research studies on narcolepsy

Clinical Trials

Displaying 11 studies

This study will involve in-depth, qualitative interviews with adults who have a diagnosis of NT2 (N = 15), who meet the agreed inclusion/exclusion criteria. All interviews will be undertaken in the United States (US). Each participant will take part in two interviews; each interview will last approximately 75 minutes, and interviews will be completed within seven days of each other. The interviews will be semi-structured, using a discussion guide, and all will be conducted by a trained interviewer. The interviews will be conducted via telephone, or face-to-face using a web-assisted platform. Interview 1 will consist of a concept elicitation (CE) ...

The purpose of this study is to assess the safety and efficacy of AXS-12 in narcoleptic subjects with cataplexy and excessive daytime sleepiness (EDS).

The purpose of this study is to evaluate the clinical presentations, polysomnographic features, treatment patterns of all children with narcolepsy in multiple CTSA (Clinical and Translational Science Award) centers.Comparison between recent cases (2009-June 30, 2012) and old cases (prior to 2009) will be performed.  To assess the role of infection and other triggering factors in early onset Narcolepsy.

The purpose of this study is to assess the safety and effectiveness of AXS-12 in narcoleptic subjects with cataplexy and excessive daytime sleepiness (EDS).

The purpose of this study is to provide access to treatment with pitolisant while a U.S. New Drug Application (NDA) is being prepared and submitted for review for marketing approval. This program will be open to adult patients in the U.S. with Excessive Daytime Sleepiness (EDS) associated with narcolepsy, with or without cataplexy. Pitolisant will be made available through treating physicians participating in the program.

The purpose of this study is to determine whether FT218 is safe and effective for the treatment of excessive daytime sleepiness and cataplexy in subjects with narcolepsy.

Primary objective: To evaluate the effectiveness of SUVN-G3031 compared with placebo as measured by an improvement in the Maintenance of Wakefulness Test (MWT) score. Secondary objectives: To evaluate the effectiveness of SUVN-G3031 compared with placebo as measured by subjective measures including an improvement in the Clinical Global Impression of Severity (CGI-S) score related to excessive daytime sleepiness (EDS) and the change in total Epworth Sleepiness Scale (ESS) score.

The purpose of this study is to document the long-term outcomes of secondary (symptomatic) narcolepsy in the pediatric patient population at the Mayo Clinic using chart review and mailed questionnaire.  

The purpose of this study is to assess the safety and effectiveness of JZP-110 in the treatment of excessive sleepiness in adult subjects with narcolepsy.

The objectives of this study are to demonstrate that patients with CNS hypersomnias exhibit cardiovascular and cognitive disturbances, and to demonstrate that CNS medications medications impact these cardiovascular and cognitive disturbances.

This is a Phase 3 study to assess the long-term safety and maintenance of efficacy of JZP-110 in subjects who have completed Study 14-002, 14-003, 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202.

Mayo Clinic Footer

• Request Appointment
• About Mayo Clinic
• About This Site

Legal Conditions and Terms

• Terms and Conditions
• Privacy Policy
• Notice of Privacy Practices
• Notice of Nondiscrimination
• Manage Cookies

Advertising

Mayo Clinic is a nonprofit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any of the third party products and services advertised.

• Advertising and sponsorship policy
• Advertising and sponsorship opportunities

Reprint Permissions

A single copy of these materials may be reprinted for noncommercial personal use only. "Mayo," "Mayo Clinic," "MayoClinic.org," "Mayo Clinic Healthy Living," and the triple-shield Mayo Clinic logo are trademarks of Mayo Foundation for Medical Education and Research.

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Published: 09 February 2017
• Birgitte R. Kornum 1 , 2 ,
• Stine Knudsen 3 ,
• Hanna M. Ollila 4 ,
• Fabio Pizza 5 , 6 ,
• Poul J. Jennum 2 ,
• Yves Dauvilliers 7 &
• Sebastiaan Overeem 8 , 9  

Nature Reviews Disease Primers volume  3 , Article number:  16100 ( 2017 ) Cite this article

8853 Accesses

178 Citations

48 Altmetric

Metrics details

• Sleep disorders

Narcolepsy is a chronic sleep disorder that has a typical onset in adolescence and is characterized by excessive daytime sleepiness, which can have severe consequences for the patient. Problems faced by patients with narcolepsy include social stigma associated with this disease, difficulties in obtaining an education and keeping a job, a reduced quality of life and socioeconomic consequences. Two subtypes of narcolepsy have been described (narcolepsy type 1 and narcolepsy type 2), both of which have similar clinical profiles, except for the presence of cataplexy, which occurs only in patients with narcolepsy type 1. The pathogenesis of narcolepsy type 1 is hypothesized to be the autoimmune destruction of the hypocretin-producing neurons in the hypothalamus; this hypothesis is supported by immune-related genetic and environmental factors associated with the disease. However, direct evidence in support of the autoimmune hypothesis is currently unavailable. Diagnosis of narcolepsy encompasses clinical, electrophysiological and biological evaluations, but simpler and faster procedures are needed. Several medications are available for the symptomatic treatment of narcolepsy, all of which have quite good efficacy and safety profiles. However, to date, no treatment hinders or slows disease development. Improved diagnostic tools and increased understanding of the pathogenesis of narcolepsy type 1 are needed and might lead to therapeutic or even preventative interventions.

This is a preview of subscription content, access via your institution

Access options

Access Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

24,99 € / 30 days

cancel any time

Subscribe to this journal

Receive 1 digital issues and online access to articles

92,52 € per year

only 92,52 € per issue

Rent or buy this article

Prices vary by article type

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment

Claudio L. A. Bassetti, Antoine Adamantidis, … Yves Dauvilliers

The immunopathogenesis of narcolepsy type 1

Roland S. Liblau, Daniela Latorre, … Emmanuel J. Mignot

Sleep and neurological autoimmune diseases

Alex Iranzo

American Academy of Sleep Medicine. International Classification of Sleep Disorders 3rd edn (American Academy of Sleep Medicine, 2014). Includes current classification of NT1 and NT2 and detailed descriptions of the two narcolepsy subtypes.

Yoss, R. E. & Daly, D. D. Narcolepsy. Med. Clin. North Am. 44 , 953–968 (1960).

Google Scholar  

Lecendreux, M. et al . Attention-deficit/hyperactivity disorder (ADHD) symptoms in pediatric narcolepsy: a cross-sectional study. Sleep 38 , 1285–1295 (2015).

Rocca, F. L. et al . Psychosocial profile and quality of life in children with type 1 narcolepsy: a case–control study. Sleep 39 , 1389–1398 (2016).

Plazzi, G. et al . Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain 134 , 3477–3489 (2011).

Poli, F. et al . High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy. Sleep 36 , 175–181 (2013).

Andlauer, O. et al . Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep 35 , 1247–1255 (2012).

Knudsen, S., Jennum, P., Alving, J., Sheikh, S. P. & Gammeltoft, S. Validation of the ICSD-2 criteria for CSF hypocretin-1 measurements in the diagnosis of narcolepsy in the Danish population. Sleep 33 , 169–176 (2010).

Lopez, R. et al . Temporal changes in the cerebrospinal fluid level of hypocretin-1 and histamine in narcolepsy. Sleep 9 Sept 2016 [epub ahead of print].

Pizza, F. et al . Primary progressive narcolepsy type 1: the other side of the coin. Neurology 83 , 2189–2190 (2014).

Peyron, C. et al . A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 6 , 991–997 (2000). First description of hypocretin deficiency in patients with narcolepsy.

Thannickal, T. C. et al . Reduced number of hypocretin neurons in human narcolepsy. Neuron 27 , 469–474 (2000).

Thannickal, T. C., Nienhuis, R. & Siegel, J. M. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep 32 , 993–998 (2009).

Gerashchenko, D. et al . Relationship between CSF hypocretin levels and hypocretin neuronal loss. Exp. Neurol. 184 , 1010–1016 (2003).

Nishino, S. et al . CSF hypocretin levels in Guillain–Barré syndrome and other inflammatory neuropathies. Neurology 61 , 823–825 (2003).

Plazzi, G. et al . Narcolepsy with cataplexy associated with holoprosencephaly misdiagnosed as epileptic drop attacks. Mov. Disord. 25 , 788–790 (2010).

Moghadam, K. K. et al . Narcolepsy is a common phenotype in HSAN IE and ADCA-DN. Brain 137 , 1643–1655 (2014).

Silber, M. H., Krahn, L. E., Olson, E. J. & Pankratz, V. S. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 25 , 197–202 (2002). One of the largest population-based studies of the prevalence of narcolepsy.

Heier, M. S. et al . Prevalence of narcolepsy with cataplexy in Norway. Acta Neurol. Scand. 120 , 276–280 (2009).

Hublin, C., Partinen, M., Kaprio, J., Koskenvuo, M. & Guilleminault, C. Epidemiology of narcolepsy. Sleep 17 , S7–S12 (1994).

Hublin, C. et al . The prevalence of narcolepsy: an epidemiological study of the Finnish Twin Cohort. Ann. Neurol. 35 , 709–716 (1994).

Ohayon, M. M., Priest, R. G., Zulley, J., Smirne, S. & Paiva, T. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology 58 , 1826–1833 (2002).

Thorpy, M. J. & Krieger, A. C. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med. 15 , 502–507 (2014).

Luca, G. et al . Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J. Sleep Res. 22 , 482–495 (2013). Description of the large European Narcolepsy Network Database.

Serra, L., Montagna, P., Mignot, E., Lugaresi, E. & Plazzi, G. Cataplexy features in childhood narcolepsy. Mov. Disord. 23 , 858–865 (2008).

Pizza, F. et al . Clinical and polysomnographic course of childhood narcolepsy with cataplexy. Brain 136 , 3787–3795 (2013).

Dauvilliers, Y. et al . Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 57 , 2029–2033 (2001).

Wing, Y. K. et al . The prevalence of narcolepsy among Chinese in Hong Kong. Ann. Neurol. 51 , 578–584 (2002).

Shin, Y. K. et al . Prevalence of narcolepsy-cataplexy in Korean adolescents. Acta Neurol. Scand. 117 , 273–278 (2008).

Juji, T., Matsuki, K., Tokunaga, K., Naohara, T. & Honda, Y. Narcolepsy and HLA in the Japanese. Ann. NY Acad. Sci. 540 , 106–114 (1988).

Wilner, A. et al . Narcolepsy-cataplexy in Israeli Jews is associated exclusively with the HLA DR2 haplotype. A study at the serological and genomic level. Hum. Immunol. 21 , 15–22 (1988).

al Rajeh, S. et al . A community survey of neurological disorders in Saudi Arabia: the Thugbah study. Neuroepidemiology 12 , 164–178 (1993).

Longstreth, W. T. Jr et al . Prevalence of narcolepsy in King County, Washington, USA. Sleep Med. 10 , 422–426 (2009).

Miller, E. et al . Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 346 , f794 (2013).

Liu, R. S. et al . Childhood infections, socioeconomic status, and adult cardiometabolic risk. Pediatrics 137 , e20160236 (2016).

Montplaisir, J. & Poirier, G. Narcolepsy in monozygotic twins. Neurology 37 , 1089 (1987).

Chabas, D., Taheri, S., Renier, C. & Mignot, E. The genetics of narcolepsy. Annu. Rev. Genomics Hum. Genet. 4 , 459–483 (2003).

Ohayon, M. M., Ferini-Strambi, L., Plazzi, G., Smirne, S. & Castronovo, V. Frequency of narcolepsy symptoms and other sleep disorders in narcoleptic patients and their first-degree relatives. J. Sleep Res. 14 , 437–445 (2005).

Mignot, E. et al . Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet. 68 , 686–699 (2001). Describes the strong association in NT1 with HLA-DQB1*06:02.

Tafti, M. et al . DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 37 , 19–25 (2014).

Ollila, H. M. et al . HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am. J. Hum. Genet. 96 , 136–146 (2015). By carefully adjusting for HLA class II effects, these authors discovered HLA class I associations in NT1.

Hor, H. et al . Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat. Genet. 42 , 786–789 (2010).

Molari, A. & Carcassi, C. HLA and narcolepsy-cataplexy in the Sardinian population. J. Sleep Res. 19 , 624–625 (2010).

Han, F. et al . HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. Sleep 37 , 1601–1608 (2014).

Han, F. et al . 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. PLoS Genet. 9 , e1003880 (2013).

Tafti, M. et al . Narcolepsy-associated HLA class I alleles implicate cell-mediated cytotoxicity. Sleep 39 , 581–587 (2016).

Hallmayer, J. et al . Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat. Genet. 41 , 708–711 (2009). First genome-wide association study of NT1 and the discovery of an association with a T cell receptor gene.

Faraco, J. et al . ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet. 9 , e1003270 (2013).

Kornum, B. R. et al . Common variants in P2RY11 are associated with narcolepsy. Nat. Genet. 43 , 66–71 (2011).

Toyoda, H. et al . A polymorphism in CCR1/CCR3 is associated with narcolepsy. Brain Behav. Immun. 49 , 148–155 (2015).

Hor, H. et al . A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. Am. J. Hum. Genet. 89 , 474–479 (2011).

Nohynek, H. et al . AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS ONE 7 , e33536 (2012). One of the first papers to describe the increased risk of narcolepsy following vaccination with Pandemrix.

Bardage, C. et al . Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden. BMJ 343 , d5956 (2011).

Heier, M. S. et al . Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. Sleep Med. 14 , 867–871 (2013).

O'Flanagan, D. et al . Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009–December 2010. Euro Surveill. 19 , 15–25 (2014).

Dauvilliers, Y. et al . Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain 136 , 2486–2496 (2013).

Montplaisir, J. et al . Risk of narcolepsy associated with inactivated adjuvanted (AS03) A/H1N1 (2009) pandemic influenza vaccine in Quebec. PLoS ONE 9 , e108489 (2014).

Vaarala, O. et al . Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for Pandemrix-associated narcolepsy risk. PLoS ONE 9 , e114361 (2014).

Picchioni, D., Hope, C. R. & Harsh, J. R. A case–control study of the environmental risk factors for narcolepsy. Neuroepidemiology 29 , 185–192 (2007).

Han, F. et al . Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann. Neurol. 70 , 410–417 (2011).

Han, F., Lin, L., Li, J., Dong, X. S. & Mignot, E. Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic. Ann. Neurol. 73 , 560 (2013).

Melen, K. et al . No serological evidence of influenza A H1N1pdm09 virus infection as a contributing factor in childhood narcolepsy after Pandemrix vaccination campaign in Finland. PLoS ONE 8 , e68402 (2013).

Aran, A. et al . Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 32 , 979–983 (2009).

Koepsell, T. D., Longstreth, W. T. & Ton, T. G. Medical exposures in youth and the frequency of narcolepsy with cataplexy: a population-based case–control study in genetically predisposed people. J. Sleep Res. 19 , 80–86 (2010).

Ambati, A. et al . Increased beta-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases. J. Intern. Med. 278 , 264–276 (2015).

Chang, C. Neonatal autoimmune diseases: a critical review. J. Autoimmun. 38 , J223–J238 (2012).

Lin, L. et al . The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98 , 365–376 (1999).

Chemelli, R. M. et al . Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98 , 437–451 (1999).

Nishino, S., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355 , 39–40 (2000).

Mahler, S. V., Moorman, D. E., Smith, R. J., James, M. H. & Aston-Jones, G. Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat. Neurosci. 17 , 1298–1303 (2014). Comprehensive review of the function of the hypocretin system.

Li, J., Hu, Z. & de Lecea, L. The hypocretins/orexins: integrators of multiple physiological functions. Br. J. Pharmacol. 171 , 332–350 (2014).

Blouin, A. M. et al . Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy. Neurology 65 , 1189–1192 (2005).

Crocker, A. et al . Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65 , 1184–1188 (2005).

Savvidou, A. et al . Hypocretin deficiency develops during onset of human narcolepsy with cataplexy. Sleep 36 , 147–148 (2013).

Martinez-Orozco, F. J., Vicario, J. L., De Andres, C., Fernandez-Arquero, M. & Peraita-Adrados, R. Comorbidity of narcolepsy type 1 with autoimmune diseases and other immunopathological disorders: a case–control study. J. Clin. Med. Res. 8 , 495–505 (2016).

Barateau, L. et al . Comorbidity between central disorders of hypersomnolence and immune-based disorders. Neurology 88 , 93–100 (2016).

Plazzi, G. et al . Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy. J. Neurol. 255 , 1549–1554 (2008).

Valko, P. O., Khatami, R., Baumann, C. R. & Bassetti, C. L. No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy. J. Neurol. 255 , 1900–1903 (2008).

Fronczek, R., Verschuuren, J. & Lammers, G. J. Response to intravenous immunoglobulins and placebo in a patient with narcolepsy with cataplexy. J. Neurol. 254 , 1607–1608 (2007).

Dauvilliers, Y., Abril, B., Mas, E., Michel, F. & Tafti, M. Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. Neurology 73 , 1333–1334 (2009).

Bergman, P. et al . Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proc. Natl Acad. Sci. USA 111 , E3735–E3744 (2014).

Black, J. L. III, Krahn, L. E., Pankratz, V. S. & Silber, M. Search for neuron-specific and nonneuron-specific antibodies in narcoleptic patients with and without HLA DQB1*0602. Sleep 25 , 719–723 (2002).

Black, J. L. III et al . Analysis of hypocretin (orexin) antibodies in patients with narcolepsy. Sleep 28 , 427–431 (2005).

Deloumeau, A. et al . Increased immune complexes of hypocretin autoantibodies in narcolepsy. PLoS ONE 5 , e13320 (2010).

Knudsen, S., Mikkelsen, J. D. & Jennum, P. Antibodies in narcolepsy-cataplexy patient serum bind to rat hypocretin neurons. Neuroreport 18 , 77–79 (2007).

Overeem, S. et al . Immunohistochemical screening for autoantibodies against lateral hypothalamic neurons in human narcolepsy. J. Neuroimmunol. 174 , 187–191 (2006).

Tanaka, S., Honda, Y., Inoue, Y. & Honda, M. Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy. Sleep 29 , 633–638 (2006).

van der Heide, A., Hegeman-Kleinn, I. M., Peeters, E., Lammers, G. J. & Fronczek, R. Immunohistochemical screening for antibodies in recent onset type 1 narcolepsy and after H1N1 vaccination. J. Neuroimmunol. 283 , 58–62 (2015).

Cvetkovic-Lopes, V. et al . Elevated tribbles homolog 2-specific antibody levels in narcolepsy patients. J. Clin. Invest. 120 , 713–719 (2010). Describes the presence of autoantibodies that target hypocretin neurons in blood samples from patients with NT1.

Kawashima, M. et al . Anti-tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy. Sleep 33 , 869–874 (2010).

Toyoda, H. et al . Anti-tribbles homolog 2 autoantibodies in Japanese patients with narcolepsy. Sleep 33 , 875–878 (2010).

Lind, A. et al . A/H1N1 antibodies and TRIB2 autoantibodies in narcolepsy patients diagnosed in conjunction with the Pandemrix vaccination campaign in Sweden 2009–2010. J. Autoimmun. 50 , 99–106 (2014).

Jego, S. et al . Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nat. Neurosci. 16 , 1637–1643 (2013).

Ahmed, S. S. et al . Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci. Transl Med. 7 , 294ra105 (2015).

Katzav, A. et al . Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice. J. Autoimmun. 45 , 24–30 (2013).

Dauvilliers, Y. et al . Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy. JAMA Neurol. 70 , 1305–1310 (2013).

Overeem, S. et al . Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology 62 , 138–140 (2004).

