Sleep Disorders¶
Chapter 33 | Part 2: Cardinal Manifestations and Presentation of Diseases
KEY CLINICAL POINTS¶
- Over 50% of U.S. adults experience intermittent sleep disturbance; 50-70 million Americans suffer from chronic sleep disorders, with >80% remaining undiagnosed
- Sleep is regulated by two principal systems: the ascending arousal system (monoamines, glutamate, acetylcholine, orexin) and the sleep-promoting system (GABAergic neurons in preoptic area)
- Chronic sleep deficiency is associated with diabetes, obesity, metabolic syndrome, cardiovascular disease, cognitive impairment, Alzheimer's disease, and increased mortality
- Obstructive sleep apnea affects 24% of middle-aged men and 9% of women; narcolepsy type 1 is caused by loss of orexin-producing neurons
- Circadian rhythm disorders result from misalignment between the endogenous ~24.15-hour pacemaker (SCN) and desired sleep-wake cycle
1. PHYSIOLOGY OF SLEEP AND WAKEFULNESS¶
Most adults need 7-9 hours of sleep per night for optimal health. Sleep stages are defined by characteristic patterns in electroencephalogram (EEG), electrooculogram (EOG), and electromyogram (EMG). Polysomnography is the continuous recording of these parameters to define sleep and wakefulness.
Sleep Architecture by Age¶
| Parameter | Young Adults | Older Adults (>70 years) |
|---|---|---|
| N3 (Slow-wave) Sleep | 15-25% of total sleep | Often absent or minimal |
| REM Sleep | 20-25% of total sleep | Relatively preserved |
| NREM N1/N2 | 50-60% of total sleep | Increased proportion |
| Sleep Fragmentation | Minimal | Frequent awakenings |
| Total Sleep Time | 7-9 hours | ~1 hour less than young adults |
1.1 Sleep Stages¶
Two basic states of sleep exist: (1) Rapid Eye Movement (REM) sleep and (2) Non-REM (NREM) sleep. NREM sleep is subdivided into three stages (N1, N2, N3) characterized by increasing arousal threshold and EEG slowing. REM sleep features low-amplitude mixed-frequency EEG, rapid eye movements in bursts, and absent skeletal muscle EMG activity (brainstem-mediated paralysis).
1.2 Organization of Human Sleep¶
After sleep onset, sleep progresses through NREM stages N1-N3 within 45-60 minutes. N3 (slow-wave sleep) predominates in the first third of the night, comprising 15-25% of total sleep in young adults. First REM episode usually occurs in the second hour. NREM and REM alternate with an ultradian cycle of 60-160 minutes. In healthy young adults: REM = 20-25% of total sleep; NREM N1/N2 = 50-60%.
1.3 Age-Related Changes¶
N3 sleep is most intense during childhood and decreases with puberty and across the second/third decades. In older adults, N3 may be completely absent with more frequent awakenings. REM sleep accounts for 50% of total sleep in infancy but falls to 25% in young adults. Adults >70 years sleep approximately 1 hour less than young adults.
1.4 Effects of Sleep Deprivation¶
Sleep deprivation degrades cognitive performance, particularly vigilance tests. 24 hours of continuous wakefulness impairs reaction time comparable to blood alcohol concentration of 0.10 g/dL. Chronic sleep deficiency is associated with: glucose intolerance, diabetes, obesity, metabolic syndrome, impaired immune responses, accelerated atherosclerosis, cardiac disease, cognitive impairment, Alzheimer's disease, and stroke.
2. NEURAL REGULATION OF WAKE AND SLEEP¶
Two principal neural systems govern sleep and wakefulness, functioning as a 'flip-flop switch' to promote rapid transitions between states while avoiding intermediate states.
Brain Systems Regulating Sleep-Wake States¶
| System | Location | Neurotransmitters | Function |
|---|---|---|---|
| Ascending Arousal System | Upper pons to hypothalamus/basal forebrain | NE, DA, 5-HT, histamine, glutamate, ACh | Promotes wakefulness |
| Orexin System | Lateral hypothalamus | Orexin (hypocretin) | Stabilizes wakefulness, lost in narcolepsy |
| Sleep-Promoting System | Preoptic area, pons | GABA | Inhibits arousal system, promotes sleep |
| MCH Neurons | Lateral hypothalamus | Melanin-concentrating hormone | Promotes REM sleep |
2.1 Ascending Arousal System¶
Located from upper pons to hypothalamus and basal forebrain. Activates cerebral cortex and thalamus. Neurotransmitters include: monoamines (norepinephrine, dopamine, serotonin, histamine), glutamate, and acetylcholine. Basal forebrain neurons use GABA to inhibit cortical inhibitory interneurons. Orexin (hypocretin) neurons in hypothalamus reinforce and stabilize arousal.
2.2 Sleep-Promoting System¶
GABAergic neurons in preoptic area and pons inhibit the arousal system. Melanin-concentrating hormone neurons in lateral hypothalamus promote REM sleep. Mutual inhibition between arousal and sleep-promoting systems forms the flip-flop switch mechanism.
