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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 Apnea-hypopnea index BPAP Bi-level positive airway pressure CPAP Continuous positive airway pressure CSA Central sleep apnea ECG Electrocardiography EEG Electroencephalography EMG Electromyography EOG Electro-oculography FEV1 Forced expiratory volume in 1 second GABA Gamma-aminobutyric acid N1 NREM stage 1 sleep N2 NREM stage 2 sleep N3 NREM stages 3 (and 4) sleep NREM Non-rapid eye movement O2 Oxygen OSA Obstructive sleep apnea PaCO2 Partial pressure of arterial carbon dioxide PaO2 Partial pressure of arterial oxygen REM Rapid eye movement sleep SaO2 Oxygen saturation SOREMP Sleep onset REM period

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Table of contents Introduction 15 Neurobiology of sleep 16 Neural systems generating wakefulness 16 Neural systems generating NREM sleep 16 Neural systems generating REM sleep 16 Main neurotransmitters 17 Acetylcholine 17 Adenosine 17 Dopamine 17 Gamma-aminobutyric acid 17 Glutamate 17 Glycine 17 Histamine 18 Hypocretin 18 Melatonin 18 Norepinephrine 18 Serotonin 18 Physiology during sleep 19 Autonomic nervous system 19 Respiratory system 19

Respiratory patterns 19 Cardiovascular system 19 Gastrointestinal system 20 Renal and genito-urinary systems 20 Endocrine system 20

Growth hormone 20 Thyroid stimulating hormone 20 Cortisol 20 Melatonin 21 Testosterone 21 Insulin 21 Leptin 21 Ghrelin 21

Musculoskeletal system 21 Pupillary changes 21

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Immune system 21 Thermoregulation 21 Metabolic rate 22 Dreaming 22 Regulation of sleep and waking 23 Sleep homeostasis 23 Circadian neurosystem 23 Suprachiasmatic nucleus 24 Melatonin 25 Sleep deprivation 26 Consequences 26

Central nervous system 26 Autonomic nervous system 26 Cognition 26 Respiratory system 26 Endocrine system 26 Metabolism 26 Immune system 26 Behavioral and psychiatric effects 26

Polysomnographic features 27 Insomnia 28 General changes in sleep architecture 28 Prevalence 28 Mechanisms 28 Risk factors 28 Consequences 29 Classification 29 Specific causes 29 Adjustment insomnia 29 Altitude insomnia 30 Behavioral insomnia of childhood 30

Limit-setting sleep disorder 30 Sleep-onset association disorder 30

Fatal familial insomnia 30 Idiopathic insomnia 31 Inadequate sleep hygiene 32 Paradoxical insomnia 32 Psychophysiologic insomnia 32

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Medications 33 Evaluation of insomnia 33 Polysomnographic features 33 Therapy of insomnia 33 Sleep hygiene 33 Cognitive-behavioral treatments for insomnia 34

Cognitive therapy 34 Paradoxical intention 34 Relaxation techniques 35 Sleep restriction 35 Stimulus control 35 Multi-component behavioral therapy 35

Pharmacotherapy of insomnia 35 Benzodiazepines 37 Benzodiazepine receptor agonists 37 Melatonin receptor agonist 37 Antidepressants and antipsychotics 38 Non-prescription hypnotic agents 38 Melatonin 38 Botanical compounds 38

Excessive sleepiness 39 Prevalence 39 Consequences 39 Mechanisms 39 Specific causes of excessive sleepiness 39

Insufficient sleep syndrome 39 Idiopathic hypersomnia 40 Recurrent hypersomnia 40 Medical, neurological or psychiatric 41 Medications 41

Evaluation of excessive sleepiness 41 Subjective tests of sleepiness 41 Polysomnography 41 Multiple sleep latency test 41 Maintenance of wakefulness test 41

Effective countermeasures for sleepiness 42 Narcolepsy 43 Excessive sleepiness 43 Cataplexy 43

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Status cataplecticus 43 Sleep hallucinations 44 Sleep paralysis 44 Sleep disturbance 44 Other important clinical features 44 Consequences 44 Prevalence 44 Clinical course 44 Pathophysiology 45 Narcolepsy without cataplexy 45 Secondary narcolepsy 45 Evaluation 46

