Narcolepsy: Difference between revisions

	Narcolepsy;
ICD-10	G47.4
ICD-9	347
OMIM	161400
DiseasesDB	8801
MedlinePlus	000802
MeSH	D009290

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Latest revision as of 03:01, 7 August 2020

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Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Muhammad Waleed Haider, M.D.[2]

Synonyms and keywords: Narcolepsy, Cataplexy, Hypocretin/Orexin, Human Leukocyte Antigen (HLA), Rapid eye movement (REM) sleep, Gamma hydroxybutyrate

Overview

Narcolepsy is a debilitating lifelong rapid eye movement (REM) sleep disorder that has a typical onset during adolescence or early adulthood and is characterized by a classic tetrad of Excessive Daytime Sleepiness (EDS), cataplexy (sudden symmetric loss of muscle tone during wakefulness that is evoked by strong emotions), sleep paralysis and hypnagogic hallucinations (hallucinations while falling asleep). Other features include frequent irresistible sleep attacks, fragmented night sleep, loss of concentration and memory, hypnopompic hallucinations (hallucinations during waking up) and blurry vision. Narcolepsy is of two types: narcolepsy type 1 (formerly narcolepsy with cataplexy) and narcolepsy type 2 (formerly narcolepsy without cataplexy). Narcolepsy can have severe consequences for the patient with impairments in academic, social and occupational performances. Problems may include social stigma associated with the disease, reduced quality of life, difficulty in obtaining an education and keeping a job and socioeconomic consequences. It can restrict patients from having certain careers and activities. Narcolepsy is often under-diagnosed and 5-10 years of delay is common before making a firm diagnosis.

Historical Perspective

The earliest account of narcolepsy was described by Thomas Willis (1621-1675) in patients, "with a sleepy disposition who suddenly falls fast asleep." The first-ever descriptions of narcolepsy were reported by Westphal (1877) and Fisher (1878) in Germany.^[1] They also observed a hereditary factor; the mother of Westphal's patient and a sister of Fisher's patient had similar features. French physician Jean-Baptiste-Édouard Gélineau (1880) described this condition in a wine merchant as neurosis or a functional condition. He gave narcolepsy its name, which is the English form of the French word narcolepsie, and also recognized this disorder as a specific clinical entity.^[2] The term narcolepsy is derived by combining the Greek narke numbness, stupor and lepsis attack, to seize. [Source: entry Narcolepsy. In the Online Etymology Dictionary. Douglas Harper, Historian. 18 Sep 2007. [3] Cataplexy from the Greek kataplexis (fixation of the eyes), was first named by Loëwenfeld (1902). Kinnier Wilson (1928) first coined the term, "sleep paralysis." Large case series of narcolepsy were reported by Addie (1926), Wilson (1927), and Daniels (1934). Review of narcolepsy-cataplexy by Daniels is considered by many as one of the most insightful clinical reviews published. The classic description of narcolepsy tetrad was possible due to further work by Yoss and Daly at the Mayo clinic in 1957 and Bedrich Roth in Prague. Various methods were initially proposed in the treatment of narcolepsy until Prinzmetal and Bloomberg introduced amphetamines in 1935. After the discovery of tricyclic antidepressants in 1957, Akimoto, Honda, and Takahashi used imipramine in the treatment of human cataplexy. Methylphenidate was introduced by Yoss and Daly in the 1960s. REM sleep at the onset of sleep attack in narcoleptic patients was first ever recorded and reported by Vogel (1960), an observation extended by Rechschaffen and Dement in 1967. Hishikawa (1968) studied the EEG of narcoleptic patients. These authors together first articulated the now classical hypothesis of dissociated REM sleep and explained some symptoms of narcolepsy. Their discovery established a multiple sleep latency test as a standard diagnostic test for narcolepsy in 1970. Further research work by Nathaniel Kleitman at the University of Chicago and William Dement and Dr. Christian Guilleminault at Stanford University in the 1970's helped in establishing this classical hypothesis of dissociated REM sleep in narcolepsy. Various causes or lesions were proposed for narcolepsy. Tumors situated in relation to the third ventricle were suggested as a possible cause of narcolepsy by Wilson. Von Economo first recognized the posterior hypothalamus as a crucial region governing wakefulness. Canine narcolepsy in various breeds of dogs was identified in 1973, by Knecht and Mitler. The first epidemiological studies of narcolepsy were performed by Roth (1980) and Dement (1972-73). Link with the HLA-DQB1*0602 gene on chromosome 6 was established in 1980s. As many HLA associated disorders are also autoimmune in nature, it raised the possibility that narcolepsy may be an autoimmune disorder. Hypocretins (orexins) were identified in 1990s. In 1998, DeLecea and Sakurai identified hypocretins/orexins almost simultaneously with a difference of a few weeks. Hypocretin deficiency was associated with human narcolepsy by Nishino and Ripley in 2000.

Pathophysiology

The pathophysiology of narcolepsy is only partly understood with the involvement of both genetic and environmental factors. 75% discordance rate for narcolepsy in all described monozygotic twins supports the hypothesis that narcolepsy is a multifactorial disorder. Narcolepsy is considered to arise from multiple hits: the environmental factors, genetic predisposition, and triggering events lead to the selective, immune-mediated destruction, silencing or dysfunction of orexin-producing neurons. One study, published in 2018, described the presence of autoreactive CD4+ and CD8+ T cells in narcolepsy. Three subsequent publications further supported the hypothesis of a pivotal role of specific T cells in the neuronal damage seen in narcolepsy. The exact mechanism leading to the loss of the hypocretin producing neurons in most patients with narcolepsy and cataplexy is unknown. The loss of these neurons is highly selective, sparing the melanin-concentrating hormone (MCH) producing neurons, also in the lateral hypothalamus. This observation supports the prevailing hypothesis of narcolepsy being an autoimmune disorder. The autoimmune hypothesis is further supported by a strong association between narcolepsy, HLA-DQB1*06:02 allele, and polymorphisms in other immune-related genes. In addition, the incidence of narcolepsy follows a specific seasonal pattern, indicating an infectious trigger, although this observation was not found in all studies.^[3] Although circumstantial evidence supporting the autoimmune pathogenesis of narcolepsy is strong, direct evidence supporting this hypothesis is lacking with no clear signs of inflammatory processes in the central nervous system (CNS) of patients with narcolepsy and a clear increase in the incidence of narcolepsy in patients suffering from other autoimmune disorders has not been observed on a consistent basis.^[4]^[5] Immune modulating therapy did not show any improvement in the symptoms or alter the course of narcolepsy, even when administered close to the onset of disease, except for a single exceptional case report.^[6]^[7]^[8]^[9]

Hypocretins

Hypocretins (the alternative name is orexins, from the Greek orexis for appetite) is neuroexcitatory peptides that promote wakefulness, stabilize behavioral states, couple the consciousness of wakefulness with the postural muscle tone, which is generally associated with it. Sakurai, T. et al. (1998) proposed that primary function of hypocretin (orexin) was related to food intake, because administration of hypocretin 1 in rodents lead to increased food intake.^[10] Research on the role of hypocretin (orexin) neurons in rodents revealed that stimulation of these neurons increases the probability of transitions from sleep to wakefulness while silencing of hypocretin neurons induces sleep during the inactive phase in rodents.^[11]^[12] Additional crucial and complex functions of hypocretins besides regulation of sleep and wakefulness include autonomic regulation, emotional processing, energy homeostasis, metabolic and endocrine functions, as well as consummatory and reward associated behaviors. Blouin and Fried (2013) reported that hypocretin and melanin-concentrating hormone levels in humans are linked to emotions and social interactions. They identified that concentrations of hypocretins in the brains of participants were highest during social interactions, or when participants experienced either positive emotion or anger, and were lowest before sleeping or when they were experiencing pain. Orexin A and B are small neuropeptides, which excite target neurons through orexin receptors type 1 and 2, respectively. The hypocretin system in humans comprises of almost 70,000 neurons that produce hypocretin in the lateral and posterior hypothalamus. These neurons project to almost the entire neuraxis.^[13]^[14] Hypocretin neurons have excitatory connections to wakefulness-promoting areas of the brain, including dopaminergic (ventral tegmental area and ventral periaqueductal grey matter), serotonergic (raphe nuclei), adrenergic (locus ceruleus), and histaminergic (tuberomammillary nucleus) regions in the brainstem and midbrain, among others. Loss of this crucial system leads to a general hypoarousal state, with a lower threshold required to fall asleep, which results in the symptoms of narcolepsy and disrupts function of multiple frontal, limbic, diencephalic and brainstem networks.

The regulation of transitions from sleep to wakefulness and distinct regions promoting sleep and wakefulness with mutually inhibitory connections resulting in a switching mechanism to avoid intermediate sleep and wake states explains the hypersomnia phenotype of narcolepsy patients. The normal hypocretin system of neurons stabilizes the switching mechanism by stimulating the wakefulness when the pressure of sleep rises during the day. Abnormal hypocretin system in narcolepsy patients with hypocretin deficiency results in an unstable switch mechanism, with uncontrolled daytime sleep attacks and excessive daytime sleepiness (EDS).^[15] After the discovery of the hypocretin neuropeptides, Lin, L. et al. (1999) identified an autosomal recessive loss of function mutation in HCRTR2 (also known as OXR2, which encodes hypocretin receptor 2), which was the cause of narcolepsy in Doberman pinschers.^[16] Chemelli, R. M. et al. (1999) reported in the same year that mice lacking hypocretin had a narcolepsy like phenotype.^[17] These studies on canines and mice lead to the discovery that narcolepsy patients lacked hypocretin.^[18] Hypocretin (orexins) deficiency (Hypocretin is profoundly decreased in CSF of narcolepsy patients^[19]) causes the disease, but hypocretin genes are not mutated, suggesting a more complex cause in humans. Immunostaining of hypocretin (orexin) neurons in humans revealed a concomitant loss of other markers (besides hypocretin) of hypocretin producing neurons (e.g, dynorphin, NARP) in the brains of narcolepsy patients, which supported the common belief that entire hypocretin neurons are missing from the brains of narcolepsy patients.^[20]^[21] Patients with narcolepsy are born with hypocretin producing neurons, but deficiency of hypocretin develops later in life and is closely linked to the onset of symptoms of narcolepsy.^[22]^[23] Postmortem brain analysis in a three autopsy series in patients with narcolepsy showed substantial (75-95%) or complete elimination of hypocretin-producing neurons in the lateral hypothalamus.^[24] It is also possible that some of these neurons are undetectable (due to silencing of orexin expression) but are not lost irreversibly.

Postmortem analysis did not reveal any effect on the other adjacent neurons of the lateral hypothalamus (such as melanin-concentrating hormone (MCH) producing neurons). Histopathology of the brain tissue showed increased gliosis but no inflammatory or neurodegenerative changes. Both Valko, P. and John, J. along with their respective teams independently reported in 2013, that narcolepsy patients have an increased number of histamine neurons (usually >50% higher than in healthy individuals) in their hypothalamic tuberomammillary nucleus, which is possibly a compensatory response to the loss of excitatory drive due to orexins.^[25]^[26] The immune-mediated process might also be the underlying reason for this increase in the number of histamine producing neurons in humans. Neuronal firing and release of histamine are maximal during wakefulness, which is usually diminished as a consequence of loss of histamine producing neurons or the inhibition of signaling of these neurons. Several studies in patients with narcolepsy and other central hypersomnias reported no differences in levels of histamine or its metabolite tele-methylhistamine, compared to healthy controls, suggesting that despite an increased number of histamine producing neurons in the brains of narcolepsy patients, the cerebrospinal fluid (CSF) levels of histamine and its metabolite are not useful biomarkers for narcolepsy.^[27]^[28] Narcolepsy patients with and without cataplexy may have normal levels of orexin in the CSF, while some patients with hypothalamic damage and subsequent low or absent levels of orexin in the CSF may not have any symptoms of narcolepsy or cataplexy. This observation suggests that a deficiency in orexin is not (always) necessary nor (always) sufficient to cause narcolepsy in humans.^[29]^[30]^[31]^[32]^[33]^[34]

Genetic and epigenetic factors

Studies conducted in twins for narcolepsy revealed only ~25% (20-35%) of concordance rate in monozygotic twins and concordance rate in other first-degree relatives was 1-2%, which suggests that genetic factors play an important role in the pathogenesis of narcolepsy with cataplexy.^[35]^[36] Only 1-2% cases of narcolepsy are familial. Less than 2% of patients with narcolepsy have more than 1 affected family member, while multiplex families (families with more than 2 members) are rare. Up to 11% of first-degree relatives of patients with narcolepsy have also reported symptoms of this disease.^[37] Variants of genes, which encode MHC class II are the main genetic risk factors of this disorder. Narcolepsy has a close association with the human leukocyte antigen (HLA) class II (HLA genes encode MHC molecules that present antigenic peptides to CD4+ helper T cells) region.^[38] HLA-DQB1*06:02 is expressed in 86–98% of patients with narcolepsy type 1 and in ~40–50% of patients with narcolepsy type 2.^[39] HLA-DQB1*06:02 allele is the main genetic risk factor for narcolepsy with cataplexy.^[40]^[41]^[42] Other human leukocyte antigen (HLA) class II alleles are also associated with narcolepsy, although to a lesser extent than HLA-DQB1*06:02.^[43]^[41] Some individuals in the general population (5-38%) can also express HLA-DQB1*06:02, while only 1 individual out of 1,000 carriers of this allele will eventually develop narcolepsy.^[44] Almost all patients with narcolepsy type 1 (except at least 2%) carry the HLA-DQB1*06:02 alleles, whether this represents a fundamentally different disease or a similar disease with only a minor variation is unknown. Although the latter explanation is supported by the finding of an over represented, very rare HLA-DPB1*09/10 alleles in narcolepsy patients without HLA-DQB1*06:02 alleles, which suggests similar disease mechanism in these patients, except antigen, is presented by a different MHC molecule.^[45]

Association between HLA-DQB1*06:02 positivity in the general population and shorter REM sleep latency, suggest that this EEG finding during sleep might represent a (first) biomarker of an increased risk of developing narcolepsy.^[46] Jewish, Sardinian and Saudi populations have a low frequency of this allele (< 5%), which might explain rare cases of narcolepsy in these populations.^[47]^[48]^[49] Higher frequency of HLA-DQB1*06:02 allele in Northern European (25%) and African American (38%) populations explains higher prevalence of narcolepsy in these populations.^[50] Extremely high linkage is present between HLA‑DQB1*06:02 and HLA-DQA1*01:02, which suggests that patients carrying HLA-DQB1*06:02 alleles also carry HLA-DQA1*01:02 on the same chromosome. HLA-DQA1*01:02 can also be carried by other HLA-DQB1 alleles, but the risk of narcolepsy in those cases is increased only slightly or remains unchanged. Other genes, which encode MHC class II proteins (e.g, variants of HLA-DQ and HLA-DP) can also predispose individuals to develop narcolepsy, although to a lesser extent. HLA-DQB1*03:01 allele increases the risk of narcolepsy by 1.5‑fold while the onset of narcolepsy in Asian carriers of this allele was 2 years earlier than those who were non-carriers.^[43] HLA-DPB1 alleles also affect the risk of developing narcolepsy. HLA-DPB1*05:01 predispose individuals to develop narcolepsy, while HLA-DPB1*04:01 and HLA-DPB1*04:02 protect against the development of narcolepsy.

Weak association between human leukocyte antigen (HLA) class I genes (A, B and C) and narcolepsy has also been reported, which suggests that pathogenesis of narcolepsy involves cytotoxic immune mechanism (response mediated either by cytotoxic CD8+ T cells or natural killer (NK) cells) and these patients might have an increased genetic susceptibility to infections. Human leukocyte antigen (HLA) class I genes encode MHC class I molecules that present antigenic peptides to CD8+ T cells.^[41]^[51] Genome-wide association study (2010) identified protective alleles in both human leukocyte antigen (HLA) class I and class II genes, which might explain the role played by these protective alleles in causing the delay (or absence) of the evolution of narcolepsy seen in some patients.^[42] Genome-wide association study also reported an association between susceptibility to narcolepsy and polymorphism in TRAC (which encodes the T cell receptor α-constant domain), further supporting the hypothesis that narcolepsy is an immune-mediated disease.^[43]^[52] Associations between the narcolepsy and polymorphisms in other immune related genes have also been reported, including P2RY11 (modulates an autoimmune response to the infection and encodes P2Y receptor 11), TNFSF4 (which encodes tumor necrosis factor (TNF) ligand superfamily member 4), the chemokine receptor CCR1-CCR3 region and CTSH (which encodes pro-cathepsin H).^[53]^[54]^[55]^[56] No consistent associations were reported on performing gene sequencing studies in patients with familial narcolepsy, although mutations were identified in MOG (which encodes myelin oligodendrocyte glycoprotein), HCRT (which encodes the hypocretin, orexin), and P2RY11 genes, which modulate the immune response.^[19]^[57]^[58] These rare mutations point towards an entirely different pathogenesis of the disease.

Immunologic factors

Narcolepsy occasionally occurs in association with autoimmune diseases, such as celiac disease, multiple sclerosis and systemic lupus erythematosus (SLE) and paraneoplastic syndromes, which suggests that narcolepsy may have an autoimmune pathogenesis.^[59] Cvetikovic-Lopes, V. (2010) and Bergman, H. (2014) reported the presence of a few types of autoantibodies in the sera of narcolepsy patients. Although this finding is nonspecific as these antibodies were also detected in the sera from healthy controls and patients with other sleep disorders. Most of the studies, with a few exceptions, trying to find circulating autoantibodies as an evidence of autoimmunity and a possible underlying cause of hypocretin deficiency in patients with narcolepsy, yielded negative results.^[60]^[61]^[62]^[63]^[64]^[65]^[66]^[67] Antibodies against tribbles homolog 2 (TRIB2), which is a protein produced by many cells including hypocretin neurons, have been identified in many patients with narcolepsy, usually less than one year after the onset of disease. ^[68]^[69] These autoantibodies have also been found in patients with autoimmune uveitis.^[70] However, TRIB2 antibodies were not reported in patients with narcolepsy associated with H1N1 influenza immunization.^[71] Most likely, TRIB2 autoantibodies do not have a direct causative role in narcolepsy, because these autoantibodies have also been found in other neuronal populations and cell types. Other autoantibodies have been detected in the sera of patients with narcolepsy including antibodies against the common carboxy-terminal epitope of the neuropeptide glutamic acid-isoleucine and α‑melanocyte stimulating hormone (NEI/αMSH). The anti-NEI/αMSH antibodies bind to melanin concentrating hormone (MCH) producing neurons, which are connected at functional levels with hypocretin neurons and regulate sleep processes.^[72] Ahmed, S. S. et al. (2015) reported autoantibodies against hypocretin (orexin) receptor 2 (HCRTR2) in 17 out of 20 Finnish patients with narcolepsy.^[73]

In both of these studies, the autoantibodies were also reported in some healthy controls and in the sera of patients with other sleep-related disorders (e.g., sleep apnea, idiopathic hypersomnia, parasomnias, major depressive disorder, and restless legs syndrome), which argues against a causal relationship of these autoantibodies with narcolepsy. Katzav, A. et al. (2013) reported passive transfer of narcolepsy into mice with intracerebral and intraventricular administration of anti‑TRIB2 antibodies or anti-NEI/αMSH antibodies, which revealed changes in sleep patterns suggesting some functional relevance.^[74] Injection of anti-NEI/αMSH antibodies induced a strong increase in sleep fragmentation, which is an important symptom of narcolepsy. No other symptoms of narcolepsy were reported in these mice, so clear evidence pointing towards the role of these autoantibodies in the development of narcolepsy is still missing. These autoantibodies could possibly be due to neuronal damage (owing to an immune-mediated process) or could be present before the onset of disease and confer a higher risk of developing narcolepsy in some individuals. Anti-Ma encephalitis can destroy hypocretin neurons, leading to narcolepsy like symptoms, but screening of anti-Ma antibodies in patients with narcolepsy did not reveal the presence of these antibodies.^[75]^[76] Blood samples from patients with narcolepsy identified CD4+ helper T cells with reactivity towards hypocretin. However, whether the presence of CD4+ helper T cells is specific to narcolepsy or these cells trigger the disease or they appear in response to the destruction of hypocretin neurons is not clear yet. Although the presence of these cells strongly supports the autoimmune hypothesis of narcolepsy.