2.3 REM Sleep Regulation¶
GABAergic REM-Off neurons in lower midbrain inhibit REM-On neurons in upper pons. REM-On group contains GABAergic neurons (inhibit REM-Off group) and glutamatergic neurons (project widely). REM-On neurons activate inhibitory interneurons causing motor neuron hyperpolarization (REM paralysis). Cholinergic input favors REM transitions; monoaminergic input prevents REM sleep.
2.4 Homeostatic and Allostatic Regulation¶
Adenosine levels rise with prolonged wakefulness, acting through A1 receptors to inhibit arousal regions and through A2a receptors to promote sleep (blocked by caffeine). Prostaglandin D2 also promotes sleep. Both adenosine and PGD2 activate ventrolateral preoptic nucleus sleep-promoting neurons. Stress responses (allostasis) can severely impact sleep, causing insomnia in anxiety and psychiatric disorders.
3. PHYSIOLOGY OF CIRCADIAN RHYTHMICITY¶
The suprachiasmatic nuclei (SCN) of the hypothalamus serve as the master circadian pacemaker. The genetically determined endogenous period averages ~24.15 hours in humans and is synchronized to the 24-hour light-dark cycle through retinal input from intrinsically photosensitive ganglion cells.
3.1 Circadian Timing and Sleep¶
Circadian rhythm for wake propensity peaks just before habitual bedtime; sleep propensity peaks near habitual wake time. This timing opposes homeostatic sleep tendency, promoting consolidated sleep and wakefulness. Misalignment causes insomnia, decreased alertness, and impaired performance. People with short circadian cycles (e.g., 23.5 hours) due to clock gene mutations prefer early bedtimes (advanced sleep phase disorder).
3.2 Light Sensitivity¶
Humans are exquisitely sensitive to light's phase-resetting effects, particularly shorter wavelengths (460-500 nm) in the blue spectrum. Small differences in circadian period contribute to variations in diurnal preference.
3.3 Melatonin Physiology¶
Secreted from pineal gland predominantly at night under SCN control. Does not require sleep but is inhibited by ambient light. Sleep efficiency is highest when sleep coincides with endogenous melatonin secretion. Exogenous melatonin (3 mg 30 min before bedtime) may help patients with sympathetic denervation of pineal (spinal cord injury, Parkinson's disease) who have low melatonin levels.
4. PHYSIOLOGIC EFFECTS OF SLEEP¶
All major physiologic systems are influenced by sleep, with important clinical implications.
4.1 Cardiovascular¶
Blood pressure and heart rate decrease during NREM sleep (especially N3). During REM sleep, bursts of eye movements cause large variations in BP and HR via autonomic nervous system. Cardiac dysrhythmias may occur selectively during REM sleep.
4.2 Respiratory¶
Respiratory rate becomes slower and more regular during NREM sleep (especially N3), irregular during REM eye movement bursts. Minute ventilation decreases out of proportion to metabolic rate, resulting in slightly higher PCO2.
4.3 Endocrine¶
N3 sleep associated with growth hormone secretion in men. Sleep augments prolactin secretion in both sexes. Sleep onset inhibits TSH and ACTH-cortisol axis (superimposed on circadian rhythms). LH: sleep increases secretion during puberty but inhibits it in early follicular phase in postpubertal women.
4.4 Brain Clearance¶
During sleep, intracellular volume reduces, expanding extracellular space with higher calcium and lower potassium concentrations. This enhances clearance of substances like β -amyloid peptide via CSF flow. Lack of adequate sleep may contribute to β -amyloid accumulation (Alzheimer's pathogenesis).
4.5 Thermoregulation¶
Skin warming increases firing of warm-responsive neurons in preoptic area, causing body temperature fall and promoting NREM sleep onset. REM sleep is associated with reduced thermoregulatory responsiveness.
5. APPROACH TO THE PATIENT WITH SLEEP DISORDERS¶
Patients seek help for: (1) daytime sleepiness/tiredness; (2) difficulty initiating/maintaining sleep (insomnia); or (3) unusual behaviors during sleep (parasomnias).