Kallweit, U., Bassetti, C. & Sallusto, F. Hypocretin-reactive CD4 + T cells in narcoleptic patients. Presented at the23rd Congress of the European Sleep Research Society abstr. 202 (2016).

Dauvilliers, Y. et al . Cerebrospinal fluid and serum cytokine profiles in narcolepsy with cataplexy: a case–control study. Brain Behav. Immun. 37 , 260–266 (2014).

Lecendreux, M. et al . Impact of cytokine in type 1 narcolepsy: role of pandemic H1N1 vaccination? J. Autoimmun. 60 , 20–31 (2015).

Kornum, B. R. et al . Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. Brain Behav. Immun. 49 , 54–58 (2015). Describes how it is not possible to detect markers of neuroinflammation in the CSF of patients with NT1 even within 1 month of disease onset.

John, J. et al . Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. Ann. Neurol. 74 , 786–793 (2013).

Valko, P. O. et al . Increase of histaminergic tuberomammillary neurons in narcolepsy. Ann. Neurol. 74 , 794–804 (2013). References 102 and 103 simultaneously describe that patients with NT1 have increased numbers of histaminergic neurons in the brain.

Shan, L., Dauvilliers, Y. & Siegel, J. M. Interactions of the histamine and hypocretin systems in CNS disorders. Nat. Rev. Neurol. 11 , 401–413 (2015).

Dauvilliers, Y. et al . Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions. Sleep 35 , 1359–1366 (2012).

Sakurai, T. et al . Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92 , 573–585 (1998).

Adamantidis, A. R., Zhang, F., Aravanis, A. M., Deisseroth, K. & de Lecea, L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450 , 420–424 (2007). Provides optogenetic proof that activation of the hypocretin neurons induces wakefulness.

Tsunematsu, T. et al . Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice. J. Neurosci. 31 , 10529–10539 (2011).

Broughton, R. et al . Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy: a laboratory perspective. Sleep 9 , 205–215 (1986).

Saper, C. B., Chou, T. C. & Scammell, T. E. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 24 , 726–731 (2001).

Sorensen, G. L., Knudsen, S. & Jennum, P. Sleep transitions in hypocretin-deficient narcolepsy. Sleep 36 , 1173–1177 (2013).

Pizza, F. et al . Nocturnal sleep dynamics identify narcolepsy type 1. Sleep 38 , 1277–1284 (2015).

Knudsen, S., Gammeltoft, S. & Jennum, P. J. Rapid eye movement sleep behaviour disorder in patients with narcolepsy is associated with hypocretin-1 deficiency. Brain 133 , 568–579 (2010).

Saper, C. B., Fuller, P. M., Pedersen, N. P., Lu, J. & Scammell, T. E. Sleep state switching. Neuron 68 , 1023–1042 (2010). Describes in detail how sleep-state switching is regulated and includes both wake-to-sleep transitions and NREM–REM-stage switches.

Overeem, S., Lammers, G. J. & van Dijk, J. G. Weak with laughter. Lancet 354 , 838 (1999).

Overeem, S., Lammers, G. J. & van Dijk, J. G. Cataplexy: ‘tonic immobility’ rather than ‘REM-sleep atonia’? Sleep Med. 2 , 471–477 (2002).

Schwartz, S. et al . Abnormal activity in hypothalamus and amygdala during humour processing in human narcolepsy with cataplexy. Brain 131 , 514–522 (2008).

Meletti, S. et al . The brain correlates of laugh and cataplexy in childhood narcolepsy. J. Neurosci. 35 , 11583–11594 (2015).

Kok, S. W. et al . Hypocretin deficiency in narcoleptic humans is associated with abdominal obesity. Obes. Res. 11 , 1147–1154 (2003).

Hara, J., Yanagisawa, M. & Sakurai, T. Difference in obesity phenotype between orexin-knockout mice and orexin neuron-deficient mice with same genetic background and environmental conditions. Neurosci. Lett. 380 , 239–242 (2005).

van Holst, R. J. et al . Aberrant food choices after satiation in human orexin-deficient narcolepsy type 1. Sleep 39 , 1951–1959 (2016).

Fortuyn, H. A. et al . High prevalence of eating disorders in narcolepsy with cataplexy: a case–control study. Sleep 31 , 335–341 (2008).

Baimel, C. et al . Orexin/hypocretin role in reward: implications for opioid and other addictions. Br. J. Pharmacol. 172 , 334–348 (2015).

Johns, M. W. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 14 , 540–545 (1991).

Nishiyama, T. et al . Criterion validity of the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale for the diagnosis of sleep disorders. Sleep Med. 15 , 422–429 (2014).

Kushida, C. A. et al . Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep 28 , 499–521 (2005).

Morgenthaler, T. et al . Practice parameters for the use of actigraphy in the assessment of sleep and sleep disorders: an update for 2007. Sleep 30 , 519–529 (2007).

Jennum, P., Ibsen, R., Knudsen, S. & Kjellberg, J. Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study. Sleep 36 , 835–840 (2013).

Plazzi, G., Khatami, R., Serra, L., Pizza, F. & Bassetti, C. L. Pseudocataplexy in narcolepsy with cataplexy. Sleep Med. 11 , 591–594 (2010).

Vassalli, A. et al . Electroencephalogram paroxysmal theta characterizes cataplexy in mice and children. Brain 136 , 1592–1608 (2013).

Littner, M. R. et al . Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 28 , 113–121 (2005).

Vogel, G. Studies in psychophysiology of dreams. Arch. Gen. Psychiatry 2 , 421–428 (1960).

Dement, W., Rechtschaffen, A. & Gulevich, G. The nature of the narcoleptic sleep attack. Neurology 16 , 18–18 (1966).

Trotti, L. M., Staab, B. A. & Rye, D. B. Test–retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J. Clin. Sleep Med. 9 , 789–795 (2013).

Andlauer, O. et al . Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol. 70 , 891–902 (2013).

Mignot, E. Correlates of sleep-onset REM periods during the multiple sleep latency test in community adults. Brain 129 , 1609–1623 (2006).

Marti, I., Valko, P. O., Khatami, R., Bassetti, C. L. & Baumann, C. R. Multiple sleep latency measures in narcolepsy and behaviourally induced insufficient sleep syndrome. Sleep Med. 10 , 1146–1150 (2009).

Drakatos, P. et al . Sleep stage sequence analysis of sleep onset REM periods in the hypersomnias. J. Neurol. Neurosurg. Psychiatry 84 , 223–227 (2013).

Bourgin, P., Zeitzer, J. M. & Mignot, E. CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol. 7 , 649–662 (2008). Reports on the levels of hypocretin 1 in the CSF in a large range of neurological disorders.

Hirtz, C. et al . From radioimmunoassay to mass spectrometry: a new method to quantify orexin-A (hypocretin-1) in cerebrospinal fluid. Sci. Rep. 6 , 25162 (2016).

Billiard, M. et al . Modafinil: a double-blind multicentric study. Sleep 17 , S107–S112 (1994).

Broughton, R. J. et al . Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 49 , 444–451 (1997). References 141 and 142 describe the efficacy of modafinil for treating excessive daytime sleepiness in narcolepsy.

Volkow, N. D. et al . Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA 301 , 1148–1154 (2009).

Mitler, M. M., Harsh, J., Hirshkowitz, M. & Guilleminault, C. Long-term efficacy and safety of modafinil (PROVIGIL ® ) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Med. 1 , 231–243 (2000).

Mignot, E. J. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics 9 , 739–752 (2012).

Aran, A. et al . Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. Sleep 33 , 1457–1464 (2010).

Mitler, M. M., Aldrich, M. S., Koob, G. F. & Zarcone, V. P. Narcolepsy and its treatment with stimulants. ASDA standards of practice. Sleep 17 , 352–371 (1994).

Mitler, M. M., Shafor, R., Hajdukovich, R., Timms, R. M. & Browman, C. P. Treatment of narcolepsy: objective studies on methylphenidate, pemoline, and protriptyline. Sleep 9 , 260–264 (1986).

Auger, R. R. et al . Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case–control study. Sleep 28 , 667–672 (2005).

Mantyh, W. G., Auger, R. R., Morgenthaler, T. I., Silber, M. H. & Moore, W. R. Examining the frequency of stimulant misuse among patients with primary disorders of hypersomnolence: a retrospective cohort study. J. Clin. Sleep Med. 12 , 659–662 (2016).

Maitre, M. The gamma-hydroxybutyrate signalling system in brain: organization and functional implications. Prog. Neurobiol. 51 , 337–361 (1997).

Huang, Y. S. & Guilleminault, C. Narcolepsy: action of two gamma-aminobutyric acid type B agonists, baclofen and sodium oxybate. Pediatr. Neurol. 41 , 9–16 (2009).

Boscolo-Berto, R. et al . Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): a systematic review and meta-analysis of randomized controlled trials. Sleep Med. Rev. 16 , 431–443 (2012). Reviews the available evidence of the efficacy of sodium oxybate as a treatment for narcolepsy.

Black, J., Pardi, D., Hornfeldt, C. S. & Inhaber, N. The nightly administration of sodium oxybate results in significant reduction in the nocturnal sleep disruption of patients with narcolepsy. Sleep Med. 10 , 829–835 (2009).

Black, J. & Houghton, W. C. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 29 , 939–946 (2006).

Lammers, G. J. et al . Gammahydroxybutyrate and narcolepsy: a double-blind placebo-controlled study. Sleep 16 , 216–220 (1993).

van Schie, M. K. et al . Improved vigilance after sodium oxybate treatment in narcolepsy: a comparison between in-field and in-laboratory measurements. J. Sleep Res. 25 , 486–496 (2016).

Bogan, R. K., Roth, T., Schwartz, J. & Miloslavsky, M. Time to response with sodium oxybate for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. J. Clin. Sleep Med. 11 , 427–432 (2015).

Mamelak, M. et al . A 12-week open-label, multicenter study evaluating the safety and patient-reported efficacy of sodium oxybate in patients with narcolepsy and cataplexy. Sleep Med. 16 , 52–58 (2015).

Wang, Y. G., Swick, T. J., Carter, L. P., Thorpy, M. J. & Benowitz, N. L. Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion. J. Clin. Sleep Med. 5 , 365–371 (2009).

[No authors listed.] The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J. Toxicol. Clin. Toxicol. 41 , 131–135 (2003).

Moller, L. R. & Ostergaard, J. R. Treatment with venlafaxine in six cases of children with narcolepsy and with cataplexy and hypnagogic hallucinations. J. Child Adolesc. Psychopharmacol. 19 , 197–201 (2009).

Broderick, M. & Guilleminault, C. Rebound cataplexy after withdrawal from antidepressants. Sleep Med. 10 , 403–404 (2009).

Vignatelli, L., D'Alessandro, R. & Candelise, L. Antidepressant drugs for narcolepsy. Cochrane Database Syst. Rev. 1 , CD003724 (2008).

Zhang, S. et al . Clinical effect of atomoxetine hydrochloride in 66 children with narcolepsy. Zhonghua Er Ke Za Zhi 53 , 760–764 (in Chinese) (2015).

Izzi, F. et al . Effective treatment of narcolepsy-cataplexy with duloxetine: a report of three cases. Sleep Med. 10 , 153–154 (2009).

Mansukhani, M. P. & Kotagal, S. Sodium oxybate in the treatment of childhood narcolepsy-cataplexy: a retrospective study. Sleep Med. 13 , 606–610 (2012).

Lecendreux, M. et al . Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy. J. Sleep Res. 21 , 481–483 (2012).

Thorpy, M., Zhao, C. G. & Dauvilliers, Y. Management of narcolepsy during pregnancy. Sleep Med. 14 , 367–376 (2013).

Roth, T. et al . Disrupted nighttime sleep in narcolepsy. J. Clin. Sleep Med. 9 , 955–965 (2013).

Naumann, A., Bellebaum, C. & Daum, I. Cognitive deficits in narcolepsy. J. Sleep Res. 15 , 329–338 (2006).

Van Schie, M. K. M. et al . Sustained attention to response task (SART) shows impaired vigilance in a spectrum of disorders of excessive daytime sleepiness. J. Sleep Res. 21 , 390–395 (2012).

Mullington, J. & Broughton, R. Scheduled naps in the management of daytime sleepiness in narcolepsy-cataplexy. Sleep 16 , 444–456 (1993).

Rogers, A. E., Aldrich, M. S. & Lin, X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep 24 , 385–391 (2001).

Khatami, R. et al . Challenging sleep homeostasis in narcolepsy-cataplexy: implications for non-REM and REM sleep regulation. Sleep 31 , 859–867 (2008).

Kapella, M. C. et al . Health-related stigma as a determinant of functioning in young adults with narcolepsy. PLoS ONE 10 , e0122478 (2015).

Ohayon, M. M. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 14 , 488–492 (2013).

Jennum, P., Ibsen, R., Petersen, E. R., Knudsen, S. & Kjellberg, J. Health, social, and economic consequences of narcolepsy: a controlled national study evaluating the societal effect on patients and their partners. Sleep Med. 13 , 1086–1093 (2012).

Dauvilliers, Y. et al . Psychological health in central hypersomnias: the French Harmony study. J. Neurol. Neurosurg. Psychiatry 80 , 636–641 (2009).

Dodel, R. et al . The socioeconomic impact of narcolepsy. Sleep 27 , 1123–1128 (2004).

Rieger, M., Mayer, G. & Gauggel, S. Attention deficits in patients with narcolepsy. Sleep 26 , 36–43 (2003).

Thomann, J., Baumann, C. R., Landolt, H.-P. & Werth, E. Psychomotor vigilance task demonstrates impaired vigilance in disorders with excessive daytime sleepiness. J. Clin. Sleep Med. 10 , 1019–1024 (2014).

Philip, P. et al . Maintenance of Wakefulness Test scores and driving performance in sleep disorder patients and controls. Int. J. Psychophysiol. 89 , 195–202 (2013).

Pizza, F. et al . Car crashes and central disorders of hypersomnolence: a French study. PLoS ONE 10 , e0129386 (2015).

Hegmann, K. T., Andersson, G. B., Greenberg, M. I., Phillips, B. & Rizzo, M. FMCSA's medical review board: five years of progress in commercial driver medical examinations. J. Occup. Environ. Med. 54 , 424–430 (2012).

Philip, P. et al . Modafinil improves real driving performance in patients with hypersomnia: a randomized double-blind placebo-controlled crossover clinical trial. Sleep 37 , 483–487 (2014).

Pizza, F., Tartarotti, S., Poryazova, R., Baumann, C. R. & Bassetti, C. L. Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients. Eur. Neurol. 70 , 22–26 (2013).

Sansa, G., Iranzo, A. & Santamaria, J. Obstructive sleep apnea in narcolepsy. Sleep Med. 11 , 93–95 (2010).

Donjacour, C. E. et al . Glucose and fat metabolism in narcolepsy and the effect of sodium oxybate: a hyperinsulinemic-euglycemic clamp study. Sleep 37 , 795–801 (2014).

Huang, Y. S., Guilleminault, C., Chen, C. H., Lai, P. C. & Hwang, F. M. Narcolepsy-cataplexy and schizophrenia in adolescents. Sleep Med. 15 , 15–22 (2014).

Szakacs, A., Hallbook, T., Tideman, P., Darin, N. & Wentz, E. Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccination. Sleep 38 , 615–621 (2015). Investigates the psychiatric and cognitive problems in children with NT1.

Antelmi, E., Vandi, S., Pizza, F., Liguori, R. & Plazzi, G. Parkinsonian tremor persisting during cataplexy. Sleep Med. 17 , 174–176 (2016).

Economou, N. T., Manconi, M., Ghika, J., Raimondi, M. & Bassetti, C. L. Development of Parkinson and Alzheimer diseases in two cases of narcolepsy-cataplexy. Eur. Neurol. 67 , 48–50 (2012).

Sorensen, G. L. et al . Attenuated heart rate response is associated with hypocretin deficiency in patients with narcolepsy. Sleep 36 , 91–98 (2013).

van der Meijden, W. P. et al . Time- and state-dependent analysis of autonomic control in narcolepsy: higher heart rate with normal heart rate variability independent of sleep fragmentation. J. Sleep Res. 24 , 206–214 (2015).

Ohayon, M. M. et al . Increased mortality in narcolepsy. Sleep 37 , 439–444 (2014).

Jennum, P., Mayer, G., Ju, Y. E. & Postuma, R. Morbidities in rapid eye movement sleep behavior disorder. Sleep Med. 14 , 782–787 (2013).

Tesoriero, C. et al . H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice. Proc. Natl Acad. Sci. USA 113 , E368–E377 (2016).

Nishino, S. & Mignot, E. Article reviewed: plasma orexin-A is lower in patients with narcolepsy. Sleep Med. 2 , 377–378 (2002).

Pizza, F. et al . Daytime continuous polysomnography predicts MSLT results in hypersomnias of central origin. J. Sleep Res. 22 , 32–40 (2013).

Lin, J. S. et al . An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: studies in orexin −/− mice and patients. Neurobiol. Dis. 30 , 74–83 (2008).

Dauvilliers, Y. et al . Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 12 , 1068–1075 (2013).

Deadwyler, S. A., Porrino, L., Siegel, J. M. & Hampson, R. E. Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J. Neurosci. 27 , 14239–14247 (2007).

Weinhold, S. L. et al . The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav. Brain Res. 262 , 8–13 (2014).

Nagahara, T. et al . Design and synthesis of non-peptide, selective orexin receptor 2 agonists. J. Med. Chem. 58 , 7931–7937 (2015).

Hasan, S. et al . How to keep the brain awake? The complex molecular pharmacogenetics of wake promotion. Neuropsychopharmacology 34 , 1625–1640 (2009).

Ruoff, C. et al . Effect of oral JZP-110 (ADX-N05) on wakefulness and sleepiness in adults with narcolepsy: a phase 2b study. Sleep 39 , 1379–1387 (2016).

Bogan, R. K. et al . Effect of oral JZP-110 (ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy. Sleep Med. 16 , 1102–1108 (2015).

Hara, J. et al . Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30 , 345–354 (2001).

Tabuchi, S. et al . Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J. Neurosci. 34 , 6495–6509 (2014).

Bernard-Valnet, R. et al . CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice. Proc. Natl Acad. Sci. USA 113 , 10956–10961 (2016).

Rose, N. R. & Bona, C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunol. Today 14 , 426–430 (1993).

Mignot, E. Why we sleep: the temporal organization of recovery. PLoS Biol. 6 , e106 (2008).

Barateau, L., Lopez, R. & Dauvilliers, Y. Treatment options for narcolepsy. CNS Drugs 30 , 369–379 (2016).

Lavie, P. & Peled, R. Narcolepsy is a rare disease in Israel. Sleep 10 , 608–609 (1987).

Darwish, M., Kirby, M., Hellriegel, E. T. & Robertson, P. Jr. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies. Clin. Drug Investig. 29 , 613–623 (2009).

Scharf, M. B., Lai, A. A., Branigan, B., Stover, R. & Berkowitz, D. B. Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients. Sleep 21 , 507–514 (1998).

Download references

Acknowledgements

B.R.K. has received funding from the Lundbeck Foundation. S.K. has received funding from the Norwegian Ministry of Health and Care Services. H.M.O. has received funding from the Finnish Cultural Foundation, Jalmari and Rauha Ahokas Foundation, Sigrid Juselius Foundation, Emil Aaltonen Foundation, Päivikki and Sakari Sohlberg Foundation, Orion Farmos Research Foundation and Instrumentarium Science Foundation.

Author information

Authors and affiliations.

