Disorders of Sleep Part 1

Sleep and wakefulness are two basic biologic processes that have independent functions and controls. Sleep has been defined on the basis of behavioral criteria (e.g., lack of mobility or slight mobility, closed eyes, a markedly reduced response to external stimulation, a characteristic sleeping posture, and a reversibly unconscious state) and physiologic criteria (e.g., readings obtained by electroencephalography [EEG], electro-oculography [EOG], and electromyography [EMG]).1-3

The exact biologic functions of sleep are not known, although it is known that sleep is essential and that sleep deprivation leads to impaired attention and decreased performance, in addition to sleepiness. Sleep is believed to have restorative, conservative, adaptive, thermoregulatory, and consolidative functions. Sleep is also required for maintenance of synaptic and neuronal network integrity.1 The theory that memory reinforcement and consolidation take place during sleep has been strengthened by scientific data.4,5 Although the exact physiologic functions of dreaming are unknown, they may include activation of the neural networks of the brain, restructuring and reinterpretation of data stored in memory, and removal of unnecessary and useless information from the brain.

Primary care physicians should have a high index of suspicion for the presence of sleep disorders. Most sleep disorders, once recognized, can be managed with limited consultation. The initial step is to treat any condition that may be secondarily responsible for hypersomnia or insomnia. However, the treatment of primary sleep disorders is best handled by a sleep specialist.

Physiology of Sleep

Sleep architecture and stages

Sleep is divided into two independent states: non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. NREM sleep is further divided into four stages [see Non-Rapid Eye Movement Sleep, below], primarily on the basis of electroencephalographs criteria [see Figure 1a]; together, stage III and stage IV NREM sleep constitute slow wave sleep. NREM and REM sleep alternate, with each cycle lasting about 90 to 100 minutes. Four to six such cycles are noted during a normal sleep period. The first third of a normal sleep period is dominated by slow wave sleep (see below), and the last third is dominated by REM sleep.

Non-Rapid Eye Movement Sleep

In stage I NREM sleep, the alpha wave (8 to 13 Hz) rhythms characteristic of wakefulness diminish to less than 50% in an epoch (i.e., a 30-second segment of a polysomnography tracing with a speed of 10 mm/sec), and a mixture of slower rhythms called theta waves (4 to 7 Hz) appears; EMG activity decreases slightly, and slow, rolling eye movements may be apparent [see Figure 1b]. Toward the end of stage I NREM sleep, vertex sharp waves appear. In normal persons, stage II NREM sleep begins after about 10 to 12 minutes of stage I NREM sleep. The characteristic EEG features of stage II NREM sleep are sleep spindles (12 to 18 Hz, most often 14 Hz) and K complexes intermixed with vertex sharp waves [see Figure 1c]. The background rhythms of stage II NREM sleep consist of theta waves and delta waves (< 4 Hz). Less than 20% of the epoch is occupied by delta waves. Stage II NREM sleep lasts for about 30 to 60 minutes. During stage III NREM sleep, the delta waves occupy 20% to 50% of the epoch [see Figure 1d], and during stage IV NREM sleep, the delta waves occupy more than 50% of the epoch [see Figure 1e].

Figure 1 Human sleep and wakefulness stages are characterized by readings obtained by electroencephalography (EEG), electro-oculography (EOG), and electromyography (EMG). (a) An EEG tracing shows the alpha wave (9 to 10 Hz) activity representative of wakefulness in adults. (b) Stage I non-rapid eye movement (NREM) sleep is characterized by low-amplitude theta wave (4 to 7 Hz) activity mixed with a small amount (< 50%) of alpha wave activity and vertex sharp waves in the EEG tracing; slow, rolling movements in right and left eye EOG recordings; and tonic chin EMG activity. (c) EEG tracings of stage II NREM show sleep spindles. (d) EEG tracings reveal that in stage III NREM sleep, 20% to 50% of an epoch is occupied by waves of 2 Hz or less with an amplitude of greater than 75 mV. (e) In stage IV NREM sleep, these waves make up more than 50% of an epoch. Together, stages III and IV constitute slow wave sleep. (f REM sleep is characterized on EEG tracings by low-amplitude mixed-frequency theta wave and beta wave (> 13 Hz) activity, including a small amount of alpha waves without sleep spindles or K complexes. Rapid eye movements are seen in the EOG readouts. The chin EMG shows marked reduction or absence of tonic activity.

