Somnology Jr. - Montana Sleep Society

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To Grace Zamudio and Zoe Lee-Chiong.
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Preface
Carpe noctem.
Teofilo Lee-Chiong MD
Professor of Medicine
Division of Sleep Medicine
National Jewish Health
Denver, Colorado
University of Colorado Denver
School of Medicine
Denver, Colorado
Chief Medical Liaison
Philips Respironics
Murrysville, Pennsylvania
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Abbreviations
AHI
BPAP
CPAP
CSA
ECG
EEG
EMG
EOG
FEV1
GABA
N1
N2
N3
NREM
O2
OSA
PaCO2
PaO2
REM
SaO2
SOREMP
Apnea-hypopnea index
Bi-level positive airway pressure
Continuous positive airway pressure
Central sleep apnea
Electrocardiography
Electroencephalography
Electromyography
Electro-oculography
Forced expiratory volume in 1 second
Gamma-aminobutyric acid
NREM stage 1 sleep
NREM stage 2 sleep
NREM stages 3 (and 4) sleep
Non-rapid eye movement
Oxygen
Obstructive sleep apnea
Partial pressure of arterial carbon dioxide
Partial pressure of arterial oxygen
Rapid eye movement sleep
Oxygen saturation
Sleep onset REM period
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Table of contents
Introduction
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Neurobiology of sleep
Neural systems generating wakefulness
Neural systems generating NREM sleep
Neural systems generating REM sleep
Main neurotransmitters
Acetylcholine
Adenosine
Dopamine
Gamma-aminobutyric acid
Glutamate
Glycine
Histamine
Hypocretin
Melatonin
Norepinephrine
Serotonin
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Physiology during sleep
Autonomic nervous system
Respiratory system
Respiratory patterns
Cardiovascular system
Gastrointestinal system
Renal and genito-urinary systems
Endocrine system
Growth hormone
Thyroid stimulating hormone
Cortisol
Melatonin
Testosterone
Insulin
Leptin
Ghrelin
Musculoskeletal system
Pupillary changes
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Immune system
Thermoregulation
Metabolic rate
Dreaming
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Regulation of sleep and waking
Sleep homeostasis
Circadian neurosystem
Suprachiasmatic nucleus
Melatonin
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Sleep deprivation
Consequences
Central nervous system
Autonomic nervous system
Cognition
Respiratory system
Endocrine system
Metabolism
Immune system
Behavioral and psychiatric effects
Polysomnographic features
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Insomnia
General changes in sleep architecture
Prevalence
Mechanisms
Risk factors
Consequences
Classification
Specific causes
Adjustment insomnia
Altitude insomnia
Behavioral insomnia of childhood
Limit-setting sleep disorder
Sleep-onset association disorder
Fatal familial insomnia
Idiopathic insomnia
Inadequate sleep hygiene
Paradoxical insomnia
Psychophysiologic insomnia
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Medications
Evaluation of insomnia
Polysomnographic features
Therapy of insomnia
Sleep hygiene
Cognitive-behavioral treatments for insomnia
Cognitive therapy
Paradoxical intention
Relaxation techniques
Sleep restriction
Stimulus control
Multi-component behavioral therapy
Pharmacotherapy of insomnia
Benzodiazepines
Benzodiazepine receptor agonists
Melatonin receptor agonist
Antidepressants and antipsychotics
Non-prescription hypnotic agents
Melatonin
Botanical compounds
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Excessive sleepiness
Prevalence
Consequences
Mechanisms
Specific causes of excessive sleepiness
Insufficient sleep syndrome
Idiopathic hypersomnia
Recurrent hypersomnia
Medical, neurological or psychiatric
Medications
Evaluation of excessive sleepiness
Subjective tests of sleepiness
Polysomnography
Multiple sleep latency test
Maintenance of wakefulness test
Effective countermeasures for sleepiness
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Narcolepsy
Excessive sleepiness
Cataplexy
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Status cataplecticus
Sleep hallucinations
Sleep paralysis
Sleep disturbance
Other important clinical features
Consequences
Prevalence
Clinical course
Pathophysiology
Narcolepsy without cataplexy
Secondary narcolepsy
Evaluation
Polysomnographic features
Multiple sleep latency test
Maintenance of wakefulness test
Cerebrospinal fluid hypocretin-1
Human leukocyte antigen typing
Therapy
Excessive sleepiness
Sleep disturbance
Cataplexy
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Obstructive sleep apnea
Apnea
Hypopnea
Respiratory effort-related arousal
Complex sleep apnea
Apnea-hypopnea index
Prevalence
Pathophysiology
Risk factors
Clinical features
Physical examination
Consequences
Evaluation
Polysomnographic features
Multiple sleep latency test
Upper airway imaging studies
Therapy
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General measures
Positional therapy
Oxygen therapy
Pharmacologic treatments
Positive airway pressure therapy
Oral devices
Upper airway surgery
Residual sleepiness
Upper airway resistance syndrome
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Central sleep apnea
Polysomnography
Classification
Primary central sleep apnea
Cheyne Stokes respiration
High altitude periodic breathing
Medication use
Congestive heart failure
Sleep-onset central apneas
During positive airway pressure titration
Therapy of central sleep apnea
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Hypoventilation syndromes
Mechanisms
Medical and neurological disorders
Idiopathic alveolar hypoventilation
Congenital central alveolar hypoventilation
Polysomnography
Therapy
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Parasomnias
Disorders of arousal
Parasomnias occurring during REM sleep
Catathrenia
Confusional arousals
Exploding head syndrome
Isolated sleep paralysis
Nightmare disorder
REM sleep behavior disorder
Sleep enuresis
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Sleep-related eating disorder
Sleep terrors
Sleepwalking
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Restless legs syndrome and
Periodic limb movement disorder
Prevalence
Classification
Risk factors
Consequences
Evaluation
Suggested immobilization test
Polysomnography
Differential diagnosis
Pathophysiology
Therapy
Dopaminergic agents
Benzodiazepines
Opioid agents
Anticonvulsant agents
Periodic limb movements during sleep
Periodic limb movement disorder
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Circadian rhythm sleep disorders
Advanced sleep phase syndrome
Delayed sleep phase syndrome
Free-running circadian rhythm syndrome
Irregular sleep-wake rhythm syndrome
Jet lag
Shift work sleep disorder
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Medical disorders
Asthma
Chronic obstructive pulmonary disease
Cardiac arrhythmias
Chronic pain syndromes
Congestive heart failure
Coronary artery disease
Diaphragm paralysis
End-stage renal disease
Fibromyalgia
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Gastroesophageal reflux
Human immunodeficiency virus infection
Hypertension
Restrictive pulmonary diseases
Sleeping sickness
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Neurological disorders
Alzheimer’s dementia
Amyotrophic lateral sclerosis
Attention deficit hyperactivity disorder
Blindness
Cerebral degenerative disorders
Down syndrome
Headache syndromes
Multiple system atrophy
Neuromuscular disorders
Parkinson disease
Seizure disorders
Stroke
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Psychiatric disorders
Anxiety disorders
Acute stress disorder
Generalized anxiety disorder
Post-traumatic stress disorder
Panic disorder
Eating disorders
Mood disorders
Major depressive episode
Manic episode
Hypomanic episode
Mixed episode
Major depressive disorder
Bipolar disorder
Seasonal affective disorder
Atypical depression
Schizophrenia
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Miscellaneous sleep disorders
Alcohol-dependent sleep disorder
Alternating leg muscle activation
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Benign sleep myoclonus of infancy
Environmental sleep disorder
Fragmentary myoclonus
Hypnagogic foot tremor
Hypnotic-dependent sleep disorder
Long sleeper
Propriospinal myoclonus at sleep onset
Rhythmic movement disorder
Short sleeper
Sleep hyperhidrosis
Sleep-related abnormal swallowing
Sleep-related bruxism
Sleep-related choking syndrome
Sleep-related laryngospasm
Sleep-related neurogenic tachypnea
Sleep-related painful erections
Sleep-related leg cramps
Sleep start
Sleep talking
Snoring
Stimulant-dependent sleep disorder
Sudden infant death syndrome
Sudden unexplained nocturnal death
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Infants and children
Milestones in sleep architecture
Sleep stages in the first 6 months of age
Sleep stages after 6 months of age
Milestones in sleep-related behaviors
Aggregate hours of sleep per day
Insomnia in children
Excessive daytime sleepiness
Childhood obstructive sleep apnea
Apnea of prematurity
Infant sleep apnea
Apparent life-threatening event
Snoring
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Aging
Physiologic changes with aging
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Changes in sleep architecture
Insomnia
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Sleep in women
Obstructive sleep apnea
Central sleep apnea
Menstruation
Polycystic ovarian syndrome
Pregnancy
Postpartum period
Menopause
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Medications and their effects on sleep
Alcohol
Antidepressants
Antipsychotics
Drugs of abuse
Hypnotic agents
Opioids
Stimulants
Agents that can cause insomnia
Agents that can cause sedation
Agents causing restless legs syndrome
Agents causing REM behavior disorder
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Polysomnography and other sleep tests
Indications
Polygraph
Derivation
Electroencephalography
Electroencephalographic waveforms
Electro-oculography
Chin electromyography
Electrocardiography
Measuring airflow
Measuring respiratory effort
Measuring oxygenation and ventilation
Identifying snoring
Electromyography of the anterior tibialis
Scoring sleep stages
Adult sleep stages
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Stage wake
Stage N1 sleep
Stage N2 sleep
Stage N3 sleep
Stage REM sleep
Major body movements
Pediatric sleep stage scoring rules
Sleep scoring in newborns
Arousals
Adult respiratory events
Pediatric respiratory events
Movement events
Definitions of polysomnographic parameters
Artifacts
Epworth sleepiness scale
Stanford sleepiness scale
Multiple sleep latency test
Maintenance of wakefulness test
Actigraphy
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Introduction
Sleep is a complex reversible state. Its principal characteristics
include behavioral quiescence and diminished responsiveness to
external stimuli compared to the waking state. Sleep is generated
and maintained by central neural networks utilizing specific
neurotransmitters that are located in specific areas of the brain;
these networks are generally redundant and destruction of any
particular localized area is unlikely to completely abolish the sleep
state. Although a comprehensive theory of the function/s of sleep
remains elusive (i.e., sleep may address multiple physiologic
needs), it is unquestioned that sleep is central to the development
and optimal operation of the brain.
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Neurobiology of sleep
Wake, NREM sleep and REM sleep are each generated and
maintained by different neurons and neural networks utilizing
specific neurotransmitters.
Neural systems generating wakefulness include the ascending
reticular formation in the medulla, pons and midbrain
(neurotransmitter: glutamate). Afferent pathways project to the
thalamus and cerebral cortex. The two major pathways of the
ascending reticular formation are (a) the dorsal thalamocortical
pathway, with neural circuits from the reticular formation to the
cerebral cortex via the midline and intralaminar thalamic nuclei;
and (b) the ventral pathway, that consists of afferent neurons from
the reticular formation to the posterior hypothalamus,
subthalamus and basal forebrain prior to reaching the cerebral
cortex. Additional neural systems that generate the waking state
include the basal forebrain (pedunculopontine and laterodorsal
thalamic nuclei; neurotransmitter: acetylcholine); hypothalamus
(neurotransmitter: hypocretin); locus ceruleus (neurotransmitter:
norepinephrine), tuberomammillary nucleus (neurotransmitter:
histamine); and ventral tegmental area (neurotransmitter:
dopamine).
Neural systems generating NREM sleep consist of the
ventrolateral
preoptic
area
of
the
hypothalamus
(neurotransmitters: gamma aminobutyric acid and galanin); basal
forebrain (neurotransmitters: gamma aminobutyric acid and
adenosine); solitary tract nuclei; orbitofrontal cortex; and
thalamus. Sleep spindles are generated by reticular thalamic
nuclei.
Neural systems generating REM sleep are the caudal
mesencephalon and rostral pons (pedunculopontine and
laterodorsal nuclei); and nucleus magnocellularis in the
ventromedial medulla. Ponto-geniculo-occipital (PGO) waves are
generated in the dorsolateral pons accompanied by activation of
the lateral geniculate nucleus and occipital cortex. REM sleep is
associated with activation of “REM-on” cholinergic neurons and
inhibition of “REM-off” noradrenergic (locus ceruleus),
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serotonergic (dorsal raphe) and histaminergic (tuberomammillary
nuclei) neurons.
Main neurotransmitters involved in the generation of the wake
state include acetylcholine, dopamine, glutamate, histamine,
hypocretin (orexin) and norepinephrine. On the other hand, main
neurotransmitters involved in the generation of sleep include
acetylcholine (REM sleep), adenosine, gamma aminobutyric acid
and glycine. Gamma aminobutyric acid is the main NREM sleep
neurotransmitter, whereas acetylcholine is the main REM sleep
neurotransmitter.
Acetylcholine is both a wake and a REM sleep neurotransmitter.
Its neurons are located primarily in the basal forebrain and
pedunculopontine and laterodorsal tegmentum in the brainstem.
Acetylcholine is responsible for cortical electroencephalographic
desynchronization during wake and REM sleep. Adenosine is a
sleep neurotransmitter, with neurons located primarily in the basal
forebrain. Levels of adenosine progressively increase during
prolonged wakefulness and decrease during sleep. Adenosine is
believed to be responsible for the homeostatic sleep drive.
Dopamine is involved with both wake and REM sleep, and its
neurons are located in the substantia nigra and ventral tegmental
area of the brainstem. Gamma-aminobutyric acid (GABA) is a
sleep neurotransmitter. It is the main central nervous system
inhibitory neurotransmitter. Gamma aminobutyric acid neurons
are located primarily in the ventrolateral preoptic area, thalamus,
hypothalamus, basal forebrain and cerebral cortex. Barbiturates,
benzodiazepines and benzodiazepine receptor agonists, such as
eszopiclone, zaleplon and zolpidem, act via the GABA-A receptor.
Gamma hydroxybutyrate (sodium oxybate) acts via the GABA-B
receptor. GABA-A, the major GABA receptor, is a membrane
chloride ion channel that consists of five subunits, often two alpha,
two beta and one gamma, each with several subtypes. Binding of
benzodiazepine agonists to their receptors at the alpha-gamma
subunit of the GABA complex increases the chloride current at the
GABA receptor site.
Glutamate is the main central nervous system excitatory
neurotransmitter, and glycine is the main inhibitory
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neurotransmitter in the spinal cord. Glycine is responsible for
hyperpolarization (inhibition) of spinal motoneurons that causes
REM sleep-related muscle atonia/hypotonia. Histamine is a wake
neurotransmitter. Histaminergic neurons are located primarily in
the posterior hypothalamic tuberomammillary nucleus and project
to the forebrain.
Hypocretin (orexin) is a wake neurotransmitter, and its neurons
are located primarily in the lateral hypothalamic perifornical
region. Hypocretin acts on other central nervous system centers
related to sleep-wake regulation, including the dorsal raphe, basal
forebrain, locus ceruleus, tuberomammillary nucleus and spinal
cord.
Melatonin is produced by the pineal gland during the night, and
its secretion is inhibited by light exposure. Melatonin receptors are
present in the suprachiasmatic nucleus, where it participates in
circadian rhythm regulation, as well as in the hypothalamus,
where it is involved in thermoregulation.
Norepinephrine is a wake neurotransmitter, the neurons of which
are located primarily in the locus ceruleus. Serotonin is another
wake neurotransmitter. Its neurons are located primarily in the
raphe nuclei and thalamus, with projections to the forebrain. The
activity of norepinephrine and serotonin neurons are greater
during waking compared to NREM sleep, and are least during
REM sleep.
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Physiology during sleep
There are significant changes in various physiologic processes
during NREM and REM sleep, including that of the autonomic
nervous system. During NREM sleep compared to wake, there is
a reduction in sympathetic activity accompanied by an increase in
parasympathetic activity. During REM sleep compared to NREM
sleep, there is a further fall in sympathetic activity as well as
increase in parasympathetic activity. In contrast, a transient
increase in sympathetic activity typically occurs during phasic
REM sleep.
The respiratory system is also significantly affected by sleep.
Control of respiration, which is usually under both metabolic (i.e.,
pH, PaO2 and PaCO2) and behavioral control during waking, is
only under metabolic control during sleep. Hypoxic and
hypercapnic ventilatory responses as well as upper airway dilator
muscle tone decrease during NREM sleep compared to wake,
with a further fall during REM sleep. Tidal volume and minute
ventilation, too, are reduced during sleep compared to wake.
Because of these changes, blood gas parameters during sleep
often reflect a fall in PaO2 by 2 to 12 mmHg, rise of PaCO2 by 2 to
8 mmHg, and reduction in SaO2 by 2% compared to wake.
Respiratory patterns change during sleep as well. Periodic
breathing, with episodes of hypopneas and hyperpneas, is
typically present during N1 sleep; stable and regular frequency
and amplitude of respiration develop during N3 sleep; and
irregular pattern of respiration as well as variable respiratory rates
and tidal volumes occur during REM sleep. Central apneas or
periodic breathing may be seen during phasic REM sleep.
Changes in the cardiovascular system include reductions in
heart rate, cardiac output and blood pressure during NREM sleep
compared to wake, with further reductions in these cardiovascular
parameters during tonic REM sleep. Conversely, there are
transient increases in heart rate, cardiac output and blood
pressure during phasic REM sleep compared to NREM and tonic
REM sleep, as well as during awakenings, the latter as a result of
enhanced sympathetic tone. Finally, nighttime systolic blood
pressure is commonly about 10% less than daytime systolic blood
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pressure, referred to as “dipping” phenomenon.
Gastrointestinal system changes during sleep include
reductions in swallowing rate, salivary production and esophageal
motility. There is a circadian rhythmicity in basal gastric acid
secretion, with a peak between 10 pm and 2 am, and a nadir
between 5 am and 11 am.
Changes in the renal and genito-urinary systems during sleep
consist of greater water reabsorption as well as a reduction in
glomerular filtration. Penile tumescence in men, and clitoral
tumescence and vaginal engorgement in women occur during
REM sleep.
Secretion of various hormones of the endocrine system varies
throughout the nocturnal sleep period. During the first half of the
sleep period, there is increased secretion of growth hormone, and
lesser secretion of cortisol and adrenocorticotropic hormone.
Conversely, secretion of growth hormone declines and levels of
both cortisol and adrenocorticotropic hormone rise during the
second half of the sleep period.
Release of growth hormone occurs primarily during N3 sleep;
nonetheless, growth hormone secretion can also occur without N3
sleep, such as during relaxed supine position. There is one peak
in growth hormone secretion occurring at sleep onset in men,
whereas several peaks in growth hormone secretion occurring
throughout the day and night may be seen in women. Secretion of
thyroid stimulating hormone is linked to both sleep and
circadian rhythms; thyroid stimulating hormone levels are low
during the daytime, with a nadir between 10 am and 7 pm,
increase during the night between 9 pm and 6 am, and peak prior
to sleep onset. In addition, thyroid stimulating hormone secretion
is inhibited by sleep, particularly N3, and increases with
awakenings and sleep deprivation. Cortisol secretion is linked
primarily to the circadian rhythm rather than to sleep. Cortisol
levels begin to rise about 2 hours prior to awakening, with peak
levels at 8 to 9 am; thereafter, cortisol levels decline with a nadir
at 12 am. Sleep, especially N3, suppresses cortisol secretion.
Secretion of cortisol increases during prolonged awakenings.
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Levels of melatonin rise in the evening, peak in the early morning
between 2 and 5 am, and decline thereafter, even if no sleep
occurs during the night; the synthesis and secretion of melatonin
is suppressed by light exposure. Secretion of testosterone is
primarily linked to sleep, and levels increase during sleep in
young adult men, peaking at about 90 minutes prior to the first
REM period. Levels of insulin fall during sleep; nevertheless,
insulin secretion may increase during early sleep. Insulin levels
are higher in NREM sleep compared to REM sleep. Sleep
deprivation can give rise to insulin resistance.
Leptin is released from peripheral adipocytes, and is involved
with regulation of energy balance by reducing appetite. Secretion
of leptin is influenced by both sleep and circadian rhythms, being
greater at night (highest levels from 12 pm to 4 am and lowest
levels from 1 to 2 pm), and declining during sleep restriction.
Ghrelin stimulates appetite and increases food intake. Levels of
ghrelin increase at night and decline during the daytime. Ghrelin
promotes N3 sleep.
Musculoskeletal system Sleep is associated with skeletal
muscle relaxation (hypotonia or atonia) and inhibition of deep
tendon reflexes.
Pupillary changes include pupillary constriction during NREM
and tonic REM sleep, and dilatation during phasic REM sleep.
Pro-inflammatory cytokines involved in the immune system,
including interleukin (IL)-1β and tumor necrosis factor (TNF)-α,
enhance sleep, specifically NREM sleep, and promotes the
expression of delta electroencephalographic waves. On the other
hand, anti-inflammatory cytokines, such as IL-4, IL-10 and
transforming growth factor-beta, suppress sleep. Acute infectious
and inflammatory processes can give rise to sleepiness.
Neurons involved with thermoregulation are located in the
preoptic and anterior hypothalamus (POAH). Activity of warmthsensing neurons increase during sleep and decrease during
wake, while activity of cold-sensing neurons decrease during
sleep and increase with waking. Mild increases in local
temperature of the POAH shorten sleep onset latency and
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enhance N3 sleep. Activation of POAH warmth-sensing neurons
promotes sleep by inhibiting ascending activating systems.
Conversely, mild decreases in local POAH temperature prolong
sleep onset latency and reduce N3 sleep. Core body temperature
peaks in the late afternoon and early evening between 6 and 8
pm, and falls at the onset of sleep. Temperature nadir occurs
about 2 to 4 hours prior to the usual wake time, generally at 4 to 5
am. Changes in thermoregulation during sleep include (a) fall in
core body temperature; (b) decline in thermal set point; (c)
reduced thermoregulatory responses to thermal challenges; (d)
reduced metabolic heat production, with loss of heat production
from shivering during REM sleep; and (e) increased heat loss as a
result of sweating and peripheral vasodilatation.
Sleep latency and architecture are influenced by changes in body
temperature at bedtime. Exposure to extreme hot or cold
environmental temperatures suppresses sleep onset and causes
sleep disruption. In contrast, mild whole-body warming 1 to 2
hours before bedtime can enhance sleep due to mild activation of
heat response mechanisms. Nocturnal sleep typically occurs
during the falling phase of the temperature rhythm, after maximum
core body temperature, whereas awakening occurs during the
rising phase of the temperature rhythm, after minimum core body
temperature. Initiating sleep during the falling phase of the
temperature rhythm shortens sleep onset latency, increases total
sleep time, and enhances N3 sleep. On the other hand, initiating
sleep during the rising phase of the temperature rhythm generally
causes a prolongation of sleep onset latency, reduction of total
sleep time and N3 sleep, and increase in REM sleep.
Metabolic rate decreases during NREM sleep compared to wake.
During REM sleep, metabolic rate is either similar to or greater
than that during NREM sleep.
Dreaming can occur during both REM (accounting for 80% of
dreams) and NREM (20% of dreams) sleep. Compared to REM
sleep-related dreams that tend to be more complex and irrational,
NREM dreams are generally simpler and more realistic.
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Regulation of sleep and waking
Biological rhythms are ubiquitous and are characterized by
specific frequency (number of oscillations per unit time), period
length (interval between two consecutive events), amplitude
(maximal excursion from peak to trough), and phase (temporal
position in relation to an external cue). A circadian rhythm
consists of one oscillation occurring approximately every 24
hours.
Circadian rhythms free-run at a genetically determined frequency,
which is generally slightly over 24 hours (most commonly about
24.2 hours). This endogenous circadian period is referred to as
“tau”. Entrainment adjusts and synchronizes the endogenous
circadian rhythm to the external 24-hour period, using
environmental cues called zeitgebers. These external stimuli can
either be photic (dominant synchronizer) or nonphotic (e.g., meals
or activity). Phase advance refers to a shift of the circadian period
to an earlier time in the 24-hour cycle, whereas phase delay
involves a shift of the period to a later time in the 24-hour cycle.
Two basic intrinsic components interact to regulate the timing and
consolidation of sleep and wake, namely sleep homeostasis,
which is dependent on the sleep-wake cycle; and circadian
rhythm, which is independent of the sleep-wake cycle. These two
processes influence sleep latency, duration and quality. Timing of
sleep is also determined by behavioral influences (e.g., social
activities and work schedules).
Sleep homeostasis refers to an increase in sleep pressure that is
related to the duration of prior wakefulness (i.e., the longer a
person is awake, the sleepier one becomes). This sleep pressure
declines following a sufficient duration of sleep time. Adenosine, a
neurotransmitter, likely has a major role in sleep homeostasis.
The main role of the circadian neurosystem is to promote
wakefulness during the day. There are two circadian rhythmrelated peaks in wakefulness (wake-maintenance zones), namely
in the late morning and early evening. There are also two periods
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of circadian troughs in alertness (increased sleep propensity) in
the early morning and early-mid afternoon.
Circadian rhythms are controlled by transcription-translation
positive and negative feedback loops involving positive, negative
and regulatory components. Positive components are Clock and
Bmal1; negative components consist of Period, Cryptochrome
and Timeless; and regulatory components include Casein kinase
1 epsilon.
The suprachiasmatic nucleus in the anterior hypothalamus,
located above the optic chiasm, is the master circadian rhythm
generator in mammals. It is likely that other anatomical sites may
also harbor endogenous clocks. Activity of the suprachiasmatic
nucleus is independent of the environment, firing more frequently
during the daytime than at night. The main actions of the
suprachiasmatic nucleus include promotion of wakefulness during
the day, and consolidation of sleep during the night. Ablation of
the suprachiasmatic nucleus results in random distribution of
sleep throughout the day and night as well as, in some, reduction
in duration of waking periods.
There are several afferent inputs, both photic and non-photic, to
the suprachiasmatic nucleus. The main afferent connection
utilizes glutamate and pituitary adenylate cyclase-activating
polypeptide as its neurotransmitters; this glutamatergic pathway
for photic stimuli, originates from photosensitive retina ganglion
cells containing the photopigment, melanopsin, in the eye, and
reaches the suprachiasmatic nucleus via the retinohypothalamic
tract. The retinal photoreceptors are most sensitive to shorter
wavelength light from 450 nm [blue] to 500 nm [blue-green]. An
alternate afferent connection for photic stimuli uses neuropeptide
γ and gamma-aminobutyric acid as its neurotransmitters, and
passes the thalamic intergeniculate leaflet of the lateral geniculate
nuclei and geniculohypothalamic tract on its way to the
suprachiasmatic nucleus. Light entrainment is lost with disruption
of the retinohypothalamic tract but not with interruption of the
alternate geniculohypothalamic tract. Lastly, there are also
histaminergic and cholinergic afferent pathways for photic stimuli
as well as serotonergic tracts for non-photic stimuli.
24
The suprachiasmatic nucleus has efferent projections to the basal
forebrain, hypocretin neurons, hypothalamus, locus ceruleus,
pineal gland, thalamus and ventrolateral preoptic nucleus. For
instance, the neural pathway from the suprachiasmatic nucleus to
the pineal gland involves the para/subventricular nuclei of the
hypothalamus, medial forebrain bundle, intermediolateral gray
column neurons of the spinal cord, superior cervical ganglion,
and, finally ending at the pineal gland.
Melatonin is synthesized and released by the pineal gland, by a
process that involves the conversion of tryptophan into serotonin
(5-hydroxytryptamine), then finally to melatonin (N-acetyl-5methoxytryptamine). Secretion of melatonin is greatest at night,
and is inhibited by light exposure. Melatonin exerts several effects
on the suprachiasmatic nucleus, including (a) phase delay of
circadian sleep-wake rhythms when taken in the morning; and (b)
phase advance of circadian sleep-wake rhythms when given in
the afternoon or early evening. However, melatonin is less
effective in phase shifting circadian rhythms than light exposure.
There are two melatonin receptors, namely MT1 that acts to
inhibit firing of the suprachiasmatic nucleus, and MT2, which
possesses phase-shifting action. Finally, melatonin also
possesses mild hypnotic properties.