In 2009, Dauvilliers, Y., Abril, B., and Mas, E. reported that patients with narcolepsy respond to immunomodulatory treatment. Luo, F. et al. (2018) suggested that molecular mimicry of a particular piece of the influenza haemagglutinin protein might trigger an autoimmune process targeting orexin neurons.^[77]^[78] Further support for hypothesis that an autoimmune process contributes to narcolepsy includes the occasional presence of inflammatory findings in cerebrospinal fluid (e.g, pleocytosis and oligoclonal bands), although evidence for the presence of disease specific antibodies is lacking.^[62]^[79]^[80]^[81]^[82] Increased levels of CD4+ T cells (helper T cells), some cytokines (Tumor necrosis factor (TNF) and interferon-gamma (IFNγ)), and activation of CD4+ and CD8+ T cells (cytotoxic T cells), have been reported in the serum and to some extent also in the cerebrospinal fluid (CSF) of patients with narcolepsy.^[83]^[84]^[85]^[86] However, studies assessing the levels of interleukin 6 (IL-6) and tumor necrosis factor (TNF) in the serum of patients with narcolepsy revealed inconsistent results. Some studies reported differences in the levels of interleukin 4 (IL-4) and CC-chemokine ligand 3 (CCL3) in the cerebrospinal fluid (CSF) between patients with narcolepsy and healthy controls.^[87]^[85] However, there was no consistent alteration of cytokine levels in patients with narcolepsy and cataplexy, even very close to the onset of symptoms.^[88] Autoreactive CD4+ and CD8+ T cells have been identified in patients with narcolepsy, which specifically target antigens expressed by orexin neurons.^[89]^[90]^[91]^[92]

Environmental factors

75% discordance rate for narcolepsy in all described monozygotic twins points to a contribution of environmental factors. Reported association between the risk of narcolepsy and season of birth in some but not all studies suggested that early life exposure to viruses, bacteria or toxins might alter the immune system development and thereby predispose individuals to narcolepsy. Subsequent exposure of these predisposed individuals to these or other environmental factors (infections) might trigger or reactivate an immune response leading to the destruction of orexin neurons. Symonds, C. (1922), Redlich, E. (1924), and Mankowski, B. (1926) initially reported a temporal association between influenza or epidemic encephalitis lethargica and the onset of narcolepsy. Aran, A. et al. (2009) reported elevated titers of antistreptococcal antibodies in patients with recent-onset narcolepsy, which suggested an association of narcolepsy with other upper respiratory tract infections, particularly β-hemolytic streptococcal infections.^[93] Increased levels of antistreptococcal antibodies were reported in patients with narcolepsy compared to healthy controls, with higher titres in individuals with a recent onset of narcolepsy.^[94] Ambati, A. et al. (2015) reported an increased Beta-hemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular (mediated by cytotoxic T cells) immune responses to streptococcal antigens in samples of Swedish narcolepsy patients.^[95] Further support towards the role of streptococcal infections and the development of narcolepsy was provided with a reported association between infection with streptococcus pyogenes and other neurological disorders and some autoimmune neuropsychiatric disorders in children that target basal ganglia neurons.^[96]

The most important reported association of narcolepsy with infections involves the influenza A virus (subtype H1N1). In 2009-2010, a statistically significant six to a ninefold increase in the risk of narcolepsy was reported in the northern European countries (eg, Finland, Sweden, Norway), Ireland, France and the United Kingdom, subsequent to vaccination campaign (with the Pandemrix vaccine) against the pandemic H1N1 influenza.^[97]^[98]^[99]^[100]^[101]^[102]^[103] The highest risk of developing narcolepsy after immunization with the Pandemrix vaccine was reported in individuals less than 20 years of age, but the risk was also slightly increased in adult patients. Although the relative risk was generally three to twelve-fold high, the incidence of narcolepsy remained low with only 1 reported case per 16,000 individuals that were immunized. This inflation of association between Pandemrix vaccine and narcolepsy might be explained by increased media attention and detection as well as inclusion bias, while the true association is probably lower. However, this increased risk of narcolepsy due to immunization with the Pandemrix vaccine was observed in most countries, regardless of media coverage. This association was not observed with any other influenza vaccines that targeted H1N1 influenza A virus (e.g, Arepanrix, an almost identical vaccine used in South America and Canada), which might be explained due to the differences in vaccine content of different influenza vaccines.^[73]^[104]^[105]^[106] Childhood onset of narcolepsy might also be related to the H1N1 influenza infections pandemic of 2010-2011, which suggests that H1N1 influenza virus infection itself or some influenza vaccines might trigger the development of narcolepsy. Narcolepsy has also been reported to occur following other vaccinations (e.g, Post Tick-borne encephalitis virus vaccination narcolepsy with cataplexy), these associations could be coincidental or not causal.^[107]

A case-control study (2007) of the environmental risk factors for narcolepsy in the United States showed that the strongest risk factor for narcolepsy was self-reported flu during the previous year.^[108] Han, F., Lin, L., and Li, J. (2013) reported a peak in the incidence of H1N1 influenza infections in China in late 2009, due to absence of the influenza vaccination, which was subsequently followed by a threefold increase in the incidence of narcolepsy during the winter of 2009–2010, compared with both previous and subsequent years.^[109] This observation suggested a temporal association between the peak in the infections due to the H1N1 influenza A virus and a peak in the incidence of narcolepsy, 3 to 6 months later.^[110] Return of the incidence of narcolepsy back to baseline in the following years suggested an association between infection with the 2009 H1N1 influenza virus strain and the onset of narcolepsy. A review of Chinese data before 2009 revealed a seasonal pattern in the onset of narcolepsy with most cases of sleepiness being reported within 6 months after the winter season. Although a peak in the incidence of narcolepsy was reported in China, it was not observed in Taiwan despite exposure to the same epidemic.^[111] Whether infection with H1N1 influenza A virus was the underlying factor for the development of narcolepsy in Northern European patients remains unknown, but one study argued against this hypothesis, as only 2.2% of narcolepsy patients with immunization history with Pandemrix vaccine had infection specific antibodies against the H1N1 influenza A virus.^[112] Lankford, D. (1994) and Silber, M. H. (2005) reported occurrence of narcolepsy after traumatic brain injury.^[113]

Epidemiology and Demographics

The prevalence of narcolepsy in white individuals from North America and Europe is estimated to be ~200–500 cases per million individuals.^[114]^[115]^[116] Although prevalence in most Asian populations is similar to white populations, possible differences specific to each population do exist.^[117]^[118] The highest prevalence of narcolepsy occurs in Japanese population (1,600 cases per million individuals), while the lowest prevalence occurs in Arabic and Jewish populations (2–40 cases per million individuals).^[40]^[47]^[48] African-Americans have a prevalence of 420 cases of narcolepsy per million individuals.^[50] The differences of prevalence between populations is possibly explained by the exposure to environmental factors (e.g infections) or the prevalence of genetic risk factors.^[99] African-Americans usually have lower than average socioeconomic status, which could also influence the prevalence of narcolepsy, as lower socioeconomic status in general causes an increased risk of infections and morbidity.^[119] The global prevalence of narcolepsy in the overall population is 25-50 cases (0.025%-0.05%) per 100,000 individuals.^[120]^[121]^[122] The exact incidence of narcolepsy with cataplexy remains unknown, because of uncertainties regarding the narcoleptic borderland (particularly narcolepsy type 2). Narcolepsy can occur in both men and women, although in some studies, it affected more male than female individuals, which may be due to contribution by genetic and environmental factors. Whether this higher risk of narcolepsy in males compared to females (1.6–1.8 males per 1 female) is due to a true sex effect or referral bias is unknown, because most of the epidemiological studies included too few cases to look at sex differences.^[115] Male patients in European populations with narcolepsy showed a later onset of the daytime sleepiness symptoms but with a shorter delay to diagnosis. Morbidity and mortality data of middle-aged and elderly narcoleptics indicating increased mortality in patients with narcolepsy remains controversial.^[123]^[124] Although narcolepsy can occur at any age (ranging from 3 years of age to 80 years), most cases of narcolepsy usually start in adolescence, with a small second peak of onset occurring at around 35 years of age (ranging from 30 to 39 years of age).^[125]^[126] In some patients (10-15%), narcolepsy may start before the age of 10 years.^[127] However, childhood-onset narcolepsy was systematically studied only in rare studies before the current century.^[128]^[129]^[130] Long diagnostic delay of 8 to 12 years from the onset of disease can underestimate the prevalence of narcolepsy.^[126]^[131] However, in recent years, more cases (especially in children) have been diagnosed sooner after onset, probably due to increasing awareness of the disease.^[132]^[133]

Narcolepsy can have an acute, chronic, or a progressive course, which possibly reflects different pathophysiologic mechanisms. In the acute course, symptoms usually develop within a few days or weeks after a triggering event (e.g, immunization, stress, head trauma). In the chronic course, onset of symptoms is difficult to determine, while in progressive course onset of different symptoms is separated by years or even decades.^[23] In a series of studies regarding the clinical spectrum of narcolepsy with cataplexy, cataplexy and excessive daytime sleepiness (EDS) both developed at the same time in 49% of the study participants, while cataplexy developed after excessive daytime sleepiness (EDS) in 43% of patients.^[131] Cataplexy developed before excessive daytime sleepiness (EDS) in only 8% of the study participants. These studies revealed that the usual interval between the onset of excessive daytime sleepiness (EDS) and onset of cataplexy is usually less than 2 to 3 years but it can exceed up to 40 to 50 years.^[134]^[135]^[136] Narcolepsy patients without cataplexy can enter remission as it can be a transient presentation, whereas remission in patients with narcolepsy with cataplexy is very unlikely (remission of narcolepsy with cataplexy has been reported only once in a patient who received immunotherapy soon after the onset of disease.^[137]^[138]^[9] Symptoms of narcolepsy often improve over time and the severity of both, excessive daytime sleepiness (EDS) and cataplexy usually decrease with increasing age, possibly due to coping mechanisms.

According to an estimation, as many as 3 million people worldwide are affected by narcolepsy. Narcolepsy is as widespread as Parkinson's disease or multiple sclerosis and it is more prevalent than cystic fibrosis, but it is a less well-known disease. Narcolepsy can be mistaken for depression, epilepsy, or as a side effect of some medication. There is strong evidence that narcolepsy is a familial disorder and may run in the families; 8-12% of people with narcolepsy usually have a close relative with this neurologic disorder. There is an average delay of 15 years between onset and correct diagnosis which may contribute substantially to the disabling features of the disorder. Cognitive, educational, occupational, and psychosocial problems have a reported association with the excessive daytime sleepiness of narcolepsy. These problems are especially damaging in teenagers, who are developing their self-image, getting an education, and making their occupational choices in the meantime. While cognitive impairment does occur in patients with narcolepsy, it may only be a reflection of the excessive daytime sleepiness (EDS).

Diagnosis

Diagnosis is relatively easy when all the symptoms of narcolepsy are present. But if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult.

Two tests that are commonly used in diagnosing narcolepsy are the polysomnogram and the multiple sleep latency test. These tests are usually performed by a sleep specialist. The polysomnogram involves continuous recording of sleep brain waves and a number of nerve and muscle functions during nighttime sleep. When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may awaken often during the night. The polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness.

For the multiple sleep latency test, a person is given a chance to sleep every 2 hours during normal wake times. Observations are made of the time taken to reach various stages of sleep. This test measures the degree of daytime sleepiness and also detects how soon REM sleep begins. Again, people with narcolepsy fall asleep rapidly and enter REM sleep early.

DSM-V Diagnostic Criteria for Narcolepsy^[120]

“

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 three times per week over the past 3 months.

AND

B. The presence of at least one 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.
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 immuno reactivity 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 showing a mean sleep latency less than or equal to 8 minutes and two or more sleep-onset REM periods.

Specify whether:

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 CS 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 subtype 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.

Specify current severity:

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).

”

Symptoms

Narcolepsy patients usually have a variable combination of symptoms, related to sleep and wakefulness, as well as cognitive, motor, emotional, psychiatric, autonomic and, metabolic disturbances reflecting the hypothalamic origin of the disease.

Excessive daytime sleepiness

Excessive daytime sleepiness (EDS) is usually most disabling and the leading symptom of narcolepsy, which typically presents as an inability to stay awake or as a subjective feeling of sleepiness with difficulty in sustaining attention, even after adequate night time sleep. Excessive daytime sleepiness (EDS) is typically irresistible, often already present in the morning hours and patients experience sleep attacks with rapid transition into sleep, often at inappropriate times and places. Khatami, R. et al. (2016) reported involuntary napping in 80% of 1,079 European patients with narcolepsy.^[139] These episodes of overwhelming, excessive daytime sleepiness (EDS) predominantly occur in monotonous situations but can also occur in active patients. Naps are usually but not invariably short (with a duration of 15 to 20 minutes), refreshing (only for a few hours), and are also associated with oneiric experiences.^[134]^[140] These daytime naps can occur several times during the day, may occur without warning and can be physically irresistible. Patients with excessive daytime sleepiness (EDS) can develop automatic behaviors (e.g, writing over the border of a piece of paper, abnormal behaviors upon waking such as putting salt in the coffee or driving to the wrong destination).^[141] These so-called automatic behaviors are experienced as blackouts because patients can be amnesic during these episodes. Resisting sleep might increase the risk of developing such behaviors in patients with narcolepsy, but they can also manifest with nonspecific symptoms such as hypoacusis, headache, and sensory or visual disturbances. Excessive daytime sleepiness (EDS) must be distinguished from fatigue, which is reported by up to 60% of patients with narcolepsy and is more resistant to therapy than excessive daytime sleepiness (EDS).^[142]^[143] Fatigue also increases the burden of excessive daytime sleepiness (EDS) by impairing daytime activity, which is a major measure to combat excessive daytime sleepiness (EDS). Narcolepsy patients are usually unable to maintain vigilance during the daytime with an inability to maintain sleep states during the night time (nocturnal sleep may be fragmented with frequent awakenings), but the total amount of sleep is usually not increased over the course of the day.^[144] Narcolepsy patients have sleep instability with increased transitions between non-rapid eye movement (NREM) and rapid eye movement (REM) sleep and increased transitions from non-rapid eye movement (NREM) sleep to wakefulness, which further supports the hypothesis of hypocretin involvement in stabilizing sleep stages.^[145]^[146] Narcolepsy patients can also have REM sleep behavior disorder (defined as REM sleep without muscle atonia and increased intermittent activity of muscles during REM sleep), also linked to hypocretin deficiency.^[147] Additional associated clinical symptoms include dream enactment, increased motor activity during sleep, and disturbed sleep.

Cataplexy

Cataplexy, the only specific symptom of narcolepsy (generally considered to be unique to narcolepsy), is an episodic condition, defined as brief episodes of bilateral loss of muscle tone triggered by strong emotions with a normal state of consciousness.^[148] The person suffering from cataplexy remains conscious throughout the episode. Partial attacks of cataplexy are very short, usually lasting only 2 to 10 seconds unless the trigger remains present. Muscle atonia manifests as face drooping, sagging of the jaw, eyelid closure, passive tongue protrusion, dysarthria, and bilateral loss of motor control of the extremities. In children, atonia of the facial muscles (also known as facies cataplectica) with mouth opening and tongue protrusion can also be observed.^[149]^[132] Cataplexy can range from slight muscle weakness (e.g, limpness at the neck or knees, inability to speak clearly) to complete body collapse. Cataplectic immobility (complete inability to move) is reported by only a few patients. Although one-third of patients report falls, injuries are rare. Typically, deep tendon reflexes (DTRs) are transiently abolished but can persist in patients who suffer from partial or mild episodes.^[150] Babinski sign, which is upward movement (dorsiflexion) of the big toe after stimulation of the sole of the foot, rather than normal downward movement (plantar flexion) in adults, can appear transiently while Parkinson disease-related tremor might persist.^[151]

Partial attacks of cataplexy can evolve over seconds to complete attacks, which usually have a duration of fewer than 2 minutes; cataplexy attack duration of more than 5 minutes is unusual and often related to the withdrawal of anti-cataplectic drugs.^[152] Unilateral dominance of symptoms is atypical,^[153] and cataplexy attacks that involve single muscles are exceptional.^[154] The frequency of cataplexy attacks can vary from dozens per day to a few per year.^[155] Hyperkinesias, in the form of tonic (tongue protrusion, facial grimacing or extension of the neck), phasic (facial muscles twitching), and repetitive motor activities, are sometimes superimposed on muscle atonia and can be misdiagnosed as epilepsy or a movement disorder. These positive motor phenomena are usually more common at the onset of disease and in children.^[156]^[157]^[158]^[159]^[160]

Four other classic symptoms of narcolepsy, which may not occur in all patients, are cataplexy, sleep paralysis, hypnogogic hallucinations, and automatic behavior. Episodes of cataplexy may be triggered by sudden emotional reactions such as laughter, anger, surprise, or fear, and may last from a few seconds to several minutes. Sleep paralysis is the temporary inability to talk or move when waking up. It may last a few seconds to minutes. This is often frightening but is not dangerous. Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening. Automatic behavior means that a person continues to function (talking, putting things away, etc.) during sleep episodes, but awakens with no memory of performing such activities. It is estimated that up to 40 percent of people with narcolepsy experience automatic behavior during sleep episodes. Daytime sleepiness, sleep paralysis, and hypnagogic hallucinations also occur in people who do not have narcolepsy, more frequently in people who are suffering from extreme lack of sleep.

In most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. The other symptoms may begin alone or in combination months or years after the onset of the daytime naps. There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms. The excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not.

Although these are the common symptoms of narcolepsy, many (although less than 40% of people with narcolepsy) also suffer from insomnia for extended periods of time. This is most often from

An excess of sleep.
Use of self-medications such as energy drinks, or caffeinated drinks.

The symptoms of narcolepsy, especially the excessive daytime sleepiness and cataplexy, often become severe enough to cause serious problems in a person's social, personal, and professional life.

Normally, when an individual is awake, brain waves show a regular rhythm. When a person first falls asleep, the brain waves become slower and less regular. This sleep state is called non-rapid eye movement (NREM) sleep. After about an hour and a half of NREM sleep, the brain waves begin to show a more active pattern again. This sleep state, called REM sleep (rapid eye movement sleep), is when most remembered dreaming occurs. Associated with the EEG observed waves during REM sleep muscle atonia is present (called REM atonia).

In narcolepsy, the order and length of NREM and REM sleep periods are disturbed, with REM sleep occurring at sleep onset instead of after a period of NREM sleep. Thus, narcolepsy is a disorder in which REM sleep appears at an abnormal time. Also, some of the aspects of REM sleep that normally occur only during sleep — lack of muscular control, sleep paralysis, and vivid dreams — occur at other times in people with narcolepsy. For example, the lack of muscular control can occur during wakefulness in a cataplexy episode; it is said that there is intrusion of REM atonia during wakefulness. Sleep paralysis and vivid dreams can occur while falling asleep or waking up. Simply put, the brain does not pass through the normal stages of dozing and deep sleep but goes directly into (and out of) rapid eye movement (REM) sleep. This has several consequences:

Nighttime sleep does not include much deep sleep, so the brain tries to "catch up" during the day, hence EDS
May visibly fall asleep at any moment (such motions as head bobbing are common)
People with narcolepsy fall quickly into what appears to be very deep sleep
They wake up suddenly and can be disoriented when they do (dizziness is a common occurrence)
They have very vivid dreams, which they often remember
People with narcolepsy may dream even when they only fall asleep for a few seconds.

Treatment

The drowsiness is normally treated using amphetamine-like stimulants such as methylphenidate, racemic amphetamine, dextroamphetamine, and methamphetamine, or modafinil, a new stimulant with a different pharmacologic mechanism.

Other medications used are codeine^[161] and selegiline. Another drug that is used is atomoxetine^[162] (Strattera), a non-stimulant and Norepinephrine reuptake inhibitor (NRI), that has little or no abuse potential^[163]. In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS to a low or non-existent level. Cataplexy is frequently treated with tricyclic antidepressants such as clomipramine, imipramine, or protriptyline. Venlafaxine, a newer antidepressant which blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy. Gamma-hydroxybutyrate (GHB), a medication recently approved by the US Food and Drug Administration, is the only medication specifically indicated for cataplexy. Gamma-hydroxybutyrate has also been shown to reduce symptoms of EDS associated with narcolepsy. While the exact mechanism of action is unknown, GHB is thought to improve the quality of nocturnal sleep.

Treatment is tailored to the individual based on symptoms and therapeutic response. The time required to achieve optimal control of symptoms is highly variable, and may take several months or longer. Medication adjustments are also frequently necessary, and complete control of symptoms is seldom possible. While oral medications are the mainstay of narcolepsy treatment, lifestyle changes are also important. The main treatment of excessive daytime sleepiness in narcolepsy is with a group of drugs called central nervous system stimulants. For cataplexy and other REM-sleep symptoms, antidepressant medications and other drugs that suppress REM sleep are prescribed.

In addition to drug therapy, an important part of treatment is scheduling short naps (10 to 15 minutes) two to three times per day to help control excessive daytime sleepiness and help the person stay as alert as possible. Daytime naps are not a replacement for nighttime sleep.

Ongoing communication between the health care provider, patient, and the patient's family members is important to optimal management of narcolepsy.

Coping with Narcolepsy

Learning as much about narcolepsy as possible and finding a support system can help patients and families deal with the practical and emotional effects of the disorder, possible occupational limitations, and situations that might cause injury. A variety of educational and other materials are available from sleep medicine or narcolepsy organizations.

Support groups exist to help persons with narcolepsy and their families.

Individuals with narcolepsy, their families, friends, and potential employers should know that:

Narcolepsy is a life-long condition that may require continuous medication.
Although there is no cure for narcolepsy at present, several medications can help reduce its symptoms.
People with narcolepsy can lead productive lives if they are provided with proper medical care.
If possible, individuals with narcolepsy should avoid jobs that require driving long distances or handling hazardous equipment or that require alertness for lengthy periods.
Parents, teachers, spouses, and employers should be aware of the symptoms of narcolepsy. This will help them avoid the mistake of confusing the person's behavior with laziness, hostility, reject ion, or lack of interest and motivation. It will also help them provide essential support and cooperation.
Employers can promote better working opportunities for individuals with narcolepsy by permitting special work schedules and nap breaks.

Doctors generally agree that lifestyle changes can be very helpful to those suffering with narcolepsy. Suggested self-care tips, from the National Sleep Foundation, University at Buffalo, and Mayo Clinic, include:

Take several short daily naps (10-15 minutes) to combat excessive sleepiness and sleep attacks.
Develop a routine sleep schedule – try to go to sleep and awaken at the same time every day.
Alert your employers, coworkers and friends in the hope that others will accommodate your condition and help when needed.
Do not drive or operate dangerous equipment if you are sleepy. Take a nap before driving if possible. Consider taking a break for a nap during a long driving trip.
Join a support group.
Break up larger tasks into small pieces and focusing on one small thing at a time.
Take several short walks during the day.
Carry a tape recorder, if possible, to record important conversations and meetings.

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Template:Diseases of the nervous system

af:Narkolepsie da:Narkolepsi de:Narkolepsie et:Narkolepsia ko:기면증 is:Drómasýki it:Narcolessia he:נרקולפסיה nl:Narcolepsie no:Narkolepsi simple:Narcolepsy sk:Narkolepsia fi:Narkolepsia sv:Narkolepsi

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[161] "Codeine treatment".