Polysomnographic features 46 Multiple sleep latency test 46 Maintenance of wakefulness test 46 Cerebrospinal fluid hypocretin-1 46 Human leukocyte antigen typing 47

Therapy 47 Excessive sleepiness 47 Sleep disturbance 47 Cataplexy 47

Obstructive sleep apnea 48 Apnea 48 Hypopnea 48 Respiratory effort-related arousal 48 Complex sleep apnea 48 Apnea-hypopnea index 48 Prevalence 48 Pathophysiology 49 Risk factors 49 Clinical features 49 Physical examination 50 Consequences 50 Evaluation 51

Polysomnographic features 51 Multiple sleep latency test 51 Upper airway imaging studies 52

Therapy 52

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General measures 52 Positional therapy 52 Oxygen therapy 52 Pharmacologic treatments 52 Positive airway pressure therapy 52 Oral devices 55 Upper airway surgery 56 Residual sleepiness 57

Upper airway resistance syndrome 57 Central sleep apnea 59 Polysomnography 59 Classification 59 Primary central sleep apnea 60 Cheyne Stokes respiration 60 High altitude periodic breathing 60 Medication use 61 Congestive heart failure 61 Sleep-onset central apneas 61 During positive airway pressure titration 61 Therapy of central sleep apnea 61 Hypoventilation syndromes 63 Mechanisms 63 Medical and neurological disorders 63 Idiopathic alveolar hypoventilation 63 Congenital central alveolar hypoventilation 63 Polysomnography 64 Therapy 64 Parasomnias 65 Disorders of arousal 65 Parasomnias occurring during REM sleep 65 Catathrenia 65 Confusional arousals 66 Exploding head syndrome 66 Isolated sleep paralysis 66 Nightmare disorder 67 REM sleep behavior disorder 67 Sleep enuresis 69

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Sleep-related eating disorder 69 Sleep terrors 70 Sleepwalking 70 Restless legs syndrome and Periodic limb movement disorder 71 Prevalence 71 Classification 71 Risk factors 71 Consequences 72 Evaluation 72

Suggested immobilization test 72 Polysomnography 72

Differential diagnosis 72 Pathophysiology 72 Therapy 73

Dopaminergic agents 73 Benzodiazepines 73 Opioid agents 73 Anticonvulsant agents 73

Periodic limb movements during sleep 73 Periodic limb movement disorder 74 Circadian rhythm sleep disorders 75 Advanced sleep phase syndrome 75 Delayed sleep phase syndrome 75 Free-running circadian rhythm syndrome 76 Irregular sleep-wake rhythm syndrome 77 Jet lag 77 Shift work sleep disorder 78 Medical disorders 79 Asthma 79 Chronic obstructive pulmonary disease 79 Cardiac arrhythmias 80 Chronic pain syndromes 80 Congestive heart failure 80 Coronary artery disease 81 Diaphragm paralysis 81 End-stage renal disease 81 Fibromyalgia 81

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Gastroesophageal reflux 81 Human immunodeficiency virus infection 82 Hypertension 82 Restrictive pulmonary diseases 83 Sleeping sickness 83 Neurological disorders 84 Alzheimer’s dementia 84 Amyotrophic lateral sclerosis 84 Attention deficit hyperactivity disorder 84 Blindness 84 Cerebral degenerative disorders 84 Down syndrome 85 Headache syndromes 85 Multiple system atrophy 86 Neuromuscular disorders 86 Parkinson disease 86 Seizure disorders 87 Stroke 88 Psychiatric disorders 89 Anxiety disorders 89

Acute stress disorder 89 Generalized anxiety disorder 89 Post-traumatic stress disorder 90 Panic disorder 90

Eating disorders 90 Mood disorders 90

Major depressive episode 90 Manic episode 90 Hypomanic episode 91 Mixed episode 91

Major depressive disorder 91 Bipolar disorder 91 Seasonal affective disorder 91 Atypical depression 92 Schizophrenia 92 Miscellaneous sleep disorders 93 Alcohol-dependent sleep disorder 93 Alternating leg muscle activation 93