25
Sleep deprivation
Vulnerability to sleep deprivation varies within individuals across
time, referred to as state instability, as well as between individuals
or differential tolerance. The physiological and neurocognitive
consequences of total sleep deprivation appear to differ in some
ways from those of chronic sleep restriction. Persons often
underestimate the negative impact of sleep deprivation on their
cognition and performance. In general, older adults are more
resilient to the adverse effects of sleep deprivation compared to
younger adults.
Consequences of sleep deprivation include (a) increase in
morbidity; (b) increase in mortality, when total sleep times are
either less than 6.5 or greater than 7.5 hours per night; (c) greater
sleepiness; (d) diminished vigilance; and (e) reduced vigor.
Hypothermia can develop with severe sleep deprivation.
Sleep deprivation also has profound effects on the various organ
systems, including (a) central nervous system [decreased pain
tolerance, reduced seizure threshold, hyperactive gag and deep
tendon reflexes, nystagmus, ptosis, sluggish corneal reflexes,
slurring of speech, tremors and decreased cerebral glucose
metabolism, particularly in the subcortical frontal and mid-brain
regions]; (b) autonomic nervous system [increase in
sympathetic activity]; (c) cognition [diminished cognitive
performance, reduced attention, impairment of working memory,
executive functioning, information-processing and decisionmaking, slowing of response time, and the development of
hyperactivity in children]; (d) respiratory system [decreased
ventilatory responsiveness]; (e) endocrine system [increase in
cortisol, ghrelin and insulin resistance as well as reductions in
growth hormone, leptin activity, prolactin and thyroid hormone]; (f)
metabolism [increase in hunger and appetite with a preference
for salty, sweet and starchy foods as well as increase in caloric
intake resulting in weight gain and increased risk of obesity]; (g)
immune system [increase in pro-inflammatory cytokines,
diminished antibody titers to influenza and hepatitis A vaccination
acutely, reduced febrile response to endotoxin, and decreased
resistance to infection]; and (h) behavioral and psychiatric
26
effects [negative impact on mood as well as temporary remission
of major depressive disorder in an estimated 50% of affected
persons].
Sleep deprivation is associated with greater medical errors, both
of omission and commission, and increase in motor vehicle
accidents.
Polysomnographic features of sleep deprivation include
shortened sleep onset latency (that is also seen in the multiple
sleep latency test) and greater total sleep time. N3 sleep generally
increases during the first night following sleep deprivation, with
REM sleep increasing during the second night after sleep
deprivation. Sleep architecture usually normalizes by the third
night of recovery sleep.
27
Insomnia
Insomnia is a disorder characterized by repeated difficulty with
either falling or staying asleep, despite adequate opportunity,
condition and time to do so. The sleep disturbance is associated
with impairment of daytime function and occurs at least three
nights a week. Insomnia can be defined as (a) sleep-onset with
difficulty falling asleep; (b) sleep-maintenance, if there are
frequent or prolonged awakenings; (c) terminal, when the final
morning awakening is earlier than desired; or (d) nonrestorative
sleep with an unrefreshed feeling upon awakening. Persons with
insomnia often report greater subjective estimates of sleep
disturbance compared to objective polysomnographic measures
of sleep, and may overestimate sleep onset latency as well as
underestimate total sleep time.
General changes in sleep architecture include (a) sleep onset
latency of 30 minutes or longer; (b) wake time after sleep onset of
at least 30 minutes; (c) sleep efficiency of less than 85%; or (d)
total sleep time of less than 6 to 6.5 hours.
Insomnia is the most common sleep disorder, with an estimated
prevalence of 30% to 50% of adults for occasional insomnia, and
10% to 30% for chronic insomnia. Prevalence of insomnia is
greater among women, older adults, shift workers, and persons
who are poor, widowed or divorced. Many persons with insomnia
have either an underlying psychiatric pathology, or an increased
risk of developing a new-onset psychiatric illness.
There are several mechanisms that are responsible for sleep
disturbance in persons with insomnia. These include somatic and
cognitive hyperarousal; persistent sensory perception and
information processing; intrinsic sleep instability; later minimum
core body temperature compared to good sleepers; circadian
dysrhythmia; dysregulation of homeostatic sleep drive; and
dysfunctional cognitive processes, such as propensity to worry,
unreasonable expectations about need for sleep, and unrealistic
concerns about consequences of lack of sleep.
Risk factors of insomnia are female gender; advancing age;
28
lower socioeconomic status or unemployment; being divorced or
widowed; shift work; poor health status and physical disability;
and medical, neurological and psychiatric disorders, such as
respiratory disorders, dementia, anxiety, depression and
schizophrenia.
Consequences of insomnia include increased likelihood of
accidents; increased risk of developing a psychiatric illness, such
as depression; increase in subjective sleepiness, especially
during acute insomnia; fatigue; cognitive impairment in memory,
attention and concentration; impaired academic and occupational
performance; increased absenteeism; chronic hypnotic use;
diminished quality of life; and greater healthcare utilization.
Classification of insomnia can be based on either duration or
etiology of sleep disturbance. Based on duration of sleep
disturbance, insomnia can be referred to as (a) transient when
sleep disturbance lasts for only a few days, or (b) chronic, which
persists for more than one to three months. Another useful
classification of insomnia is based on etiology of sleep
disturbance; insomnia can be either primary or comorbid if
associated with a medical, neurological or psychiatric disorder, or
medication use, abuse or withdrawal. Idiopathic insomnia,
paradoxical insomnia and psychophysiologic insomnia are
classified as primary insomnias.
Specific causes of insomnia include (a) adjustment insomnia; (b)
altitude insomnia; (c) behavioral insomnia of childhood; (d) familial
fatal insomnia; (e) idiopathic insomnia; (f) inadequate sleep
hygiene; (g) paradoxical insomnia; (h) psychophysiologic
insomnia; and (i) medication or substance use, abuse or
withdrawal.
In adjustment insomnia, sleep disturbance is due to an
identifiable acute stressor, such as momentous life event, change
in sleeping environment, or an acute illness. Duration of insomnia
is generally less than 3 months. Sleep normalizes with resolution
of the acute stressor or once the individual adapts sufficiently to
the stressor. Prevalence is greater among older adults and
women.
29
Sleep disturbance secondary to altitude insomnia develops
during ascent to over 2 to 4 thousand meters. Altitude insomnia is
due to periodic breathing during sleep as a result of hypoxia and
respiratory alkalosis. Arousals can occur during the hyperpneic
phase of periodic breathing. Symptoms resolve with
acclimatization or after descent to lower altitudes. Oxygen therapy
may decrease periodic breathing but does not consistently
improve sleep quality. Acetazolamide stimulates respiration via
production of metabolic acidosis; it improves hypoxemia, periodic
breathing and sleep quality.
Behavioral insomnia of childhood can be either of the limitsetting type (bedtime resistance due to inadequate enforcement
of bedtime by caregiver), or sleep-onset association type
(problematic associations required for sleep to occur). Behavioral
insomnia of childhood can be encountered in about 10% to 30%
of children.
Limit-setting sleep disorder may present as repetitive stalling or
refusal to go to sleep at an appropriate time when requested to do
so; sleep comes naturally and quickly when limits to further
activities are strictly enforced. Limit-setting sleep disorder is seen
in children 2 years of age or older when they start to develop
verbal communication skills. Polysomnography typically shows
normal sleep architecture.
Sleep-onset association disorder involves an inability to fall
asleep unless certain desired conditions, such as a favorite toy or
presence of a caregiver, are present at bedtime. Although mainly
seen in children, sleep-onset association disorder may persist into
adulthood. Polysomnographic features are variable and depends
on whether required associations are absent (prolonged sleep
onset latency) or present (normal sleep architecture) at bedtime.
Fatal familial insomnia is an autosomal dominant disorder
secondary to a prion disease. In this disorder, there is progressive
sleep disturbance and insomnia, with sleep loss eventually
becoming total. Vivid dreaming and spontaneous lapses into a
dreamlike state (oneiric stupor) with motor activity can occur. It
terminates in stupor, coma and death generally within 12 months
to a few years after its onset. The hereditary form of fatal familial
30
insomnia is due to a GAC to AAC mutation (substitution of
aspartic acid with asparagine) at codon 178 of the prion PRNP
gene at chromosome 20. This cosegregates with a methionine
polymorphism at codon 129. Cases of sporadic fatal insomnia do
not demonstrate the mutation at codon 178 but possess the
codon 129-methionine polymorphism on both alleles.
Classification of fatal familial insomnia is based on methionine
polymorphism at codon 129 and consists of methionine
homozygous, with a shorter disease course, and duration of
survival under 12 months; or methionine-valine heterozygous,
which is associated with a longer disease course, and duration of
survival of 1 to 6 years. Associated features of fatal familial
insomnia include loss of circadian rhythms of body temperature,
hemodynamic parameters and endocrine hormones; autonomic
hyperactivity (hyperthermia, hypertension, excessive salivation
and sweating); neurological abnormalities (myoclonus, tremors,
hallucinations, dystonia, ataxia and dysarthria); tachypnea and
dyspnea; and generalized body wasting (in terminal stage). This is
a rare condition, with onset during adulthood. Pathologic features
consist of degeneration and reactive gliosis of thalamic nuclei and
inferior olivary nucleus, and grey matter deposition of proteinase
K-resistant prion protein type 2, but without associated
inflammation. In early stages, periods of wakefulness alternating
with electroencephalographic desynchronization, bursts of REM
activity, and loss of muscle tone may be appreciated during
polysomnography. Progressive loss of sleep spindles, K
complexes and delta waves develop as can fragmentation of REM
sleep, which may occur without muscle atonia. Flattening and
unreactive electroencephalography may be seen in terminal
disease. There is no known specific therapy.
Idiopathic insomnia is defined as longstanding insomnia that is
not associated with any identifiable etiology. It has a prevalence
of 0.7% in adolescents and 1% in young adults, and accounts for
less than 10% of persons with complaints of insomnia presenting
to the sleep clinics. Onset is often during infancy or early
childhood, and course is chronic and life-long without periods of
remission. Diagnosis is made by clinical history and sleep diaries.
Polysomnography is not routinely indicated.
31
With inadequate sleep hygiene, sleep disturbance is due
primarily to activities or behavior that increase arousal or
decrease sleep propensity, and that are under a person’s control.
Paradoxical insomnia, or sleep state misperception, involves
subjective reports of chronic severe insomnia, with very minimal
or no sleep, during most nights associated with no
polysomnographic evidence of significant sleep disturbance.
Persons often overestimate sleep onset latency and
underestimate total sleep time compared to objective measures of
sleep. There is no daytime napping or impairment of daytime
functioning. Paradoxical insomnia accounts for less than 5% of
cases of chronic insomnia. Onset is commonly during early to
mid-adulthood. Women are affected more commonly than men.
Course tends to be chronic. Typical polysomnographic features
include normal or near normal sleep onset latency, sleep quality
and sleep architecture despite subjective reports of minimal or no
sleep during the sleep study. Total sleep time is often greater than
6.5 hours. Multiple sleep latency test is either normal or suggests
mild sleepiness.
Psychophysiologic insomnia refers to chronic sleep
disturbance, of at least one month in duration, secondary to
heightened cognitive (rumination and intrusive thoughts) and
somatic (increased agitation and muscle tone) arousal at bedtime.
Associated features include learned maladaptive sleep-preventing
behavior as well as excessive anxiety and frustration about
inability to sleep. Conditioned arousal is limited to a person’s own
bed and bedroom, and sleep is frequently better in another room.
Psychophysiologic insomnia has an estimated prevalence of 1%
to 2% in the general population, and accounts for 15% of cases of
chronic insomnia. Onset of sleep disturbance is generally during
adolescence or early adulthood. It tends to affect women more
than men. Course is chronic and may progressively worsen if
untreated. Persons with psychophysiologic insomnia may have an
increased risk of developing depression. Diagnosis is made by
clinical history, and polysomnography is not routinely indicated.
“First-night effect” and “reverse first-night effect” (worse or better
sleep than usual during the first sleep laboratory night,
respectively) may be present during polysomnography; the latter
32
may also be normal. Multiple sleep latency test demonstrates a
normal daytime mean sleep onset latency.
Common medications that can cause insomnia include
antidepressants, such as fluoxetine or protriptyline; β-Blockers;
bronchodilators; decongestants; steroids; and stimulants.
Evaluation of insomnia starts with a comprehensive history and
sleep diary. Psychometric tests may be considered for selected
patients
in
whom
mood
disorders
are
suspected.
Polysomnography, actigraphy and laboratory tests are not
routinely indicated. Nonetheless, polysomnography may be
considered for insomnia suspected to be due to sleep-related
breathing disorders, periodic limb movement disorder or
paradoxical insomnia.
Common polysomnographic features of insomnia include
prolonged sleep onset latency, decreased sleep efficiency,
reduced total sleep time, and increase in wake time after sleep
onset. Some individuals with insomnia may have reduced N3 and
REM sleep. Polysomnography may also be completely normal. A
prolonged mean sleep onset latency can be present in some
during multiple sleep latency testing.
Therapy of insomnia consists of general measures, including
sleep hygiene; non-pharmacologic therapy; and the use of
pharmacologic agents.
General measures include addressing factors that can precipitate
or perpetuate sleep disturbance; identifying and treating comorbid
causes of insomnia, such as obstructive sleep apnea, restless
legs syndrome or mood disorder; and referral to a sleep clinician
specializing in the treatment of insomnia for cases of intractable or
atypical sleep disturbance.
Sleep hygiene is a necessary component of therapy for
insomnia, but is rarely sufficiently effective, by itself, to reverse
sleep disturbance. It includes encouraging bedtime activities and
behaviors that enhance sleep propensity, such as maintaining a
regular bedtime and waking time, as well as eliminating activities
and behaviors that curtail sleep propensity. The latter include
33
avoidance of (a) prolonged naps during the day, especially in the
late afternoon and early evening; (b) excessive time spent awake
in bed; (c) ingestion of alcohol and caffeine close to bedtime; (d)
smoking close to bedtime; (e) use of medications that can cause
insomnia; (f) stimulating activities late in the evening; (g)
environmental factors that interfere with sleep onset and
continuity, such as bright lights or excessive noise; and (h) use of
the bed and bedroom for non-sleep-related activities.
Cognitive-behavioral treatment for insomnia is the first-line
therapy for both primary and comorbid chronic insomnia. It
consists of several techniques, including cognitive therapy,
paradoxical intention, relaxation techniques, sleep restriction and
stimulus control. In addition to improving sleep in both primary
and comorbid insomnia, benefits of non-pharmacologic treatments
for insomnia include (a) decrease in subjective symptoms of sleep
disturbance and increase in subjective sleep quality; (b)
decreased use of hypnotic medications; (c) reduced healthcare
utilization; (d) shortened sleep onset latency; (e) decrease in
wake time after sleep onset; (f) longer total sleep time; (g) and
improved sleep efficiency. Subjective reports of improvements in
sleep are generally greater than objective measures obtained with
polysomnography. Short-term benefits are comparable to
pharmacologic therapy. Unlike pharmacotherapy, beneficial
effects are sustained over time after the initial treatment period. At
long-term follow-up, cognitive behavioral therapy is more effective
than pharmacotherapy. However, combination cognitive
behavioral therapy plus pharmacologic treatment may be
associated with worse outcomes than cognitive behavioral
therapy alone.
Cognitive therapy addresses dysfunctional beliefs, inappropriate
expectations and excessive worry accompanying insomnia.
Techniques include decatastrophization, cognitive restructuring,
attention shifting and reappraisal that identify irrational cognitive
processes, challenge unrealistic concerns, and provide a more
appropriate understanding of sleep disturbance and its associated
daytime impairment.
Paradoxical intention is designed to decrease performance
anxiety associated with efforts to fall asleep. Persons with
34
insomnia are instructed to go to bed at night and to try to stay
awake as long as they can.
Relaxation techniques for insomnia reduce somatic and
cognitive hyperarousal, and include progressive muscle relaxation
for somatic arousal (sequential tensing and relaxing various
muscle groups throughout the body); biofeedback for somatic
arousal; and guided imagery for cognitive arousal.
Sleep restriction is designed to increase homeostatic sleep drive
from sleep deprivation by reducing time in bed. Time in bed is
subsequently increased once sleep efficiency improves. Patients
are instructed to (a) maintain a daily sleep log; (b) limit time spent
in bed to actual sleep time only (at least 4.5 to 5 hours per night);
(c) advance or delay bedtime based on calculated sleep efficiency
([total sleep time/time in bed] X 100%) for the prior five nights until
the desired sleep duration is reached; (d) advance bedtime by 15
to 30 minutes if sleep efficiency is greater than 90%; (e) delay
bedtime by 15 to 30 minutes if sleep efficiency is less than 80%;
(f) not to change bedtime if sleep efficiency is between 80% and
90%; (g) wake up at the same time every morning; and (h) not
nap during the day.
Stimulus control strengthens the association of the bedroom and
bedtime to a conditioned response for sleep, and is useful for both
sleep-onset and sleep-maintenance insomnia. It has been shown
to shorten sleep onset latency and decrease wake time after
sleep onset. Instructions to patients include (a) using the bed only
for sleep or sex; (b) lying down to sleep only when sleepy; (c)
getting out of bed and going to another room if unable to fall
asleep within approximately 10 to 20 minutes; (d) engaging in a
restful activity and returning to bed only when sleepy; (e) waking
up at the same time every morning; and (f) not napping during the
day.
Multi-component cognitive behavioral therapy is an
individualized program for insomnia that commonly includes sleep
hygiene, cognitive therapy, relaxation techniques, sleep restriction
and stimulus control.
Pharmacotherapy of insomnia consists of short-acting agents,
35
such as ramelteon or zaleplon for sleep-onset insomnia, or
benzodiazepines, eszopiclone and zolpidem for sleep-onset and
sleep-maintenance insomnia. There is insufficient evidence
regarding the efficacy of sedating antidepressants, antipsychotic
agents, antihistamines and botanical compounds for the treatment
of insomnia. Polysomnographically, hypnotic agents shorten sleep
onset latency, enhance sleep efficiency, increase total sleep time,
and decrease wake time after sleep onset. Benzodiazepines can
increase N2 and number of sleep spindles, and decrease both N3
and REM sleep.
Hypnotic agents are indicated for transient sleep disruption, such
as jet lag or adjustment sleep disorder; chronic primary insomnia
that failed to respond to cognitive behavioral therapy; and chronic
comorbid insomnia that does not improve with cognitive
behavioral therapy and treatment of the underlying condition/s.
Hypnotic agents may be selected based on timing of insomnia,
with short-acting agents for sleep-onset insomnia, intermediateacting agents for concurrent sleep-onset and sleep-maintenance
insomnia, and long-acting agents for early morning awakenings
and daytime anxiety. Elimination half-lives of hypnotic agents are
(a) less than 1 hour [ramelteon and zaleplon]; (b) 2 to 5 hours
[eszopiclone, triazolam and zolpidem]; (c) 5 to 24 hours
[estazolam and temazepam]; and (d) greater than 40 hours
[flurazepam and quazepam].
Benzodiazepines and non-benzodiazepine benzodiazepine
receptor agonists bind to the gamma-aminobutyric acidbenzodiazepine (GABA-BZ) receptor complex. The GABA-A
receptor consists of 5 subunits, typically two alpha, two beta and
one gamma subunit. The benzodiazepine receptor is located at
the interface between an alpha and gamma subunit. Attachment
of GABA, an inhibitory neurotransmitter, to the GABA-A receptor
causes the chloride channel to open, leading to an influx of ions
into the cell and hyperpolarization. This inhibitory response is
enhanced when benzodiazepine receptor agonists attach to the
benzodiazepine site, leading to greater influx of chloride ions.
Various GABA-BZ receptor subunits have different actions (BZ1
possesses hypnotic and amnesic actions, while BZ2 and BZ3
have muscle relaxation, anti-seizure and anti-anxiety actions).
36
Benzodiazepines bind non-selectively to the different GABA-BZ
receptor subunits, BZ1, BZ2 and BZ3. Therefore, in addition to
their hypnotic properties, they are also potent anxiolytics,
myorelaxants and anticonvulsants. Adverse effects of
benzodiazepines include rebound daytime anxiety (with shortacting agents); daytime sleepiness (with long-acting agents);
cognitive and psychomotor impairment (motor incoordination,
delayed reaction time, confusion and amnesia); development of
tolerance (need for increasingly higher dosages to attain similar
therapeutic benefit during chronic use); withdrawal symptoms
(anxiety, irritability and restlessness); dependency and abuse
liability (low risk); relapse (recurrence of insomnia following drug
discontinuation); rebound insomnia (worsening of sleep
disturbance compared to pretreatment levels after drug
discontinuation; more likely to occur with long-term use of shortacting and intermediate-acting agents); respiratory depression
and worsening of obstructive sleep apnea; and increase in falls (in
some older adults).
Benzodiazepines are contraindicated during pregnancy and
lactation, and in persons with significant renal or hepatic
impairment (requires dosage adjustment), untreated obstructive
sleep apnea, and severe obstructive and restrictive ventilatory
impairment.
Non-benzodiazepine benzodiazepine receptor agonists
selectively bind to the BZ1 receptor subunit. Duration of action
from shortest to longest of the available agents is zaleplon,
zolpidem, then eszopiclone. Compared to conventional
benzodiazepines, they have similar hypnotic action but no muscle
relaxant, anticonvulsant or anxiolytic properties; are less likely to
cause rebound insomnia, withdrawal symptoms or tolerance, or to
alter sleep architecture; have minimal abuse or addiction liability;
and possess no active metabolites.
Ramelteon is a selective melatonin receptor agonist of the
receptor subtypes, MT1, responsible for attenuation of arousal,
and MT2, which acts in phase shifting of circadian rhythms.
Ramelteon has a short half-life, and is indicated for sleep-onset
insomnia. It is contraindicated in persons using fluvoxamine or
those with hepatic impairment.
37
Sedating antidepressant and antipsychotic agents are
commonly used to manage persons with insomnia; however,
there is limited published data on their appropriate use for this
condition, and is, therefore, not recommended for the treatment of
insomnia.
Similarly, non-prescription hypnotic agents are not
recommended for the treatment of insomnia due to limited
published data on their efficacy as sleep aids for insomnia. The
first generation histamine antagonists, such as diphenhydramine,
are sedating and constitute the majority of over-the-counter
hypnotic agents. They generally shorten sleep onset latency and
lengthen total sleep time. Adverse effects of histamine
antagonists include rapid development of tolerance to hypnotic
effect; residual daytime sedation because of long half-lives; anticholinergic effects, such as confusion, delirium, dizziness, blurring
of vision, dry mouth, urinary retention, constipation; and increase
in intraocular pressure in narrow angle glaucoma. In contrast,
second-generation histamine antagonists, such as loratadine and
fexofenadine, are less likely to cause sedation.
Melatonin is another common over-the-counter agent that is used
primarily for treating insomnia associated with circadian rhythm
sleep disorders. Melatonin is not FDA-approved for the therapy of
insomnia. It has a short half-life of 20 to 30 minutes.
There is inconclusive evidence for the efficacy of botanical
compounds, such as kava, passionflower, skullcap or valerian,
for the treatment of insomnia. Hepatotoxicity has been described
with kava and valerian.
38
Excessive sleepiness
Excessive sleepiness is defined as an inability to consistently
achieve and sustain wakefulness and alertness to accomplish the
tasks of daily living. It can manifest as frequent napping, sleep
attacks or microsleep episodes. Excessive sleepiness can also
present as hyperactivity in children or as automatic behavior.
Prevalence is greater among adolescents and older adults. Men
and women are affected equally.
Consequences of excessive sleepiness include increased risk of
accidents, greater absenteeism, diminished work and academic
performance, and development of mood disorder.
Mechanisms underlying excessive sleepiness include inadequate
sleep duration; sleep fragmentation; disorders of the central
nervous system sleep-wake apparatus; disturbance of circadian
rhythm timing of sleep and waking; or medication and substance
use or withdrawal.
Specific causes of excessive sleepiness include (a)
behaviorally-induced insufficient sleep syndrome, (b) idiopathic
hypersomnia, (c) narcolepsy, (d) recurrent hypersomnia, (e)
medical, neurological or psychiatric disorders, and (f) medications.
In behaviorally-induced insufficient sleep syndrome,
excessive sleepiness is due to chronic voluntary, but
unintentional, sleep deprivation. Symptoms generally improve
following longer sleep duration, such as may occur in some during
weekends or holidays. Insufficient sleep is the most common
cause of excessive sleepiness. Its prevalence is increased among
adolescents, and it is more common among males. Diagnosis of
insufficient sleep syndrome is based on clinical history and sleep
diaries, and polysomnography is not routinely indicated.
Polysomnographic features include a shortened sleep onset
latency, increased sleep efficiency, decreased wake time after
sleep onset, increase in N3 and REM sleep, as well as longer
total sleep time when sleep is permitted to continue ad lib. A
shortened sleep onset latency of less than 8 minutes, with or
39
without sleep-onset REM periods, may be present on multiple
sleep latency testing. Therapy involves sleep extension.
Idiopathic hypersomnia is characterized by constant sleepiness
despite sufficient, or even increased, amounts of nighttime sleep
and daytime napping. No definitive cause of sleepiness is readily
identified. Compared to narcolepsy, naps are longer and less
refreshing, and cataplexy is absent. Associated clinical features
include automatic behavior, confusion upon awakening,
disorientation, headaches, orthostatic hypotension, Reynaud’stype vascular symptoms and syncope. Idiopathic hypersomnia is
classified as either: (a) with long sleep time [nocturnal sleep of at
least 10 hours in duration, and at least one daytime nap of over 1
hour], or (b) without long sleep time [nocturnal sleep greater than
6 but less than 10 hours]. Both genders are equally affected.
Onset is commonly during adolescence or early adulthood, and
clinical course is typically chronic. Diagnosis requires
polysomnography and multiple sleep latency testing. Monitoring
esophageal pressures to exclude upper airway resistance
syndrome is recommended. Unlike narcolepsy, cerebrospinal fluid
levels of hypocretin-1 are normal, as is neurological examination.
Polysomnography demonstrates a shortened sleep onset latency,
increase in sleep efficiency, normal or increased total sleep time,
decreased wake time after sleep onset, and no change in REM
sleep latency. Multiple sleep latency test shows diminished sleep
onset latency of less than 8 minutes, and less than two sleep
onset REM periods. Therapy consists of sleep hygiene and
stimulant agents. However, compared to narcolepsy, response to
stimulants is generally less favorable and less predictable.
Recurrent episodes of excessive sleepiness occur weeks or
months apart, typically about 10 times annually, in persons with
recurrent hypersomnia. Sleep, alertness and general behavior
are normal between episodes. Recurrent hypersomnia can be
either monosymptomatic, with sleepiness only, such as in
menstrual-related hypersomnia; or polysymptomatic/Kleine Levin
syndrome,
presenting
with
sleepiness,
hyperphagia,
hypersexuality, aggressiveness, abnormal behavior and cognitive
impairment. With menstrual-related hypersomnia, excessive
sleepiness lasts about 1 week with rapid resolution of symptoms
at the time of menses. Use of oral contraceptives leads to
40
prolonged remission. Kleine-Levin syndrome is a rare disorder
that generally affects young men, with an onset during early
adolescence. Severity of hypersomnia may decrease over time in
Kleine-Levin syndrome. In both conditions, there is a reduction in
sleep efficiency and increase in wake time after sleep onset
during polysomnography. A 24-hour polysomnographic study may
demonstrate an increase in total sleep time (≥ 18 hours) during
episodes. Consider trial of lithium therapy in Kleine-Levin
syndrome.
Hypersomnia can also result from a variety of medical,
neurological or psychiatric disorders. Medical disorders that
can cause hypersomnia include hepatic encephalopathy,
hypothyroidism, Niemann Pick type C disease, Prader-Willi
syndrome and renal failure. Neurological disorders that can cause
hypersomnia include central nervous system infections or tumor,
head trauma, Parkinson disease and stroke. Finally, several
psychiatric disorders can cause hypersomnia; these include
atypical depression, bipolar type II mood disorder and seasonal
affective disorder.