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@@ Line 1: / Line 1: @@
+<div style="-webkit-user-select: none;">
 __NOTOC__
 '''For patient information click [[Narcolepsy (patient information)|here]]'''
@@ Line 17: / Line 18: @@
 }}
 {{Search infobox}}
-{{CMG}}; {{AE}} {{KS}}
+{{CMG}}; {{AE}} {{MWH}}
-{{SK}} Narcolepsy-cataplexy
+{{SK}} Narcolepsy, Cataplexy, Hypocretin/Orexin, Human Leukocyte Antigen (HLA), Rapid eye movement (REM) sleep, Gamma hydroxybutyrate
 ==Overview==
-'''Narcolepsy''' is a [[neurological]] condition most characterized by [[Excessive Daytime Sleepiness]] (EDS). A narcoleptic will most likely experience disturbed nocturnal sleep, confused with [[insomnia]], and disorder of [[Rapid eye movement sleep|REM]] or rapid eye movement sleep. It is one of the [[dyssomnia]]s. <!--The name of the condition is derived from the ancient greek words "ναρχάω" (narcao, which means "to grow stiff") and "λεπις" (lepis, which means "shell" or sometimes "unconscious")-->
+Narcolepsy is a debilitating lifelong [[rapid eye movement]] ([[REM sleep|REM]]) sleep disorder that has a typical onset during [[adolescence]] or early adulthood and is characterized by a classic tetrad of [[Excessive Daytime Sleepiness]] ([[EDS]]), [[cataplexy]] (sudden [[symmetric]] loss of [[muscle tone]] during wakefulness that is evoked by strong emotions), [[sleep paralysis]] and [[hypnagogic hallucinations]] ([[Hallucination|hallucinations]] while falling asleep). Other features include frequent irresistible [[sleep attacks]], fragmented night sleep, loss of concentration and memory, [[Hypnopompia|hypnopompic]] [[Hallucination|hallucinations]] ([[Hallucination|hallucinations]] during waking up) and [[blurry vision]]. Narcolepsy is of two types: [[narcolepsy type 1]] (formerly narcolepsy with [[cataplexy]]) and narcolepsy type 2 (formerly narcolepsy without [[cataplexy]]). Narcolepsy can have severe consequences for the patient with impairments in academic, social and occupational performances. Problems may include [[social stigma]] associated with the disease, reduced quality of life, difficulty in obtaining an education and keeping a job and socioeconomic consequences. It can restrict patients from having certain careers and activities. Narcolepsy is often under-diagnosed and 5-10 years of delay is common before making a firm diagnosis.
 ==Historical Perspective==
-The term narcolepsy derives from the French word ''narcolepsie'' created in 1880 by the French physician [[Jean-Baptiste-Édouard Gélineau]] (1859-1928) by combining the Greek '''narke''' ''numbness, stupor'' and '''lepsis''' ''attack, seizure.'' [Source: entry '''Narcolepsy.''' in the '''Online Etymology Dictionary.''' Douglas Harper, Historian. 18 Sep 2007. [http://dictionary.reference.com/browse/Narcolepsy]
+The earliest account of narcolepsy was described by Thomas Willis (1621-1675) in [[patients]], "with a sleepy disposition who suddenly falls fast asleep." The first-ever descriptions of narcolepsy were reported by Westphal (1877) and Fisher (1878) in Germany.<ref name="pmid17561602">{{cite journal| author=Schenck CH, Bassetti CL, Arnulf I, Mignot E| title=English translations of the first clinical reports on narcolepsy and cataplexy by Westphal and Gélineau in the late 19th century, with commentary. | journal=J Clin Sleep Med | year= 2007 | volume= 3 | issue= 3 | pages= 301-11 | pmid=17561602 | doi= | pmc=2564780 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17561602  }} </ref> They also observed a [[hereditary]] factor; the mother of Westphal's [[patient]] and a sister of Fisher's [[patient]] had similar [[Features (pattern recognition)|features]]. French [[physician]] [[Jean-Baptiste-Édouard Gélineau]] (1880) described this [[condition]] in a wine merchant as [[neurosis]] or a functional [[condition]]. He gave narcolepsy its name, which is the English form of the French word '''narcolepsie''', and also recognized this [[disorder]] as a specific [[clinical]] entity.<ref name="pmid9132972">{{cite journal| author=Janković S, Susić V, Sokić D, Lević Z| title=[Dr. John Baptiste Edouard Gélineau]. | journal=Srp Arh Celok Lek | year= 1996 | volume= 124 | issue= 11-12 | pages= 331-5 | pmid=9132972 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9132972  }} </ref> The term narcolepsy is derived by combining the Greek '''narke''' ''[[numbness]], [[stupor]]'' and '''lepsis''' ''attack, to seize.'' [Source: entry '''Narcolepsy.''' In the '''Online Etymology Dictionary.''' Douglas Harper, [[Historian (medical)|Historian]]. 18 Sep 2007. [http://dictionary.reference.com/browse/Narcolepsy] [[Cataplexy]] from the Greek kataplexis ([[Fixation (visual)|fixation]] of the [[eyes]]), was first named by Loëwenfeld (1902). Kinnier Wilson (1928) first coined the term, "[[sleep paralysis|sleep paralysis.]]" Large [[case series]] of narcolepsy were reported by Addie (1926), Wilson (1927), and Daniels (1934). Review of narcolepsy-[[cataplexy]] by Daniels is considered by many as one of the most insightful [[clinical]] [[Review|reviews]] published. The classic description of narcolepsy [[tetrad]] was possible due to further work by Yoss and Daly at the Mayo clinic in 1957 and Bedrich Roth in Prague. Various methods were initially proposed in the [[treatment]] of narcolepsy until Prinzmetal and Bloomberg introduced [[amphetamines]] in 1935.  After the discovery of [[tricyclic antidepressants]] in 1957, Akimoto, Honda, and Takahashi used [[imipramine]] in the [[treatment]] of [[human]] [[cataplexy]]. [[Methylphenidate]] was introduced by Yoss and Daly in the 1960s. [[REM sleep]] at the onset of [[sleep]] attack in narcoleptic [[patients]] was first ever recorded and reported by Vogel (1960), an [[observation]] extended by Rechschaffen and Dement in 1967. Hishikawa (1968) studied the [[EEG]] of narcoleptic [[patients]]. These authors together first articulated the now classical [[hypothesis]] of dissociated [[REM sleep]] and explained some [[symptoms]] of narcolepsy. Their discovery established a multiple [[sleep latency]] test as a [[standard]] [[diagnostic test]] for narcolepsy in 1970. Further [[research]] work by Nathaniel Kleitman at the University of Chicago and William Dement and Dr. Christian Guilleminault at Stanford University in the 1970's helped in establishing this classical [[hypothesis]] of dissociated [[REM sleep]] in narcolepsy. Various [[causes]] or [[lesions]] were proposed for narcolepsy. [[Tumors]] situated in relation to the [[third ventricle]] were suggested as a possible [[Causes|cause]] of narcolepsy by Wilson. Von Economo first recognized the [[posterior]] [[hypothalamus]] as a crucial region governing [[wakefulness]]. [[Canine]] narcolepsy in various breeds of dogs was identified in 1973, by Knecht and Mitler. The first [[Epidemiological study|epidemiological studies]] of narcolepsy were performed by Roth (1980) and Dement (1972-73). Link with the [[HLA-DQB1]]*0602 [[gene]] on [[chromosome]] 6 was established in 1980s. As many [[HLA]] associated [[disorders]] are also [[autoimmune]] in nature, it raised the possibility that narcolepsy may be an [[Autoimmune disease|autoimmune disorder]]. [[Hypocretin]]<nowiki/>s ([[orexins]]) were identified in 1990s. In 1998, DeLecea and Sakurai identified [[hypocretin]]<nowiki/>s/[[orexins]] almost simultaneously with a difference of a few weeks. [[Hypocretin]] [[deficiency]] was associated with [[human]] narcolepsy by Nishino and Ripley in 2000.
 == Pathophysiology ==
-While the cause of narcolepsy has not yet been determined, scientists have discovered conditions that may increase an individual's risk of having the disorder. Specifically, there appears to be a strong link between narcoleptic individuals and certain genetic conditions. One factor that may predispose an individual to narcolepsy involves an area of Chromosome 6 known as the [[human leukocyte antigen|HLA]] complex. There appears to be a correlation between narcoleptic individuals and certain variations in HLA genes, although it is not required for the condition to occur.
-Certain variations in the HLA complex are thought to increase the risk of an [[auto-immune]] response to [[protein]] producing neurons in the brain. The protein produced, called [[hypocretin]] or [[orexin]], is responsible for controlling appetite and sleep patterns. Individuals with narcolepsy often have reduced numbers of these protein-producing neurons in their brains.
+The [[pathophysiology]] of narcolepsy is only partly understood with the involvement of both [[genetic]] and [[environmental factor]]<nowiki/>s. 75% discordance rate for narcolepsy in all described [[monozygotic twins]] supports the [[hypothesis]] that narcolepsy is a [[Multifactorial inheritance|multifactorial]] [[disorder]]. Narcolepsy is considered to arise from multiple hits: the [[environmental factor]]<nowiki/>s, [[genetic predisposition]], and triggering events lead to the selective, [[Immune-mediated disease|immune-mediated]] destruction, silencing or [[dysfunction]] of [[orexin]]-producing [[neurons]]. One [[Study design|study]], published in 2018, described the presence of autoreactive [[CD4+ T cells|CD4+]] and [[CD8+ T cells]] in narcolepsy. Three subsequent publications further supported the [[hypothesis]] of a pivotal role of specific [[T cells]] in the [[neuronal]] damage seen in narcolepsy. The exact [[Mechanism (biology)|mechanism]] leading to the loss of the [[hypocretin]] producing [[neurons]] in most [[patients]] with narcolepsy and [[cataplexy]] is unknown. The loss of these [[neurons]] is highly selective, sparing the [[melanin-concentrating hormone]] (MCH) producing [[neurons]], also in the [[lateral hypothalamus]]. This [[observation]] [[Support|supports]] the prevailing [[hypothesis]] of narcolepsy being an [[autoimmune disorder]]. The [[autoimmune]] [[hypothesis]] is further [[Support|supported]] by a [[strong]] [[Association (statistics)|association]] between narcolepsy, [[HLA-DQB1]]*06:02 [[allele]], and [[Polymorphism|polymorphisms]] in other [[immune]]-related [[genes]]. In addition,  the [[incidence]] of narcolepsy follows a specific seasonal pattern, indicating an [[infectious]] [[trigger]], although this [[observation]] was not found in all [[Study design|studies]].<ref name="pmid21866560">{{cite journal| author=Han F, Lin L, Warby SC, Faraco J, Li J, Dong SX | display-authors=etal| title=Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. | journal=Ann Neurol | year= 2011 | volume= 70 | issue= 3 | pages= 410-7 | pmid=21866560 | doi=10.1002/ana.22587 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21866560  }} </ref> Although circumstantial [[evidence]] [[Support|supporting]] the [[autoimmune]] [[pathogenesis]] of narcolepsy is strong, direct [[evidence]] [[Support|supporting]] this [[hypothesis]] is lacking with no clear [[signs]] of [[inflammatory]] processes in the [[central nervous system]] ([[CNS]]) of [[Patient|patients]] with narcolepsy and a clear increase in the [[incidence]] of narcolepsy in [[patients]] suffering from other [[autoimmune disorders]] has not been observed on a consistent basis.<ref name="pmid27298657">{{cite journal| author=Martinez-Orozco FJ, Vicario JL, De Andres C, Fernandez-Arquero M, Peraita-Adrados R| title=Comorbidity of Narcolepsy Type 1 With Autoimmune Diseases and Other Immunopathological Disorders: A Case-Control Study. | journal=J Clin Med Res | year= 2016 | volume= 8 | issue= 7 | pages= 495-505 | pmid=27298657 | doi=10.14740/jocmr2569w | pmc=4894018 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27298657  }} </ref><ref name="pmid27864522">{{cite journal| author=Barateau L, Lopez R, Arnulf I, Lecendreux M, Franco P, Drouot X | display-authors=etal| title=Comorbidity between central disorders of hypersomnolence and immune-based disorders. | journal=Neurology | year= 2017 | volume= 88 | issue= 1 | pages= 93-100 | pmid=27864522 | doi=10.1212/WNL.0000000000003432 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27864522  }} </ref> [[Immune]] modulating [[therapy]] did not show any improvement in the [[symptoms]] or alter the [[Course (medicine)|course]] of narcolepsy, even when administered close to the onset of [[disease]], except for a single exceptional [[case report]].<ref name="pmid18769859">{{cite journal| author=Plazzi G, Poli F, Franceschini C, Parmeggiani A, Pirazzoli P, Bernardi F | display-authors=etal| title=Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy. | journal=J Neurol | year= 2008 | volume= 255 | issue= 10 | pages= 1549-54 | pmid=18769859 | doi=10.1007/s00415-008-0983-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18769859  }} </ref><ref name="pmid18825431">{{cite journal| author=Valko PO, Khatami R, Baumann CR, Bassetti CL| title=No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy. | journal=J Neurol | year= 2008 | volume= 255 | issue= 12 | pages= 1900-3 | pmid=18825431 | doi=10.1007/s00415-008-0996-2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18825431  }} </ref><ref name="pmid17762946">{{cite journal| author=Fronczek R, Verschuuren J, Lammers GJ| title=Response to intravenous immunoglobulins and placebo in a patient with narcolepsy with cataplexy. | journal=J Neurol | year= 2007 | volume= 254 | issue= 11 | pages= 1607-8 | pmid=17762946 | doi=10.1007/s00415-007-0594-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17762946  }} </ref><ref name="pmid19841387">{{cite journal| author=Dauvilliers Y, Abril B, Mas E, Michel F, Tafti M| title=Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. | journal=Neurology | year= 2009 | volume= 73 | issue= 16 | pages= 1333-4 | pmid=19841387 | doi=10.1212/WNL.0b013e3181bd1344 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19841387  }} </ref>
+=== '''<big>Hypocretins</big>''' ===
+[[Hypocretin]]<nowiki/>s (the alternative name is [[orexins]], from the Greek '''''orexis''''' for [[appetite]]) is neuroexcitatory [[peptides]] that promote [[wakefulness]], stabilize [[behavioral]] states, couple the [[consciousness]] of [[wakefulness]] with the postural [[muscle tone]], which is generally associated with it. Sakurai, T. et al. (1998) proposed that primary [[Function (biology)|function]] of [[hypocretin]] ([[orexin]]) was related to [[food]] intake, because administration of [[hypocretin]] 1 in [[Rodent|rodents]] lead to increased [[food]] intake.<ref name="pmid9491897">{{cite journal| author=Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H | display-authors=etal| title=Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. | journal=Cell | year= 1998 | volume= 92 | issue= 4 | pages= 573-85 | pmid=9491897 | doi=10.1016/s0092-8674(00)80949-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9491897  }} </ref> [[Research]] on the role of [[hypocretin]] ([[orexin]]) [[neurons]] in [[Rodent|rodents]] revealed that stimulation of these [[neurons]] increases the [[probability]] of [[Transition|transitions]] from [[sleep]] to [[wakefulness]] while silencing of [[hypocretin]] [[neurons]] induces [[sleep]] during the inactive phase in [[Rodent|rodents]].<ref name="pmid17943086">{{cite journal| author=Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L| title=Neural substrates of awakening probed with optogenetic control of hypocretin neurons. | journal=Nature | year= 2007 | volume= 450 | issue= 7168 | pages= 420-4 | pmid=17943086 | doi=10.1038/nature06310 | pmc=6744371 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17943086  }} </ref><ref name="TsunematsuKilduff2011">{{cite journal|last1=Tsunematsu|first1=T.|last2=Kilduff|first2=T. S.|last3=Boyden|first3=E. S.|last4=Takahashi|first4=S.|last5=Tominaga|first5=M.|last6=Yamanaka|first6=A.|title=Acute Optogenetic Silencing of Orexin/Hypocretin Neurons Induces Slow-Wave Sleep in Mice|journal=Journal of Neuroscience|volume=31|issue=29|year=2011|pages=10529–10539|issn=0270-6474|doi=10.1523/JNEUROSCI.0784-11.2011}}</ref> Additional crucial and [[Complex (chemistry)|complex]] [[Function (biology)|functions]] of [[hypocretin]]<nowiki/>s besides regulation of [[sleep]] and [[wakefulness]] include [[autonomic]] regulation, [[emotional]] processing, energy [[homeostasis]], [[metabolic]] and [[endocrine]] [[Function (biology)|functions]], as well as consummatory and [[Reward system|reward]] associated behaviors. Blouin and Fried (2013) reported that [[hypocretin]] and [[melanin-concentrating hormone]] levels in humans are linked to [[emotions]] and [[social interaction]]<nowiki/>s. They identified that [[concentrations]] of [[hypocretin]]<nowiki/>s in the [[Brain|brains]] of participants were highest during [[social interaction]]<nowiki/>s, or when participants experienced either positive [[emotion]] or [[anger]], and were lowest before sleeping or when they were experiencing [[pain]]. [[Orexin]] A and B are small [[neuropeptides]], which excite target [[neurons]] through [[orexin receptor]]<nowiki/>s type 1 and 2, respectively. The [[hypocretin]] [[system]] in [[Human|humans]] comprises of almost 70,000 [[neurons]] that produce [[hypocretin]] in the [[lateral]] and [[posterior]] [[hypothalamus]]. These [[neurons]] project to almost the entire [[neuraxis]].<ref name="pmid25254979">{{cite journal| author=Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G| title=Motivational activation: a unifying hypothesis of orexin/hypocretin function. | journal=Nat Neurosci | year= 2014 | volume= 17 | issue= 10 | pages= 1298-303 | pmid=25254979 | doi=10.1038/nn.3810 | pmc=4335648 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25254979  }} </ref><ref name="pmid24102345">{{cite journal| author=Li J, Hu Z, de Lecea L| title=The hypocretins/orexins: integrators of multiple physiological functions. | journal=Br J Pharmacol | year= 2014 | volume= 171 | issue= 2 | pages= 332-50 | pmid=24102345 | doi=10.1111/bph.12415 | pmc=3904255 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24102345  }} </ref> [[Hypocretin]] [[neurons]] have [[Excitatory synapses|excitatory]] connections to [[wakefulness]]-promoting [[Area|areas]] of the [[brain]], including [[dopaminergic]] ([[ventral tegmental area]] and [[ventral]] [[Periaqueductal grey|periaqueductal grey matter]]), [[serotonergic]] ([[raphe nuclei]]), [[adrenergic]] ([[locus ceruleus]]), and [[Histamine|histaminergic]] ([[tuberomammillary nucleus]]) regions in the [[brainstem]] and [[midbrain]], among others. Loss of this crucial [[system]] leads to a general hypoarousal state, with a lower [[Threshold potential|threshold]] required to fall asleep, which results in the [[symptoms]] of narcolepsy and disrupts function of multiple [[frontal]], [[Limbic system|limbic]], [[diencephalic]] and [[brainstem]] networks.
+The regulation of transitions from [[sleep]] to [[wakefulness]] and distinct regions promoting [[sleep]] and [[wakefulness]] with mutually [[inhibitory]] connections resulting in a switching [[Mechanism (biology)|mechanism]] to avoid intermediate [[sleep]] and wake states explains the [[hypersomnia]] [[phenotype]] of narcolepsy [[patients]]. The normal [[hypocretin]] [[system]] of [[neurons]] stabilizes the switching [[Mechanism (biology)|mechanism]] by stimulating the [[wakefulness]] when the [[pressure]] of [[sleep]] rises during the day. [[Abnormal]] [[hypocretin]] [[system]] in narcolepsy [[patients]] with [[hypocretin]] [[deficiency]] results in an unstable switch [[Mechanism (biology)|mechanism]], with uncontrolled daytime [[sleep]] attacks and [[excessive daytime sleepiness]] ([[EDS]]).<ref name="pmid11718878">{{cite journal| author=Saper CB, Chou TC, Scammell TE| title=The sleep switch: hypothalamic control of sleep and wakefulness. | journal=Trends Neurosci | year= 2001 | volume= 24 | issue= 12 | pages= 726-31 | pmid=11718878 | doi=10.1016/s0166-2236(00)02002-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11718878  }} </ref> After the [[Discovery system|discovery]] of the [[hypocretin]] [[Neuropeptide|neuropeptides]], Lin, L. et al. (1999) identified an [[autosomal recessive]] loss of function [[mutation]] in HCRTR2 (also known as OXR2, which encodes [[Hypocretin (orexin) receptor 2|hypocretin receptor 2]]), which was the [[Causes|cause]] of narcolepsy in Doberman pinschers.<ref name="pmid10458611">{{cite journal| author=Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X | display-authors=etal| title=The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. | journal=Cell | year= 1999 | volume= 98 | issue= 3 | pages= 365-76 | pmid=10458611 | doi=10.1016/s0092-8674(00)81965-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10458611  }} </ref>  Chemelli, R. M. et al. (1999) reported in the same [[year]] that mice lacking [[hypocretin]] had a narcolepsy like [[phenotype]].<ref name="pmid10481909">{{cite journal| author=Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C | display-authors=etal| title=Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. | journal=Cell | year= 1999 | volume= 98 | issue= 4 | pages= 437-51 | pmid=10481909 | doi=10.1016/s0092-8674(00)81973-x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10481909  }} </ref> These studies on [[canines]] and mice lead to the [[Discovery system|discovery]] that narcolepsy [[patient]]<nowiki/>s lacked [[hypocretin]].<ref name="pmid10615891">{{cite journal| author=Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E| title=Hypocretin (orexin) deficiency in human narcolepsy. | journal=Lancet | year= 2000 | volume= 355 | issue= 9197 | pages= 39-40 | pmid=10615891 | doi=10.1016/S0140-6736(99)05582-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10615891  }} </ref> [[Hypocretin]] ([[orexins]]) deficiency ([[Hypocretin]] is profoundly decreased in [[CSF]] of narcolepsy patients<ref name="pmid10973318">{{cite journal| author=Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y | display-authors=etal| title=A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. | journal=Nat Med | year= 2000 | volume= 6 | issue= 9 | pages= 991-7 | pmid=10973318 | doi=10.1038/79690 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10973318  }} </ref>) causes the disease, but [[hypocretin]] [[genes]] are not [[mutated]], suggesting a more complex cause in humans. [[Immunostaining]] of [[hypocretin]] ([[orexin]]) [[neurons]] in [[humans]] revealed a concomitant loss of other [[Marker|markers]] (besides [[hypocretin]]) of [[hypocretin]] producing [[neurons]] (e.g, [[dynorphin]], [[NARP]]) in the [[Brain|brains]] of narcolepsy [[Patient|patients]], which [[Support|supported]] the common belief that entire [[hypocretin]] [[neurons]] are missing from the [[Brain|brains]] of narcolepsy [[patients]].<ref name="pmid16135770">{{cite journal| author=Blouin AM, Thannickal TC, Worley PF, Baraban JM, Reti IM, Siegel JM| title=Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy. | journal=Neurology | year= 2005 | volume= 65 | issue= 8 | pages= 1189-92 | pmid=16135770 | doi=10.1212/01.wnl.0000175219.01544.c8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16135770  }} </ref><ref name="pmid16247044">{{cite journal| author=Crocker A, España RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T | display-authors=etal| title=Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. | journal=Neurology | year= 2005 | volume= 65 | issue= 8 | pages= 1184-8 | pmid=16247044 | doi=10.1212/01.wnl.0000168173.71940.ab | pmc=2254145 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16247044  }} </ref> [[Patients]] with narcolepsy are born with [[hypocretin]] producing [[neurons]], but [[deficiency]] of [[hypocretin]] develops later in [[life]] and is closely linked to the onset of [[symptoms]] of narcolepsy.<ref name="pmid23288981">{{cite journal| author=Savvidou A, Knudsen S, Olsson-Engman M, Gammeltoft S, Jennum P, Palm L| title=Hypocretin deficiency develops during onset of human narcolepsy with cataplexy. | journal=Sleep | year= 2013 | volume= 36 | issue= 1 | pages= 147-8 | pmid=23288981 | doi=10.5665/sleep.2320 | pmc=3524537 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23288981  }} </ref><ref name="pmid25355832">{{cite journal| author=Pizza F, Vandi S, Liguori R, Parchi P, Avoni P, Mignot E | display-authors=etal| title=Primary progressive narcolepsy type 1: the other side of the coin. | journal=Neurology | year= 2014 | volume= 83 | issue= 23 | pages= 2189-90 | pmid=25355832 | doi=10.1212/WNL.0000000000001051 | pmc=4276406 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25355832  }} </ref> [[Postmortem]] brain analysis in a three [[autopsy]] series in patients with narcolepsy showed substantial (75-95%) or complete elimination of [[hypocretin]]-producing [[neurons]] in the [[lateral hypothalamus]].<ref name="pmid11055430">{{cite journal| author=Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M | display-authors=etal| title=Reduced number of hypocretin neurons in human narcolepsy. | journal=Neuron | year= 2000 | volume= 27 | issue= 3 | pages= 469-74 | pmid=11055430 | doi=10.1016/s0896-6273(00)00058-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11055430  }} </ref> It is also possible that some of these [[neurons]] are undetectable (due to silencing of [[orexin]] [[expression]]) but are not lost irreversibly.
