Sleep and sleep disorders

Sleep is a physiologically recurring state of rest characterized by relative suspension of consciousness and inaction of voluntary muscles. It is regulated by the circadian rhythm and usually consists of 4–5 sleep cycles that include three stages of non-rapid eye movement sleep (NREM sleep) and one stage of rapid eye movement sleep (REM sleep). Sleep disorders can be grouped into primary disorders (i.e., due to an intrinsic disorder of the sleep-wake cycle) and secondary disorders (i.e., due to an underlying medical condition). Primary sleep disorders are further divided into dyssomnias and parasomnias. Symptoms include difficulty falling asleep, difficulty remaining asleep, or abnormal behavior during sleep. Environmental factors (e.g., long working hours, irregular sleep schedules, alcohol consumption) can also lead to sleep loss. Symptoms include excessive daytime sleepiness and cognitive impairment. Treatment of sleep disorders and sleep loss may include sleep hygiene practice, phototherapy, and sedative pharmacotherapy.

Narcolepsy, restless legs syndrome, and obstructive sleep apnea are discussed in separate articles.

Normal sleep cycle ^[1]

• Sleep latency: the length of time required to fall asleep
• Sleep stages
  • A full night's rest typically consists of 4–5 sleep cycles of 90–120 minutes each.
  • Every cycle consists of 3 NREM sleep stages and one REM sleep stage with the percentage of REM sleep gradually increasing as the night progresses. ^[2]
• Circadian rhythm
  • Definition: a 24-hour cycle of biophysical changes that regulate sleep patterns, feeding patterns, hormone production (e.g., release of melatonin, prolactin, ACTH, norepinephrine), and body temperature
  • Regulation of sleep: decrease in light is detected by photosensitive melanopsin-containing retinal ganglion cells (mRGCs) → retinohypothalamic tract (RHT) stimulation → norepinephrine release from the suprachiasmatic nucleus of the hypothalamus → melatonin release from the pineal gland → sleep induction

Normal sleep phases ^[1][3]

“For BETTER (read “beta”) WAVES, Ask The Silent Surfer Dozing at the Beach:” Beta waves while awake; Alpha waves with eye closure; Theta waves during N1; Sleep spindles during N2; Delta waves during N3; Beta waves during REM sleep).

“I saw the t(w)ooth fairy fleeing and the three little pigs peeing:” teeth grinding occurs during N2 stage and bedwetting during N3 stage NREM sleep.

Primary sleep disorders

Dyssomnias

• Definition: : a group of primary sleeping disorders characterized by difficulty falling/staying asleep or hypersomnia (excessive daytime sleepiness)
• Types of dyssomnias
  • Circadian rhythm sleep-wake disorder ^[6]
    • Delayed sleep phase disorder
    • Advanced sleep phase disorder
    • Jet lag disorder
    • Shift-work disorder
    • Non-24 hour sleep-wake disorder
  • Insomnia disorder
  • Hypersomnolence disorder
  • Narcolepsy
  • Central sleep apnea
  • Obstructive sleep apnea

Parasomnias ^[6]

• Definition: : a group of primary sleeping disorders characterized by abnormal behaviors or experiences that occur while falling asleep, during sleep, or while waking up
• Types of parasomnias
  • NREM-related parasomnia: a group of parasomnias characterized by repeated episodes of brief but incomplete awakenings that typically occur during the first third of sleep
    • Sleepwalking disorder
    • Sleep terror disorder
  • REM-related parasomnias: a group of parasomnias characterized by a dissociation between REM sleep and the awake state
    • Nightmare disorder
    • REM sleep behavior disorder
    • Recurrent isolated sleep paralysis

Sleep-related movement disorders ^[7]

• Restless legs syndrome
• Periodic limb movement disorder
• Sleep-related bruxism

Secondary sleep disorders

• See “Sleep-phase-specific disorders” in “Sleep physiology” section above.