Medications, such as use or abuse of sedative-hypnotic agents,
and withdrawal from stimulant agents, can also give rise to
excessive sleepiness.
Evaluation of excessive sleepiness starts with a thorough sleep
history, aided by sleep diaries and, occasionally, actigraphy.
Subjective tests of sleepiness, including the Epworth
sleepiness scale and Stanford sleepiness scale, are useful and
commonly used. With the Epworth sleepiness scale, an aggregate
score from 0 to 9 is considered normal, whereas any score of 10
or more is indicative of the presence of sleepiness and, therefore,
advice
from
a
sleep
specialist
is
recommended.
Polysomnography is indicated to exclude obstructive sleep
apnea and periodic limb movement disorder.
Sleepiness is defined by a mean sleep onset latency of less than
8 minutes in a multiple sleep latency test; and less than 40
minutes in a maintenance of wakefulness test.
41
Effective countermeasures for excessive sleepiness consist
of: (a) sleep extension for insufficient sleep syndrome; (b)
napping; (c) bright light therapy for shift work sleep disorder and
jet lag; (d) caffeine intake; and (e) use of stimulant agents, such
as amphetamines, methylphenidate, modafinil or armodafinil.
42
Narcolepsy
Narcolepsy is a neurological disorder characterized by the clinical
tetrad of excessive sleepiness and manifestations of REM sleep
physiology during wakefulness, including cataplexy, sleep
paralysis and sleep hallucinations. However, only about 10% to
15% of persons with narcolepsy demonstrate this full tetrad.
Excessive sleepiness is generally the first, primary and most
disabling symptom of narcolepsy. Brief naps, usually lasting 10 to
20 minutes, occur repeatedly throughout the day. Sleepiness
transiently improves after awakening from a nap but gradually
increases within two to three hours. The repetitive short naps
seen in adults contrast with the prolonged sleep periods seen in
children. Sleep attacks, or sudden, irresistible episodes of
sleepiness that occur abruptly without warning leading to sleep
during inappropriate places or circumstances, may also occur.
Cataplexy refers to abrupt and transient episodes of muscle
atonia or hypotonia during wakefulness that are typically
precipitated by intense emotion, such as laughter, anger or
excitement. Cataplexy may also be triggered during the switch to
modafinil from amphetamines. Recovery from cataplexy is
immediate and complete, but prolonged episodes may give rise to
REM sleep. Episodes generally last less than two minutes in
duration. Most commonly affected areas are the lower extremities,
face, jaw and neck. Respiratory and oculomotor muscles are
spared, but blurring of vision may occur. Memory and
consciousness are typically unaffected. Episodes of cataplexy
commonly occur one to three times weekly, but this can be highly
variable. Frequency of cataplexy may decrease over time.
Physical examination during an episode of cataplexy may
demonstrate muscle flaccidity, reduction or absence of deep
tendon reflexes, and a positive Babinski sign. Although cataplexy
is the only pathognomonic symptom of narcolepsy, the absence of
cataplexy does not exclude a diagnosis of narcolepsy. The term,
status cataplecticus, refers to repetitive episodes of cataplexy
occurring in succession that may develop following withdrawal of
REM sleep suppressant agents.
43
Sleep hallucinations consist of hallucinatory phenomena that
may be visual, auditory, tactile or kinetic. They may occur during
wakefulness at sleep onset, referred to as hypnagogic, or upon
awakening or hypnopompic. Hallucinations may be accompanied
by sleep paralysis. Sleep hallucinations are not pathognomonic
for narcolepsy, since recurrent sleep hallucinations are present in
about 4% of healthy individuals.
–
Sleep paralysis is characterized by transient muscle paralysis
that occurs either at sleep onset or hypnagogic, or upon
awakening or hypnopompic, and lasts for a few seconds or
minutes. It affects voluntary muscles with sparing of respiratory,
oculomotor and sphincter muscles. Sensorium is unaffected, and
recovery is immediate and complete.
Sleep disturbance is common in narcolepsy, and persons may
complain of poor sleep quality with repetitive arousals and
awakenings as well as sleep-maintenance insomnia.
Other important clinical features of narcolepsy include memory
impairment; automatic behavior; visual changes, such as blurring
of vision, diplopia and ptosis; sleep drunkenness (transient
confusion and diminished alertness immediately after an
awakening); and hyperactivity and learning disability in children.
Consequences of narcolepsy include increased risk of
developing obstructive sleep apnea, central sleep apnea, periodic
limb movements during sleep and REM sleep behavior disorder.
Narcolepsy is also associated with increased risk of developing
depression and type II diabetes mellitus. Finally, there is high
prevalence of psychopathology on the Minnesota Multiphasic
Personality Inventory (MMPI).
Narcolepsy is estimated to have a prevalence of 0.05% in the
U.S. general population. Prevalence is higher in Japan, and lower
in Israel. Both genders are affected equally; however, there might
be a male predominance in cases of narcolepsy with cataplexy.
Clinical course of narcolepsy is characteristic. Excessive
sleepiness is usually the presenting symptom, followed months to
years later by the emergence of cataplexy, sleep paralysis and
44
sleep hallucinations. Onset of symptoms is generally during
adolescence and early adulthood, from 15 to 25 years of age, and
rarely before five years or after 60 years of age. Clinical course is
typically chronic; excessive sleepiness is generally persistent,
whereas severity of cataplexy may decrease over time.
The pathophysiology of excessive sleepiness is related to the
loss of hypothalamic hypocretin neurons, with increase in gliosis.
Other possible mechanisms responsible for excessive sleepiness
include defective cholinergic system regulating REM sleep;
defective monoaminergic regulation of cholinergic mechanisms;
and impairment of the dopamine system.
Cataplexy results from loss of hypocretin-induced excitation of
locus ceruleus (noradrenergic) and dorsal raphe (serotonergic)
neurons leading to disinhibition of cholinergic neurons in the
laterodorsal tegmental and pedunculopontine tegmental nuclei.
This, in turn, gives rise to stimulation of nucleus magnocellularis
and, finally, to glycine-mediated hyperpolarization of the anterior
horn cells of the spinal cord.
Narcolepsy without cataplexy is not associated with cataplexy,
but cataplexy-like symptoms, such as prolonged episodes of
tiredness, or muscle weakness associated with atypical triggers
(e.g., exercise) may be present. Narcolepsy without cataplexy
accounts for 10% to 50% of cases of narcolepsy. Most persons
with this condition have normal cerebrospinal fluid hypocretin-1
levels, especially those who are negative for HLA DQB1*0602. In
contrast, low cerebrospinal fluid hypocretin-1 levels are present in
10% to 20% of HLA DQB1*0602-positive persons with this
disorder. Loss of hypocretin-containing hypothalamic neurons is
believed to be less severe than in narcolepsy with cataplexy.
Narcolepsy that develops secondary to medical disorders is
referred to as secondary narcolepsy. Common medical
conditions that can cause narcolepsy symptoms include
hypothalamic lesions, such as tumors, multiple sclerosis or
sarcoidosis; brainstem lesions that are either degenerative,
infectious or inflammatory in nature; paraneoplastic syndrome
with anti-Ma2 antibodies; Neiman-Pick type C disease; head
trauma; Parkinson disease; multiple system atrophy; unspecified
45
viral illnesses; disseminated encephalomyelitis; myotonic
dystrophy; and Prader-Willi syndrome. In these disorders,
cerebrospinal fluid hypocretin-1 levels are low, either less than or
equal to 110 pg/mL or less than one-third of mean normal control
values.
Evaluation requires a complete clinical history. Narcolepsy with
cataplexy can be diagnosed by history alone. Polysomnography
followed by multiple sleep latency test is indicated when cataplexy
is absent, atypical or equivocal. Other tests, such as subjective
scales of sleepiness (Epworth sleepiness scale) and performance
vigilance testing, are of less certain diagnostic utility.
Polysomnographic features of narcolepsy include a shortened
sleep onset latency of less than 10 minutes. Sleep onset REM
periods, with REM sleep latency of less than 10 to 15 minutes,
can be present in 25% to 50% of cases. There may also be an
increase in N1 sleep; increased wake time after sleep onset;
repetitive awakenings; decreased or normal total sleep time; and
normal REM sleep.
Multiple sleep latency test in persons with narcolepsy
characteristically reveals a mean sleep onset latency of less than
or equal to 8 minutes, which is present in 90% of persons with
narcolepsy, but also in 15% to 30% of normal individuals; and at
least two sleep onset REM periods (SOREMPs). The combination
of a shortened sleep onset latency and SOREMPs is present in
only about 60% to 85% of cases. Multiple SOREMPs are more
specific for narcolepsy than a shortened sleep onset latency.
Other common causes of shortened mean sleep onset latency,
often with SOREMPs, are sleep deprivation, obstructive sleep
apnea and delayed sleep phase syndrome. The absence of
SOREMPs does not exclude the presence of narcolepsy, and
their presence does not establish its diagnosis.
Maintenance of wakefulness test may be used to monitor
treatment response to stimulant medications used for excessive
sleepiness.
Cerebrospinal fluid hypocretin-1 level of less than or equal to
110 pg/mL or less than one-third of mean normal control values in
46
the absence of severe brain pathology, is highly specific and
sensitive for narcolepsy with cataplexy. A normal test does not
exclude the diagnosis of narcolepsy with cataplexy since normal
levels are present in 10% of this population. Normal levels are
usually noted in narcolepsy without cataplexy. Possible uses of
cerebrospinal fluid hypocretin-1 measurements include (a) current
use of medications, such as stimulants or REM sleep
suppressants, which may interfere with proper interpretation of
multiple sleep latency test results; (b) persons who are too young
to undergo multiple sleep latency tests; and (c) early in the
disease course prior to the development of cataplexy.
Human leukocyte antigen (HLA) typing is of limited diagnostic
utility.
Therapy of narcolepsy should include education on proper sleep
hygiene; maintenance of regular sleep-wake schedules; obtaining
sufficient nocturnal sleep duration; treatment of other concurrent
sleep disorders that can cause excessive sleepiness; avoidance
of potentially dangerous activities, such as driving, until excessive
sleepiness is adequately managed; and scheduled naps. These
general measures, however, are seldom sufficient as sole therapy
for excessive sleepiness secondary to narcolepsy.
Excessive sleepiness may be reduced with the use of
armodafinil or modafinil (schedule IV drugs); dextroamphetamine;
or methylphenidate (schedule II drug). Hypnotic agents or γhydroxybutyrate (sodium oxybate) are useful for the management
of sleep disturbance. Finally, treatment of cataplexy, sleep
paralysis and sleep hallucinations requires the use of REM sleep
suppressant agents, such as selective serotonin reuptake
inhibitors, tricyclic antidepressants, non-tricyclic serotoninnorepinephrine reuptake inhibitors or monoamine oxidase
inhibitors; or γ-hydroxybutyrate.
47
Obstructive sleep apnea
Obstructive sleep apnea is characterized by repetitive reduction or
cessation of airflow, despite the presence of respiratory efforts,
due to partial or complete upper airway occlusion during sleep.
An apnea is an adult is defined as the cessation of nasal and oral
airflow for at least 10 seconds. The event is considered central if
respiratory efforts are absent; obstructive if respiratory efforts are
present; or mixed when an initial central apnea is followed by
obstructive apnea. Hypopnea refers to a reduction of airflow by at
least 30% from baseline for at least 10 seconds plus oxygen
desaturation of 4% or more. A respiratory effort-related arousal
(RERA) is scored when there is a reduction in airflow despite
increasing respiratory effort (progressively more negative
esophageal pressures) for at least 10 seconds that ends with an
arousal; and is not associated with significant oxygen desaturation
(less than 4% fall in SaO2). The term complex sleep apnea
refers to the development of central apneas during continuous
positive airway pressure (CPAP) titration for obstructive sleep
apnea.
Apnea-hypopnea index (AHI) is defined as the sum of apneas
and hypopneas per hour of sleep. Severity of obstructive sleep
apnea can be classified based on the apnea-hypopnea index as
mild (5 to 15); moderate (16 to 30); or severe (more than 30).
Other factors that influence the clinical severity of obstructive
sleep apnea include (a) degree of sleepiness, (b) nadir of oxygen
saturation, (c) extent of sleep fragmentation, (d) presence of
nocturnal arrhythmias, and (e) comorbid cardiovascular or
neurological disorders.
The prevalence of obstructive sleep apnea is estimated at 24% of
adult men and 9% of adult women, if the disorder is defined by an
apnea-hypopnea index of at least 5; or 4% of adult men and 2%
of adult women, if it is defined by an apnea-hypopnea index of at
least 5 plus complaints of excessive sleepiness. This disorder is
present in about 30% to 80% of older adults. Men are affected
more often than women; prevalence in women increases with
menopause.
48
Pathophysiology of obstructive sleep apnea involves repetitive
upper airway obstruction due to reduced activity of upper airway
dilating muscles during sleep. These events are associated with
episodic falls in oxygen saturation; snoring, often alternating with
periods of silence; arrhythmias, most commonly involving relative
bradycardia during airway obstruction followed by tachycardia
during termination of apnea; arousal at the termination of the
event; and an increase in blood pressure in the immediate postapneic period. Compared to persons without obstructive sleep
apnea, those with the disorder tend to have narrower upper
airways that are more vulnerable to collapse. The most common
sites of upper airway obstruction are retropalatal (behind the
palate) and retrolingual (behind the tongue).
Risk factors for obstructive sleep apnea include (a) family history
of the disorder; (b) male gender (for adults); (c) menopausal state
in women; (d) aging; (e) excess body weight; (f) snoring; (g)
specific cranio-facial or oropharyngeal features, such as
increased neck circumference [greater than 17 inches in men and
more than 16 inches in women), nasal narrowing or congestion,
macroglossia, low-lying soft palate, enlarged tonsils and
adenoids, mid-face hypoplasia, retrognathia, micrognathia,
mandibular hypoplasia, tracheal stenosis and laryngomalacia; (h)
hereditary syndromes, such as Apert, Crouzon, Down, Pfeiffer,
Pierre-Robin and Treacher Collins; (i) race, such as AfricanAmericans, Mexican-Americans, Asians and Pacific Islanders
compared to Caucasians; (j) smoking and alcohol use; (k)
medications, such as muscle relaxants, sedatives, anesthetics
and opioid analgesics; and (l) miscellaneous primary disorders,
including acromegaly, androgen therapy, amyloidosis, heart
failure, narcolepsy, neuromuscular disorders, polycystic ovarian
syndrome and stroke.
Common clinical features of obstructive sleep apnea are
daytime sleepiness; attention deficit and/or hyperactivity in
children; changes in mood, particularly treatment-resistant
depression; decline in performance at work or school; dry mouth
or throat sensation upon awakening; fatigue; gastroesophageal
reflux; impaired cognition, memory and concentration; insomnia;
morning
headaches;
nighttime
diaphoresis;
nocturia;
nonrestorative or unrefreshing sleep or naps; repeated
49
awakenings with gasping or choking; snoring; and witnessed
apneas.
On physical examination, persons with obstructive sleep apnea
may have a crowded posterior pharyngeal space; dental
malocclusion; enlarged tonsils and adenoids; prominent tonsillar
pillars; excess body weight, with body mass index greater than
25; high, narrow hard palate; large neck circumference; large
uvula; low-lying soft palate; macroglossia; narrow oropharynx;
nasal septal deviation or turbinate hypertrophy; or retro- or
micrognathia. Nevertheless, physical examination findings may be
entirely unremarkable.
Untreated obstructive sleep apnea is associated with several
important adverse health consequences. Mortality rates are
increased, especially among young and middle-age adults. Risk
of driving and work-related accidents is increased, particularly in
sleepy persons. It has a negative impact on school and work
performance.
Obstructive sleep apnea can give rise to oxygen desaturation and
increase in both systemic and pulmonary artery pressures.
Adverse neurocognitive and psychiatric effects include depression
and anxiety, an “irritable” mood, diminished quality of life, reduced
alertness and vigilance, and impairment of neurocognitive
performance, such as executive function, learning and memory.
Cardiovascular consequences of untreated obstructive sleep
apnea include the development or worsening of systemic
hypertension; coronary artery disease; congestive heart failure;
cardiac
arrhythmias;
pulmonary
hypertension;
and
cerebrovascular disease. Sinus arrhythmia is the most common
arrhythmia encountered in persons with obstructive sleep apnea.
Other arrhythmias, including atrioventricular block, bradycardia,
premature ventricular contractions, sinus pause and ventricular
tachycardia can also be seen. In addition, there is an increased
likelihood of recurrence of atrial fibrillation after successful
cardioversion in untreated obstructive sleep apnea. Pulmonary
hypertension and cor pulmonale may develop in persons with
obstructive sleep apnea. The degree of oxygen desaturation may
be predictive of the development of pulmonary hypertension, with
50
greater likelihood in persons with daytime hypoxemia and
hypercapnia, morbid obesity, or underlying chronic obstructive
pulmonary disease. The degree of pulmonary hypertension is
generally mild and lower than that in primary pulmonary
hypertension.
The risk of strokes is increased in persons with obstructive sleep
apnea; conversely, the risk of obstructive sleep apnea is
increased following strokes. Finally, other consequences of
obstructive
sleep
apnea
include
erectile
dysfunction,
gastroesophageal reflux, insulin resistance, nocturia, and greater
healthcare utilization.
Evaluation of obstructive sleep apnea should start with a
thorough clinical history and physical examination. The need for
laboratory testing should be individualized, and routine screening
for hypothyroidism is not indicated unless other clinical features
suggestive of hypothyroidism are present. Polysomnography is
required for the diagnosis of obstructive sleep apnea since neither
clinical nor physical examination features are sufficiently sensitive
or specific for the disorder. The current standard of practice is a
laboratory study with technologist-attended positive airway
pressure titration using either full-night protocol, with separate
diagnostic and positive airway pressure titration studies; or splitnight protocol, consisting of an initial diagnostic portion and a
subsequent positive airway pressure titration on the same night.
Polysomnographic features of obstructive sleep apnea include
greater wake time after sleep onset, increase in stages N1 and N2
sleep, as well as decreased N3 and REM sleep. Respiratory
events are generally more frequent, last longer, and are
associated with more profound oxygen desaturation during REM
sleep compared to NREM sleep. Paradoxical breathing, or “out-ofphase” motion of the ribcage and abdomen, may be appreciated,
as are large inspiratory and expiratory pressure swings during
esophageal manometry.
Multiple sleep latency test is indicated if excessive sleepiness
persists despite optimal positive airway pressure therapy. Upper
airway imaging studies, such as lateral cephalometric views,
computed tomography (CT) or magnetic resonance imaging (MRI)
51
of the upper airway may be considered for persons with
craniofacial syndromes, especially prior to surgical therapy.
Therapy of obstructive sleep apnea consists of general
measures, positive airway pressure therapy, oral devices and
upper airway surgery.
General measures, which are applicable for most persons with
obstructive sleep apnea, include (a) avoidance of alcohol,
benzodiazepines, opioids and muscle relaxants that can decrease
upper airway muscle activity; (b) avoidance of smoking; (c) proper
sleep hygiene and avoidance of sleep deprivation; (d) safety
counseling, such as the avoidance of driving whenever drowsy;
and (e) optimal weight management and regular exercise.
Positional therapy, which involves the avoidance of a supine
sleep position, may be considered in persons whose respiratory
events occur exclusively or predominantly during a supine sleep
position and in whom polysomnography demonstrates a normal
apnea-hypopnea index in the lateral or prone sleep position.
Oxygen therapy, although not indicated as sole therapy for
obstructive sleep apnea, may be helpful for persons with
significant nocturnal hypoxemia due to obstructive sleep apnea
that is not controlled by positive airway pressure therapy alone.
Useful pharmacologic treatments for obstructive sleep apnea
include topical nasal corticosteroids, which may be used as
adjunct to primary therapies in persons with concurrent rhinitis;
administration of thyroid hormone for hypothyroid states; hormone
replacement therapy for postmenopausal women (efficacy data
are conflicting); and modafinil or armodafinil for treating residual
excessive sleepiness in persons on effective positive airway
pressure therapy and with no other known cause for excessive
sleepiness.
Positive airway pressure therapy is the treatment of choice for
most persons with obstructive sleep apnea. This device functions
as a pneumatic splint that maintains upper airway patency by
increasing intraluminal upper airway pressure above critical
closing pressure (PCRIT). Higher pressures may be required to
52
control respiratory events during supine REM sleep.
Generally, positive airway pressure therapy is indicated if the
apnea-hypopnea index is at least 15 events per hour; or if the
apnea-hypopnea index is between 5 and 14 in the presence of
complaints of excessive sleepiness, impaired cognition, mood
disorder or insomnia, or documented hypertension or coronary
artery disease, or history of stroke. The apnea-hypopnea index is
commonly based on at least 2 hours of polysomnographicallyrecorded sleep.
Several positive airway pressure modalities can be used for
persons with clinically significant obstructive sleep apnea.
Continuous positive airway pressure (CPAP) consists of a single
constant pressure that is provided throughout the respiratory
cycle. With CPAP with expiratory pressure relief technology
(Cflex), a single pressure is also provided but the device allows a
transient reduction in pressure during expiration and a
subsequent return of pressure to baseline setting before initiation
of the next inspiration. Bi-level positive airway pressure (BPAP)
refers to the provision of two pressure levels during the respiratory
cycle, namely a higher level during inspiration (inspiratory positive
airway pressure [IPAP]) and a lower pressure during expiration
(expiratory positive airway pressure [EPAP]). Auto-titrating
positive airway pressure (APAP) devices deliver variable
pressures using device-specific diagnostic and therapeutic
algorithms, and automatically and continuously adjust the
delivered positive airway pressure to maintain upper airway
patency. Adaptive servoventilation utilizes variable pressure
support (difference between EPAP and IPAP), which increases
during hypoventilation and decreases during hyperventilation.
Lastly, nocturnal non-invasive positive pressure ventilation, which
consists of two pressure levels that are provided at a set rate to
assist ventilation, may be required.
There are three methods with which to determine an optimal
continuous positive airway pressure, namely (a) full-night,
laboratory,
attended
polysomnography,
(b)
split-night
polysomnography, and (c) titration using an auto-titrating positive
airway pressure device. A split-night polysomnography consists of
an initial diagnostic portion followed by continuous positive airway
53
pressure titration during the same sleep study night; this is
generally performed after at least 2 hours of recorded sleep time
during the initial diagnostic portion of the study; and if (a) the
apnea-hypopnea index is either greater than 40 events per hour,
or if the apnea-hypopnea index is between 20 and 40 events per
hour accompanied by significant oxygen desaturation; and (b) at
least 3 hours are available for adequate continuous positive
airway pressure titration with the documentation of supine REM
sleep.
Positive airway pressure therapy for obstructive sleep apnea is
associated with several important clinical benefits. These include
reduction in mortality; decreased subjective and objective
measures of sleepiness; increase in sleep-related oxygen
saturation; improved blood pressure control; improved heart
function in persons with concurrent heart failure; and decreased
healthcare utilization. Data relating to improvements in quality of
life, mood, and neurocognitive function are inconsistent.
Positive airway pressure use should be monitored objectively
since individuals commonly overestimate their utilization.
Objective compliance, defined commonly as use for greater than
4 hours per night for at least 70% of nights, ranges from 50% to
80%, with an average nightly use of about 5 hours. Patterns of
adherence to positive airway pressure therapy can often be
discerned within the first few days of starting therapy. Common
reasons for non-adherence to positive airway pressure therapy
include complaints of difficulty exhaling against high expiratory
pressures; excessively high pressures; claustrophobia; and
gastric distention due to aerophagia. Other adverse
consequences of positive airway pressure therapy for obstructive
sleep apnea are frequent arousals; barotrauma, such as
pneumothorax (rare); chest discomfort and tightness; eye
irritation, such as conjunctivitis; facial skin irritation, rash or
abrasion; nasal congestion, dryness, epistaxis or rhinorrhea; and
sinus discomfort or pain. Interventions that have been
demonstrated to improve adherence to positive airway pressure
therapy include patient education and the use of heated
humidification. Bi-level positive airway pressure, expiratory
pressure relief technology, ramping mechanism, or changing a
problematic or poorly fitting nasal mask after therapy has started
54
have not been consistently shown to improve compliance.
Nevertheless, bi-level positive airway pressure therapy may be
considered in persons who complain of difficulty breathing out
against high continuous positive airway pressures; have gastric
distention due to aerophagia; have concurrent obstructive or
restrictive lung disease; or have an underlying hypoventilation
syndrome with persistent oxygen desaturation despite continuous
positive airway pressure therapy.
Auto-titrating positive airway pressure (APAP) devices are used
for either (a) APAP titration, to identify a single fixed pressure for
subsequent treatment with a conventional continuous positive
airway pressure device, or (b) APAP treatment, when used in a
self-adjusting mode for nightly therapy of obstructive sleep apnea.
Auto-titrating positive airway pressure devices are not
recommended for split-night positive airway pressure titration, and
non-snorers should not be titrated with APAP devices using
diagnostic algorithms that rely solely on vibration or sound
production. This modality is contraindicated in persons with
congestive heart failure; significant respiratory disease (e.g.,
chronic obstructive pulmonary disease), daytime hypoxemia and
respiratory failure; or nocturnal oxygen desaturation unrelated to
obstructive sleep apnea, such as in those with obesity
hypoventilation syndrome. Compared to conventional continuous
positive airway pressure, auto-titrating positive airway pressure is
associated with lower mean airway pressure but potentially higher
peak airway pressure if mouth or mask leaks are not well
controlled. Therefore, proper mask fitting is crucial prior to
unattended APAP use.
Non-invasive positive pressure ventilation may be considered for
persistent sleep-related hypoventilation and carbon dioxide
retention that persist despite positive airway pressure and
supplemental oxygen therapy.
Oral devices are indicated for the treatment of snoring as well as
mild to moderate obstructive sleep apnea. There are two types of
oral devices used, namely mandibular repositioners that displace
the mandible and tongue anteriorly, and are the most commonly
used devices; and tongue-retaining devices that secure the tip of
the tongue in a soft bulb located anterior to the teeth in order to
55
hold the tongue in an anterior position. Tongue-retaining devices
are preferred for edentulous persons or those with compromised
dentition. Oral devices have been shown to increase sleep-related
oxygen saturation, reduce daytime sleepiness, decrease apneahypopnea index, and enhance quality of life. It appears to be less
effective than positive airway pressure therapy in reducing blood
pressure. Reported efficacy of oral devices range from 40% to
80%, and compliance is about 50% to 80%. Follow-up
polysomnography after optimal fit has been achieved is
recommended to assure therapeutic efficacy as are periodic
assessments by a dentist and sleep physician. Oral devices are
contraindicated in persons who are unable to breathe nasally;
when sleep apnea is primarily central in nature; and in growing
children. Mandibular repositioners should not be used in those
with inadequate or compromised dentition, or significant temporomandibular joint dysfunction. Complications from the use of oral
devices include dry mouth sensation, excessive salivation, dental
pain, undesirable dental movements with mandibular
repositioners, and jaw or temporo-mandibular joint pain.
Upper airway surgery may be considered for persons with
definitive craniofacial or upper airway abnormalities that are
believed to be primarily responsible for obstructive sleep apnea.
Several types of surgery have been described, including
tonsillectomy and adenoidectomy, which are particularly effective
in childhood cases of obstructive sleep apnea due to
adenotonsillar enlargement. There are techniques designed to (a)
increase dimensions of the nasal airway, such as septoplasty,
polyp removal and turbinectomy; (b) increase dimensions of the
retropalatal airspace, such as uvulopalatopharyngoplasty
[excision of the uvula, posterior portion of the soft palate,
redundant pharyngeal tissue and tonsils, and trimming of the
tonsillar pillars]; (c) increase dimensions of the retrolingual airway,
such as laser midline glossectomy and lingualplasty, tongue base
reduction with hyoepiglottoplasty, genioglossal advancement,
hyoid myotomy and suspension, and mandibular advancement;
(d) increase dimensions of the retrolingual, retropalatal and
transpalatal airway, such as uvulopalatopharyngoglossoplasty
and maxillo-mandibular advancement; and (e) bypass the upper
airway, such as tracheotomy. Tracheotomy is indicated for severe
life-threatening obstructive sleep apnea that is unresponsive to
56
other types of therapy, and is the only surgical procedure that is
consistently effective as sole procedure for the disorder.