+[[Postmortem]] analysis did not reveal any effect on the other adjacent [[neurons]] of the [[lateral hypothalamus]] (such as [[melanin-concentrating hormone]] (MCH) producing [[neurons]]). [[Histopathology]] of the [[brain]] [[tissue]] showed increased [[gliosis]] but no [[inflammatory]] or [[neurodegenerative]] changes. Both Valko, P. and John, J. along with their respective teams independently reported in 2013, that narcolepsy [[patients]] have an increased [[number]] of [[histamine]] [[neurons]] (usually >50% higher than in [[healthy]] individuals) in their [[hypothalamic]] [[tuberomammillary nucleus]], which is possibly a compensatory response to the loss of [[Excitatory neurotransmitter|excitatory]] drive due to [[orexins]].<ref name="pmid23821583">{{cite journal| author=John J, Thannickal TC, McGregor R, Ramanathan L, Ohtsu H, Nishino S | display-authors=etal| title=Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. | journal=Ann Neurol | year= 2013 | volume= 74 | issue= 6 | pages= 786-93 | pmid=23821583 | doi=10.1002/ana.23968 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23821583  }} </ref><ref name="pmid24006291">{{cite journal| author=Valko PO, Gavrilov YV, Yamamoto M, Reddy H, Haybaeck J, Mignot E | display-authors=etal| title=Increase of histaminergic tuberomammillary neurons in narcolepsy. | journal=Ann Neurol | year= 2013 | volume= 74 | issue= 6 | pages= 794-804 | pmid=24006291 | doi=10.1002/ana.24019 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24006291  }} </ref> The [[Immune-mediated disease|immune-mediated]] process might also be the underlying reason for this increase in the [[number]] of [[histamine]] producing [[neurons]] in [[humans]]. [[Neuronal]] firing and release of [[histamine]] are maximal during [[wakefulness]], which is usually diminished as a consequence of loss of [[histamine]] producing [[neurons]] or the [[inhibition]] of [[Cell signaling|signaling]] of these [[neurons]]. Several studies in [[patients]] with narcolepsy and other [[central]] [[Hypersomnia|hypersomnias]] reported no differences in levels of [[histamine]] or its [[metabolite]] tele-methylhistamine, compared to [[healthy]] [[Control group|controls]], suggesting that despite an increased [[number]] of [[histamine]] producing [[neurons]] in the [[Brain|brains]] of narcolepsy [[patients]], the [[cerebrospinal fluid]] ([[CSF]]) levels of [[histamine]] and its [[metabolite]] are not useful [[Biomarker|biomarkers]] for narcolepsy.<ref name="pmid26100750">{{cite journal| author=Shan L, Dauvilliers Y, Siegel JM| title=Interactions of the histamine and hypocretin systems in CNS disorders. | journal=Nat Rev Neurol | year= 2015 | volume= 11 | issue= 7 | pages= 401-13 | pmid=26100750 | doi=10.1038/nrneurol.2015.99 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26100750  }} </ref><ref name="pmid23024434">{{cite journal| author=Dauvilliers Y, Delallée N, Jaussent I, Scholz S, Bayard S, Croyal M | display-authors=etal| title=Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions. | journal=Sleep | year= 2012 | volume= 35 | issue= 10 | pages= 1359-66 | pmid=23024434 | doi=10.5665/sleep.2114 | pmc=3443762 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23024434  }} </ref> Narcolepsy [[Patient|patients]] with and without [[cataplexy]] may have normal levels of [[orexin]] in the [[CSF]], while some patients with [[hypothalamic]] damage and subsequent low or absent levels of [[orexin]] in the [[CSF]] may not have any symptoms of narcolepsy or [[cataplexy]]. This [[observation]] suggests that a deficiency in [[orexin]] is not (always) necessary nor (always) sufficient to cause narcolepsy in [[Human|humans]].<ref name="pmid16006155">{{cite journal| author=Nishino S, Kanbayashi T| title=Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. | journal=Sleep Med Rev | year= 2005 | volume= 9 | issue= 4 | pages= 269-310 | pmid=16006155 | doi=10.1016/j.smrv.2005.03.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16006155  }} </ref><ref name="pmid16009905">{{cite journal| author=Baumann CR, Stocker R, Imhof HG, Trentz O, Hersberger M, Mignot E | display-authors=etal| title=Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury. | journal=Neurology | year= 2005 | volume= 65 | issue= 1 | pages= 147-9 | pmid=16009905 | doi=10.1212/01.wnl.0000167605.02541.f2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16009905  }} </ref><ref name="pmid19847903">{{cite journal| author=Baumann CR, Bassetti CL, Valko PO, Haybaeck J, Keller M, Clark E | display-authors=etal| title=Loss of hypocretin (orexin) neurons with traumatic brain injury. | journal=Ann Neurol | year= 2009 | volume= 66 | issue= 4 | pages= 555-9 | pmid=19847903 | doi=10.1002/ana.21836 | pmc=2770195 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19847903  }} </ref><ref name="pmid20203518">{{cite journal| author=Baumann CR, Bassetti CL, Hersberger M, Jung HH| title=Excessive daytime sleepiness in Behçet's disease with diencephalic lesions and hypocretin dysfunction. | journal=Eur Neurol | year= 2010 | volume= 63 | issue= 3 | pages= 190 | pmid=20203518 | doi=10.1159/000290252 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20203518  }} </ref><ref name="pmid12374492">{{cite journal| author=Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S | display-authors=etal| title=The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. | journal=Arch Neurol | year= 2002 | volume= 59 | issue= 10 | pages= 1553-62 | pmid=12374492 | doi=10.1001/archneur.59.10.1553 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12374492  }} </ref><ref name="pmid16247037">{{cite journal| author=Bassetti CL| title=Narcolepsy: selective hypocretin (orexin) neuronal loss and multiple signaling deficiencies. | journal=Neurology | year= 2005 | volume= 65 | issue= 8 | pages= 1152-3 | pmid=16247037 | doi=10.1212/01.wnl.0000186118.96509.94 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16247037  }} </ref>
+=== '''<big>Genetic and epigenetic factors</big>''' ===
+[[Study design|Studies]] conducted in [[twins]] for narcolepsy revealed only ~25% (20-35%) of [[Concordance (genetics)|concordance]] rate in [[monozygotic twins]] and [[Concordance (genetics)|concordance]] rate in other [[First degree relative|first-degree relatives]] was 1-2%, which suggests that [[genetic]] factors play an important role in the [[pathogenesis]] of narcolepsy with [[cataplexy]].<ref name="pmid3587636">{{cite journal| author=Montplaisir J, Poirier G| title=Narcolepsy in monozygotic twins. | journal=Neurology | year= 1987 | volume= 37 | issue= 6 | pages= 1089 | pmid=3587636 | doi=10.1212/wnl.37.6.1089 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3587636  }} </ref><ref name="pmid14527309">{{cite journal| author=Chabas D, Taheri S, Renier C, Mignot E| title=The genetics of narcolepsy. | journal=Annu Rev Genomics Hum Genet | year= 2003 | volume= 4 | issue=  | pages= 459-83 | pmid=14527309 | doi=10.1146/annurev.genom.4.070802.110432 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14527309  }} </ref> Only 1-2% cases of narcolepsy are [[familial]]. Less than 2% of patients with narcolepsy have more than 1 affected family member, while multiplex families (families with more than 2 members) are rare. Up to 11% of [[First degree relative|first-degree relatives]] of [[Patient|patients]] with narcolepsy have also reported [[symptoms]] of this [[disease]].<ref name="pmid16364145">{{cite journal| author=Ohayon MM, Ferini-Strambi L, Plazzi G, Smirne S, Castronovo V| title=Frequency of narcolepsy symptoms and other sleep disorders in narcoleptic patients and their first-degree relatives. | journal=J Sleep Res | year= 2005 | volume= 14 | issue= 4 | pages= 437-45 | pmid=16364145 | doi=10.1111/j.1365-2869.2005.00476.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16364145  }} </ref> Variants of [[genes]], which encode [[MHC class II]] are the main [[genetic]] [[risk factors]] of this [[disorder]]. Narcolepsy has a close [[Association (statistics)|association]] with the [[human leukocyte antigen]] ([[HLA]]) class II ([[HLA]] [[genes]] encode [[MHC]] [[molecules]] that present [[antigenic]] [[peptides]] to [[CD4+]] [[helper T cells]]) region.<ref name="pmid2768960">{{cite journal| author=Taheri SA, Wormer T, Lazar L, Cullen J, Burgio H| title=Experimental prosthetic vein valve. | journal=Int Angiol | year= 1989 | volume= 8 | issue= 1 | pages= 7-9 | pmid=2768960 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2768960  }} </ref> [[HLA-DQB1]]*06:02 is expressed in 86–98% of patients with narcolepsy type 1 and in ~40–50% of patients with narcolepsy type 2.<ref name="pmid24381371">{{cite journal| author=Tafti M, Hor H, Dauvilliers Y, Lammers GJ, Overeem S, Mayer G | display-authors=etal| title=DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. | journal=Sleep | year= 2014 | volume= 37 | issue= 1 | pages= 19-25 | pmid=24381371 | doi=10.5665/sleep.3300 | pmc=3865351 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24381371  }} </ref> [[HLA-DQB1]]*06:02 [[allele]] is the main [[genetic]] [[Risk factors|risk factor]] for narcolepsy with [[cataplexy]].<ref name="pmid2905117">{{cite journal| author=Juji T, Matsuki K, Tokunaga K, Naohara T, Honda Y| title=Narcolepsy and HLA in the Japanese. | journal=Ann N Y Acad Sci | year= 1988 | volume= 540 | issue=  | pages= 106-14 | pmid=2905117 | doi=10.1111/j.1749-6632.1988.tb27056.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2905117  }} </ref><ref name="pmid25574827">{{cite journal| author=Ollila HM, Ravel JM, Han F, Faraco J, Lin L, Zheng X | display-authors=etal| title=HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. | journal=Am J Hum Genet | year= 2015 | volume= 96 | issue= 1 | pages= 136-46 | pmid=25574827 | doi=10.1016/j.ajhg.2014.12.010 | pmc=4289679 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25574827  }} </ref><ref name="pmid20711174">{{cite journal| author=Hor H, Kutalik Z, Dauvilliers Y, Valsesia A, Lammers GJ, Donjacour CE | display-authors=etal| title=Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. | journal=Nat Genet | year= 2010 | volume= 42 | issue= 9 | pages= 786-9 | pmid=20711174 | doi=10.1038/ng.647 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20711174  }} </ref> Other [[human leukocyte antigen]] ([[HLA]]) class II [[alleles]] are also associated with narcolepsy, although to a lesser extent than [[HLA-DQB1]]*06:02.<ref name="McCarthyHan2013">{{cite journal|last1=McCarthy|first1=Mark I.|last2=Han|first2=Fang|last3=Faraco|first3=Juliette|last4=Dong|first4=Xiao Song|last5=Ollila|first5=Hanna M.|last6=Lin|first6=Ling|last7=Li|first7=Jing|last8=An|first8=Pei|last9=Wang|first9=Shan|last10=Jiang|first10=Ke Wei|last11=Gao|first11=Zhan Cheng|last12=Zhao|first12=Long|last13=Yan|first13=Han|last14=Liu|first14=Ya Nan|last15=Li|first15=Qing Hua|last16=Zhang|first16=Xiao Zhe|last17=Hu|first17=Yan|last18=Wang|first18=Jing Yu|last19=Lu|first19=Yun Hui|last20=Lu|first20=Chang Jun|last21=Zhou|first21=Wei|last22=Hallmayer|first22=Joachim|last23=Huang|first23=Yu Shu|last24=Strohl|first24=Kingman P.|last25=Pollmächer|first25=Thomas|last26=Mignot|first26=Emmanuel|title=Genome Wide Analysis of Narcolepsy in China Implicates Novel Immune Loci and Reveals Changes in Association Prior to Versus After the 2009 H1N1 Influenza Pandemic|journal=PLoS Genetics|volume=9|issue=10|year=2013|pages=e1003880|issn=1553-7404|doi=10.1371/journal.pgen.1003880}}</ref><ref name="pmid25574827">{{cite journal| author=Ollila HM, Ravel JM, Han F, Faraco J, Lin L, Zheng X | display-authors=etal| title=HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. | journal=Am J Hum Genet | year= 2015 | volume= 96 | issue= 1 | pages= 136-46 | pmid=25574827 | doi=10.1016/j.ajhg.2014.12.010 | pmc=4289679 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25574827  }} </ref> Some individuals in the general [[population]] (5-38%) can also [[Gene expression|express]] [[HLA-DQB1]]*06:02, while only 1 individual out of 1,000 [[carrier]]<nowiki/>s of this [[allele]] will eventually develop narcolepsy.<ref name="pmid9484418">{{cite journal| author=Mignot E| title=Genetic and familial aspects of narcolepsy. | journal=Neurology | year= 1998 | volume= 50 | issue= 2 Suppl 1 | pages= S16-22 | pmid=9484418 | doi=10.1212/wnl.50.2_suppl_1.s16 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9484418  }} </ref> Almost all patients with narcolepsy type 1 (except at least 2%) carry the [[HLA-DQB1]]*06:02 [[alleles]], whether this represents a fundamentally different [[disease]] or a similar [[disease]] with only a minor variation is unknown. Although the latter [[explanation]] is [[Support|supported]] by the finding of an over represented, very [[rare]] [[HLA-DPB1]]*09/10 [[alleles]] in narcolepsy [[Patient|patients]] without [[HLA-DQB1]]*06:02 [[alleles]], which suggests similar [[disease]] [[Mechanism (biology)|mechanism]] in these [[Patient|patients]], except [[antigen]], is presented by a different [[MHC]] [[molecule]].<ref name="pmid25197808">{{cite journal| author=Han F, Lin L, Schormair B, Pizza F, Plazzi G, Ollila HM | display-authors=etal| title=HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. | journal=Sleep | year= 2014 | volume= 37 | issue= 10 | pages= 1601-8 | pmid=25197808 | doi=10.5665/sleep.4066 | pmc=4173917 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25197808  }} </ref>
+[[Association (statistics)|Association]] between [[HLA-DQB1]]*06:02 [[Positivity effect|positivity]] in the general [[population]] and shorter [[Rapid eye movement sleep|REM sleep]] latency, suggest that this [[EEG]] finding during [[sleep]] might represent a (first) [[biomarker]] of an increased risk of developing narcolepsy.<ref name="pmid9504524">{{cite journal| author=Mignot E, Young T, Lin L, Finn L, Palta M| title=Reduction of REM sleep latency associated with HLA-DQB1*0602 in normal adults. | journal=Lancet | year= 1998 | volume= 351 | issue= 9104 | pages= 727 | pmid=9504524 | doi=10.1016/S0140-6736(05)78496-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9504524  }} </ref> Jewish, Sardinian and Saudi [[population]]<nowiki/>s have a low [[frequency]] of this [[allele]] (< 5%), which might explain rare cases of narcolepsy in these [[Population|populations]].<ref name="pmid2896649">{{cite journal| author=Wilner A, Steinman L, Lavie P, Peled R, Friedmann A, Brautbar C| title=Narcolepsy-cataplexy in Israeli Jews is associated exclusively with the HLA DR2 haplotype. A study at the serological and genomic level. | journal=Hum Immunol | year= 1988 | volume= 21 | issue= 1 | pages= 15-22 | pmid=2896649 | doi=10.1016/0198-8859(88)90077-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2896649  }} </ref><ref name="pmid8272177">{{cite journal| author=al Rajeh S, Bademosi O, Ismail H, Awada A, Dawodu A, al-Freihi H | display-authors=etal| title=A community survey of neurological disorders in Saudi Arabia: the Thugbah study. | journal=Neuroepidemiology | year= 1993 | volume= 12 | issue= 3 | pages= 164-78 | pmid=8272177 | doi=10.1159/000110316 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8272177  }} </ref><ref name="MolariCarcassi2010">{{cite journal|last1=Molari|first1=Andrea|last2=Carcassi|first2=Carlo|title=HLA and narcolepsy-cataplexy in the Sardinian population|journal=Journal of Sleep Research|volume=19|issue=4|year=2010|pages=624–625|issn=09621105|doi=10.1111/j.1365-2869.2010.00849.x}}</ref> Higher frequency of [[HLA-DQB1]]*06:02 [[allele]] in Northern European (25%) and African American (38%) [[Population|populations]] explains higher [[prevalence]] of narcolepsy in these [[Population|populations]].<ref name="pmid19013100">{{cite journal| author=Longstreth WT, Ton TG, Koepsell T, Gersuk VH, Hendrickson A, Velde S| title=Prevalence of narcolepsy in King County, Washington, USA. | journal=Sleep Med | year= 2009 | volume= 10 | issue= 4 | pages= 422-6 | pmid=19013100 | doi=10.1016/j.sleep.2008.05.009 | pmc=2754568 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19013100  }} </ref> Extremely high [[linkage]] is present between [[HLA-DQ1|HLA‑DQB1]]*06:02 and [[HLA-DQA1]]*01:02, which suggests that [[Patient|patients]] carrying [[HLA-DQB1]]*06:02 [[allele|alleles]] also carry [[HLA-DQA1]]*01:02 on the same [[chromosome]]. [[HLA-DQA1]]*01:02 can also be carried by other [[HLA-DQB1]] [[alleles]], but the risk of narcolepsy in those cases is increased only slightly or remains unchanged. Other [[genes]], which encode [[MHC class II]] [[proteins]] (e.g, variants of [[HLA-DQ]] and [[HLA-DP]]) can also predispose individuals to develop narcolepsy, although to a lesser [[Extent of reaction|extent]]. [[HLA-DQB1]]*03:01 [[allele]] increases the risk of narcolepsy by 1.5‑fold while the onset of narcolepsy in Asian [[carrier]]<nowiki/>s of this [[allele]] was 2 [[Year|years]] earlier than those who were non-carriers.<ref name="McCarthyHan2013">{{cite journal|last1=McCarthy|first1=Mark I.|last2=Han|first2=Fang|last3=Faraco|first3=Juliette|last4=Dong|first4=Xiao Song|last5=Ollila|first5=Hanna M.|last6=Lin|first6=Ling|last7=Li|first7=Jing|last8=An|first8=Pei|last9=Wang|first9=Shan|last10=Jiang|first10=Ke Wei|last11=Gao|first11=Zhan Cheng|last12=Zhao|first12=Long|last13=Yan|first13=Han|last14=Liu|first14=Ya Nan|last15=Li|first15=Qing Hua|last16=Zhang|first16=Xiao Zhe|last17=Hu|first17=Yan|last18=Wang|first18=Jing Yu|last19=Lu|first19=Yun Hui|last20=Lu|first20=Chang Jun|last21=Zhou|first21=Wei|last22=Hallmayer|first22=Joachim|last23=Huang|first23=Yu Shu|last24=Strohl|first24=Kingman P.|last25=Pollmächer|first25=Thomas|last26=Mignot|first26=Emmanuel|title=Genome Wide Analysis of Narcolepsy in China Implicates Novel Immune Loci and Reveals Changes in Association Prior to Versus After the 2009 H1N1 Influenza Pandemic|journal=PLoS Genetics|volume=9|issue=10|year=2013|pages=e1003880|issn=1553-7404|doi=10.1371/journal.pgen.1003880}}</ref> [[HLA-DPB1]] [[alleles]] also [[affect]] the risk of developing narcolepsy. [[HLA-DPB1]]*05:01 predispose individuals to develop narcolepsy, while [[HLA-DPB1]]*04:01 and [[HLA-DPB1]]*04:02 protect against the [[development]] of narcolepsy.