Common features of circadian rhythm sleep-wake disorders

• Insomnia
• Excessive daytime somnolence
• Irritability
• Frequent waking during abnormal hours
• Headaches and impaired concentration

Delayed sleep phase disorder

• Definition: a sleep-wake disorder characterized by a recurrent delay in sleep onset and waking times
• Risk factors: puberty, use of stimulants (e.g., caffeine), irregular sleep
• Treatment
  • Phototherapy in the morning
  • Melatonin receptor agonist (e.g., ramelteon, administered at night) ^[8]
  • Chronotherapy

Advanced sleep phase disorder

• Definition: a sleep-wake disorder characterized by earlier than desired sleep onset and awakening times
• Risk factor: : associated with older age
• Treatment
  • Reassurance
  • Phototherapy in the evening ^[8]

Jet lag disorder

• Definition: a circadian rhythm sleep disorder characterized by insomnia or hypersomnia due to travel across time zones
• Risk factor: sleep deprivation prior to travel
• Treatment
  • Resolves spontaneously
  • Exposure to sunlight in the new time zone can accelerate the recovery. ^[9]

Shift-work disorder

• Definition: : a sleep-wake disorder characterized by misaligned circadian rhythm due to nightly working hours and sleep deprivation
• Risk factors: shifts > 16 hours and/or night shifts
• Treatment
  • Modafinil if severe
  • Bright light therapy at night to adapt to work shift

Non-24 hour sleep-wake disorder ^[10]

• Definition: a circadian rhythm sleep disorder characterized by an individual's inability to align with the environmental 24-hour rhythm
• Risk factors: blindness, impaired light sensitivity
• Treatment
  • Combination of phototherapy and scototherapy (for the resynchronization of patient’s circadian rhythm)
  • Melatonin receptor agonist (tasimelteon)

Overview ^[11][12][13]

• Definition: a dissatisfying quantity or quality of sleep that leads to some form of daytime dysfunction
• Epidemiology: most common sleep-wake disorder (global prevalence ∼ 10%)
• Etiology: complex and not fully understood
  • Predisposing factors include:
    • A chronic state of cognitive and physiological hyperarousal
    • Medical comorbidities, including mood and anxiety disorders ^[12]
  • Precipitating (acutely triggering) factors: e.g., stressful events (acute or chronic)
  • Perpetuating factors: e.g., poor sleep hygiene
• Clinical features include:
  • Difficulty falling asleep, maintaining sleep, or early morning awakening
  • Nonrefreshing sleep
  • Impaired daytime functioning
    • Fatigue
    • Cognitive impairment
    • Mood disturbance
    • Difficulty with social, academic, or occupational functioning
• Potential health consequences
  • Development of mood disorders and increased risk of suicide ^[13]
  • Workplace injuries
  • Reduced quality of life

Insomnia is the most common sleep-wake disorder, affecting ∼ 10% of the population worldwide. Prevalence is higher in women, shift workers, and people with physical or mental disorders or disabilities.

Diagnosis ^{[11][12][13][14]}

Clinical assessment

Obtain a detailed clinical history, including symptoms and contributing factors; the Insomnia Severity Index or the Pittsburgh Sleep Quality Index are commonly used standardized assessment tools.

• Sleep-related symptoms
  • Inquire about sleeping habits and bedtime routine.
  • Determine symptom onset, triggers, and interventions already tried.
  • Identify nighttime symptoms and assess their frequency and pattern. ^[13]
    • Difficulty falling asleep, staying asleep, and/or waking early
    • Behaviors during sleep (including snoring, witnessed apneas, and leg kicking)
  • Ask about daytime impaired functioning and/or sleepiness.
• Medical and psychiatric history should include: ^[13][15]
  • Comorbid conditions and associated symptoms that could interfere with sleep
  • Medication use (prescription and over-the-counter) and the time at which medications are taken
  • Alcohol consumption, use of stimulants (e.g., nicotine, caffeine), and sedatives (e.g., opioids, benzodiazepines)
  • Occupation, school, and working hours
• Physical exam: Check BMI, neck circumference, and airway to evaluate for OSA.

Medications that may interfere with sleep include decongestants (e.g., pseudoephedrine or phenylephrine), bronchodilators (e.g., albuterol or theophylline), antidepressants, antihypertensives (e.g., beta blockers, calcium channel blockers, diuretics), glucocorticoids, sedatives, and hypnotics.

Diagnostic criteria for insomnia disorder

The most common sets of criteria are the International Classification of Sleep Disorders (ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which are largely consistent with one another.

Additional studies ^[13]

Diagnostic studies are not required to diagnose insomnia, but they may be useful in select patients:

• Actigraphy may be useful if:
  • Patient history is incomplete or unreliable
  • A circadian rhythm disorder is suspected
• Polysomnography may be useful if:
  • The patient is not responding to typical treatment
  • OSA or periodic limb movement disorder is suspected

Management ^[17][18][19]

Approach ^[20]

• All patients
  • Provide sleep hygiene education.
  • Optimize management of comorbid conditions.
• Short-term insomnia
  • Address triggers. ^[12][14]
  • Start a brief course of pharmacotherapy for insomnia. ^[20]
• Chronic insomnia ^[17][18][20]
  • First line: multicomponent cognitive behavioral therapy for insomnia (CBT-I)
  • If CBT-I is not successful:
    • Reassess the diagnosis (e.g., consider other sleep-wake disorders), comorbidities, and exacerbating factors.
    • Consider pharmacotherapy for select patients; use a shared decision-making strategy. ^[17]
    • Refer to a sleep specialist.

