Skip to content
Download PDF

Sleep Disorders

Part 2: Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation · Chapter 33

Key Clinical Points

  1. Most adults require 7–9 h of sleep per night; only 30% of U.S. adults consistently obtain sufficient sleep.
  2. Polysomnographic profiles define two basic states: (1) rapid eye movement (REM) sleep and (2) non–rapid eye movement (NREM) sleep.
  3. Narcolepsy is characterized by difficulty sustaining wakefulness, poor regulation of REM sleep, and disturbed nocturnal sleep.
  4. Cataplexy is distinguished by sudden onset of postural weakness triggered by strong emotions (e.g., laughing).
  5. 24 hours of continuous wakefulness impairs reaction time as much as a blood alcohol concentration of 0.10 g/dL.
  6. The suprachiasmatic nuclei (SCN) of the hypothalamus drive the 24-h wake-sleep cycle and other 24-h rhythms; they are highly sensitive to blue light (460–500 nm).
  7. Adenosine levels rise with prolonged wakefulness, acting through A1 receptors to inhibit arousal-promoting regions; A2a receptors are blocked by caffeine.
  8. Obstructive sleep apnea (OSA) is prevalent in overweight men and the elderly; failure to treat increases risk of hypertension, myocardial infarction, and stroke.
  9. Narcolepsy has a strong HLA association: HLA DQB1*06:02 is found in >90% of people with type 1 narcolepsy (vs. 12–25% of the general population).
  10. Sleep deprivation is associated with glucose intolerance, obesity, metabolic syndrome, and increased risk of Alzheimer’s disease.

1. DEFINITION & OVERVIEW

• Prevalence: Over half of U.S. adults experience at least intermittent sleep disturbance; 50–70 million Americans suffer from a chronic disorder of sleep and wakefulness. • Economic Impact: >80% of patients with sleep disorders remain undiagnosed and untreated, costing the U.S. economy >$400 billion annually in healthcare costs, lost productivity, accidents, and injuries. • Sleep Physiology Basics: ◦ Duration: Most adults need 7–9 h of sleep per night to promote optimal health. ◦ NREM Stages: Progress through N1–N3 within 45–60 min; N3 (slow-wave sleep) predominates in the first third of the night and comprises 15–25% of total nocturnal sleep time in young adults. ◦ REM Sleep: Typically begins in the second hour of sleep; constitutes 20–25% of total sleep in healthy young adults. ◦ Ultradian Cycles: NREM and REM sleep alternate with an average period of 60–160 min. • Cognitive Impairment Assessment: ◦ Frontal Network Syndrome: Preferred term for conditions where the responsible lesions lie within a distributed network; distinguishes from 'frontal lobe syndrome' (which requires specific evidence of cortical disease). ◦ Diaschisis: Initial deficits after stroke or trauma may arise from remote dysfunction in interconnected regions; improvement can occur for up to 2 years as these areas normalize.

2. EPIDEMIOLOGY

• General Prevalence: High across all cultures; expected to increase as the global population ages. • Obstructive Sleep Apnea (OSA): Particularly prevalent in overweight men and the elderly; often remains undiagnosed. • Risk Factors for Insufficient Sleep: Common among shift workers, individuals with multiple jobs, lower socioeconomic groups, and historically minority populations. • Adolescent Sleep: Most teenagers need ≥9 h of sleep; many fail to meet this due to circadian phase delay and social/school pressures.

2.1 Age and Sex Distribution

• Elderly (>70 years): Sleep on average about one hour less than young adults; N3 sleep may be completely absent, and remaining NREM sleep is often more fragmented. ◦ Infants: REM sleep can account for 50% of total sleep time in infancy, falling sharply to ~25% in young adults.

2.2 Prevalence of Sleep Disorders

• Sleep Disturbance: >50% of U.S. adults. ◦ Respiratory Events: 24% of middle-aged men and 9% of middle-aged women experience 'dozens or more' breathing interruptions per night; 9% of men and 4% of women experience more than a hundred times per night.