+Weak [[Association (statistics)|association]] between [[human leukocyte antigen]] ([[HLA]]) class I [[genes]] (A, B and C) and narcolepsy has also been reported, which suggests that [[pathogenesis]] of narcolepsy involves [[cytotoxic]] [[immune mechanism]] (response mediated either by [[Cytotoxic T cell|cytotoxic]] [[CD8+ T cells]] or [[Natural Killer Cells|natural killer]] ([[Natural killer cell|NK]]) [[cells]]) and these patients might have an increased [[genetic]] susceptibility to [[infections]]. [[Human leukocyte antigen]] ([[HLA]]) class I [[genes]] encode [[MHC class I]] [[molecules]] that present [[antigenic]] [[peptides]] to [[CD8+ T cells]].<ref name="pmid25574827">{{cite journal| author=Ollila HM, Ravel JM, Han F, Faraco J, Lin L, Zheng X | display-authors=etal| title=HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. | journal=Am J Hum Genet | year= 2015 | volume= 96 | issue= 1 | pages= 136-46 | pmid=25574827 | doi=10.1016/j.ajhg.2014.12.010 | pmc=4289679 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25574827  }} </ref><ref name="pmid26518595">{{cite journal| author=Tafti M, Lammers GJ, Dauvilliers Y, Overeem S, Mayer G, Nowak J | display-authors=etal| title=Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity. | journal=Sleep | year= 2016 | volume= 39 | issue= 3 | pages= 581-7 | pmid=26518595 | doi=10.5665/sleep.5532 | pmc=4763366 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26518595  }} </ref> [[Genome-wide association study]] (2010) identified protective [[alleles]] in both [[human leukocyte antigen]] ([[HLA]]) class I and class II [[genes]], which might explain the role played by these protective [[alleles]] in causing the delay (or absence) of the [[Evolution as theory and fact|evolution]] of narcolepsy seen in some patients.<ref name="pmid20711174">{{cite journal| author=Hor H, Kutalik Z, Dauvilliers Y, Valsesia A, Lammers GJ, Donjacour CE | display-authors=etal| title=Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. | journal=Nat Genet | year= 2010 | volume= 42 | issue= 9 | pages= 786-9 | pmid=20711174 | doi=10.1038/ng.647 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20711174  }} </ref> [[Genome-wide association study]] also reported an [[Association (statistics)|association]] between susceptibility to narcolepsy and [[polymorphism]] in TRAC (which encodes the [[T cell receptor]] α-constant [[domain]]), further supporting the [[hypothesis]] that narcolepsy is an [[immune-mediated disease]].<ref name="McCarthyHan2013">{{cite journal|last1=McCarthy|first1=Mark I.|last2=Han|first2=Fang|last3=Faraco|first3=Juliette|last4=Dong|first4=Xiao Song|last5=Ollila|first5=Hanna M.|last6=Lin|first6=Ling|last7=Li|first7=Jing|last8=An|first8=Pei|last9=Wang|first9=Shan|last10=Jiang|first10=Ke Wei|last11=Gao|first11=Zhan Cheng|last12=Zhao|first12=Long|last13=Yan|first13=Han|last14=Liu|first14=Ya Nan|last15=Li|first15=Qing Hua|last16=Zhang|first16=Xiao Zhe|last17=Hu|first17=Yan|last18=Wang|first18=Jing Yu|last19=Lu|first19=Yun Hui|last20=Lu|first20=Chang Jun|last21=Zhou|first21=Wei|last22=Hallmayer|first22=Joachim|last23=Huang|first23=Yu Shu|last24=Strohl|first24=Kingman P.|last25=Pollmächer|first25=Thomas|last26=Mignot|first26=Emmanuel|title=Genome Wide Analysis of Narcolepsy in China Implicates Novel Immune Loci and Reveals Changes in Association Prior to Versus After the 2009 H1N1 Influenza Pandemic|journal=PLoS Genetics|volume=9|issue=10|year=2013|pages=e1003880|issn=1553-7404|doi=10.1371/journal.pgen.1003880}}</ref><ref name="pmid19412176">{{cite journal| author=Hallmayer J, Faraco J, Lin L, Hesselson S, Winkelmann J, Kawashima M | display-authors=etal| title=Narcolepsy is strongly associated with the T-cell receptor alpha locus. | journal=Nat Genet | year= 2009 | volume= 41 | issue= 6 | pages= 708-11 | pmid=19412176 | doi=10.1038/ng.372 | pmc=2803042 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19412176  }} </ref> [[Association (statistics)|Associations]] between the narcolepsy and [[polymorphisms]] in other [[immune]] related [[genes]] have also been reported, including [[P2RY11]] (modulates an [[autoimmune]] response to the [[infection]] and encodes [[P2Y receptor]] 11), [[Tumor necrosis factors|TNF]]SF4 (which encodes [[tumor necrosis factor]] ([[TNF]]) [[ligand]] superfamily member 4), the [[chemokine]] [[receptor]] [[CCR1]]-[[CCR3 (gene)|CCR3]] region and [[CTSH (gene)|CTSH]] (which encodes pro-[[cathepsin H]]).<ref name="pmid23459209">{{cite journal| author=Faraco J, Lin L, Kornum BR, Kenny EE, Trynka G, Einen M | display-authors=etal| title=ImmunoChip study implicates antigen presentation to T cells in narcolepsy. | journal=PLoS Genet | year= 2013 | volume= 9 | issue= 2 | pages= e1003270 | pmid=23459209 | doi=10.1371/journal.pgen.1003270 | pmc=3573113 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23459209  }} </ref><ref name="pmid21170044">{{cite journal| author=Kornum BR, Kawashima M, Faraco J, Lin L, Rico TJ, Hesselson S | display-authors=etal| title=Common variants in P2RY11 are associated with narcolepsy. | journal=Nat Genet | year= 2011 | volume= 43 | issue= 1 | pages= 66-71 | pmid=21170044 | doi=10.1038/ng.734 | pmc=3019286 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21170044  }} </ref><ref name="pmid23497937">{{cite journal| author=Singh AK, Mahlios J, Mignot E| title=Genetic association, seasonal infections and autoimmune basis of narcolepsy. | journal=J Autoimmun | year= 2013 | volume= 43 | issue=  | pages= 26-31 | pmid=23497937 | doi=10.1016/j.jaut.2013.02.003 | pmc=4118764 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23497937  }} </ref><ref name="pmid25986216">{{cite journal| author=Toyoda H, Miyagawa T, Koike A, Kanbayashi T, Imanishi A, Sagawa Y | display-authors=etal| title=A polymorphism in CCR1/CCR3 is associated with narcolepsy. | journal=Brain Behav Immun | year= 2015 | volume= 49 | issue=  | pages= 148-55 | pmid=25986216 | doi=10.1016/j.bbi.2015.05.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25986216  }} </ref> No consistent [[Association (statistics)|association]]<nowiki/>s were reported on performing [[gene sequencing]] studies in patients with [[familial]] narcolepsy, although [[mutations]] were identified in MOG (which encodes [[myelin oligodendrocyte glycoprotein]]), HCRT (which encodes the [[hypocretin]], [[orexin]]), and [[P2RY11]] [[genes]], which modulate the [[immune response]].<ref name="pmid10973318">{{cite journal| author=Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y | display-authors=etal| title=A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. | journal=Nat Med | year= 2000 | volume= 6 | issue= 9 | pages= 991-7 | pmid=10973318 | doi=10.1038/79690 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10973318  }} </ref><ref name="pmid21907016">{{cite journal| author=Hor H, Bartesaghi L, Kutalik Z, Vicário JL, de Andrés C, Pfister C | display-authors=etal| title=A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. | journal=Am J Hum Genet | year= 2011 | volume= 89 | issue= 3 | pages= 474-9 | pmid=21907016 | doi=10.1016/j.ajhg.2011.08.007 | pmc=3169816 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21907016  }} </ref><ref name="pmid28460015">{{cite journal| author=Degn M, Dauvilliers Y, Dreisig K, Lopez R, Pfister C, Pradervand S | display-authors=etal| title=Rare missense mutations in P2RY11 in narcolepsy with cataplexy. | journal=Brain | year= 2017 | volume= 140 | issue= 6 | pages= 1657-1668 | pmid=28460015 | doi=10.1093/brain/awx093 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28460015  }} </ref> These [[rare]] [[mutations]] point towards an entirely different [[pathogenesis]] of the [[disease]].
+=== '''<big>Immunologic factors</big>''' ===
-The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to REM sleep with little or no intervening non-REM sleep. The changes in the motor and [[proprioceptive]] systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem [[alpha motor neuron]] [[depolarization]] produces almost complete [[atonia]] of [[skeletal muscle]]s via an inhibitory descending reticulospinal pathway. [[Acetylcholine]] may be one of the [[neurotransmitter]]s involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy is believed identical to that seen in normal REM sleep.
+Narcolepsy occasionally occurs in [[Association (statistics)|association]] with [[autoimmune diseases]], such as [[celiac disease]], [[multiple sclerosis]] and [[systemic lupus erythematosus]] ([[SLE]]) and [[paraneoplastic syndromes]], which suggests that narcolepsy may have an [[autoimmune]] [[pathogenesis]].<ref name="pmid29974206">{{cite journal| author=Kallweit U, Bassetti CLA, Oberholzer M, Fronczek R, Béguin M, Strub M | display-authors=etal| title=Coexisting narcolepsy (with and without cataplexy) and multiple sclerosis : Six new cases and a literature review. | journal=J Neurol | year= 2018 | volume= 265 | issue= 9 | pages= 2071-2078 | pmid=29974206 | doi=10.1007/s00415-018-8949-x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29974206  }} </ref> Cvetikovic-Lopes, V. (2010) and Bergman, H. (2014) reported the presence of a few types of [[autoantibodies]] in the [[Serum|sera]] of narcolepsy [[patients]]. Although this finding is nonspecific as these [[antibodies]] were also detected in the  [[Serum|sera]] from [[healthy]] [[Control group|controls]] and [[patients]] with other [[sleep disorders]]. Most of the [[Study design|studies]], with a few exceptions, trying to find circulating [[autoantibodies]] as an [[evidence]] of [[autoimmunity]] and a possible underlying [[Causes|cause]] of [[hypocretin]] [[deficiency]] in [[patients]] with narcolepsy, [[Yield (chemistry)|yielded]] negative [[Result|results]].<ref name="BergmanAdori2014">{{cite journal|last1=Bergman|first1=P.|last2=Adori|first2=C.|last3=Vas|first3=S.|last4=Kai-Larsen|first4=Y.|last5=Sarkanen|first5=T.|last6=Cederlund|first6=A.|last7=Agerberth|first7=B.|last8=Julkunen|first8=I.|last9=Horvath|first9=B.|last10=Kostyalik|first10=D.|last11=Kalmar|first11=L.|last12=Bagdy|first12=G.|last13=Huutoniemi|first13=A.|last14=Partinen|first14=M.|last15=Hokfelt|first15=T.|title=Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns|journal=Proceedings of the National Academy of Sciences|volume=111|issue=35|year=2014|pages=E3735–E3744|issn=0027-8424|doi=10.1073/pnas.1412189111}}</ref><ref name="pmid12405606">{{cite journal| author=Black JL, Krahn LE, Pankratz VS, Silber M| title=Search for neuron-specific and nonneuron-specific antibodies in narcoleptic patients with and without HLA DQB1*0602. | journal=Sleep | year= 2002 | volume= 25 | issue= 7 | pages= 719-23 | pmid=12405606 | doi=10.1093/sleep/25.7.719 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12405606  }} </ref><ref name="pmid16171287">{{cite journal| author=Black JL, Silber MH, Krahn LE, Fredrickson PA, Pankratz VS, Avula R | display-authors=etal| title=Analysis of hypocretin (orexin) antibodies in patients with narcolepsy. | journal=Sleep | year= 2005 | volume= 28 | issue= 4 | pages= 427-31 | pmid=16171287 | doi=10.1093/sleep/28.4.427 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16171287  }} </ref><ref name="pmid20967199">{{cite journal| author=Deloumeau A, Bayard S, Coquerel Q, Déchelotte P, Bole-Feysot C, Carlander B | display-authors=etal| title=Increased immune complexes of hypocretin autoantibodies in narcolepsy. | journal=PLoS One | year= 2010 | volume= 5 | issue= 10 | pages= e13320 | pmid=20967199 | doi=10.1371/journal.pone.0013320 | pmc=2954157 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20967199  }} </ref><ref name="pmid17259865">{{cite journal| author=Knudsen S, Mikkelsen JD, Jennum P| title=Antibodies in narcolepsy-cataplexy patient serum bind to rat hypocretin neurons. | journal=Neuroreport | year= 2007 | volume= 18 | issue= 1 | pages= 77-9 | pmid=17259865 | doi=10.1097/WNR.0b013e328010baad | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17259865  }} </ref><ref name="pmid16563524">{{cite journal| author=Overeem S, Verschuuren JJ, Fronczek R, Schreurs L, den Hertog H, Hegeman-Kleinn IM | display-authors=etal| title=Immunohistochemical screening for autoantibodies against lateral hypothalamic neurons in human narcolepsy. | journal=J Neuroimmunol | year= 2006 | volume= 174 | issue= 1-2 | pages= 187-91 | pmid=16563524 | doi=10.1016/j.jneuroim.2006.02.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16563524  }} </ref><ref name="pmid16774153">{{cite journal| author=Tanaka S, Honda Y, Inoue Y, Honda M| title=Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy. | journal=Sleep | year= 2006 | volume= 29 | issue= 5 | pages= 633-8 | pmid=16774153 | doi=10.1093/sleep/29.5.633 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16774153  }} </ref><ref name="pmid26004157">{{cite journal| author=van der Heide A, Hegeman-Kleinn IM, Peeters E, Lammers GJ, Fronczek R| title=Immunohistochemical screening for antibodies in recent onset type 1 narcolepsy and after H1N1 vaccination. | journal=J Neuroimmunol | year= 2015 | volume= 283 | issue=  | pages= 58-62 | pmid=26004157 | doi=10.1016/j.jneuroim.2015.04.008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26004157  }} </ref> [[Antibodies]] against tribbles [[homolog]] 2 ([[TRIB2]]), which is a [[protein]] produced by many [[cells]] including [[hypocretin]] [[neurons]], have been identified in many [[patients]] with narcolepsy, usually less than one [[year]] after the onset of [[disease]]. <ref name="pmid20160349">{{cite journal| author=Cvetkovic-Lopes V, Bayer L, Dorsaz S, Maret S, Pradervand S, Dauvilliers Y | display-authors=etal| title=Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. | journal=J Clin Invest | year= 2010 | volume= 120 | issue= 3 | pages= 713-9 | pmid=20160349 | doi=10.1172/JCI41366 | pmc=2827962 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20160349  }} </ref><ref name="pmid20614846">{{cite journal| author=Kawashima M, Lin L, Tanaka S, Jennum P, Knudsen S, Nevsimalova S | display-authors=etal| title=Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy. | journal=Sleep | year= 2010 | volume= 33 | issue= 7 | pages= 869-74 | pmid=20614846 | doi=10.1093/sleep/33.7.869 | pmc=2894428 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20614846  }} </ref> These [[autoantibodies]] have also been found in [[patients]] with [[autoimmune]] [[uveitis]].<ref name="pmid20614847">{{cite journal| author=Toyoda H, Tanaka S, Miyagawa T, Honda Y, Tokunaga K, Honda M| title=Anti-Tribbles homolog 2 autoantibodies in Japanese patients with narcolepsy. | journal=Sleep | year= 2010 | volume= 33 | issue= 7 | pages= 875-8 | pmid=20614847 | doi=10.1093/sleep/33.7.875 | pmc=2894429 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20614847  }} </ref> However, [[TRIB2]] [[antibodies]] were not [[Reporting results|reported]] in [[patients]] with narcolepsy [[Association (statistics)|associated]] with [[H1N1 influenza virus|H1N1 influenza]] [[immunization]].<ref name="pmid24485154">{{cite journal| author=Lind A, Ramelius A, Olsson T, Arnheim-Dahlström L, Lamb F, Khademi M | display-authors=etal| title=A/H1N1 antibodies and TRIB2 autoantibodies in narcolepsy patients diagnosed in conjunction with the Pandemrix vaccination campaign in Sweden 2009-2010. | journal=J Autoimmun | year= 2014 | volume= 50 | issue=  | pages= 99-106 | pmid=24485154 | doi=10.1016/j.jaut.2014.01.031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24485154  }} </ref> Most likely, [[TRIB2]] [[autoantibodies]] do not have a direct [[Causality|causative]] role in narcolepsy, because these [[autoantibodies]] have also been found in other [[neuronal]] [[Population|populations]] and [[cell types]]. Other [[autoantibodies]] have been detected in the [[Serum|sera]] of [[patients]] with narcolepsy including [[antibodies]] against the common carboxy-terminal [[epitope]] of the [[neuropeptide]] [[glutamic acid]]-[[isoleucine]] and α‑[[melanocyte stimulating hormone]] (NEI/α[[MSH]]). The anti-NEI/α[[Melanocyte-stimulating hormone|MSH]] [[antibodies]] [[Binding (molecular)|bind]] to [[melanin concentrating hormone]] (MCH) producing [[neurons]], which are connected at functional levels with [[hypocretin]] [[neurons]] and regulate [[sleep]] processes.<ref name="pmid24056699">{{cite journal| author=Jego S, Glasgow SD, Herrera CG, Ekstrand M, Reed SJ, Boyce R | display-authors=etal| title=Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. | journal=Nat Neurosci | year= 2013 | volume= 16 | issue= 11 | pages= 1637-43 | pmid=24056699 | doi=10.1038/nn.3522 | pmc=4974078 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24056699  }} </ref> Ahmed, S. S. et al. (2015) reported [[autoantibodies]] against [[hypocretin (orexin) receptor 2]] (HCRTR2) in 17 out of 20 Finnish [[patients]] with narcolepsy.<ref name="pmid26136476">{{cite journal| author=Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A | display-authors=etal| title=Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. | journal=Sci Transl Med | year= 2015 | volume= 7 | issue= 294 | pages= 294ra105 | pmid=26136476 | doi=10.1126/scitranslmed.aab2354 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26136476  }} </ref>
-In 2004 researchers in Australia induced narcolepsy-like symptoms in mice by injecting them with antibodies from narcoleptic humans. The research has been published in the Lancet providing strong evidence suggesting that some cases of narcolepsy might be caused by autoimmune disease.<ref>{{cite web|url=http://news.bbc.co.uk/1/hi/health/4081225.stm |title=BBC News article}}</ref>
+In both of these studies, the [[autoantibodies]] were also reported in some [[healthy]] [[Control group|controls]] and in the [[Serum|sera]] of [[patients]] with other [[sleep]]-related [[disorders]] (e.g., [[sleep apnea]], [[idiopathic]] [[hypersomnia]], [[Parasomnia|parasomnias]], [[major depressive disorder]], and [[restless legs syndrome]]), which argues against a [[Causality|causal]] relationship of these [[autoantibodies]] with narcolepsy. Katzav, A. et al. (2013) reported [[Passive transport|passive]] [[Transferability (chemistry)|transfer]] of narcolepsy into mice with intracerebral and [[intraventricular]] administration of anti‑[[TRIB2]] [[antibodies]] or anti-NEI/α[[MSH]] [[antibodies]], which revealed changes in [[sleep]] patterns suggesting some functional relevance.<ref name="pmid23834844">{{cite journal| author=Katzav A, Arango MT, Kivity S, Tanaka S, Givaty G, Agmon-Levin N | display-authors=etal| title=Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice. | journal=J Autoimmun | year= 2013 | volume= 45 | issue=  | pages= 24-30 | pmid=23834844 | doi=10.1016/j.jaut.2013.06.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23834844  }} </ref> [[Injection]] of anti-NEI/α[[MSH]] [[antibodies]] induced a [[strong]] increase in [[sleep]] [[Fragmentation (biology)|fragmentation]], which is an [[Symptoms|important symptom of narcolepsy. No other symptoms]] of narcolepsy were reported in these mice, so clear [[evidence]] pointing towards the role of these [[autoantibodies]] in the [[development]] of narcolepsy is still missing. These [[autoantibodies]] could possibly be due to [[neuronal]] damage (owing to an [[Immune-mediated disease|immune-mediated]] process) or could be present before the onset of [[disease]] and confer a higher risk of developing narcolepsy in some individuals. Anti-Ma [[encephalitis]] can destroy [[hypocretin]] [[neurons]], leading to narcolepsy like [[symptoms]], but [[screening]] of anti-Ma [[antibodies]] in [[patients]] with narcolepsy did not reveal the presence of these [[antibodies]].<ref name="pmid23939463">{{cite journal| author=Dauvilliers Y, Bauer J, Rigau V, Lalloyer N, Labauge P, Carlander B | display-authors=etal| title=Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy. | journal=JAMA Neurol | year= 2013 | volume= 70 | issue= 10 | pages= 1305-10 | pmid=23939463 | doi=10.1001/jamaneurol.2013.2831 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23939463  }} </ref><ref name="pmid14718718">{{cite journal| author=Overeem S, Dalmau J, Bataller L, Nishino S, Mignot E, Verschuuren J | display-authors=etal| title=Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. | journal=Neurology | year= 2004 | volume= 62 | issue= 1 | pages= 138-40 | pmid=14718718 | doi=10.1212/01.wnl.0000101718.92619.67 | pmc=2574537 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14718718  }} </ref> [[Blood]] samples from [[patients]] with narcolepsy identified [[CD4+ lymphocytes|CD4+]] [[Helper T cell|helper T cells]] with reactivity towards [[hypocretin]]. However, whether the presence of [[CD4+ lymphocytes|CD4+]] [[helper T cells]] is specific to narcolepsy or these [[Cells (biology)|cells]] trigger the [[disease]] or they appear in response to the destruction of [[hypocretin]] [[neurons]] is not clear yet. Although the presence of these [[Cells (biology)|cells]] strongly [[Support|supports]] the [[autoimmune]] [[hypothesis]] of narcolepsy.
-Narcolepsy is strongly associated with HLA DQB1*0602 [[genotype]]. There is also an association with HLA DR2 and HLA DQ1. This may represent [[linkage disequilibrium]].
+In 2009, Dauvilliers, Y., Abril, B., and Mas, E. reported that patients with narcolepsy respond to [[immunomodulatory]] treatment. Luo, F. et al. (2018) suggested that [[molecular mimicry]] of a particular piece of the [[influenza]] [[haemagglutinin]] [[protein]] might trigger an [[autoimmune]] process targeting [[orexin]] [[neurons]].<ref name="pmid30541895">{{cite journal| author=Luo G, Ambati A, Lin L, Bonvalet M, Partinen M, Ji X | display-authors=etal| title=Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. | journal=Proc Natl Acad Sci U S A | year= 2018 | volume= 115 | issue= 52 | pages= E12323-E12332 | pmid=30541895 | doi=10.1073/pnas.1818150116 | pmc=6310865 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30541895  }} </ref><ref name="Al RajehBademosi1993">{{cite journal|last1=Al Rajeh|first1=S.|last2=Bademosi|first2=O.|last3=Ismail|first3=H.|last4=Awada|first4=A.|last5=Dawodu|first5=A.|last6=Al-Freihi|first6=H.|last7=Assuhaimi|first7=S.|last8=Borollosi|first8=M.|last9=Al-Shammasi|first9=S.|title=A Community Survey of Neurological Disorders in Saudi Arabia: The Thugbah Study|journal=Neuroepidemiology|volume=12|issue=3|year=1993|pages=164–178|issn=0251-5350|doi=10.1159/000110316}}</ref> Further [[support]] for [[hypothesis]] that an [[autoimmune]] process contributes to narcolepsy includes the occasional presence of [[inflammatory]] findings in [[cerebrospinal fluid]] (e.g, [[pleocytosis]] and [[oligoclonal bands]]), although [[evidence]] for the presence of [[disease]] specific [[antibodies]] is lacking.<ref name="pmid16171287">{{cite journal| author=Black JL, Silber MH, Krahn LE, Fredrickson PA, Pankratz VS, Avula R | display-authors=etal| title=Analysis of hypocretin (orexin) antibodies in patients with narcolepsy. | journal=Sleep | year= 2005 | volume= 28 | issue= 4 | pages= 427-31 | pmid=16171287 | doi=10.1093/sleep/28.4.427 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16171287  }} </ref><ref name="Tanaka">Honda2006">{{cite journal|last1=Tanaka|first1=Susumu|last2=>Honda|first2=Yutaka|last3=Inoue|first3=Yuichi|last4=Honda|first4=Makoto|title=Detection of Autoantibodies Against Hypocretin, hcrtr1, and hcrtr2 in Narcolepsy: Anti-Hcrt System Antibody in Narcolepsy|journal=Sleep|volume=29|issue=5|year=2006|pages=633–638|issn=1550-9109|doi=10.1093/sleep/29.5.633}}</ref><ref name="pmid28364500">{{cite journal| author=Giannoccaro MP, Waters P, Pizza F, Liguori R, Plazzi G, Vincent A| title=Antibodies Against Hypocretin Receptor 2 Are Rare in Narcolepsy. | journal=Sleep | year= 2017 | volume= 40 | issue= 2 | pages=  | pmid=28364500 | doi=10.1093/sleep/zsw056 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28364500  }} </ref><ref name="pmid3486441">{{cite journal| author=Langdon N, Lock C, Welsh K, Vergani D, Dorow R, Wachtel H | display-authors=etal| title=Immune factors in narcolepsy. | journal=Sleep | year= 1986 | volume= 9 | issue= 1 Pt 2 | pages= 143-8 | pmid=3486441 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3486441  }} </ref><ref name="pmid2353575">{{cite journal| author=Fredrikson S, Carlander B, Billiard M, Link H| title=CSF immune variables in patients with narcolepsy. | journal=Acta Neurol Scand | year= 1990 | volume= 81 | issue= 3 | pages= 253-4 | pmid=2353575 | doi=10.1111/j.1600-0404.1990.tb00978.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2353575  }} </ref> Increased levels of [[CD4+ T cells]] ([[helper T cells]]), some [[cytokines]] ([[Tumor necrosis factor]] ([[TNF]]) and [[interferon-gamma]] ([[Interferon|IFN]]γ)), and activation of [[CD4+]] and [[CD8+ T cells]] ([[cytotoxic T cells]]), have been reported in the [[serum]] and to some extent also in the [[cerebrospinal fluid]] ([[CSF]]) of patients with narcolepsy.<ref name="pmid27821550">{{cite journal| author=Hartmann FJ, Bernard-Valnet R, Quériault C, Mrdjen D, Weber LM, Galli E | display-authors=etal| title=High-dimensional single-cell analysis reveals the immune signature of narcolepsy. | journal=J Exp Med | year= 2016 | volume= 213 | issue= 12 | pages= 2621-2633 | pmid=27821550 | doi=10.1084/jem.20160897 | pmc=5110028 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27821550  }} </ref><ref name="pmid28364420">{{cite journal| author=Ramberger M, Högl B, Stefani A, Mitterling T, Reindl M, Lutterotti A| title=CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1. | journal=Sleep | year= 2017 | volume= 40 | issue= 3 | pages=  | pmid=28364420 | doi=10.1093/sleep/zsw070 | pmc=5806576 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28364420  }} </ref><ref name="pmid25892508">{{cite journal| author=Lecendreux M, Libri V, Jaussent I, Mottez E, Lopez R, Lavault S | display-authors=etal| title=Impact of cytokine in type 1 narcolepsy: Role of pandemic H1N1 vaccination ? | journal=J Autoimmun | year= 2015 | volume= 60 | issue=  | pages= 20-31 | pmid=25892508 | doi=10.1016/j.jaut.2015.03.