Evaluation of the Patient with Excessive Daytime Sleepiness¶
| Findings on History/Physical | Diagnostic Evaluation | Diagnosis | Therapy |
|---|---|---|---|
| Difficulty waking in morning, rebound sleep on weekends/vacations with improvement | Sleep log | Insufficient sleep | Sleep education, behavioral modification to increase sleep |
| Obesity, snoring, hypertension | Polysomnogram or home sleep test | Obstructive sleep apnea | CPAP; upper airway surgery (UPPP); dental appliance; weight loss |
| Cataplexy, hypnagogic hallucinations, sleep paralysis | Polysomnogram and MSLT | Narcolepsy | Stimulants (modafinil, methylphenidate); REM-suppressing antidepressants (venlafaxine); pitolisant; solriamfetol; sodium oxybate |
| Restless legs, kicking movements during sleep | Assessment for iron deficiency, renal failure | Restless legs syndrome ± periodic limb movements | Treat predisposing condition; dopamine agonists (pramipexole, ropinirole); gabapentin; pregabalin; opiates |
| Sedating medications, head trauma, systemic inflammation, Parkinson's, hypothyroidism, encephalopathy | Thorough medical/neurologic examination | Sleepiness due to drug or medical condition | Change medications, treat underlying condition, consider stimulants |
5.1 Clinical Assessment¶
Essential history elements: duration, severity, consistency of symptoms; consequences on waking function; typical bed/wake times; awakenings during sleep; morning restfulness; daytime napping. Additional inquiries: snoring, witnessed apneas, restless legs, movements during sleep, depression, anxiety, behaviors around sleep. Physical examination: airway size, tonsils, neurologic/medical findings. A 2-week sleep log documenting sleep timing and daily alertness is diagnostically useful.
5.2 Diagnostic Studies¶
Polysomnography: measures sleep stages, respiratory effort/airflow, oxygen saturation, limb movements, heart rhythm. Required for diagnosing sleep apnea, narcolepsy, and periodic limb movement disorder. Home sleep test: focuses on respiratory measures, useful for moderate-high probability obstructive sleep apnea. Multiple Sleep Latency Test (MSLT): measures propensity to sleep during day; average latency <8 min indicates excessive sleepiness; REM in ≥ 2 naps supports narcolepsy diagnosis. Must be preceded by adequate overnight sleep. Maintenance of Wakefulness Test: measures ability to sustain wakefulness; evaluates therapy efficacy.
6. INSUFFICIENT SLEEP¶
Probably the most common cause of excessive daytime sleepiness. The average adult needs 7.5-8 hours of sleep, but U.S. adults average only 6.75 hours on weeknights. Only 30% report consistently obtaining sufficient sleep.
6.1 At-Risk Populations¶
Shift workers, individuals working multiple jobs, lower socioeconomic groups, historically minority populations. Most teenagers need ≥ 9 hours but get less due to circadian phase delay plus social pressures. Late evening light exposure, homework, television, video-gaming, social media, and smartphone use delay bedtimes.
6.2 Clinical Features¶
Inattention, irritability, poor motivation, depression, difficulty with school/work/driving. Patients may be unaware of biological need for more sleep, especially if masking with caffeine.
6.3 Diagnosis and Treatment¶
Two-week sleep log documenting timing and alertness is useful. Ask how much sleep patient obtains on quiet vacation without restrictions. Treatment: extend sleep to optimal amount on regular basis.
7. SLEEP APNEA SYNDROMES¶
At least 24% of middle-aged men and 9% of middle-aged women have reduction or cessation of breathing dozens or more times each night, with 9% of men and 4% of women doing so >100 times per night. Episodes may be obstructive, central, or mixed. >80% remain undiagnosed.
7.1 Risk Factors and Consequences¶
Particularly prevalent in overweight men and elderly. Failure to recognize and treat increases risk of: sleep-related motor vehicle crashes, depression, hypertension, myocardial infarction, diabetes, stroke, and mortality.
7.2 Diagnosis¶
Polysomnogram or home sleep test (see Chapter 308 for comprehensive review).
7.3 Treatment¶
CPAP, upper airway surgery (uvulopalatopharyngoplasty), dental appliances, weight loss.
8. NARCOLEPSY¶
Characterized by difficulty sustaining wakefulness, poor REM sleep regulation, and disturbed nocturnal sleep. Affects approximately 1 in 2000 people in the United States. Typically begins between ages 10-20 and persists for life.
Narcolepsy Classification and Features¶
| Type | Cataplexy | CSF Orexin | Orexin Neuron Loss | HLA Association |
|---|---|---|---|---|
| Type 1 Narcolepsy | Present (~50% of all narcolepsy) | Very low or undetectable | Nearly complete | DQB1*06:02 in >90% |
| Type 2 Narcolepsy | Absent | Usually normal | Partial or other mechanism | Less strong association |
Medications for Narcolepsy¶
| Drug | Dose | Mechanism | Primary Indication |
|---|---|---|---|
| Modafinil | 200-400 mg qAM | Wake-promoting | Sleepiness |
| Methylphenidate | 10-20 mg bid | Stimulant | Sleepiness |
| Dextroamphetamine | 10 mg bid | Stimulant | Sleepiness |
| Solriamfetol | 75-150 mg daily | NE-DA reuptake inhibitor | Sleepiness |
| Pitolisant | 8.9-35.6 mg daily | H3 receptor antagonist | Sleepiness |
| Venlafaxine | 37.5-150 mg qAM | SNRI | Cataplexy |
| Fluoxetine | 10-40 mg qAM | SSRI | Cataplexy |
| Sodium oxybate | Bedtime + 3-4h later | GABA-B agonist | Cataplexy, sleep consolidation |
8.1 Clinical Features¶
All patients have excessive daytime sleepiness—usually moderate to severe. Patients feel well-rested upon awakening then tired throughout the day. REM sleep intrusion symptoms: (1) Cataplexy—sudden muscle weakness without loss of consciousness triggered by strong emotions (laughing, surprise, anger); can be severe (collapse) or mild (facial/neck weakness); (2) Hypnagogic (sleep onset) or hypnopompic (awakening) hallucinations; (3) Sleep paralysis upon awakening.