Rapid Eye Movement Sleep

Sixty to 90 minutes after the onset of sleep, the first REM sleep episode is noted. The EEG tracings during REM sleep are characterized by fast rhythms and theta wave activities, some of which may have a sawtooth appearance [see Figure 1f]. The hallmark of REM sleep is the presence of rapid eye movements in all directions and the marked diminution or absence of muscle activities in the chin EMG. Tonic REM sleep is characterized by a desyn-chronized EEG and muscle atonia, and phasic REM sleep is characterized by REMs as well as phasic swings in blood pressure and heart rate, irregular respiration, and phasic tongue movements. A few periods of apnea or hypopnea may arise during REM sleep.

Sleep patterns across the lifespan

Sleep requirements change dramatically from infancy to old age. Newborns have a polyphasic sleep pattern, with a total of 16 hours of sleep a day. By the time a child is 3 to 5 years of age, the sleep requirement falls to about 10 hours a day. In preschool children, sleep assumes a biphasic pattern. Adults exhibit a monopha-sic sleep pattern, with an average duration of 7.5 to 8.0 hours a night, but the pattern reverts to biphasic in elderly persons.

In newborn infants, the amount of sleep time spent in the REM state is about 50%, but by 6 years of age, REM sleep has decreased to the normal adult pattern of 25%. By 3 months of age, the NREM-REM cyclic pattern of adult sleep is established and sleep spindles appear. K complexes are first seen in infants at about 6 months of age. Attenuation of the amplitude of delta waves and repeated awakenings—including early morning awakenings—are important features of sleep in elderly persons.

Functional neuroanatomy

The neuroanatomic substrates for REM sleep and NREM sleep are located in separate parts of the central nervous sys-tem.2,6 REM sleep is generated by neurons in the pontomesencephalic region.6,7 The cells that activate REM sleep are choliner-gic neurons located in the pedunculopontine tegmental nucleus and the laterodorsal tegmental nucleus in the pontomesen-cephalic region; these cells fire maximally during REM sleep. The cells that deactivate REM sleep are aminergic neurons located in the locus coeruleus and raphe nuclei; these cells are inactive during REM sleep. A reciprocal interaction in the brain stem between REM-activating and REM-deactivating neurons is responsible for REM generation and maintenance.

The active hypnogenic neurons for NREM sleep are located primarily in the preoptic area of the hypothalamus, the basal forebrain area, and the solitary nucleus region of the medulla. The reticular nucleus of the thalamus is thought to be responsible for sleep spindle generation.

Sleep most likely results from both passive and active mecha-nisms.6 Muscle hypotonia during REM sleep is thought to depend on the inhibitory postsynaptic potentials generated by dorsal pontine descending axons.8,9 The roles of neurotransmitters and neuropeptides are not clearly delineated; they are believed to modulate various sleep stages and cycles. It has been shown that adenosine may fulfill the major criteria for neural sleep factor, which mediates the somnogenic effects of prolonged wakefulness.