Polysomnography
following
upper
airway
surgery
is
recommended to determine its therapeutic efficacy, and long-term
follow-up is required.
Persons with obstructive sleep apnea may complain of significant
residual sleepiness despite positive airway pressure therapy. It
is important to assure optimal pressure and adherence as well as
to distinguish excessive sleepiness from fatigue. Other disorders
that can give rise to excessive sleepiness, such as insufficient
sleep, narcolepsy or mood disorder, should be properly identified
and managed. Use of sedating medications should be eliminated,
if possible, or reduced. Modafinil or armodafinil may be
considered as adjunct therapy for improving alertness and
wakefulness, but neither drug reverses the negative impact of
obstructive sleep apnea on cardiovascular morbidity, and should
not be used to replace positive airway pressure therapy for this
disorder.
Upper airway resistance syndrome is a condition characterized
by repetitive sleep-related episodes of decreased inspiratory
airflow due to increasing upper airway resistance, and
accompanied by increased or constant respiratory effort as well
as arousals from sleep, referred to as respiratory event related
arousals (RERAs). Both genders are affected equally. This
condition can give rise to sleep fragmentation, insomnia,
excessive sleepiness and fatigue. During polysomnography, these
respiratory events are not associated with oxygen desaturation,
and the apnea-hypopnea index is less than 5 per hour. Snoring
may be absent. Electroencephalographic arousals are seen
following decrement in airflow and increased respiratory effort,
and there may be an increase in wake time after sleep onset.
Diagnosis can be made using either esophageal or nasal
pressure monitoring. Esophageal pressure monitoring reveals
increasingly negative esophageal pressure excursions preceding
arousals, followed by less negative esophageal pressure swings
as airflow increases during arousals. Nasal pressure monitoring
may show an inspiratory flattening followed by a rounded contour
during arousals. Therapy of upper airway resistance syndrome
57
consists of positive airway pressure, oral devices or upper airway
surgery.
58
Central sleep apnea
Central sleep apnea is defined as repetitive cessation of airflow
during sleep due to reduction or loss of ventilatory effort. While
central sleep apnea can give rise to sleep fragmentation,
insomnia or excessive sleepiness, certain persons with this
disorder may remain asymptomatic.
Polysomnography is necessary for the diagnosis of central sleep
apnea, and demonstrates cessation of respiration and ventilatory
effort lasting at least 10 seconds. Five or more central apneas are
present
per
hour
of
sleep.
Respiratory
inductance
plethysmography or strain gauges demonstrate absence of chest
and abdominal movement; no respiratory muscle activity is seen
with diaphragmatic electromyography; no changes in pressure is
present with esophageal pressure monitoring; and a rounded
profile is noted on nasal pressure monitoring. Respiratory events
are most common during sleep onset and N1/N2 sleep. Snoring
may occur but is less prominent than in obstructive sleep apnea.
Classification of central sleep apnea is based on either level of
ventilation (hypercapnic or non-hypercapnic) or etiology
(idiopathic [primary] or secondary). Hypercapnic central apnea is
characterized by hypoventilation during sleep, and high sleep
PaCO2 levels due primarily to reduced ventilatory responsiveness
to hypercapnia; included in this category are central alveolar
hypoventilation, neuromuscular disorders and chronic use of longacting opioids. Non-hypercapnic central apnea is not associated
with daytime hypoventilation. There are normal or low waking
PaCO2 levels due to increased ventilatory response to hypercapnia. As PaCO2 levels increase during sleep, brief arousals
trigger a hyperventilatory “overshoot” that lowers PaCO2 below its
apneic threshold and gives rise to central apneas. Causes of nonhypercapnic central apnea are idiopathic central sleep apnea;
sleep-onset or post-arousal central sleep apnea; central sleep
apnea due to congestive heart failure; high altitude periodic
breathing; and complex sleep apnea. Secondary central sleep
apnea is more common than the primary form, and may result
from a number of cardiac, renal and neurological disorders, such
as congestive heart failure, renal failure, brainstem lesions, head
59
injury, neuromuscular disorders, stroke and autonomic
dysfunction; or from chronic use of long-acting opioids.
Primary central sleep apnea is a rare condition of unknown
etiology. Males are affected more commonly, and prevalence is
greater in middle-aged and older adults.
Cheyne Stokes respiration is characterized by periodic
breathing with recurring episodes of crescendo-decrescendo
ventilation separated by central apneas or hypopneas. Central
apneas are mainly post-hyperventilatory in nature, are present
during NREM sleep, and improve or resolve during REM sleep. It
generally affects older adults greater than 60 years of age. It may
be present in about of 25% to 40% of persons with congestive
heart failure, and in 10% of stroke patients. With heart failure, risk
factors of central sleep apnea include male gender, age greater
than 60 years, atrial fibrillation and hypocapnia. Pathophysiologic
mechanisms involve prolonged lung-to-chemoreceptor circulation
time (in some), with cycle lengths related inversely to cardiac
output and directly to circulation time; lower daytime and sleeprelated PaCO2 levels (less than 45 mmHg); and increased
hypercapnic respiratory drive.
High altitude periodic breathing consists of cycles of central
apnea and hyperpnea developing on ascent to high altitude,
usually greater than 4,000 to 7,600 meters. Risk factors include
greater hypoxic ventilatory drive, higher elevation, faster speed of
ascent and male gender. Periodic breathing occurs primarily
during NREM sleep, and respiration becomes more regular
during REM sleep. High altitude periodic breathing develops due
to hypoxia-induced hyperventilation that results in hypocapnic
alkalosis and central apneas. Ventilation, then, resumes when
PaCO2 rises above the apneic threshold, but hyperventilation and
ventilatory overshoot once again cause PaCO2 to fall below
apneic threshold and give rise to a central apnea. During
polysomnography, cyclic periods of central apneas and
hyperpneas are seen with cycle lengths of 12 to 34 seconds, and
frequency of greater than five central apneas per hour of sleep.
Central apnea lasts at least 10 seconds, and is associated with
oxygen desaturation.
60
Central sleep apnea due to medication use results from
depression of hypercapnic respiratory drive, giving rise to central
apneas, periodic respiration, Biot breathing or hypoventilation.
These respiratory patterns are related to chronic use of longacting opioids, such as methadone.
Central sleep apnea, Cheyne Stokes respiration and obstructive
sleep apnea can develop in persons with congestive heart
failure. Central sleep apnea is present in about 50% of persons
with heart failure, with the prevalence and severity of the former
correlated with left ventricular function. Mortality in person with
heart failure and Cheyne-Stokes respiration is higher than in
those without the latter condition.
Sleep-onset central apneas develop if PaCO2, which is higher
during sleep and lower during wakefulness, fluctuates above or
below the apnea threshold. Episodes of central apneas are
generally transient, and resolve as sleep progresses.
Nonetheless, repetitive sleep-onset central apneas can give rise
to sleep-initiation insomnia.
Central sleep apnea during positive airway pressure titration,
also referred to as complex sleep apnea, refers to the
development of central sleep apnea or Cheyne Stokes respiration
during acute application of continuous positive airway pressure in
persons with predominantly obstructive or mixed apneas during
the initial diagnostic study. Complex sleep apnea is estimated to
occur in 15% of persons with obstructive sleep apnea titrated with
continuous positive airway pressure, and is believed to be related
to high loop gain.
Therapy of central sleep apnea should be individualized and
begins with treatment of any underlying causes, such as
congestive heart failure. Avoidance of respiratory depressants,
including benzodiazepines and opioid narcotics, in hypercapnic
central sleep apnea is important. Oxygen therapy may benefit
some persons with non-hypercapnic central sleep apnea (e.g.,
Cheyne Stokes respiration), and is indicated for high-altitude
periodic breathing. However, oxygen administration may result in
worsening hypercapnia in persons with hypercapnic central sleep
apnea. Inhaled carbon dioxide or addition of dead space has been
61
described as therapy of non-hypercapnic central sleep apnea, but
their indications are not well established. Several pharmacologic
agents may be useful; these include acetazolamide for highaltitude periodic breathing; theophylline for central sleep apnea or
Cheyne Stokes respiration related to congestive heart failure; and
medroxyprogesterone for obesity-hypoventilation syndrome.
Persons presenting with sleep-onset central apneas may benefit
from a trial of hypnotic agents. Positive airway pressure therapy
may be considered for persons with central sleep apnea or
Cheyne Stokes respiration due to congestive heart failure; in this
population, it might improve cardiac function but may have no
benefit on mortality. Adaptive servoventilation is effective for
persistent complex sleep apnea. Finally, nocturnal non-invasive
ventilation may be required for persons with severe hypercapnic
central sleep apnea.
62
Hypoventilation syndromes
Sleep-related hypoventilation syndromes are characterized by
oxygen desaturation and elevated PaCO2 levels during sleep.
Waking arterial blood gas values may be normal or abnormal.
Several mechanisms may be responsible for sleep-related
increase in PaCO2 levels, namely diminished minute ventilation,
reduced
tidal
volume,
abnormal
ventilation-perfusion
relationships, or sleep-related reductions in ventilatory
chemosensitivity and respiratory load responsiveness.
Several medical and neurological disorders can cause alveolar
hypoventilation, including respiratory disorders, such as interstitial
lung disease, pulmonary hypertension, bronchiectasis, chronic
obstructive pulmonary disease or kyphoscoliosis; or neurological
disorders, such as amyotrophic lateral sclerosis, diaphragm
paralysis, muscular dystrophy, myasthenia gravis, myopathy, post
polio syndrome, spinal cord injury and brainstem stroke.
Idiopathic alveolar hypoventilation arises from diminished
chemoresponsiveness to carbon dioxide. Respiratory mechanics
are normal, and there are no respiratory, chest wall or
neuromuscular abnormalities. Sleep-related hypoventilation is
more pronounced during REM sleep. Men are affected more
frequently than women, and onset of the disease is commonly
during adolescence or early adulthood.
Congenital central alveolar hypoventilation syndrome refers
to failure of automatic control of breathing, resulting in hypoxemia
and hypercapnia. Hypoventilation is worse during sleep than
wakefulness, and is more severe during N3 sleep than REM
sleep. Responsiveness of central and peripheral chemoreceptors
to oxygen and carbon dioxide is reduced. It is a rare condition that
affects both genders equally. Onset of hypoventilation is usually
during infancy, when it may present as respiratory failure,
cyanosis, apparent life-threatening event or cor pulmonale.
Associated features include autonomic dysfunction, with reduced
heart rate variability; Hirschsprung's disease; neural crest tumors
(ganglioneuromas); ocular abnormalities, such as strabismus; and
swallowing dysfunction. Many cases involve de novo mutations of
63
the PHOX2B gene, and an autosomal dominant transmission with
incomplete penetrance.
During polysomnography, oxygen saturation during sleep is
below 90% for greater than 5 minutes with a nadir of at least 85%;
oxygen saturation is less than 90% for greater than 30% of total
sleep time; and PaCO2 is elevated, with the latter either greater
than 45 mmHg, or less than 45 mmHg but is abnormally
increased relative to waking levels.
Therapy of hypoventilation syndromes consists of specific
treatment of underlying disorder/s as well as ventilatory
assistance during sleep.
64
Parasomnias
Parasomnias are physical or experiential phenomena that occur
during the sleep period. They manifest as activation of skeletal
muscles or autonomic nervous system during sleep. Parasomnias
can occur at the sleep-wake transition, during NREM sleep, or
during REM sleep.
Disorders of arousal occur predominantly in N3 sleep, during the
first third of the sleep period, and consist of confusional arousals,
sleep terrors and sleepwalking. Disorders of arousal are generally
encountered in children, with onset usually from 4 to 6 years of
age. Most cases spontaneously resolve by adolescence. Risk
factors consist of sleep deprivation, obstructive sleep apnea and
periodic limb movement disorder. Therapy of disorders of arousal
includes instructions on sleep hygiene; and scheduled awakening,
which involves waking patients about 15 to 30 minutes before the
time when parasomnia typically occurs and then allowing them to
return to sleep.
Parasomnias occurring during REM sleep include nightmares,
REM sleep behavior disorder and isolated sleep paralysis. These
parasomnias tend to occur during the second half of the sleep
period when REM sleep becomes relatively more common.
Specific parasomnias include catathrenia, confusional arousals,
exploding head syndrome, isolated sleep paralysis, nightmare
disorder, REM sleep behavior disorder, sleep enuresis, sleeprelated eating disorder, sleep terrors and sleepwalking.
Catathrenia is characterized by intermittent expiratory groaning
or moaning during sleep, predominantly in REM sleep. Other
features of the disorder include hoarseness on waking and,
occasionally, mild daytime fatigue. There is no associated
respiratory distress, emotional anguish, abnormal motor activity,
oxygen desaturation or cardiac arrhythmias. Neurological and
upper airway examinations are generally normal. Catathrenia is a
rare disorder that predominantly affects males, and has a chronic
clinical course. Polysomnography demonstrates normal sleep
architecture.
65
Confusional arousals consist of episodes of confusion following
spontaneous or forced arousals from sleep. The main clinical
features of this disorder are disorientation; inappropriate behavior
that is occasionally violent; anterograde and retrograde amnesia;
inconsolability;
diminished
vigilance
and
cognitive
responsiveness; minimal or no signs of fear or autonomic
hyperactivity; and blunted responsiveness to questioning and
other external stimuli. Events can be precipitated by sleep
deprivation, which is the most important risk factor. Other risk
factors of confusional arousals include alcohol use, forced
awakenings, idiopathic hypersomnia, narcolepsy, obstructive
sleep apnea, periodic limb movement disorder, shift work, sleep
terrors and sleepwalking. Most episodes last from 5 to 15
minutes. There is a strong familial pattern. Both genders are
affected equally, and prevalence is greater among children and
adults younger than 35 years of age. Prevalence is approximately
16% in the 3 to 13 year age group, and about 4% in those older
than 15 years. Severity decreases with aging. There are two
clinical variants of this disorder, namely severe sleep inertia and
sleep sex. Polysomnographic features during episodes consist of
either brief delta activity, N1 sleep, microsleep periods, or diffuse
and poorly reactive alpha rhythm. Therapy may consist of
avoidance of sleep deprivation and trial of sleep extension;
scheduled awakenings; psychotherapy for cases associated with
marked psychological distress; and, rarely, off-label use of
benzodiazepines.
Persons with exploding head syndrome describe an awakening
with a loud sound or sensation of explosion in the head. This
syndrome may be a variant of sleep starts. Onset is usually in
adulthood, with women affected more commonly than men.
Exploding head syndrome is not associated with pain or
neurological complications, but, if frequent, can give rise to
insomnia.
Isolated sleep paralysis refers to the persistence of REM-sleep
muscle atonia during wakefulness. Respiration is unaffected,
consciousness is preserved, and there is generally full recall of
the event. Episodes can be accompanied by hallucinations in 25%
to 75% of affected persons. Onset is generally during
adolescence. Both genders are affected equally. Risk factors of
66
isolated sleep paralysis include sleep deprivation, irregular sleepwake schedules and supine sleep position. Other disorders may
be associated with sleep paralysis; these include narcolepsy as
well as a familial form of sleep paralysis.
Nightmare disorder is defined by unpleasant and frightening
dreams that often abruptly awaken the sleeper. Nightmares
typically occur during REM sleep in the second half of the
nocturnal sleep period; however, nightmares developing after
acute stress disorder or post-traumatic stress disorder may occur
during NREM sleep, particularly in N2 sleep. Main clinical features
of nightmares include full alertness and good recall of the
preceding dream on awakening; delayed return to sleep; and
minimal autonomic changes with no significant tachycardia or
tachypnea. Whereas both genders are affected equally during
childhood, women are affected more commonly among
adolescent and adult cases of nightmares. Onset of the disorder
is usually at 3 to 6 years, with a peak prevalence at 6 to 10 years.
Nightmares generally become less frequent during adulthood. In
contrast, post-traumatic nightmares can start at any age and can
persist throughout life. Nightmares can be precipitated by other
disorders, such as obstructive sleep apnea, narcolepsy or
psychiatric disorders; febrile illness; medications; trauma; and
alcohol ingestion. Medications that can cause nightmares include
amphetamines,
antidepressants,
antihypertensives
(beta
blockers), barbiturates and dopamine agonists. Withdrawal from
alcohol and REM sleep suppressants can also precipitate
nightmares. Frequent nightmares can lead to insomnia, excessive
sleepiness and anxiety. Polysomnographic features include
shortened REM sleep latency, increase in REM density, and
greater REM sleep. Therapy consists of reassurance; sleep
hygiene; behavioral therapy, such as image rehearsal;
psychotherapy; trial of REM sleep suppressants for severe cases;
and prazosin in post-traumatic stress disorder-related nightmares.
REM sleep behavior disorder (RBD) consists of abnormal
“dream enacting” behavior and complex motor activity during
REM sleep, associated with loss of REM-related muscle atonia or
hypotonia. Its key features include rapid awakening and full
alertness, and good dream recall. Activation of the autonomic
nervous system is infrequent. Episodes are more common during
67
the second half of the nocturnal sleep period. Several clinical
subtypes have been described, including (a) subclinical REM
sleep behavior disorder, which involves an increase in muscle
tone during REM sleep but without clinical features of the
disorder; (b) parasomnia overlap syndrome with the cooccurrence of REM sleep behavior disorder and disorders of
arousal; and (c) status dissociatus that consists of abnormal
dream-related behaviors, and admixture of waking, NREM and
REM sleep as well as the absence of identifiable sleep stages
during polysomnography. Predisposing factors for REM sleep
behavior disorder include aging, dementia with Lewy bodies, male
gender, medication use (e.g., tricyclic antidepressants, selective
serotonin reuptake inhibitors or monoamine oxidase inhibitors),
multiple system atrophy, Parkinson disease and stroke. REM
sleep behavior disorder has a prevalence of less than 1% in the
general population. Men are affected more commonly than
women, and the disorder is more prevalent in adults 50 years of
age or older. It has a chronic and progressive course, and can be
complicated by injuries to self or bed partner as well as sleep
fragmentation. There is typically no history of violent or aggressive
behavior during the day while awake. Evaluation should include
comprehensive neurological testing. Periodic reassessment is
recommended for delayed emergence of Parkinson disease or
other neurodegenerative disorders several years or decades after
the onset of REM sleep behavior disorder. Polysomnography
(with additional electromyographic monitoring of the upper
extremities [flexor digitorum] and time-synchronized video
recording) is indicated for diagnosis. Polysomnography generally
demonstrates a normal sleep architecture, although some
persons may have increases in N3 sleep and REM density. An
increase in muscle tone or phasic electromyographic activity
during REM sleep may be appreciated. Sleep onset latency is
typically normal during multiple sleep latency test. Therapy
consists of low-dose clonazepam at bedtime, which is effective in
about 90% of patients. Clonazepam decreases REM sleep
behavior disorder-related arousals and behaviors but does not
significantly alter the elevated electromyographic tone during
REM sleep. Melatonin may restore REM sleep-related muscle
atonia and can also be tried. Environmental precautions are
essential to assure the safety of the sleeper and bed partner.
68
Sleep enuresis is defined as recurrent involuntary voiding during
sleep that occurs at least twice a week after 5 years of age. It is
classified as primary, if a child has never been consistently dry
during sleep for six consecutive months; or secondary, if a child or
adult, who had previously been dry for 6 consecutive months,
begins bedwetting at least twice a week for a period of 3 months
or more. The prevalence of primary sleep enuresis is increased in
children with attention deficit hyperactivity disorder or in those
living in disorganized families, but decreases with aging, and is
about 30% at 4 years, 10% at 6 years, 5% at 10 years, and 1% at
15 years. The spontaneous cure rate of primary sleep enuresis is
estimated at 15% annually. Risk factors for secondary sleep
enuresis include congestive heart failure, chronic constipation,
dementia, depression, diabetes, obstructive sleep apnea,
seizures, stress, substance or medication use (alcohol, caffeine or
diuretics) and urinary tract infection or pathology. Structural
urinary tract pathology should be suspected when concurrent
daytime enuresis, abnormalities in the initiation of urination, or
abnormal urinary flow are present. Evaluation commonly consists
of a urinalysis and urine culture. Urologic evaluation is indicated
for suspected structural urinary tract disorders. Treatment of
enuresis includes bell and pad therapy, which is about 70%
effective; bladder training; or pharmacotherapy using
desmopressin or imipramine. Drug therapy may be particularly
helpful for acute control, such as during sleepovers.
Sleep-related eating disorder is characterized by repetitive
bouts of eating or drinking during arousals from sleep. Arousals
appear to be triggered by learned behavior rather than by real
hunger or thirst. These events are accompanied by lack of, or
partial, awareness of the abnormal behavior; total or partial
amnesia; and consumption of high-caloric foods or inappropriate
substances. Onset is often during early adulthood, and women
are affected more commonly than men. It has a chronic course,
and episodes often occur nightly and at any time during the sleep
period. Risk factors for sleep-related eating disorder include poor
sleep hygiene; primary sleep disorders, such as narcolepsy,
obstructive sleep apnea, periodic limb movement disorder and
sleepwalking; stress; mood disorder; and medications, such as
zolpidem. Consequences include weight gain, dyspepsia, sleep
fragmentation and excessive sleepiness. Polysomnography, if
69
performed, demonstrates arousals
occasionally, from REM sleep.
from
N3
sleep
and,
Sleep terrors, or pavor nocturnus, refers to abrupt awakenings
with profound fear and intense autonomic discharge, including
tachycardia, tachypnea, sweating and mydriasis. These
awakenings generally occur during N3 sleep, and often in the first
third of the night. Key features consist of vocalizations,
ambulation, confusion and amnesia. Onset is usually during
prepubertal childhood, and spontaneous resolution generally
occurs by adolescence. A related condition is parasomnia overlap
disorder, which is defined by the co-occurrence of sleep terrors or
sleepwalking, and REM sleep behavior disorder. Therapy consists
of avoidance of sleep deprivation and trial of sleep extension;
scheduled awakenings; low-dose benzodiazepines; and hypnosis.
Sleepwalking, or ambulation during the sleep period, can be
accompanied by confusion, amnesia for the episode,
inappropriate behavior, violent activity and diminished
arousability. The sleepwalker’s eyes are usually open, in contrast
to the closed eyes of REM sleep behavior disorder. Sleepwalking
most frequently occurs in stage N3 sleep, during the first half of
the night, but may occasionally emerge from stage N2 sleep.
Prevalence ranges from 17% in children to 4% in adults, with a
peak prevalence between 8 to 12 years of age. Prevalence of
childhood cases is strongly linked to family history, and is about
20% when neither parent is affected, 40% when one parent is
affected, and 60% when both parents are affected. In children,
sleepwalking, sleep talking and night terrors commonly co-exist.
Sleep deprivation is the most common precipitating factor for
sleepwalking; other factors include febrile states; acute stress;
obstructive sleep apnea; internal or external stimuli, such as a
distended bladder or noise; and medication or alcohol use.
Childhood cases generally resolve spontaneously by puberty.
Treatment consists of anticipatory scheduled awakenings or
hypnosis. Medications, such as benzodiazepinesmay be tried
when cases are frequent or associated with injuries.
70
Restless legs syndrome and Periodic limb
movement disorder
Restless legs syndrome (RLS) is a neurological disorder
characterized by an urge to move, or unpleasant sensations,
involving the legs, and less commonly the arms, that begin or
worsen during periods of rest or inactivity; are relieved transiently
by movement; and are worse, or occur only, at night. Among
children, between 2 and 12 years of age, diagnosis of RLS
requires either (a) presence of all adult criteria and description of
leg discomfort in the child’s own words; or (b) presence of all adult
criteria and at least two of the following factors, namely sleep
disturbance, restless legs syndrome in a parent or sibling, or a
periodic limb movement index of five or more per hour.
Restless legs syndrome has a prevalence of 3% to 15% in the
general population, with an increased likelihood among persons
with anemia or uremia, during pregnancy, or with aging.
Prevalence is also higher among Caucasians compared to
Asians, and among women compared to men. This disorder is
most commonly seen in middle-aged and older adults.
Onset of restless legs syndrome can occur at any age, and its
clinical course tends to be chronic. It is estimated that 70% to
90% of persons with restless legs syndrome have periodic limb
movements during sleep (PLMS), and one-third of persons with
PLMS have restless legs syndrome.
Restless legs syndrome can be classified as either primary or
secondary. Primary (idiopathic) RLS may be related to
abnormalities in dopaminergic systems, and consist of two
subtypes, namely early onset, characterized by the start of
symptoms before 35 to 45 years of age, more gradual progression
of symptoms, and more frequent family history of restless legs
syndrome; and late onset.
Risk factors for restless legs syndrome include iron deficiency
anemia; uremia; pregnancy; peripheral neuropathy; attention
deficit hyperactivity disorder; Parkinson disease; diabetes
mellitus; rheumatoid arthritis; alcohol or caffeine ingestion;
71
smoking; gastric surgery; and medications, such as selective
serotonin
reuptake
inhibitors,
tricyclic
antidepressants,
monoamine oxidase inhibitors, antihistamines, neuroleptics,
lithium and dopamine antagonists.
Restless legs syndrome is associated with several important
consequences. These include sleep-onset and sleepmaintenance insomnia; bedtime resistance and problematic night
wakings in children; and excessive sleepiness due to sleep
fragmentation.
Evaluation of persons suspected of having restless legs
syndrome consists of a thorough clinical history, physical and
neurological examination, and laboratory evaluation including
complete blood count, serum iron, ferritin, folate, electrolytes,
thyroid function tests, fasting glucose and renal panel.
Suggested immobilization test may be considered for equivocal
or ambiguous cases. In this test, polysomnography is performed
for 1 hour prior to habitual evening bedtime with the patient
awake, sitted upright in bed, and with legs outstretched. Periodic
limb movements during waking (PLMW) of greater than 40 events
per hour supports the diagnosis of restless legs syndrome.
Polysomnography is not routinely indicated; if performed for
other reasons, it may demonstrate prolonged sleep onset latency,
reduced sleep efficiency, diminished total sleep time, and
increased wake time after sleep onset. In addition, periodic limb
movements during waking prior to sleep onset, or periodic limb
movements during sleep may be noted.
Differential diagnosis of restless legs syndrome includes
akathisia related to the use of neuroleptic agents or dopamine
receptor antagonists, and peripheral neuropathy.
Pathophysiology involves (a) dysregulation of the dopaminergic
system, with reduced dopamine receptor binding, presynaptic
dopaminergic hypofunction, and decreased tyrosine hydroxylase
in the substantia nigra; and (b) abnormal iron metabolism.
Reduced brain iron in the putamen, red nucleus and substantia
nigra has been described, as hav decreased levels of ferritin and
72
increased transferin in the cerebrospinal fluid. Low levels of serum
ferritin are associated with impaired iron uptake and transport
across the blood-brain barrier. Ferritin is a necessary cofactor for
tyrosine hydroxylation, a rate-limiting step in dopamine synthesis.
Therapy of restless legs syndrome consists of (a) treatment of
underlying
causes
or
precipitating
factors;
(b)
iron
supplementation if serum ferritin is less than 50 μg/L; (c)
dopaminergic agents, including levodopa, pramipexole and
ropinirole; (d) benzodiazepines, such as clonazepam; (e) opioid
agents, including oxycodone and propoxyphene; and (f)
anticonvulsant agents.