8.2 Pathophysiology¶
Type 1 narcolepsy: caused by loss of orexin-producing hypothalamic neurons. Very low/undetectable CSF orexin levels. Autoimmune mechanism likely—HLA DQB1*06:02 found in >90% (vs. 12-25% general population). Immune response against influenza/Streptococcus may damage orexin neurons via molecular mimicry (explains 8-12 fold increase in narcolepsy after Pandemrix H1N1 vaccine in European children). Type 2 narcolepsy: no cataplexy, usually normal orexin levels, may have partial orexin neuron loss or other causes. Rare causes: anti-Ma2 paraneoplastic antibodies, severe traumatic brain injury, tumors, strokes damaging orexin neurons.
8.3 Diagnosis¶
Clinical: sudden onset of chronic sleepiness plus cataplexy (pathognomonic) or other symptoms. Refreshment after brief naps is characteristic. Hypnagogic hallucinations and sleep paralysis occur in ~20% of general population, so less specific. Polysomnogram followed by MSLT: average sleep latency <8 min; REM in ≥ 2 naps; REM within 15 min of nighttime sleep onset. Stimulants stopped 1 week before, antidepressants 3 weeks before MSLT. Adequate sleep ( ≥ 8 hours/night) for 1 week prior.
8.4 Treatment¶
Lifestyle: adequate nighttime sleep, 15-20 min afternoon nap. Wake-promoting medications: Modafinil 200-400 mg each morning (preferred due to fewer side effects, longer half-life); Methylphenidate 10-20 mg bid; Dextroamphetamine 10 mg bid (concerns: sympathomimetic effects, anxiety, abuse potential); Solriamfetol 75-150 mg daily (NE-DA reuptake inhibitor); Pitolisant 8.9-35.6 mg daily (selective H3 receptor antagonist). Cataplexy treatment: Antidepressants increasing noradrenergic/serotonergic tone (suppress REM): Venlafaxine 37.5-150 mg each morning; Fluoxetine 10-40 mg each morning; Tricyclics (protriptyline 10-40 mg/d, clomipramine 25-50 mg/d)—potent but anticholinergic side effects limit use. Sodium oxybate (given at bedtime and 3-4 h later): promotes continuous slow wave sleep, improves alertness and reduces cataplexy. Also available in low-sodium and once-nightly versions. Side effects at high doses: sedation, nausea, confusion.
9. INSOMNIA¶
Complaint of poor sleep presenting as difficulty initiating and/or maintaining sleep. Chronic insomnia (>3 months) affects ~10% of adults; acute insomnia affects >30% of adults. More common in women, older adults, lower socioeconomic status, and those with medical/psychiatric/substance abuse disorders.
Methods to Improve Sleep Hygiene in Insomnia Patients¶
| Helpful Behaviors | Behaviors to Avoid |
|---|---|
| Use bed only for sleep and sex | Napping, especially after 3:00 PM |
| If cannot sleep within 20 min, get out of bed and do relaxing activities in dim light | Attempting to sleep too early |
| Make quality sleep a priority | Caffeine after lunchtime |
| Go to bed and wake at same time each day | Heavy eating in 2-3 h before bedtime |
| Ensure restful environment (comfortable bed, quiet/dark room) | Smoking or alcohol in 2-3 h before bedtime |
| Develop consistent bedtime routine (20-30 min relaxation) | Vigorous exercise in 2-3 h before bedtime |
| Take a warm bath | Solving problems when trying to fall asleep |
| Thinking about life issues or reviewing day's events |
9.1 Predisposing Factors¶
Many patients report easily disturbed sleep predating insomnia, suggesting lighter-than-normal sleep. Clinical studies show insomnia is associated with activation during sleep of brain areas normally active only during wakefulness. PET studies show hyperactivation of ascending arousal system and limbic targets (cingulate cortex, amygdala). Limbic areas send excitatory outputs back to arousal system—vicious cycle of anxiety about insomnia.
9.2 Precipitating Factors¶
Acute insomnia often triggered by: major illness/loss, change of occupation, medications, substance abuse. Can lead to chronic insomnia if maladaptive behaviors develop (increased nocturnal light exposure, clock-checking, excessive napping).