Department of Clinical Biochemistry, Molecular Sleep Laboratory, Rigshospitalet, Forskerparken, Nordre Ringvej 69, Glostrup, 2600, Denmark

Birgitte R. Kornum

Department of Clinical Neurophysiology, Danish Center for Sleep Medicine, Rigshospitalet, Glostrup, Denmark

Birgitte R. Kornum & Poul J. Jennum

Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Oslo University Hospital, Oslo, Norway

Stine Knudsen

Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences, Stanford University, Stanford, California, USA

Hanna M. Ollila

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

Fabio Pizza

IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, AUSL di Bologna, Bologna, Italy

Department of Neurology, Sleep Unit, Narcolepsy Reference Center, Gui de Chauliac Hospital, Montpellier, INSERM 1061, France

Yves Dauvilliers

Sleep Medicine Center Kempenhaeghe, Heeze, The Netherlands

Sebastiaan Overeem

Department of Industrial Design, Eindhoven University of Technology, Eindhoven, The Netherlands

You can also search for this author in PubMed   Google Scholar

Contributions

Introduction (B.R.K.); Epidemiology (H.M.O.); Mechanisms/pathophysiology (S.O., Y.D. and B.R.K.); Diagnosis, screening and prevention (F.P.); Management (S.K., Y.D. and S.O.); Quality of life (S.K. and P.J.J.); Outlook (B.R.K., F.P. and Y.D.); Overview of Primer (B.R.K.).

Corresponding author

Correspondence to Birgitte R. Kornum .

Ethics declarations

Competing interests.

B.R.K. has received an unrestricted investigator-driven project grant from UCB Pharma. H.M.O. has acted as a consultant for Jazz Pharmaceuticals. P.J.J. has received funds from UCB Pharma. Y.D. has received funds for seminars, board engagements and travel to conferences by UCB Pharma, Jazz Pharmaceuticals, Theranexus, GlaxoSmithKline, Actelion and BioProject. S.O. has received an unrestricted investigator-driven project grant from UCB Pharma and conference travel support from UCB Pharma, Novartis and Boehringer Ingelheim. S.K. and F.P. declare no competing interests.

PowerPoint slides

Powerpoint slide for fig. 1, powerpoint slide for fig. 2, powerpoint slide for fig. 3, powerpoint slide for fig. 4, powerpoint slide for fig. 5, powerpoint slide for fig. 6, rights and permissions.

Reprints and permissions

About this article

Cite this article.

Kornum, B., Knudsen, S., Ollila, H. et al. Narcolepsy. Nat Rev Dis Primers 3 , 16100 (2017). https://doi.org/10.1038/nrdp.2016.100

Download citation

Published : 09 February 2017

DOI : https://doi.org/10.1038/nrdp.2016.100

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Genetics of circadian rhythms and sleep in human health and disease.

• Jacqueline M. Lane
• Jingyi Qian
• Richa Saxena

Nature Reviews Genetics (2023)

Alexithymia, impulsiveness, emotion, and eating dyscontrol: similarities and differences between narcolepsy type 1 and type 2

• Chiara Del Bianco
• Martina Ulivi
• Francesca Izzi

Sleep and Biological Rhythms (2023)

Evidence of Accidental Dosing Errors with Immediate-Release Sodium Oxybate: Data from the US Food and Drug Administration Adverse Event Reporting System

• Jennifer Gudeman
• Danielle Burroughs

Drugs - Real World Outcomes (2023)

Harriet Tubman’s Hypersomnia: Insights from Historical and Medical Perspectives

• Evan A. Balmuth
• Thomas E. Scammell

Journal of General Internal Medicine (2023)

Serum metabolomics study of narcolepsy type 1 based on ultra-performance liquid chromatography–tandem mass spectrometry

• Qingqing Zhan

Amino Acids (2023)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

• See us on facebook
• See us on twitter
• See us on youtube
• See us on linkedin
• See us on instagram

Stanford researcher shows once-nightly narcolepsy drug is safe, effective

A phase 3 study has found that an extended-release version of sodium oxybate reduces daytime sleepiness and attacks of muscle weakness in narcolepsy patients.

September 8, 2021 - By Janelle Weaver

A Stanford study shows that a new formulation of a narcolepsy medication is effective without a middle-of-the-night dose.  ALPA PROD/Shutterstock.com

A new version of a narcolepsy drug that patients take once at bedtime — rather than at bedtime and again in the middle of the night — safely and effectively improved symptoms in a trial led by a researcher at Stanford Medicine .

The drug the researchers were investigating, ON-SXB, is an extended-release version of sodium oxybate, which requires twice-nightly dosing. Sodium oxybate is approved by the Food and Drug Administration for the treatment of multiple narcolepsy symptoms, including excessive daytime sleepiness and cataplexy — sudden muscle weakness while awake.

In the trial, ON-SXB decreased cataplexy attacks and daytime sleepiness more effectively than a placebo, while increasing clinicians’ ratings of the overall condition of study participants. Its safety profile was favorable, with side effects that were similar to those caused by the twice-nightly version of sodium oxybate. Eliminating the need for a second dose at night, ON-SXB could help patients adhere to the medication regimen, reduce the risk of falls leading to injury, and improve nocturnal sleep and overall quality of life.

“Sodium oxybate has largely become a first-line treatment for patients with narcolepsy,” said Clete Kushida , MD, PhD, a professor of psychiatry and behavioral sciences. “Clinicians can be confident that a single bedtime dose of sodium oxybate has demonstrated efficacy for both objective and subjective symptoms of narcolepsy.”

The study was published Aug. 6 in Sleep. Kushida is the lead author.

Clete Kushida

Seeking sound sleep

Narcolepsy is a chronic neurological disorder that affects between 135,000 and 200,000 people in the U.S. In addition to excessive daytime sleepiness and cataplexy, symptoms include disrupted nighttime sleep, sleep paralysis, and hallucinations when falling asleep or waking up. All patients experience excessive daytime sleepiness, which can manifest as sleep attacks that last several seconds or minutes and can occur while talking, eating or driving.

Cataplexy, which is another common symptom, is often triggered by strong emotions and sometimes causes falls. This collection of features can interfere with psychological and cognitive function and development; it can also severely impede daily life, including school attendance, employment and social activities.   

Sodium oxybate is effective at treating multiple narcolepsy symptoms, including disrupted nighttime sleep. But because its half-life is approximately 30 minutes to 1 hour, a second dose is required 2 ½  to 4 hours after the first dose. Waking in the middle of the night to take the medication can be highly disruptive, especially considering that patients typically already experience fragmented sleep and poor sleep quality.

A study in Europe showed that 27% of patients with narcolepsy did not take sodium oxybate on the recommended time schedule. When patients need to take medications more than once daily, they tend to miss doses: This problem has been seen with other conditions, including depression, schizophrenia, epilepsy, Type 2 diabetes, cardiovascular disease, chronic obstructive pulmonary disease and HIV.

“A medication that is taken twice daily — in the morning and evening — is more challenging than a once-daily medication, but it’s even more problematic for a chronic medication requiring middle-of-the-night awakening,” Kushida said. “Although the labeling advises patients to remain in bed to take the second dose, falls leading to injury and, in some cases, hospitalization have been reported when patients rise from bed.”

No-awakening alternative

The trial was conducted from November 2016 to March 2020 at 71 centers in the United States, Australia, Canada and Europe. In total, 222 narcolepsy patients, ages 16 or older, were randomly assigned to take ON-SXB, in varying amounts, or a placebo.

Compared with placebo, participants on the three highest doses of ON-SXB had significantly less daytime sleepiness, a decrease in weekly cataplexy attacks, lower self-rated sleepiness in everyday situations, and higher overall condition scores from their clinicians. For example, 72% of participants taking the highest dose of ON-SXB were considered much or very much improved, compared with 31.6% in the placebo group.

The side effects of ON-SXB are similar to those of the twice-nightly version of sodium oxybate and include nausea, headache, vomiting, dizziness, involuntary urination and decreased appetite. But with ON-SXB, rates of headaches, nausea and dizziness were lower.

ON-SXB is under review at the FDA for the treatment of excessive daytime sleepiness and cataplexy in adults with narcolepsy. It has received orphan drug designation from the FDA because it may be clinically superior to the twice-nightly formulation of sodium oxybate already approved for the same condition. Orphan status is provided to drugs for the treatment, diagnosis or prevention of rare diseases that either affect fewer than 200,000 people in the United States, or are otherwise not expected to recover the development and marketing costs. Drug companies receive financial benefits for developing orphan drugs.

 “If approved, ON-SXB may be a major advance for patients experiencing the burdensome symptoms of narcolepsy and for physicians who manage their patients with this chronic, incapacitating sleep disorder,” Kushida said.

Researchers from the University of Toronto; Henry Ford Health System; Montefiore Medical Center; Sleep Management Institute; Florida Pediatric Research Institute; Neurotrials Research Inc.; Ohio Sleep Medicine and Neuroscience Institute; Avadel Pharmaceuticals; and Gui-de-Chauliac Hospital also contributed to the study.

The work was supported by Avadel Ireland.

• Janelle Weaver

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

Artificial intelligence

Exploring ways AI is applied to health care

What is narcolepsy?

Narcolepsy is a chronic neurological disorder that affects the brain's ability to control sleep-wake cycles. People with narcolepsy may feel rested after waking, but then feel very sleepy throughout much of the day. Many individuals with narcolepsy also experience uneven and interrupted sleep that can involve waking up frequently during the night.

Narcolepsy can greatly affect daily activities. People may unwillingly fall asleep even if they are in the middle of an activity like driving, eating, or talking. Other symptoms may include sudden muscle weakness while awake that makes a person go limp or unable to move (cataplexy), vivid dream-like images or hallucinations, and total paralysis just before falling asleep or just after waking up (sleep paralysis).

In a normal sleep cycle, a person enters rapid eye movement (REM) sleep after about 60 to 90 minutes. Dreams occur during REM sleep, and the brain keeps muscles limp during this sleep stage, which prevents people from acting out their dreams. People with narcolepsy frequently enter REM sleep rapidly, within 15 minutes of falling asleep. Also, the muscle weakness or dream activity of REM sleep can occur during wakefulness or be absent during sleep. This helps explain some symptoms of narcolepsy.

If left undiagnosed or untreated, narcolepsy can interfere with psychological, social, and cognitive function and development and can inhibit academic, work, and social activities.

Narcolepsy is a lifelong problem, but it does not usually worsen as the person ages. Symptoms can partially improve over time, but they will never disappear completely. The most typical symptoms are:

• Excessive daytime sleepiness (EDS)—All individuals with narcolepsy have EDS, and it is often the most obvious symptom. EDS is characterized by persistent sleepiness, regardless of how much sleep an individual gets at night. However, sleepiness in narcolepsy is more like a “sleep attack,” where an overwhelming sense of sleepiness comes on quickly. In between sleep attacks, individuals have normal levels of alertness, particularly if doing activities that keep their attention.
• Cataplexy—This sudden loss of muscle tone while a person is awake leads to weakness and a loss of voluntary muscle control. It is often triggered by sudden, strong emotions such as laughter, fear, anger, stress, or excitement. The symptoms of cataplexy may appear weeks or even years after the onset of EDS. Some people may only have one or two attacks in a lifetime, while others may experience many attacks a day. In about 10 percent of cases of narcolepsy, cataplexy is the first symptom to appear and can be misdiagnosed as a seizure disorder. Attacks may be mild and involve only a momentary sense of minor weakness in a limited number of muscles, such as a slight drooping of the eyelids. The most severe attacks result in a total body collapse during which individuals are unable to move, speak, or keep their eyes open. But even during the most severe episodes, people remain fully conscious, a characteristic that distinguishes cataplexy from fainting or seizure disorders. The loss of muscle tone during cataplexy resembles paralysis of muscle activity that naturally occurs during REM sleep. Episodes last a few minutes at most and resolve almost instantly on their own. While scary, the episodes are not dangerous as long as the individual finds a safe place in which to collapse.
• Sleep paralysis—The temporary inability to move or speak while falling asleep or waking up usually lasts only a few seconds or minutes and is similar to REM-induced inhibitions of voluntary muscle activity. Sleep paralysis resembles cataplexy except it occurs at the edges of sleep. As with cataplexy, people remain fully conscious. Even when severe, cataplexy and sleep paralysis do not result in permanent dysfunction—after episodes end, people rapidly recover their full capacity to move and speak.
• Hallucinations—Very vivid and sometimes frightening images can accompany sleep paralysis and usually occur when people are falling asleep or waking up. Most often the content is primarily visual, but any of the other senses can be involved.

Additional symptoms include:

• Fragmented sleep and insomnia—While individuals with narcolepsy are very sleepy during the day, they usually also experience difficulties staying asleep at night. Sleep may be disrupted by insomnia, vivid dreaming, sleep apnea, acting out while dreaming, and periodic leg movements.
• Automatic behaviors—Individuals with narcolepsy may experience temporary sleep episodes that can be very brief, lasting no more than seconds at a time. A person falls asleep during an activity (e.g., eating, talking) and automatically continues the activity for a few seconds or minutes without conscious awareness of what they are doing. This happens most often while people are engaged in habitual activities such as typing or driving. They cannot recall their actions, and their performance is almost always impaired. Their handwriting may, for example, degenerate into an illegible scrawl, or they may store items in bizarre locations and then forget where they placed them. If an episode occurs while driving, individuals may get lost or have an accident. People tend to awaken from these episodes feeling refreshed, finding that their drowsiness and fatigue has temporarily subsided.

There are two major types of narcolepsy:

• Type 1 narcolepsy (previously known as narcolepsy with cataplexy)—This diagnosis is based on the individual either having low levels of a brain hormone (hypocretin) or reporting cataplexy and having excessive daytime sleepiness on a special nap test.
• Type 2 narcolepsy (previously known as narcolepsy without cataplexy)—People with this condition experience excessive daytime sleepiness but usually do not have muscle weakness triggered by emotions. They usually also have less severe symptoms and have normal levels of the brain hormone hypocretin.

A condition known as secondary narcolepsy can result from an injury to the hypothalamus, a region deep in the brain that helps regulate sleep. In addition to experiencing the typical symptoms of narcolepsy, individuals may also have severe neurological problems and sleep for long periods (more than 10 hours) each night.

Who is more likely to get narcolepsy?

Narcolepsy affects both males and females equally. Symptoms often start in childhood, adolescence, or young adulthood (ages 7 to 25), but can occur at any time in life. Since people with narcolepsy are often misdiagnosed with other conditions, such as psychiatric disorders or emotional problems, it can take years for someone to get the proper diagnosis.

Narcolepsy may have several causes. Nearly all people with narcolepsy who have cataplexy have extremely low levels of the naturally occurring chemical hypocretin, which promotes wakefulness and regulates REM sleep. Hypocretin levels are usually normal in people who have narcolepsy without cataplexy.

Although the cause of narcolepsy is not completely understood, current research suggests that narcolepsy may be the result of a combination of factors working together to cause a lack of hypocretin. These factors include:

• Autoimmune disorders—When cataplexy is present, the cause is most often the loss of brain cells that produce hypocretin. Although the reason for this cell loss is unknown, it appears to be linked to abnormalities in the immune system. Autoimmune disorders occur when the body's immune system turns against itself and mistakenly attacks healthy cells or tissue. Researchers believe that in individuals with narcolepsy, the body's immune system selectively attacks the hypocretin-containing brain cells because of a combination of genetic and environmental factors.
• Family history—Most cases of narcolepsy are sporadic, meaning the disorder occurs in individuals with no known family history. However, clusters in families sometimes occur—up to 10 percent of individuals diagnosed with narcolepsy with cataplexy report having a close relative with similar symptoms.
• Brain injuries—Rarely, narcolepsy results from traumatic injury to parts of the brain that regulate wakefulness and REM sleep or from tumors and other diseases in the same regions.

In the past few decades, scientists have made considerable progress in understanding narcolepsy and identifying genes strongly associated with the disorder. Groups of neurons in several parts of the brain interact to control sleep, and the activity of these neurons is controlled by a large number of genes. The loss of hypocretin-producing neurons in the hypothalamus is the primary cause of type 1 narcolepsy. These neurons are important for stabilizing sleep and wake states.

The human leukocyte antigen (HLA) system of genes  plays an important role in regulating the immune system. This gene family provides instructions for making a group of related proteins called the HLA complex, which helps the immune system distinguish between good proteins from an individual's own body and bad ones made by foreign invaders like viruses and bacteria.

One of the genes in this family is HLA-DQB1. A variation in this gene, called HLA-DQB1*06:02, increases the chance of developing narcolepsy, particularly the type of narcolepsy with cataplexy and a loss of hypocretins (also known as orexins). HLA-DQB1*06:02 and other HLA gene variations may increase susceptibility to an immune attack on hypocretin neurons, causing these cells to die. Most people with narcolepsy have this gene variation and may also have specific versions of closely related HLA genes.

However, it is important to note that these gene variations are common in the general population and only a small portion of the people with the HLA-DQB1*06:02 variation will develop narcolepsy. This indicates that other genetic and environmental factors are important in determining if an individual will develop the disorder.

Narcolepsy follows a seasonal pattern and is more likely to develop in the spring and early summer after the winter season, a time when people are more likely to get sick. By studying people soon after they develop the disorder, scientists have discovered that individuals with narcolepsy have high levels of anti-streptolysin O antibodies, indicating an immune response to a recent bacterial infection such as strep throat. Also, the H1N1 influenza epidemic in 2009 resulted in a large increase in the number of new cases of narcolepsy. Together, this suggests that individuals with the HLA-DQB1*06:02 variation are at risk for developing narcolepsy after they are exposed to a specific trigger, like certain infections that trick the immune system to attack the body.

How is narcolepsy diagnosed and treated?

Diagnosing narcolepsy

A clinical examination and detailed medical history are essential for diagnosis and treatment of narcolepsy. Individuals may be asked by their doctor to keep a sleep journal noting the times of sleep and symptoms over a one- to two-week period. A physical exam can rule out or identify other neurological conditions that may be causing the symptoms.

Two specialized tests, which can be performed in a sleep disorders clinic, are required to establish a diagnosis of narcolepsy:

• Polysomnogram (PSG or sleep study)—The PSG is an overnight recording of brain and muscle activity, breathing, and eye movements. A PSG can help reveal whether REM sleep occurs early in the sleep cycle and if an individual's symptoms result from another condition such as sleep apnea.
• Multiple sleep latency test (MSLT)—The MSLT assesses daytime sleepiness by measuring how quickly a person falls asleep and whether they enter REM sleep.

Occasionally, it may be helpful to measure the level of hypocretin in the fluid that surrounds the brain and spinal cord. To perform this test, a doctor will withdraw a sample of the cerebrospinal fluid using a lumbar puncture (also called a spinal tap) and measure the level of hypocretin-1.

Treating narcolepsy

Although there is no cure for narcolepsy, some of the symptoms can be treated with medicines and lifestyle changes.

Medications

• Modafinil—The initial line of treatment is usually a central nervous system stimulant such as modafinil. Modafinil is usually prescribed first because it is less addictive and has fewer side effects than older stimulants. For most people these drugs are generally effective at reducing daytime drowsiness and improving alertness.
• Amphetamine-like stimulants—In cases where modafinil is not effective, doctors may prescribe amphetamine-like stimulants such as methylphenidate to alleviate EDS. However, these medications must be carefully monitored because they can have side effects.
• Antidepressants—Two classes of antidepressant drugs have proven effective in controlling cataplexy in many individuals: tricyclics (including imipramine, desipramine, clomipramine, and protriptyline) and selective serotonin and noradrenergic reuptake inhibitors (including venlafaxine, fluoxetine, and atomoxetine).
• Sodium oxybate—Sodium oxybate (also known as gamma hydroxybutyrate or GHB) has been approved by the U.S. Food and Drug Administration (FDA) to treat cataplexy and excessive daytime sleepiness in individuals with narcolepsy. Due to safety concerns associated with the use of this drug, the distribution of sodium oxybate is tightly restricted.
• Histamine 3 receptor antagonist/inverse agonist—Pitolisant was recently approved by FDA as the only non-scheduled product for treating excessive daytime sleepiness or cataplexy in adults with narcolepsy. Pitolisant, which has been commercially available in the U.S. since 2019, is thought to increase histamine levels in the brain. The most common adverse reactions to Pitolisant are insomnia, nausea, and anxiety.