Table 1 Behavioral and Physiologic Characteristics of States of Awareness

	Characteristics	Awake	NREM Sleep	REM Sleep
	Posture	Erect, sitting, or recumbent	Recumbent	Recumbent
	Mobility	Normal	Mildly reduced to absent;	Moderately reduced to absent; myoclonic jerks
			postural shifts
	Response to stimulation	Normal	Mildly to markedly reduced	Moderately reduced to absent
	Alertness level	Alert	Reversibly unconscious	Reversibly unconscious
	Eye position and movements	Open	Closed	Closed
		WEMs	SEMs	REMs
	EEG	Alpha waves Desynchronized	Synchronized	Theta or sawtooth waves Desynchronized
	EMG (muscle tone)	Normal	Mildly reduced	Moderately to severely reduced or absent
	EOG	WEMs	SEMs	REMs
	Heart rate	Normal sinus rhythm	Bradycardia	Bradytachyarrhythmia
	Blood pressure	Normal	Decreases	Variable
	Cardiac output	Normal	Decreases	Decreases further
	Respiratory rate	Normal	Decreases	Variable
				Apneas may occur
	Alveolar ventilation	Normal	Decreases	Decreases further
	Upper airway muscle tone	Normal	Mildly reduced	Moderately to markedly reduced or absent
	Upper airway resistance	Normal	Moderately increased	Markedly increased
	Cerebral blood flow	Normal	Decreased or normal	Markedly increased
	Parasympathetic activity	Normal	Moderately increased	Markedly increased
	Sympathetic activity	Normal	Mildly reduced	Moderately to markedly reduced or variable
	Penile or clitoral tumescence	Normal	Normal	Markedly increased
	Thermoregulation	Normal	Mildly reduced	Absent

NREM—non-rapid eye movement

REM—rapid eye movement

SEM—slow eye movement

WEM—waking eye movement

The recently described hypocretin (orexin) peptidergic system, which is located in the lateral hypothalamic region and peri-fornical area and has widespread ascending and descending projections, is thought to play a role in the control of sleep and wakefulness.11-13 Sleepiness may be induced by reduction of activity of the hypocretin projections to the locus coeruleus; mid-line raphe; and the mesopontine, posterior hypothalamic, and tuberomammillary regions.

Physiologic changes during sleep

A variety of behavioral and physiologic changes occur during normal wakefulness, NREM sleep, and REM sleep [see Table 1]. These changes are most commonly noted in the somatic and au-tonomic nervous systems (ANS); in the respiratory, cardiovascular, and gastrointestinal systems; in endocrine, renal, and sexual function; and in thermoregulation.2,14 The fundamental changes in the ANS consist of an increase in the parasympathetic tone and a decrease in sympathetic activity during NREM sleep, with further increase of parasympathetic tone and decrease in sympathetic activity during REM sleep. During the REM sleep phase, however, sympathetic activity increases intermittently. Sympathetic nerve activity in muscle and the vascular beds of the skin, as measured by microneurographic technique, is reduced during NREM sleep but is increased during REM sleep.

During both NREM and REM sleep, the respiratory neurons in the pontomedullary region show a decreased firing rate. Muscle tone in the upper airway decreases in NREM sleep and disappears in REM sleep, resulting in an increase in upper airway resistance. Two separate systems—the metabolic (or automatic) and voluntary (or behavioral) systems—control respiration during sleep and wakefulness. Both the metabolic and the voluntary system operate during wakefulness, whereas only the metabolic system operates during NREM sleep. The wakefulness stimuli that act through the ascending reticular activating system also act as tonic stimuli to ventilation. Hypercapnic and hypoxic ven-tilatory responses are moderately reduced in NREM sleep but are more markedly decreased during REM sleep. Tidal volume and alveolar ventilation decrease during sleep; arterial oxygen tension is mildly decreased and arterial carbon dioxide tension is increased during both NREM and REM sleep. Thus, respiration is vulnerable during normal sleep, and a few periods of apnea may occur, especially at the onset of sleep and during REM sleep. Heart rate, blood pressure, cardiac output, and peripheral vascular resistance decrease during NREM sleep and decrease still further during REM sleep. Cerebral blood flow and cerebral metabolic rates for glucose and oxygen decrease during NREM sleep but increase to above waking values during REM sleep.