9.3 Contributing Factors¶
Psychophysiological: negative expectations, conditioned arousal, bedtime anxiety, clock-checking; may sleep better in new environment. Inadequate sleep hygiene: daytime napping, irregular schedule, caffeine/tobacco near bedtime, alerting activities before bed, using bedroom for non-sleep activities. Psychiatric conditions (~80% of psychiatric patients have sleep complaints; ~50% of chronic insomnia associated with psychiatric disorder): depression (early morning awakening, onset/maintenance issues), mania/hypomania (reduced total sleep), anxiety (racing thoughts, rumination, nocturnal panic attacks), schizophrenia (fragmented sleep, less N3, day-night reversal). Medications/drugs: caffeine (half-life 6-9 h, disrupts sleep for 8-14 h), prescription drugs near bedtime (antidepressants, stimulants, glucocorticoids, theophylline), withdrawal from sedating medications (alcohol, narcotics, benzodiazepines). Alcohol shortens sleep latency but causes rebound insomnia 2-3 h later. Medical conditions: pain (rheumatologic, neuropathic), respiratory conditions (asthma, COPD, CHF, restrictive lung disease), menopause, gastroesophageal reflux, OSA. ~60% of long COVID patients report insomnia. Neurologic disorders: dementia (napping, altered circadian rhythms, weakened sleep-promoting mechanisms), Parkinson's disease (rigidity, dementia, urinary frequency, RBD, RLS). Fatal familial insomnia (prion disease)—rare, presents with dementia, myoclonus, dysarthria, autonomic dysfunction.
10. TREATMENT OF INSOMNIA¶
Treatment improves quality of life and long-term health. Improved sleep reduces daytime fatigue, improves cognition and energy. Treating insomnia at diagnosis of major depression improves antidepressant response and reduces relapse risk.
Benzodiazepine Receptor Agonists for Insomnia¶
| Drug | Dose | Half-Life | Clinical Use |
|---|---|---|---|
| Zaleplon | 5-20 mg | 1-2 hours | Sleep onset insomnia |
| Zolpidem | 5-10 mg | 2-4 hours | Sleep onset insomnia |
| Triazolam | 0.125-0.25 mg | 2-4 hours | Sleep onset insomnia |
| Eszopiclone | 1-3 mg | 5-8 hours | Sleep onset and maintenance |
| Temazepam | 15-30 mg | 8-20 hours | Sleep maintenance |
Other Medications for Insomnia¶
| Drug Class | Examples/Dose | Mechanism | Notes |
|---|---|---|---|
| Antihistamines | Diphenhydramine | H1 antagonist | OTC; tolerance; anticholinergic effects |
| Heterocyclic antidepressants | Trazodone 25-100 mg | 5-HT2 antagonist, antihistamine | No abuse potential; t½ 5-9 h |
| Orexin antagonists | Suvorexant 10-20 mg, Lemborexant 5-10 mg, Daridorexant 25-50 mg | Block orexin receptors | Morning sedation; rare hallucinations/sleep paralysis |
| Gabapentinoids | Gabapentin 100-300 mg qhs | Calcium channel modulation | Useful for chronic pain with insomnia |
10.1 General Principles¶
Target all contributing factors: establish good sleep hygiene, treat medical disorders, use behavioral therapies for anxiety/negative conditioning, pharmacotherapy/psychotherapy for psychiatric disorders. Behavioral therapies should be first-line treatment, followed by judicious medication use if needed.
10.2 Cognitive Behavioral Therapy (CBT)¶
Combines multiple techniques. Therapist uses cognitive psychology to reduce excessive worry about sleep and reframe faulty beliefs about insomnia and daytime consequences. Relaxation techniques: progressive muscle relaxation, meditation. Sleep restriction may improve sleep continuity but chronic restriction may adversely affect daytime performance.
10.3 Pharmacotherapy¶
Antihistamines (diphenhydramine): primary ingredient in OTC sleep aids. Beneficial intermittently but can produce tolerance and anticholinergic effects (dry mouth, constipation), limiting use in elderly. Benzodiazepine receptor agonists (BzRAs): bind GABA-A receptor, potentiate postsynaptic GABA response. Effective and well-tolerated. Agents chosen based on desired duration of action. Heterocyclic antidepressants: most common BzRA alternatives due to no abuse potential and low cost. Trazodone (25-100 mg)—shorter half-life (5-9 h), less anticholinergic than tricyclics. Orexin receptor antagonists: suvorexant (10-20 mg), lemborexant (5-10 mg), daridorexant (25-50 mg). Block wake-promoting orexin effects. Medium-long half-lives may cause morning sedation; rarely produce hypnagogic hallucinations and sleep paralysis.
10.4 Medication Cautions¶
All sedatives increase fall and confusion risk in elderly—use lowest effective dose. Consider duration of action for morning sedation affecting driving/judgment. Benzodiazepines carry addiction/abuse risk, especially with prior alcohol/sedative abuse history. Sedatives can worsen depression. Some medications worsen sleep apnea. Sedatives can produce complex sleep behaviors (sleepwalking, sleep eating) especially at higher doses.
11. RESTLESS LEGS SYNDROME (RLS)¶
Irresistible urge to move the legs with creepy-crawly, tingly, or unpleasant deep ache within thighs or calves. Severe cases may involve arms. Symptoms are much worse in evening/first half of night, appear with inactivity, and are temporarily relieved by movement, stretching, or massage. Affects 5-10% of adults; more common in women and older adults.
