Narcolepsy

Narcolepsy is a sleep disorder characterized by sleepiness with recurrent daytime naps or lapses into sleep. Sleepiness typically occurs daily. Narcolepsy also generally produces cataplexy, which most commonly presents as brief episodes (seconds to minutes) of sudden, bilateral loss of muscle tone precipitated by emotions, typically laughing and joking. Narcolepsy-cataplexy is almost always due to loss of hypothalamic hypocretin (orexin)-producing cells, causing hypocretin deficiency.

Prevalence

Narcolepsy-cataplexy affects 0.02%-0.04% of the general population in most countries. Narcolepsy affects both genders, with possibly a slight male dominance.

Criterion A

Recurrent periods of an irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day. These must have been occurring at least 3 times per week over the past 3 months.

Criterion B

The presence of at least 1 of the following:

  1. Episodes of cataplexy, defined as either (A) or (B), occurring at least a few times per month: (A) In individuals with long-standing disease, brief (seconds to minutes) episodes of sudden bilateral loss of muscle tone with maintained consciousness that are precipitated by laughter or joking, OR (B) In children or in individuals within 6 months of onset, spontaneous grimaces or jaw-opening episodes with tongue thrusting or a global hypotonia, without any obvious emotional triggers.
  2. Hypocretin deficiency, as measured using cerebrospinal fluid (CSF) hypocretin-1 immunoreactivity values (less than or equal to one-third of values obtained in healthy subjects tested using the same assay, or less than or equal to 110 pg/mL). Low CSF levels of hypocretin-1 must not be observed in the context of acute brain injury, inflammation, or infection.
  3. Nocturnal sleep polysomnography showing rapid eye movement (REM) sleep latency less than or equal to 15 minutes, or a multiple sleep latency test showing a mean sleep latency less than or equal to 8 minutes and two or more sleep-onset REM periods.
Specifiers

Specifiers

Specify if:

  • Narcolepsy without cataplexy but with hypocretin deficiency: Criterion B requirements of low CSF hypocretin-1 levels and positive polysomnography/ multiple sleep latency test are met, but no cataplexy is present (Criterion B1 not met).
  • Narcolepsy with cataplexy but without hypocretin deficiency: In this rare subtype (less than 5% of narcolepsy cases), Criterion B requirements of cataplexy and positive polysomnography/multiple sleep latency test are met, but CSF hypocretin-1 levels are normal (Criterion B2 not met).
  • Autosomal dominant cerebellar ataxia, deafness, and narcolepsy: This subtype is caused by exon 21 DNA (cytosine-5)-methyltransferase-1 mutations and is characterized by late-onset (age 30-40 years) narcolepsy (with low or intermediate CSF hypocretin-1 levels), deafness, cerebellar ataxia, and eventually dementia.
  • Autosomal dominant narcolepsy, obesity, and type 2 diabetes: Narcolepsy, obesity, and type 2 diabetes and low CSF hypocretin-1 levels have been described in rare cases and are associated with a mutation in the myelin oligodendro cyte glycoprotein gene.
  • Narcolepsy secondary to another medical condition: This sub type is for narcolepsy that develops secondary to medical conditions that cause infectious (e.g., Whipple’s disease, sarcoidosis), traumatic, or tumoral destruction of hypocretin neurons.

Severity Specifier

Specify if:

  • Mild: Infrequent cataplexy (less than once per week), need for naps only once or twice per day, and less disturbed nocturnal sleep.
  • Moderate: Cataplexy once daily or every few days, disturbed nocturnal sleep, and need for multiple naps daily.
  • Severe: Drug-resistant cataplexy with multiple attacks daily, nearly constant sleepiness, and disturbed nocturnal sleep (i.e., movements, insomnia, and vivid dreaming).

Narcolepsy-cataplexy nearly always results from the loss of hypothalamic hypocretin (orexin)-producing cells, causing hypocretin deficiency. The loss is likely due to autoimmune causes.

Hypocretin (Orexin)

Cerebrospinal Fluid (CSF) hypocretin-1 measurement is the gold standard. A lumbar puncture is performed to obtain CSF. Hypocretin deficiency is diagnosed when there is less than or equal to one-third of control values, or 110 pg/mL in most laboratories). Very rarely, low CSF levels of hypocretin-1 can occur without cataplexy, mostly in youths who may develop cataplexy later. It is important to remember that associated severe conditions (neurological, inflammatory, infectious, trauma) that can interfere with the assay.

Genotyping (DQB1*06:02)

Approximately 99% of affected individuals carry HLA-DQBl*06:02. Genotyping for the presence of DQB1*06:02 prior to a lumbar puncture for evaluation of CSF hypocretin-1 immunoreactivity may be useful.

Polysomnography

Nocturnal polysomnography (PSG) followed by an MSLT is also used to confirm the diagnosis, prior to treatment or if there is no measured hypocretin deficiency. The test should be performed in the absence of psychotropic drugs and after regular sleep-wake patterns have been documented.

  • Other hypersomnias
  • Sleep deprivation and insufficient nocturnal sleep
  • Sleep apnea syndromes
  • Major depressive disorder
  • Conversion disorder (functional neurological symptom disorder)
  • Attention-deficit/hyperactivity disorder or other behavioral problems
  • Seizures
  • Chorea and movement disorders
  • Schizophrenia