Cognitive behavioral therapy is the first-line treatment for chronic insomnia. ^[17]

Nonpharmacological management ^[15][19]

There are multiple nonpharmacological interventions that can improve sleep and their impact is greater when used in combination.

CBT-I combines cognitive therapy, stimulus control, and sleep restriction therapy, possibly with the addition of relaxation training. ^[15]

Avoid sleep restriction in patients with seizure disorders or bipolar disorders, as it can lower the threshold for seizures or precipitate manic episodes. ^[13]

Patients using sleep restriction to manage insomnia should avoid driving and operating heavy machinery. ^[13]

Pharmacotherapy for insomnia ^[13][20][21]

• The evidence supporting the benefits of pharmacotherapy for treating insomnia is relatively weak overall.
• Some examples of commonly used drugs include: ^[18]
  • Sleep-onset insomnia
    • Melatonin, ramelteon
    • Z-drugs (eszopiclone, zaleplon, zolpidem)
    • Benzodiazepines (preferably short-acting benzodiazepines like triazolam)
    • Suvorexant (orexin antagonist)
  • Sleep-maintenance insomnia: Z-drugs (eszopiclone, zolpidem), doxepin, suvorexant
  • Early-morning awakening: doxepin, suvorexant ^[13]
  • Older adults (> 65 years old): doxepin, melatonin, ramelteon
  • Comorbid depression: doxepin, mirtazapine, trazodone
  • Pregnancy: doxylamine, diphenhydramine ^[21]

Benzodiazepines carry a high risk of addiction and should therefore only be considered for short-term use.

Short-acting agents are useful for sleep-onset insomnia; longer-acting agents are useful for sleep-maintenance insomnia but increase the risk of next-day effects.

Avoid the use of benzodiazepine receptor agonists as a first-line medication for the treatment of insomnia in older adults and in patients with a history of substance use disorder or drug dependence. ^[11][21]

Inpatients frequently experience insomnia due to disruptive changes in routine and the fact that the hospital environment is not always conducive to sleep. ^[22][23][24]

• Insomnia prevention: Reduce insomnia triggers.
  • Optimize management of comorbid conditions.
    • Treat pain and other disturbing symptoms (e.g., cough, itching, nausea).
    • Reconcile inpatient orders with home medications to assess for changes that could affect sleep.
  • Reduce or eliminate medical care-related interruptions.
    • Avoid nonessential blood draws and vital sign monitoring overnight.
    • Consider whether medication schedules could be adjusted to avoid interrupting sleep.
  • Educate the patient about sleep hygiene (modifying recommendations for the inpatient environment).
• Insomnia management
  • Optimize the sleep environment: Reduce ambient noise and light as much as possible.
  • Start nonpharmacological interventions
  • Pharmacological therapy: Start only if alternative measures have failed (see “Pharmacotherapy for insomnia” above for dosages).
    • Potential initial options: melatonin or ramelteon
    • Alternatives
      • Younger adults: Consider Z-drugs (e.g., zolpidem) or antihistamines (e.g., hydroxyzine).
      • Older adults: Consider doxepin.
    • Off-label medications : antidepressants, antipsychotics (e.g., quetiapine), and anxiolytics (e.g., clonazepam)
• Screen for sleep disorders: Evaluate for untreated chronic insomnia or OSA.

Carefully consider adverse effects and medication interactions before prescribing medications for insomnia.