11.1 Etiology¶
Iron deficiency: most common treatable cause (replace if ferritin <75 ng/mL). Other causes: peripheral neuropathies, uremia. Worsening factors: pregnancy, caffeine, alcohol, antidepressants, lithium, neuroleptics, antihistamines. Genetic factors: polymorphisms in BTBD9, MEIS1, MAP2K5/LBXCOR, and PTPRD genes. ~1/3 of patients (especially early onset) have multiple affected family members.
11.2 Treatment¶
Address underlying cause (iron deficiency). Symptomatic treatment: Alpha-2-delta calcium channel ligands: gabapentin 300-900 mg at 7 PM, gabapentin enacarbil 300-600 mg at 5 PM, pregabalin 150-450 mg at 7 PM. Effective; also sedating and analgesic—especially helpful with concomitant pain, neuropathy, or anxiety. Dopamine D2/3 agonists: pramipexole 0.25-0.5 mg at 7 PM, ropinirole 0.5-4 mg at 7 PM. Usually effective but ~25% develop augmentation (worsening with earlier symptom onset, spread to other body regions). Side effects: nausea, morning sedation, increased rewarding behaviors (sex, gambling). Refractory cases: opioids, benzodiazepines.
12. PERIODIC LIMB MOVEMENT DISORDER (PLMD)¶
Rhythmic leg twitches during sleep resembling triple flexion reflex with great toe extension and foot dorsiflexion lasting 0.5-5.0 seconds, recurring every 20-40 seconds during NREM sleep in episodes lasting minutes to hours. Movements frequently cause brief arousals disrupting sleep, resulting in insomnia and daytime sleepiness.
12.1 Diagnosis¶
Polysomnogram with anterior tibialis EMG recordings. EEG shows arousals associated with movements.
12.2 Treatment¶
Caused by same factors as RLS. Improves with dopamine agonists and other RLS treatments. Genetic polymorphisms associated with both RLS and PLMD suggest common pathophysiology.
13. PARASOMNIAS¶
Abnormal behaviors or experiences arising from or occurring during sleep. NREM parasomnias include confusional arousals, sleepwalking, night terrors. REM parasomnias include REM sleep behavior disorder (RBD) and nightmares.
Comparison of Common Parasomnias¶
| Feature | Sleepwalking | Sleep Terrors | REM Sleep Behavior Disorder |
|---|---|---|---|
| Sleep Stage | NREM N3 | NREM N3 | REM |
| Timing | First third of night | First few hours | Throughout night (esp. later) |
| Age Group | Children/adolescents | Young children | Older adults (>70 years) |
| Recall | None or minimal | None | Dream recall matches behavior |
| Autonomic Signs | Minimal | Prominent (sweating, tachycardia) | Minimal |
| Motor Activity | Ambulation, complex behaviors | Sitting up, screaming | Punching, kicking, calling out |
| Neurodegenerative Association | None | None | Strong (synucleinopathies) |
13.1 Sleepwalking (Somnambulism)¶
Automatic motor activities ranging from simple to complex (walking, urinating inappropriately, eating, exiting house, driving). Minimal awareness; may be difficult to arouse and may respond to awakening with agitation/violence. Safest to lead patient back to bed. Arises from NREM N3 sleep in first few hours of night. EEG shows slow cortical activity even when patient is moving. Most common in children/adolescents (15% have occasional episodes); persists in ~1% of adults. Unknown cause; familial in ~1/3 of cases. Worsened by stress, alcohol, and insufficient sleep. Treatment: address stress/alcohol/insufficient sleep; some efficacy with antidepressants and benzodiazepines; relaxation techniques and hypnosis; improve home safety (replace glass doors, remove low tables).
13.2 Sleep Terrors¶
Occurs primarily in young children during first few hours of sleep (NREM N3). Child sits up and screams with autonomic arousal (sweating, tachycardia, large pupils, hyperventilation). Difficult to arouse; rarely recalls episode in morning. Treatment: reassure parents condition is self-limited and benign; may improve by avoiding insufficient sleep.
13.3 Sleep Enuresis¶
Nocturnal bedwetting during sleep in young. Before age 5-6 is normal development. Usually improves spontaneously by puberty; persists in 1-3% of adolescents; rare in adults. Treatment: bladder training exercises, behavioral therapy. Adult pharmacotherapy: desmopressin 0.2 mg qhs, oxybutynin chloride 5 mg qhs, or imipramine 10-25 mg qhs. Important causes in previously continent patients: UTI, urinary tract malformations, cauda equina lesions, emotional disturbances, epilepsy, sleep apnea, certain medications.
13.4 Sleep Bruxism¶
Involuntary forceful grinding of teeth during sleep; affects 10-20% of population. Patient usually unaware. Typical onset age 17-20; spontaneous remission usually by age 40. Diagnosis often during dental examination. Minor cases: no treatment needed. Severe cases: mouth guard to prevent tooth injury. Additional options: stress management, benzodiazepines, biofeedback (when stress-related).
