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% to 0.04% of the general population.
    • Narcolepsy type 1 (with cataplexy) has a prevalence between 0.025 to 0.05%
    • Narcolepsy type 2 (without cataplexy) has a prevalence between 0.02 to 0.034%
  • Narcolepsy affects both genders, with possibly a slight male dominance.
  • There is a bimodal age of onset, at ages 15 to 25, and ages 30 to 35.[1]
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 (MSLT) showing a mean sleep latency less than or equal to 8 minutes and two or more sleep-onset REM periods.

Narcolepsy Tetrad

The classic symptoms of narcolepsy, often referred to as the “tetrad of narcolepsy” are: cataplexy (pathognomonic), sleep paralysis (essential), hypnagogic hallucinations, and excessive daytime sleepiness.
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 oligodendrocyte 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).
  • Hypnagogic and hypnopompic hallucinations can occur in up to 30% of individuals with narcolepsy.[2]. These are usually visual and involve elements of the individual's environment.
  • Individuals with narcolepsy may also experience sleep paralysis.
  • Cataplexy is a sudden, brief loss of voluntary muscle tone, and often can be triggered by strong emotions such as laughing.
    • The individual retains full awareness and alertness during the episode, and there is no confusion before or after the event.
  • Cataplexy is thought to result from intrusion of REM sleep paralysis into a state of wakefulness
  • Cataplexy typically develops several years after onset of sleepiness symptoms and occurs in 70% of individuals with narcolepsy
  • Respiratory function and eye muscles are not affected, and the weakness lasts only a few seconds to a few minutes (but can be as long as 30 minutes).
  • Sleep attacks are different from episodes of cataplexy, and not the same thing!
  • These attacks involve irresistible urges to sleep that last usually for 10 to 20 minutes
    • However, can last as long as an hour
  • An individual will have between 2 to 6 episodes of these sleep attacks each day (whether intentional or unintentional)
  • The sleep episodes are restorative, but sleepiness usually returns within several hours

Narcolepsy Type 1 vs. Type 2

Type Narcolepsy Type 1 Narcolepsy Type 2
Polysomnogram Sleep onset REM periods (SOREMPs) may be present.* Sleep onset REM periods (SOREMPs) may be present.*
Multiple Sleep Latency Test (MSLT) Sleep onset latency (SOL) must be <8 minutes and 2 SOREMPs are required (one may be substituted from previous night PSG) Sleep onset latency (SOL) must be <8 minutes and 2 SOREMPs are required (one may be substituted from previous night PSG)
Cataplexy Yes No
CSF Orexin-1 <110pg/mL or <1/3 of mean values >110pg/mL or >1/3 of mean values
  • Narcolepsy-cataplexy nearly always is due to the loss of hypothalamic hypocretin (also known as orexin)-producing cells, causing a orexin (hypocretin) deficiency.
    • Orexin is a neuropeptide, and is made in the lateral hypothalamus and promotes wakefulness (associated with the locus coeruleus, raphe nuclei and tuberomamillary nucleus)
  • The loss of orexin signalling can be due to multiple causes including autoimmune causes, traumatic brain injuries, viral infections, or streptococcal infection.
  • 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

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.

  • Approximately 99% of affected individuals with narcolepsy plus cataplexy will carry the HLA-DQBl*06:02.
    • However, it is only present in about 40% of those with narcolepsy without cataplexy (and 20 to 25% in the general population)
  • Genotyping for the presence of DQB1*06:02 prior to a lumbar puncture for evaluation of CSF hypocretin-1 immunoreactivity may be useful.
  • 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.
  • Good sleep hygiene (scheduled naps, regular sleep schedule)