Sedatives and hypnotics are often overprescribed to inpatients. Clinicians should avoid them if possible and, when necessary, they should be prescribed carefully, after weighing the risk of potential adverse events and pharmacological interactions. ^[22]

Overview

• Epidemiology
  • Prevalence: ∼ 15% of population in the US ^[25]
  • Sex: ♂ = ♀
  • Age of onset: 15–25 years of age
• Etiology
  • Genetic (may be autosomal dominant)
  • Head trauma
  • Viral infections (e.g., HIV)
• Classification
  • Acute: < 3 months
  • Chronic: ≥ 3 months

Clinical features

• Excessive sleep (with decreased sleep quality)
• Difficulty awakening from sleep
• Sleep inertia (impaired alertness or excessive fatigue after waking)
• Automatic behaviors (with no memory of the episode after waking)

DSM-5 diagnostic criteria ^[26]

• Excessive sleepiness despite ≥ 7 hours of sleep with at least one of the following:
  • Recurrent periods of sleep on the same day
  • > 9 hours of sleep that is nonrestorative
  • Impaired alertness after awakening
• Symptoms occur ≥ 3 days/week for ≥ 3 months
• Symptoms cause functional impairment or distress
• Symptoms not caused by an underlying substance or medication use
• Symptoms occur despite having enough time to sleep
• No underlying or coexisting psychiatric or medical disorder that explains symptoms

Treatment

• Regularly scheduled naps
• First-line therapy: modafinil or methylphenidate
• Second-line therapy: atomoxetine

Sleepwalking disorder

• Definition: a NREM-related parasomnia characterized by walking or performing other activities during the first third of the sleep cycle
• Epidemiology: Discrete episodes are common (up to 7% of adults and 30% of children), but the disorder is rare. ^[27][28]
• Etiology: idiopathic or genetic (inherited in 80% of cases)
• Risk factors
  • Sleep deprivation
  • Irregular sleep schedules
  • Stress or fatigue
  • Obstructive sleep apnea
  • Nocturnal seizures
  • Fever
  • Drugs (e.g., benzodiazepines, z-drugs, antidepressants, antipsychotics, β-blockers) ^[29]
• Clinical features
  • Recurrent episodes during the first third of the sleep cycle, including sitting up, walking, or eating
  • Blank stare and difficulty arousing patient during the episode
  • Followed by amnesia of the event
• Treatment
  • Education and reassurance
  • Ensuring safe sleep environment to reduce the risk of physical harm or wandering outdoors
  • In refractory cases, benzodiazepines

Sleep terror disorder

• Definition: a NREM-related parasomnia that occurs during the N3 sleep stage (slow-wave sleep), characterized by episodes of sleep terror
• Epidemiology: : Discrete episodes of sleep terrors are relatively common in children (∼ 20% of children and ∼ 2% of adults), but the disorder is rare.
• Etiology: unknown; presumed to be genetic (family history)
• Risk factors
  • Stress or fatigue
  • Fever
  • Sleep deprivation
  • Obstructive sleep apnea
  • Nocturnal seizures
  • Drugs (e.g., lithium)
• Clinical features
  • Screaming or crying suddenly upon awakening, usually in the first part of the night (rarely during daytime naps) ^[30]
  • Intense fear and agitation
  • Tachypnea, diaphoresis, tachycardia during episodes
  • Difficulty arousing patients during episodes
  • Patients usually return to sleep after the episode.
  • Typically no recollection of the arousal episode (unlike with nightmare disorder)
• Treatment
  • Education and reassurance (disorder usually self-limited)
  • Removal of dangerous objects from bedroom to reduce risk of self-injury
  • In refractory cases, benzodiazepines

Nightmare disorder

• Definition: a REM-related parasomnia characterized by recurrent nightmares
• Epidemiology
  • Prevalence: most common in early adulthood; occurs in 2–5% of the adult population ^[31]
  • Sex: ♀ > ♂
  • Peak incidence is 5-7 years
• Risk factors: post-traumatic stress disorder (PTSD)
• Clinical features
  • Recurrent frightening dreams during the second half of sleep cycle (middle of the night or early in the morning)
  • Patient remembers the dream after awakening (unlike in sleep terror disorder).
  • Causes functional impairment or distress
• Treatment
  • Reassurance if the disorder is mild
  • Imagery rehearsal therapy: involves modifying a recurrent nightmare by writing it down and rehearsing new endings that make nightmares less frightening when they occur again
  • Antidepressants or prazosin if associated with PTSD ^[32]

REM sleep behavior disorder

• Definition: a REM-related parasomnia characterized by dream enactment due to loss of REM sleep atonia
• Epidemiology
  • Prevalence: ∼ 1% in the general population ^[33]
  • Sex: ♂ > ♀
  • Usually in older patients (> 50 years)
• Risk factors
  • Narcolepsy
  • Psychiatric medications (e.g., antidepressants)
  • Neurodegenerative disorders (e.g., Parkinson disease, Lewy body dementia)
• Clinical features
  • Physically acting out dreams during sleep (e.g., yelling, moving limbs, walking, punching), sometimes leading to injury to self or others
  • Patient is alert and orientated after awakening, and remembers the dream.
• Treatment
  • Remove dangerous objects from the bedroom to reduce risk of self-injury.
  • If applicable, discontinue causative medications.
  • Pharmacotherapy ^[33]
    • Melatonin receptor agonist (first-line treatment)
    • Benzodiazepines (e.g., clonazepam)
• Prognosis: Most patients with idiopathic RBD eventually develop a disorder of α-synuclein neurodegeneration, most commonly Parkinson disease.