Profound changes in endocrine secretions are registered during sleep. Growth hormone secretion exhibits a pulsatile increase during NREM sleep in the first third of the normal sleep period. Prolactin secretion also rises 30 to 90 minutes after the onset of sleep. Sleep inhibits cortisol secretion. Secretion of thyroid-stimulating hormone reaches a peak in the evening and then decreases throughout the night. Testosterone levels in men increase during sleep, rising from trough levels at 8 P.M. to peak levels at 8 A.M., but no clear relation has been demonstrated between levels of gonadotropic hormones and the sleep-wake cycle in children or adults. Melatonin, which is released by the pineal gland, attains its highest secretion level between 3 A.M. and 5 A.M., then decreases to low levels during the day.

Body temperature begins to fall at the onset of sleep and reaches its lowest point during the third sleep cycle. Thermoreg-ulation is maintained during NREM sleep but is nonexistent in REM sleep. Penile erection and clitoral tumescence occur during REM sleep.

Circadian rhythms

Circadian means a period of about 24 hours; however, the human circadian rhythm cycle is about 25 hours. The existence of circadian rhythms has been known since 1731, when the French astronomer J. J. D. de Mairan noted a circadian rhythm in a plant.16 The suprachiasmatic nucleus of the hypothalamus is thought to be the site of this biologic clock. The body temperature rhythm closely follows the circadian rhythm of sleep and wakefulness but is independent of it. Dysfunction of circadian rhythms results in some important human sleep disorders.17

General Approach to Disorders of Sleep

Sleep complaints are very common in the general population. According to the report of the National Center on Sleep Disorders Research, more than 40 million persons in the United States suffer from chronic disorders of sleep and wakefulness.18

Classification

The second edition of the International Classification of Sleep Disorders (ICSD-2) lists eight categories of sleep disorders.

Diagnosis

Clinical Manifestations

The four major sleep-related complaints for which patients seek medical attention are excessive daytime somnolence (EDS), insomnia, abnormal movements or behavior during sleep, and an inability to sleep at the desired time. Insomnia patients may complain of some or all of the following: difficulty initiating or maintaining sleep, repeated awakenings or early morning awakenings, nonrestorative sleep, daytime fatigue, lack of concentration, irritability, anxiety, depression, and muscle aches and pains. Insomnia may be idiopathic (i.e., no cause is found) or co-morbid with other conditions [see Table 3]. Patients with hyper-somnia may complain of EDS, a lack of relief of symptoms after additional nighttime sleep, inability to concentrate, and impaired cognition and motor skills. The most common cause of EDS is behaviorally induced insufficient sleep syndrome (sleep deprivation) [see Table 2]. Some patients with restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), or cir-cadian rhythm sleep disorders may also experience hypersom-nolence in the daytime.

The first step in assessing a patient with a sleep disturbance is obtaining a history, which should include a family history and directed inquiries on sleeping habits, drug and alcohol consumption, and previous or current psychiatric, medical, and neurologic illnesses. Diagnostic tests must be confirmatory and subservient to the clinical history and physical examination. Electrophysiologic investigation of patients with suspected sleep disorders is resource intensive and is best planned in consultation with a sleep specialist.