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25892508  }} </ref><ref name="pmid28107375">{{cite journal| author=Lecendreux M, Churlaud G, Pitoiset F, Regnault A, Tran TA, Liblau R | display-authors=etal| title=Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells. | journal=PLoS One | year= 2017 | volume= 12 | issue= 1 | pages= e0169836 | pmid=28107375 | doi=10.1371/journal.pone.0169836 | pmc=5249232 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28107375  }} </ref> However, [[Study design|studies]] assessing the levels of [[interleukin 6]] ([[IL-6]]) and [[tumor necrosis factor]] ([[TNF]]) in the [[serum]] of [[patients]] with narcolepsy revealed inconsistent [[Result|results]]. Some studies reported [[Difference (philosophy)|differences]] in the levels of [[interleukin 4]] ([[IL-4]]) and CC-[[chemokine]] [[ligand]] 3 ([[CCL3]]) in the [[cerebrospinal fluid]] ([[CSF]]) between [[patients]] with narcolepsy and [[healthy]] [[Control group|controls]].<ref name="pmid24394344">{{cite journal| author=Dauvilliers Y, Jaussent I, Lecendreux M, Scholz S, Bayard S, Cristol JP | display-authors=etal| title=Cerebrospinal fluid and serum cytokine profiles in narcolepsy with cataplexy: a case-control study. | journal=Brain Behav Immun | year= 2014 | volume= 37 | issue=  | pages= 260-6 | pmid=24394344 | doi=10.1016/j.bbi.2013.12.019 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24394344  }} </ref><ref name="pmid25892508">{{cite journal| author=Lecendreux M, Libri V, Jaussent I, Mottez E, Lopez R, Lavault S | display-authors=etal| title=Impact of cytokine in type 1 narcolepsy: Role of pandemic H1N1 vaccination ? | journal=J Autoimmun | year= 2015 | volume= 60 | issue=  | pages= 20-31 | pmid=25892508 | doi=10.1016/j.jaut.2015.03.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25892508  }} </ref> However, there was no consistent alteration of [[cytokine]] levels in [[patients]] with narcolepsy and [[cataplexy]], even very close to the onset of [[symptoms]].<ref name="pmid25771509">{{cite journal| author=Kornum BR, Pizza F, Knudsen S, Plazzi G, Jennum P, Mignot E| title=Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. | journal=Brain Behav Immun | year= 2015 | volume= 49 | issue=  | pages= 54-8 | pmid=25771509 | doi=10.1016/j.bbi.2015.03.004 | pmc=4567452 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25771509  }} </ref> Autoreactive [[CD4+ T cells|CD4+]] and [[CD8+ T cells]] have been identified in patients with narcolepsy, which specifically target [[antigens]] expressed by [[orexin]] [[neurons]].<ref name="pmid30232458">{{cite journal| author=Latorre D, Kallweit U, Armentani E, Foglierini M, Mele F, Cassotta A | display-authors=etal| title=T cells in patients with narcolepsy target self-antigens of hypocretin neurons. | journal=Nature | year= 2018 | volume= 562 | issue= 7725 | pages= 63-68 | pmid=30232458 | doi=10.1038/s41586-018-0540-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30232458  }} </ref><ref name="pmid30445542">{{cite journal| author=Lippert J, Young P, Gross C, Meuth SG, Dräger B, Schirmacher A | display-authors=etal| title=Specific T-cell activation in peripheral blood and cerebrospinal fluid in central disorders of hypersomnolence. | journal=Sleep | year= 2019 | volume= 42 | issue= 2 | pages=  | pmid=30445542 | doi=10.1093/sleep/zsy223 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30445542  }} </ref><ref name="LuoAmbati2018">{{cite journal|last1=Luo|first1=Guo|last2=Ambati|first2=Aditya|last3=Lin|first3=Ling|last4=Bonvalet|first4=Mélodie|last5=Partinen|first5=Markku|last6=Ji|first6=Xuhuai|last7=Maecker|first7=Holden Terry|last8=Mignot|first8=Emmanuel Jean-Marie|title=Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy|journal=Proceedings of the National Academy of Sciences|volume=115|issue=52|year=2018|pages=E12323–E12332|issn=0027-8424|doi=10.1073/pnas.1818150116}}</ref><ref name="PedersenHolm2019">{{cite journal|last1=Pedersen|first1=Natasja Wulff|last2=Holm|first2=Anja|last3=Kristensen|first3=Nikolaj Pagh|last4=Bjerregaard|first4=Anne-Mette|last5=Bentzen|first5=Amalie Kai|last6=Marquard|first6=Andrea Marion|last7=Tamhane|first7=Tripti|last8=Burgdorf|first8=Kristoffer Sølvsten|last9=Ullum|first9=Henrik|last10=Jennum|first10=Poul|last11=Knudsen|first11=Stine|last12=Hadrup|first12=Sine Reker|last13=Kornum|first13=Birgitte Rahbek|title=CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens|journal=Nature Communications|volume=10|issue=1|year=2019|issn=2041-1723|doi=10.1038/s41467-019-08774-1}}</ref>
-Despite the experimental evidence in human narcolepsy that there may be an inherited basis for at least some forms of narcolepsy, the mode of inheritance remains unknown.
+=== '''<big>Environmental factors</big>''' ===
-Some cases are associated with genetic diseases such as [[Niemann-Pick disease]]<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12841368&query_hl=3&itool=pubmed_docsum|title=Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C}}</ref> or [[Prader-Willi syndrome]]<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11336895&query_hl=1&itool=pubmed_docsum|title=Hypersomnia in the Prader Willi syndrome}}</ref>.
+% discordance rate for narcolepsy in all described [[monozygotic twins]] points to a contribution of [[environmental factor]]<nowiki/>s. Reported [[Association (statistics)|association]] between the risk of narcolepsy and season of [[birth]] in some but not all studies suggested that early life [[Exposure effect|exposure]] to [[viruses]], [[bacteria]] or [[toxins]] might alter the [[immune system]] development and thereby predispose individuals to narcolepsy. Subsequent exposure of these predisposed individuals to these or other [[environmental factor]]<nowiki/>s ([[infections]]) might [[trigger]] or reactivate an [[immune response]] leading to the destruction of [[orexin]] [[neurons]]. Symonds, C. (1922), Redlich, E. (1924), and Mankowski, B. (1926) initially reported a temporal [[Association (statistics)|association]] between [[influenza]] or [[epidemic]] [[encephalitis lethargica]] and the onset of narcolepsy. Aran, A. et al. (2009) reported elevated [[titer]]<nowiki/>s of [[antistreptococcal antibodies]] in [[patients]] with recent-onset narcolepsy, which suggested an [[Association (statistics)|association]] of narcolepsy with other [[upper respiratory tract infections]], particularly β-hemolytic [[streptococcal infections]].<ref name="pmid19725248">{{cite journal| author=Aran A, Lin L, Nevsimalova S, Plazzi G, Hong SC, Weiner K | display-authors=etal| title=Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. | journal=Sleep | year= 2009 | volume= 32 | issue= 8 | pages= 979-83 | pmid=19725248 | doi=10.1093/sleep/32.8.979 | pmc=2717204 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19725248  }} </ref> Increased levels of [[antistreptococcal antibodies]] were reported in [[patients]] with narcolepsy compared to [[healthy]] [[Control group|controls]], with higher [[Titre|titres]] in individuals with a recent onset of narcolepsy.<ref name="pmid19732319">{{cite journal| author=Koepsell TD, Longstreth WT, Ton TG| title=Medical exposures in youth and the frequency of narcolepsy with cataplexy: a population-based case-control study in genetically predisposed people. | journal=J Sleep Res | year= 2010 | volume= 19 | issue= 1 Pt 1 | pages= 80-6 | pmid=19732319 | doi=10.1111/j.1365-2869.2009.00756.x | pmc=3345136 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19732319  }} </ref> Ambati, A. et al. (2015) reported an increased [[Beta-hemolytic streptococci|Beta-hemolytic]] [[Group A streptococcal infection|group A streptococcal]] M6 [[serotype]] and streptodornase B-specific [[cellular]] (mediated by [[cytotoxic T cells]]) [[immune responses]] to [[streptococcal]] [[antigens]] in samples of Swedish narcolepsy [[patients]].<ref name="pmid25683265">{{cite journal| author=Ambati A, Poiret T, Svahn BM, Valentini D, Khademi M, Kockum I | display-authors=etal| title=Increased β-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases. | journal=J Intern Med | year= 2015 | volume= 278 | issue= 3 | pages= 264-76 | pmid=25683265 | doi=10.1111/joim.12355 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25683265  }} </ref> Further [[support]] towards the role of [[Streptococcal infection|streptococcal infections]] and the [[development]] of narcolepsy was provided with a reported [[Association (statistics)|association]] between [[infection]] with [[streptococcus pyogenes]] and other [[neurological disorders]] and some [[autoimmune]] [[neuropsychiatric]] [[disorders]] in [[children]] that target [[basal ganglia]] [[neurons]].<ref name="pmid22402339">{{cite journal| author=Chang C| title=Neonatal autoimmune diseases: a critical review. | journal=J Autoimmun | year= 2012 | volume= 38 | issue= 2-3 | pages= J223-38 | pmid=22402339 | doi=10.1016/j.jaut.2011.11.018 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22402339  }} </ref>
+The most important reported [[Association (statistics)|association]] of narcolepsy with [[infections]] involves the [[influenza A virus]] (subtype [[H1N1 influenza virus|H1N1]]). In 2009-2010, a [[statistically significant]] six to a ninefold increase in the risk of narcolepsy was reported in the northern European countries (eg, Finland, Sweden, Norway), Ireland, France and the United Kingdom, subsequent to [[vaccination]] campaign (with the Pandemrix [[vaccine]]) against the [[pandemic]] [[H1N1 influenza virus|H1N1 influenza]].<ref name="pmid24849861">{{cite journal| author=Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O| title=Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. | journal=Lancet Neurol | year= 2014 | volume= 13 | issue= 6 | pages= 600-13 | pmid=24849861 | doi=10.1016/S1474-4422(14)70075-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24849861  }} </ref><ref name="pmid23884811">{{cite journal| author=Dauvilliers Y, Arnulf I, Lecendreux M, Monaca Charley C, Franco P, Drouot X | display-authors=etal| title=Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. | journal=Brain | year= 2013 | volume= 136 | issue= Pt 8 | pages= 2486-96 | pmid=23884811 | doi=10.1093/brain/awt187 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23884811  }} </ref><ref name="MillerAndrews2013">{{cite journal|last1=Miller|first1=E.|last2=Andrews|first2=N.|last3=Stellitano|first3=L.|last4=Stowe|first4=J.|last5=Winstone|first5=A. M.|last6=Shneerson|first6=J.|last7=Verity|first7=C.|title=Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis|journal=BMJ|volume=346|issue=feb26 2|year=2013|pages=f794–f794|issn=1756-1833|doi=10.1136/bmj.f794}}</ref><ref name="pmid24821121">{{cite journal| author=O'Flanagan D, Barret AS, Foley M, Cotter S, Bonner C, Crowe C | display-authors=etal| title=Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010. | journal=Euro Surveill | year= 2014 | volume= 19 | issue= 17 | pages= 15-25 | pmid=24821121 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24821121  }} </ref><ref name="pmid23773727">{{cite journal| author=Heier MS, Gautvik KM, Wannag E, Bronder KH, Midtlyng E, Kamaleri Y | display-authors=etal| title=Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. | journal=Sleep Med | year= 2013 | volume= 14 | issue= 9 | pages= 867-71 | pmid=23773727 | doi=10.1016/j.sleep.2013.03.020 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23773727  }} </ref><ref name="pmid21994316">{{cite journal| author=Bardage C, Persson I, Ortqvist A, Bergman U, Ludvigsson JF, Granath F| title=Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden. | journal=BMJ | year= 2011 | volume= 343 | issue=  | pages= d5956 | pmid=21994316 | doi=10.1136/bmj.d5956 | pmc=3192001 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21994316  }} </ref><ref name="pmid22470453">{{cite journal| author=Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J | display-authors=etal| title=AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. | journal=PLoS One | year= 2012 | volume= 7 | issue= 3 | pages= e33536 | pmid=22470453 | doi=10.1371/journal.pone.0033536 | pmc=3314666 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22470453  }} </ref> The highest risk of developing narcolepsy after [[immunization]] with the Pandemrix [[vaccine]] was reported in individuals less than 20 [[Year|years]] of [[age]], but the risk was also slightly increased in [[adult]] [[patients]]. Although the [[relative risk]] was generally three to twelve-fold high, the [[incidence]] of narcolepsy remained low with only 1 reported case per 16,000 individuals that were immunized. This inflation of [[Association (statistics)|association]] between Pandemrix [[vaccine]] and narcolepsy might be explained by increased media [[attention]] and detection as well as inclusion [[bias]], while the true [[Association (statistics)|association]] is probably lower. However, this increased risk of narcolepsy due to [[immunization]] with the Pandemrix [[vaccine]] was observed in most countries, regardless of media coverage. This [[Association (statistics)|association]] was not observed with any other [[influenza vaccine]]<nowiki/>s that targeted [[H1N1 influenza virus|H1N1 influenza A virus]] (e.g, Arepanrix, an almost identical [[vaccine]] used in South America and Canada), which might be explained due to the differences in [[vaccine]] content of different [[influenza vaccine]]<nowiki/>s.<ref name="pmid26136476">{{cite journal| author=Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A | display-authors=etal| title=Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. | journal=Sci Transl Med | year= 2015 | volume= 7 | issue= 294 | pages= 294ra105 | pmid=26136476 | doi=10.1126/scitranslmed.aab2354 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26136476  }} </ref><ref name="pmid26227560">{{cite journal| author=Saariaho AH, Vuorela A, Freitag TL, Pizza F, Plazzi G, Partinen M | display-authors=etal| title=Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus. | journal=J Autoimmun | year= 2015 | volume= 63 | issue=  | pages= 68-75 | pmid=26227560 | doi=10.1016/j.jaut.2015.07.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26227560  }} </ref><ref name="SambharaMontplaisir2014">{{cite journal|last1=Sambhara|first1=Suryaprakash|last2=Montplaisir|first2=Jacques|last3=Petit|first3=Dominique|last4=Quinn|first4=Marie-Josée|last5=Ouakki|first5=Manale|last6=Deceuninck|first6=Geneviève|last7=Desautels|first7=Alex|last8=Mignot|first8=Emmanuel|last9=De Wals|first9=Philippe|title=Risk of Narcolepsy Associated with Inactivated Adjuvanted (AS03) A/H1N1 (2009) Pandemic Influenza Vaccine in Quebec|journal=PLoS ONE|volume=9|issue=9|year=2014|pages=e108489|issn=1932-6203|doi=10.1371/journal.pone.0108489}}</ref><ref name="RodriguesVaarala2014">{{cite journal|last1=Rodrigues|first1=Mauricio Martins|last2=Vaarala|first2=Outi|last3=Vuorela|first3=Arja|last4=Partinen|first4=Markku|last5=Baumann|first5=Marc|last6=Freitag|first6=Tobias L.|last7=Meri|first7=Seppo|last8=Saavalainen|first8=Päivi|last9=Jauhiainen|first9=Matti|last10=Soliymani|first10=Rabah|last11=Kirjavainen|first11=Turkka|last12=Olsen|first12=Päivi|last13=Saarenpää-Heikkilä|first13=Outi|last14=Rouvinen|first14=Juha|last15=Roivainen|first15=Merja|last16=Nohynek|first16=Hanna|last17=Jokinen|first17=Jukka|last18=Julkunen|first18=Ilkka|last19=Kilpi|first19=Terhi|title=Antigenic Differences between AS03 Adjuvanted Influenza A (H1N1) Pandemic Vaccines: Implications for Pandemrix-Associated Narcolepsy Risk|journal=PLoS ONE|volume=9|issue=12|year=2014|pages=e114361|issn=1932-6203|doi=10.1371/journal.pone.0114361}}</ref> [[Childhood]] onset of narcolepsy might also be related to the [[H1N1 influenza virus|H1N1 influenza]] [[infections]] [[pandemic]] of 2010-2011, which suggests that [[H1N1 influenza virus]] [[infection]] itself or some [[influenza vaccine]]<nowiki/>s might trigger the development of narcolepsy. Narcolepsy has also been reported to occur following other [[vaccinations]] (e.g, Post [[Tick-borne encephalitis]] [[virus]] [[vaccination]] narcolepsy with [[cataplexy]]), these [[Association (statistics)|association]]<nowiki/>s could be coincidental or not [[Causality|causal]].<ref name="pmid27397572">{{cite journal| author=Hidalgo H, Kallweit U, Mathis J, Bassetti CL| title=Post Tick-Borne Encephalitis Virus Vaccination Narcolepsy with Cataplexy. | journal=Sleep | year= 2016 | volume= 39 | issue= 10 | pages= 1811-1814 | pmid=27397572 | doi=10.5665/sleep.6160 | pmc=5020363 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27397572  }} </ref>
+A [[case-control study]] (2007) of the [[Environmental epidemiology|environmental]] [[risk factors]] for narcolepsy in the [[United States]] showed that the strongest [[risk factor]] for narcolepsy was self-reported [[flu]] during the previous [[year]].<ref name="pmid18043003">{{cite journal| author=Picchioni D, Hope CR, Harsh JR| title=A case-control study of the environmental risk factors for narcolepsy. | journal=Neuroepidemiology | year= 2007 | volume= 29 | issue= 3-4 | pages= 185-92 | pmid=18043003 | doi=10.1159/000111581 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18043003  }} </ref> Han, F., Lin, L., and Li, J. (2013) reported a peak in the [[incidence]] of [[H1N1 influenza virus|H1N1 influenza]] [[infections]] in China in late 2009, due to absence of the [[influenza vaccination]], which was subsequently followed by a threefold increase in the [[Incidence (epidemiology)|incidence]] of narcolepsy during the winter of 2009–2010, compared with both previous and subsequent [[Year|years]].<ref name="pmid23225098">{{cite journal| author=Han F, Lin L, Li J, Dong XS, Mignot E| title=Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic. | journal=Ann Neurol | year= 2013 | volume= 73 | issue= 4 | pages= 560 | pmid=23225098 | doi=10.1002/ana.23799 | pmc=4403642 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23225098  }} </ref> This [[observation]] suggested a temporal [[Association (statistics)|association]] between the peak in the [[infections]] due to the [[H1N1 influenza virus|H1N1 influenza A virus]] and a peak in the [[incidence]] of narcolepsy, 3 to 6 months later.<ref name="HanLin2011">{{cite journal|last1=Han|first1=Fang|last2=Lin|first2=Ling|last3=Warby|first3=Simon C.|last4=Faraco|first4=Juliette|last5=Li|first5=Jing|last6=Dong|first6=Song X.|last7=An|first7=Pei|last8=Zhao|first8=Long|last9=Wang|first9=Ling H.|last10=Li|first10=Qian Y.|last11=Yan|first11=Han|last12=Gao|first12=Zhan C.|last13=Yuan|first13=Yuan|last14=Strohl|first14=Kingman P.|last15=Mignot|first15=Emmanuel|title=Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in china|journal=Annals of Neurology|volume=70|issue=3|year=2011|pages=410–417|issn=03645134|doi=10.1002/ana.22587}}</ref> Return of the [[Incidence (epidemiology)|incidence]] of narcolepsy back to [[Baseline (medicine)|baseline]] in the following [[Year|years]] suggested an [[Association (statistics)|association]] between [[infection]] with the 2009 [[H1N1 influenza virus]] [[Strain (biology)|strain]] and the onset of narcolepsy. A [[review]] of Chinese [[data]] before 2009 revealed a seasonal [[pattern]] in the onset of narcolepsy with most cases of [[sleepiness]] being reported within 6 months after the winter season. Although a peak in the [[Incidence (epidemiology)|incidence]] of narcolepsy was reported in China, it was not observed in Taiwan despite exposure to the same [[epidemic]].<ref name="pmid29855798">{{cite journal| author=Sarkanen T, Alakuijala A, Julkunen I, Partinen M| title=Narcolepsy Associated with Pandemrix Vaccine. | journal=Curr Neurol Neurosci Rep | year= 2018 | volume= 18 | issue= 7 | pages= 43 | pmid=29855798 | doi=10.1007/s11910-018-0851-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29855798  }} </ref> Whether [[infection]] with [[H1N1 influenza virus|H1N1 influenza A virus]] was the underlying factor for the [[development]] of narcolepsy in Northern European [[patients]] remains unknown, but one [[Study design|study]] argued against this [[hypothesis]], as only 2.2% of narcolepsy [[patients]] with [[immunization]] history with Pandemrix [[vaccine]] had [[infection]] specific [[antibodies]] against the [[H1N1 influenza virus|H1N1 influenza A virus]].<ref name="St-PierreMelén2013">{{cite journal|last1=St-Pierre|first1=Yves|last2=Melén|first2=Krister|last3=Partinen|first3=Markku|last4=Tynell|first4=Janne|last5=Sillanpää|first5=Maarit|last6=Himanen|first6=Sari-Leena|last7=Saarenpää-Heikkilä|first7=Outi|last8=Hublin|first8=Christer|last9=Olsen|first9=Päivi|last10=Ilonen|first10=Jorma|last11=Nohynek|first11=Hanna|last12=Syrjänen|first12=Ritva|last13=Kilpi|first13=Terhi|last14=Vuorela|first14=Arja|last15=Kirjavainen|first15=Turkka|last16=Vaarala|first16=Outi|last17=Julkunen|first17=Ilkka|title=No Serological Evidence of Influenza A H1N1pdm09 Virus Infection as a Contributing Factor in Childhood Narcolepsy after Pandemrix Vaccination Campaign in Finland|journal=PLoS ONE|volume=8|issue=8|year=2013|pages=e68402|issn=1932-6203|doi=10.1371/journal.pone.0068402}}</ref> Lankford, D. (1994) and Silber, M. H. (2005) reported occurrence of narcolepsy after [[traumatic brain injury]].<ref name="pmid17561630">{{cite journal| author=Silber MH| title=Narcolepsy, head injury, and the problem of causality. | journal=J Clin Sleep Med | year= 2005 | volume= 1 | issue= 2 | pages= 157-8 | pmid=17561630 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17561630  }} </ref>
-==Differential Diagnosis==
-*[[Attention-deficit/hyperactivity disorder]] or other behavioral problems<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
-*[[Brain tumor]]
-*Cerebrovascular insufficiency
-*[[Chorea]] and movement disorders<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
-*[[Conversion disorder]] (functional neurological symptom disorder)<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
-*[[Encephalopathy]]
-*[[Head trauma]]
-*[[Hereditary]]
-*Insufficient nocturnal sleep<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
-*[[Major depressive disorder]]<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
-*Hypersomnolence<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
-*[[Schizophrenia]]<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
-*[[Seizures]]<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
-*[[Sleep apnea syndrome]]<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
-*Sleep deprivation<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
 == Epidemiology and Demographics  ==
-It is estimated that as many as 3 million people worldwide are affected by narcolepsy. In the [[United States]], it is estimated that this condition afflicts as many as 200,000 Americans, but fewer than 50,000 are diagnosed. It is as widespread as [[Parkinson's disease]] or [[multiple sclerosis]] and more prevalent than [[cystic fibrosis]], but it is less well known. Narcolepsy is often mistaken for [[clinical depression|depression]], [[epilepsy]], or the [[Adverse effect (medicine)|side effects]] of medications.