3. ETIOLOGY & PATHOPHYSIOLOGY

• Ascending Arousal System: ◦ Location: Extends from the upper pons to the hypothalamus and basal forebrain; activates the cerebral cortex, thalamus, and other forebrain regions. ◦ Neurotransmitters: Monoamines (norepinephrine, dopamine, serotonin, histamine), glutamate, or acetylcholine; GABA is used by some neurons to inhibit cortical inhibitory interneurons. ◦ Orexin (Hypocretin): Produced in the hypothalamus; reinforces activity in other arousal-promoting cell groups. Loss of orexin neurons → narcolepsy. ◦ Thalamus: Isolated damage leads to loss of the content of wakefulness (persistent vegetative state), while wake-sleep cycles are largely preserved. • Sleep-Promoting System: ◦ Location: Preoptic area and pons; uses GABA to inhibit the arousal system. ◦ REM Promotion: Neurons in the lateral hypothalamus containing melanin-concentrating hormone promote REM sleep. ◦ Flip-flop Switch: Mutual inhibition between the arousal- and sleep-promoting systems. • Circadian Rhythmicity: ◦ Suprachiasmatic Nucleus (SCN): Located in the hypothalamus; only tissue that maintains rhythm in isolation. ◦ Light Sensitivity: Highly sensitive to blue light (460–500 nm) for synchronization with the external world. ◦ Advanced Sleep Phase Disorder: Result of short circadian cycles (e.g., 23.5 h) due to mutations of clock genes. • Homeostatic and Allostatic Inputs: ◦ Adenosine: Accumulates during wakefulness; acts on A1 receptors to inhibit arousal-promoting regions; blocked by caffeine at A2a receptors. ◦ Prostaglandin D: Also activates sleep-promoting neurons in the ventrolateral preoptic nucleus. ◦ Allostasis: Stress responses (e.g., anxiety) can cause hyperactivation of the ascending arousal system and limbic targets (cingulate cortex, amygdala), creating a cycle of anxiety about insomnia. • Narcolepsy & Autoimmunity: ◦ HLA Association: HLA DQB106:02 found in >90% of type 1 narcolepsy; only 12–25% of the general population. ◦ Molecular Mimicry: Potential immune response to infections (e.g., H1N1/Pandemix) may damage orexin neurons. ◦ Other Causes:* Anti-Ma2 paraneoplastic antibodies, severe TBI, tumors, or stroke.

4. CLINICAL FEATURES

• Sleepiness vs. Fatigue: ◦ Sleepiness: Result of reduced sleep quantity/quality or impaired arousal; impacts judgment similarly to ethanol. ◦ Fatigue: Common in inflammatory conditions (cancer, multiple sclerosis, post-COVID syndrome, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome) or endocrine deficiencies (hypothyroidism, Addison’s disease). • Thermoregulation: REM sleep has reduced thermoregulatory response.

4.1 Sleep Apnea Syndromes

• Consequences: Failure to treat OSA increases risk of hypertension, myocardial infarction, and stroke.

4.2 Narcolepsy Symptoms

• Core Features: Excessive daytime sleepiness (EDS), poor regulation of REM sleep, and disturbed nocturnal sleep. ◦ Cataplexy: Sudden onset of postural weakness triggered by strong emotions (e.g., laughing). ◦ REM Intrusion: Includes hypnagogic hallucinations (at sleep onset) and hypnopompic hallucinations (upon awakening). ◦ Sleep Paralysis: Muscle paralysis upon awakening.

4.3 Parasomnias and Seizures

• N3-Related Parasomnias: Sleepwalking, night terrors, enuresis (common in children). ◦ REM Behavior Disorder: Older adults failing to maintain paralysis during REM; characterized by calling out or thrashing. ◦ Sleep Seizures: Rare; occur during NREM sleep; may present as generalized tonic-clonic movements or stereotyped movements.

5. DIAGNOSTIC APPROACH

  1. Initial Assessment: ◦ Identify primary domain of impairment (e.g., sleepiness vs. fatigue). ◦ Evaluate impact on daily life and safety.
  2. Polysomnogram (PSG): ◦ Required for: Sleep apnea, narcolepsy, and periodic limb movement disorder (PLMD).
  3. Home Sleep Test (HST): ◦ Used primarily to assess respiratory measures in patients with likely obstructive sleep apnea.
  4. Multiple Sleep Latency Test (MSLT): ◦ Prerequisite: Must be preceded by an overnight PSG to ensure adequate night sleep. ◦ Procedure: 5 x 20-min nap opportunities every 2 hours. ◦ Evaluation Criteria: ◦ Average sleep latency <8 min → evidence of excessive daytime sleepiness (EDS). ◦ Presence of REM in ≥2 naps → support for diagnosis of narcolepsy.