13.5 REM Sleep Behavior Disorder (RBD)¶
Distinct from other parasomnias—occurs during REM sleep. Patient/bed partner reports calling out and agitated/violent behavior during sleep. If awakened, patient can report dream matching movements. Normal REM paralysis is absent; dramatic limb movements (punching, kicking) lasting seconds to minutes occur during REM. Patient or bed partner injury is common. Prevalence increases with age (~2% of adults >70 years); more common in men. Neurodegenerative disease association: within 12 years, 50% of RBD patients develop synucleinopathy (Parkinson's disease, dementia with Lewy bodies, multiple system atrophy); >90% by 25 years. Patients with latent synucleinopathy can be distinguished by detecting alpha-synuclein aggregates in CSF or peripheral nerves (skin biopsy). Can occur with antidepressants—may unmask early indicator of neurodegeneration. Also occurs in ~30% with narcolepsy (different underlying cause, no increased neurodegeneration risk). Treatment: melatonin up to 10 mg nightly (sustained improvement in many); clonazepam 0.5-2.0 mg qhs (prevents attacks but increases fall/confusion risk at night).
14. CIRCADIAN RHYTHM SLEEP DISORDERS¶
Disorders of sleep timing rather than sleep generation. May be inherent (abnormal circadian pacemaker) or environmental/behavioral (disruption of synchronizers). Therapeutic goal is to entrain circadian rhythm of sleep propensity to appropriate behavioral phase.
Circadian Rhythm Sleep Disorders¶
| Disorder | Sleep Timing | Population | Treatment |
|---|---|---|---|
| Delayed Sleep-Wake Phase Disorder (DSWPD) | Later than desired | Young adults | Morning phototherapy, evening melatonin |
| Advanced Sleep-Wake Phase Disorder (ASWPD) | Earlier than desired | Older adults; familial variant | Evening phototherapy |
| Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD) | Progressive daily delay | Blind patients; sighted with abnormal light exposure | Low-dose melatonin (0.5 mg) nightly |
| Shift-Work Disorder | Misaligned with work schedule | Night-shift workers | Caffeine, strategic naps, timed light exposure, modafinil/armodafinil |
| Jet Lag Disorder | Misaligned with new time zone | Travelers | Outdoor light exposure, low-dose melatonin |
14.1 Delayed Sleep-Wake Phase Disorder (DSWPD)¶
Characterized by: (1) sleep onset/wake times persistently later than desired; (2) actual sleep times at nearly same clock hours daily; (3) normal polysomnography if conducted at habitual delayed sleep time. ~50% have abnormally delayed endogenous circadian phase. Dim-light melatonin onset (DLMO) typically 8-9 PM in healthy people, later in DSWPD. Patients tend to be young adults. Causes: abnormally long intrinsic circadian period, reduced phase-advancing capacity, slower homeostatic sleep drive buildup, irregular prior sleep-wake schedule with frequent late nights with artificial light. Treatment: phototherapy with blue-enriched light during morning hours, melatonin administration in evening. High relapse rate.
14.2 Advanced Sleep-Wake Phase Disorder (ASWPD)¶
Converse of DSWPD. Most common in older people (15% cannot sleep past 5 AM; 30% complain of early awakening several times/week). Patients are sleepy during evening hours even in social settings. Distinguished from early-morning insomnia by early onset of DLMO. Early-onset familial variant: autosomal dominant inheritance due to missense mutations in circadian clock components (PER2 casein kinase binding domain; casein kinase I delta) that shorten circadian period. Treatment: bright light and/or blue-enriched phototherapy during evening hours to reset pacemaker to later hour.
14.3 Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD)¶
Most common when primary synchronizing input (light-dark cycle) is lost, as in many blind people with no light perception. Maximal phase-advancing capacity cannot accommodate difference between 24-hour day and intrinsic pacemaker period. Sleep restricted to nighttime by social/occupational demands but cannot maintain stable phase relationship. Patients present with intermittent bouts of insomnia. When endogenous rhythms are out of phase: nighttime insomnia coexists with excessive daytime sleepiness. When in phase: symptoms remit. Interval between symptomatic phases: weeks to months. Treatment: nightly low-dose melatonin (0.5 mg) or melatonin receptor agonist may improve sleep and induce synchronization. Sighted patients: N24SWD can be caused by self-selected artificial light exposure entraining pacemaker to >24-hour schedule—presents with incremental pattern of successive sleep timing delays.
