Narcolepsy

Narcolepsy is a neurological disorder that disrupts the circadian sleep-wake rhythm. It often begins in adolescence with short diurnal sleep attacks. Primary narcolepsy is either due to orexin deficiency (type 1) or idiopathic (type 2). Secondary narcolepsy may occur as a result of metabolic or structural brain damage or as a symptom of other genetic syndromes. The characteristic symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, hallucinations upon waking or falling asleep, and sleep paralysis. The diagnosis requires an established history based on questionnaires or a sleep diary. Additional requirements are 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 helped 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
• Incidence: ∼ 0.8/100,000 people per year
• Sex: ♂ > ♀
• Bimodal distribution: : teens and early twenties; another smaller peak at around age 35

References:^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

• Primary narcolepsy
  • Narcolepsy type 1
    • Loss of hypothalamic neurons producing orexin A and orexin B (or hypocretin-1 and hypocretin-2) → severe orexin deficiency
    • Various genetic and unknown environmental factors are important in the development of type 1 narcolepsy.
  • Narcolepsy type 2
    • Idiopathic
    • No changes in orexin levels
• Secondary narcolepsy
  • Cerebral damage (e.g., tumors, stroke, inflammation, vascular malformations)
  • Certain genetic syndromes (e.g., Niemann-Pick disease type C and Prader-Willi syndrome)

References:^[1]

• Excessive daytime sleepiness; : patients experience an irresistible urge to sleep → sudden, short sleep attacks (< 30 minutes), often at inappropriate times or in inappropriate situations (e.g., while driving a car)
• Abnormal REM sleep
  • Cataplexy (in ∼ 80% of cases): sudden muscle weakness in a fully conscious patient, triggered by strong emotions (e.g., patients may experience buckling of the knees upon laughing)
    • Cataplexy usually resolves within a few seconds, at most two minutes.
    • Often as partial cataplexy: isolated weakness of distinct muscle groups (e.g., neck muscles → head tilts forward involuntarily, leg muscles → patient falls down)
  • Sleep paralysis; (in ∼ 50% of cases): complete paralysis occurring for 1–2 minutes after waking or before falling asleep. External stimuli (e.g., stirring or addressing the patient) can release the patient from this condition.
  • Hypnagogic hallucinations; (in ∼ 50% of cases): vivid, often frightening visual or auditory hallucinations occurring as the patient falls asleep. Hallucinations experienced while waking up (hypnopompic hallucinations) are less common.
• Automatic behavior: During narcoleptic attacks, patients often start or continue routine, dull, or repetitive tasks automatically without conscious awareness, perception of their environment, or memory.
• Other: : depression, obesity, low sex drive or impotence, headaches, decreased functional performance

References:^[1][2][3][4]

• Diagnostic criteria according to the International Classification of Sleep Disorders
  • Daily irresistible urge to sleep, which lasts 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 (hypocretin-1) levels
• History
  • Sleep diary
  • Narcolepsy questionnaires
• Sleep studies
  • Polysomnography (PSG)
    • Conducted in a sleep laboratory, 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) during sleep. In addition, it registers breathing flow, breathing pauses, oxygen saturation, snoring noises, and movements of the chest and abdomen while breathing.
    • Rapid onset of EEG beta waves (shortened REM sleep latency)
  • Multiple sleep latency test (MSLT)
    • Measures daytime tendency to fall asleep (to assess excessive daytime sleepiness)
    • A period of at least six hours of normal sleep as assessed by PSG prior to the test is needed for a meaningful MSLT.
    • Procedure: the patient is given five opportunities to fall asleep (in 2-hour intervals) . Latency until sleep onset and occurrence of sleep onset REM periods (SOREMPs) are recorded.
    • Supports diagnosis if patient both:
      • Falls asleep with a mean latency of ≤ 8 minutes
      • Shows SOREMPs within 15 minutes after onset of sleep in at least 2 out of the 5 opportunities provided
• Decreased CSF orexin-A (hypocretin-1) levels: supports diagnosis if ≤ 110 pg/mL or < ⅓ of mean values in healthy persons
• Additional tests
  • Human leukocyte antigen (HLA) haplotype testing: not used as a routine tool; may be helpful in cases where additional objective evidence of narcolepsy is wanted.
  • Diagnostics to rule out secondary narcolepsy (e.g., brain imaging)

References:^[1][2][5][6]

General approach

• Sleep hygiene
  • 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 rhythm (e.g., alcohol, antipsychotics, opiates)
• Psychosocial counseling with family and employer (narcoleptics require a place to sleep at their workplace)

Automobile accidents are a concern!

Medical therapy

• Choice of medication depends on the occurrence and relative extent of diurnal sleepiness and cataplexy/nocturnal sleep disturbances. Many patients require more than one medication. Individual contraindications must be observed.
• For diurnal sleepiness
  • CNS stimulants
    • Drug of choice: modafinil
    • Alternatives: methylphenidate and amphetamines
  • Alternative: sodium oxybate (sodium salt of gamma-hydroxybutyric acid, GHB)
• For cataplexy, sleep paralysis, and sleep hallucinations:
  • First-line therapy: sodium oxybate
  • Alternative: SSRIs (e.g, citalopram) or SNRIs (e.g., venlafaxine)

Sodium oxybate (gamma-hydroxybutyric acid, GHB) should never be taken with alcohol or other CNS depressants, as this may cause life-threatening respiratory depression!

Because of sodium oxybate's potential for abuse – it is often referred to as "liquid ecstasy" by recreational users (although the mode of action is entirely different from that of MDMA) and has become notorious for its use as a "date-rape" drug – the drug is tightly regulated. Before prescribing the drug, the legal regulations pertaining to it should be consulted.

References:^[7][8]]^[9][10]