Table 2 International Classification of Sleep Disorders, Second Edition¹⁷

Insomnia	Other sleep-related breathing disorder
Acute insomnia	Sleep apnea/sleep-related breathing disorder, unspecified
Psychophysiologic insomnia Paradoxical insomnia (sleep-state misperception)	Hypersomnias of Central Origin Not Due to a Circadian Rhythm Sleep Disorder, Sleep-Related Breathing Disorder, or Other Cause of Disturbed
Idiopathic insomnia	Nocturnal Sleep
Insomnia due to mental disorder	Narcolepsy with cataplexy
Inadequate sleep hygiene	Narcolepsy without cataplexy
Behavioral insomnia of childhood	Narcolepsy due to medical condition
Insomnia due to drug or substance	Narcolepsy, unspecified
Insomnia due to medical condition	Recurrent hypersomnia
Insomnia not due to substance or known physiologic condition, unspecified (nonorganic)	Kleine-Levin syndrome
Physiologic insomnia, unspecified (organic)	Menstrual-related hypersomnia
	Idiopathic hypersomnia with long sleep time
Sleep-Related Breathing Disorders	Idiopathic hypersomnia without long sleep time
Central sleep apnea syndromes	Behaviorally induced insufficient sleep syndrome
Primary central sleep apnea	Hypersomnia due to medical condition
Central sleep apnea due to Cheyne-Stokes breathing pattern	Hypersomnia due to drug or substance
Central sleep apnea due to high-altitude periodic breathing	Hypersomnia not due to substance or known physiologic condition (nonorganic hypersomnia, not otherwise specified [NOS])
Central sleep apnea due to medical condition not Cheyne-Stokes
	Physiologic (organic) hypersomnia, unspecified (organic
Central sleep apnea due to drug or substance	hypersomnia, NOS)
Primary sleep apnea of infancy (formerly primary sleep apnea of newborn)	Circadian Rhythm Sleep Disorders
Obstructive sleep apnea syndromes	Circadian rhythm sleep disorder, delayed-sleep-phase type (delayed-sleep-phase disorder)
Obstructive sleep apnea, adult
Obstructive sleep apnea, pediatric	Circadian rhythm sleep disorder, advanced-sleep-phase type (advanced-sleep-phase disorder)
Sleep-related hypoventilation/hypoxemic syndromes
Sleep-related nonobstructive alveolar hypoventilation, idiopathic	Circadian rhythm sleep disorder, irregular sleep-wake type (irregular sleep-wake rhythm)
Congenital central alveolar hypoventilation syndrome	Circadian rhythm sleep disorder, free-running type (nonentrained type)
Sleep-related hypoventilation/hypoxemia due to medical condition	Circadian rhythm sleep disorder, jet-lag type (jet-lag disorder)
Sleep-related hypoventilation/hypoxemia due to pulmonary parenchymal or vascular pathology	Circadian rhythm sleep disorder, shift work type (shift-work disorder)
	Circadian rhythm sleep disorder due to medical condition
Sleep-related hypoventilation/hypoxemia due to lower airway obstruction	Other circadian rhythm sleep disorder (circadian rhythm disorder, NOS)
Sleep-related hypoventilation/hypoxemia due to neuro-muscular and chest wall disorders
	Other circadian rhythm sleep disorder due to drug or substance

Laboratory Studies

The two most important laboratory tests for sleep disorders are the all-night polysomnography (PSG) study and the Multiple Sleep Latency Test (MSLT). All-night PSG studies simultaneously record several physiologic variables (i.e., EEG, EMG, EOG, electrocardiography, airflow at the nose and mouth, respiratory effort, and oxygen saturation) and are important in confirming a diagnosis of EDS or obstructive sleep apnea syndrome (OSAS), as well as documenting the severity of sleep apnea, hypoxemia, and sleep fragmentation. Overnight PSG determines the optimal pressure for continuous positive airway pressure (CPAP)—a treatment for OSAS—and is also helpful for supporting the diagnosis of narcolepsy and the parasomnias. Overnight PSG with simultaneous video recording can confirm REM sleep behavior disorder (RBD) and is particularly useful for the documentation of unusual movements and behavior during nighttime sleep in patients with parasomnias and nocturnal seizures.

The MSLT is essential in documenting pathologic sleepiness (e.g., sleep-onset latency of less than 5 minutes)19 and in diagnosing narcolepsy. The presence of two sleep-onset REMs on four or five nap studies and sleep-onset latency of less than 8 minutes strongly suggest a diagnosis of narcolepsy.

Another important laboratory test for assessing sleep disorders is actigraphy.20 This technique utilizes an actigraph (also known as an actometer) worn on the wrist or ankle to record acceleration or deceleration of body movements, which indirectly indicates sleep-wakefulness. Actigraphy for days or weeks is a useful laboratory test in patients with insomnia and circadian rhythm sleep disorders, as well as in some patients with prolonged daytime sleepiness.