Dopaminergic agents reduce restless legs symptoms, decrease
the frequency of periodic limb movements during sleep, and
improve sleep quality. Its use, however, can be associated with
several adverse effects, such as augmentation (earlier onset or
increased severity of symptoms, or involvement of other body
parts such as the arms, and is more likely with levodopa than
pramipexole or ropinirole); and rebound (recurrence of symptoms
later in the night or early morning, and, again, is more likely with
levodopa). Nausea, sleepiness, orthostasis and development of
compulsive disorder have been described for both pramipexole
and ropinirole. Pergolide use has been associated with the
development of pleuropulmonary and cardiac valve fibrosis.
Benzodiazepines, such as clonazepam, reduce both restless
legs symptoms and periodic limb movement during sleep-related
arousals, and improve sleep quality, but do not reduce frequency
of periodic limb movements during sleep. Opioid agents,
including oxycodone and propoxyphene, also reduce restless legs
symptoms and periodic limb movements during sleep, and may
be considered for persons with severe symptoms refractory to
other therapy. Finally, anticonvulsant agents, such as
carbamazepine and neurontin, may be tried for restless legs
syndrome; neurontin may be particularly useful for cases of
restless legs syndrome that are accompanied by pain.
Periodic limb movements during sleep consist of recurrent leg
movements that commonly presents as partial flexion of the ankle,
knee and hip, and extension of the big toe. Involvement of the
73
upper extremity consists of flexion at the elbow. Periodic limb
movements can also occur while sitting or lying during restful
wakefulness, referred to as periodic limb movements during
wakefulness (PLMW). Periodic limb movements during sleep
have a prevalence of about 5% in the general population, and are
more common among middle-aged and older adults. Both
genders are affected equally. Periodic limb movements during
sleep share many of the risk factors of restless legs syndrome; in
addition to restless legs syndrome, disorders that are associated
with periodic limb movements during sleep include narcolepsy,
REM sleep behavior disorder, obstructive sleep apnea and spinal
cord injury. Polysomnography is required for diagnosing periodic
limb
movements
during
sleep,
and
demonstrates
electromyographic activation of the anterior tibialis muscles, with a
duration of 0.5 to 5 seconds, occurring in a series of at least four
consecutive contractions, with an interval between movements of
5 to 90 seconds from the onset of one limb movement to the
onset of the next, and having an electromyographic amplitude of
at least 25% greater than baseline levels noted during
biocalibration. Muscle contractions occurring simultaneously in
both legs are counted as one movement, and leg movements
occurring during arousals due to sleep-related breathing disorder
are not counted. The periodic limb movement index (PLMI) is the
total number of periodic limb movements during sleep per hour of
total sleep time; it is considered abnormal if greater than five per
hour in children, or over fifteen events per hour in adults.
Periodic limb movement disorder is defined by symptomatic
periodic limb movements during sleep and accompanied by
complaints of sleep disturbance or excessive sleepiness. The
periodic limb movement index, unfortunately, does not correlate
well with degree of sleep disturbance or excessive sleepiness.
Therapy of periodic limb movement disorder is similar to that of
restless legs syndrome. Specific therapy is not indicated for
asymptomatic periodic limb movements during sleep.
74
Circadian rhythm sleep disorders
Circadian rhythm sleep disorders are caused by recurrent or
persistent misalignment between the desired sleep schedule and
the circadian sleep-wake rhythm, and can be associated with
insomnia, excessive sleepiness, or both. Six different circadian
rhythm sleep disorders have been described, namely (a)
advanced sleep phase syndrome; (b) delayed sleep phase
syndrome; (c) free running circadian rhythm syndrome; (d)
irregular sleep-wake rhythm syndrome; (e) jet lag; and (f) shift
work sleep disorder.
Advanced sleep phase syndrome is characterized by an early
bedtime, commonly from 6 to 9 pm, and an equally early wake
time from 2 to 5 am, associated with an inability to delay sleep
time. Sleep, itself, is normal for age. Persons with this syndrome
present with excessive sleepiness in the late afternoon or early
evening, or may complain of morning awakenings that are earlier
than desired. Onset of advanced sleep phase syndrome is
commonly during middle age. It is estimated to affect 1% of
middle-aged and older adults. Both genders are affected equally.
Diagnosis requires sleep logs or actigraphy performed over
several days. Depression, which may also present with early
morning awakenings, should be excluded. Polysomnography is
normal if performed during the preferred advanced sleep time, but
demonstrates shortened sleep onset latency, decreased total
sleep time and reduced REM sleep latency if performed during a
conventional later sleep time. Therapy consists of early evening
bright light therapy. Chronotherapy, or gradually shifting the usual
sleep time until the desired bedtime is achieved, may be tried.
Delayed sleep phase syndrome involves a chronic inability to
fall asleep until the early morning hours, often from 1 to 6 am, and
difficulty arising until late morning or early afternoon, typically after
10 am to 2 pm. In short, the major nocturnal sleep period occurs
habitually later than the desired or socially acceptable bedtime.
There is no difficulty remaining asleep following the onset of
sleep. Occasionally, marked difficulty with awakening in the
morning may be associated with confusion (sleep inertia). This
disorder is due to a phase delay of the circadian sleep-wake
75
rhythm coupled with an inability to phase advance in order to
correct the disturbance. Onset is often during adolescence.
Prevalence is estimated at 0.1% to 0.2% of the general
population. It is more commonly encountered among adolescents
and young adults with a prevalence of 2% to 15% in this age
group, and among men. Course is chronic, but severity of
symptoms may diminish with increasing age. Diagnosis is made
by history and sleep diaries. Actigraphic monitoring for 7 days or
longer reveals a stable delay of the habitual sleep period.
Polysomnography is not routinely indicated for diagnosis; it
generally demonstrates prolonged sleep onset latency and
decreased total sleep time when performed during desired
conventional sleep-wake times; or a normal sleep architecture
when performed during the habitually delayed sleep period. Bright
light therapy (timed early morning light exposure) is effective in
advancing the nocturnal sleep period. Light exposure should be
administered after minimum core body temperature, which is often
about 1 to 2 hours after the habitual mid-sleep time. Light therapy
should be complemented by appropriate light restriction at the
start of the sleep period. Retinopathy is a contraindication to light
therapy. Chronotherapy, either progressive phase delay or
progressive phase advancement of the major sleep episode until
the desired bedtime is reached, may be tried. Melatonin
administered in the early evening may also be considered, but the
phase shifting effect of melatonin is less potent than bright light
therapy.
Free-running circadian rhythm syndrome, or non-entrained,
non-24-hour sleep-wake rhythm, consists of a progressive daily
delay in sleep-onset and wake times that result in periodically
recurring problems of insomnia or excessive sleepiness. The
major sleep period progressively “marches” throughout the day,
afternoon and evening. Free-running circadian rhythm syndrome
arises from an abnormal synchronization between the
endogenous sleep-wake circadian rhythm and the 24-hour
environmental light-dark cycle. Freed of exogenous entraining
influences such as light, the sleep-wake pattern relies solely on
free-running intrinsic biologic rhythms that behave with a
periodicity of slightly over 24 hours. It is rare in the general
population, and most affected persons are totally blind and lack
photic entrainment. Among blind persons, 70% complain of
76
chronically disturbed sleep, and 40% have recurring and cyclical
insomnia. However, sleep is normal in some blind persons due to
a functional retinohypothalamic pathway with melatonin
suppression from light exposure, or to entrainment by non-photic
cues. Free-running circadian rhythm syndrome may also affect
sighted persons with dementia, mental retardation or psychiatric
disorders. Onset can occur at any age, and clinical course tends
to be chronic. Diagnosis is made by history as well as sleep
diaries or actigraphy performed over several days.
Polysomnography is not routinely indicated for diagnosis; if
performed, it may demonstrate normal sleep efficiency; and either
(a) progressively longer sleep onset latency and shorter total
sleep time when recorded at a fixed period over several days, or
(b) normal sleep duration if patients are allowed to sleep ad
libitum. Therapy consists of evening administration of melatonin.
Bright light therapy may be tried for sighted persons or blind
persons with light perception. It is important to establish regular
sleep-wake and daytime activity schedules.
No stable circadian sleep-wake rhythm is seen in irregular sleepwake rhythm syndrome. Sleep-wake periods are variable,
inconsistent from one day to another, and consist of multiple sleep
and nap periods throughout the day and night. Nonetheless,
aggregate sleep time over a 24-hour period is normal. Persons
with this condition may present with insomnia or excessive
sleepiness. Irregular sleep-wake rhythm syndrome is a rare
disorder, and is most frequently seen in association with
neurological disorders, such as dementia or mental retardation.
Clinical course tends to be chronic. Clinical history, sleep diaries
and, occasionally, actigraphy, are required for an accurate
diagnosis. Therapy consists of proper sleep hygiene and evening
administration of melatonin.
In jet lag, transient insomnia or excessive sleepiness develops
following rapid eastward or westward air travel across multiple
time zones due to a lack of synchrony to the new local time zone.
Eastward flights can be associated with sleep-onset insomnia and
difficulty awakening the next day, whereas westward flights can
give rise to early evening sleepiness and early morning
awakenings. Symptoms of jet lag are generally worse following
eastward travel; with greater amounts and rates of time zone
77
transitions; and with increasing age of the traveler. Jet lag has a
self-limited course, and symptoms remit spontaneously within
approximately a day for every time zone change.
Polysomnographic features of jet lag include diminished sleep
efficiency and increase in wake time after sleep onset. Prolonged
sleep onset latency may occur with eastbound travel. Therapy of
jet lag consists of phototherapy, with timed bright light exposure
accompanied by appropriate light restriction depending on the
direction of travel as well as the number of time zone changes.
Short-acting hypnotic agents or melatonin at bedtime may be
helpful for insomnia arising from jet lag.
Shift work sleep disorder is characterized by sleep disturbance
that is directly related to non-standard work schedules, and is due
to a disparity between the timing of work and the requirement for
sleep. About 20% of the workforce in industrialized countries is
involved in some form of non-standard work schedule, such as
rotating shifts or permanent nighttime work schedules. An
estimated 10% of shift workers develop shift work sleep disorder.
Shift workers may complain of sleepiness and decreased
alertness during night shifts, insomnia during daytime sleep
periods, and non-restorative sleep. Several factors increase the
risk of developing shift work sleep disorder; these include aging,
female gender, “morningness” circadian rhythm preference, and
backward or counterclockwise shift rotation schedules. The
consequences of shift work sleep disorder include greater workrelated accidents as well as diminished quality of life. Evaluation
of shift work sleep disorder includes sleep diaries recorded over
several days. Actigraphy may aid diagnosis. Polysomnography is
not routinely indicated. Therapy involves measures that increase
nighttime alertness, including appropriately timed bright light
exposure in the workplace; napping before, or during, night work;
and administration of psychostimulants, such as caffeine,
modafinil or armodafinil, during evening work hours.
Enhancement of daytime sleep with the use of hypnotics,
including melatonin, prior to post-shift daytime sleep; and
restricted daytime light exposure, such as using dark sunglasses,
during the morning trip home from work, may also help.
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Medical disorders
Asthma is characterized by episodic dyspnea, wheezing or
coughing due to reversible bronchoconstriction and airway
hyperreactivity to specific and nonspecific stimuli. Possible
mechanisms responsible for nocturnal bronchoconstriction include
circadian variability in airflow (lowest in the early morning) and
sleep-related changes in autonomic nervous system activity
(greater parasympathetic tone and decrease in sympathetic
activity), lung capacity and inflammatory mediators. Episodes may
be precipitated or aggravated by gastroesophageal reflux. Sleeprelated complaints associated with nocturnal asthma include
insomnia, sleep fragmentation, excessive sleepiness and
nocturnal hypoxemia. The diagnosis of nocturnal asthma is
supported by reductions in evening peak expiratory flow rates or
FEV1 compared to daytime values. Polysomnography may
demonstrate prolonged sleep onset latency, diminished sleep
efficiency, increase in wake time after sleep onset, and decreased
total sleep time. Therapy consists of inhaled corticosteroids and
long-acting bronchodilators. Short-acting beta-agonists may be
necessary for acute control of asthma symptoms. Lastly, positive
airway pressure therapy for patients with concurrent asthma and
obstructive sleep apnea may improve symptoms.
Chronic obstructive pulmonary disease includes emphysema
and chronic bronchitis, both of which are characterized by
progressive, not fully reversible, airflow limitation. Sleep
disturbance is common especially in advanced disease, and
consists of repetitive awakenings, insomnia, non-restorative sleep
or excessive sleepiness. Factors responsible for sleep
disturbance are nocturnal coughing or dyspnea, hypoxemia and
hypercapnia, and use of medications, such as methylxanthines
and beta-adrenergic agonists. Nocturnal oxygen desaturation may
develop in moderate to severe disease; episodes of oxygen
desaturation are more frequent, of greater duration, and more
severe during REM sleep compared to NREM sleep. The
occurrence and severity of oxygen desaturation during sleep are
influenced by baseline lung function as well as wake PaO2 and
PaCO2 levels. Significant nocturnal oxygen desaturation is more
likely with lower PaO2 or oxygen saturation, and higher PaCO2
79
levels during waking. Mechanisms responsible for sleep-related
oxygen desaturation include hypoventilation (most important),
ventilation-perfusion mismatching and decrease in lung volumes.
Sleep-related hypoxemic episodes appear to be more common
among persons with chronic bronchitis than in those with
emphysema. Polysomnographic features of chronic obstructive
pulmonary disease include prolonged sleep onset latency,
diminished sleep efficiency, increase in wake time after sleep
onset, and decreased total sleep time. “Overlap syndrome” refers
to the presence of both chronic obstructive pulmonary disease
and obstructive sleep apnea. Compared to isolated chronic
obstructive pulmonary disease, overlap syndrome is associated
with lower PaO2, higher PaCO2, and higher mean pulmonary
artery pressures. Therapy of chronic obstructive pulmonary
disease consists of long-acting beta-agonists or long-acting
anticholinergic agents. Oxygen therapy may be considered for
significant nocturnal oxygen desaturation, although it is uncertain
whether treating nocturnal oxygen desaturation alone, in the
absence of daytime hypoxemia, improves survival. Positive airway
pressure therapy is indicated for overlap syndrome.
Several cardiac arrhythmias are more frequent during sleep.
Although the prevalence of premature ventricular contractions is
decreased during sleep due, in part, to greater parasympathetic
tone, it may increase during arousals from sleep. In obstructive
sleep apnea, heart rate slows at the onset of the apneic episode
and increases after the termination of the event.
Chronic pain syndromes are commonly accompanied by
significant sleep fragmentation, which, in turn, leads to excessive
sleepiness and fatigue. Polysomnography may demonstrate
prolonged sleep onset latency, diminished sleep efficiency,
increase in wake time after sleep onset, and decreased total sleep
time.
Congestive heart failure is associated with greater risk of
obstructive sleep apnea, central sleep apnea and Cheyne Stokes
respiration. Cheyne Stokes respiration occurs predominantly
during N1 and N2 sleep. The presence of concurrent obstructive
sleep apnea may contribute to worsening left ventricular
dysfunction.
80
The risk of coronary artery disease is increased in middle-aged
persons with obstructive sleep apnea. Possible mechanisms for
this
increased
likelihood
are
endothelial
dysfunction,
hypercoagulability, insulin resistance, greater pro-inflammatory
cytokines and adhesion molecules, oxidative stress, and
enhanced sympathetic activity during sleep.
Persons with diaphragm paralysis may develop nocturnal
hypoxemia, which is worse during REM sleep, and sleep-related
breathing disorders.
Sleep disturbance can develop in about 60% to 80% of patients
with end-stage renal disease. Common complaints include
excessive sleepiness or insomnia; reversal of day-night sleep
patterns may also develop. This disorder is associated with a
relatively higher prevalence of obstructive sleep apnea, restless
legs syndrome and periodic limb movement disorder.
Polysomnographic features of end-stage renal disease include
prolonged sleep onset latency, diminished sleep efficiency,
increase in wake time after sleep onset, and decreased total sleep
time. Both N3 and REM sleep may be reduced.
Fibromyalgia is associated with multiple tender areas throughout
the body as well as fatigue. Persons with fibromyalgia may
complain of nonrestorative sleep. Polysomnographic features
include diminished sleep efficiency and reduced N3 sleep. AlphaNREM electroencephalographic sleep (i.e., intrusion of alpha
waves into NREM sleep) may or may not be present in
fibromyalgia; it can also be seen in primary sleep disorders
(obstructive sleep apnea, narcolepsy, periodic limb movement
disorder and psychophysiologic insomnia), chronic pain
syndromes, and, occasionally, in normal persons. Severity of
daytime symptoms may decrease with improved sleep quality.
Gastroesophageal reflux refers to the backflow of gastric acid
and other gastric contents into the esophagus due to incompetent
barriers at the gastroesophageal junction (i.e., transient relaxation
of the lower esophageal sphincter and, to a lesser extent, upper
esophageal sphincter). Episodes occur more frequently during
wake compared to sleep, when gastroesophageal reflux develops
during brief arousals. Sleep-related gastroesophageal reflux is
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associated with longer acid contact time due to delayed
esophageal acid clearance and decreased production of
neutralizing saliva during sleep. Person with sleep-related
gastroesophageal reflux may experience sleep fragmentation,
insomnia, excessive sleepiness, nocturnal heartburn, dyspnea,
coughing, choking, retrosternal chest pain, or a bitter or sour
taste. The prevalence of nighttime symptoms in patients with
gastroesophageal reflux is about 80%; prevalence rate increases
with aging and, perhaps, obstructive sleep apnea. Complications
include morning hoarseness, esophagitis, esophageal strictures,
Barrett esophagus, chronic cough, asthma exacerbation,
pharyngitis, laryngitis, bronchitis, pneumonia and pulmonary
fibrosis. Diagnosis requires continuous esophageal pH testing
during polysomnography, which demonstrates repetitive arousals
accompanying episodic reductions in distal esophageal pH
followed by swallowing. Esophageal manometry may be abnormal
with decreased lower esophageal sphincter pressure, more
frequent transient lower esophageal sphincter relaxations, and
diminished amplitude of peristalsis. Treatment of sleep-related
gastroesophageal reflux consists of elevation of the head of the
bed; histamine-2 antagonists or proton pump inhibitors; or antireflux surgery. Positive airway pressure therapy may decrease the
frequency of nocturnal gastroesophageal reflux in patients with
obstructive sleep apnea.
About a third of persons with human immunodeficiency virus
(HIV) infection develop sleep disturbance, and complain of either
insomnia, sleep fragmentation or excessive sleepiness.
Polysomnographic features of the disorder include shortened
sleep onset latency, diminished sleep efficiency, and increase in
wake time after sleep onset. Antiviral therapy can, itself, disturb
sleep. Efavirenz use is associated with insomnia, frequent
awakenings and vivid dreams.
Obstructive sleep apnea is a risk factor for hypertension
independent of other known confounding factors. There may be
loss of the nocturnal fall in blood pressure (“dipping”
phenomenon) in obstructive sleep apnea. Positive airway
pressure therapy in persons with co-existing obstructive sleep
apnea and hypertension may improve blood pressure control.
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Restrictive pulmonary diseases are characterized by reduced
lung volumes due to disorders involving the lung parenchyma,
pleura or chest wall, and include kyphoscoliosis, interstitial lung
disease and severe obesity. Sleep disturbance, frequent
awakenings, non-restorative sleep and excessive sleepiness are
common complaints. Nocturnal oxygen desaturation can be either
transient or sustained, and is worse during REM sleep compared
to NREM sleep.
Sleeping sickness, or Human African trypanosomiasis, is caused
by Trypanosoma brucei or T. rhodesiense, which are transmitted
by the bite of an infected tsetse fly. It is endemic in certain regions
of intertropical Africa. There are two main stages of human
disease, namely an initial hemolymphatic stage, characterized by
fever, cervical adenopathy and cardiac arrhythmias, and a
terminal meningo-encephalitic stage, with the development of
excessive sleepiness, sensory deficits and abnormal reflexes. The
infection culminates in altered consciousness, cachexia, coma
and eventually death, if untreated. Infected persons may present
with complaints of excessive sleepiness, insomnia (not
uncommon)
and
reversal
of
sleep-wake
periods.
Polysomnographic features consist of few vertex sharp waves,
sleep spindles and K complexes; and reduced REM sleep latency.
Diagnosis is established by demonstrating the pathogen in the
blood, bone marrow, lymph node aspirates or cerebrospinal fluid.
Therapy consists of anti-parasitic medications.
83
Neurological disorders
Alzheimer’s dementia is characterized by significant, and often
progressive, neurocognitive impairment. Sleep-related complaints
include insomnia and excessive sleepiness. The risk of
obstructive sleep apnea may be increased in the presence of the
apolipoprotein ε4 (APOE4) allele. Reversal of day-night circadian
rhythmicity, and nocturnal confusion and wandering, referred to as
"sun downing" may pose significant management challenges.
Lastly, persons who have dementia with Lewy bodies have a
greater risk of developing REM sleep behavior disorder.
Amyotrophic lateral sclerosis is associated with several sleeprelated conditions, including excessive sleepiness, insomnia and
sleep-related breathing disorders, such as obstructive sleep
apnea and central sleep apnea. Obstructive sleep apnea in
persons with amyotrophic lateral sclerosis is seen predominantly
during REM sleep. Nocturnal oxygen desaturation may occur due
to hypoventilation and diaphragmatic dysfunction. Noninvasive
positive pressure ventilation should be considered for patients
with muscle dysfunction or sleep-related breathing disorders.
In attention deficit hyperactivity disorder, some symptoms of
inattention and hyperactivity are present prior to 7 years of age,
leading to impairments at home, school or work. Persons with this
condition may present with variable sleep-wake schedules, sleeponset insomnia, bedtime resistance, problematic night waking,
sleep fragmentation and excessive sleepiness. There may also be
an increased prevalence of sleep-related breathing disorders and
periodic limb movement disorder. Finally, sleep deprivation may
exacerbate symptoms of inattention and hyperactivity.
Blindness can give rise to disturbed sleep, and blind persons
may complain of insomnia, problematic night wakings and
excessive sleepiness. The prevalence of circadian rhythm sleep
disorders, particularly free-running circadian rhythm syndrome, is
increased in blind persons with no light perception.
Persons with cerebral degenerative disorders, such as
Huntington disease, musculorum deformans, olivopontocerebellar
84
and spinocerebellar degeneration and spastic torticollis, have
abnormalities in cognition, behavior or movement. Muscle
contractions may develop during sleep and are most prominent in
N1 and N2 sleep. Persons with olivopontocerebellar degeneration
may present with central sleep apnea, nocturnal stridor,
obstructive sleep apnea or REM sleep behavior disorder.
Risk of obstructive sleep apnea is increased in Down syndrome.
Certain headache syndromes occur during both sleep and
waking, including migraine, cluster headache and chronic
paroxysmal hemicrania, whereas others occur only during sleep,
such as hypnic headaches. Polysomnographic features of
headache syndromes generally consist of prolonged sleep onset
latency, diminished sleep efficiency, increase in wake time after
sleep onset, and reduced total sleep time. Migraine headaches
are episodic headaches, often unilateral, which are associated
with nausea, vomiting, photophobia or phonophobia. An aura
consisting of scintillating scotomas and homonymous visual field
defects precedes a “classic migraine”, but is absent in “common
migraine”. Cluster headaches consist of excruciating, unilateral
(periorbital or temporal) headaches that occur in “clusters”. During
cluster periods, one to three headache attacks can occur daily,
often at the same hour each day. Each individual attack lasts for
about a few hours. Cluster headaches may be accompanied by
lacrimation, conjunctival injection, rhinorrhea or nasal stuffiness,
miosis, ptosis and increased ipsilateral forehead sweating. These
headaches may be triggered by obstructive sleep apnea. Chronic
paroxysmal hemicranias are severe unilateral headaches (e.g.,
temporal, orbital or supraorbital) that are responsive to therapy
with indomethacin. Hypnic headaches are generalized or
unilateral headaches that occur during sleep and may be
accompanied by nausea. Migraines, cluster headaches and
chronic paroxysmal hemicrania commonly have their onset during
sleep. Migraine headaches can occur during N3 or REM sleep.
Cluster headaches and chronic paroxysmal hemicrania tend to
occur during REM sleep. Hypnic headaches occur only during
sleep, most commonly during REM sleep and, less commonly,
during N3 sleep. Persons with obstructive sleep apnea may
present with transient early morning headaches that occur upon
awakening.
85
In multiple system atrophy, sudden death may occur during
sleep due to vocal cord abductor paralysis; this syndrome
presents as nocturnal stridor, and is associated with a worse
outcome. Laryngoscopy during sleep aids in diagnosis.
Management, in many cases, consists of tracheotomy. Other
sleep-related conditions associated with multiple system atrophy
are REM sleep behavior disorder and sleep-related breathing
disorders. Persons with Shy-Drager syndrome can develop sleeprelated breathing disorders (obstructive sleep apnea, central sleep
apnea, Cheyne Stokes respiration, apneustic breathing and
inspiratory gasping), nocturnal hypoxemia, insomnia and REM
sleep behavior disorder.
The clinical course of neuromuscular disorders can be
complicated by the development of nocturnal hypoventilation,
which is most pronounced during REM sleep, and can precede
abnormalities occurring during waking by months to years. The
risk of sleep-related oxygen desaturation is greater if maximal
inspiratory pressure is less than 60 cmH2O, and forced vital
capacity is less than 50% of predicted. Persons with
neuromuscular disorders may also report insomnia, nocturnal
dyspnea or excessive sleepiness. Risk of obstructive sleep apnea
is increased.
Parkinson disease is characterized by the clinical triad of muscle
rigidity, hypokinesia and resting tremors. This disorder may be
associated with several sleep-related complaints, such as sleepmaintenance insomnia, sleep fragmentation and excessive
sleepiness. Sleep attacks occur in about 5% of affected persons.
Parasomnias, including REM sleep behavior disorder, nightmares,
hallucinations, restless legs syndrome and periodic limb
movements may also develop as may sleep-related breathing
disorders, such as central sleep apnea, obstructive sleep apnea
and hypoventilation. Finally, persons with Parkinson disease may
present with reversal of circadian day-night rhythms or “sun
downing”. Many mechanisms are responsible for the sleep
disturbance seen in this disorder; these include (a) nocturnal
motor symptoms, such as akinesia, dyskinesia, myoclonus and
tremors; (b) rigidity and inability to turn over in bed; (c) nocturia;
(d) painful leg cramps; (e) dementia and/or depression; and (f)
use of dopaminergic medications. Excessive sleepiness and sleep
86
attacks can develop during therapy with dopaminergic agents,
such as pramipexole or ropinirole. Polysomnographic features of
Parkinson disease include prolonged sleep onset latency,
diminished sleep efficiency, reduced total sleep time, increased
wake time after sleep onset, and decreased REM sleep.
Seizure disorders consist of abnormal and stereotypic events
arising from abnormal cortical neuronal discharges. Sleep can
precipitate seizure activity, and sleep deprivation can increase
interictal discharges. About 20% to 30% of persons have seizures
only during sleep, and 75% have seizures during both waking and
sleep. There are two peaks in the timing of nocturnal seizures,
namely two hours after bedtime; and from 4 to 5 am. Sleeprelated seizures are most frequent during N1 and N2 sleep and
less frequent during REM sleep. Certain clinical features should
raise one’s suspicion of sleep-related seizures; these are a history
of daytime seizures; abnormal stereotypical motor activity (e.g.,
tonic clonic or focal movements, automatisms or tongue biting);
unexplained abrupt awakenings; and urinary incontinence,
especially if recent in onset. Sleep-related seizures may be
precipitated by irregular sleep schedules, obstructive sleep apnea
or sleep deprivation. Seizures that occur predominantly or
exclusively during sleep include benign epilepsy of childhood with
centrotemporal spikes; continuous spike waves during NREM
sleep; generalized tonic-clonic seizures on awakening; juvenile
myoclonic epilepsy; autosomal dominant nocturnal frontal lobe
epilepsy; and tonic seizures. Diagnosis requires an expanded
electroencephalographic montage. Video-polysomnography may
aid diagnosis.
Benign epilepsy of childhood with centrotemporal spikes is also
known as benign rolandic epilepsy, and is the most common form
of partial seizure in children. It presents as hemifacial perioral
numbness and focal clonic twitching of the face and mouth.
