What do we really know about narcolepsy?

Sleep disorders are among the conditions that affect the most people and inexorably impact everyone's daily well-being. It is a proven fact: when we sleep poorly, too much, or not enough, we do not feel well. Thus, narcolepsy is one of those sleep disorders that, when it affects us, all too often makes life difficult and renders our sleep chaotic. Narcolepsy is a rare disease whose causes cannot be treated but, nevertheless, it is possible to live with it by limiting its repercussions.

But by the way, what exactly is narcolepsy?

You have probably already heard about narcolepsy¹ around you or in the media, and for good reason, this sleep disorder gets a lot of attention. And not in a good way, of course. Narcolepsy is a severe wakefulness disorder that strongly disrupts the circadian rhythm. It is also called “Gélineau's disease” in reference to the French doctor, Dr. Jean-Baptiste Gélineau, who was one of the very first scientists to classify this disease as such. This discovery was notably made because of (or thanks to, depending on how you see it) a patient who collapsed from sleep during a visit to the Jardin des Plantes in 1880… just as a monkey had made faces at her! Speaking of animals, it is worth noting that narcolepsy was diagnosed in dogs starting in 1972, and even described as a "genetic autosomal recessive disease"² (whose genetic transmission affects both men and women in humans³) for breeds such as Doberman or Labrador. This sleep disorder is characterized by episodes of REM sleep that can occur suddenly at any time, but also by a constant feeling of fatigue, as well as daytime sleepiness. In other words, narcolepsy is an irresistible urge to sleep, anywhere and anytime. It can be accompanied by a cataplexy attack, which is a sudden and temporary loss of muscle tone that ends with the victim falling down. You understand, a nap that comes without warning and at any moment is a serious problem that can cause many issues. A disease to be taken seriously and the subject of an association to help patients (The French Association of Narcolepsy Cataplexy and Rare Hypersomnias⁴), narcolepsy impacts all aspects of life: personal, professional, family, and social.

It should be known that for a sleep disorder to be considered narcolepsy, it must be accompanied by at least one of the following three factors:

• Cataplexy: it is a sudden and temporary loss of muscle tone, resulting in the individual collapsing.
• Hypnopompic (upon awakening) or hypnagogic (at sleep onset) hallucinations
• Sleep paralysis: it is a sleep disorder ("parasomnia") characterized by an inability to move or perform a voluntary movement, linked to a loss of muscle tone.

Besides cataplexy, hallucinations, or sleep paralysis, the DSM IV diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders⁵) also require "a minimum duration of at least one month of episodes of sleepiness" to characterize narcolepsy. The DSM IV is the "Diagnostic and Statistical Manual of Mental Disorders⁶". It is the international reference for mental health professionals.

Narcolepsy statistics

Why is narcolepsy considered a rare disease? according to European legislation⁷, it is classified as a chronic rare disease because it affects no more than one person in two thousand. In France, this corresponds to just under 30,000 individuals, or about 1 person in 2800⁸, that is 0.028% of the population (for the most precise "math lovers"!). Narcolepsy affects both men and women, especially between 15 and 35 years old, regardless of geographical origin. Moreover, according to INSERM⁹ (National Institute of Health and Medical Research), "70% of people with narcolepsy also experience cataplexy." While the figures concerning this disease might suggest it does not affect many people, it is probably wise to put this apparent "rarity" into perspective by the fact that many narcoleptics do not know they have it, as narcolepsy is sometimes difficult to diagnose! Indeed, only 1 in 5 patients is correctly diagnosed. However, according to Prof. Damien Léger (sleep specialist and director of sleep and vigilance at Hôtel-Dieu in Paris), where it used to take between 15 and 20 years to diagnose narcolepsy a few years ago, "today, only 5 to 10 years are necessary" thanks to the establishment of reference centers¹⁰ following the "Rare Diseases Plan 2004-2008." Therefore, do not hesitate to consult a specialist within these centers if you have doubts!

What are the causes of narcolepsy?

The causes of narcolepsy are not yet fully understood. However, many studies tend to highlight its status as an autoimmune disease¹¹. You have probably already heard this term which refers to a disease where the immune system, supposed to bravely defend our body, turns against its own body and plays very bad tricks by fueling the disease it should prevent! Of course, autoimmune diseases are all the more difficult to treat given their "complicity" with our body's defenses.

These autoimmune disorders manifest as the destruction and degeneration of brain cells present in the hypothalamus. The neurons attacked are those that secrete hypocretin, a neurotransmitter involved in the sleep mechanism. Thus, lack of hypocretin is an important cause of narcolepsy¹². Added to these causes is a form of genetic heredity through family history and, to a lesser extent, traumatic brain injuries.

In summary, the autoimmune nature and genetic predisposition seem to be the two main causes of narcolepsy.

Indeed, a study¹³ showed that 85 to 95% of people suffering from narcolepsy have a particular HLA group (an individual's cell recognition system): the DR15 DQB10602. This is the marker of the degeneration of neurons responsible for the secretion of hypocretin. However, carrying this genetic marker does not necessarily mean one will suffer from narcolepsy: 20% of the population has this tissue group, and only 0.028% of the population suffers from narcolepsy. Therefore, it is only an indicator of susceptibility to the disease

How does narcolepsy manifest?

Narcolepsy is characterized by 3 main symptoms, and other "accessory" symptoms (not necessary for diagnosis):

• Daytime sleepiness of varying intensity depending on the person.
• Sudden and uncontrollable daytime sleep attack that can last from 10 minutes to 1 hour.
• Cataplexy attack (loss of muscle tone causing a fall, often triggered by a strong emotion).
• Sleep paralysis upon waking or when falling asleep (inability to move and/or speak for a few moments).
• Hypnagogic hallucinations (at sleep onset) and hypnopompic hallucinations (upon waking) which can be visual and/or auditory.