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Benign sleep myoclonus of infancy 93 Environmental sleep disorder 93 Fragmentary myoclonus 94 Hypnagogic foot tremor 94 Hypnotic-dependent sleep disorder 94 Long sleeper 94 Propriospinal myoclonus at sleep onset 95 Rhythmic movement disorder 95 Short sleeper 95 Sleep hyperhidrosis 96 Sleep-related abnormal swallowing 96 Sleep-related bruxism 96 Sleep-related choking syndrome 97 Sleep-related laryngospasm 97 Sleep-related neurogenic tachypnea 97 Sleep-related painful erections 97 Sleep-related leg cramps 98 Sleep start 98 Sleep talking 98 Snoring 98 Stimulant-dependent sleep disorder 99 Sudden infant death syndrome 99 Sudden unexplained nocturnal death 99 Infants and children 100 Milestones in sleep architecture 100 Sleep stages in the first 6 months of age 100 Sleep stages after 6 months of age 101 Milestones in sleep-related behaviors 101 Aggregate hours of sleep per day 101 Insomnia in children 102 Excessive daytime sleepiness 103 Childhood obstructive sleep apnea 104 Apnea of prematurity 104 Infant sleep apnea 105 Apparent life-threatening event 105 Snoring 105 Aging 106 Physiologic changes with aging 106

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Changes in sleep architecture 106 Insomnia 106 Sleep in women 107 Obstructive sleep apnea 107 Central sleep apnea 107 Menstruation 107 Polycystic ovarian syndrome 108 Pregnancy 108 Postpartum period 108 Menopause 108 Medications and their effects on sleep 110 Alcohol 110 Antidepressants 110 Antipsychotics 111 Drugs of abuse 111 Hypnotic agents 111 Opioids 111 Stimulants 112 Agents that can cause insomnia 112 Agents that can cause sedation 112 Agents causing restless legs syndrome 112 Agents causing REM behavior disorder 112 Polysomnography and other sleep tests 113 Indications 113 Polygraph 113 Derivation 113 Electroencephalography 114 Electroencephalographic waveforms 114 Electro-oculography 115 Chin electromyography 115 Electrocardiography 115 Measuring airflow 116 Measuring respiratory effort 116 Measuring oxygenation and ventilation 116 Identifying snoring 117 Electromyography of the anterior tibialis 117 Scoring sleep stages 117 Adult sleep stages 117

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Stage wake 117 Stage N1 sleep 118 Stage N2 sleep 119 Stage N3 sleep 120 Stage REM sleep 121

Major body movements 121 Pediatric sleep stage scoring rules 122 Sleep scoring in newborns 122 Arousals 123 Adult respiratory events 123 Pediatric respiratory events 125 Movement events 126 Definitions of polysomnographic parameters 127 Artifacts 127 Epworth sleepiness scale 129 Stanford sleepiness scale 130 Multiple sleep latency test 130 Maintenance of wakefulness test 131 Actigraphy 132

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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 warmth-sensing 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 rhythm-related 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.

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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-5-methoxytryptamine). 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.

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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 decision-making, 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

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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.

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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;

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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.

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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 limit-setting 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

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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.

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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

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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

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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

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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,

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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, intermediate-acting 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 acid-benzodiazepine (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).

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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 short-acting 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 short-acting 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.

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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; anti-cholinergic 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.

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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

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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’s-type 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

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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.

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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.

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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.

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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

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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

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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

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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 γ-hydroxybutyrate (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 serotonin-norepinephrine reuptake inhibitors or monoamine oxidase inhibitors; or γ-hydroxybutyrate.

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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.

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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 post-apneic 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 African-Americans, 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

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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

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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 split-night 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-of-phase” 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)

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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

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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 polysomnographically-recorded 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

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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

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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

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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 apnea-hypopnea 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 temporo-mandibular 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

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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

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consists of positive airway pressure, oral devices or upper airway surgery.

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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 long-acting 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 hyper-capnia. 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 non-hypercapnic 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

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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 sleep-related 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.

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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 long-acting 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

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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 high-altitude 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.

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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

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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.