Consciousness is preserved. Secondarily generalized tonic-clonic
seizures may develop. Its onset is often during childhood. Clinical
course is benign with spontaneous resolution in adulthood.
Electroencephalography demonstrates centrotemporal spike and
sharp waves. Continuous spike waves during NREM sleep,
formerly referred to as electrical status epilepticus of sleep, is
seen primarily in children. Although it may present without any
87
visible movements or clinical complaints, this condition can be
associated with neurocognitive and motor impairment. Continuous
and diffuse slow spike-wave complexes occurring throughout
NREM sleep are seen during electroencephalography; these
discharges decrease during REM sleep and disappear with
awakening. Generalized tonic-clonic seizures on awakening have
their onset typically in the second decade of life, and have a
favorable response to therapy. Juvenile myoclonic epilepsy
consists of three seizure types, namely myoclonic jerks,
generalized tonic-clonic seizures, and absence seizures. Bilateral
massive myoclonic jerks affecting the limbs can develop on
awakening, and generalized tonic-clonic seizures can occur
during sleep or on awakening. This disorder has its onset during
adolescence. Electroencephalography demonstrates symmetric
and synchronous 4 to 6 Hz polyspike and wave discharges.
Nocturnal frontal lobe epilepsy is defined by dystonic-dyskinetic,
choreoathetoid or ballistic posturing, and semi-purposeful activity
occurring repeatedly during NREM sleep. Important clinical
features include abnormal behavior, such as sleep terrors or
sleepwalking; sleep fragmentation and frequent arousals;
vocalization and automatisms; and excessive sleepiness. Onset is
often during childhood. No evident abnormal ictal or interictal
discharges are seen during electroencephalography. Nocturnal
temporal lobe epilepsy presents as motionless staring,
automatisms (e.g., lip smacking), impaired consciousness and
post-ictal confusion.
Strokes are associated with an increased risk of obstructive and
central sleep apnea, and can give rise to insomnia, excessive
sleepiness and altered dreams.
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Psychiatric disorders
Sleep disturbances are common in psychiatric and behavioral
disorders. Conversely, sleep disturbance and sleep deprivation
can adversely influence the course of some psychiatric and
behavioral disorders. Common polysomnographic features of
psychiatric disorders include prolonged sleep onset latency,
diminished sleep efficiency, decreased total sleep time, and
increased frequency of arousals. Decrease in N3 and REM sleep
latency can develop persons with depression, manic disorder,
schizophrenia, eating disorder or borderline personality disorder.
Polysomnographic abnormalities may persist even after clinical
remission. Medications used to treat psychiatric disorders may
also cause significant sleep disturbance.
Sleep-related complaints associated with anxiety disorders
consist of insomnia, frequent nighttime awakenings, recurring
anxiety dreams or excessive sleepiness. Prolonged sleep onset
latency, reduced sleep efficiency, decreased total sleep time,
increased wake time after sleep onset, and decrease in N3 and
REM sleep can be seen during polysomnography. Treatment of
anxiety disorders generally involves the use of benzodiazepines,
selective serotonin reuptake inhibitors or tricyclic antidepressants
along with behavioral and relaxation therapy. Included in the
category of anxiety disorders are (a) acute stress disorder; (b)
generalized anxiety disorder; (c) post-traumatic stress disorder;
and (d) panic disorder.
Acute stress disorder involves the development of excessive
anxiety within 4 weeks of a traumatic experience. Persons may
present with detachment, depersonalization, re-experiencing of
the traumatic event, and avoidance of factors that might lead to
recall of the event. Insomnia is common.
In generalized anxiety disorder, excessive anxiety is present for
at least 6 months. Insomnia is common. Sleep disturbance should
be distinguished from that due to psychophysiologic insomnia, in
which anxiety is restricted primarily to sleep disturbance rather
than generalized in nature.
89
Post-traumatic stress disorder manifests as chronic
hyperarousal and anxiety associated with preoccupation and
repetitive re-experiencing (flashbacks) of a severely traumatic or
life-threatening event. Sleep-related complaints include insomnia
and excessive sleepiness. Re-experiencing of the original
traumatic event in anxiety dreams, sleep terrors and nightmares
may be present. Bedtime resistance can develop in children.
Polysomnography may show prolonged sleep onset latency,
reduced sleep efficiency, decreased total sleep time, increased
wake time after sleep onset, and decrease in REM sleep.
Panic disorder is characterized by attacks of extreme anxiety or
fear that begin spontaneously and without an identifiable
precipitating factor. Persons may relate recurrent episodes of
nocturnal panic attacks, with abrupt awakenings and immediate
and sustained wakefulness, good recall of the event, and delayed
return to sleep. Nocturnal panic attacks tend to more common
during NREM than REM sleep, and can be triggered by sleep
deprivation. Insomnia and fear of going to sleep may develop. In
some, polysomnography may demonstrate prolonged sleep onset
latency and reduced sleep efficiency. Behavioral treatment,
including relaxation therapy, as well as pharmacotherapy with
selective serotonin reuptake inhibitors, tricyclic antidepressants or
benzodiazepines may be helpful.
Eating disorders may be accompanied by various sleep-related
complaints, such as insomnia and repetitive nighttime
awakenings.
Mood disorders are characterized by major depressive, manic,
hypomanic or mixed episodes. A major depressive episode is
defined by a persistently depressed mood and anhedonia
accompanied by significant functional impairment. Sleep-related
complaints are common and consist of insomnia (most common)
or excessive sleepiness. Insomnia and sleep disturbance are
directly related to severity of mood disorder in most persons, and
insomnia may persist following remission of depression.
Polysomnography may demonstrate prolonged sleep onset
latency, reduced sleep efficiency, decreased total sleep time,
increased wake time after sleep onset, reduced N3 sleep,
shortened REM sleep latency and increased REM density. Manic
90
episodes are defined by marked and persistent elevation of
mood, with irritability and euphoria. Persons typically have
reduced sleep requirements and may present with complaints of
insomnia. Polysomnographic features are similar to that of major
depressive episodes. A persistently elevated mood, diminished
sleep need and complaints of insomnia are also present in a
hypomanic episode although they are less severe than during
manic episodes. In a mixed episode, a person’s mood rapidly
alternates between major depressive and manic episodes, and
there may be reduced sleep requirements as well as complaints
of insomnia.
Major depressive disorder is characterized by at least one major
depressive episode without any manic, hypomanic or mixed
episodes. Sleep-related complaints consist of insomnia or
excessive sleepiness. Polysomnography may demonstrate
prolonged sleep onset latency, reduced sleep efficiency,
decreased total sleep time, increased wake time after sleep onset,
reduced N3 sleep particularly during the first NREM period,
reduced REM sleep latency, and increased REM density.
Reductions of both N3 sleep and REM sleep latency may persist
during clinical remission. Therapy involves the use of
antidepressant agents and psychotherapy.
Bipolar disorder can either be bipolar 1, defined by at least one
manic, hypomanic or mixed episode with or without a major
depressive episode; or bipolar 2, which consists of at least one
major depressive episode plus at least one hypomanic episode,
without manic or mixed episodes. During the depressive phase, a
person may complain of excessive sleepiness with increase in
total sleep time as well as reduced REM sleep latency.
Sleeplessness, decreased total sleep time, and diminished sleep
requirements may develop during the manic phase. Nightmares
may become more frequent. Therapy of bipolar disorder consists
of antidepressant agents and psychotherapy with or without
mood-stabilizing drugs, such as lithium.
In seasonal affective disorder, depressive episodes occur
during the fall and winter, and are absent during spring and
summer, when some persons may experience hypomanic
symptoms. In this disorder, sleep requirements increase and
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excessive sleepiness develops during fall and winter, whereas
some persons may experience a decrease in sleep requirements
during spring and summer. Phototherapy and, occasionally,
antidepressant agents, are generally effective.
Atypical depression is characterized by lethargy, increase in
appetite, weight gain and sensitivity to rejection. Excessive
sleepiness may develop, with polysomnography demonstrating an
increase in total sleep time and shortened REM sleep latency.
Schizophrenia is a chronic psychiatric disorder characterized by
hallucinations, delusions, disorganized speech, affective
flattening, limited goal-directed behavior, and restricted thought
and speech production. Persons with schizophrenia may complain
of insomnia, excessive sleepiness, frightening dreams, polyphasic
sleep periods or reversal of day-night sleep patterns. Insomnia is
common during acute psychotic decompensation, when a person
may remain awake for prolonged periods. Excessive sleepiness
can develop during the waning phase of schizophrenia or during
residual schizophrenia. Sleep disruption can aggravate psychosis.
Polysomnographic features of schizophrenia include prolonged
sleep onset latency, reduced sleep efficiency, decreased total
sleep time, increased wake time after sleep onset, reduced N3
sleep, and shortened REM sleep latency. There is diminished
REM sleep rebound after sleep deprivation. Total sleep time and
REM sleep are reduced during the waxing phase of the disorder,
but normalize during the waning, post-psychotic and remission
phases of the disorder. REM sleep latency also improves with
successful therapy of schizophrenia. Therapy of schizophrenia
involves antipsychotic medications. Clozapine and olanzapine are
the most sedating of the newer antipsychotic agents; risperidone
is less sedating. Acute psychotic decompensation may be
heralded by worsening sleep disturbance.
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Miscellaneous sleep disorders
Alcohol-dependent sleep disorder refers to the habitual use of
alcohol prior to anticipated bedtime only for its sedative effects,
and is not associated with other patterns of behavior seen with
overt alcoholism.
Alternating leg muscle activation consists of brief activity of the
anterior tibialis muscle of one leg that alternates with activity of
the same muscle in the other leg. Events can occur with or
without arousals. This is a rare disorder that is most common
among middle-aged adults, and is more frequently seen in men
than women. Episodes may be triggered by antidepressant
medications. Course is generally benign. There is repetitive,
alternating activation of the anterior tibialis electromyography
during polysomnography, with each activation lasting between 0.1
to 0.5 seconds; at least four muscle activations occurring in
sequence lasting from 1 to 30 seconds; and less than 2 seconds
between activations.
Benign sleep myoclonus of infancy is characterized by
repetitive, brief and bilateral myoclonic jerks involving large
muscle groups, such as the trunk, limbs or even the entire body
that occur only during sleep, predominantly during quiet sleep.
These motor phenomena are not accompanied by seizure activity
or arousals. This rare condition can be observed in neurologically
normal infants during the first 6 months of life, with onset
generally during the first week of life. Benign sleep myoclonus of
infancy is a benign disorder with a self-limited course. During
polysomnography, myoclonus recurs every three to fifteen
minutes. No specific therapy is necessary.
In environmental sleep disorder, sleep complaints, including
insomnia, excessive sleepiness or parasomnia, are directly due to
adverse environmental factors, such as excessive noise. Sleep
disturbance due to this disorder is more common among older
adults, and is more apparent during the second half of the sleep
period. Both sleep architecture and sleep duration are normal if
polysomnography is performed in the sleep laboratory, but may
be abnormal with delayed sleep onset latency, reduced total sleep
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time and sleep efficiency, and greater wake time after sleep onset
if the sleep study is performed in the usual sleep environment.
Treatment consists of removal of the offending agent/s.
Fragmentary myoclonus consists of episodes of asynchronous
and asymmetric twitch-like contractions of the muscles of the
face, trunk and extremities that last from 10 minutes to over an
hour. Fragmentary myoclonus may accompany obstructive sleep
apnea, central sleep apnea, hypoventilation syndromes,
narcolepsy, insomnia, periodic limb movement disorder, restless
legs syndrome and Niemann-Pick (type C) disease. It is a rare
disorder that affects men more commonly. Onset is generally
during adulthood, and it has a benign course. Most affected
persons are asymptomatic, with many cases identified merely as
an incidental electromyographic finding during polysomnography;
nonetheless, this condition can give rise to sleep disturbance and
excessive sleepiness. Polysomnographic features of fragmentary
myoclonus include five or more brief electromyographic
discharges
per
minute
without
any
associated
electroencephalographic abnormalities.
Hypnagogic foot tremor refers to rhythmic tremors of the feet or
toes that occur during the wake-sleep transition or during stages
N1 or N2 sleep. This disorder is more common among middleaged adults, and affects both genders equally. Hypnagogic foot
tremor may be a normal phenomenon, but can result in sleeponset insomnia or sleep disruption if severe. During
polysomnography, recurrent trains of 1 to 2 Hz leg or foot
electromyographic potentials lasting 10 to 15 seconds are seen.
Sleep disturbance due to hypnotic-dependent sleep disorder is
related to the habitual use of hypnotic agents with development of
the insomnia during abrupt drug withdrawal or residual sleepiness
following use of long-acting medications. Benzodiazepine use
may also precipitate or aggravate snoring and obstructive sleep
apnea.
Long sleeper refers to a person whose sleep time is substantially
longer than typical for the person’s age group (i.e., greater than
10 hours for a young adult). Excessive sleepiness develops if total
sleep time is less than the required amount of sleep. Onset of this
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condition is commonly during childhood, and its course tends to
be chronic. Diagnosis is aided by sleep logs or actigraphy.
Polysomnography is not routinely indicated, but, if performed,
demonstrates normal sleep efficiency and increased total sleep
time. Multiple sleep latency test is normal if the usual amount of
nighttime sleep is obtained prior to testing.
Propriospinal myoclonus at sleep onset is defined by the
presence of spontaneous muscle jerks that occur during the
transition from wake to sleep, and that disappear at sleep onset.
Myoclonus starts in the abdominal and truncal muscles and
spread slowly rostrally and caudally. This is a rare disorder that
tends to affect men more commonly than women. Its etiology is
unknown. Onset is typically during adulthood, with a chronic
course.
Rhythmic movement disorder consists of repetitive, stereotypic
and rhythmic movements occurring during sleep onset and light
sleep. If frequent, it can give rise to sleep-onset insomnia. This
disorder includes head banging, head rolling, body rolling and
body rocking. Prevalence decreases with aging, and is
approximately 60% at 9 months of age, less than 50% at 18
months of age, and 10% at 4 years of age. Adult cases may be
associated with autism, mental retardation or significant
psychopathology. It appears to be more common among men
than women. Risk factors include stress and lack of environmental
stimulation, such as with child abuse or neglect.
Polysomnographic features consist of 0.5 to 2 movements per
second lasting less than 15 minutes. Behavioral therapy and
benzodiazepines may be considered for refractory cases.
A short sleeper habitually sleeps less than 5 hours daily despite
voluntary attempts to lengthen sleep duration. Sleep onset,
quality, continuity and consolidation are normal, and there is
characteristically no impairment in daytime functioning. Onset of
this syndrome is often during early adolescence or young
adulthood, with more females affected than males. Course is
chronic and lifelong. Polysomnographic features include a
shortened sleep onset latency and decrease in total sleep time.
Multiple sleep latency test results are typically normal. No specific
therapy is necessary.
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Sleep hyperhidrosis refers to profuse sweating that occurs
during sleep. Excessive sweating may also be related to
obstructive sleep apnea, febrile illness or pregnancy, and can lead
to frequent awakenings and sleep fragmentation.
With sleep-related abnormal swallowing syndrome, pooling of
saliva in the oral cavity during sleep, due to abnormal swallowing
mechanisms, can result in arousals accompanied by coughing
and choking. A characteristic "gurgling" sound can be heard
preceding each coughing spell. This condition is rare and its
clinical course is unknown.
Sleep-related bruxism is defined by repetitive grinding of teeth or
clenching of the jaw during sleep. Risk factors for sleep-related
bruxism include stress; anxiety; use of psychoactive medications
(selective serotonin reuptake inhibitors, antipsychotics and
amphetamine), recreational drugs, alcohol or caffeine; smoking;
cerebral palsy; mental retardation; and, possibly, dental disease,
such as malocclusion or mandibular malformation. Certain
primary sleep disorders, including obstructive sleep apnea,
restless legs syndrome and REM sleep behavior disorder, are
also associated with an increased likelihood of sleep bruxism.
Prevalence of this disorder is highest during childhood and
decreases with aging, and is about 16% among children; 12% in
adolescents and young adults; 8% in middle-aged adults; and 4%
in older adults. Both genders are affected equally. Onset of sleeprelated bruxism is commonly during the first and second decades
of life. There is a strong familial tendency with 20% to 50% of
persons having a family member with a history of bruxism.
Pathophysiology appears to involve a microarousal event
associated with an exaggerated form of oromotor masticatory
muscle activity. Consequences of sleep-related bruxism include
abnormal dental wear and damage; periodontal tissue injury;
facial or jaw pain (including temporo-mandibular joint syndrome);
headaches; and unpleasant noises that might disrupt the bed
partner’s sleep. Diagnosis requires a current history of witnessed
teeth grinding or jaw clenching during sleep, and evidence of
tooth wear. During polysomnography, overall sleep architecture is
generally normal, and it may demonstrate episodic increases in
electromyographic activity of the chin and masseter muscles.
Bruxism may appear as artifacts on the electroencephalographic
96
or electro-oculographic channels that are referenced to the
masseter or auricular electrodes. Episodes of bruxism are more
common during N1 and N2 sleep compared to REM sleep, but
there may be large night-to-night variability in severity. Episodes
may be associated with arousals. Therapy includes intra-oral
splint
devices;
short-term
pharmacotherapy
using
benzodiazepines, muscle relaxants or local administration of
botulinum toxin in the masseter muscles; and behavioral therapy,
(muscle relaxation exercises). When episodes are related to
obstructive sleep apnea, successful treatment of the latter may
reduce or eliminate sleep-related bruxism.
In sleep-related choking syndrome, there are abrupt
awakenings with a choking sensation or inability to breathe
accompanied by fear and anxiety. Stridor is absent. Repetitive
episodes can give rise to insomnia or sleep fragmentation. This is
a rare disorder, and is most often seen during early to middle
adulthood. Women tend to be affected more frequently than men.
Persons with sleep-related laryngospasm describe acute
breathlessness due to total or near-total cessation of airflow while
asleep that is followed by a sudden awakening accompanied by
inspiratory stridor. Associated features include temporary
hoarseness and cyanosis. Episodes last from several seconds to
several minutes, and may be due to vocal cord spasm or tracheal
swelling. This syndrome is probably rare, is most prevalent among
middle-aged adults, and more commonly affects men than
women.
Sleep-related neurogenic tachypnea, a rare condition, is
characterized by sustained tachypnea that develops during sleep.
These events, if frequent or severe, may lead to sleep
fragmentation and excessive sleepiness.
Sleep-related painful erections involve painful penile erections
occurring during REM sleep, without any apparent penile disorder
or pain during sexual erections while awake. Persons with this
condition may complain of sleep-maintenance insomnia.
Sleep-related leg cramps refer to sleep disturbance due to
painful spasms or tightening of the muscles of the calf or foot. Leg
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cramps are relieved by forcible dorsiflexion of the foot or by local
massage. Risk factors include aging, dehydration and electrolyte
imbalance, endocrine disorders, vigorous exercise, oral
contraceptive use, Parkinson disease and pregnancy. Frequent
leg cramps can result in insomnia or excessive sleepiness.
Diagnosis is based on clinical history. Polysomnography, if
performed, shows an awakening that coincides with non-periodic
bursts of high frequency electromyographic activity in the
gastrocnemius muscle.
Sleep start, or hypnic jerk, is a sudden muscle contraction of part
or all of the body that occurs at sleep onset. It can involve (a) a
single, brief body jerk accompanied by a sensation of "falling"; (b)
flashes of light or vivid imagery; (c) loud sound; or (d) somesthetic
(floating) sensation. Sleep starts occur in 60% to 70% of the
general population, are seen in all age groups, and affect both
genders equally. Precipitating factors include sleep deprivation,
stress, excessive caffeine ingestion, stimulant use or intense
physical activity close to bedtime. Polysomnographic features of a
sleep start consist of an arousal or awakening from drowsiness or
N1 sleep accompanied by brief electromyographic potentials. Its
course is generally benign and it commonly requires no therapy.
Sleep talking, or somniloquy, refers to vocalization during sleep.
Sleep talking occurs in all sleep stages. There is no gender
difference among children, but adult cases have a male
predominance. Precipitating factors include sleep deprivation,
obstructive sleep apnea, REM sleep behavior disorder, sleep
terrors, confusional arousals, sleepwalking, sleep-related eating
disorder, stress and febrile illness. There are no apparent clinical
or psychological consequences. Specific therapy is not generally
indicated.
Snoring involves the production of sound during sleep due to
vibration of the upper airway structures. It is estimated to affect
10% to 12% of children, 20% to 40% of middle-aged adults, and
up to 40% to 60% of older adults. Males are more commonly
affected than women, the prevalence among the latter increasing
during pregnancy. Obstructive sleep apnea is thought to be
present in about 25% to 95% of snorers. Risk factors of snoring
consist of obesity, positive family history, sleep deprivation,
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supine sleep position, nasal obstruction, and medication (muscle
relaxants, opioids or benzodiazepines), tobacco, alcohol and
substance use. Polysomnography is not routinely indicated for
diagnosis of snoring, but may be considered to exclude the
presence of obstructive sleep apnea when upper airway surgery
is being considered. During polysomnography, snoring is often
loudest during stage N3 sleep and diminishes during REM sleep,
and respiratory events are not associated with arousals, oxygen
desaturation, apnea-hypopneas, hypoventilation or significant
cardiac arrhythmias. Treatment of snoring includes the avoidance
of precipitating factors; non-supine sleep posture if snoring occurs
exclusively or predominantly during a supine sleep position; use
of earplugs for the bed partner; nasal or upper airway surgery;
and oral devices.
Stimulant-dependent sleep disorder consists of insomnia or
excessive sleepiness related to the use or discontinuation,
respectively, of stimulant medications.
Sudden infant death syndrome refers to an abrupt, unexpected
death in an apparently healthy infant, the cause of which remains
undetermined even after comprehensive history, postmortem
examination and death scene investigation. The syndrome occurs
predominantly prior to 6 months of age. Risk factors include
prematurity; prone sleeping position; pre- and postnatal exposure
to tobacco smoke; maternal substance abuse; multiple births;
teenage pregnancy; siblings with sudden infant death syndrome;
and lower socioeconomic status. Prevention consists of having
infants sleep on their back.
Sudden unexplained nocturnal death syndrome is
characterized by sudden death occurring during sleep without any
apparent cause. It mostly affects healthy adult Southeast Asian
males between the ages of 25 to 44 years. Victims have been
described to display moaning, screaming, violent motor activity or
labored breathing for a few minutes prior to death. Pathogenetic
mechanisms are unknown, but mutation in the SCN5A gene is
present in some families with this syndrome.
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Infants and children
There are significant differences in sleep architecture and
manifestations of sleep disorders between children and adults.
Newborn sleep is polyphasic and occurs repetitively and randomly
throughout the 24-hour day. Monophasic sleep, occurring once,
generally at night, develops during early childhood between the
ages of 3 and 5 years when napping ceases. The daily duration of
sleep decreases from newborn infants, in whom sleep occupy
70% of a 24-hour day to adults whose sleep average 25% to 35%
of a 24-hour day.
In the first 6 months of life, sleep is classified as (a) active sleep,
(REM sleep-equivalent), (b) quiet sleep (NREM sleep equivalent),
(c) indeterminate sleep, or (d) transitional sleep. Classification of
sleep in infants older than 6 months of age is similar to that of
adults, with alternating NREM and REM sleep stages. The initial
sleep episode can either be active [REM] sleep in infants less
than 3 months of age, or quiet [NREM] sleep in those greater than
3 to 4 months of age. The proportion of NREM-REM sleep is
50:50 in infants compared to 75:25 among adolescents and
adults. Stage N3 sleep as percentage of total sleep time is
greatest during early childhood and declines with aging.
Percentage of REM sleep also decreases with aging, from 50% of
total sleep time among infants, to 25% of total sleep time among
adolescents and adults. The NREM-REM cycle length is about 50
to 60 minutes during infancy and increases to 90 to 120 minutes
in adults. Lastly, neonates, from birth to 2 months, are more likely
to awaken from active, rather than quiet, sleep.
There are several important developmental milestones in sleep
architecture. Active sleep first appears at 28 to 30 weeks of
gestation, whereas quiet sleep is first apparent between 32 weeks
(trace’ discontineau) and 36 weeks (trace’ alternant) of gestation.
Sleep spindles, delta waves and K complexes first develop at 1, 3
and 6 months, respectively, and distinct electroencephalographic
features that allow differentiation among N1, N2 and N3 sleep are
seen at 6 months of age.
The four distinct sleep stages in the first 6 months of age
100
consist of (a) active sleep, which is the first behavioral sleep state
to appear and the predominant sleep state in the newborn period,
is characterized by body and facial twitches and jerks, rapid eye
movements, and irregular respiration; (b) quiet sleep, which
becomes the predominant sleep state by 3 months of age, is
distinguished by its minimal or no body movements, regular
respiration, and electroencephalographic patterns (high-voltage,
slow-wave activity or trace' alternant [high voltage, slow activity
interrupted by electrical silence]); (c) intermediate sleep, which is
scored if the sleep stage does not fully meet criteria for either
active or quiet sleep; and (d) transitional sleep that occurs in the
transition between active, quiet and intermediate sleep.
Sleep stages after 6 months of age include (a) stage NREM 1
sleep (desynchronized [low voltage, mixed frequency]
electroencephalographic activity, no eye movements, low muscle
tone, and regular respiration and heart rate); (b) stage NREM 2
(rhythmic electroencephalographic activity [e.g., sleep spindles
and K-complexes], no eye movements, low muscle tone, and
regular respiration and heart rate); (c) stage NREM 3 (high
voltage, slow [less than 4 Hz] frequency electroencephalographic
activity, no eye movements, low muscle tone, and regular
respiration and heart rate); and (d) stage REM (desynchronized
[low voltage, mixed frequency] electroencephalographic activity,
episodic rapid eye movements during phasic REM sleep, muscle
atonia, and irregular respiration and heart rate).
There is great individual variability in the ages during which
developmental milestones in sleep-related behaviors occur.
Therefore, a specific sleep behavior in a child may be considered
“normal-for-age” or “problematic” depending on physiological
maturity, cultural perceptions and parental expectations.
Generally, nocturnal sleep consolidation, or the ability to sleep
through the night, first develops at 6 to 9 months, and cessation of
daytime napping occurs at 3 to 5 years of age. Endogenous
circadian sleep phase preference (i.e., eveningness vs.
morningness) first develops between 6 to 12 years of age, and
development of sleep phase delay (in some children) occurs
between 12 to 18 years of age.
Aggregate hours of sleep per day gradually decreases
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throughout childhood, averaging 16 to 19 hours in neonates
(newborn to 2 months), 12 to 16 hours in infants (2 to 12 months),
11 to 12 hours in toddlers (1 to 3 years), 10 to 12 hours in
preschool children (3 to 5 years), 8 to 11 hours during preadolescence (5 to 14 years), and 7 to 9 hours during adolescence
(14 to 18 years).
Insomnia in children can be due to a variety of causes, including
adjustment sleep disorder from acute stress or change in
bedroom environment; bedtime resistance, which generally starts
with the development of autonomy and independence during the
toddler years; colic, which generally starts at 3 weeks of age and
usually resolves by 3 to 4 months of age; food allergy; limit-setting
sleep disorder; nighttime fears, such as anxiety about being left
alone in the dark; psychophysiologic insomnia; separation
anxiety; and sleep-onset association disorder. An infant’s or
child’s ability to self soothe back to sleep without caregiver
intervention determines whether spontaneous arousals are brief
vs. prolonged and problematic.