Other parasomnias

• Nocturnal enuresis
• Restless leg syndrome

“I REMember my NIGHTMARE, and there were NO memorable TERRORists:” Nightmare disorder occurs during REM sleep and the experience is remembered, while sleep terror disorder occurs during non-REM sleep and is not remembered.

• Definition: : a condition characterized by periodic limb movements of sleep (PLMS) that is not associated with any other disease
• Etiology: unknown
• Pathophysiology: idiopathic malfunction of the dopaminergic system
• Clinical features
  • Frequent and stereotypic involuntary movement in the legs (e.g., flexion and extension of the toes, ankles, knees, and hips) and/or in the arms (less common) during sleep.
  • Clinically significant sleep disturbance or functional impairment not explained by any other disorder
• Diagnostics: Polysomnography
• Treatment: benzodiazepines, dopaminergic agents, OR antiepileptics drugs (e.g, gabapentin)

Normal changes in sleep architecture occur with aging, and include:

• Decreased total sleep time ^[34]
  • Decreased time spent in deep sleep and REM sleep
  • Increased sleep latency
  • More frequent nighttime awakenings that are likely multifactorial (e.g., due to nocturia, pain, and/or less time spent in deeper stages of sleep)
• Advanced circadian rhythms resulting in earlier bedtimes and thus morning awakenings ^[34]

• Definition: a state of inadequate quality and/or quantity of sleep ^[37]
• Epidemiology
  • Prevalence: approx. 20% ^[37]
  • Risk factors
    • Prolonged working hours; shift work
    • Irregular sleep schedules
    • Increased exposure to nocturnal blue light (e.g., due to cell phone use and/or watching television before sleep)
    • Being a parent to young children
• Etiology ^[35][36]
  • Environmental causes, e.g.:
    • Substance use (e.g., alcohol, stimulants such as caffeine, cocaine, amphetamines)
    • Sleeping circumstances (e.g., exposure to increased noise or light at night)
  • Sleep disorders, e.g.:
    • Dyssomnias (see above) include:
      • Delayed sleep phase disorder,
      • Advanced sleep phase disorder
      • Central sleep apnea
      • Obstructive sleep apnea
      • Insomnia disorder
    • Parasomnias (see above)
  • Other medical conditions, including:
    • Metabolic syndrome
    • Acute and chronic pain
    • Neurodegenerative diseases
    • Psychiatric disorders (e.g., major depressive disorder, anxiety, bipolar disorder)
• Classification
  • Acute sleep deprivation: 1–2 days of reduced or no sleep
  • Chronic sleep deprivation (sleep restriction): reduced sleep for months
• Clinical features
  • Fatigue
  • Excessive daytime sleepiness
  • Cognitive impairment (e.g., poor focus, impaired memory, reduced alertness)
  • Mood disturbances (e.g., depressed mood)
  • Lower self-reported quality of life
• Diagnostics
  • Assessment of quality and quantity of sleep
  • Polysomnography
• Differential diagnosis
  • Hypersomnolence disorder
  • Chronic fatigue syndrome
• Management
  • Treatment of underlying conditions (e.g., obesity, sleep apnea, psychiatric disorders)
  • Behavioral modification
    • Patient education
    • Improvement of sleep hygiene (eliminate behavioral habits that adversely affect sleep)
  • In case other options fail: sedative-hypnotic drugs
  • In case life circumstances can not be changed (e.g., shift work): use of substances helping with wakefulness (e.g., caffeine)
• Complications
  • Increased rates of accidents and injuries
  • Increased rates of errors (e.g., doctors, pilots)
  • Organ-related complications
    • Obesity, diabetes mellitus, and impaired glucose tolerance
    • Cardiovascular diseases and hypertension
    • Anxiety and depressive disorders

• One-Minute Telegram 70-2023-3/3: Sleep tight and keep your heart right

Interested in the newest medical research, distilled down to just one minute? Sign up for the One-Minute Telegram in “Tips and links” below.