Narcolepsy

Group Members: Heba Ahmed, Ifra Jamil, Josephine Chan, Ashba Raza, Melani Joseph

Narcolepsy is a neurological disorder and is a common cause of chronic sleepiness. It is often observed to have symptoms that include odd mixtures of sleep and wakefulness [1]. Individuals with narcolepsy experience excessive daytime sleepiness and there are many other symptoms that can be experienced including sleep paralysis, hypnagogic hallucinations and cataplexy [1]. Approximately 0.02% of the population is affected by the disease [2]. In 1998, the pair of hypothalamic neuropeptides termed orexin-A and –B (or hypocretin 1 and 2) was discovered, along with their receptors (OX1 and OX2) [1]. The disease has been associated with the loss of hypothalamic orexin (hypocretin)-producing neurons in the lateral hypothalamus [2]. Cell loss in this region is thought to be selective because neurons such as melanin-concentrating hormone (MCH) seem to be unaffected, while endogenous opiate dynorphin and NARP (protein involved in glutamate signaling) are absent in the lateral hypothalamus of patients affected [1]. There is not as much understood about the neuropathology of narcolepsy without cataplexy than with cataplexy [1]. There is an autoimmune hypothesis based on the strong genetic association with a selected human leukocyte antigen (HLA) allele [2]. However, there are still several weaknesses to this hypothesis. This neurowiki will provide more insight into the background of narcolepsy building upon this summary, look at the causes, the diagnosis, the treatment of the disease, and discuss the current research being conducted.

Bibliography
1. Burgess C, Scammell T. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci. 32(36), 12305-12311 (2013).
2. De la Herran-Arita A, Garcia-Garcia F. Narcolepsy as an Immune-Mediated Disease. Sleep Disord. (2014).


Background of Narcolepsy

main article: Background of Narcolepsy
author: Melani Joseph
Narcolepsy is a neurological disorder and a common cause of chronic sleepiness. Typically starting in adolescence, it affects about 1 in 20,000 people and in 24% of the affected individuals it can lead to disability [1 [2]. Most of the time, individuals with narcolepsy are observed to have symptoms including odd mixtures of sleep and wakefulness [1]. They tend to experience excessive daytime sleepiness and various other symptoms such as sleep paralysis, hypnagogic hallucinations and cataplexy [1]. A pair of neuropeptides have been discovered and termed hypocretin-1 and -2 (also referred to as orexin A and B), and they are produced in hypothalamic neurons [3]. These neuropeptides are ligands that go along with the two G-protein coupled receptors, known as OX1 and OX2 [3]. The hypocretinergic system is thought to play a vital role in the regulation of sleep/wake behaviour [3]. As a result, narcolepsy has been associated with the loss of hypothalamic hypocretin-producing neurons in the lateral hypothalamus [2]. Cell loss in this region is thought to be selective because neurons such as melanin-concentrating hormone (MCH) seem to be unaffected, while endogenous opiate dynorphin and NARP (protein involved in glutamate signaling) are absent in the lateral hypothalamus of patients affected [1].

Bibliography
1. Burgess C, Scammell T. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci. (2012); 32(36): 12305-12311.
2. De la Herran-Arita A, Garcia-Garcia F. Narcolepsy as an immune-mediated disease. Sleep Disord. (2014).
3. Baier PC, Hallschmid M, Seeck-Hirschner M, Weinhold SL, Burkert S, Diessner N, Goder R, Aldenhoff JB, Hinze-Selch D. Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy. Sleep Med 12(10): 941-946.


Causes of Narcolepsy

main article: Causes of Narcolepsy
author: (account deleted)

Causes of Narcolepsy
Taylor Smith a Certified Medical Assistant talks about
what the potential causes of Narcolepsy might be.
Video source: http://www.youtube.com/embed/HTP2wvSg6Go

Narcolepsy is a neurological sleep disorder that causes uncontrollable sleep and wakefulness cycles [1]. Symptoms of narcolepsy are increased levels of sleepiness in the daytime, sleep paralysis and cataplexy. This disorder affects around 0.02% of the population, men and women are affected equally and symptoms usually appear around young adulthood or adolescence [1]. The exact cause of narcolepsy is not known however, a factor that causes predisposition to this disorder is deficiency in hypocretin or Orexin A and –B and their receptors OX1 and OX2 produced by Human Leukocyte Antigen (HLA) complex variations[2]. These excitatory neuropeptides produced in the lateral hypothalamus are important in regulating wakefulness and appetite. In 2009, the cause of this deficiency was discovered to an autoimmune process that caused progressive degeneration of these neuropeptides in the brain. This neurowiki will provide more insight into the causes of narcolepsy[2].

Bibliography
1. Burgess C, Scammell T. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci. (2012); 32(36): 12305-12311.
2. Hungs M, Mignot E. Hypocretin/orexin, sleep and narcolepsy. Bioessays. (2001); 23(5): 397-408.


