Why Is Narcolepsy Difficult To Cure?

Clinically, narcolepsy is caused by defective neurotransmission via hypocretin neuropeptides, resulting from a selective and irreversible loss of orexinergic neurons in the lateral hypothalamus. The disease etiology till date remains unclear.

There are two major types of narcolepsy: type 1 and type 2. Type 1 narcolepsy was previously described as narcolepsy with cataplexy, whereas, type 2 characterized as narcolepsy without cataplexy. Type 1 is diagnosed on the individual who has low levels of a brain hormone like hypocretin or reporting cataplexy (muscle weakness) with excessive daytime sleepiness. And type 2 people experience excessive daytime sleepiness but do not have muscle weakness. They usually have normal levels of the brain hormone hypocretin (1). No, at present, there is no cure or it cannot go away on its own. In rare cases, it disappears completely, but in most patients it becomes better controlled (7).

Though several advancements in the medicine, as the etiology are not clear hence, it cannot presently be reversed. It is a permanent problem and will never go completely. However, it does not usually worsen as the person ages. Symptoms can be minimized with regular prescriptions, scheduled naps and good lifestyles (2).

Why Is Narcolepsy Difficult To Cure?

Narcolepsy may have several causes. Narcolepsy in humans is sporadic in most cases and is caused by multiple genetic and environmental factors (3). Hence, study on pathogenesis of narcolepsy is much required. The diagnosis of narcolepsy is often delayed by up to 12 years, because its signs and symptoms are often confused with other conditions and because of the absence of easily measurable biomarkers.

Orexin (Hypocretin) Role In Humans

Orexin A and orexin B (hypocretin 1 and hypocretin 2) are neuropeptides that regulate arousal, wakefulness, and appetite and are produced exclusively by neurons in the lateral hypothalamic area. In humans, the orexin A level is severely reduced or undetectable in the cerebrospinal fluid of approximately 90% of patients with type 1. Type 1 is characterized by a low orexin A level and cataplexy. In contrast, patients with type 2 have normal orexin A levels and do not exhibit cataplexy (4).

Genetics Of Narcolepsy

Type 1 is a multifactorial disease, and genetic variations at multiple loci are associated. All patients with type 1 carry the specific human leukocyte antigen (HLA) allele HLA-DQB1*06:02. Genome-wide association studies have uncovered >10 genomic variations associated with type 1. Rare variants associated with type 1 have also been identified by DNA genome sequencing. Type 2 is also a complex disorder, but its underlying genetic architecture is poorly understood. However, several studies have revealed loci that increase susceptibility to type 2. The currently identified loci cannot explain the heritability of narcolepsy (5). The future genomic research will provide important contributions to our understanding of the genetic basis and pathogenesis of narcolepsy.

Conclusion

Misdiagnosis and inappropriate resource utilization further add to the challenge of early treatment, resulting in increased total costs associated with narcolepsy. The annual direct medical costs are approximately twice as high in patients with narcolepsy as in controls without this condition. Narcolepsy has no known cure and requires lifelong treatment, which further increases the economic burden (6). Cataplexy often improves with advancing age. In rare cases, it disappears completely, but in most patients it becomes better controlled (probably after the patient has learned to control his emotions) (7).

References:

  1. Baumann CR, Mignot E, Lammers GJ, et al. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Sleep. 2014;37(6):1035–1042. Published 2014 Jun 1. doi:10.5665/sleep.3756
  2. Jun Zhang and Fang Han, Sleepiness in Narcolepsy, Sleep Medicine Clinics, 12, 3, (323), (2017).
  3. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Narcolepsy-Fact-Sheet
  4. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M Cell. 1998 Mar 6; 92(5):1 page following 696.
  5. Miyagawa T, Tokunaga K. Genetics of narcolepsy. Hum Genome Var. 2019;6:4. Published 2019 Jan 8. doi:10.1038/s41439-018-0033-7
  6. Thorpy MJ, Hiller G. The Medical and Economic Burden of Narcolepsy: Implications for Managed Care. Am Health Drug Benefits. 2017;10(5):233–241.
  7. Billiard M, Besset A, Cadilhac J. The clinical and polygraphic development of narcolepsy. In: Guilleminault C, Lugaresi E, editors. Sleep/wake disorders: natural history, epidemiology and longterm evolution. New York: Raven Press; 1983. pp. 171–185.

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