environmental disturbances	Behavioral Disorders Inadequate sleep hygiene Psychophysiologic insomnia Adjustment sleep disorder
GERD, gastroesophageal reflux disease; COPD, chronic obstructive pulmonary disease.

5. Treatment

The treatment of insomnia always begins with instructions on sleep hygiene. Encourage patients to establish a regular sleep–wake schedule on weekdays as well as weekends; ensure a cool, dark, quiet sleep environment; avoid any activities and remove any stimuli from the bedroom not associated with sleep or sexual activity; institute a 30-minute wind down time before sleep; if the patient spends >30 minutes in bed worrying, they should be encouraged to move elsewhere for other quiet activity until sleepiness sets in; limit caffeine to the morning; avoid using alcohol as a sedative; avoid excessive alcohol or cigarette smoking in the evening; try a high tryptophan-containing snack at night (e.g., milk, banana); institute a regular exercise program but try to avoid exercising within 3 hours of bedtime.
Psychotherapy may be of use to reduce anxiety and reinforcement of insomnia, and develop alternative sleep strategies. Cognitive behavioral therapy (CBT) and relaxation training are useful for this purpose, with CBT shown to be effective in randomized clinical trials. CBT is considered more useful than medication in the treatment of chronic primary insomnia. In individuals older than 60 years with marginal cognitive function or balance issues, behavioral treatment of insomnia is especially preferred because sedative hypnotic agents tend to increase the risk of cognitive dysfunction and falling.⁷

The treatment of secondary insomnias due to other sleep disorders, medical or psychiatric conditions, or substance abuse should be directed to the primary disorder, and should also include instructions for proper sleep hygiene. Sedative hypnotic treatment is generally reserved for transient insomnia, such as that seen in jet lag, stress reactions, or transient medical conditions; for secondary insomnia unresponsive to treatment of the primary disorder; or for chronic primary insomnia that has not responded to sleep hygiene and CBT approaches.

Benzodiazepine hypnotic agents are not indicated for the long-term treatment of chronic insomnia because of the risks of tolerance, dependency, daytime attention and concentration compromise, incoordination, and rebound insomnia. They should be avoided in the elderly, in pregnant or breast-feeding women, in substance abusers, and in
patients with suicidal or parasuicidal behaviors. Owing to the risk of respiratory depression benzodiazepines should be avoided in patients with untreated obstructive apnea and chronic pulmonary disease.

When benzodiazepine hypnotics are used, their use should be limited to two to three times per week to avoid the above mentioned risks. Transient insomnia related to anxiety may be treated with benzodiazepine hypnotics (see Table 13.8). Insomnia due to medical or psychiatric conditions may be treated with nonbenzodiazepine short half-life hypnotic agents if treatment of the underlying cause is unsuccessful in improving sleep (Table 13.8). These agents produce less tolerance and rebound insomnia on discontinuation than benzodiazepine hypnotics. For prolonged use in chronic insomnia daily dosage of eszopiclone 1 to 3 mg has been studied over a 6-month period without evidence of tolerance or rebound insomnia on discontinuation. Ramelteon, the first agent released in the new class of selective melatonin agonists, is effective in sleep onset insomnia and does not appear to produce tolerance, withdrawal, or rebound insomnia. It may be safer than benzodiazepine agonists in the elderly or in individuals vulnerable to confusion but does not prolong total sleep time. In selecting an agent for treatment of insomnia, half-life should be taken into account. Short half-life agents are used for sleep onset insomnia. Only zaleplon may be safely taken in the middle of the night without prolonged morning side effects. Intermediate half-life agents (temazepam, zolpidem, eszopiclone) or prolonged release agents (zolpidem ER) are used for sleep onset and sleep maintenance insomnia, and should be taken 8 hours or more before alertness is required the next morning. Mirtazapine 15 to 60 mg may be chosen for treatment of depression when insomnia is a prominent symptom. Serotonergic tricyclic antidepressants, such as amitriptyline and doxepin, may be used for depression when insomnia is a prominent complaint if suicide risk is minimal. Their use should be avoided in PLMD, however, because of a tendency to exacerbate this disorder. Trazodone, another serotonergic antidepressant, has been shown to be effective in combination with selective serotonin reupltake inhibitor (SSRI) agents in depressed individuals if the SSRI alone is not effective for insomnia⁸ but it has not been shown to be effective for long-term use in primary insomnia. Serotonergic antidepressants are not U.S. Food and Drug Administration (FDA) approved for treatment of primary insomnia and increase the risk of serotonin syndrome if used in combination with SSRI agents. Sedating neuroleptics (e.g., quetiapine) should not be used to treat primary insomnia in the absence of psychotic symptoms. Diphenhydramine has no proven efficacy in primary

insomnia and may contribute to cognitive dysfunction and gait instability in vulnerable individuals. There is no data to support the use of melatonin or valerian in primary insomnia.

TABLE 13.8 Pharmacologic Treatment of Insomnia

Medication Class	Drug	Dose	Half-life	Active Metabolites
Benzodiazepine hypnotics	Intermediate acting Temazepam Oxazepam Long acting Alprazolam Lorazepam Clonazepam Diazepam	7.5–30 mg 10–30 mg 0.25–1 mg 0.5–2 mg 0.5–2 mg 2.5–10 mg 0.5–2 mg 2.5–10 mg	8–12 h 5–15 h 12–20 h 10–22 h 22–38 h 20–50 h 22–38 h 20–50 h	No No (renal excretion) Yes No No Yes No Yes
Nonbenzodiazepine benzodiazepine receptor agonists	Zaleplon Zolpidem Zolpidem ER Eszopiclone	5–20 mg 2.5–10 mg 1–3 mg 1–3 mg	1–1.5 h 1.5–4 h 5–7 h 5–7 h	Yes No No Yes
Melatonin receptor agonist	Ramelteon	8 mg	1–2.6 h	Yes
Serotonergic antidepressants	Trazodone	25–200 mg	3–9 h	Yes
	Doxepin	25–150 mg	6–8 h	Yes
	Amitriptyline	25–150 mg	10–50 h	Yes
	Mirtazapine	15–60 mg	20–40 h	Yes
γ-Hydroxy butyrate	Sodium oxybate	4.5–9 mg	40 min	No