Lifestyle changes

Drug therapy should accompany various lifestyle changes. Remembering the following seven tips may be helpful:

• Take short naps. Many individuals take short, regularly scheduled naps at times when they tend to feel sleepiest.
• Maintain a regular sleep schedule. Going to bed and waking up at the same time every day, even on the weekends, can help people sleep better.
• Avoid caffeine or alcohol before bed. Individuals should avoid alcohol and caffeine for several hours before bedtime.
• Avoid smoking, especially at night.
• Exercise daily. Exercising for at least 20 minutes per day at least four or five hours before bedtime also improves sleep quality and can help people with narcolepsy avoid gaining excess weight.
• Avoid large, heavy meals right before bedtime. Eating very close to bedtime can make it harder to sleep.
• Relax before bed. Relaxing activities such as a warm bath before bedtime can help promote sleepiness. Also make sure the sleep space is cool and comfortable.

Safety precautions, particularly when driving, are important for everyone with narcolepsy. Suddenly falling asleep or losing muscle control can transform actions that are ordinarily safe, such as walking down a long flight of stairs, into hazards.

The Americans with Disabilities Act (ADA) requires employers to provide reasonable accommodations for all employees with disabilities. Adults with narcolepsy can often negotiate with employers to modify their work schedules so they can take naps when necessary and perform their most demanding tasks when they are most alert.

Similarly, children and adolescents with narcolepsy may be able to work with school administrators to accommodate special needs, like taking medications during the school day, modifying class schedules to fit in a nap, and other strategies.

Additionally, support groups can be extremely beneficial for people with narcolepsy.

What are the latest updates on narcolepsy?

The mission of the National Institute of Neurological Disorders and Stroke ( NINDS ) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The NINDS, a component of the National Institutes of Health ( NIH ), along with several other NIH Institutes and Centers, supports research on narcolepsy and other sleep disorders through grants to medical institutions across the country.

Additionally, the National Heart, Lung, and Blood Institute (NHLBI) manages the National Center on Sleep Disorders Research (NCSDR) , which coordinates federal government sleep research activities, promotes doctoral and postdoctoral training programs, and educates the public and health care professionals about sleep disorders. 

Genetics and biochemicals NINDS-sponsored researchers are conducting studies devoted to further clarifying the wide range of genetic—both HLA genes and non-HLA genes—and environmental factors that may cause narcolepsy. Other investigators are using animal models to better understand hypocretin and other chemicals such as glutamate that may play a key role in regulating sleep and wakefulness. Researchers are also investigating wake-promoting compounds to widen the range of available therapeutic options and create treatment options that reduce undesired side effects and decrease the potential for abuse. A greater understanding of the complex genetic and biochemical bases of narcolepsy will eventually lead to new therapies to control symptoms and may lead to a cure.

Immune system Abnormalities in the immune system may play an important role in the development of narcolepsy. NINDS-sponsored scientists have demonstrated the presence of unusual immune system activity in people with narcolepsy. Further, strep throat and certain varieties of influenza are now thought to be triggers in some at-risk individuals. Other NINDS researchers are also working to understand why the immune system destroys hypocretin neurons in narcolepsy in the hopes of finding a way to prevent or cure the disorder.

Sleep biology NINDS continues to support investigations into the basic biology of sleep, such as examining the brain mechanisms involved in generating and regulating REM sleep and other sleep behaviors. Since sleep and circadian rhythms are controlled by networks of neurons in the brain, NINDS researchers are also examining how neuronal circuits function in the body and contribute to sleep disorders like narcolepsy. A more comprehensive understanding of the complex biology of sleep will give scientists a better understanding of the processes that underlie narcolepsy and other sleep disorders.

How can I or my loved one help improve care for people with narcolepsy?

The NeuroBioBank serves as a central point of access to collections that span neurological, neuropsychiatric, and neurodevelopmental diseases and disorders. Tissue from individuals with narcolepsy is needed to enable scientists to study this disorder more intensely. Participating groups include brain and tissue repositories, researchers, NIH program staff, information technology experts, disease advocacy groups, and, most importantly, individuals seeking information about opportunities to donate.

Additionally, NINDS supports genetic and immunological research in narcolepsy at the Stanford University Center for Narcolepsy . Blood samples from individuals with narcolepsy can be sent by mail and are needed to enable scientists to study this disorder more intensely.

Consider participating in a clinical trial so clinicians and scientists can learn more about narcolepsy and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of volunteers are needed— those who are healthy or may have an illness or disease— of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research visit NIH Clinical Research Trials and You . Learn about clinical trials currently looking for people with narcolepsy at Clinicaltrials.gov .

Where can I find more information about narcolepsy? Information may be available from the following organizations: Narcolepsy Network Phone: 401-667-2523 or 888-292-6522 National Heart, Lung, and Blood Institute (NHLBI) Phone: 301-592-8573 or 800-575-9355 National Library of Medicine Phone: 301-594-5983 or 888-346-3656 National Sleep Foundation Phone: 703-243-1697 Wake Up Narcolepsy Phone: 978-751-3693

Narcolepsy Presentation in Diverse Populations: an Update

• Sleep and Health Disparities (A Shelton, Section Editor)
• Published: 25 November 2020
• Volume 6 , pages 239–250, ( 2020 )

Cite this article

• Karen Spruyt   ORCID: orcid.org/0000-0002-2914-9074 1  

5268 Accesses

3 Citations

36 Altmetric

Explore all metrics

Purpose of Review

We performed a literature search to generate incidence and prevalence rates of narcolepsy in diverse populations based on current available data.

Recent Findings

With an onset in childhood, narcolepsy often has a delayed diagnosis due to symptoms of excessive daytime sleepiness not being recognized or being misdiagnosed. Clinical, electrophysiological, and biological tests are needed in order to diagnose narcolepsy. At the same time, the discovery of the link with the immunoregulatory human leukocyte antigen complex and the adverse events in relation to the H1N1 pandemic vaccines have shuffled the epidemiological numbers.

In this meta-review, we pooled incidence rates and prevalence rates reported in 30 countries or from 209 sets of data. Findings are reported per age, continent, and proxy race/ethnicity as well as period (i.e., before/after the pandemic). This meta-review showed that narcolepsy occurs in 0.87–1.21 of the world population, with specifically NT1 being investigated. Its pooled incidence rate in vaccinated samples is 1.58. There is furthermore an underreporting of narcolepsy in ethnic/race and gender minorities, of childhood narcolepsy type 2 and potential comorbid conditions masking the clinical complaints and hence timely diagnosis.

Similar content being viewed by others

The Role of Magnesium in Sleep Health: a Systematic Review of Available Literature

Arman Arab, Nahid Rafie, … Fatemeh Shirani

Effect of melatonin supplementation on sleep quality: a systematic review and meta-analysis of randomized controlled trials

Gholami Fatemeh, Moradi Sajjad, … Mirzaei Khadijeh

Impact of Sleep Deprivation in the Neurological Intensive Care Unit: A Narrative Review

Victoria A. Chang, Robert L. Owens & Jamie N. LaBuzetta

Avoid common mistakes on your manuscript.

Introduction

Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness with or without cataplexy, or episodes of muscle weakness triggered by strong emotions: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2), respectively [ 1 ]. Both genetic and epidemiological evidence suggest an autoimmune mechanism in the destruction, or a highly specific loss, of orexin/hypocretin neurons, while influenza A infection and immunization have been proposed as the highest environmental risk factors [ 2 •, 3 ].

Overnight polysomnography and the multiple sleep latency test (MSLT) reveal short sleep latencies and rapid eye movement (REM) periods characterizing the sleep architecture of individuals with narcolepsy [ 1 ]. Human leukocyte antigen (HLA) typing has been suggested as a useful test to screen familial risk [ 4 ••]; however, susceptibility for a number of neurodegenerative diseases, for example, Alzheimer disease, equally associates to this immunoregulatory complex.

To date, the diagnosis of narcolepsy is still secured by clinical, electrophysiological, and biological evaluations often leading to a delayed diagnosis, e.g., 8.7 to 22.1 years [ 5 ], at risk of misdiagnosis [ 6 ]. In 2010, Sweden and Finland flagged adverse events to the H1N1 pandemic vaccinations as narcolepsy [ 7 ]. At the same time, two upsurges are noticed in the scientific literature: studies applying the Brighton Collaboration case definitions towards narcolepsy diagnosis, and alternatively, studies debating the roles of HLA [ 8 ] and H1N1 [ 9 ] in narcolepsy. Consequently, both issues suggest that the year 2009 is a turning point for narcolepsy research.

In an era of increased sleepiness complaints at societal level; a new pandemic, COVID-19; and personalized medicine, we aim to systematically review the literature concerning the presentation of narcolepsy in diverse populations.

A systematic literature search in PubMed, Scopus, and Web of Science was executed. The terms narcolepsy combined with ethnicity, race, neurodevelopmental disorder, neurologic disorder, psychopathology, sleep disorder, and epidemiology were used, and studies were selected per PRISMA guidelines (Fig.  1 ). Because a substantial amount of studies “hit” on “gender” due to, for instance, matching on gender of study samples, we searched narcolepsy with “gender” in title separately. The search was limited to 2017 up until 31 August 2020. All types of study designs were allowed.

Flowchart of selected databases

Statistical Analyses

Statistica (TIBCO version 13) will be used for descriptive analyses. Means with standard deviations (SD) or percentages when applicable will be printed. Comprehensive meta-analysis software (version 3.3.070) was used for the meta-analyses.

We will report only the point estimate with 95% confidence intervals (95% CI) or standard error, and the number of datasets ( k ) included. Given that rates will be mainly population-based, i.e., huge n s, they will not be printed. The I -square ( I 2 ) with thresholds of 25%, 50%, and 75% will be considered low, moderate, and high heterogeneity, being the percentage of true observed total variance across studies. A two-tailed P value < 0.05 was applied as statistically significant.

Data Management: Continent, Race/Ethnicity, Age, and Pandemic Information

From the literature, we extracted when possible the event and sample size to (re)calculate the point estimate and its 95% CI such that rounding errors of reported rates would not jeopardize further statistical analysis. In addition, when possible, we (re)calculated incidence to prevalence rates, and vice versa.

Population-based data were divided into continents and ethnicity/race groups. Countries encountered were European continent : Czech-Republic, Denmark, Finland, France, Germany, Ireland, Italy, Norway, Slovakia, Spain, Switzerland, and the UK; North America : Brazil, Canada, Mexico, and the USA; and Asia : China, India, Iran, Israel, Japan, Kuwait, Korea, Saudi-Arabia, Singapore, Taiwan, and Turkey. Unless specifically reported, the ethnicity/race was inferred from the country/continent, that is, Amerindian : North, South, and Central America; Asian : Far East and South East Asia, Indian subcontinent, China, India, Japan, and Korea; Black : data were from the USA; and White/Caucasian : Europe, Middle East, and North Africa. This categorization is based on the National Institute of Health Diversity Programs definitions (see NOT-OD-15-053). Also, regarding age, we applied a categorization when possible: children < 19 years, adults > 19 years, and all-encompassing the child-adult age range as well as a combination of these three categories as a total age group (excluding overlaps of equivalent sets of data). Of note, the child-adult age range category reflects sets of data including ages below and above 19 years old that could not be split into children/adults separately. When reported, we also extracted data specific to NT1 and NT2. Lastly, we categorized data based on reports before the pandemic (i.e., roughly < 2009), during/after (i.e., period of the influenza and/or vaccinations, > 2009), and the mixture (i.e., including data from before and after 2009). Of note, studies will be used within their proper categorization for instance; we did not compile data from children and adult studies together to generate studies reporting child-adult age ranges.

Review Papers Published on Diverse Narcolepsy Populations Since 2017

In total, 17 review papers have been published (Table 1 ): a majority are narrative reviews, but there are also three systematic reviews and two meta-reviews. The meta-analyses focused on the role of HLA-DQB1*06:02 [ 4 ••] and the H1N1 pandemic [ 17 ••]. The remainder showed a nearly equal distributed objective, i.e., reviews with a general aim [ 3 , 10 •, 11 , 15 , 16 ]; a health focus [ 12 , 14 , 19 , 20 , 21 , 22 ]; and a focus on associations with cognitive, behavioral, and emotional functioning [ 13 , 18 , 23 •, 24 ]. Particularly, those with an interest in health-related issues often started from, or are published with, a case report. From Dodd et al. [ 11 ], data was extracted to calculate pooled effect sizes.

Incidence—Prevalence Rates in Diverse Populations

In our endeavor, to be complete, we extracted data from two papers published before 2017 reporting epidemiological data (Fig. 1 ) and scattered literature reports if the data was not yet included: Longstreth et al. [ 25 ] and Wijnans et al. [ 26 ]. Our PRISMA search generated 11 new papers from which data was used. Table 2 and Table 3 show the different rates extracted from that literature collection approach. Ultimately, a total of 209 sets of data were analyzed with > 5% of the data extracted representing samples of Sweden, Netherlands, Finland, the UK, Spain, Korea, Denmark, the USA, Canada, and Taiwan.

Pooled Incidence Rates of Narcolepsy

Given that data were population-based, pooled sample sizes are substantial (hence not reported), and also, heterogeneity rapidly inflated as the number of countries (databases) increased (Table 2 , but also the other tables).

Before the H1N1 pandemic, the pooled incidence rates (IR) ranged from 0.36 to 1.37 across diverse populations, with a global pooled IR of 0.87 (95% CI: 0.66–1.09) based on 20 datasets. The highest pooled IR upper boundary can be seen in European children (upper 95% CI: 1.87). During/after the H1N1 pandemic in unvaccinated populations, i.e., data collected in and after 2009 with varying time limits applied, the pooled IR ranged from 0.69 to 1.58 across diverse populations, with a global pooled IR of 0.98 (95% CI: 0.87–1.08) based on 40 datasets. An outlier is the hazard ratio of 4.39 in Norway covering child-adult age ranges [ 27 ]. During/after the influenza period, however, the highest upper boundary is seen for adults in Asia(n) (upper 95% CI: 2.51). Overall, the pooled IR between these two periods (Table 2 A versus B) in the world are comparable ( p value = 0.823).

During/after the H1N1 pandemic in vaccinated populations, the world pooled IR almost doubled, but is not significantly different from the other periods (Table 2 A: p value = 0.4935 and B: p value = 0.4971). The lowest and highest pooled IR were reported in children, and in Asia(n) (pooled IR: 0.13) and in Europe (Caucasian) (pooled IR: 8.82) for this period, respectively.

About 20 sets of data generated IR overarching the before-after H1N1 pandemic period in unvaccinated samples (Table 2 D). Asia demonstrated the lowest and highest pooled IR depending on the age of the population, respectively, a pooled IR of 0.29 (95%CI: 0.27–0.32) when reflecting child-adult age ranges and a pooled IR of 1.37 (95% CI: 1.27–1.48) for children only. Korea [ 28 ] is an outlier here by reporting a crude incidence rate (adult pooled IR: 8.15). No significant differences were found upon comparing to the other world pooled IR in the other periods ( p values for comparisons versus A = 0.7247, B = 0.7847, and C = 0.7356).

Pooled Prevalence Rates of Narcolepsy

Only a handful more studies reported prevalence rates. These studies, in contrast to those reporting incidence rates, often involve smaller sample sizes. In addition, we pooled data from case reports to enlarge the dataset for that population when possible (e.g., Ray et al. [ 16 ]). Based on 37 databases, a world pooled prevalence rates (PR) of 2.06 (95% CI: 1.92–2.19) before the H1N1 pandemic was found. The highest prevalence rate should be interpreted with caution since selection criteria applied in the county also included “doubtful” narcolepsy [ 29 ]. Nevertheless, higher prevalence rates can be noted in childhood.

The pooled PR of the world almost tripled during/after the H1N1 pandemic in unvaccinated populations at 6.13 (95% CI: 5.43–6.83) (Table 3 A versus B: p value = 0.0004). The two largest pooled PRs reflect populations [ 27 , 30 ] where the selection criteria and sampling may have skewed percentages.

Likely, due to the retrospective nature of data collection, fewer individual studies reported on vaccinated samples, contrary to, for instance, adverse event registries following pharmacological treatment. The pooled PR during/after the H1N1 pandemic in vaccinated populations for the world was 4.22 (95% CI: 3.49–4.94). Although the world pooled PR doubles in vaccinated populations, the 95% CI remains within the before H1N1 pandemic boundaries (Table 3 A versus C: p  = 0.076). Also, high pooled PRs are noted in European/Caucasian children. The world PR in vaccinated and unvaccinated was found to be comparable (Table 3 B versus C: p  = 0.1567) during the same period, i.e., > 2009.

The highest pooled PR for the world was found for the period overarching before and after the H1N1 pandemic, namely 9.66 (95% CI: 7.01–12.31) based on 21 datasets of unvaccinated samples. This pooled PR was also significantly different from the others (Table 3 D versus A =  p  < 0.00001, B = 0.0033, C = 0.0001). While the pooled PRs before 2009 tend to be high in childhood, a shift can be noted towards adulthood as regards data collected over the mixture of time periods.

Caution is needed in interpreting these pooled rates, because the year 2009 (or H1N1 pandemic circulation) is a crude time point applied in different ways throughout the literature, particularly in combination with the recollection of the onset of symptoms of narcolepsy. Data generated from vaccinated samples however were often provided through census data and/or registries for adverse events.

Prevalence Rates of Narcolepsy Type 1 and Narcolepsy Type 2 in Narcolepsy Samples

Fewer studies explicitly detailed on NT1 (maximum k  = 13, Table 4 ) and NT2 (maximum k  = 6, Table 5 ) in samples characterized by narcolepsy (Fig.  2 ). In samples exhibiting narcolepsy symptomatology before the H1N1 pandemic, the pooled PR of the world was 46.02 ± 3.5 ( k  = 13) for NT1 and 14.22 ± 2.91 ( k  = 6) for NT2, especially the first pooled PR might be biased by doubtful selection criteria applied before 2009. Yet this pooled PR remains high also for data reflecting the > 2009 period in unvaccinated samples: 53.86 ± 13.63 ( k  = 8) for NT1 and 38.27 ± 18.76 ( k  = 5) for NT2. Data reporting before as well as after 2009 prevalence rates in narcolepsy samples, pooled as 49.52 ± 31.26 ( k  = 3) for NT1 and 16.58 ± 9.25 ( k  = 3) for NT2 in the world. In a vaccinated sample of people presenting narcolepsy symptomatology across the world, NT1 (only Europe) was reported in 4.27 ± 0.51 ( k  = 3).

World Pooled Prevalence rate for narcolepsy type 1 and narcolepsy type 2. NT1, narcolepsy type 1 (black bar); NT2, narcolepsy type 2 (gray bar). Striped bar : only NT1

Given that study samples rather report the PR as found in a convenience sample, contrary to PRs generated from epidemiological studies, extreme caution is warranted in interpreting these pooled PR of NT1 and NT2. However, several tendencies become clear when looking at Tables  4 and 5 , that is, an underreporting of specific PR in children and minorities, or alternatively an overreliance on adult and “white” samples. More studies are needed in NT2 samples in general, and similarly in children and minorities. Contrary to NT1 pooled PRs, the H1N1 pandemic may have boosted the NT2 prevalence, or narcolepsy without cataplexy symptomatology.