Behavioral treatment of childhood insomnia consists of (a)
parental education; (b) maintenance of consistent bedtimes; (c)
restful nighttime activities; (d) age-appropriate bedtime; (e)
establishment of optimal bedroom environment; (f) appropriate
use of transitional objects, such as a doll or blanket, for sleeponset association disorder; (g) consistent and predictable parental
setting of limits for limit-setting sleep disorder; (h) placing a child
to bed while drowsy but still awake (to teach a child to fall asleep
independently) beginning at 2 to 4 months of age; (i) transitioning
the infant to the final sleep environment (e.g., crib in infant’s room)
by 3 months of age; (j) discontinuation of nighttime feedings in
children 6 months of age or older; (k) faded bedtime, in which
bedtime is progressively delayed by about 30 minutes until the
child is able to fall asleep rapidly, and subsequent bedtimes are
then advanced or delayed depending on sleep onset latency until
the desired bedtime is reached; (l) positive bedtime routines with
the establishment of consistent and relaxing pre-bedtime
activities; (m) scheduled awakenings; (n) extinction procedures;
and (o) cognitive behavioral therapy [sleep restriction, stimulus
control and cognitive therapy as in adults].
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With scheduled awakenings, the child is a awakened by the
parent slightly before the usual spontaneous time of awakening,
reassured, and then allowed to return to sleep. Frequency of
scheduled awakenings is progressively decreased until they are
discontinued completely once the child is able to sleep through
the night. A disadvantage of this approach to managing childhood
insomnia is that children are not taught sleep initiation skills.
There are three general types of extinction techniques for
childhood insomnia, namely fast approach, gradual approach, or
extinction with parental presence. Fast approach (absolute
extinction) involves putting the child in bed, leaving the child alone
in the room, and ignoring inappropriate behavior or unreasonable
demands until the next morning. Although generally effective
within 3 to 7 days, a worsening of behavior (“extinction burst”)
may occur between 5 to 30 days from initiation of the fast
approach extinction therapy. Gradual approach (graduated
extinction) differs from the fast approach in that parents are
allowed to respond to a child’s inappropriate demands in a
gradually decreasing fashion (i.e., longer duration between
interventions or shorter period of intervention) until parental
intervention is finally stopped. Lastly, extinction with parental
presence permits the parent to sleep in a separate bed in the
child’s bedroom but not to respond to any inappropriate behavior
by the child.
No hypnotic agent is currently approved by the US Food and Drug
Administration for use in children. Neither the efficacy nor safety
of melatonin has been established for children.
Excessive daytime sleepiness should be considered in any
child 5 years of age or older who continue to nap during the day,
especially if unplanned; or sleep for at least 2 hours more on
weekends than on weekdays (“weekend oversleep”). Other
common features of excessive sleepiness in children include
falling asleep at inappropriate times and situations; behavioral
problems, such as inattentiveness, irritability, hyperactivity or
impulsiveness; cognitive problems or academic difficulties;
changes in mood (depression or anxiety); and fatigue and
lethargy.
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Childhood obstructive sleep apnea differs in several ways from
its adult counterpart. Complaints of excessive sleepiness are less
common than in adults, and are present in only about 30% of
children with obstructive sleep apnea. Rather, children may be
observed to have unusual sleep postures (e.g., hyperextended
neck), labored or paradoxical breathing, thoracic retractions,
cognitive or behavioral difficulties, secondary enuresis, bedtime
resistance or problematic night waking. Adenotonsillar
enlargement is the most important risk factor in children.
However, size of the tonsils and adenoids is not predictive of
obstructive sleep apnea in individual patients. The overall
prevalence of obstructive sleep apnea in children is 1% to 5%,
and is greatest between the ages of 2 and 6 years. Childhood
obstructive sleep apnea affects both genders equally. Left
untreated, it can give rise to growth failure and developmental
delay, cognitive or behavioral problems (attention deficit,
hyperactivity, aggressiveness, irritability or
intellectual
impairment), mood disorder, poor academic performance, and
increased frequency of sleepwalking or sleep terrors.
Polysomnographic features consist of either (a) pauses in
breathing or reduction in airflow by greater than 30% to 50%
compared to baseline, lasting 2 or more normal respiratory cycles,
and occurring at a frequency of at least one scoreable respiratory
event per hour; or (b) obstructive hypoventilation with prolonged
periods of persistent partial upper airway obstruction,
hypercapnia and oxygen desaturation. Consider monitoring endtidal or transcutaneous CO2 when assessing suspected childhood
obstructive sleep apnea. Radiologic studies, such as lateral
cephalometric radiographs, are recommended for children with
significant craniofacial abnormalities. Adenotonsillectomy is the
treatment of choice for most children with obstructive sleep
apnea. It is important to assess its therapeutic efficacy six to eight
weeks after surgery. Continuous positive airway pressure (CPAP)
therapy may be considered if upper airway surgery is not
indicated, contraindicated or ineffective; this, too, requires regular
clinical and polysomnographic reassessment. Oral devices may
be tried in older adolescents when growth of craniofacial bones
and upper airway soft tissues are largely complete.
Apnea of prematurity refers to the occurrence of obstructive,
central or mixed apneas or hypopneas, or periodic breathing, in
104
infants less than 37 weeks of gestation. Respiratory events may
be associated with bradycardia, hypoxemia or need for caregiver
intervention. Prevalence of apnea of prematurity is inversely
related to gestational age at birth, and spontaneous resolution
occurs with maturation. In infant sleep apnea, obstructive or
central apneas or hypopneas develop in infants greater than 37
weeks of gestation. Central events are more common than
obstructive events. Respiratory events can be associated with
hypoxemia, brady-tachycardia, cyanosis and arousals, and occur
more frequently during REM sleep. Risk factors of infant sleep
apnea include (a) low-birth weight, (b) medical and neurological
disorders (anemia, lung disease, gastroesophageal reflux,
metabolic derangements or infection), and (c) medication use,
including anesthesia. Infant sleep apnea is not an independent
risk factor for sudden infant death syndrome.
An apparent life-threatening event is characterized by the
presence of apnea, change in color or tone (limpness), and
choking or gagging.
All children should be screened for snoring. Snoring in children
may be associated with excessive sleepiness, behavioral and
cognitive problems (attention, language, memory and executive
function) and mood disorders. Polysomnography is required to
distinguish primary snoring from obstructive sleep apnea.
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Aging
Sleep requirements do not decline with aging. However, aging is
associated with greater nocturnal sleep disturbance, excessive
sleepiness and daytime napping, and there is a higher prevalence
of insomnia, obstructive sleep apnea, central sleep apnea,
restless legs syndrome, periodic limb movement disorder, REM
sleep behavior disorder and advanced sleep phase syndrome.
While some of the sleep disturbance can be attributed to normal
aging itself, most are due to comorbid medical, neurological,
psychiatric, and primary sleep disorders, and the adverse effects
on sleep of medications used to treat them.
Physiologic changes with aging include diminished secretion of
melatonin; earlier sleep onset and offset relative to melatonin
secretion; reduced amplitude of circadian sleep-wake rhythms;
phase advancement of circadian sleep-wake rhythms and body
temperature (in some); lowered arousal threshold with greater
sensitivity to adverse environmental factors; and reduced
secretion of growth hormone during sleep.
Aging-related changes in sleep architecture include reduced
sleep efficiency, prolonged sleep onset latency, greater wake time
after sleep onset, decrease in N3 sleep and increase in REM
sleep latency. Total sleep time may either be normal or
decreased.
Insomnia is the most common sleep complaint among older
adults, and manifests more frequently as sleep-maintenance
insomnia. Risk factors for insomnia with aging include depression,
disability, poor health, multiple medical disorders, respiratory
symptoms, sedative use and widowhood; insomnia is rarely due
exclusively to aging itself.
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Sleep in women
Women generally have greater subjective complaints of
insufficient or nonrestorative sleep as well as increased need for
sleep compared to men.
Obstructive sleep apnea is less common in pre-menopausal
women than in men, and risk of this disorder increases in women
during menopause. In addition, the prevalence of obstructive
sleep apnea among postmenopausal women who use hormone
replacement therapy is less compared to women not on hormone
replacement therapy. Nonetheless, data do not conclusively
support the use of hormone replacement therapy as therapy for
obstructive sleep apnea among postmenopausal women. Central
sleep apnea is also less common in premenopausal women than
in men due to a lower hypopcapnic apneic threshold in the former
group.
Sleep quality can deteriorate prior to and during the first several
days of menstruation, with women complaining of insomnia and
excessive sleepiness due to abdominal bloating and cramping,
anxiety, breast tenderness, headaches and mood changes.
Compared to the follicular phase, the luteal phase is associated
with greater subjective sleepiness, and, in some, longer sleep
onset latency and lower sleep efficiency.
Dysmenorrhea, defined as painful uterine cramps that occur
during menses, may be accompanied by diminished sleep quality
and sleep efficiency as well as complaints of excessive
sleepiness. Endometriosis, or the presence of endometrial tissue
outside the uterus, such as in the abdomen or pelvis, can give rise
to sleep disturbance secondary to pain. Premenstrual syndrome
refers to the development of abdominal bloating, greater irritability
and increased fatigue occurring prior to menses, with symptoms
remitting with menses. Sleep-related complaints associated with
this syndrome include insomnia, frequent awakenings, nonrestorative sleep, unpleasant dreams or nightmares, and
excessive sleepiness. Finally, premenstrual dysphoric disorder
presents as fatigue, mood changes and daytime impairment that
107
occur prior to menses; either insomnia or excessive sleepiness
may develop during this time.
Polycystic ovarian syndrome is characterized by irregular or
absent menstrual cycles, infertility, weight gain, insulin resistance
and hirsutism, as a result of increased ovarian production of male
sex hormones. The risk for obstructive sleep apnea is increased
in this disorder, with the severity of apnea-hypopnea index
appearing to correlate with serum levels of testosterone.
Pregnancy is associated with changes in sleep quality, which is
worse during the first trimester, improves during the second
trimester, and is worst during the third trimester. Common causes
of sleep disturbance during pregnancy are anxiety, back pain,
breast tenderness, dyspnea, fetal movements, heartburn and
gastroesophageal reflux, leg cramps, nausea and vomiting
(morning sickness), nocturia, restless legs syndrome, snoring,
and obstructive sleep apnea. There may also be an increase in
daytime napping. Conversely, pregnancy increases the risk for
snoring, obstructive sleep apnea, restless legs syndrome/periodic
limb movement disorder, nocturnal leg cramps and excessive
sleepiness. Significant obstructive sleep apnea is relatively
uncommon unless it was present prior to pregnancy. Pregnancyinduced hypertension (pre-eclampsia) is characterized by
hypertension, proteinuria, pedal edema and headaches. It is
associated with a higher prevalence of snoring, obstructive sleep
apnea and periodic limb movements during sleep.
Sleep-related complaints during the postpartum period consist
of excessive sleepiness and changes in mood. There is an
increase in frequency of napping. Polysomnographic changes
include reduced sleep efficiency, decreased total sleep time, and
greater wake time after sleep onset.
Menopause is defined as the cessation of menstruation, and is
due to declining estrogen and progesterone levels. Common
complaints related to menopause include hot flashes, night
sweats, insomnia, mood changes, fatigue and excessive
sleepiness.
Compared to premenopause, there is greater
subjective complaints of sleep disturbance; and increased
prevalence of insomnia and obstructive sleep apnea.
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Polysomnography may demonstrate longer sleep onset latency
and lower sleep efficiency. Hormone replacement therapy for
significant menopausal symptoms may have beneficial effects on
sleep, including improvement in sleep quality, and decreased
prevalence of obstructive sleep apnea, insomnia and hot flashes.
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Medications and their effects on sleep
Medications can be sedating, alerting or both at different
occasions, as a direct drug action, adverse reaction or withdrawal
effect.
Alcohol has a biphasic effect on sleep and waking: it is
stimulating at low doses and on the rising phase of alcohol levels,
but sedating at high doses and on the falling phase of alcohol
levels. Alcohol use, especially if excessive, can trigger
nightmares, vivid dreams, enuresis, restless legs, sleep terrors
and sleepwalking. It can worsen snoring and obstructive sleep
apnea. Acute alcohol withdrawal can result in insomnia, frequent
awakenings accompanied by headaches and diaphoresis, and
vivid, disturbing dreams. Sleep disturbance, including insomnia,
can persist for several years of abstinence. Polysomnographic
features of acute alcohol ingestion include shortened sleep onset
latency, reduced wake time after sleep onset, increase in N3
sleep, prolonged REM sleep latency and decreased REM sleep
during the first part of sleep period; and increase in wake time
after sleep onset, reduced N3 sleep and increased REM sleep
during the second part of sleep period. Alcohol withdrawal is
associated with prolonged sleep onset latency, increased wake
time after sleep onset, decreased total sleep time, less N3 sleep,
shortened REM sleep latency and greater REM sleep (REM
rebound). During alcohol abstinence, there is reduced total sleep
time, increase in wake time after sleep onset, and reduced N3
sleep.
Antidepressants generally prolong REM sleep latency and
decrease REM sleep. Sudden discontinuation after chronic
antidepressant use can cause REM sleep rebound. Monoamine
oxidase inhibitors are the most potent REM inhibitors. There are
several notable exceptions to this general rule: (a) bupropion and
nefazodone increase REM sleep; and (b) mirtazapine and
trimipramine have no effect on REM sleep. Selective serotonin
reuptake inhibitors can cause abnormal slow eye movements
during NREM sleep, so called “Prozac eyes”. Selective serotonin
reuptake inhibitors and tricyclic antidepressants can be sedating
(amitriptyline, doxepin, fluvoxamine, imipramine and paroxetine)
110
or alerting (citalopram, fluoxetine and protriptyline). Except for
bupropion, antidepressants can precipitate or worsen restless
legs syndrome and periodic limb movement disorder. Selective
serotonin reuptake inhibitors and tricyclic antidepressants can
induce REM sleep behavior disorder.
Antipsychotics are generally sedating. They tend to shorten
sleep onset latency, increase total sleep time, and reduce REM
sleep. The most sedating antipsychotic agents are
chlorpromazine,
clozapine,
olanzapine,
quetiapine
and
thioridazine.
Drugs of abuse include cocaine, heroin and marijuana. Cocaine
use can result in reductions in both total sleep time and REM
sleep, whereas acute cocaine withdrawal increases both total
sleep time and REM sleep. Heroin use is also associated with
decreases in total sleep time, N3 sleep and REM sleep.
Marijuana, or tetrahydrocannabinol, is sedating at low doses, and
hallucinatory at high doses. Marijuana use decreases REM sleep,
and REM sleep rebound may develop during withdrawal.
Hypnotic agents, such as barbiturates, benzodiazepine receptor
agonists and chloral hydrate act via the gamma aminobutyric acid
(GABA) receptor complex. They are sedating and shorten sleep
onset latency, enhance sleep efficiency, and increase total sleep
time. Benzodiazepines also decrease N3 and REM sleep; REM
sleep rebound (with nightmares) may develop during drug
withdrawal. Rebound insomnia following benzodiazepine
discontinuation is more severe with short-acting compared to
longer-acting agents. On the other hand, eszopiclone, zaleplon
and zolpidem have minimal effects on N3 and REM sleep.
Benzodiazepines can increase both spindle (12 to 14 Hz) and
“pseudo-spindles” (14 to 18 Hz) density. Barbiturates and
benzodiazepines can worsen snoring and obstructive sleep
apnea.
Opioids are sedating, and decrease both N3 and REM sleep.
Insomnia and nightmares can develop during opioid
discontinuation. Opioids may worsen obstructive sleep apnea, but
improve symptoms of restless legs syndrome.
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Stimulants are alerting, and generally prolong sleep onset
latency, reduce sleep efficiency, diminish total sleep time, and
reduce both N3 and R sleep. Abrupt withdrawal can give rise to
excessive sleepiness and REM sleep rebound. Modafinil is
indicated for excessive sleepiness secondary to narcolepsy and
shift work sleep disorder, as well as for residual sleepiness in
persons with obstructive sleep apnea who are being treated with
positive airway pressure therapy.
Common agents that can cause insomnia include alcohol
(withdrawal from); anorectic agents; antidepressants (bupropion,
fluoxetine, protriptyline and venlafaxine) ; antihypertensives
(metoprolol and propanolol); antiparkinsonian drugs (high doses
of levodopa); bronchodilators (albuterol and theophylline);
decongestants (phenylpropanolamine and pseudoephedrine);
nicotine; steroids (prednisone); and stimulants (armodafinil,
caffeine, cocaine, dextroamphetamine, methamphetamine,
methylphenidate and modafinil).
Common agents that can cause sedation include
anticonvulsants (carbamazepine, gabapentin, phenobarbital,
phenytoin, tiagabine and valproic acid); antidepressants
(amitriptyline, desipramine, doxepin, fluvoxamine, imipramine,
lithium, mirtazapine, nefazodone, nortriptyline, paroxetine and
trazodone);
antiemetics
(metoclopramide,
ondansetron,
phenothiazines
and
scopolamine);
antihistamines
(diphenhydramine); antiparkinsonian drugs (pramipexole and
ropinirole); antipsychotics (chlorpromazine, clozapine, haloperidol,
olanzapine and thioridazine); barbiturates; benzodiazepine
receptor agonists; chloral hydrate; gamma hydroxybutyrate;
melatonin and melatonin receptor agonists (ramelteon); muscle
relaxants; narcotic agents; and neuroleptic agents.
Common agents that can cause restless legs syndrome or
periodic limb movement disorder include antidepressants,
dopamine antagonists and lithium.
Common agents that can cause REM sleep behavior disorder
include alcohol (withdrawal), antidepressants, barbiturates and
caffeine.
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Polysomnography and other sleep tests
Polysomnography involves the continuous and simultaneous
recording of several physiologic variables during sleep.
Indications for polysomnography include diagnosis of sleeprelated breathing disorders; positive airway pressure titration for
sleep-related breathing disorders; follow-up after upper airway
surgery or dental devices for obstructive sleep apnea; diagnosis
of narcolepsy (followed by multiple sleep latency test on the day
following polysomnography); diagnosis of periodic limb movement
disorder; and evaluation of atypical or injurious parasomnias, or
suspected
nocturnal
seizures
(with
additional
scalp
electroencephalographic derivations and video recording).
A polygraph, consisting of a series of alternating current (AC)
and direct current (DC) amplifiers and filters, records several
physiologic variables during sleep. High-frequency (fast)
physiologic
variables, such as
electroencephalography,
electromyography and electrocardiography are recorded using AC
amplifiers. With AC amplifiers, high-frequency filters are used to
reduce fast, presumably non-physiologic, potentials, whereas lowfrequency filters are used to reduce slow potentials that might
interfere with proper recording. In contrast, low-frequency (slow)
physiologic variables, such as oxygen saturation and continuous
positive airway pressure levels are recorded using DC amplifiers;
DC amplifiers are not equipped with low-frequency filters. Airflow
and respiratory effort are recorded using either AC or DC
amplifiers.
A derivation is the difference in voltage between two electrodes.
It can be either bipolar or referential. A bipolar derivation consists
of two standard electrodes that are matched to each other. In a
referential derivation, a standard electrode is matched to a
reference electrode.
Polysomnography records several physiologic parameters
simultaneously; these include electroencephalography (EEG),
electro-oculography (EOG), electromyography (EMG) of the chin
and lower extremities, electrocardiography (ECG), airflow,
snoring, thoracic and abdominal movement, and oxygen
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saturation (SaO2). Other sensors that may be used during
polysomnography include esophageal pressure monitors, endtidal carbon dioxide (PetCO2), transcutaneous carbon dioxide
(PtcCO2), positive airway pressure level, and additional
electroencephalographic channels for evaluation of suspected
nocturnal seizures, video-monitoring for evaluation of suspected
parasomnias or seizures, and esophageal pH sensors for
evaluation of suspected gastroesophageal reflux.
Electroencephalography involves placement of scalp electrodes
based on the International 10-20 system. In this system, each
electrode is provided with a letter that represents the
corresponding region of the brain, such as frontal (F), central (C),
occipital (O) and mastoid (M), and a numerical subscript. Odd
numbered subscripts are given for left-sided electrodes; even
numbers are used for right-sided electrodes; and Z is used for
midline electrodes. The recommended electrode placements are
F4M1, C4M1 and O2M1. Backup electrode placements are F3M2,
C3M2 and O1M2. Alternative electrode placements are FzCz,
CzOz and C4M1. Additional electroencephalographic electrodes
may be used when evaluating nocturnal seizure activity.
Frequency of electroencephalographic waves can be divided into
delta (< 4 Hz), theta (4-7 Hz), alpha (8-13 Hz) and beta (greater
than 13 Hz).
Several specific electroencephalographic waveforms are
important in the staging of sleep. A K complex is a high-amplitude,
biphasic wave, with an initial sharp negative deflection
immediately followed by a positive high-voltage slow wave, lasting
0.5 seconds or more, and is seen maximally over the vertex. Sawtooth waves, on the other hand, consist of theta waves with a
notched waveform that occur during REM sleep, and are more
prominent over the vertex and frontal leads. Sleep spindles are
brief oscillations with a frequency of 12 to 14 Hz and lasting 0.5 to
1.5 seconds. Amplitude is generally less than 50 µV. Sleep
spindles are generated in the midline thalamic nuclei, are more
prominent over the central leads, and are seen in N2 and N3
sleep. “Pseudo-spindles” or “drug spindles” related to
benzodiazepine use have a higher frequency of about 15 Hz.
Finally, vertex sharp deflections refer to sharp negative waves
with amplitude less than 250 µV, and are maximal over the vertex.
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Electro-oculography records the difference in potentials (dipole)
between the positively-charged cornea and the negativelycharged retina. This dipole changes with eye movements. A
positive voltage, which results in a downward deflection, is
recorded when the eye moves toward an electrode; and a
negative voltage, with an upward deflection, accompanies an eye
movement away from an electrode. The recommended electrode
placements are E1M2 and E2M2, with E1 being 1 cm below the
left outer canthus; E2 at 1 cm above the right outer canthus; and
M2 at the right mastoid process. These electrode distances may
be reduced to 0.5 cm for children. These electrode placements
create out-of-phase deflections in the two channels with conjugate
eye movements, while artifacts produce in-phase deflections.
There are two general patterns of eye movements, namely (a)
slow rolling eye movements that occur during relaxed drowsiness
with closed eyes, N1 sleep or brief awakenings; and (b) rapid eye
movements that occur during waking with open eyes, seen as eye
blinks, or during REM sleep. Use of selective serotonin reuptake
inhibitors or tricyclic antidepressants may be associated with eye
movements during N2 and N3 sleep, so called “Prozac eyes”.
Chin electromyography is recorded using three electrodes: one
in a midline position, 1 cm above the inferior edge of the
mandible; a second at 2 cm to the right of midline and 2 cm below
the inferior edge of the mandible; and a third at 2 cm to the left of
midline and 2 cm below the inferior edge of the mandible. These
electrode distances are reduced to 1 cm for children. Derivation
for the chin electromyography consists of either one of the
electrodes below the mandible referred to the electrode placed
above the mandible. The other inferior electrode can be used as a
back-up if the initial electrodes fail. An additional electrode may be
placed over the masseter muscle to detect the presence of
bruxism.
For electrocardiography, a single modified lead II with
electrodes placed below the right clavicle near the sternum and
over the lateral chest wall at the left sixth or seventh intercostal
space. Important cardiac rhythms include (a) asystole, which is
defined by a cardiac pause that is greater than 3 seconds in
duration for patients 6 years of age or older; (b) sinus bradycardia
in which the heart rate falls to under 40 beats per minute for
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patients 6 years of age or older; (c) sinus tachycardia for heart
rates greater than 90 beats per minute in adult patients; sinus
rates are generally faster in young children; (d) narrow-complex
tachycardia if the heart rate is greater than 100 beats per minute
and if there are at least three consecutive beats with QRS
duration less than 120 msec; (e) wide-complex tachycardia when
heart rate is greater than 100 beats per minute, with at least three
consecutive beats when the QRS duration is equal to or greater
than 120 msec; and (f) atrial fibrillation, which is characterized by
an irregularly irregular rhythm with no clearly identifiable P waves.
Techniques for measuring airflow include nasal pressure
monitoring, pneumotachography, thermistors, thermocouples and
end-tidal carbon dioxide (PetCO2) monitoring. The reference
standard for detecting obstructive apnea-hypopneas is
pneumotachography. Thermal sensing devices and PetCO2
monitoring provide only indirect and qualitative measures of
airflow. With nasal pressure monitoring, obstructive respiratory
events are associated with a plateau, or flattening, of the
inspiratory flow signal whereas central respiratory events are
associated with reduced but rounded signals. For identifying
apneas, the recommended technique is oronasal thermal sensing;
acceptable alternative methods are nasal air pressure transducer
for adults, and PetCO2 or summed calibrated inductance
plethysmography for children. For identifying hypopneas, the
recommended device is the nasal air pressure transducer;
inductance plethysmography or oronasal thermal sensors are
acceptable alternatives.
Measuring respiratory effort is important in distinguishing
obstructive, central and mixed apneas. Techniques include
esophageal pressure monitoring, surface diaphragmatic
electromyography, strain gauges, respiratory inductance
plethysmography or thoracic impedance. The recommended
sensor for measuring respiratory effort is esophageal manometry
or inductance plethysmography. Diaphragmatic and intercostal
electromyography are accepted alternative sensors.
Adequately measuring oxygenation and ventilation is crucial
during polysomnography. The recommended sensor for oxygen
saturation is pulse oximetry, and for alveolar hypoventilation in
116
children is transcutaneous carbon dioxide (PtcCO2) or PetCO2.
Identifying snoring can be done using a microphone.
Electromyography of the anterior tibialis lower extremity
muscles is used to detect periodic limb movements. Additional
electrodes can be placed over the extensor digitorum communis
muscles of the upper extremities to help identify REM sleep
behavior disorder.
For scoring sleep stages, polysomnographic data are divided
into 30-second time periods or epochs. The standard sleep study
paper speed is 10 mm per second, or 30 cm per epoch page.
Identification of seizure activity is enhanced by faster paper
speeds of at least 15 mm per second, preferably 30 mm per
second, or adequate digital electroencephalographic sampling
rates. Each epoch is assigned a single sleep stage that comprises
the greatest percentage of the epoch.
Adult sleep stages are divided into NREM stages N1, N2 and
N3, and REM sleep. In stage wake (W), at least 50% of the
epoch has alpha electroencephalographic waves over the
occipital region with eye closure; if alpha waves are absent, stage
W is defined by the presence of any of the following: (a) conjugate
vertical eye blinks [0.5 to 2 Hz]; (b) reading eye movements that
consists of conjugate slow movement followed by a rapid
movement in the opposite direction; or (c) voluntary rapid open
eye movements. Chin electromyography tone is usually relatively
high during stage W.
117
Figure: Stage Wake
Alpha electroencephalographic waves are replaced by low
voltage, mixed frequency (4 to 7 Hz) waves that occupy at least
50% of the epoch in stage N1 sleep. In persons who do not
generate alpha waves, the start of this stage is marked by the
presence of 4 to 7 Hz waves accompanied by slowing of
background electroencephalographic activity by 1 Hz or more
compared to stage W; vertex sharp waves with duration of less
than 0.5 seconds, and that are maximal over the central region; or
the presence of slow, but not rapid, eye movements. Both K
complexes and sleep spindles are absent, and tonic chin
electromyography levels are typically lower than during relaxed
wakefulness.
118
Figure: Stage N1 sleep
The start of stage N2 sleep is defined by the presence of K
complexes (which are not associated with arousals), or of sleep
spindles during the first half of the epoch or during the last half of
the previous epoch, and if criteria for stage N3 are absent. The
continuation of stage N2 is defined by the presence of low
amplitude, mixed frequency electroencephalographic rhythms,
and if the epoch contains, or is preceded, by K complexes (which
are not associated with arousals), or by sleep spindles.
119
Figure: Stage N2 sleep
In stage N3 sleep, at least 20% of the epoch is occupied by slow
wave (0.5 to 2 Hz and greater than 75 µV)
electroencephalographic activity over the frontal regions.
Figure: Stage N3 sleep
120
Lastly, scoring stage REM sleep requires the presence of all of
the
following:
(a)
low
amplitude,
mixed
frequency
electroencephalographic activity; (b) rapid eye movements in the
electro-oculographic channels; and (c) chin electromyography
demonstrating a low tone that is either at the lowest level in the
study or at least no higher than the other sleep stages. The
continuation of stage REM is defined by the presence of low
amplitude, mixed frequency electroencephalographic activity, low
chin electromyographic tone, and no K complexes or sleep
spindles in epochs that either contain rapid eye movements or
that are preceded by stage REM sleep.