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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, sleep-related 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.

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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

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isolated sleep paralysis include sleep deprivation, irregular sleep-wake 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

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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 co-occurrence 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.

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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

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performed, demonstrates arousals from N3 sleep and, occasionally, from REM sleep. 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.

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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;

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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 sleep-maintenance 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

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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

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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.

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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

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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

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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 sleep-wake 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

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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 work-related 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. Sleep-related 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

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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.

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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. Alpha-NREM 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 anti-reflux 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.

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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 sleep-related 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, sleep-onset 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

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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.

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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 sleep-related 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 sleep-maintenance 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

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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. Sleep-related 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

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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.

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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

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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 middle-aged adults, and affects both genders equally. Hypnagogic foot tremor may be a normal phenomenon, but can result in sleep-onset 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 sleep-related 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

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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

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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 pre-adolescence (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 sleep-onset 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 end-tidal 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

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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, non-restorative sleep, unpleasant dreams or nightmares, and excessive sleepiness. Finally, premenstrual dysphoric disorder presents as fatigue, mood changes and daytime impairment that

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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. Pregnancy-induced 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)

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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 sleep-related 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 low-frequency 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, end-tidal 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. Saw-tooth 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 negatively-charged 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

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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.

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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.

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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.

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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

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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, electro-oculography 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) high-voltage 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] high-amplitude 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).

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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

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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

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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

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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

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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, square-shaped 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.

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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

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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

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(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 long-acting 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

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of four nap opportunities performed at two-hour intervals. A forty-minute 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.

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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.

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References 1. Lee-Chiong T. Sleep Medicine: Essentials and Review.

Oxford University Press, 2008. 2. Lee-Chiong TL (Ed). Sleep: A Comprehensive Handbook.

John Wiley & Sons, Hoboken, New Jersey, 2006. 3. Lee-Chiong TL, Sateia M, Carskadon M (eds). Sleep

Medicine. Hanley & Belfus Elsevier, Philadelphia, 2002. 4. Berry RB. Sleep Medicine Pearls [2nd Edition]. Hanley &

Belfus, Philadelphia. 2002. 5. Chokroverty S. Clinical Companion to Sleep Disorders

Medicine Second Edition. Butterworth-Heinemann. 2000. 6. Reite M, Ruddy J, Nagel K. Concise Guide to Evaluation and

Management of Sleep Disorders, Third Edition. American Psychiatric Publishing. April 2002.

7. Barkoukis TJ. Review of Sleep Medicine. Butterworth-Heinemann. 2002.

8. Lavie P, Pillar G, Malhotra A. Sleep Disorders Handbook. Taylor & Francis. 2002.

9. Perlis ML, Lichstein KL (eds). Treating Sleep Disorders: Principles and Practice of Behavioral Sleep Medicine. John Wiley & Sons, Hoboken, New Jersey, 2003.

10. Sleep Research Society. SRS Basics of Sleep Guide. Sleep Research Society. 2005.

11. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Brain Information Service/Brain Research Institute. University of California. 1968.

12. American Academy of Sleep Medicine. The International Classification of Sleep Disorders, Second Edition: Diagnostic and Coding Manual. American Academy of Sleep Medicine. 2005.

13. Iber C, Ancoli-Israel S, Chesson A, and Quan SF for the American Academy of Sleep Medicine. The AASM Manual for the Scoring of Sleep and Associated Event Rules: Terminology and Technical Specifications, 1st ed: Westchester, Illinois: American Academy of Sleep Medicine, 2007.

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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

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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

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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

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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

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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

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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

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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

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 _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________ ___________ _______________________

Important numbers Sleep laboratory 1. _______________ __________________ 2. _______________ __________________ 3. _______________ __________________ Sleep medicine clinic 1. _______________ __________________ 2. _______________ __________________ 3. _______________ __________________ Medical center 1. _______________ __________________ 2. _______________ __________________ Emergency department __________________ Pharmacy __________________ Security __________________ Medical director _________________ __________________ Sleep center director _________________ __________________ Sleep lab manager _________________ __________________ Sleep physician 1. _______________ __________________ 2. _______________ __________________ 3. _______________ __________________