This meta-review showed that narcolepsy occurs in 0.87–1.21 of the world population, with specifically NT1 being investigated. There is furthermore an underreporting of narcolepsy in minorities and of NT2 in children. This meta-review reported pooled IR and PR rates within the range of previously published epidemiological studies. The upper-boundaries in particular may have clinical relevance towards concerted efforts improving timely diagnosis and management.

Narcolepsy is a life-long, severe, multifaceted disease often arising in childhood or adolescence as characterized by excessive daytime sleepiness. Although hypersomnia is not uncommon in the general population, the complex series of tests and the detailed history taking towards diagnosis of the specific types of narcolepsy [ 1 , 31 , 32 ] may jeopardize epidemiological “numbering.” That is, between the age of diagnosis and the age of onset, there is the patient’s recollection, complaints, and subjectivity of excessive somnolence, which, in the absence of cataplexy, may make the diagnosis challenging. As a consequence, diagnosis may occur 10–16 years later [ 33 ].

More recently, the H1N1 pandemic [ 28 , 34 ] and/or AS03-adjuvanted vaccines [ 35 , 36 ] may have shifted some numbers [ 17 , 37 ]. Our pooled data confirms these aspects. Firstly, a high preponderance in childhood was demonstrated. Secondly, mirroring the inconsistency in the literature, a doubling or tripling was shown alongside the 2009 influenza circulation and/or vaccinations. These vaccines, and their timed campaigns, however differed across countries, and consequently, their adverse events may or may not have reached registries or other databases.

Our findings concur that the incidence rate of narcolepsy varies by age, country, and period [ 11 ]. Although vaccination doubled the pooled IR/PR in the world, overall rates were comparable. We may, however, infer that while originally European children showed a high occurrence, a shift has occurred over the H1N1 pandemic period towards increased rates in Asia. Combined with outliers, caution is still warranted towards overgeneralization or even causality assumptions. Namely, methods of calculation (e.g., the denominator) and similarly selection criteria applied vary widely across the studies—countries—included, as expressed by very high I 2 s. This applies even more so to the pooled PR findings, since individual study data often reports frequencies in convenience samples contrary to epidemiological databases. Alternatively, such large-scale prevalence studies have to rely on carefully designed surveys such as Ohayon et al. [ 38 ].

The gap in epidemiological data concerning minorities and gender disparities was striking, as shown in this meta-review. Hence, our current knowledge and therefore management strategies represent mainly European and Caucasian samples. For instance, the first (racist) report in an African-American sample dates from 1945, and only in the 1990s, some other data surfaced [ 25 , 39 ]. A dominance of a handful of countries correspondingly is apparent. Regarding, the variable “gender” that is commonly applied for matching purposes in studies investigating narcolepsy samples, few specific epidemiological (or treatment [ 40 ]) studies were found. In addition, NT2 populations particularly in childhood seem to be overlooked. The reviews published since 2017 moreover highlight the gap in knowledge regarding co-occurrence of disorders that may mask symptomatology of narcolepsy. Especially given the associated features of narcolepsy, such as hypnagogic/hypnopompic hallucinations, sleep paralysis, and obesity, misdiagnosis might be common [ 41 , 42 ].

Nonetheless, data reported here, and hence in the literature, are challenged by several biases towards accurate “numbering.” Firstly, the ascertainment and recall bias of excessive somnolence may affect the reported rates. In other words, in the absence of a simple (non-invasive) objective test, the data principally depends on the patient’s complaint. Yet, in the case of H1N1 vaccination, the adverse event may have been “captured.” Secondly, the studies included noticeably have a selection bias given the age at onset/diagnosis gap, the health care triage system, and the time periods investigated, that is, the criteria applied in recruitment varies greatly. Subsequently, a confirmation bias might be present. We, therefore, agree with Verstraeten et al. [ 36 ] that the H1N1 influenza has certainly complicated the clinical picture, which is directly observable in how studies report on their samples or the data collected. The process of sampling over time, or the unsystematic collection of data in somnolent samples potentially introduces a sampling bias as well. While the search for markers such as the HLA gene complex in an era of an influenza may exemplify a potential measurement bias. Lastly, the influenza may have introduced a chronology bias in data. For these reasons, studies and epidemiological reports would become more homogeneous if consensus criteria for reporting of narcolepsy would be outlined, eventually advancing its scientific investigation given that the burden of illness is omnipresent [ 15 , 43 ].

This meta-review has some limitations to address. Most are related to the lack of consensus in reporting data, e.g., regarding age at onset, whether a sleep study was performed at some point, regards comorbidities or treatments, and even the period under investigation. Consequently, our categorizations remain crude. Similarly, our race and ethnicity categorization remains a proxy unless clearly stipulated in the (few) study. Lastly, several incidence rates and prevalence rates were difficult to trace and therefore directly used (i.e., not recalculated) which may have created some degree of error in our rates.

In conclusion, the H1N1 influenza may have created an increased risk of narcolepsy as reflected by the rates before/after 2009 but similarly plausible is that a certain degree of research bias is present. Nevertheless, though the number of studies varied, vaccination doubled the rate of narcolepsy occurrence and the pooled prevalence rates of narcolepsy and NT1 are akin suggesting some concurrence. By the same token, the childhood preponderance shifted along with the H1N1 influenza period to Asia.

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

American Academy of Sleep Medicine International Classification of Sleep Disorders. 3rd ed. Darien: IL American Academy of Sleep Medicine; 2014. https://www.textbooks.com/International-Classification-of-Sleep-Disorders-3rd-Edition/9780991543410/American-Academy-of-Sleep-Medicine.php?CSID=AZBSBMWWUKJWMCTOACC2KUSMB .

• Bonvalet M, Ollila HM, Ambati A, Mignot E. Autoimmunity in narcolepsy. Curr Opin Pulm Med. 2017;23(6):522–9. https://doi.org/10.1097/MCP.0000000000000426 This paper summarizes the recent findings in narcolepsy focusing on the environmental and genetic risk factors in disease development.

Dye TJ, Gurbani N, Simakajornboon N. Epidemiology and pathophysiology of childhood narcolepsy. Paediatr Respir Rev. 2018;25:14–8. https://doi.org/10.1016/j.prrv.2016.12.005 .

•• Capittini C, De Silvestri A, Terzaghi M, Scotti V, Rebuffi C, Pasi A, et al. Correlation between HLA-DQB1*06:02 and narcolepsy with and without cataplexy: approving a safe and sensitive genetic test in four major ethnic groups. A systematic meta-analysis. Sleep Med. 2018;52:150–7. https://doi.org/10.1016/j.sleep.2018.08.024 This paper provides meta-analytic data on HLA testing for narcolepsy diagnosis in four major ethnical groups: Asians, Afro-Americans, Amerindians, and Caucasians.

Çökmüş FP, Aydın O, Dikici DS, Sapmaz ŞY. Quickly diagnosed and treated prepubertal type 1 narcolepsy case. Psychiatry Clin Psychopharmacol. 2018;28(2):227–9. https://doi.org/10.1080/24750573.2017.1408230 .

Gupta AK, Sahoo S, Grover S. Narcolepsy in adolescence—a missed diagnosis: a case report. Innov Clin Neurosci. 2017;14(7–8):20–3.

Harris T, Wong K, Stanford L, Fediurek J, Crowcroft N, Deeks S. Did narcolepsy occur following administration of AS03-adjuvanted A(H1N1) pandemic vaccine in Ontario, Canada? A review of post-marketing safety surveillance data. Euro Surveill. 2014 Sep 11;19(36):20900. https://doi.org/10.2807/1560-7917.es2014.19.36.20900 .

Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355(9197):39–40. https://doi.org/10.1016/S0140-6736(99)05582-8 .

Mahlios J, De la Herran-Arita AK, Mignot E. The autoimmune basis of narcolepsy. Curr Opin Neurobiol. 2013;23(5):767–73. https://doi.org/10.1016/j.conb.2013.04.013 .

• Pillen S, Pizza F, Dhondt K, Scammell TE, Overeem S. Cataplexy and its mimics: Clinical recognition and management. Curr Treat Options Neurol. 2017 Jun;19(6):23. https://doi.org/10.1007/s11940-017-0459-0 . This paper reviews the diagnosis and management of cataplexy: attacks of bilateral loss of muscle tone, triggered by emotions and with preserved consciousness.

Dodd CN, de Ridder M, Huang WT, Weibel D, Giner-Soriano M, Perez-Vilar S, et al. Incidence rates of narcolepsy diagnoses in Taiwan, Canada, and Europe: the use of statistical simulation to evaluate methods for the rapid assessment of potential safety issues on a population level in the SOMNIA study. PLoS One. 2018;13(10):e0204799. https://doi.org/10.1371/journal.pone.0204799 .

Kallweit U, Bassetti CLA, Oberholzer M, Fronczek R, Béguin M, Strub M, et al. Coexisting narcolepsy (with and without cataplexy) and multiple sclerosis: six new cases and a literature review. J Neurol. 2018;265(9):2071–8. https://doi.org/10.1007/s00415-018-8949-x .

Ludwig B, Smith S, Heussler H. Associations between neuropsychological, neurobehavioral and emotional functioning and either narcolepsy or idiopathic hypersomnia in children and adolescents. JCSM: 2018;14(4):661–74. https://doi.org/10.5664/jcsm.7066 .

Maia Palhano AC, Kim LJ, Moreira GA, Santos Coelho FM, Tufik S, Levy AM. Narcolepsy, precocious puberty and obesity in the pediatric population: a literature review. Pediatr Endocrinol Rev. 2018;16(2):266–74. https://doi.org/10.17458/per.vol16.2018.Narcolepsypubertyobesity .

Plazzi G, Clawges HM, Owens JA. Clinical characteristics and burden of illness in pediatric patients with narcolepsy. Pediatr Neurol. 2018;85:21–32. https://doi.org/10.1016/j.pediatrneurol.2018.06.008 .

Ray A, Kanabar K, Upadhyay V, Sharma SK. A four year experience in narcolepsy from a sleep clinic at a tertiary care centre with a short review of contemporary indian literature. Indian J Med Res. 2018;148(6):748–51. https://doi.org/10.4103/ijmr.IJMR_888_16 .

•• Sarkanen TO, Alakuijala APE, Dauvilliers YA, Partinen MM. Incidence of narcolepsy after H1N1 influenza and vaccinations: systematic review and meta-analysis. Sleep Med Rev. 2018;38:177–86. https://doi.org/10.1016/j.smrv.2017.06.006 This paper provides an analyzis of the magnitude of H1N1 vaccination-related risk and examined if there was any association with H1N1 infection itself.

Schiappa C, Scarpelli S, D'Atri A, Gorgoni M, De Gennaro L. Narcolepsy and emotional experience: a review of the literature. Behavioral And Brain Functions: BBF. 2018;14(1):19. https://doi.org/10.1186/s12993-018-0151-x .

Weil AG, Muir K, Hukin J, Desautels A, Martel V, Perreault S. Narcolepsy and hypothalamic region tumors: presentation and evolution. Pediatr Neurol. 2018;84:27–31. https://doi.org/10.1016/j.pediatrneurol.2017.12.016 .

Gohil A, Eugster E. Growth hormone deficiency and excessive sleepiness: a case report and review of the literature. Pediatr Endocrinol Rev: PER. 2019;17(1):41–6. https://doi.org/10.17458/per.vol17.2019.ge.ghdeficiencyandsleepiness .

Hershner S, Dauvilliers Y, Chung F, Singh M, Wong J, Gali B, et al. Knowledge gaps in the perioperative management of adults with narcolepsy: a call for further research. Anesth Analg. 2019;129(1):204–11. https://doi.org/10.1213/ane.0000000000004088 .

Antelmi E, Pizza F, Franceschini C, Ferri R, Plazzi G. REM sleep behavior disorder in narcolepsy: A secondary form or an intrinsic feature? Sleep Med Rev. 2020 Apr;50:101254. https://doi.org/10.1016/j.smrv.2019.101254 .

• BaHammam AS, Alnakshabandi K, Pandi-Perumal SR. Neuropsychiatric correlates of narcolepsy. Curr Psychiatry Rep. 2020 Jun 5;22(8):36. https://doi.org/10.1007/s11920-020-01159-y . This paper summarizes recent evidence for the association between narcolepsy and neuropsychiatric disorders.The review discusses the use of stimulants and anticataplectic medications that may pose diagnostic difficulties in terms of underlying neuropsychiatric comorbidities.

Kim J, Lee GH, Sung SM, Jung DS, Pak K. Prevalence of attention deficit hyperactivity disorder symptoms in narcolepsy: a systematic review. Sleep Med. 2020;65:84–8. https://doi.org/10.1016/j.sleep.2019.07.022 .

Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep. 2007;30(1):13–26. https://doi.org/10.1093/sleep/30.1.13 .

Wijnans L, Lecomte C, de Vries C, Weibel D, Sammon C, Hviid A, et al. The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine. 2013;31(8):1246–54. https://doi.org/10.1016/j.vaccine.2012.12.015 .

Trogstad L, Bakken IJ, Gunnes N, Ghaderi S, Stoltenberg C, Magnus P, et al. Narcolepsy and hypersomnia in Norwegian children and young adults following the influenza A(H1N1) 2009 pandemic. Vaccine. 2017;35(15):1879–85. https://doi.org/10.1016/j.vaccine.2017.02.053 .

Choe YJ, Bae GR, Lee DH. No association between influenza A(H1N1)pdm09 vaccination and narcolepsy in South Korea: an ecological study. Vaccine. 2012;30(52):7439–42. https://doi.org/10.1016/j.vaccine.2012.10.030 .

Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep. 2002;25(2):197–202. https://doi.org/10.1093/sleep/25.2.197 .

Qasrawi SQ, Albarrak AM, Alharbi AS, Nashwan S, Almeneessier AS, Pandi-Perumal SR, et al. Narcolepsy in Saudi patients before and after the 2009 H1N1 vaccination. The experience of 2 referral centers. Saudi Med J. 2017;38(12):1196–200. https://doi.org/10.15537/smj.2017.12.21046 .

Lopez R, Arnulf I, Drouot X, Lecendreux M, Dauvilliers Y. French consensus. Management of patients with hypersomnia: Which strategy? Rev Neurol. 2017;173(1–2):8–18. https://doi.org/10.1016/j.neurol.2016.09.018 .

Monaca C, Franco P, Philip P, Dauvilliers Y. French consensus. Type 1 and type 2 narcolepsy: investigations and follow-up. Rev Neurol. 2017;173(1):25–31. https://doi.org/10.1016/j.neurol.2016.09.016 .

Hale L, Guan S, Emanuele E. Epidemiology of narcolepsy. In: Goswami M, Thorpy MJ, Pandi-Perumal SR, editors. Narcolepsy: a clinical guide. Cham: Springer International Publishing; 2016. p. 37–43.

Duffy J, Weintraub E, Vellozzi C, DeStefano F. Narcolepsy and influenza A(H1N1) pandemic 2009 vaccination in the United States. Neurology. 2014;83(20):1823–30. https://doi.org/10.1212/wnl.0000000000000987 .

Stassijns J, Bollaerts K, Baay M, Verstraeten T. A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children. Vaccine. 2016;34(6):714–22. https://doi.org/10.1016/j.vaccine.2015.12.024 .

Verstraeten T, Cohet C, Dos Santos G, Ferreira GL, Bollaerts K, Bauchau V, et al. Pandemrix™ and narcolepsy: A critical appraisal of the observational studies. Hum Vaccin Immunother. 2016;12(1):187–93. https://doi.org/10.1080/21645515.2015.1068486 .

Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7(3):e33536. https://doi.org/10.1371/journal.pone.0033536 .

Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology. 2002;58(12):1826–33. https://doi.org/10.1212/wnl.58.12.1826 .

Mignot E, Lin X, Arrigoni J, Macaubas C, Olive F, Hallmayer J, et al. DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans. Sleep. 1994;17(8 Suppl):S60–7. https://doi.org/10.1093/sleep/17.suppl_8.s60 .

Won C, Mahmoudi M, Qin L, Purvis T, Mathur A, Mohsenin V. The impact of gender on timeliness of narcolepsy diagnosis. JCSM 2014;10(1):89–95. https://doi.org/10.5664/jcsm.3370 .

Yeh JY, Shyu YC, Lee SY, Yuan SS, Yang CJ, Yang KC, et al. Comorbidity of narcolepsy and psychotic disorders: a nationwide population-based study in Taiwan. Front Psychiatry. 2020;11:205. https://doi.org/10.3389/fpsyt.2020.00205 .

Morse AM. Narcolepsy in children and adults: a guide to improved recognition, diagnosis and management. Medical Sciences (Basel, Switzerland). 2019;7(12):106. https://doi.org/10.3390/medsci7120106 .

Nordstrand SH, Hansen BH, Kamaleri Y, Nilsen KB, Rootwelt T, Karlsen TI, et al. Changes in quality of life in individuals with narcolepsy type 1 after the H1N1-influenza epidemic and vaccination campaign in Norway: a two-year prospective cohort study. Sleep Med. 2018;50:175–80. https://doi.org/10.1016/j.sleep.2018.05.037 .

Download references

Author information

Authors and affiliations.

School of Medicine, INSERM, University Claude Bernard, Lyon, France

Karen Spruyt

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Karen Spruyt .

Ethics declarations

Conflict of interest.

The author has nothing to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Sleep and Health Disparities

Rights and permissions

Reprints and permissions

About this article

Spruyt, K. Narcolepsy Presentation in Diverse Populations: an Update. Curr Sleep Medicine Rep 6 , 239–250 (2020). https://doi.org/10.1007/s40675-020-00195-7

Download citation

Accepted : 29 October 2020

Published : 25 November 2020

Issue Date : December 2020

DOI : https://doi.org/10.1007/s40675-020-00195-7

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Excessive daytime somnolence

Advertisement

• Find a journal
• Publish with us
• Track your research

• Patient Care & Health Information
• Diseases & Conditions

Your health care provider may suspect narcolepsy based on your symptoms of excessive daytime sleepiness and sudden loss of muscle tone, known as cataplexy. Your provider will likely refer you to a sleep specialist. Formal diagnosis requires staying overnight at a sleep center for an in-depth sleep analysis.

A sleep specialist will likely diagnose narcolepsy and determine how severe it is based on:

• Your sleep history. A detailed sleep history can help with a diagnosis. You'll likely fill out the Epworth Sleepiness Scale. The scale uses short questions to measure your degree of sleepiness. You'll answer how likely it is that you would fall asleep in certain times, such as sitting down after lunch.

Your sleep records. You may be asked to write down your sleep pattern for a week or two. This allows your provider to compare how your sleep pattern may relate to how alert you feel.

Your health care provider also may ask you to wear an actigraph. This device is worn like a watch. It measures periods of activity and rest. It provides an indirect measure of how and when you sleep.

• A sleep study, known as polysomnography. This test measures signals during sleep using flat metal discs called electrodes placed on your scalp. For this test, you must spend a night at a medical facility. The test measures your brain waves, heart rate and breathing. It also records your leg and eye movements.
• Multiple sleep latency test. This test measures how long it takes you to fall asleep during the day. You'll be asked to take four or five naps at a sleep center. Each nap needs to be two hours apart. Specialists will observe your sleep patterns. People who have narcolepsy fall asleep easily and enter into rapid eye movement (REM) sleep quickly.
• Genetic tests and a lumbar puncture, known as a spinal tap. Occasionally, a genetic test may be performed to see if you're at risk of type 1 narcolepsy. If so, your sleep specialist may recommend a lumbar puncture to check the level of hypocretin in your spinal fluid. This test is only done in specialized centers.