Diagnosis and Misdiagnosis of Narcolepsy

main article: Diagnosis and Misdiagnosis of Narcolepsy
author: Heba Ahmed
According to the International Classification of Sleep Disorders, a tetrad of symptoms are required for the diagnosis of narcolepsy[1]. These include Excessive Day-Time Sleepiness (EDS), sleep paralysis, cataplexy and hallucinations[1]. Diagnostic tests are carried out in the sleep clinic in order to measure each of these symptoms, thereby confirming presence of narcolepsy in patients. The standard test used to measure sleep drive it the Multiple Latency Test (MSLT), which is preceded by the Polysomnography used to differentiate narcolepsy from other sleep disorders[2]. Furthermore, current research has shown a direct relationship between the hypocretin-1 levels in the cerebrospinal fluid of narcolepsy which has a major impact on diagnostic accuracy[2]. Although no gold standard test has been agreed upon, evidence suggests that pairing the polysomnography with the MSLT is a reliable and valid method in diagnosing narcolepsy, with or without cataplexy.

Bibliography
1. Peacock, J., & Benca, R. (2010). Narcolepsy: Clinical features, co-morbidities & treatment. Indian J Med Res, 131, 338-349.
2. Nishino, S. (2007). Clinical and neurobiological aspects of narcolepsy. Sleep Medicine, 8, 373-399.
3. Dauvilliers, Y., Arnulf, I., & Mignot, E. (2007). Narcolepsy with cataplexy. Lancet, 369, 499-511.
4. Coelho, F., Georgsson, H., & Murray, B. (2011). Benefit of repeat multiple sleep latency testing in confirming a possible narcolepsy diagnosis. Journal of Clinical Neurophysiology, 28, 412-414.


Narcolepsy Treatments

main article: Narcolepsy Treatments
author: JosephineChan

Image Unavailable

There is no known single cure for narcolepsy; however, there are several different methods that treat the symptoms of narcoleptic patients. Targeted symptoms include: excessive daytime sleepiness (EDS), cataplexy, disturbed nighttime sleep, and sleep paralysis[1]. To target the more common symptoms of narcolepsy, EDS and cataplexy, stimulants and anti-depressants medication were initially used as treatments [2] Currently, modafinil and sodium oxybate are most commonly used [12-11]. There are also non-pharmacological approaches, and there exists a new treatment under consideration called pitolisant [12-5].

Bibliography
1. U.S. Xyrem Multicenter Study Group. (2003). A 12-month, Open-Label, Multicenter Extension
Trial of Orally Administered Sodium Oxybate for the Treatment of Narcolepsy. Sleep, 26 (1), 31-35.
2. Nishino, S., & Mignot E. (1997). Pharmacological Aspects of Human and Canine Narcolepsy, 52, 27-78.
3. Mayer, G. (2012). The use of sodium oxybate to treat narcolepsy. Expert Rev. Neurother, 12 (5), 519-529.
4. Chemelli, R., Willie, J., Sinton, C., Elmquist, J., Scaemmell, T., Lee, C., Richardson, J., Williams, S., Xiong, Y., Kisanuki, Y., Fitch, T., Nakazato, M., Hammer, R., Saper, C., Yanagisawa, M. (1992). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 98, 437-451.
5. Lin, J., Sakai, K., Jouvet, M. (1988) Evidence for histaminnergic arousal mechanisms in the hypothalamus of cat. Neuropharmacology, 27, 111-122.


Recent Research In Narcolepsy

main article: Recent Research In Narcolepsy
author: Ifra Jamil

DQB1*0602
Image Unavailable
Figure 1. Structure of DQB1*0602 allele. Image Source: HLA-DQB1

In recent years, significant scientific breakthrough has been made in understanding the cause of narcolepsy. One aspect of narcolepsy being currently researched is what makes narcolepsy an autoimmune disease. It is currently known that there is an autoimmune basis for the disease based on T cell activation by H1N1 epitopes (which mimic hypocretin peptide sequences) that result in damage to the hypocretin neurons, a main cause of narcolepsy. One specific gene hypothesized to be involved in an immune response is DQB1∗06:02 (Figure 1) [1]. This gene is part of the Human Leukocyte Antigen (HLA) system, which is involved in immune system function, as well as protection against diseases, in humans. Tafti et al. investigated the HLA, DQB1∗06:02, in narcoleptic patients. The authors found that DQB1*06:02 positive patients had a 251-fold higher risk of having narcolepsy. In addition, 99.32% of patients with narcolepsy in the study had this specific HLA gene variant [1]. Along with the gene DQB1*06:02, four additional DQB1 genes are involved in immune system protection against narcolepsy. These are DQB1*06:03, DQB1*05:01, DQB1*06:09 and DQB1*02 [2]. In turn, the DQB1 locus is thought to be involved greatly in causing a genetic predisposition to narcolepsy. Activation of DQB1*0602 is thought to activate the immune system’s destruction of hypocretin cells [1].

As an autoimmune disease, one current area of research involving narcolepsy is the investigation of environmental factors, such as bacterial infections, which may be causing narcolepsy [3]. In addition, the autoimmune hypothesis is supported by studies that account for an increase in the occurrence of narcolepsy in children and adolescents in several European countries (ie. Finland, Sweden) after the use of the H1N1 vaccine [4, 5]

Bibliography
1. Tafti, M et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep. 37(1), 19-25 (2014).
2. Han et al. HLA-DQ association and allele competition in Chinese narcolepsy. Tissue Antigens 80, 328–335 (2012).
3. Aran A, Lin L, Nevsimalova S, Plazzi G, Hong SC, et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 32, 979–983 (2009).
4. Nohynek H et al.: AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS ONE 7, e33536 (2012).
5. Szakács A, N. Darin, T. Hallböök, Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology 80, 1315–1321 (2013).



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