6. MANAGEMENT & TREATMENT

  1. Insufficient Sleep: ◦ Treatment: Sleep education and behavioral modification to increase amount of sleep.
  2. Obstructive Sleep Apnea (OSA): ◦ Treatment: Continuous positive airway pressure (CPAP); upper airway surgery; dental appliance; weight loss.
  3. Narcolepsy: ◦ Treatment: Stimulants (modafinil, methylphenedine); REM-suppressing antidepressants (venlafaxine); pitolisant; solriamfetol; sodium oxybate.
  4. Restless Legs Syndrome (with/without PLM): ◦ Treatment: Address predisposing conditions (iron deficiency, renal failure); dopamine agonists (pramipexole, ropinirole); gabapentin; pregabalin; opiates.
  5. Drug or Medical Condition Induced Sleepiness: ◦ Treatment: Change medications; treat underlying condition; consider stimulants.
  6. Sleep Hygiene (Table 2): ◦ Helpful Behaviors: ◦ Use the bed only for sleep and sex. ◦ If not asleep within 20 min → get out of bed, perform relaxing activity in dim light. ◦ Establish consistent routine (20–30 min preparation: music, meditation, yoga). ◦ Take a warm bath. ◦ Behaviors to Avoid: ◦ Napping after 3:00 PM. ◦ Attempting to sleep too early. ◦ Caffeine after lunch. ◦ Solving problems or thinking about life issues when trying to fall asleep.

7. SPECIAL CONSIDERATIONS

• Elderly: Characterized by reduced N3 sleep, fragmented sleep, and increased risk of falls/cognitive impairment. • Neurodegenerative Conditions: Differentiation between 'Frontal Network Syndrome' (distributed lesions) and 'Frontal Lobe Syndrome'. • Shift Workers: High risk for circadian disruption and insufficient sleep.

8. KEY PEARLS & CLINICAL TRAPS

• Narcolepsy Hallmark: Cataplexy is triggered by emotions; REM intrusion into wakefulness (hallucinations, paralysis). ◦ Diagnostic Rule: MSLT average latency <8 min → EDS; ≥2 REM naps → Narcolepsy. ◦ Sleep Apnea Risk: Untreated OSA leads to hypertension, MI, and stroke. ◦ Circadian Biology: SCN is the master clock; blue light (460–500 nm) is a primary synchronizer. ◦ Adenosine/Caffeine: Adenosine promotes sleep via A1; caffeine blocks A2a. ◦ Sleep vs. Fatigue: Sleepiness is a failure of arousal/sleep quality; fatigue is often systemic/inflammatory (e.g., cancer, MS, post-COVID).

Reference Tables

TABLE 33-1 Evaluation of the Patient with Excessive Daytime Sleepiness

Harrison's 22e, p.213

FINDINGS ON HISTORY AND PHYSICAL
EXAMINATION		 DIAGNOSTIC EVALUATION DIAGNOSIS THERAPY
Difficulty waking in the morning, rebound sleep
on weekends and vacations with improvement in
sleepiness		 Sleep log Insufficient sleep Sleep education and behavioral modification to
increase amount of sleep
Polysomnogram or home sleep
test		 Obstructive sleep apnea
(Chap. 308)
Cataplexy, hypnagogic hallucinations, sleep
paralysis		 Polysomnogram and multiple sleep
latency test		 Narcolepsy Stimulants (e.g., modafinil, methylphenidate);
rapid eye movement (REM) sleep-suppressing
antidepressants (e.g., venlafaxine); pitolisant;
solriamfetol; sodium oxybate
Assessment for predisposing
medical conditions (e.g., iron
deficiency or renal failure)		 Restless legs syndrome
with or without periodic
limb movements
Sedating medications, stimulant withdrawal,
head trauma, systemic inflammation, Parkinson’s
disease and other neurodegenerative disorders,
hypothyroidism, encephalopathy		 Thorough medical history and
examination including detailed
neurologic examination		 Sleepiness due to a drug
or medical condition		 Change medications, treat underlying condition,
consider stimulants

TABLE 33-2 Methods to Improve Sleep Hygiene in Insomnia Patients

Harrison's 22e, p.216

HELPFUL BEHAVIORS BEHAVIORS TO AVOID
Use the bed only for sleep and sex
• If you cannot sleep within 20 min,
get out of bed and read or do other
relaxing activities in dim light before
returning to bed		 Avoid behaviors that interfere with
sleep physiology, including:
• Napping, especially after 3:00 PM
• Attempting to sleep too early
• Caffeine after lunchtime
Develop a consistent bedtime routine.
For example:
• Prepare for sleep with 20–30 min
of relaxation (e.g., soft music,
meditation, yoga, pleasant reading)
• Take a warm bath		 When trying to fall asleep, avoid:
• Solving problems
• Thinking about life issues
• Reviewing events of the day