These tests also can help rule out other possible causes of your symptoms. Excessive daytime sleepiness could also be caused by sleep deprivation, the use of sedating medicines and sleep apnea.

• Care at Mayo Clinic

Our caring team of Mayo Clinic experts can help you with your narcolepsy-related health concerns Start Here

More Information

Narcolepsy care at Mayo Clinic

• Polysomnography (sleep study)

There is no cure for narcolepsy, but medicines and lifestyle changes can help you manage the symptoms.

Medications

Medicines for narcolepsy include:

Stimulants. Drugs that stimulate the central nervous system are the primary treatment to help people with narcolepsy stay awake during the day. Your health care provider may recommend modafinil (Provigil) or armodafinil (Nuvigil). These medicines aren't as habit-forming as older stimulants. They also don't produce the highs and lows associated with older stimulants. Side effects are uncommon but may include headache, nausea or anxiety.

Solriamfetol (Sunosi) and pitolisant (Wakix) are newer stimulants used for narcolepsy. Pitolisant also may be helpful for cataplexy.

Some people need treatment with methylphenidate (Ritalin, Concerta, others) or amphetamines (Adderall XR 10, Dexedrine, others). These medicines are effective but can be habit-forming. They may cause side effects such as nervousness and a fast heartbeat.

Serotonin and norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs). These medicines suppress REM sleep. Health care providers prescribe these medicines to help ease the symptoms of cataplexy, hallucinations and sleep paralysis.

They include venlafaxine (Effexor XR), fluoxetine (Prozac) and sertraline (Zoloft). Side effects can include weight gain, insomnia and digestive problems.

• Tricyclic antidepressants. These older antidepressants can treat cataplexy. But they can cause side effects such as dry mouth and lightheadedness. These medicines include protriptyline, imipramine (Tofranil) and clomipramine (Anafranil).

Sodium oxybate (Xyrem) and oxybate salts (Xywav). These medicines work well at relieving cataplexy. They help improve nighttime sleep, which is often poor in narcolepsy. They also may help control daytime sleepiness. It's taken in two doses, one at bedtime and one up to four hours later.

Xywav is a newer formulation with less sodium.

These medicines can have side effects, such as nausea, bed-wetting and sleepwalking. Taking them together with other sleeping tablets, narcotic pain relievers or alcohol can lead to trouble breathing, coma and death.

If you take medicines for other health problems, ask your health care provider how they may interact with narcolepsy medicines.

Certain medicines that you can buy without a prescription can cause drowsiness. They include allergy and cold medicines. If you have narcolepsy, your doctor may recommend that you don't take these medicines.

Researchers are studying other potential treatments for narcolepsy. Medicines being studied include those that target the hypocretin chemical system. Researchers also are studying immunotherapy. Further research is needed before these medicines become available.

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

Lifestyle changes are important in managing the symptoms of narcolepsy. You may benefit if you:

• Stick to a schedule. Go to sleep and wake up at the same time every day, including weekends.
• Take naps. Schedule short naps at regular intervals during the day. Naps of 20 minutes during the day may be refreshing. They also may reduce sleepiness for 1 to 3 hours. Some people may need longer naps.
• Avoid nicotine and alcohol. Using these substances, especially at night, can worsen your symptoms.
• Get regular exercise. Plan for moderate, regular exercise at least 4 to 5 hours before bedtime. It may help you sleep better at night and feel more awake during the day.

Coping and support

Dealing with narcolepsy can be a challenge. Consider these tips:

Talk about it. Tell your employer or teachers about your condition. Then work with them to find ways to adjust to your needs. This may include taking naps during the day. Or you might break up repetitive tasks. You might record meetings or classes to refer to later. You also might find it helps to stand during meetings or lectures, and to take brisk walks during the day.

The Americans with Disabilities Act prohibits discrimination against workers with narcolepsy. Employers are required to provide reasonable accommodation to qualified employees.

• Be safe while driving. If you must drive a long distance, work with your health care provider to find ways to make a safe trip. Create a medicine schedule that is most likely to keep you awake during your drive. Stop for naps and exercise breaks whenever you feel drowsy. Don't drive if you feel too sleepy.

Support groups and counseling can help you and your loved ones cope with narcolepsy. Ask your health care provider to help you locate a group or qualified counselor in your area.

Preparing for your appointment

You're likely to start by seeing your primary care provider. But if narcolepsy is suspected, you may be referred to a sleep specialist.

Here's some information to help you prepare for your appointment.

What you can do

• Be aware of any pre-appointment restrictions. At the time you make the appointment, be sure to ask if there's anything you need to do in advance.
• Write down any symptoms you're experiencing, including any that may seem unrelated to the reason for which you scheduled the appointment.
• Write down key personal information, including any major stresses or recent life changes.
• Make a list of all medicines, vitamins or supplements you're taking.
• Ask a family member or friend to go with you. Sometimes it can be difficult to recall all the information you get during an appointment. Someone who accompanies you may remember something that you missed or forgot.
• Write down questions to ask your health care provider.

Preparing a list of questions for your provider will help you make the most of your time together. List your questions from most important to least important. For narcolepsy, some basic questions to ask your doctor include:

• What's the most likely cause of my symptoms?
• Are there other possible causes?
• What kinds of tests do I need?
• Do I need a sleep study?
• Is my condition likely temporary or long lasting?
• What treatment do you recommend?
• What are the alternatives to the primary approach you're suggesting?
• I have these other health conditions. How can I best manage these conditions together?
• Is there a generic alternative to the medicine you're prescribing?
• Are there any brochures or other printed material that I can take home with me? What websites do you recommend?

Don't hesitate to ask other questions anytime during your appointment.

What to expect from your doctor

Your doctor is likely to ask you a number of questions, including:

• When did you begin experiencing symptoms?
• Have your symptoms been continuous or occasional?
• How often do you fall asleep during the day?
• How severe are your symptoms?
• Does anything improve your symptoms?
• What, if anything, appears to worsen your symptoms?
• Does anyone in your family have similar symptoms?
• Kryger M, et al., eds. Principles and Practice of Sleep Medicine. 7th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed Dec. 19, 2022.
• Martin VP, et al. Sleepiness in adults: An umbrella review of a complex construct. Sleep Medicine Reviews. 2022; doi:10.1016/j.smrv.2022.101718.
• Ferri FF. Narcolepsy. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed Dec. 19, 2022.
• Ropper AH, et al. Sleep and its abnormalities. In: Adams and Victor's Principles of Neurology. 11th ed. McGraw Hill; 2019. https://accessmedicine.mhmedical.com. Accessed Dec. 19, 2022.
• Narcolepsy fact sheet. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Narcolepsy-Fact-Sheet. Accessed Dec. 19, 2022.
• Chien P-Y, et al. Pharmacological interventions for excessive daytime sleepiness in adults with narcolepsy: A systematic review and network meta-analysis. Journal of Clinical Medicine. 2022; doi:10.3390/jcm11216302.
• Narcolepsy following 2009 Pandemrix influenza vaccination in Europe. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccinesafety/concerns/history/narcolepsy-flu.html. Accessed Dec. 30, 2022.
• Justinussen JL, et al. How hypocretin agonists may improve the quality of wake in narcolepsy. Trends in Molecular Medicine. 2023; doi:10.1016/j.molmed.2022.10.008.
• Sodium oxybate oral. Facts & Comparisons eAnswers. https://fco.factsandcomparisons.com. Accessed Jan. 4, 2023.
• Oxybate salts (calcium, magnesium, potassium and sodium). Facts & Comparisons eAnswers. https://fco.factsandcomparisons.com. Accessed Jan. 4, 2023.
• Ami TR. Allscripts EPSi. Mayo Clinic. July 6, 2022.

Associated Procedures

Products & services.

• A Book: Mayo Clinic Family Health Book, 5th Edition
• Newsletter: Mayo Clinic Health Letter — Digital Edition
• Symptoms & causes
• Diagnosis & treatment
• Doctors & departments

Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission.

• Opportunities

Mayo Clinic Press

Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press .

• Mayo Clinic on Incontinence - Mayo Clinic Press Mayo Clinic on Incontinence
• The Essential Diabetes Book - Mayo Clinic Press The Essential Diabetes Book
• Mayo Clinic on Hearing and Balance - Mayo Clinic Press Mayo Clinic on Hearing and Balance
• FREE Mayo Clinic Diet Assessment - Mayo Clinic Press FREE Mayo Clinic Diet Assessment
• Mayo Clinic Health Letter - FREE book - Mayo Clinic Press Mayo Clinic Health Letter - FREE book

Your gift holds great power – donate today!

Make your tax-deductible gift and be a part of the cutting-edge research and care that's changing medicine.

• Privacy Policy
• Terms of Service

• Breathing Disorders
• Hypersomnias
• Movement Disorders
• Circadian Rhythm Disorders
• Parasomnias
• In-Lab Tests
• Home Based/Out of Lab
• Connected Care
• Consumer Sleep Tracking
• Therapy Devices
• Pharmaceuticals
• Surgeries & Procedures
• Behavioral Sleep Medicine
• Demographics
• Sleep & Body Systems
• Prevailing Attitudes
• Laws & Regulations
• Human Resources
• Continuing Education
• Edition Archive

Select Page

Jazz to Highlight Narcolepsy and IH Research at AAN 2024

Apr 11, 2024 | Idiopathic Hypersomnia , Narcolepsy | 0 |

The research includes an oral presentation revealing that individuals with idiopathic hypersomnia experienced higher odds of comorbid conditions, such as cardiovascular disease.

Summary: Jazz Pharmaceuticals will present five abstracts at the 76th Annual American Academy of Neurology Meeting in Denver that focus on narcolepsy and idiopathic hypersomnia. Key findings include a real-world claims analysis showing increased risks of comorbid conditions with idiopathic hypersomnia and research on the benefits of low-sodium Xywav for sleep inertia and narcolepsy treatment. The meeting will feature both oral and poster presentations.

Key Takeaways: 

• An oral presentation will detail results from the Real-World Idiopathic Hypersomnia Total Health Model (RHYTHM) study, revealing higher odds of comorbid conditions, including cardiovascular issues, in individuals with idiopathic hypersomnia compared to those without.
• Two posters will assess the impact of Xywav oral solution on sleep inertia in individuals with idiopathic hypersomnia, presenting data from a phase 3 trial, demonstrating its efficacy as the first low-sodium oxybate.
• A poster from the SEGUE study will report final results on adults with narcolepsy transitioning from high-sodium Xyrem to low-sodium Xywav, showing minimal dosage adjustments required for the switch.
• Another poster will review data from five clinical studies evaluating the effects of high-sodium oxybates on sleep quality and architecture in narcolepsy patients, indicating their effectiveness in improving sleep measures despite the high-sodium content.

Jazz Pharmaceuticals plc will present one oral presentation and four poster presentations on narcolepsy and idiopathic hypersomnia at the 76th Annual American Academy of Neurology Meeting, which will take place April 13-18 in Denver.

A key oral presentation will detail results from a real-world claims analysis that demonstrated the increased risk of comorbid conditions, such as stroke or cardiovascular disease , in individuals living with idiopathic hypersomnia compared to those without the condition. 

Poster presentations include the evaluation of Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution on sleep inertia and sleep quality in patients with idiopathic hypersomnia and narcolepsy, along with detailed findings from the SEGUE study on transitioning narcolepsy patients from high-sodium to low-sodium oxybate treatments .

“Jazz’s presentations at the 2024 AAN Annual Meeting reflect our leadership in sleep and rare epilepsies, as well as our commitment to developing therapies for debilitating, and often overlooked, neurological disorders,” says Rob Iannone, MD, MSCE, executive vice president and global head of research and development of Jazz Pharmaceuticals, in a release. “We remain committed to expanding our knowledge of the patient experience, including the real-world impact and effectiveness of our products, in order to achieve our purpose of transforming the lives of patients and their families.”

Highlights at the 2024 AAN Annual Meeting include:

• An oral presentation showcasing results from the Real-World Idiopathic Hypersomnia Total Health Model (RHYTHM) study which, using claims data, compared the comorbid conditions of individuals diagnosed with idiopathic hypersomnia with those experienced by individuals without idiopathic hypersomnia. Results revealed that individuals with idiopathic hypersomnia experienced higher odds of comorbid conditions across multiple clinical categories, including cardiovascular conditions, reaffirming the importance of considering the patient’s full clinical profile when evaluating treatment options for patients living with idiopathic hypersomnia.
• Two posters assessing the impact of Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution, the first and only low-sodium oxybate, on sleep inertia in individuals living with idiopathic hypersomnia, including results from a phase 3 trial.
• One poster reporting the final results from the SEGUE study of adults with narcolepsy transitioning from Xyrem (sodium oxybate) oral solution, a high-sodium oxybate, to Xywav, showing that participants switched from high-sodium to low-sodium oxybate with minimal adjustments to their dosing.
• A poster reviewing key data from five clinical studies evaluating the impact of all once- and twice-nightly high-sodium oxybates on sleep quality, sleep architecture, and measures of disrupted nighttime sleep in narcolepsy. The review found that oxybate was effective in improving measures of sleep architecture and disrupted nighttime sleep in patients with narcolepsy. Xyrem is indicated for the treatment of cataplexy and/or excessive daytime sleepiness in narcolepsy patients.

The 2024 AAN Annual Meeting abstracts are available here .

Photo  142024457  ©  Mary981  |  Dreamstime.com

Related Posts

Sleep healthcenters opens new center in worcester.

August 7, 2006

Family Want Compensation for Sleep Disorder

March 22, 2015

Provigil Gets Under Users’ Skin

September 26, 2007

Enhancing Sleep After Brain Injury Reduces Brain Damage and Cognitive Decline in Rats

March 24, 2016

Leave a reply Cancel reply

Your email address will not be published. Required fields are marked *

Save my name, email, and website in this browser for the next time I comment.

Upcoming Events

Dentures and partials: mastering the foundational skills, 2024 west virginia sleep society conference, 7th international sleep disorder academy congress, the women’s cardiometabolic health and wellness masterclass, sleep and circadian rhythms in cardiovascular resilience: mechanisms, implications, and applications.

Alkermes reports data from Phase Ib narcolepsy treatment trial

A lkermes has shared positive topline data from the narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) cohorts of a Phase Ib study of ALKS 2680 as a potential once-daily treatment for narcolepsy.

The study assessed the tolerability, safety, pharmacokinetics, and pharmacodynamics of ALKS 2680 given as a single daily oral dose.

Nine patients with NT2 and eight with IH were enrolled in a four-way crossover study, where they received either 5mg, 12mg, or 25mg doses of ALKS 2680 and a placebo, with washout periods between treatments.

An investigational oral orexin 2 receptor (OX2R) agonist, ALKS 2680 demonstrated statistically significant improvements in mean sleep latency on the Maintenance of Wakefulness Test (MWT) from baseline, compared to a placebo, across all doses tested in the trial, with a clear dose response.

In addition, the therapy was found to be well tolerated in subject group populations at all doses tested.

In NT2 patients, all treatment-emergent adverse events (TEAEs) were transient and self-resolving, with no serious adverse events (AEs) or discontinuations reported.

Alkermes plans to initiate a Phase II study for NT2 patients in the second half of this year.

The IH patient group also had TEAEs that were transient and self-resolving in nature.

Alkermes research and development chief medical officer and executive vice-president Craig Hopkinson said: “We’re pleased to share these topline results in patients with narcolepsy type 2 and idiopathic hypersomnia, which build upon our previously disclosed Phase Ib data in narcolepsy type 1.

“These data further validate our hypothesis that an orexin agonist with appropriate pharmaceutical properties has the potential to provide significant clinical benefits for both narcolepsy type 1 and type 2 patient populations.

“With these data now in hand, we are moving quickly to select doses for a Phase II study in narcolepsy type 2, which we plan to initiate in the second half of this year.”

"Alkermes reports data from Phase Ib narcolepsy treatment trial" was originally created and published by Clinical Trials Arena , a GlobalData owned brand.

The information on this site has been included in good faith for general informational purposes only. It is not intended to amount to advice on which you should rely, and we give no representation, warranty or guarantee, whether express or implied as to its accuracy or completeness. You must obtain professional or specialist advice before taking, or refraining from, any action on the basis of the content on our site.

• Search Menu
• Advance Articles
• Supplements
• Editor's Choice
• Virtual Issues
• Virtual Roundtables
• Abstract Supplements
• Basic Science
• Circadian Disorders
• Cognitive, Affective and Behavioral Neuroscience of Sleep
• Neurological Disorders
• Sleep Across the Lifespan
• Sleep and Metabolism
• Sleep Disordered Breathing
• Sleep Health and Safety
• Author Guidelines
• Instructions for Reviewers
• Submission Site
• Open Access Options
• Additional Resources
• Self-Archiving Policy
• About SLEEP
• Editorial Board
• Dispatch Dates
• Permissions
• Advertising & Corporate Services
• Journals Career Network
• Reprints and ePrints
• Sponsored Supplements
• Journals on Oxford Academic
• Books on Oxford Academic

Article Contents

• Introduction
• Materials and Methods
• Supplementary Material
• Acknowledgments
• Disclosure Statement
• Data Availability
• < Previous

Downregulation of hypocretin/orexin after H1N1 Pandemrix vaccination of adolescent mice

• Article contents
• Figures & tables
• Supplementary Data

Nicolai Pagh-Berendtsen, Artem Pavlovskyi, Daniel Flores Téllez, Christine Egebjerg, Mie Gunni Kolmos, Jessica Justinussen, Birgitte Rahbek Kornum, Downregulation of hypocretin/orexin after H1N1 Pandemrix vaccination of adolescent mice, Sleep , Volume 47, Issue 4, April 2024, zsae014, https://doi.org/10.1093/sleep/zsae014

• Permissions Icon Permissions

Narcolepsy type 1 (NT1), characterized by the loss of hypocretin/orexin (HCRT) production in the lateral hypothalamus, has been linked to Pandemrix vaccination during the 2009 H1N1 pandemic, especially in children and adolescents. It is still unknown why this vaccination increased the risk of developing NT1. This study investigated the effects of Pandemrix vaccination during adolescence on Hcrt mRNA expression in mice. Mice received a primary vaccination (50 µL i.m.) during prepubescence and a booster vaccination during peri-adolescence. Hcrt expression was measured at three-time points after the vaccinations. Control groups included both a saline group and an undisturbed group of mice. Hcrt expression was decreased after both Pandemrix and saline injections, but 21 days after the second injection, the saline group no longer showed decreased Hcrt expression, while the Pandemrix group still exhibited a significant reduction of about 60% compared to the undisturbed control group. This finding suggests that Pandemrix vaccination during adolescence influences Hcrt expression in mice into early adulthood. The Hcrt mRNA level did not reach the low levels known to induce NT1 symptoms, instead, our finding supports the multiple-hit hypothesis of NT1 that states that several insults to the HCRT system may be needed to induce NT1 and that Pandemrix could be one such insult.

• immunologic adjuvants
• pharmaceutical adjuvants
• autoimmunity
• down-regulation
• rna, messenger
• vaccination
• swine influenza
• saline solutions

Email alerts

• Hypocretin loss in Pandemrix-vaccinated mice

Citing articles via

Looking for your next opportunity.