Major body movements are defined by the presence of
movement
or
muscle
artifact
that
obscures
the
electroencephalographic tracings for at least 50% of the epoch.
An epoch with a major body movement is scored the same stage
as the epoch that follows it, but is scored as stage W if alpha
rhythm is present or if it is preceded, or followed, by a stage W
epoch.
Figure: Stage REM sleep
Stage N1 sleep typically accounts for 5% of the total sleep time
among adults. The corresponding percentages for the other sleep
stages are 45% for N2, 25% for N3, and 25% for REM sleep. The
period from NREM stages N1 to N3 sleep to REM sleep is called
a sleep cycle. There are commonly three to five NREM-REM
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sleep cycles during the night, each occurring every 90 to 120
minutes in adults. Stage N3 sleep predominates in the first half of
the night whereas REM sleep percentage is greater during the
second half of the night. Normal sleep in an adult is characterized
by short sleep onset latency of less than 15 minutes; high sleep
efficiency of greater than 95%; and few and relatively brief
awakenings. Sleep is typically entered into through NREM sleep.
Pediatric sleep stage scoring rules apply to infants 2 months
post-term or older. Stage W is scored if more than 50% of the
epoch
contains
alpha
or
dominant
posterior
electroencephalographic rhythm. In stage N1, alpha or dominant
posterior electroencephalographic rhythm is replaced by low
amplitude, mixed frequency (4 to 7 Hz) waves occupying more
than 50% of the epoch. In infants who do not generate a dominant
posterior rhythm, the start of N1 is determined by the presence of
4 to 7 Hz waves with slowing of the background activity by at least
1 to 2 Hz compared to stage W; vertex sharp waves; slow eye
movements; rhythmic anterior theta activity; hypnagogic
hypersynchrony; or diffuse or occipital-predominant high
amplitude 3 to 5 Hz rhythmic activity. Scoring of stages N2, N3
and R follow adult scoring rules. Infant sleep is scored as stage N
(NREM) if K complexes, sleep spindles and slow wave activity are
all absent in epochs of NREM sleep.
Sleep scoring in newborns also follows an “epoch” approach
using behavior, respiration, electroencephalography, electrooculography and electromyography data. Sleep is classified as
either active REM sleep or quiet sleep. The term “intermediate
sleep” is used when epochs do not fully meet criteria for active or
quiet sleep. In stage wake, newborns display visible movements
and vocalizations; eyes are open and demonstrate waking eye
movements; respiration is variable; electroencephalography
shows mixed slow wave (theta) pattern with occasional beta and
delta waveforms; and the electromyography demonstrates
sustained tone with bursts of phasic activity. Stage active REM
sleep is characterized by closed eyes; visible movements, such
as facial grimaces, smiles or movements of body and limbs;
vocalizations; irregular respiration; low-voltage irregular or mixed
electroencephalographic patterns; eye movements; and low
electromyographic tone. In stage quiet sleep, eyes are closed and
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there are no body movements; respiration is regular; high-voltage
slow, trace alternant or mixed electroencephalographic pattern is
present; no eye movements are evident; and electromyographic
tone is high. Electroencephalography is classified as (a) highvoltage slow pattern (continuous, medium- to high-amplitude [50
to 150 µV] waveforms, and frequencies from 0.5 to 4 Hz), which
are present during quiet sleep; (b) low-voltage irregular pattern
with low-amplitude [14 to 35 µV] waveforms and frequencies from
5 to 8 Hz, which are present during active REM sleep; (c) trace
alternant pattern, defined by bursts of slow [0.5 to 3 Hz] highamplitude waves, fast low-amplitude waves, and sharp waves [2
to 4 Hz] lasting several seconds interspersed with periods of
relative quiescence (mixed frequency waveforms) lasting 4 to 8
seconds, which are present during quiet sleep; and (d) mixed
pattern with both high- and low-voltage waveforms that are
present during both quiet and active REM sleep.
Arousals are scored if there are abrupt electroencephalographic
frequency shifts, such as alpha, theta or frequencies greater than
16 Hz but not spindles, lasting at least 3 seconds and preceded
by at least 10 seconds of stable NREM or REM sleep. In addition,
REM sleep arousals must be accompanied by an increase in chin
electromyographic tone that is at least 1 second in duration. The
number of arousals per hour of sleep is referred to as the arousal
index.
Adult respiratory events include apneas, hypopneas, respiratory
effort-related arousals, hypoventilation and Cheyne Stokes
respiration. An apnea is defined by a decrease in peak thermal
sensor amplitude by at least 90% of baseline for a duration of 10
seconds or longer. Apneic events can either be obstructive
(inspiratory effort is present throughout the entire event), central
(inspiratory effort is absent throughout the entire event), or mixed
(absent inspiratory effort in the initial part of the event followed by
emergence of inspiratory effort).
123
Figure: Obstructive apnea
Figure: Central apnea
Figure: Mixed apnea
A hypopnea is a decrease in nasal pressure by at least 30% of
baseline for a duration of 10 seconds or longer accompanied by at
least a 4% oxygen desaturation. The apnea index is the number
of apneas per hour of sleep, whereas the apnea-hypopnea index
represents the number of apneas and hypopneas per hour of
sleep.
Figure: Hypopnea
With respiratory effort-related arousals, breaths are associated
with increasing respiratory efforts, or flattening of the nasal
124
pressure waveform, with duration of at least 10 seconds; these
event precedes an arousal, but does not meet criteria for either
apnea or hypopnea.
Figure: Respiratory effort-related arousal
Hypoventilation is present if there is an increase in PaCO2 during
sleep by 10 mmHg or more compared to supine wake values.
Cheyne Stokes respiration is characterized by at least three
consecutive cycles of crescendo-decrescendo amplitude in
respiration.
Figure: Cheyne Stokes respiration
Scoring rules for pediatric respiratory events apply to children
less than 18 yrs of age. Apnea is scored if there is a 90% or
greater fall in signal amplitude lasting at least 2 missed breaths;
events can either be obstructive, central or mixed. Hypopnea
refers to a 50% or greater reduction in nasal pressure amplitude
compared to baseline, associated with arousal, awakening, or at
least 3% oxygen desaturation, lasting for a duration of at least two
missed breaths. Respiratory effort-related arousals are defined
125
either by a nasal pressure sensor criteria (reduction in sensor
signal to less than 50% of baseline levels, associated with
flattening of the waveform, snoring, increase in PtcCO2 or
PetCO2, or visible increase in work of breathing lasting at least
two breath cycles); or a esophageal pressure sensor criteria
(progressive increase in inspiratory effort accompanied by
snoring, increase in PtcCO2 or PetCO2, or visible increase in work
of breathing lasting at least two breath cycles). With
hypoventilation, PtcCO2 or PetCO2 is greater than 50 mmHg in
over 25% of total sleep time. Periodic breathing is characterized
by more than three episodes of central apneas with duration of
greater than 3 sec separated by 20 seconds or less of normal
respiration.
Movement events include alternating leg muscle activation,
bruxism, excessive fragmentary myoclonus, hypnagogic foot
tremor, periodic limb movements of sleep, REM sleep behavior
disorder or rhythmic movement disorder. Alternating leg muscle
activation is scored when four or more electromyographic bursts,
0.5 to 3 Hz in frequency, alternate between legs, with a duration
of 100 to 500 msec. With bruxism, an increase in chin
electromyographic activity that is at least twice above the
background electromyographic tone is present, and separated by
at least 3 seconds of stable muscle tome. Sleep bruxism is
defined by the presence of two or more audible bruxism episodes
per night.
Figure: Bruxism
With excessive fragmentary myoclonus, five or more
electromyographic bursts (each with a maximum duration of 150
msec) per minute occur for 20 or more minutes of NREM sleep.
Hypnagogic foot tremor is defined by the presence of at least four
electromyographic bursts, each with a frequency of 0.3 to 4 Hz
and a with duration of 250 to 1000 msec. Periodic limb
126
movements of sleep is scored if four or more consecutive leg
movements, each 0.5 to 10 seconds in duration with an amplitude
equal to or greater than 8 µV above resting muscle tone, are
present. Period lengths are 5 to 90 seconds between onsets of
consecutive movements. Leg movements on different legs are
counted as one movement if they are separated by less than 5
seconds between movement onsets. The periodic limb movement
index refers to the number of periodic limb movements per hour of
sleep.
With REM sleep behavior disorder, either sustained chin
electromyographic activity, or excessive transient chin or limb
muscle activity, or both are present during REM sleep. Rhythmic
movement disorder is characterized by four or more individual
movements, each with a frequency of 0.5 to 2 Hz, and an
amplitude equal to or greater than twice resting electromyographic
tone.
There are several important definitions of polysomnographic
parameters. An alpha-delta pattern refers to the presence of
alpha waves during N3 sleep. Bedtime is the time when a person
gets into bed and attempts to fall asleep, whereas final awakening
is the time when a person awakens for the final time. Lights out
refers to the time when sleep recording started, and lights on is
the time when sleep recording ended. Oxygen desaturation index
is the number of oxygen desaturation events per hour of sleep.
REM sleep latency is measured from the onset of sleep to the first
epoch of REM sleep, and is about 60 to 120 minutes in healthy
adults. Sleep efficiency is the ratio of total sleep time [TST] to time
in bed [TIB] or (TST X 100)/TIB. Sleep onset latency refers to the
time from lights out to sleep onset (i.e., first epoch of any stage of
sleep), and is less than 15 to 30 minutes in healthy adults. Sleep
onset REM periods are defined by the occurrence of REM sleep
within 10 to 15 min of sleep onset. Time in bed is the duration of
monitoring between “lights out” to “lights on”, while total sleep time
refers to the sum of all sleep stages (NREM stages 1-3 sleep plus
REM sleep) in minutes. Finally, wake time after sleep onset is
defined as the time spent awake during the period from sleep
onset to final awakening.
Artifacts are unwanted recordings during polysomnography that
127
arise either from faulty electrode placement, defective monitoring
devices or amplifiers, or contamination by physiologic or
environmental variables. Artifacts can be generalized, affecting
several or most channels; or localized, when limited to a single
channel. Generalized artifacts suggest a defective reference
electrode that is common to the affected channels, whereas
localized artifacts suggest a defect in the specific electrode itself.
The 60 Hz interference artifact appears as a dense, squareshaped EEG tracing, and is due to either interference by 60 Hz
electrical activity from power lines; high and unequal electrode
impedance; or lead failure. It can be corrected by fixing the
electrode placement or changing leads; use of a 60 Hz filter may
be considered as a last resort if the previous interventions fail to
minimize or eliminate the 60 Hz interference artifact.
Figure: 60-Hz interference artifact
Electrode popping artifacts are sudden, sharp, high-amplitude
deflections due to pulling of electrode leads away from the skin by
body movements or respiration; the patient lying on the electrode;
faulty electrode placement; or drying out of the electrode gel.
Corrective measures consist of fixing electrode placements,
changing leads, or applying more electrode gel.
128
Figure: Electrode popping artifact
Sweat artifacts are slow undulating movements that are
synchronous with respiration, and result from alterations in
electrode potentials by the salt content in sweat. Decreasing room
temperature is an effective preventive and corrective intervention.
Figure: Sweat artifact
Epworth sleepiness scale is an eight-item questionnaire that
measures a person’s general propensity to fall asleep in various
situations in recent times, including (a) sitting and reading; (b)
watching television; (c) sitting and inactive in a public place; (d) as
a passenger in a car for an hour without a break; (e) lying down to
rest in the afternoon; (f) sitting and talking to someone; (g) sitting
quietly after lunch without drinking alcohol; and (h) stopped in a
car for a few minutes in traffic. Chances of dozing are scored as
either: 0 (never), 1 (slight chance), 2 (moderate chance) or 3 (high
chance). An aggregate score between 0-9 is considered normal,
whereas 10 or more is suggestive of sleepiness and a sleep
specialist advice is, therefore, recommended. Unfortunately,
correlation between Epworth sleepiness scale, multiple sleep
latency test and maintenance of wakefulness test is poor. Epworth
129
sleepiness scale scores in persons with obstructive sleep apnea
are elevated, but improve with effective therapy of the disorder.
Stanford sleepiness scale is a seven-point subjective measure
of perception of sleepiness at a given time, ranging from “wide
awake, vital and alert” to “unable to remain awake with sleep
onset imminent”.
Multiple sleep latency test (MSLT) is an objective measure of
the physiologic tendency to fall asleep in quiet situations, and is
indicated for evaluation of unexplained excessive sleepiness, or
suspected narcolepsy, and to distinguish between narcolepsy and
idiopathic hypersomnia. An adequate sleep duration and regular
sleep-wake schedules should be maintained for at least one to
two weeks prior to the study. Medications that can potentially
affect sleep onset latency and REM sleep, such as stimulants,
hypnotics, sedatives, REM sleep suppressants and opioids,
should be discontinued for at least two weeks, or at least five
times the half-life of the drug and its longest-acting metabolite,
before the study. A nocturnal polysomnography should be
performed immediately before a test to exclude other causes of
excessive sleepiness, including obstructive sleep apnea or
periodic limb movement disorder. The test should not be
performed after a split-night polysomnography. There should be
an adequate duration of nocturnal sleep (at least 6 hours) during
the preceding polysomnography. Obstructive sleep apnea, if
present, should be adequately treated before performing the test.
If the patient uses positive airway pressure therapy for obstructive
sleep apnea, it should be used during both the preceding
polysomnography and multiple sleep latency test. The study
consists of 4 to 5 nap opportunities. Each nap trial is 20 minutes
in duration, and is performed every 2 hours starting about 1.5 to 3
hours after awakening from the previous night’s sleep. Smoking
and stimulating activities should be stopped before each nap trial,
and caffeine and vigorous physical activity avoided during the day
of the study. A urine drug screen should be performed during test
day. Standard biocalibrations are performed before and after each
trial. During the trial, the patient is asked to lie down in a
comfortable position in a dark, quiet room, close his/her eyes and
try to fall asleep. Standard leads include electroencephalography,
electro-oculography, electrocardiography and electromyography
130
(chin). Sleep onset latency is defined as the time from lights out to
the onset of sleep (i.e., first epoch of any stage of sleep for clinical
MSLT). If no sleep occurs during a nap trial, its sleep onset
latency is recorded as 20 minutes. In addition, the occurrence of
sleep onset REM periods (greater than 15 seconds of REM sleep
in a 30-second epoch) is determined for each nap trial. REM
sleep latency is the time from the first epoch of sleep to the
beginning of the first epoch of REM sleep. The nap trial is
terminated after 20 minutes if no sleep is recorded. If sleep is
recorded, the test is continued for an additional 15 minutes to
allow REM sleep to occur. The test is stopped after the first epoch
of unequivocal REM sleep. The patient is asked to get out of bed
and to remain awake between nap trials. A shorter 4-nap test
may be considered if two or more sleep onset REM periods have
already occurred during earlier nap trials, and if the mean sleep
onset latency is abnormal. Sleep onset latency tends to be
shortest during the third (noon) and fourth (early afternoon) naps
and longest in the fifth nap (late afternoon). A short mean sleep
onset latency suggests the presence of excessive sleepiness.
Mean sleep latencies (mean ± SD [minutes]) are 3 ± 3 for
narcolepsy; 6 ± 3 for idiopathic hypersomnia; 10 ± 4 for normal
controls during a 4-nap MSLT; and 11 ± 5 for normal controls
during a 5-nap MSLT. A short sleep onset latency is present in up
to 15 to 30% of normal individuals. Other causes of a short sleep
onset latency include sleep deprivation, delayed sleep phase
syndrome, obstructive sleep apnea, periodic limb movement
disorder, acute withdrawal of stimulant agents, and use of longacting hypnotic agents on the night preceding the test. The
propensity for REM sleep is greatest during the first nap. Causes
of sleep onset REM periods include narcolepsy, obstructive sleep
apnea, delayed sleep phase syndrome, withdrawal from REM
suppressants, alcohol withdrawal, depression and sleep
deprivation. Sleep onset REM periods are present in 1% to 3% of
normal healthy adults. Normative MLST parameters are not well
established for children less than 8 years of age.
Maintenance of wakefulness test (MWT) is an objective
measure of a person’s ability to remain awake in quiet situations
for a specified period of time. This test is indicated to assess an
individual’s ability to maintain wakefulness, and to assess
response to treatment for excessive sleepiness. An MWT consists
131
of four nap opportunities performed at two-hour intervals. A fortyminute protocol for each nap is recommended. The first nap trial
is started about 1.5 to 3 hours after the person’s customary wake
time. The need for polysomnography prior to MWT should be
individualized as determined by the clinician. During each nap
trial, a person is asked to sit in bed in a semi-reclined position and
in a dark, quiet room. The person is instructed to try to stay awake
during the test. However, measures to stay awake, such as
singing, are not allowed during nap trials. The use of tobacco,
caffeine and stimulant agents should be avoided during test day.
Drug screening may be considered. Standard biocalibrations are
performed before and after each nap trial. Standard leads include
electroencephalography,
electro-oculography
and
chin
electromyography. Each nap trial is terminated if either
unequivocal sleep occurs (i.e., three consecutive epochs of N1
sleep, or one epoch of any other sleep stage); or if no sleep is
recorded after 40 minutes. Sleep onset latency is defined as the
time from lights out to the first epoch of sleep for each nap. Mean
sleep onset latency correlates with the ability to stay awake, and
any value less than 8 minutes is considered abnormal; values
greater than 8 minutes but less than 40 minutes is of uncertain
significance; and a value of 40 minutes is considered normal and
may provide an appropriate expectation for individuals who
require the highest level of alertness for safety. This test is less
sensitive than the multiple sleep latency test in measuring
sleepiness.
Actigraphy is a technique that can be used to determine periods
of inactivity, either rest or sleep, vs. activity using sensors that can
detect movement. Movements are detected using accelerometers
that are typically worn on the wrist, and data can be recorded over
a period of several days to weeks. Movement data are summated
for a specified epoch time, and each epoch is scored as either
“active” or inactive” based on predetermined thresholds for activity
counts. Data that can be obtained with actigraphy include total
wake time, total sleep time, sleep onset latency (if used with an
event monitor to mark the time when a person desires to fall
asleep) and wake time after sleep onset. Actigraphy is indicated
for the evaluation of certain circadian rhythm sleep disorders and
their response to therapy. It may also be considered to aid in the
diagnosis of insomnia, particularly paradoxical insomnia.
132
Actigraphic monitoring should include at least three consecutive
24-hour periods. Actigraphy it is better at measuring total sleep
time than identifying sleep onset latency. The degree of
correlation between polysomnography and actigraphy for total
sleep time, total awake time, and sleep continuity is greater
among normal sleepers than in persons with insomnia or sleep
disturbances. In general, polysomnography tends to detect more
sleep time compared to actigraphy in both normal sleepers and in
persons with insomnia.
133
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134
Index
Acetylcholine 17
Actigraphy 132
Acute stress disorder 89
Adenosine 17
Adjustment insomnia 29
Adult respiratory events 123
Adult sleep stages 117
Advanced sleep phase syndrome 75
Agents causing REM behavior disorder 112
Agents causing restless legs syndrome 112
Agents that can cause insomnia 112
Agents that can cause sedation 112
Aging 106
Alcohol 110
Alcohol-dependent sleep disorder 93
Alternating leg muscle activation 93
Altitude insomnia 30
Alzheimer’s dementia 84
Amyotrophic lateral sclerosis 84
Anticonvulsant agents 73
Antidepressants 38, 110
Antipsychotics 38, 111
Anxiety disorders 89
Apnea of prematurity 104
Apnea 48
Apnea-hypopnea index 48
Apparent life-threatening event 105
Arousals 123
Artifacts 127
Asthma 79
Attention deficit hyperactivity disorder 84
Atypical depression 92
Autonomic nervous system 19, 26
Behavioral insomnia of childhood 30
Benign sleep myoclonus of infancy 93
Benzodiazepine receptor agonists 37
Benzodiazepines 37, 73
Bipolar disorder 91
Blindness 84
135
Botanical compounds 38
Cardiac arrhythmias 80
Cardiovascular system 19
Cataplexy 43, 47
Catathrenia 65
Central nervous system 26
Central sleep apnea 59, 107
Cerebral degenerative disorders 84
Cerebrospinal fluid hypocretin-1 46
Cheyne Stokes respiration 60
Childhood obstructive sleep apnea 104
Chin electromyography 115
Chronic obstructive pulmonary disease 79
Chronic pain syndromes 80
Circadian neurosystem 23
Circadian rhythm sleep disorders 75
Cognition 26
Cognitive therapy 34
Cognitive-behavioral treatments for insomnia 34
Complex sleep apnea 48, 61
Confusional arousals 66
Congenital central alveolar hypoventilation 63
Congestive heart failure 61, 80
Coronary artery disease 81
Cortisol 20
Delayed sleep phase syndrome 75
Derivation 113
Diaphragm paralysis 81
Disorders of arousal 65
Dopamine 17
Dopaminergic agents 73
Down syndrome 85
Dreaming 22
Drugs of abuse 111
Eating disorders 90
Effective countermeasures for sleepiness 42
Electrocardiography 115
Electroencephalographic waveforms 114
Electroencephalography 114
Electromyography of the anterior tibialis 117
Electro-oculography 115
136
Endocrine system 20, 26
End-stage renal disease 81
Environmental sleep disorder 93
Epworth sleepiness scale 129
Excessive sleepiness 39, 43, 47, 103
Exploding head syndrome 66
Fatal familial insomnia 30
Fibromyalgia 81
Fragmentary myoclonus 94
Free-running circadian rhythm syndrome 76
Gamma-aminobutyric acid 17
Gastroesophageal reflux 81
Gastrointestinal system 20
Generalized anxiety disorder 89
Ghrelin 21
Glutamate 17
Glycine 17
Growth hormone 20
Headache syndromes 85
High altitude periodic breathing 60
Histamine 18
Human immunodeficiency virus infection 82
Human leukocyte antigen typing 47
Hypertension 82
Hypnagogic foot tremor 94
Hypnotic agents 111
Hypnotic-dependent sleep disorder 94
Hypocretin 18
Hypomanic episode 91
Hypopnea 48
Hypoventilation syndromes 63
Idiopathic alveolar hypoventilation 63
Idiopathic hypersomnia 40
Idiopathic insomnia 31
Immune system 21, 26
Inadequate sleep hygiene 32
Infant sleep apnea 105
Infants and children 100
Insomnia 28, 106
Insomnia in children 102
Insufficient sleep syndrome 39
137
Insulin 21
Irregular sleep-wake rhythm syndrome 77
Isolated sleep paralysis 66
Jet lag 77
Leptin 21
Limit-setting sleep disorder 30
Long sleeper 94
Main neurotransmitters 17
Maintenance of wakefulness test 41, 46, 131
Major body movements 121
Major depressive disorder 91
Major depressive episode 90
Manic episode 90
Measuring airflow 116
Measuring oxygenation and ventilation 116
Measuring respiratory effort 116
Medical disorders 79
Medications and their effects on sleep 110
Melatonin 18, 21, 25, 38
Melatonin receptor agonist 37
Menopause 108
Menstruation 107
Metabolic rate 22
Metabolism 26
Milestones in sleep architecture 100
Milestones in sleep-related behaviors 101
Mixed episode 91
Mood disorders 90
Movement events 126
Multi-component behavioral therapy 35
Multiple sleep latency test 41, 46, 51, 130
Multiple system atrophy 86
Musculoskeletal system 21
Narcolepsy without cataplexy 45
Narcolepsy 43
Neural systems generating NREM sleep 16
Neural systems generating REM sleep 16
Neural systems generating wakefulness 16
Neurobiology of sleep 16
Neurological disorders 84
Neuromuscular disorders 86
138
Nightmare disorder 67
Non-prescription hypnotic agents 38
Norepinephrine 18
Obstructive sleep apnea 48, 107
Opioid agents 73, 111
Oral devices 55
Oxygen therapy 52
Panic disorder 90
Paradoxical insomnia 32
Paradoxical intention 34
Parasomnias occurring during REM sleep 65
Parasomnias 65
Parkinson disease 86
Pediatric respiratory events 125
Pediatric sleep stage scoring rules 122
Periodic limb movement disorder 71, 74
Periodic limb movements during sleep 73
Pharmacotherapy of insomnia 35
Physiologic changes with aging 106
Physiology during sleep 19
Polycystic ovarian syndrome 108
Polygraph 113
Polysomnography 41, 59, 64, 72, 113
Positional therapy 52
Positive airway pressure therapy 52
Postpartum period 108
Post-traumatic stress disorder 90
Pregnancy 108
Primary central sleep apnea 60
Propriospinal myoclonus at sleep onset 95
Psychiatric disorders 89
Psychophysiologic insomnia 32
Pupillary changes 21
Recurrent hypersomnia 40
Regulation of sleep and waking 23
Relaxation techniques 35
REM sleep behavior disorder 67
Renal and genito-urinary systems 20
Residual sleepiness 57
Respiratory effort-related arousal 48
Respiratory patterns 19
139
Respiratory system 19, 26
Restless legs syndrome 71
Restrictive pulmonary diseases 83
Rhythmic movement disorder 95
Schizophrenia 92
Scoring sleep stages 117
Seasonal affective disorder 91
Secondary narcolepsy 45
Seizure disorders 87
Serotonin 18
Shift work sleep disorder 78
Short sleeper 95
Sleep deprivation 26
Sleep enuresis 69
Sleep hallucinations 44
Sleep homeostasis 23
Sleep hygiene 33
Sleep hyperhidrosis 96
Sleep in women 107
Sleep paralysis 44
Sleep restriction 35
Sleep scoring in newborns 122
Sleep stages after 6 months of age 101
Sleep stages in the first 6 months of age 100
Sleep start 98
Sleep talking 98
Sleep terrors 70
Sleeping sickness 83
Sleep-onset association disorder 30
Sleep-onset central apneas 61
Sleep-related abnormal swallowing 96
Sleep-related bruxism 96
Sleep-related choking syndrome 97
Sleep-related eating disorder 69
Sleep-related laryngospasm 97
Sleep-related leg cramps 98
Sleep-related neurogenic tachypnea 97
Sleep-related painful erections 97
Sleepwalking 70
Snoring 98, 105, 117
Stage N1 sleep 118
140
Stage N2 sleep 119
Stage N3 sleep 120
Stage REM sleep 121
Stage wake 117
Stanford sleepiness scale 130
Status cataplecticus 43
Stimulant-dependent sleep disorder 99
Stimulants 112
Stimulus control 35
Stroke 88
Subjective tests of sleepiness 41
Sudden infant death syndrome 99
Sudden unexplained nocturnal death 99
Suggested immobilization test 72
Suprachiasmatic nucleus 24
Testosterone 21
Thermoregulation 21
Thyroid stimulating hormone 20
Upper airway imaging studies 52
Upper airway resistance syndrome 57
Upper airway surgery 56
141
Disclaimer
Every effort has been made to verify the accuracy of the facts in
this book. Any errors that were missed will be incorporated in
future editions. In the meantime, kindly accept the author’s
sincere apology if any correction has been overlooked or if any
concept has not been satisfactorily presented. The author can not
accept any legal responsibility for any errors or omissions that
may be made, and can not make any warranty related to the
material contained in this handbook. Medication usage should be
confirmed with current reference materials and medical textbooks.
Notes
Notes
Medication dosages and notes
Armodafinil
Clonazepam
Eszopiclone
Methylphenidate
Modafinil
Pramipexole
Ramelteon
Ropinirole
Sodium oxybate
Zaleplon
Zolpidem
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Important numbers
Sleep laboratory
1. _______________
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3. _______________
2.
Sleep medicine clinic
1. _______________
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3. _______________
2.
Medical center
1. _______________
2.
_______________
Emergency department
Pharmacy
Security
__________________
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Medical director
_________________
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Sleep center director
_________________
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Sleep lab manager
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Sleep physician
1. _______________
_______________
3. _______________
2.
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