Narcolepsy

Narcolepsy is a neurological disorder of the sleep-wake cycle characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, and hallucinations upon waking or falling asleep. It most commonly manifests in teens and young adults with excessive daytime sleepiness. Primary narcolepsy is either caused by orexin deficiency (type 1) or is idiopathic (type 2). Secondary narcolepsy can occur as a result of brain damage or other genetic syndromes. Diagnosis requires an established history based on questionnaires or a sleep diary as well as a polysomnogram and multiple sleep latency test or an abnormal orexin A (hypocretin-1) level in the cerebrospinal fluid (CSF). No cure has yet been found, but daytime sleepiness can be managed with CNS stimulants (e.g., modafinil) and a regimen of scheduled naps. Cataplexy, hallucinations, and sleep paralysis are treated with antidepressants 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

References:^[2][3]

Epidemiological data refers to the US, unless otherwise specified.

Primary narcolepsy

• Narcolepsy type 1
  • Loss of lateral hypothalamic neurons, which produce orexin A and orexin B (i.e., hypocretin-1 and hypocretin-2) → severe orexin deficiency → dysregulation of sleep-wake cycles
  • The exact etiology is unknown, but both genetic and environmental factors seem to be implicated.
    • Genetic predisposition ^[4]
      • Narcolepsy type 1 is strongly associated with a variation of the HLA-DQB1 gene called HLA-DQB1*06:02
      • Positive family history increases the risk
    • Environmental factors: e.g., streptococcal pharyngitis, exposure to H1N1 influenza antigens during vaccination (autoimmune cross-reactivity) ^[2]
• Narcolepsy type 2
  • Idiopathic
  • No changes in orexin levels

Secondary narcolepsy

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

References:^[2][5]

• 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 (60–70% of cases): 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; (∼ 50% of cases): 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; (∼ 50% of cases): 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.

References:^[2][3][6][7]

• Diagnostic criteria ^[8]
  • Irresistible urge to sleep or daytime sleep lapses ≥ 3 times/week for at least 3 months
  • At least one of the following:
    • Cataplexy plus specific findings on a multiple sleep latency test and polysomnography
    • Abnormal CSF orexin A levels
• History
  • Sleep diary
  • Narcolepsy questionnaires
• Sleep studies
  • Polysomnography (PSG)
    • Conducted in a sleep laboratory during sleep, typically over the course of two days
    • PSG measures brain waves via electroencephalography (EEG), eye movements via electrooculography (EOG), and muscle activity via electromyography (EMG).
    • PSG findings are characterized by EEG beta waves that appear abnormally early after falling asleep (shortened REM sleep latency).
  • Multiple sleep latency test (MSLT)
    • Measures time needed to fall asleep during daytime naps to assess excessive daytime sleepiness
    • Polysomnography is made during the day; five opportunities to nap are provided
    • For a conclusive MSLT, patients must have at least six hours of normal sleep as assessed by PSG prior to the test.
    • Supports diagnosis if patient both:
      • Falls asleep with a mean latency of ≤ 8 minutes
      • Shows sleep-onset REM periods (SOREMPs) within 15 minutes after sleep onset in at least 2 out of the 5 opportunities provided
• Decreased CSF orexin A levels: supports diagnosis if ≤ 110 pg/mL or < ⅓ of mean values in healthy persons
• Additional tests
  • Human leukocyte antigen (HLA) haplotype testing: helpful in cases where additional objective evidence of narcolepsy is wanted
  • Diagnostics to rule out secondary narcolepsy (e.g., brain imaging)

References:^{[2][3][9][10]}

General approach

• Sleep hygiene recommendations
  • Take scheduled naps throughout the day to reduce the urge to sleep.
  • Ensure regular sleep periods during the night.
• Avoid substances that disturb the sleep-wake cycle (e.g., alcohol, antipsychotics, opiates).
• Consultations with family and employer (e.g., people with narcolepsy require a place to sleep at their workplace)

Automobile accidents are a concern! Patients should take treatment and be symptom-free to be allowed to drive.

Medical therapy

Choice of medication depends on the occurrence and relative extent of excessive daytime sleepiness, cataplexy, and/or nocturnal sleep disturbances. More than one medication may be required.

• Excessive daytime sleepiness
  • CNS stimulants
    • Drug of choice: modafinil (nonamphetamine CNS stimulant)
    • Alternatives
      • Methylphenidate and amphetamines (preferred in children)
      • Solriamfetol: selective dopamine and norepinephrine reuptake inhibitor that promotes wakefulness ^[11]
      • Pitolisant: highly selective H3 receptor antagonist/inverse agonist for the treatment of EDS and cataplexy ^[12]
• Cataplexy, sleep paralysis, and sleep hallucinations
  • SSRIs (e.g, citalopram) or SNRIs (e.g., venlafaxine)
  • Nighttime sodium oxybate(a gamma-hydroxybutyrate): highly effective for severe cataplexy
    • Sodium oxybate (i.e., GHB) is used recreationally for its ability to induce sedation and euphoria, and it has a high potential for misuse.
    • The drug is tightly regulated and only distributed through a restricted program to minimize the risk of misuse, especially among young patients.

Sodium oxybate should never be taken with alcohol or other CNS depressants because doing so may cause life-threatening respiratory depression!

References: ^[13][14]]^[15][16]