Narcolepsy-cataplexy is therefore not a disease that causes "too much" sleep and, as such, it should not be confused with its distant relative, hypersomnia. The latter can be "idiopathic" (constant excessive daytime sleepiness) or called "Kleine-Levin syndrome" (recurrent hypersomnia associated with behavioral disorders). Narcolepsy is mainly associated with sudden and uncontrollable sleep attacks, as well as poor sleep quality and cataplexy attacks.

How is narcolepsy diagnosed?

Narcolepsy is a difficult disease to diagnose due to its similarities with other sleep disorders (notably hypersomnia and depression). The diagnosis of narcolepsy is primarily based on clinical signs (hypersomnolence combined at least once with a cataplexy attack) and the use of polysomnography. This involves recording the brain's electrical waves during sleep phases at night (falling asleep, sleep, waking), but also during daytime drowsiness. This process allows for the evaluation of sleep, but also to rule out other diseases thanks to the recorded respiratory parameters. Polysomnography is often followed by an iterative sleep latency test, which measures the time to fall asleep (which is short in narcoleptics), as well as the rapid onset of REM sleep. The rapid onset of REM sleep is characteristic of a case of narcolepsy and can be revealed during these tests.

Another indicator of narcolepsy can be revealed following a blood test to search for a genetic marker, namely belonging to the HLA group “DR15 DQB10602”, the latter being an index of predisposition to the disease as we have seen previously.

What are the treatments for narcolepsy?

Narcolepsy is a disease whose causes are not curable. However, no panic, fortunately, the symptoms of narcolepsy can be treated! Although it is a difficult and constraining disease to live with, its effects can still be limited through non-drug measures, but also with a specially adapted drug treatment¹⁴.

Symptomatic drug treatment

Narcolepsy-cataplexy is mainly treated with wakefulness stimulants to fight against daytime sleepiness and uncontrollable sleep attacks, as well as with anticataplectics (antidepressants or sodium oxybate which also act on cataplexies). Here are the main prescribed medications :

• modafinil: this is the treatment used as first-line for excessive daytime sleepiness and is the one best tolerated by patients.
• méthylphénidate: it is a psychostimulant with very regulated use and is used when modafinil is not effective.
• oxybate de sodium: it is a powerful sedative whose use is reserved for adults with narcolepsy who also have cataplexy attacks.
• pitolisant: it is a stimulant of neuronal activity that increases alertness.

Of course, the initial prescription of all these medications must imperatively be made by a neurologist specialist, or by a doctor working in a sleep center. Their use must obligatorily be reported to their pharmacist as well as to any new consulted doctor.

Adverse effects of drug treatment

Taking these medications is not trivial and unfortunately comes with side effects, even risks¹⁵, and they should not be overlooked! Here are the main side effects and risks:

• headaches, nausea, dizziness
• digestive disorders, decreased appetite, tachycardia
• syncope, acute chest pain
• acute behavioral disorder, depression, anxiety, sleepwalking episodes
• coma

The use of these medications can help relieve the symptoms of narcolepsy-cataplexy, that is undeniable, and sometimes unavoidable. However, it is important to be aware that, as with any medication, side effects carry risks. Therefore, one must be vigilant regarding dosages and contraindications related to each of these medications!

Non-medication measures

Education through a lifestyle adapted to the disease is strongly recommended¹⁶. By adopting sleep hygiene aligned with certain symptoms, it is possible to limit their effects. For example, instead of enduring sleepiness or a sleep attack, it is better to anticipate them by scheduling naps at regular times and of short duration (about 15 minutes). Beneficial effects could be observed. Additionally, going to bed at fixed times and eliminating situations of sleep deprivation would further help limit symptoms.

If the use of medications, with their risks, is unfortunately often necessary, establishing good sleep hygiene can increase their effectiveness. Thus, narcolepsy can be partly treated with naps and fixed bedtime schedules, in addition to taking medications.

Sources:

[1] Narcolepsy and Idiopathic Hypersomnia, site « Vidal recommandations », May 2020 [2] Canine model of narcolepsy: genetic and developmental determinants, T L Baker, A S Foutz et al, Experimental Neurology, March 1982 [3] Transmission of genetic diseases, site « Orphanet »/Training « Orphaschool », 2020 [4] The French Association of Narcolepsy Cataplexy and Rare Hypersomnias, site « ANC-Narcolepsie », 2020 [5] Impact of the DSM-IV to DSM-5 Changes on the National Survey on Drug Use and Health, site « National Center for Biotechnology Information » [6] Diagnostic and Statistical Manual of Mental Disorders, Kenneth S. Kendler, Robert Freedman et al, 2013-2015 [7] The Orphanet Notebooks, “List of rare diseases and their synonyms”, January 2020 [8] Narcolepsy Cataplexy, Orphanet Public Encyclopedia, July 2006 [9] Hypersomnias and Narcolepsy, INSERM, September 2017 [10] Rare diseases: the care offer, site of the Ministry of Solidarity and Health, April 2020 [11] Narcolepsy Fact Sheet, site « National Institute of Neurological Disorders and Stroke » (NIH Publication No. 17-1637), February 2020 [12] Narcolepsy, site « SleepFundation.org », 2020 [13] HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients, E. Mignot, R. Hayduk et al, Sleep, November 1997 [14] Narcolepsy, Prof. Y. Dauvilliers, site « Orphanet » (The portal for rare diseases and orphan drugs), October 2009 [15] Narcolepsy Cataplexy, site « Orphanet » (professional emergency sheets), 2013 [16] Treatments for Narcolepsy, site « Vidal-EurékaSanté », October 2019