+The [[prevalence]] of narcolepsy in white individuals from North America and Europe is estimated to be ~200–500 cases per million individuals.<ref name="pmid8210228">{{cite journal| author=Hublin C, Kaprio J, Partinen M, Koskenvuo M, Heikkila K, Koskimies S | display-authors=etal| title=The prevalence of narcolepsy: an epidemiological study of the Finnish Twin Cohort. | journal=Ann Neurol | year= 1994 | volume= 35 | issue= 6 | pages= 709-16 | pmid=8210228 | doi=10.1002/ana.410350612 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8210228  }} </ref><ref name="pmid11902429">{{cite journal| author=Silber MH, Krahn LE, Olson EJ, Pankratz VS| title=The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. | journal=Sleep | year= 2002 | volume= 25 | issue= 2 | pages= 197-202 | pmid=11902429 | doi=10.1093/sleep/25.2.197 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11902429  }} </ref><ref name="pmid12084885">{{cite journal| author=Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T| title=Prevalence of narcolepsy symptomatology and diagnosis in the European general population. | journal=Neurology | year= 2002 | volume= 58 | issue= 12 | pages= 1826-33 | pmid=12084885 | doi=10.1212/wnl.58.12.1826 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12084885  }} </ref> Although [[prevalence]] in most Asian [[Population (statistics)|populations]] is similar to white [[Population|populations]], possible differences specific to each [[population]] do exist.<ref name="pmid12112103">{{cite journal| author=Wing YK, Li RH, Lam CW, Ho CK, Fong SY, Leung T| title=The prevalence of narcolepsy among Chinese in Hong Kong. | journal=Ann Neurol | year= 2002 | volume= 51 | issue= 5 | pages= 578-84 | pmid=12112103 | doi=10.1002/ana.10162 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12112103  }} </ref><ref name="pmid17922892">{{cite journal| author=Shin YK, Yoon IY, Han EK, No YM, Hong MC, Yun YD | display-authors=etal| title=Prevalence of narcolepsy-cataplexy in Korean adolescents. | journal=Acta Neurol Scand | year= 2008 | volume= 117 | issue= 4 | pages= 273-8 | pmid=17922892 | doi=10.1111/j.1600-0404.2007.00930.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17922892  }} </ref> The highest [[prevalence]] of narcolepsy occurs in Japanese [[population]] (1,600 cases per million individuals), while the lowest [[prevalence]] occurs in Arabic and Jewish [[Population|populations]] (2–40 cases per million individuals).<ref name="pmid2905117">{{cite journal| author=Juji T, Matsuki K, Tokunaga K, Naohara T, Honda Y| title=Narcolepsy and HLA in the Japanese. | journal=Ann N Y Acad Sci | year= 1988 | volume= 540 | issue=  | pages= 106-14 | pmid=2905117 | doi=10.1111/j.1749-6632.1988.tb27056.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2905117  }} </ref><ref name="pmid2896649">{{cite journal| author=Wilner A, Steinman L, Lavie P, Peled R, Friedmann A, Brautbar C| title=Narcolepsy-cataplexy in Israeli Jews is associated exclusively with the HLA DR2 haplotype. A study at the serological and genomic level. | journal=Hum Immunol | year= 1988 | volume= 21 | issue= 1 | pages= 15-22 | pmid=2896649 | doi=10.1016/0198-8859(88)90077-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2896649  }} </ref><ref name="pmid8272177">{{cite journal| author=al Rajeh S, Bademosi O, Ismail H, Awada A, Dawodu A, al-Freihi H | display-authors=etal| title=A community survey of neurological disorders in Saudi Arabia: the Thugbah study. | journal=Neuroepidemiology | year= 1993 | volume= 12 | issue= 3 | pages= 164-78 | pmid=8272177 | doi=10.1159/000110316 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8272177  }} </ref> African-Americans have a [[prevalence]] of 420 cases of narcolepsy per million individuals.<ref name="pmid19013100">{{cite journal| author=Longstreth WT, Ton TG, Koepsell T, Gersuk VH, Hendrickson A, Velde S| title=Prevalence of narcolepsy in King County, Washington, USA. | journal=Sleep Med | year= 2009 | volume= 10 | issue= 4 | pages= 422-6 | pmid=19013100 | doi=10.1016/j.sleep.2008.05.009 | pmc=2754568 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19013100  }} </ref> The [[Difference (philosophy)|differences]] of [[prevalence]] between [[Population|populations]] is possibly explained by the [[Exposure effect|exposure]] to [[Environmental factor|environmental factors]] (e.g [[infections]]) or the [[prevalence]] of [[genetic]] [[risk factors]].<ref name="MillerAndrews2013">{{cite journal|last1=Miller|first1=E.|last2=Andrews|first2=N.|last3=Stellitano|first3=L.|last4=Stowe|first4=J.|last5=Winstone|first5=A. M.|last6=Shneerson|first6=J.|last7=Verity|first7=C.|title=Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis|journal=BMJ|volume=346|issue=feb26 2|year=2013|pages=f794–f794|issn=1756-1833|doi=10.1136/bmj.f794}}</ref> African-Americans usually have lower than [[average]] socioeconomic status, which could also influence the [[prevalence]] of narcolepsy, as lower socioeconomic status in general causes an increased risk of [[infections]] and [[morbidity]].<ref name="pmid27235447">{{cite journal| author=Liu RS, Burgner DP, Sabin MA, Magnussen CG, Cheung M, Hutri-Kähönen N | display-authors=etal| title=Childhood Infections, Socioeconomic Status, and Adult Cardiometabolic Risk. | journal=Pediatrics | year= 2016 | volume= 137 | issue= 6 | pages=  | pmid=27235447 | doi=10.1542/peds.2016-0236 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27235447  }} </ref> The global [[prevalence]] of narcolepsy in the overall [[population]] is 25-50 cases (0.025%-0.05%) per 100,000 individuals.<ref name="DSMV">{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref><ref name="pmid19456307">{{cite journal| author=Heier MS, Evsiukova T, Wilson J, Abdelnoor M, Hublin C, Ervik S| title=Prevalence of narcolepsy with cataplexy in Norway. | journal=Acta Neurol Scand | year= 2009 | volume= 120 | issue= 4 | pages= 276-80 | pmid=19456307 | doi=10.1111/j.1600-0404.2009.01166.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19456307  }} </ref><ref name="pmid7701204">{{cite journal| author=Hublin C, Partinen M, Kaprio J, Koskenvuo M, Guilleminault C| title=Epidemiology of narcolepsy. | journal=Sleep | year= 1994 | volume= 17 | issue= 8 Suppl | pages= S7-12 | pmid=7701204 | doi=10.1093/sleep/17.suppl_8.s7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7701204  }} </ref> The exact [[Incidence (epidemiology)|incidence]] of narcolepsy with [[cataplexy]] remains unknown, because of uncertainties regarding the narcoleptic borderland (particularly narcolepsy type 2). Narcolepsy can occur in both [[men]] and [[women]], although in some studies, it affected more [[male]] than [[female]] individuals, which may be due to contribution by [[genetic]] and [[Environmental epidemiology|environmental]] factors. Whether this higher risk of narcolepsy in [[males]] compared to [[females]] (1.6–1.8 [[males]] per 1 [[female]]) is due to a true [[Sex linkage|sex]] effect or referral [[bias]] is unknown, because most of the [[Epidemiological study|epidemiological studies]] included too few cases to look at [[sex differences]].<ref name="pmid11902429">{{cite journal| author=Silber MH, Krahn LE, Olson EJ, Pankratz VS| title=The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. | journal=Sleep | year= 2002 | volume= 25 | issue= 2 | pages= 197-202 | pmid=11902429 | doi=10.1093/sleep/25.2.197 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11902429  }} </ref> [[Male]] [[patients]] in European [[Population (statistics)|populations]] with narcolepsy showed a later onset of the [[daytime sleepiness]] [[symptoms]] but with a shorter delay to [[diagnosis]]. [[Morbidity]] and [[mortality]] [[data]] of middle-aged and [[elderly]] narcoleptics indicating increased [[mortality]] in patients with narcolepsy remains controversial.<ref name="pmid22841027">{{cite journal| author=Jennum P, Ibsen R, Petersen ER, Knudsen S, Kjellberg J| title=Health, social, and economic consequences of narcolepsy: a controlled national study evaluating the societal effect on patients and their partners. | journal=Sleep Med | year= 2012 | volume= 13 | issue= 8 | pages= 1086-93 | pmid=22841027 | doi=10.1016/j.sleep.2012.06.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22841027  }} </ref><ref name="pmid28735916">{{cite journal| author=Jennum P, Thorstensen EW, Pickering L, Ibsen R, Kjellberg J| title=Morbidity and mortality of middle-aged and elderly narcoleptics. | journal=Sleep Med | year= 2017 | volume= 36 | issue=  | pages= 23-28 | pmid=28735916 | doi=10.1016/j.sleep.2017.03.029 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28735916  }} </ref> Although narcolepsy can occur at any [[age]] (ranging from 3 [[Year|years]] of [[age]] to 80 [[Year|years]]), most cases of narcolepsy usually start in [[adolescence]], with a small second peak of onset occurring at around 35 years of [[age]] (ranging from 30 to 39 [[Year|years]] of [[age]]).<ref name="pmid11739821">{{cite journal| author=Dauvilliers Y, Montplaisir J, Molinari N, Carlander B, Ondze B, Besset A | display-authors=etal| title=Age at onset of narcolepsy in two large populations of patients in France and Quebec. | journal=Neurology | year= 2001 | volume= 57 | issue= 11 | pages= 2029-33 | pmid=11739821 | doi=10.1212/wnl.57.11.2029 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11739821  }} </ref><ref name="pmid24780133">{{cite journal| author=Thorpy MJ, Krieger AC| title=Delayed diagnosis of narcolepsy: characterization and impact. | journal=Sleep Med | year= 2014 | volume= 15 | issue= 5 | pages= 502-7 | pmid=24780133 | doi=10.1016/j.sleep.2014.01.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24780133  }} </ref> In some patients (10-15%), narcolepsy may start before the age of 10 years.<ref name="pmid25961600">{{cite journal| author=Rocca FL, Pizza F, Ricci E, Plazzi G| title=Narcolepsy during Childhood: An Update. | journal=Neuropediatrics | year= 2015 | volume= 46 | issue= 3 | pages= 181-98 | pmid=25961600 | doi=10.1055/s-0035-1550152 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25961600  }} </ref> However, [[childhood]]-onset narcolepsy was systematically studied only in [[rare]] [[Study design|studies]] before the [[current]] [[century]].<ref name="pmid13846589">{{cite journal| author=YOSS RE, DALY DD| title=Narcolepsy in children. | journal=Pediatrics | year= 1960 | volume= 25 | issue=  | pages= 1025-33 | pmid=13846589 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13846589  }} </ref><ref name="pmid7701194">{{cite journal| author=Challamel MJ, Mazzola ME, Nevsimalova S, Cannard C, Louis J, Revol M| title=Narcolepsy in children. | journal=Sleep | year= 1994 | volume= 17 | issue= 8 Suppl | pages= S17-20 | pmid=7701194 | doi=10.1093/sleep/17.suppl_8.s17 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7701194  }} </ref><ref name="pmid9450782">{{cite journal| author=Guilleminault C, Pelayo R| title=Narcolepsy in prepubertal children. | journal=Ann Neurol | year= 1998 | volume= 43 | issue= 1 | pages= 135-42 | pmid=9450782 | doi=10.1002/ana.410430125 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9450782  }} </ref> Long [[diagnostic]] delay of 8 to 12 [[Year|years]] from the onset of [[disease]] can underestimate the [[prevalence]] of narcolepsy.<ref name="pmid24780133">{{cite journal| author=Thorpy MJ, Krieger AC| title=Delayed diagnosis of narcolepsy: characterization and impact. | journal=Sleep Med | year= 2014 | volume= 15 | issue= 5 | pages= 502-7 | pmid=24780133 | doi=10.1016/j.sleep.2014.01.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24780133  }} </ref><ref name="pmid23496005">{{cite journal| author=Luca G, Haba-Rubio J, Dauvilliers Y, Lammers GJ, Overeem S, Donjacour CE | display-authors=etal| title=Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. | journal=J Sleep Res | year= 2013 | volume= 22 | issue= 5 | pages= 482-95 | pmid=23496005 | doi=10.1111/jsr.12044 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23496005  }} </ref> However, in recent [[Year|years]], more cases (especially in [[children]]) have been [[Diagnose|diagnosed]] sooner after onset, probably due to increasing awareness of the [[disease]].<ref name="pmid18307264">{{cite journal| author=Serra L, Montagna P, Mignot E, Lugaresi E, Plazzi G| title=Cataplexy features in childhood narcolepsy. | journal=Mov Disord | year= 2008 | volume= 23 | issue= 6 | pages= 858-65 | pmid=18307264 | doi=10.1002/mds.21965 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18307264  }} </ref><ref name="pmid24142146">{{cite journal| author=Pizza F, Franceschini C, Peltola H, Vandi S, Finotti E, Ingravallo F | display-authors=etal| title=Clinical and polysomnographic course of childhood narcolepsy with cataplexy. | journal=Brain | year= 2013 | volume= 136 | issue= Pt 12 | pages= 3787-95 | pmid=24142146 | doi=10.1093/brain/awt277 | pmc=3859221 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24142146  }} </ref>
-Narcolepsy can occur in both men and women at any age, although its symptoms are usually first noticed in teenagers or young adults. There is strong evidence that narcolepsy may run in families; 8 to 12 percent of people with narcolepsy have a close relative with this neurologic disorder.
+Narcolepsy can have an [[acute]], [[chronic]], or a progressive [[Course (medicine)|course]], which possibly reflects different [[Pathophysiology|pathophysiologic]] [[Mechanism (biology)|mechanisms]]. In the [[acute]] [[Course (medicine)|course]], [[symptoms]] usually develop within a few days or weeks after a [[Trigger|triggering]] event (e.g, [[immunization]], [[stress]], [[head trauma]]). In the [[chronic]] [[Course (medicine)|course]], onset of [[symptoms]] is difficult to determine, while in progressive [[Course (medicine)|course]] onset of different [[symptoms]] is separated by years or even decades.<ref name="pmid25355832">{{cite journal| author=Pizza F, Vandi S, Liguori R, Parchi P, Avoni P, Mignot E | display-authors=etal| title=Primary progressive narcolepsy type 1: the other side of the coin. | journal=Neurology | year= 2014 | volume= 83 | issue= 23 | pages= 2189-90 | pmid=25355832 | doi=10.1212/WNL.0000000000001051 | pmc=4276406 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25355832  }} </ref> In a series of [[Study design|studies]] regarding the [[clinical]] [[spectrum]] of narcolepsy with [[cataplexy]], [[cataplexy]] and [[excessive daytime sleepiness]] ([[EDS]]) both developed at the same time in 49% of the [[Study design|study]] participants, while [[cataplexy]] developed after [[excessive daytime sleepiness]] ([[EDS]]) in 43% of [[patients]].<ref name="pmid23496005">{{cite journal| author=Luca G, Haba-Rubio J, Dauvilliers Y, Lammers GJ, Overeem S, Donjacour CE | display-authors=etal| title=Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. | journal=J Sleep Res | year= 2013 | volume= 22 | issue= 5 | pages= 482-95 | pmid=23496005 | doi=10.1111/jsr.12044 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23496005  }} </ref> [[Cataplexy]] developed before [[excessive daytime sleepiness]] ([[EDS]]) in only 8% of the [[Study design|study]] participants. These [[Study design|studies]] revealed that the usual [[Interval estimation|interval]] between the onset of [[excessive daytime sleepiness]] ([[EDS]]) and onset of [[cataplexy]] is usually less than 2 to 3 [[Year|years]] but it can exceed up to 40 to 50 [[Year|years]].<ref name="pmid15560774">{{cite journal| author=Sturzenegger C, Bassetti CL| title=The clinical spectrum of narcolepsy with cataplexy: a reappraisal. | journal=J Sleep Res | year= 2004 | volume= 13 | issue= 4 | pages= 395-406 | pmid=15560774 | doi=10.1111/j.1365-2869.2004.00422.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15560774  }} </ref><ref name="pmid1756354">{{cite journal| author=van Dijk JG, Lammers GJ, Blansjaar BA| title=Isolated cataplexy of more than 40 years' duration. | journal=Br J Psychiatry | year= 1991 | volume= 159 | issue=  | pages= 719-21 | pmid=1756354 | doi=10.1192/bjp.159.5.719 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1756354  }} </ref><ref name="pmid22942503">{{cite journal| author=Andlauer O, Moore H, Hong SC, Dauvilliers Y, Kanbayashi T, Nishino S | display-authors=etal| title=Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. | journal=Sleep | year= 2012 | volume= 35 | issue= 9 | pages= 1247-55F | pmid=22942503 | doi=10.5665/sleep.2080 | pmc=3413802 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22942503  }} </ref> Narcolepsy [[patients]] without [[cataplexy]] can enter [[remission]] as it can be a [[transient]] presentation, whereas [[remission]] in [[patients]] with narcolepsy with [[cataplexy]] is very unlikely ([[remission]] of narcolepsy with [[cataplexy]] has been reported only once in a [[patient]] who received [[immunotherapy]] soon after the onset of [[disease]].<ref name="pmid23946709">{{cite journal| author=Trotti LM, Staab BA, Rye DB| title=Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. | journal=J Clin Sleep Med | year= 2013 | volume= 9 | issue= 8 | pages= 789-95 | pmid=23946709 | doi=10.5664/jcsm.2922 | pmc=3716670 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23946709  }} </ref><ref name="pmid29099966">{{cite journal| author=Lopez R, Doukkali A, Barateau L, Evangelista E, Chenini S, Jaussent I | display-authors=etal| title=Test-Retest Reliability of the Multiple Sleep Latency Test in Central Disorders of Hypersomnolence. | journal=Sleep | year= 2017 | volume= 40 | issue= 12 | pages=  | pmid=29099966 | doi=10.1093/sleep/zsx164 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29099966  }} </ref><ref name="pmid19841387">{{cite journal| author=Dauvilliers Y, Abril B, Mas E, Michel F, Tafti M| title=Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. | journal=Neurology | year= 2009 | volume= 73 | issue= 16 | pages= 1333-4 | pmid=19841387 | doi=10.1212/WNL.0b013e3181bd1344 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19841387  }} </ref> [[Symptoms]] of narcolepsy often improve over time and the severity of both, [[excessive daytime sleepiness]] ([[EDS]]) and [[cataplexy]] usually decrease with increasing [[age]], possibly due to [[Coping strategies|coping]] [[Mechanism (biology)|mechanisms]].
-Narcolepsy has its typical onset in [[adolescence]] and young adulthood. There is an average 15-year delay between onset and correct [[diagnosis]] which may contribute substantially to the disabling features of the disorder. Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. For these to occur in the crucial teen years when education, development of self-image, and development of occupational choice are taking place is especially damaging. While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence.
+According to an [[estimation]], as many as 3 million people worldwide are affected by narcolepsy. Narcolepsy is as widespread as [[Parkinson's disease]] or [[multiple sclerosis]] and it is more prevalent than [[cystic fibrosis]], but it is a less well-known disease. Narcolepsy can be mistaken for [[clinical depression|depression]], [[epilepsy]], or as a [[Adverse effect (medicine)|side effect]] of some [[medication]]. There is strong [[evidence]] that narcolepsy is a [[familial]] [[disorder]] and may run in the families; 8-12% of people with narcolepsy usually have a close relative with this [[neurologic]] [[disorder]]. There is an [[average]] delay of 15 [[Year|years]] between onset and correct [[diagnosis]] which may contribute substantially to the disabling [[Features (pattern recognition)|features]] of the [[Disorder (medicine)|disorder]]. [[Cognitive]], educational, [[Occupational Health|occupational]], and [[psychosocial]] problems have a reported [[Association (statistics)|association]] with the [[excessive daytime sleepiness]] of narcolepsy. These problems are especially damaging in teenagers, who are developing their self-image, getting an [[education]], and making their occupational choices in the meantime. While [[cognitive impairment]] does occur in [[Patient|patients]] with narcolepsy, it may only be a [[Reflection (physics)|reflection]] of the [[excessive daytime sleepiness]] ([[EDS]]).
-The prevalence of narcolepsy is 20-40 per 100,000 (0.02%-0.04%) of the overall population.<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>. It is a reason for patient visits to sleep disorder centers, and with its onset in adolescence, it is also a major cause of learning difficulty and absenteeism from school. Normal teenagers often already experience excessive daytime sleepiness because of a maturational increase in physiological sleep tendency accentuated by multiple educational and social pressures; this may be disabling with the addition of narcolepsy symptoms in susceptible teenagers. In clinical practice, the differentiation between narcolepsy and other conditions characterized by excessive somnolence may be difficult. Treatment options are currently limited. There is a paucity in the literature of controlled [[double-blind]] studies of possible effective drugs or other forms of therapy. Mechanisms of action of some of the few available therapeutic agents have been explored but detailed studies of mechanisms of action are needed before new classes of therapeutic agents can be developed.
-Narcolepsy is an under diagnosed condition in the general population. This is partly because its severity varies from obvious down to barely noticeable. Some narcoleptics do not suffer from loss of muscle control. Others may only feel sleepy in the evenings.
-==Risk Factors==
-*Genetic predisposition
-:*[[Monozygotic twins]] with narcolepsy
-:*First-degree relatives with narcolepsy
-*[[Group A streptococcal]] throat infection
-*Head trauma
-*[[Influenza]]
-*Job changes
-*Stress<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
 == Diagnosis ==
 Diagnosis is relatively easy when all the symptoms of narcolepsy are present. But if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult.
@@ Line 84: / Line 77: @@
 For the multiple sleep latency test, a person is given a chance to sleep every 2 hours during normal wake times. Observations are made of the time taken to reach various stages of sleep. This test measures the degree of daytime sleepiness and also detects how soon REM sleep begins. Again, people with narcolepsy fall asleep rapidly and enter REM sleep early.
-===DSM-V Diagnostic Criteria for Narcolepsy<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>===
+===DSM-V Diagnostic Criteria for Narcolepsy<ref name="DSMV">{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>===
 {{cquote|
-*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 three times per
+*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 three times per week over the past 3 months.
-week over the past 3 months.
