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.

• 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]

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.

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.

• 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.

The International Classification of Sleep Disorders, third edition (ICSD-3) criteria for narcolepsy is as follows:

For Narcolepsy Type 1 (also known as: Hypocretin deficiency syndrome, narcolepsy-cataplexy, narcolepsy with cataplexy), Criteria A and B must be met:

The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months.

The presence of one or both of the following:

1. Cataplexy (as defined under Essential Features) and a mean sleep latency of ≤ 8 minutes and 2 or more sleep onset REM periods (SOREMPs) on an MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may replace one of the SOREMPs on the MSLT.
2. CSF hypocretin-1 concentration, measured by immunoreactivity, is either ≤ 110 pg/mL or <1/3 of mean values obtained in normal subjects with the same standardized assay.

For Narcolepsy Type 2 (also known as: narcolepsy without cataplexy), Criteria A to E must be met:

The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months.

A mean sleep latency of ≤ 8 minutes and 2 or more sleep onset REM periods (SOREMPs) are found on a MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may replace one of the SOREMPs on the MSLT.

Cataplexy is absent.

Either CSF hypocretin-1 concentration has not been measured or CSF hypocretin-1 concentration measured by immunoreactivity is either > 110 pg/mL or > 1/3 of mean values obtained in normal subjects with the same standardized assay.

The hypersomnolence and/or MSLT findings are not better explained by other causes such as insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal.

• Cataplexy is a sudden, brief loss of voluntary muscle tone, and often can be triggered by strong emotions such as laughing. Importantly, the individual retains full awareness and alertness during the episode, and there is no confusion before or after the event (i.e. - not a seizure). Cataplexy is thought to result from intrusion of REM sleep paralysis into a state of wakefulness
  • Cataplexy is defined by the ICSD-3 as more than 1 episode of generally brief (<2 minutes) and usually bilaterally symmetrical sudden loss of muscle tone with retained consciousness.
• Cataplexy typically develops several years after onset of sleepiness symptoms and occurs in about 70% of individuals with narcolepsy
• The episodes are precipitated by strong emotions, usually positive, with almost all patients reporting some episodes being precipitated by emotions associated with laughter
  • During an episode, if observed, transient reversible loss of deep tendon reflexes is a strong diagnostic finding.
  • In children (and rarely in adults), cataplexy may present close to disease onset as facial (or generalized) hypotonia with droopy eyelids, mouth opening, and protruded tongue, or gait unsteadiness, which clearly are not related to emotion.

• 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-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)

• Treatment for excessive daytime sleepiness alone is usually managed with a stimulant, including:
  • Dextroamphetamine 5 to 30 mg BID
  • methylphenidate 10 mg to 30 mg BID
  • Modafinil (wakefulness promoting agent) 100 to 400 mg PO daily or divided doses may also be used for daytime sleepiness, but it is not first line for cataplexy.
• In cataplexy with REM intrusions, sleep paralysis, and/or hypnagogic hallucinations this can be treated with:
  • Tricyclic antidepressants such as imipramine, desipramine
  • Selective serotonin reuptake inhibitors (SSRIs)
  • Selective noepinephrine reuptake inhibitors (SNRIs), such as venlafaxine
• In those with cataplexy with combined daytime sleepiness, they may be treated with sodium oxybate (the sodium salt of γ-hydroxybutyric acid, or GHB), but because of the potential for abuse, this medication is highly regulated.