Narcolepsy

Narcolepsy is a neurological disorder of the sleep-wake cycle characterized by excessive daytime sleepiness and, in some cases, cataplexy, sleep paralysis, and hallucinations upon waking or falling asleep. It most commonly manifests in teenagers and young adults. Primary narcolepsy type 1 may manifest with cataplexy and/or orexin deficiency. Patients with type 2 primary narcolepsy have normal orexin levels. Secondary narcolepsy can occur as a result of brain damage or genetic syndromes. Diagnosis requires a history ≥ 3 months of excessive daytime sleepiness and either typical findings on polysomnography or an abnormal level of hypocretin-1 (orexin A) in the cerebrospinal fluid (CSF). There is no cure for narcolepsy but daytime sleepiness can be managed with optimized sleep hygiene and CNS stimulants or sodium oxybate.

• Prevalence: 25–50:100,000 ^[1]
• Incidence: ∼ 0.8:100,000 individuals per year
• Sex: ♂ = ♀
• Bimodal distribution
  • First peak at 15 years
  • Another smaller peak around age 35

Epidemiological data refers to the US, unless otherwise specified.

Primary narcolepsy

• Narcolepsy type 1
  • Loss of lateral hypothalamic neurons, which produce hypocretin-1 and hypocretin-2 (i.e. orexin A and orexin B) → severe hypocretin (orexin) deficiency → dysregulation of sleep-wake cycles ^[2]
  • The exact etiology is unknown, but both genetic and environmental factors seem to be implicated.
    • Genetic predisposition ^[3]
      • Narcolepsy type 1 is associated with a variation of the HLA-DQB1 gene called HLA-DQB1*0602
      • Positive family history increases the risk
    • Environmental factors: e.g., streptococcal pharyngitis, exposure to H1N1 influenza vaccine Pandemrix ^[4][5]
• Narcolepsy type 2
  • Idiopathic
  • No changes in orexin levels

The HLA-DQB1*0602 genotype alone is insufficient to cause narcolepsy (i.e., without environmental factors).

Secondary narcolepsy

• Cerebral damage (e.g., tumor, stroke, inflammation, vascular malformation)
• Genetic syndromes (e.g., Niemann-Pick disease type C and Prader-Willi syndrome)

• Excessive daytime sleepiness (EDS): Affected individuals experience an irresistible urge to sleep and sudden, short sleep attacks (< 30 minutes), which may occur in inappropriate situations (e.g., while driving a car).
  • One of the earliest manifestations of narcolepsy
  • Can occur despite adequate sleep
• Abnormal REM sleep
  • Cataplexy: sudden muscle weakness in a fully conscious person, triggered by strong emotions (e.g., laughing, crying)
    • Typically manifests months or even years after EDS
    • The loss of muscle tone is similar to that observed during REM sleep.
    • Typically manifests as partial cataplexy: isolated weakness of distinct muscle groups (e.g., neck muscles weaken and head tilts forward)
    • Usually resolves within a few seconds, at most two minutes
  • Sleep paralysis: Complete paralysis occurs for 1–2 minutes after waking or before falling asleep (either during a nocturnal or narcoleptic sleep episode, i.e., begins or ends with REM sleep)
• Sleep hallucinations
  • Hypnagogic hallucinations: vivid, often frightening visual or auditory hallucinations that occur as the patient falls asleep
  • Hypnopompic hallucinations: experienced while waking up (less common than hypnagogic hallucinations)
• Automatic behavior: During narcoleptic episodes, patients often perform routine repetitive tasks automatically without conscious awareness of their environment.
• Other: depression, obesity, impotence or low sex drive, headaches, decreased functional performance

Hypnagogic hallucinations occur while going to sleep.

Approach ^[8][9][10]

• Rule out other causes of EDS, e.g., insufficient sleep, obstructive sleep apnea, or other sleep disorders.
  • Consider using a sleep questionnaire, e.g., the Epworth sleepiness scale.
  • Recommend a sleep log for 1–2 weeks and/or actigraphy. ^[9]
  • Review sleep hygiene.
  • Assess history of stimulant use.
• Assess for cataplexy based on patient history and third-party reports.
• Order sleep studies to confirm the diagnosis and refer to sleep medicine.