14.4 Shift-Work Disorder (SWD)¶
7 million Americans regularly work at night (permanent or rotating). Many more commute to work 4-7 AM. The circadian system usually fails to adapt to inverted schedules. Misalignment causes disturbed daytime sleep, impaired alertness/performance, increased reaction time, greater safety hazards. Sleep disturbance nearly doubles fatal work accident risk. Sleep-related fatal-to-driver highway crashes peak in early morning and late afternoon (bimodal sleep tendency peaks). Expert consensus: individuals with <2 hours sleep in prior 24 hours are unfit to drive. Long-term night-shift workers: higher rates of breast, colorectal, prostate cancer; cardiac, GI, metabolic, reproductive disorders. WHO lists night-shift work as probable carcinogen. Chronic severe SWD affects 5-15% of night/early morning workers. Sleep latencies during night work average 2 min (comparable to narcolepsy or severe sleep apnea). Physician residents: 24+ hour shifts impair performance comparable to alcohol intoxication, double ICU attentional failures, increase serious medical errors (5-fold increase in serious diagnostic mistakes). 20% report fatigue-related mistake injuring patient; 5% report fatigue-related patient death.
14.5 Treatment of Shift-Work Disorder¶
Caffeine: promotes wakefulness but cannot forestall sleep indefinitely; does not shield from performance lapses. Additional strategies: postural changes, exercise, strategic nap opportunities. Properly timed blue-enriched or bright white light exposure can enhance alertness and facilitate adaptation. Pharmacotherapy: Modafinil 200 mg or Armodafinil 150 mg, 30-60 min before 8-hour overnight shift. Effective for excessive sleepiness but patients remain somewhat sleepy. Fatigue risk management programs: promote sleep education, increase awareness of hazards, screen for common sleep disorders. Work schedule design to minimize: (1) night work exposure; (2) shift rotation frequency; (3) consecutive night shifts; (4) night shift duration.
14.6 Jet Lag Disorder¶
60 million people fly across time zones annually. Results in excessive daytime sleepiness, sleep-onset insomnia, or frequent arousals (especially in latter half of night). Transient, lasting 2-14 days depending on time zones crossed, travel direction, age, and phase-shifting capacity. Travelers spending more time outdoors adapt more quickly (brighter light exposure). Strategies: avoid antecedent sleep loss; nap in afternoon before overnight travel. Low-dose melatonin may enhance sleep efficiency when taken during biological daytime (when endogenous melatonin is low). Social jet lag: behavioral pattern with weekend bedtimes/wake times 3-4+ hours later than weekdays. Common in adolescents/young adults; associated with delayed circadian phase, sleep-onset insomnia, excessive sleepiness, poorer academic performance, increased obesity and depressive symptoms.
15. MEDICAL IMPLICATIONS OF CIRCADIAN RHYTHMICITY¶
Prominent circadian variations occur in the incidence of acute myocardial infarction, sudden cardiac death, and stroke. Platelet aggregability increases in early morning, coincident with peak cardiovascular event incidence.
15.1 Metabolic Effects¶
Recurrent circadian disruption combined with chronic sleep deficiency (night-shift work) increases postprandial plasma glucose due to inadequate pancreatic insulin secretion. Night-shift workers with elevated fasting glucose have increased risk of progressing to diabetes. Blood pressure is higher in night workers with sleep apnea than day workers.
15.2 Clinical Implications¶
Diagnostic and therapeutic procedures affected by time of day: blood pressure, body temperature, dexamethasone suppression test, plasma cortisol. Drug timing (e.g., chemotherapy) affects both toxicity and effectiveness. Anesthetic agents are particularly sensitive to time-of-day effects.
15.3 Public Health Considerations¶
Physicians must be aware of public health risks associated with 24/7 schedules. National Academy of Medicine concluded scheduling resident physicians >16 consecutive hours without sleep is hazardous. Twenty-four hours of continuous wakefulness impairs reaction time comparably to blood alcohol 0.10 g/dL.
16. KEY POINTS AND CLINICAL PEARLS¶
Essential clinical takeaways for managing sleep disorders in practice.
Clinical Pearls in Sleep Medicine¶
| Topic | Pearl |
|---|---|
| Sleep Need | Most adults need 7-9 hours; teenagers need ‡9 hours; individual variation exists |
| Sleep Deprivation | 24 hours without sleep impairs reaction time equivalent to blood alcohol 0.10 g/dL |
| Insufficient Sleep | Most common cause of daytime sleepiness; only 30% of U.S. adults get sufficient sleep |
| Topic | Pearl |
|---|---|
| Driving Safety | Physicians should advise sleepy patients not to drive until treatment is effective |
| Sleep vs. Fatigue | Sleepiness = propensity to fall asleep; Fatigue = low energy without sleep tendency |
| Cataplexy | Pathognomonic for type 1 narcolepsy; sudden postural weakness triggered by strong emotions |
| RBD Prognosis | 50% develop synucleinopathy within 12 years; >90% by 25 years |
| Iron and RLS | Consider iron replacement if ferritin <75 ng/mL |
| Augmentation | ~25% of RLS patients on dopamine agonists develop worsening symptoms |
| Melatonin Timing | Effective when endogenous levels are low (biological daytime); less effective in primary insomnia |
| CBT for Insomnia | First-line treatment; behavioral approaches reduce limbic hyperactivation |
| Circadian Assessment | Dim-light melatonin onset (DLMO) distinguishes circadian from other sleep disorders |
| Shift Work | WHO lists night-shift work as probable carcinogen; associated with multiple health risks |