• Recommend to Your Librarian
• Advertising and Corporate Services

Affiliations

• Online ISSN 1550-9109
• Print ISSN 0161-8105
• Copyright © 2024 Sleep Research Society
• About Oxford Academic
• Publish journals with us
• University press partners
• What we publish
• New features  
• Open access
• Institutional account management
• Rights and permissions
• Get help with access
• Accessibility
• Advertising
• Media enquiries
• Oxford University Press
• Oxford Languages
• University of Oxford

Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide

• Copyright © 2024 Oxford University Press
• Cookie settings
• Cookie policy
• Privacy policy
• Legal notice

This Feature Is Available To Subscribers Only

Sign In or Create an Account

This PDF is available to Subscribers Only

For full access to this pdf, sign in to an existing account, or purchase an annual subscription.

25% Off Benzinga's Most Powerful Trading Tools

Traders Win More with Benzinga's Exclusive News and Squawk

• Get Benzinga Pro
• Data & APIs
• Our Services
• News Earnings Guidance Dividends M&A Buybacks Legal Interviews Management Offerings IPOs Insider Trades Biotech/FDA Politics Government Healthcare Sports
• Markets Pre-Market After Hours Movers ETFs Forex Cannabis Commodities Options Binary Options Bonds Futures CME Group Global Economics Previews Small-Cap Real Estate Cryptocurrency Penny Stocks Digital Securities Volatility
• Ratings Analyst Color Downgrades Upgrades Initiations Price Target
• Ideas Trade Ideas Covey Trade Ideas Long Ideas Short Ideas Technicals From The Press Jim Cramer Rumors Best Stocks & ETFs Best Penny Stocks Best S&P 500 ETFs Best Swing Trade Stocks Best Blue Chip Stocks Best High-Volume Penny Stocks Best Small Cap ETFs Best Stocks to Day Trade Best REITs
• Money Investing Cryptocurrency Mortgage Insurance Yield Personal Finance Forex Startup Investing Real Estate Investing Credit Cards
• Cannabis Cannabis Conference News Earnings Interviews Deals Regulations Psychedelics

Alkermes' Sleeping Disorder Studies' Data Look Excellent, Analyst Says

Zinger key points.

Jefferies increased the probability of success for ALKS-2680 to 50%, with peak sales of $1 billion, up from $700 million.

• The company plans to initiate a phase 2 study in patients with Narcolepsy Type 2 in the second half of 2024.

On Tuesday,  Alkermes plc  ALKS revealed topline results from the narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) cohorts of a phase 1b, proof-of-concept study evaluating  ALKS 2680 for narcolepsy . 

ALKS 2680 data demonstrated clinically meaningful and statistically significant improvements from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT) compared to placebo at all doses tested. 

ALKS 2680 was generally well tolerated in both patient populations at all doses tested.

In Narcolepsy Type 2 (NT2), treatment with ALKS 2680 resulted in statistically significant and clinically meaningful improvements in sleep latency, with a mean change from baseline versus placebo of 12 minutes at the 5 mg dose, 19 minutes at the 12 mg dose, and 21 minutes at the 25 mg dose.

Placebo treatment in this cohort resulted in no change in mean sleep latency. 

The company plans to initiate a phase 2 study in patients with NT2 in the second half of 2024.

In the eight patients with Idiopathic Hypersomnia (IH), treatment with ALKS 2680 resulted in statistically significant and clinically meaningful improvements in sleep latency in these patients with IH, with a mean change from baseline versus placebo of 8 minutes at the 5 mg dose, 11 minutes at the 12 mg dose, and 18 minutes at the 25 mg dose. 

Placebo treatment in this cohort reduced mean sleep latency by two minutes. 

At the 12 mg and 25 mg doses, the observed mean MWT scores over eight hours post-dose were within the reported normal range for healthy individuals.

Jefferies  writes that Alkermes’ ALKS-2680 data looks excellent. The analyst increased the  price target from $42 to $50 .

Price Action:  ALKS shares are up 3.43% at $26.82 on the last check Tuesday.

Photo via Shutterstock

© 2024 Benzinga.com. Benzinga does not provide investment advice. All rights reserved.

Trade confidently with insights and alerts from analyst ratings, free reports and breaking news that affects the stocks you care about.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List

Narcolepsy—A Neuropathological Obscure Sleep Disorder: A Narrative Review of Current Literature

Vishal chavda.

1 Department of Pathology, Stanford of School of Medicine, Stanford University Medical Centre, Palo Alto, CA 94305, USA

Bipin Chaurasia

2 Department of Neurosurgery, Neurosurgery Clinic, Birgunj 44300, Nepal

Giuseppe E. Umana

3 Department of Neurosurgery, Associate Fellow of American College of Surgeons, Trauma and Gamma-Knife Centre, Cannizzaro Hospital Catania, 95100 Catania, Italy

Santino Ottavio Tomasi

4 Department of Neurological Surgery-Christian Doppler Klinik, 5020 Salzburg, Austria

Nicola Montemurro

5 Department of Neurosurgery, Azienda Ospedaliera Universitaria Pisana (AOUP), University of Pisa, 56100 Pisa, Italy

Narcolepsy is a chronic, long-term neurological disorder characterized by a decreased ability to regulate sleep–wake cycles. Some clinical symptoms enter into differential diagnosis with other neurological diseases. Excessive daytime sleepiness and brief involuntary sleep episodes are the main clinical symptoms. The majority of people with narcolepsy experience cataplexy, which is a loss of muscle tone. Many people experience neurological complications such as sleep cycle disruption, hallucinations or sleep paralysis. Because of the associated neurological conditions, the exact pathophysiology of narcolepsy is unknown. The differential diagnosis is essential because relatively clinical symptoms of narcolepsy are easy to diagnose when all symptoms are present, but it becomes much more complicated when sleep attacks are isolated and cataplexy is episodic or absent. Treatment is tailored to the patient’s symptoms and clinical diagnosis. To facilitate the diagnosis and treatment of sleep disorders and to better understand the neuropathological mechanisms of this sleep disorder, this review summarizes current knowledge on narcolepsy, in particular, genetic and non-genetic associations of narcolepsy, the pathophysiology up to the inflammatory response, the neuromorphological hallmarks of narcolepsy, and possible links with other diseases, such as diabetes, ischemic stroke and Alzheimer’s disease. This review also reports all of the most recent updated research and therapeutic advances in narcolepsy. There have been significant advances in highlighting the pathogenesis of narcolepsy, with substantial evidence for an autoimmune response against hypocretin neurons; however, there are some gaps that need to be filled. To treat narcolepsy, more research should be focused on identifying molecular targets and novel autoantigens. In addition to therapeutic advances, standardized criteria for narcolepsy and diagnostic measures are widely accepted, but they may be reviewed and updated in the future with comprehension. Tailored treatment to the patient’s symptoms and clinical diagnosis and future treatment modalities with hypocretin agonists, GABA agonists, histamine receptor antagonists and immunomodulatory drugs should be aimed at addressing the underlying cause of narcolepsy.

1. Introduction

Narcolepsy is a chronic, life-long neurological disorder that interferes with a person’s daily sleep cycle and wakefulness. It is primarily influenced by the REM and NREM sleep cycles and has been linked to a variety of neurological disorders [ 1 ]. It is distinguished by episodic daytime sleepiness and nighttime wakefulness, as well as sleeping difficulty. It is characterized by abnormally rapid eye movement, cataplexy and mild muscular weakness, all of which lead to body collapse or paralysis [ 2 , 3 , 4 ]. Narcolepsy affects people of all ages, including children, adolescents, adults and the elderly, and symptoms range from mild to severe. A person with narcolepsy may fall asleep at any time, such as while conversing or driving. Narcolepsy is also referred to as hypersomnia, which is a chronic REM sleep disorder characterized by excessive daytime sleepiness [ 3 , 4 , 5 ]. An individual enters the premature stage of sleep in a classic sleep cycle, followed by depth sleep stages for 90 min, where the end of REM sleep occurs. In contrast, narcolepsy patients can enter REM sleep within 15 min of starting their sleep cycle during the day [ 1 ]. REM sleep causes daydreaming and muscular paralysis in this way. Narcolepsy and its associated pathology are caused by a variety of factors [ 1 ]. Traumatic brain injury, such as stroke, injury to the hypothalamus, and loss of hypocretin receptors, underlying neurological complications such as major depressive disorders and schizophrenia, a metabolic disorder such as diabetes, and other factors can all contribute to the development of narcolepsy. The exact cause and pathophysiology of narcolepsy pathology are unknown, but it has been classified into three major types based on research and clinical experience: (1) narcolepsy accompanied by cataplexy; (2) narcolepsy without cataplexy, characterized by daytime sleepiness; and (3) secondary narcolepsy, caused by hypothalamic injury and an imbalance in neuronal transmission [ 6 , 7 ]. The American Academy of Sleep Medicine Board of Directors published the International Classification of Sleep Disorders, 3rd edition (ICSD-3) in 2014. In the third edition, the most drastic change in the content was the unification of secondary insomnia categories into a single “chronic insomnia” category. In the central disorders of hypersomnolence section, the nomenclature for narcolepsy was changed to narcolepsy type 1 and type 2 [ 8 ]. The nosology of narcolepsy has also been revised, subdividing the disorder into type 1 and type 2 narcolepsy, replacing narcolepsy with and without cataplexy, respectively. This reflects a change in focus from diagnosis based on symptoms to diagnosis based on pathophysiology, in this case hypocretin (orexin) deficiency status. This change was predicated on the notion that almost all patients with cataplexy have hypocretin deficiency. In addition, “narcolepsy with cataplexy” is improper because some patients with hypocretin deficiency do not have cataplexy or have yet to develop cataplexy [ 8 ]. As an increased number of studies into narcolepsy treatment options were performed in the last decade, to facilitate the diagnosis and treatment of sleep disorders and to better understand the neuropathological mechanisms of these sleep disorders, we summarized in this review all current knowledge on narcolepsy, in particular, genetic and non-genetic associations of narcolepsy, the pathophysiology up to the inflammatory response, the neuromorphological hallmarks of narcolepsy, and possible links with other diseases, such as diabetes, ischemic stroke, and Alzheimer’s disease. This review also reports all of the most recent updated research and therapeutic advances in narcolepsy.

2. Epidemiology

Several research studies have been conducted to determine the exact prevalence of narcolepsy, which was discovered to be between 25 and 50 per 100,000 people in Europe, Japan, and the United States [ 9 , 10 , 11 ]. As a result, narcolepsy is a rare condition. Because of a lack of specific diagnosis and symptoms that mimic other diseases, the exact epidemiology is unknown. Narcolepsy is estimated to affect between 50 and 67 per 100,000 people in North America, Western Europe and Asia [ 12 ]. The prevalence of narcolepsy is very low in India and other Asian countries, and very few cases have been reported to confirm narcolepsy with a thorough investigation. In India, the prevalence is very low because cases are not properly diagnosed, are misdiagnosed or are only partially diagnosed to confirm narcolepsy [ 13 ]. Because of the mixed symptoms and other associated neurological diseases, it is frequently misdiagnosed as seizures or obstructive sleep apnea, and thus the exact prevalence of narcolepsy worldwide is thought to be low. However, if every patient is examined and diagnosed with a differential diagnosis, the true prevalence will be greater than the reported one [ 14 ].

3. Genetic and Non-Genetic Associations with Narcolepsy

Despite the fact that 2–3% of familial cases are reported, narcolepsy is primarily a sporadic disorder. In different families with familial narcolepsy, an autosomal dominant mode of inheritance and incomplete penetrance with a heterogeneously single gene mutation have been observed [ 15 ]. Patients’ first-degree relatives have a 10–40 times higher risk of developing narcolepsy than the general population [ 16 ]. Identifying defective genes, on the other hand, can provide critical information about pathological mechanisms (e.g., the type 2 hypocretin receptor mutation reported in autosomal recessive narcolepsy in dogs).

3.1. HLA Genes: HLADQB1 as Risk Factor of Narcolepsy Type 1

Sporadic narcolepsy, like most complex diseases, is thought to be the result of a complex interaction of environmental factors and several gene variants. HLA association was first reported as a result of genetic studies to help explain the pathogenesis of narcolepsy. The HLA locus on chromosome 6 encodes the HLA complex, which is divided into three sub-regions based on their function: HLA class I, II, and III. The HLA complex is critical in the recognition and processing of foreign antigens by the immune system. HLA classes I and II encode glycoproteins involved in antigen processing and presentation to cytotoxic and helper T lymphocytes, respectively. HLA class I molecules can be found on the surface of nearly all human cells, whereas HLA class II molecules can be found on the surface of antigen-presenting cells such as B cells, macrophages, dendritic cells, and so on. HLA class I molecules, such as HLA-A, HLA-B, and HLA-C, present antigenic peptides to T-cell receptors (TCR) on CD8+ T cells, whereas HLA class II molecules, such as HLA-DR, HLA-DQ, and HLA-DP, present antigenic peptides to CD4+ T cells. HLA-DRB1, DQA1, and DQB1 are vulnerable genes associated with autoimmune diseases such as Graves’ disease [ 17 ], rheumatoid arthritis [ 18 ], type I diabetes [ 19 , 20 ], and narcolepsy [ 19 , 21 ]. As immunological tolerance to the self has evolved to protect against autoimmunity, the ability to bind and present processed antigens via HLA molecules is critical for developing self-tolerance in the thymus, primarily by removing self-reactive lymphocytes and preventing inflammatory tissue-destructive reactions. As a result, HLA alleles are linked to a wide range of autoimmune diseases.

In Japan, Europe and the United States, most narcoleptic patients have a positive correlation with the HLA-DR2 haplotype (encoding HLA class II molecules). Surprisingly, precise alleles at four linked genes (HLA-DRB5*01:01, DRB1*15:01, DQA1*01:02 and DQB1*06:02) explain susceptibility haplotype in white narcoleptic patients. This link is thought to be required for the emergence of narcolepsy, but its utility as a screening or diagnostic marker is limited by the fact that approximately 12–38 percent of the healthy, general population also carries the associated HLA haplotype, so it cannot be considered an absolute risk factor for narcolepsy [ 22 ]. Consequently, the DQB1*06:02 allele is the most common predisposing allele, appearing in at least 98 percent of cataplexy narcolepsy patients. As a consequence, HLA-DQB1*06:02 in both homozygous and heterozygous patients accounts for the variation in narcolepsy risk. The interdependent heterogeneous allele of the DQB1 locus represents a relative risk in heterozygotic individuals, whereas homozygosity is associated with a two-fold increase in risk. Other DR and DQ alleles have protective or predisposing effects in other HLA-related disorders, and the HLA association is complex with clear implications. As a result, when considering a plethora of HLA alleles, large populations are required to measure individual allelic contributions. New protective alleles DQB1*06:03, DQB1*05:01, DQB1*06:09 and DQB1*02 have recently been identified. More than 85% of narcolepsy with cataplexy patients have HLA DQB1*0602, which is frequently linked to HLA DRB1*1501, whereas only about 40% of atypical, mild narcolepsy patients without cataplexy have HLA DQB1*0602, indicating greater heterogeneity in narcolepsy without cataplexy [ 23 ]. Other HLA alleles can also influence the proclivity to narcolepsy with cataplexy. Cataplexy patients who do not have HLA DQB1 have a very rare form of narcolepsy. These findings strongly suggest that the DQB1 locus is responsible for a significant portion of the narcolepsy-related genetic risk and protection. HLA typing’s sensitivity, specificity, and discriminatory power are all low, making it unsuitable as a routine diagnostic test [ 16 ]. HLA class II antigens, particularly DQ1 and DR2, are strongly linked to narcolepsy. DQB1*06:02 and DQB1:02:00 alleles code for amino acids serine at 182 positions (DQB1Ser182) and threonine at 185 positions (DQB1Thr185), respectively, and DQB1*03:05 and DQB1*03:01 alleles code for amino acids asparagine at 182 positions (DQB1Aspar182) (DQB1Asn182). This discovery demonstrates that DQB1Ser182 and DQB1Thr185 alleles are vulnerable to the development of narcolepsy, whereas DQB1Asn182 is protective [ 24 ].

3.2. Non-HLA Genetic Associations

The development of narcolepsy with cataplexy is linked to molecules that are associated with MHC proteins or that regulate autoimmunity, according to genome-wide association studies (GWAS) [ 25 ]. Aside from HLA loci, narcolepsy with cataplexy is linked to the TRA and TRB loci, which both encode T cell receptor chains [ 26 ]. The allele in the joining segment, specifically within the J24 segment, that changes the amino acid phenylalanine to leucine at the complementarity determining region 3 (CDR3) peptide binding region of the T cell receptor is in linkage disequilibrium, a phenomenon that refers to the non-random association of alleles at various loci with an allele in the joining segment, specifically within the J24 segment, that alters the amino acid phenylalanine [ 27 ]. Other antigen-presenting pathway genes linked to narcolepsy include variants of cathepsin H (CTSH, which encodes pro-cathepsin H, which processes peptides and is then presented by MHC class II on dendritic cells) and tumor necrosis factor ligand superfamily member 4 (TNFSF4, which regulates immune cell fate). IL10RB–IFNAR1 (the IL-10 and interferon receptor gene region), ZNF365 (that encodes the transcription factor ZNF365), and P2RY11 (encodes P2Y purinoceptor 11) and the chemokine receptor CCR1–CCR3 region are all linked to narcolepsy. Surprisingly, very rare mutations have been discovered in a small number of narcolepsy patients, implying that the disorder has its own pathogenesis. A single mutation in the hypocretin gene, which encodes hypocretin, has been explored, as has a mutation in the MOG gene, which encodes myelin oligodendrocyte glycoprotein, in a single pedigree with familial narcolepsy [ 7 ]. As a result, in addition to traditional HLA haplotypes, new polymorphic associations are being discovered in order to uncover the pathogenesis of narcolepsy and treat it with specific diagnostics.

3.3. Environmental Factors

Environmental factors have been identified as factors in the etiopathogenesis of narcolepsy, in addition to genetic factors. Monozygotic twin studies reveal a 25–31% narcolepsy concordance rate, demonstrating the disease’s multifactorial pathology [ 28 ]. The nature of possible environmental triggers for narcolepsy is largely unknown. TBI, stroke and a disrupted sleep–wake cycle are the nonspecific environmental factors most likely to be linked to the onset of the disease in a broader sense, as all of these could transiently or permanently modulate hypocretin levels [ 29 ]. Recent studies have shown a link between narcolepsy and streptococcal infection [ 30 , 31 , 32 , 33 , 34 ], seasonal influenza, pandemic A/H1N1 2009 influenza vaccination [ 35 , 36 ], and exposure to insecticides, format change weedicides and heavy metals [ 16 , 37 ]. One of the strongest pieces of evidence comes from the associations between Pandemrix ® vaccination and the onset of narcolepsy [ 36 ]. After a traumatic brain injury, narcolepsy may develop [ 38 ]. In addition, other environmental triggers influence the development of narcolepsy as novel unknown environmental factors may also cause narcolepsy in the future, so it is critical to investigate those factors from time to time [ 6 ].