Diagnostic criteria ^[8][10][11]

• Daily periods of excessive daytime sleepiness for ≥ 3 months AND
  • In type 1 narcolepsy, either:
    • ≥ 1 episode of cataplexy PLUS characteristic findings on a sleep study
    • OR low CSF hypocretin-1 (orexin A) levels
  • In type 2 narcolepsy: characteristic findings on a sleep study without cataplexy or reduced hypocretin levels

Sleep studies ^[12]

• Daytime multiple sleep latency test (MSLT)
  • Includes 5 opportunities for the patient to nap during the daytime and measures :
    • Sleep latency: time needed to fall asleep
    • Sleep-onset REM periods (SOREMPs): REM periods that occur within 15 minutes of falling asleep; also referred to as shortened REM sleep latency
  • Characteristic findings
    • Sleep latency < 8 minutes
    • ≥ 2 SOREMPs
• Nocturnal polysomnography (PSG)
  • Measures sleep duration, efficiency, and stages
  • Used to exclude other sleep disorders and may also show supportive findings for narcolepsy (e.g., SOREMP)

If feasible, medications affecting sleep (e.g., antidepressants and stimulants) should be paused for at least two weeks prior to a sleep study. ^[12]

Additional tests

• Lumbar puncture
  • Not routinely indicated; may be used to diagnose type 1 narcolepsy ^[13][14]
  • Supportive finding: decreased CSF hypocretin-1 (orexin A) levels (≤ 110 pg/mL or < ⅓ of the mean value in healthy persons) ^[8][10]
• MRI brain: Consider if neurological findings suggest secondary narcolepsy. ^[15]
• Human leukocyte antigen (HLA) haplotype testing: not usually useful for diagnostic purposes ^[1][10]

General measures

• Optimize sleep hygiene. ^[9]
  • Ensure regular sleep periods during the night.
  • Avoid substances that disturb the sleep-wake cycle (e.g., alcohol, antipsychotics, opiates).
• Consider scheduled naps throughout the day to reduce the urge to sleep. ^[16]

As motor vehicle collisions are a concern for patients with narcolepsy, to be allowed to drive, they should be symptom-free and taking treatment. State regulations vary on the legally required period of time that patients should be symptom-free before driving.

Medical therapy ^[17]

Principles of medical therapy

• Patients should be treated in consultation with a sleep specialist.
• The choice of medication depends on symptom severity, psychosocial history, and comorbidities.
• All first- and second-line drugs except for methylphenidate are effective treatment for excessive daytime sleepiness.
• Sodium oxybate and pitolisant are also highly effective for treating cataplexy. ^[17]
• SSRIs (e.g., citalopram) and SNRIs (e.g., venlafaxine): controversial role; no longer routinely recommended ^[16][17][18]

Commonly used agents

• First-line medications
  • Modafinil: a nonamphetamine CNS stimulant
  • Solriamfetol: selective dopamine and norepinephrine reuptake inhibitor that promotes wakefulness ^[19]
  • Pitolisant: highly selective H₃receptor antagonist/inverse agonist for the treatment of EDS and cataplexy ^[20]
  • Nighttime sodium oxybate: a sodium salt of gamma hydroxybutyric acid ^[18]
• Second-line medications
  • Armodafinil
  • Dextroamphetamine
  • Methylphenidate

Sodium oxybate (gamma-hydroxybutyrate) may cause life-threatening respiratory depression and should never be taken with alcohol or other CNS depressants. Since it is used recreationally to induce sedation and euphoria, sodium oxybate has a high potential for misuse. ^[17]

Stimulants recommended for treating narcolepsy may cause fetal harm and reduce the effectiveness of oral contraception. ^[17]

• Currently no cure available ^[16]
• Associated with higher rates of morbidity (e.g., cardiovascular disease) ^[21][22]
• Increased risk of motor vehicle accidents (adequate treatment may mitigate risk) ^[23]