 '''''AND'''''
-*B.The presence of at least one of the following:
+*B. The presence of at least one of the following:
-:*1.Episodes of [[cataplexy]], defined as either (a) or (b), occurring at least a few times per month:
+:*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.
+::*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.
-::*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.
+::*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 immuno reactivity 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.
+:*2. Hypocretin deficiency, as measured using [[cerebrospinal fluid]] (CSF) hypocretin-1 immuno reactivity 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 showing a mean sleep latency less than or equal to 8 minutes and two or more sleep-onset REM periods.
+:*3. Nocturnal sleep [[polysomnography]] showing [[rapid eye movement]] (REM) sleep latency less than or equal to 15 minutes, or a multiple sleep latency test showing a mean sleep latency less than or equal to 8 minutes and two or more sleep-onset REM periods.
 *Specify whether:
@@ Line 130: / Line 122: @@
 }}
-===Symptoms===
+===<big>Symptoms</big>===
-The main characteristic of narcolepsy is overwhelming excessive daytime sleepiness (EDS), even after adequate night time sleep. A person with narcolepsy is likely to become drowsy or to fall asleep, often at inappropriate times and places. Daytime naps may occur without warning and may be physically irresistible. These naps can occur several times a day. They are typically refreshing, but only for a few hours. Drowsiness may persist for prolonged periods of time. In addition, night-time sleep may be fragmented with frequent
+Narcolepsy [[patients]] usually have a [[variable]] combination of [[symptoms]], related to [[sleep]] and [[wakefulness]], as well as [[cognitive]], [[Motor Control|motor]], [[emotional]], [[psychiatric]], [[autonomic]] and, [[metabolic]] disturbances reflecting the [[hypothalamic]] [[origin]] of the [[disease]].
-awakenings.
-Four other classic symptoms of narcolepsy, which may not occur in all patients, are [[cataplexy]], [[sleep paralysis]], [[hypnogogic hallucination]]s, and [[automatic behavior]]. Cataplexy is an episodic condition featuring loss of muscle function, ranging from slight weakness (such as limpness at the neck or knees, sagging facial muscles, or inability to speak clearly) to complete body collapse. Episodes may be triggered by sudden emotional reactions such as [[laughter]], [[anger]], surprise, or [[fear]], and may last from a few seconds to several minutes. The person remains conscious throughout the episode. Sleep paralysis is the temporary inability to talk or move when waking up. It may last a few seconds to minutes. This is often frightening but is not dangerous. Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening. Automatic behavior means that a person continues to function (talking, putting things away, etc.) during sleep episodes, but awakens with no memory of performing such activities. It is estimated that up to 40 percent of people with narcolepsy experience automatic behavior during sleep episodes.
+==='''Excessive daytime sleepiness'''===
-Daytime sleepiness, sleep paralysis, and hypnagogic hallucinations also occur in people who do not have narcolepsy, more frequently in people who are suffering from extreme lack of sleep. Cataplexy is generally considered to be unique to narcolepsy.
+[[Excessive daytime sleepiness]] ([[EDS]]) is usually most disabling and the leading [[symptom]] of narcolepsy, which typically presents as an inability to [[Stay Awake|stay awake]] or as a subjective [[feeling]] of [[sleepiness]] with [[Difficulty paying attention|difficulty]] in sustaining [[attention]], even after adequate night time [[sleep]]. [[Excessive daytime sleepiness]] ([[EDS]]) is typically irresistible, often already present in the morning hours and [[patients]] experience [[sleep]] attacks with rapid [[transition]] into [[sleep]], often at inappropriate times and places. Khatami, R. et al. (2016) reported involuntary napping in 80% of 1,079 European [[patients]] with narcolepsy.<ref name="pmid26809504">{{cite journal| author=Khatami R, Luca G, Baumann CR, Bassetti CL, Bruni O, Canellas F | display-authors=etal| title=The European Narcolepsy Network (EU-NN) database. | journal=J Sleep Res | year= 2016 | volume= 25 | issue= 3 | pages= 356-64 | pmid=26809504 | doi=10.1111/jsr.12374 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26809504  }} </ref> These episodes of overwhelming, [[excessive daytime sleepiness]] ([[EDS]]) predominantly occur in monotonous situations but can also occur in active [[patients]]. Naps are usually but not invariably short (with a duration of 15 to 20 [[Minute|minutes]]), refreshing (only for a few hours), and are also associated with [[Oneiric (film theory)|oneiric]] experiences.<ref name="pmid15560774">{{cite journal| author=Sturzenegger C, Bassetti CL| title=The clinical spectrum of narcolepsy with cataplexy: a reappraisal. | journal=J Sleep Res | year= 2004 | volume= 13 | issue= 4 | pages= 395-406 | pmid=15560774 | doi=10.1111/j.1365-2869.2004.00422.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15560774  }} </ref><ref name="pmid28179647">{{cite journal| author=Kornum BR, Knudsen S, Ollila HM, Pizza F, Jennum PJ, Dauvilliers Y | display-authors=etal| title=Narcolepsy. | journal=Nat Rev Dis Primers | year= 2017 | volume= 3 | issue=  | pages= 16100 | pmid=28179647 | doi=10.1038/nrdp.2016.100 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28179647  }} </ref> These [[Daytime sleepiness|daytime naps]]  can occur several times during the day, may occur without warning and can be physically irresistible. [[Patients]] with [[excessive daytime sleepiness]] ([[EDS]]) can develop [[Automatic behavior|automatic behaviors]] (e.g, [[writing]] over the border of a piece of paper, [[Abnormality (behavior)|abnormal]] [[Behavior|behaviors]] upon waking such as putting [[salt]] in the [[coffee]] or driving to the wrong destination).<ref name="pmid46820">{{cite journal| author=Guilleminault C, Phillips R, Dement WC| title=A syndrome of hypersomnia with automatic behavior. | journal=Electroencephalogr Clin Neurophysiol | year= 1975 | volume= 38 | issue= 4 | pages= 403-13 | pmid=46820 | doi=10.1016/0013-4694(75)90264-3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=46820  }} </ref> These so-called [[Automatic behavior|automatic behaviors]] are experienced as [[blackouts]] because [[patients]] can be [[amnesic]] during these episodes. Resisting [[sleep]] might increase the risk of developing such [[Behavior|behaviors]] in [[patients]] with narcolepsy, but they can also manifest with nonspecific [[symptoms]] such as hypoacusis, [[headache]], and [[sensory]] or [[Visual disturbance|visual disturbances]]. [[Excessive daytime sleepiness]] ([[EDS]]) must be distinguished from [[fatigue]], which is reported by up to 60% of [[patients]] with narcolepsy and is more resistant to [[therapy]] than [[excessive daytime sleepiness]] ([[EDS]]).<ref name="pmid19014080">{{cite journal| author=Valko PO, Bassetti CL, Bloch KE, Held U, Baumann CR| title=Validation of the fatigue severity scale in a Swiss cohort. | journal=Sleep | year= 2008 | volume= 31 | issue= 11 | pages= 1601-7 | pmid=19014080 | doi=10.1093/sleep/31.11.1601 | pmc=2579971 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19014080  }} </ref><ref name="pmid21848801">{{cite journal| author=Droogleever Fortuyn HA, Fronczek R, Smitshoek M, Overeem S, Lappenschaar M, Kalkman J | display-authors=etal| title=Severe fatigue in narcolepsy with cataplexy. | journal=J Sleep Res | year= 2012 | volume= 21 | issue= 2 | pages= 163-9 | pmid=21848801 | doi=10.1111/j.1365-2869.2011.00943.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21848801  }} </ref> [[Fatigue]] also increases the burden of [[excessive daytime sleepiness]] ([[EDS]]) by impairing daytime activity, which is a major measure to combat [[excessive daytime sleepiness]] ([[EDS]]). Narcolepsy [[patients]] are usually unable to maintain vigilance during the [[Daytime sleepiness|daytime]] with an inability to maintain [[sleep]] states during the night time ([[nocturnal]] [[sleep]] may be fragmented with frequent awakenings), but the total amount of [[sleep]] is usually not increased over the course of the day.<ref name="pmid3704444">{{cite journal| author=Broughton R, Valley V, Aguirre M, Roberts J, Suwalski W, Dunham W| title=Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy: a laboratory perspective. | journal=Sleep | year= 1986 | volume= 9 | issue= 1 Pt 2 | pages= 205-15 | pmid=3704444 | doi=10.1093/sleep/9.1.205 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3704444  }} </ref> Narcolepsy [[patients]] have [[sleep]] [[instability]] with increased transitions between [[Non-rapid eye movement sleep|non-rapid eye movement]] ([[NREM sleep|NREM]]) and [[Rapid eye movement sleep|rapid eye movement]] ([[REM sleep|REM]]) [[sleep]] and increased transitions from [[Non-rapid eye movement sleep|non-rapid eye movement]] ([[NREM]]) [[sleep]] to [[wakefulness]], which further [[Support|supports]] the [[hypothesis]] of [[hypocretin]] involvement in stabilizing [[sleep]] stages.<ref name="pmid23904677">{{cite journal| author=Sorensen GL, Knudsen S, Jennum P| title=Sleep transitions in hypocretin-deficient narcolepsy. | journal=Sleep | year= 2013 | volume= 36 | issue= 8 | pages= 1173-7 | pmid=23904677 | doi=10.5665/sleep.2880 | pmc=3700714 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23904677  }} </ref><ref name="pmid25845690">{{cite journal| author=Pizza F, Vandi S, Iloti M, Franceschini C, Liguori R, Mignot E | display-authors=etal| title=Nocturnal Sleep Dynamics Identify Narcolepsy Type 1. | journal=Sleep | year= 2015 | volume= 38 | issue= 8 | pages= 1277-84 | pmid=25845690 | doi=10.5665/sleep.4908 | pmc=4507733 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25845690  }} </ref> Narcolepsy [[patients]] can also have [[REM sleep]] behavior disorder (defined as [[REM sleep]] without [[Atonia|muscle atonia]] and increased intermittent activity of [[muscles]] during [[REM sleep]]), also linked to [[hypocretin]] [[deficiency]].<ref name="pmid20129934">{{cite journal| author=Knudsen S, Gammeltoft S, Jennum PJ| title=Rapid eye movement sleep behaviour disorder in patients with narcolepsy is associated with hypocretin-1 deficiency. | journal=Brain | year= 2010 | volume= 133 | issue= Pt 2 | pages= 568-79 | pmid=20129934 | doi=10.1093/brain/awp320 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20129934  }} </ref> Additional associated [[clinical]] [[symptoms]] include [[dream]] enactment, increased motor activity during [[sleep]], and disturbed [[sleep]].
+==='''Cataplexy'''===
+[[Cataplexy]], the only specific [[symptom]] of narcolepsy (generally considered to be unique to narcolepsy), is an episodic [[condition]], defined as brief episodes of [[bilateral]] loss of [[muscle tone]] triggered by [[strong]] [[Emotion|emotions]] with a [[normal]] state of [[consciousness]].<ref name="pmid21145280">{{cite journal| author=Overeem S, van Nues SJ, van der Zande WL, Donjacour CE, van Mierlo P, Lammers GJ| title=The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency. | journal=Sleep Med | year= 2011 | volume= 12 | issue= 1 | pages= 12-8 | pmid=21145280 | doi=10.1016/j.sleep.2010.05.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21145280  }} </ref> The [[person]] suffering from [[cataplexy]] remains [[conscious]] throughout the episode. Partial attacks of [[cataplexy]] are very short, usually lasting only 2 to 10 seconds unless the [[trigger]] remains present. [[Atonia|Muscle atonia]] manifests as face drooping, sagging of the [[jaw]], [[eyelid]] closure, passive [[tongue]] protrusion, [[dysarthria]], and [[bilateral]] loss of [[motor control]] of the [[extremities]]. In [[children]], [[atonia]] of the [[facial muscles]] (also known as ''facies cataplectica'') with [[mouth]] opening and [[tongue]] protrusion can also be observed.<ref name="pmid29425380">{{cite journal| author=Pizza F, Antelmi E, Vandi S, Meletti S, Erro R, Baumann CR | display-authors=etal| title=The distinguishing motor features of cataplexy: a study from video-recorded attacks. | journal=Sleep | year= 2018 | volume= 41 | issue= 5 | pages=  | pmid=29425380 | doi=10.1093/sleep/zsy026 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29425380  }} </ref><ref name="pmid18307264">{{cite journal| author=Serra L, Montagna P, Mignot E, Lugaresi E, Plazzi G| title=Cataplexy features in childhood narcolepsy. | journal=Mov Disord | year= 2008 | volume= 23 | issue= 6 | pages= 858-65 | pmid=18307264 | doi=10.1002/mds.21965 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18307264  }} </ref> [[Cataplexy]] can range from slight [[muscle weakness]] (e.g, limpness at the [[neck]] or [[knees]], inability to speak clearly) to complete [[body]] [[collapse]]. ''Cataplectic [[immobility]]'' (complete inability to move) is reported by only a few [[patients]]. Although one-third of [[patients]] report [[falls]], [[injuries]] are [[rare]]. Typically, [[Deep tendon reflex|deep tendon reflexes]] (DTRs) are [[Transient|transiently]] abolished but can persist in [[patients]] who suffer from partial or mild episodes.<ref name="pmid29680434">{{cite journal| author=Barateau L, Pizza F, Lopez R, Antelmi E, Plazzi G, Dauvilliers Y| title=Persistence of deep-tendon reflexes during partial cataplexy. | journal=Sleep Med | year= 2018 | volume= 45 | issue=  | pages= 80-82 | pmid=29680434 | doi=10.1016/j.sleep.2017.12.011 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29680434  }} </ref> [[Babinski sign]], which is upward movement ([[dorsiflexion]]) of the [[big toe]] after stimulation of the [[sole of the foot]], rather than [[normal]] downward movement ([[plantar flexion]]) in [[Adult|adults]], can appear [[Transient|transiently]] while [[Parkinson disease]]-related [[tremor]] might persist.<ref name="AntelmiVandi2016">{{cite journal|last1=Antelmi|first1=E.|last2=Vandi|first2=S.|last3=Pizza|first3=F.|last4=Liguori|first4=R.|last5=Plazzi|first5=G.|title=Parkinsonian tremor persisting during cataplexy|journal=Sleep Medicine|volume=17|year=2016|pages=174–176|issn=13899457|doi=10.1016/j.sleep.2015.07.021}}</ref>
+Partial attacks of cataplexy can evolve over seconds to complete attacks, which usually have a duration of fewer than 2 minutes; cataplexy attack duration of more than 5 minutes is unusual and often related to the withdrawal of anti-cataplectic drugs.<ref name="pmid16186554">{{cite journal| author=Poryazova R, Siccoli M, Werth E, Bassetti CL| title=Unusually prolonged rebound cataplexy after withdrawal of fluoxetine. | journal=Neurology | year= 2005 | volume= 65 | issue= 6 | pages= 967-8 | pmid=16186554 | doi=10.1212/01.wnl.0000175978.61048.62 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16186554  }} </ref> Unilateral dominance of symptoms is atypical,<ref name="GelbGuilleminault1994">{{cite journal|last1=Gelb|first1=Michael|last2=Guilleminault|first2=Christian|last3=Kraemer|first3=Helena|last4=Lin|first4=Stephanie|last5=Moon|first5=Samina|last6=Dement|first6=William C.|last7=Mignot|first7=Emmanuel|title=Stability of Cataplexy Over Several Months—Information for the Design of Therapeutic Trials|journal=Sleep|volume=17|issue=3|year=1994|pages=265–273|issn=1550-9109|doi=10.1093/sleep/17.3.265}}</ref> and cataplexy attacks that involve single muscles are exceptional.<ref name="pmid13441766">{{cite journal| author=YOSS RE, DALY DD| title=Criteria for the diagnosis of the narcoleptic syndrome. | journal=Proc Staff Meet Mayo Clin | year= 1957 | volume= 32 | issue= 12 | pages= 320-8 | pmid=13441766 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13441766  }} </ref> The frequency of cataplexy attacks can vary from dozens per day to a few per year.<ref name="pmid10767654">{{cite journal| author=Attarian HP, Schenck CH, Mahowald MW| title=Presumed REM sleep behavior disorder arising from cataplexy and wakeful dreaming. | journal=Sleep Med | year= 2000 | volume= 1 | issue= 2 | pages= 131-133 | pmid=10767654 | doi=10.1016/s1389-9457(99)00013-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10767654  }} </ref> Hyperkinesias, in the form of tonic (tongue protrusion, facial grimacing or extension of the neck), phasic (facial muscles twitching), and repetitive motor activities, are sometimes superimposed on muscle atonia and can be misdiagnosed as epilepsy or a movement disorder. These positive motor phenomena are usually more common at the onset of disease and in children.<ref name="Rubbolid'Orsi2000">{{cite journal|last1=Rubboli|first1=G|last2=d'Orsi|first2=G|last3=Zaniboni|first3=A|last4=Gardella|first4=E|last5=Zamagni|first5=M|last6=Rizzi|first6=R|last7=Meletti|first7=S|last8=Valzania|first8=F|last9=Tropeani|first9=A|last10=Tassinari|first10=C.A|title=A video-polygraphic analysis of the cataplectic attack|journal=Clinical Neurophysiology|volume=111|year=2000|pages=S120–S128|issn=13882457|doi=10.1016/S1388-2457(00)00412-0}}</ref><ref name="Redlich1931">{{cite journal|last1=Redlich|first1=Emir|title=Epilegomena zur Narkolepsiefrage|journal=Zeitschrift für die gesamte Neurologie und Psychiatrie|volume=136|issue=1|year=1931|pages=128–173|issn=0303-4194|doi=10.1007/BF02868506}}</ref><ref>{{cite journal|doi=10.1159/isbn.978-3-318-05312-8}}</ref><ref name="pmid4346545">{{cite journal| author=Rüther E, Meier-Ewert K, Gallitz A| title=[Symptomatology of the narcoleptic syndrome]. | journal=Nervenarzt | year= 1972 | volume= 43 | issue= 12 | pages= 640-3 | pmid=4346545 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4346545  }} </ref><ref name="pmid21930661">{{cite journal| author=Plazzi G, Pizza F, Palaia V, Franceschini C, Poli F, Moghadam KK | display-authors=etal| title=Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. | journal=Brain | year= 2011 | volume= 134 | issue= Pt 12 | pages= 3477-89 | pmid=21930661 | doi=10.1093/brain/awr244 | pmc=3235554 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21930661  }} </ref>
+Four other classic symptoms of narcolepsy, which may not occur in all patients, are [[cataplexy]], [[sleep paralysis]], [[hypnogogic hallucination]]s, and [[automatic behavior]].  Episodes of cataplexy may be triggered by sudden emotional reactions such as [[laughter]], [[anger]], surprise, or [[fear]], and may last from a few seconds to several minutes.  Sleep paralysis is the temporary inability to talk or move when waking up. It may last a few seconds to minutes. This is often frightening but is not dangerous. Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening. Automatic behavior means that a person continues to function (talking, putting things away, etc.) during sleep episodes, but awakens with no memory of performing such activities. It is estimated that up to 40 percent of people with narcolepsy experience automatic behavior during sleep episodes.
+Daytime sleepiness, sleep paralysis, and hypnagogic hallucinations also occur in people who do not have narcolepsy, more frequently in people who are suffering from extreme lack of sleep.
 In most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. The other symptoms may begin alone or in combination months or years after the onset of the daytime naps. There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms. The excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not.
@@ Line 174: / Line 174: @@
 * People with narcolepsy can lead productive lives if they are provided with proper medical care.
 * If possible, individuals with narcolepsy should avoid jobs that require driving long distances or handling hazardous equipment or that require alertness for lengthy periods.
-* Parents, teachers, spouses, and employers should be aware of the symptoms of narcolepsy. This will help them avoid the mistake of confusing the person's behavior with laziness, hostility, rejection, or lack of interest and motivation. It will also help them provide essential support and cooperation.
+* Parents, teachers, spouses, and employers should be aware of the symptoms of narcolepsy. This will help them avoid the mistake of confusing the person's behavior with laziness, hostility, reject [[Category:Psychiatry]] [[Category:Sleep disorders]] ion, or lack of interest and motivation. It will also help them provide essential support and cooperation.
 * Employers can promote better working opportunities for individuals with narcolepsy by permitting special work schedules and nap breaks.
@@ Line 187: / Line 187: @@
 * Carry a tape recorder, if possible, to record important conversations and meetings.
-== See also ==
-* [[Cataplexy]]
-* [[Dyssomnia]]
-* [[Orexin]]
-* [[Microsleep]]
-* [[Polyphasic sleep]]
-* List of people with narcolepsy
 ==References==
 {{reflist|2}}
 ==Sources==
-* {{cite journal | last=Mitler | first=M M | title=Relative Efficacy of Drugs for the treatment of Sleepiness in Narcolepsy | journal=Sleep | volume=14 | issue=3 | year=1991 | month=June | pages=218
+*{{cite journal|last=Mitler|first=M M|title=Relative Efficacy of Drugs for the treatment of Sleepiness in Narcolepsy|journal=Sleep|volume=14|issue=3|year=1991|month=June|pages=218|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1680245&query_hl=4&itool=pubmed_docsum}}
- | url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1680245&query_hl=4&itool=pubmed_docsum
+*{{cite journal|last=Mayer|first=G|title=Selegiline Treatment in Narcolepsy|journal=Clinical Neuropharmacology|volume=18|issue=4|year=1995|month=August|pages=306|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8665543&query_hl=5&itool=pubmed_docsum}}
- }}
+*{{cite journal|last=Chabas|first=D|title=The Genetics of Narcolepsy|journal=Annual Review of Genomics & Human Genetics|volume=4|year=2003|month=October|pages=459|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14527309&query_hl=1&itool=pubmed_DocSum}}
-* {{cite journal | last=Mayer | first=G | title=Selegiline Treatment in Narcolepsy | journal=Clinical Neuropharmacology | volume=18 | issue=4 | year=1995 | month=August | pages=306
+*{{cite journal|last=Smith, et al.|first=A J|title=A functional autoantibody in narcolepsy|journal=Lancet|year=2004|month=June|pages=2122 – 2124}}
- | url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8665543&query_hl=5&itool=pubmed_docsum
- }}
-* {{cite journal | last=Chabas| first=D | title=The Genetics of Narcolepsy | journal=Annual Review of Genomics & Human Genetics | volume=4 | year=2003 | month=October | pages=459
- | url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14527309&query_hl=1&itool=pubmed_DocSum
- }}
-* {{cite journal | last=Smith, et al. | first=A J | title=A functional autoantibody in narcolepsy | journal=Lancet | year=2004 | month=June | pages=2122 – 2124 }}
 {{Diseases of the nervous system}}
-[[Category:Psychiatry]]
-[[Category:Sleep disorders]]
 [[af:Narkolepsie]]

Narcolepsy
ICD-10	G47.4
ICD-9	347
OMIM	161400
DiseasesDB	8801
MedlinePlus	000802
MeSH	D009290