Magnetic resonance imaging studies and other neuroimaging techniques should be performed to exclude structural neurologic lesions. Appropriate laboratory tests should always be performed to exclude any suspected medical disorders that may be the cause of the patient’s insomnia or hypersomnia.

Specific Disorders of Sleep

Obstructive sleep apnea syndrome

Apnea, or cessation of breathing during sleep, consists of three types: central, obstructive, and mixed.2 In central apnea, both the airflow at the upper airway (e.g., pharynx and nose) and the effort by the diaphragm and other respiratory muscles cease. By contrast, during obstructive apnea, the airflow stops while the effort continues [see Figure 2]. In mixed apnea, an initial period of central apnea is followed by a period of obstructive apnea. The most common type of apnea is OSAS.21 Sleep hypopnea, defined as a decrease of breathing to half the volume measured during the preceding or following respiratory cycle accompanied by an arousal or oxygen desat-uration of 3% to 4% or more, has the same significance as ap-nea.2,21 To qualify as pathologic sleep apnea or hypopnea, the decreased breathing must last for at least 10 seconds and the apnea-hypopnea index or respiratory disturbance index (i.e., the number of episodes of apnea-hypopnea per hour of sleep) must be at least five.

Table 2

Parasomnias	Snoring
Disorders of arousal (from non-rapid eye movement [REM]	Sleep talking
sleep)	Sleep starts (hypnic jerks)
Confusional arousals	Benign sleep myoclonus of infancy
Sleepwalking	Hypnagogic foot tremor and alternating leg muscle activation
Sleep terrors	during sleep
Parasomnias usually associated with REM sleep	Propriospinal myoclonus at sleep onset
REM sleep behavior disorder (including parasomnia overlap disorder and status dissociates)	Excessive fragmentary myoclonus
Recurrent isolated sleep paralysis	Other Sleep Disorders
Nightmare disorder	Other physiologic (organic) sleep disorder
Other parasomnias	Other sleep disorder not due to substance or known physio-
Sleep-related dissociative disorders	logic condition
Sleep enuresis	Environmental sleep disorder
Sleep-related groaning (catathrenia)	Sleep Disorders Associated with Conditions Classifiable Elsewhere
Exploding head syndrome	Fatal familial insomnia
Sleep-related hallucinations
Sleep-related eating disorders	Fibromyalgia
Parasomnia, unspecified	Sleep-related epilepsy
Parasomnia due to drug or substance	Sleep-related headaches
Parasomnia due to medical condition	Sleep-related gastroesophageal reflux disease
Sleep-Related Movement Disorders	Sleep-related coronary artery ischemia
Restless legs syndrome	Sleep-related abnormal swallowing, choking, and laryn-
Periodic limb movement disorder	gospasm
Sleep-related leg cramps	Other Psychiatric and Behavioral Disorders Frequently Encountered in the
Sleep-related bruxism	Differential Diagnosis of Sleep Disorders
Sleep-related rhythmic movement disorder	Mood disorders
Sleep-related movement disorder, unspecified	Anxiety disorders
Sleep-related movement disorder due to drug or substance	Somatoform disorders
Sleep-related movement disorder due to medical condition	Schizophrenia and other psychotic disorders
Isolated Symptoms, Apparently Normal Variants, and Unresolved Issues	Disorders usually first diagnosed in infancy, childhood, or
Long sleeper	adolescence
Short sleeper	Personality disorders

OSAS is common in middle-aged and elderly men. An important study indicated a prevalence of 4% in men and 2% in women between 30 and 60 years of age.22 In women, the incidence of OSAS is greater after menopause. The pathogenesis of OSAS includes local anatomic factors (e.g., narrowing of the upper airway and excessive relaxation of the upper airway muscles during sleep, with increased upper airway resistance) and neurologic factors that may cause dysfunction of the respiratory neurons in the brain stem [see 14:VI Ventilatory Control during Wakefulness and Sleep].