4. Inflammatory Response

Anatomical studies have demonstrated that hypocretin-immunoreactive neurons are localized within the hypothalamus [ 39 ]. While working with their respective groups, Peyron et al. [ 40 ] and Thannickal et al. [ 41 ] discovered a significant global loss of hypocretin neurons in the brains of narcolepsy patients with cataplexy. Human narcoleptics have shown a reduced number of hypocretin neurons in the hypothalamus [ 40 ]. Important studies on animals reported that, unlike in other animals, hypocretin deficiency in cats is caused by the loss of hypocretin neurons in the dorsolateral hypothalamus, not by hypocretin gene mutations [ 42 ]. Overall, these findings suggest that in narcolepsy patients with cataplexy, inflammatory responses may play a role in hypocretin neuron elimination [ 16 ]. Several studies have linked narcolepsy with cataplexy to differential expression of cytokines linked to chronic inflammation. Chronic inflammation has a negative impact on T cells, including Tregs, and is seen in cataplexy patients shortly before the onset of narcolepsy [ 43 ]. Changes in the expression of immunomodulatory cytokines have been linked to narcolepsy, but it is unclear whether these changes are caused by a predisposing factor for narcolepsy or by a disease or its comorbidities such as diabetes, obesity or stroke. TNF injections into the brain stimulate NREM sleep while inhibiting spontaneous sleep [ 44 ], which could explain EDS in narcolepsy patients. Sleep disturbances are known to increase IL-6, and sleep deprivation disrupts the regulation of IL-6 and TNF- [ 45 , 46 , 47 ]. Extended daytime sleepiness elevates IL-6 and TNF-, which suggests that a disrupted sleep–wake cycle modulates cytokine profile in narcolepsy patients [ 48 , 49 , 50 ]. Furthermore, polymorphisms in the TNF-promoter gene have been proposed as a possible cause of increased TNF-secretion in narcolepsy patients [ 51 ]. Increased levels of cytokines/chemokines in narcolepsy patients are also thought to be a result of microbial infection or vaccine immunization [ 52 ]. When narcoleptics were compared to controls, Mohammadi et al. [ 53 ] found higher plasma levels of IL-6 and TNF-, an insignificant difference in serum IL-6 and TNF- levels, and lower CSF IL-6 levels. In addition, narcolepsy patients’ plasma and CSF levels of IL-8 (chemotactic factor) and IL-10 (anti-inflammatory cytokine) are unchanged when compared to controls. The inconsistency of inflammatory cytokine results in narcolepsy patients explains the limited neuroinflammatory response in the lateral hypothalamus, which may make cytokine concentration measurements in CSF or serum difficult [ 54 ]. In rats, IL-8 administered intracerebroventricularly promoted NREM sleep [ 55 ]. Future research should focus on the role of inflammation responses in narcolepsy and the most cost-effective anti-inflammatory drugs for narcolepsy treatment [ 53 , 55 , 56 , 57 ].

4.1. Autoimmune Hypothesis

The exact pathological mechanism that causes the death of hypocretin neurons in most narcolepsy patients with cataplexy is unknown. The removal of hypocretin neurons is very selective, sparing the melanin-concentrating hormone-releasing neurons found in the lateral hypothalamus, supporting the popular autoimmune hypothesis for narcolepsy disease pathogenesis [ 58 , 59 ]. The strong link between the HLADQB1*06:02 allele and polymorphisms in other immune-related genes and the immunological-autoimmune response in narcolepsy patients with cataplexy support the autoimmune hypothesis ( Figure 1 ). Some studies have found a seasonal pattern in narcolepsy with cataplexy disorder [ 27 ], which could indicate infection triggers. Despite this sliver of evidence for an autoimmune mechanism underpinning narcolepsy with cataplexy disease, the autoimmune hypothesis has no direct support. There are still many pieces of evidence needed to prove that an autoimmune response is a central pathological mechanism in narcolepsy with cataplexy disorder. As a result, no definite signs of inflammatory processes in the CNS of narcolepsy patients with cataplexy and rising in the presence of other autoimmune disorders in narcolepsy patients have been consistently observed [ 40 , 60 , 61 ]. Surprisingly, no improvement in clinical symptoms or change in disease course has been observed following the administration of immunomodulatory therapy close to disease onset [ 62 , 63 , 64 ], with the exception of a single exceptional case report [ 7 , 65 ].

Schematic figure represents the possible mechanism for the autoimmune hypothesis for narcolepsy with cataplexy. Several environmental triggers are capable enough for molecular mimicry and elicit an immune response against microbiological/environmental factors. The microbiological-specific immune cells can cross-react with autoantigens and can activate autoimmune responses against hypocretin-secreting neurons in the hypothalamus, where the melanin-concentrating hormone is relatively spared.

4.2. Autoantibody and T Cell Laboratory Findings

In addition to HLA genes, non-HLA genes have been shown to have a genetic link to narcolepsy predisposition. Polymorphisms in specific T cell receptor loci have been linked to narcolepsy [ 27 , 66 ]. As a result, T cells’ apparent role in the pathophysiology of narcolepsy with cataplexy is unequivocally emphasized by their involvement. The specific HLA–TCR interactions found in narcolepsy patients with cataplexy support the autoimmune hypothesis that T cells mediate selective irreversible elimination of hypocretin neurons [ 67 ]. In order to exploit autoreactivity as a mechanism underlying hypocretin deficiency in narcolepsy, autoantibodies must be searched in order to validate the direct evidence for the autoimmune hypothesis. Autoantibodies, on the other hand, have been overlooked in a few notable studies [ 68 , 69 , 70 ]. In contrast, several studies have discovered that the TRIB-2 protein (tribbles homolog 2), which is produced by many cells including hypocretin neurons, is a putative target for autoantibodies in narcolepsy patients with cataplexy one year after onset. In mice with passively transferred TRIB2 autoantibodies, narcolepsy with cataplexy phenotype can be seen [ 43 , 67 ].

Patients with autoimmune uveitis have TRIB2 autoantibodies as well [ 71 , 72 , 73 ]. Previous research reports have supported the hypothesis that there are low levels of serum TRIB2 autoantibodies in HLA-DQB1*06:02-positive young narcolepsy patients with cataplexy, which they linked to influenza pandemic vaccination and A/H1N1 antibodies in 2009 [ 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. This discovery confirms that T cells can infiltrate the hypothalamus, but it disproves the autoimmune hypothesis due to their variable autoreactivity. Anti-Ma antibodies, on the other hand, have never been found in cataplexy patients with narcolepsy [ 81 ]. Fontana et al. [ 82 ] proposed that autoantigen-specific CD4+ T cells or superantigen-stimulated CD8+ T cells activate microglia/macrophages, which then destroy hypocretin neurons through immune-mediated destruction. Lecendreux and colleagues [ 43 ] investigated overall immune system activation in blood samples of pediatric narcolepsy patients with cataplexy. Regarding the phenotypic changes in T cells, elevated levels of activated memory effector CD4+ T cells were found to be associated with a higher absolute count of activated CD4+ T reg cells with a high frequency. In narcolepsy patients, the increase in Treg could be an attempt to reduce inflammation and restore homeostasis. Lecendreux and colleagues were the first to report the activated phenotype and changes in Treg frequency, and this finding strongly suggests that Tregs are also induced in narcolepsy with cataplexy as part of an autoimmune response [ 43 ]. According to this theory, in narcolepsy with cataplexy disorder, global but weak inflammation activates all T cell subsets, including Tregs, but Tregs are unable to maintain peripheral tolerance due to a qualitative defect, either in these Tregs or in pathogenic immune cells. Indeed, in T1D, Tregs have been shown to have a qualitative defect. Defective suppression is caused by a qualitative flaw or a dysfunctional Treg, which can lead to autoimmunity. Resistance to Treg-mediated regulation or Treg cell defect can be increased by changes in antigen presentation or the expansion of pro-inflammatory cytokines in a remodeled microenvironment (viz., Th 17 effector cells). As a result, it is an important aspect that should be investigated further in order to gain a better understanding of Treg plasticity and function in the context of autoimmune disorders [ 30 ]. Furthermore, Kornum et al. [ 83 ] found that polymorphisms in the P2RY11 gene affect the viability of natural killer, CD8+, and CD4+ T cells in narcolepsy patients with cataplexy. The disease-associated allele is linked to lower P2RY11 gene expression in CD8+ T lymphocytes and natural killer cells but not in other types of peripheral blood mononuclear cells. P2RY11 is a key regulator of immune cell survival, and it may play a role in narcolepsy with cataplexy by enhancing T cell survival [ 83 ]. TCR sequencing and deep sequencing of narcoleptic T cell subsets should be performed effectively to characterize a possible functional defect of Tregs, suppression and proliferation antigen-specific assays utilizing H1N1 peptides, as molecular mimicry has been hypothesized between hypocretinergic neurons and H1N1 virus [ 43 , 84 ]. Because the reactivity of T cells to hypocretins is unknown, T-cell transfer in narcolepsy animal models must be investigated [ 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ].

5. Narcolepsy and Neuromediator Systems

Neuromediators involved in sleep–wake cycle regulation include hypocretins, dopamine, histamine acetylcholine, norepinephrine, serotonin, glutamate and GABA. Changes in these neuromediators’ levels can affect wakefulness, sleep and circadian rhythm, which is why they are clinically important. As a result, their roles in narcolepsy should be thoroughly investigated in order to determine the precise causative effect and to develop new therapeutic avenues that are relevant to the condition.

5.1. Hypocretinergic System

The hypocretin system is made up of about 70,000 hypocretin-producing neurons in the human dorsolateral hypothalamus that project a virtual neural axis. Hypocretin neurons are a type of neuron that aids in the maintenance of the sleep–wake cycle. Hypocretins are neuroexcitatory peptides that are encoded by a hypothalamic-specific transcript and act as agonists of two G-protein-coupled receptors independently [ 87 ]. Hypocretin neurons produce two types of excitatory neuropeptides: hypocretin 1 (orexin-A) and hypocretin 2 (orexin-B). The tuberomammillary nucleus (histaminergic neurons), locus coeruleus (norepinephrine neurons), raphe nucleus (serotonergic neurons), laterodorsal tegmental nuclei (acetylcholine) and ventral tegmental areas (dopaminergic neurons) form an extensive network of projections throughout the brainstem [ 16 , 97 , 98 , 99 ]. Cataplexy is caused by hypocretin deficiency, which disables the motor excitatory systems and inhibits the motor inhibitory system in the brainstem. Depletion of hypocretin neurotransmission can increase sleepiness by disabling the cholinergic and aminergic arousal systems or disinhibiting the forebrain’s hypnogenic systems [ 97 ]. Hypocretin is a neuromodulator that keeps excitatory and inhibitory neurotransmitters such as histamine, serotonin, dopamine, acetylcholine, and norepinephrine in check. Hypocretin is a neurotransmitter that controls sleep, wakefulness, autonomic and energy homeostasis, food intake, consummatory and reward-related behaviors, pleasure-seeking behavior and emotional processing, among other things [ 16 , 87 , 99 ] ( Figure 2 ).

A representation of the normal narcolepsy state. Compared to normal individuals, narcolepsy patients with cataplexy have low levels of hypocretin (HCRT) due to a loss of hypocretin neurons. The flip-flop model of the sleep–wake state in normal conditions is balanced by stabilizing modulator hypocretin, while hypocretin deficiency unbalances the sleep–wake transition in narcoleptics. In normal individuals, hypocretin is thought to stabilize wakefulness during the day by both activating the ribocortex and stimulating the ascending arousal system to increase wake-promoting neuron activity. Sleep-promoting neurons inhibit both wake-promoting neurons and hypocretins. The wake-promoting and sleep-promoting neurons include excitatory neurotransmitters and inhibitory neurotransmitters. The main five symptoms of narcolepsy are manifested by narcolepsy patients.

5.2. Dopaminergic System

Muscle atonia during cataplexy and REM-sleep atonia are both shown to be a multistep process involving brainstem circuits that are shared by both. Inadequate activation of D1- and D2-like receptors may result in sleep attacks and cataplexy, respectively, emphasizing the importance of the dopaminergic pathway in narcolepsy [ 100 ]. The reintroduction of hypocretin into a specific brain region produces unexpected results. Hypocretin input in the locus coeruleus improves fragmented sleepiness in hypocretin receptors 1 and 2 double-knockout mice, whereas dorsal raphe specific to the serotoninergic pathway can prevent cataplexy, and activation of the GABAB pathway in hypocretin-neuron-deficient mice significantly alleviates cataplexy [ 101 ].

5.3. Histaminergic System

Histaminergic neurons, like hypocretin neurons, play an important role in promoting and stabilizing wakefulness by activating cortical neurons and wake-promoting neurons in the hypothalamic tuberomammillary nucleus. Hypocretin and histamines are neurotransmitters that work together to keep us awake and alert throughout the day. Histamine neurons either directly or indirectly inhibit non-REM sleep-promoting neurons by reinforcing the activation of wake-promoting neurons [ 89 , 102 , 103 ]. The histaminergic system has gained interest in sleep–wake regulation research in recent years, owing to the 60–80 percent augmentation of histaminergic neurons in the brains of narcolepsy and cataplexy patients [ 104 , 105 ]. Despite an increase in the number of histamine neurons in narcolepsy patients, histamine and tele-methylhistamine levels in the CSF are not useful biomarkers for narcolepsy [ 7 ].

6. Clinical Features

For people with narcolepsy, the persistent sleep–wake state instability can result in a wide range of unpredictable symptom manifestations throughout the day. Excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, vivid hallucinations and disrupted nocturnal sleep are the five main symptoms of narcolepsy [ 106 ]. These symptoms can be debilitating and make daily life difficult. Hypothalamic hypocretin neurons are critical for ensuring the predictable timing and stable boundaries required for normal sleep–wake cycles. Inadequate activation of histamine and other wake-promoting neurons results in insufficient inhibition and intermittent activation of REM and non-REM sleep-promoting neurons during the day, allowing elements of REM sleep to intrude into wakefulness or REM sleep at the wrong time. This atypical instability in sleep–wake rhythm promotes frequent and unpredictable transitions between sleep–wake states, as well as rapid transitions to REM sleep, resulting in daytime naps or non-REM sleep at the wrong time, as well as rapid transitions to REM sleep or REM at the wrong time. Cataplexy and sleep paralysis can result from REM sleep-associated muscle atonia intruding into wakefulness at sleep–wake transitions. Cataplexy refers to brief episodes of muscle weakness or loss of muscle tone that are usually triggered by strong emotions or specific circumstances while awake, whereas sleep paralysis is often a frightening inability to speak, move limbs or open one’s eyes for several moments to several minutes immediately after awakening or falling asleep [ 107 ].

In narcolepsy, excessive daytime sleepiness (EDS) is caused by impaired alertness and neurocognitive functioning, which insufficiently activates wake-promoting neurons and weakly inhibits non-REM sleep-promoting neurons, resulting in an unpredictably sleepy state throughout the day, exacerbating EDS and sleep–wake state instability. Sleepiness or drowsiness is the most difficult symptom to manage. People with narcolepsy may fall asleep unexpectedly, such as while sitting in class or working at a computer. However, their sleep duration in a 24 h period is not significantly longer than that of normal people. Most people with this disorder believe that short 15 min naps improve their alertness for few hours. This conviction implies that the unusual excessive daytime sleepiness is caused by defects in the cerebral circuits that normally induce complete alertness in the natural state, rather than by insufficient or inadequate sleep. Healthy people sleep by going through a sleep cycle that lasts an hour or more before reaching the rapid eye movement (REM) sleep stage, which is characterized by dreams. On the contrary, narcoleptics fall asleep quickly, within up to five minutes, and enter the REM phase quickly, resulting in a very realistic dream, even in short naps. Narcolepsy is a neurosynaptic disorder that impairs the ability to regulate sleep and wake cycles. As a result, people with narcolepsy have shaky boundaries between wakefulness and sleep, causing them to fall asleep quickly and even encouraging frequent lapses into sleep [ 108 , 109 ].

7. Pathophysiology and Links with Other Diseases

The REM sleep and hypocretinergic system were discovered around the turn of the millennium, and sleep research has been burgeoning since then. The discovery of hypocretins demonstrated the importance of these neurons in physiological sensory functions, as well as their compelling role in narcolepsy pathology. The pathophysiology of narcolepsy is heavily influenced by genetic and environmental factors, and the exact pathogenesis is unknown. The most likely cause of narcolepsy associated with cataplexy is the destruction of hypocretin-producing neurons and the resulting low level of hypocretin (Narcolepsy type 1). NT1, rather than narcolepsy without cataplexy (Type 2), is the most widely studied [ 59 ]. Narcolepsy is widely defined as the death of selective hypothalamic hypocretin peptide-producing neurons. The HLA class II molecule mediates macrophage and microglia activation, which results in the release of neurotoxic pro-inflammatory molecules such as Fas ligand, tumor necrosis factor, interleukin-1, glutamate, quinolinic acid, reactive oxygen species and nitric oxide, which may destroy hypocretin neurons. Quinolinic acid has been shown to have destructive sensitivity. In line with this, Katsuki et al. [ 110 ] demonstrated that NMDA has a cytotoxic effect on hypocretin and melanin-concentrating hormone (MCH) neurons [ 92 ]. The investigation of endogenous glutamate receptor agonists (i.e., kainic acid) and glutamate transporter blockers (i.e., hydroxyapatite) reveals that quinolinic acid acts as an endogenous excitotoxin that can cause specific loss of hypocretin neurons, whereas activating NMDA receptors spares MCH immunoreactive neurons. The excitotoxic consequence is the irreversible elimination of hypocretin neurons and the transient disappearance of immunoreactivity for MCH, which occurs primarily as a result of neuropeptide depletion from respective neurons released in response to excitatory stimuli due to compromised peptide synthesis under excitotoxic insults. However, many other putative intracellular mechanisms control excitotoxic effects on central neurons, and now, every possible pathophysiological pathogenesis remains to be a determinant of hypocretin neurons’ and MCH neurons’ vulnerability to excitotoxicity [ 110 ]. In narcoleptic mice, induced gene inactivation of the prepro-hypocretin (HCRT) or hypocretin gene receptors, or genetic deletion of hypocretin neurons, results in insufficient hypocretin neurotransmission and reasonable catalytic attacks [ 111 ].

7.1. Narcolepsy and Diabetes

The link between narcolepsy and diabetogenic hyperinsulinemia was first discussed five decades ago [ 112 ]. Narcolepsy is strongly associated with an increased BMI and the prevalence of type 2 diabetes [ 55 ]. Given that hypocretin regulates food intake and energy homeostasis, it appears that narcolepsy and metabolic disorders are linked. Diabetes mellitus, a well-known metabolic disorder, is strongly linked to narcolepsy. As prominent putative mechanisms for this association, changes in food intake, imbalanced energy consumption, glucose tolerance, and insulin sensitivity, as well as inflammation and genetic factors, have been proposed. The primary cause of narcolepsy, hypocretin deficiency, is associated with increased food intake and decreased basal metabolic rate (BMR), both of which lead to obesity. The anti-apoptotic effect of hypocretin on pancreatic beta-cells raises peripheral insulin sensitivity while decreasing lipolysis in adipose tissue, raising the risk of obesity and type 2 diabetes (T2D) in narcoleptic patients. Autoimmunity and inflammation are the primary pathomechanisms shared by narcolepsy and type 1 diabetes (T1D). Indeed, the main predisposing HLA gene for narcolepsy, DQB1*0602, also acts as a protective factor for T1D [ 113 ], whereas CTSH mutations are an odd factor for both T1D and narcolepsy. As a result, these two genes provide the most compelling genetic evidence for the link between narcolepsy and T1D. Narcolepsy is also linked to gestational diabetes mellitus (GDM), as it can lead to glucose intolerance, type 2 diabetes and obesity. GDM patients typically have low serum hypocretin levels, which are associated with low fasting insulin and high fasting glucose levels. Furthermore, the increased prevalence of obesity in narcolepsy patients was quickly identified as a major risk factor, emphasizing the link between narcolepsy and diabetes mellitus [ 114 ]. The effect of exercise improving narcolepsy is contradictory, but overweight or obese patients with fibromyalgia and narcolepsy should be encouraged to lose weight [ 115 , 116 ]. Patients with narcolepsy and cataplexy appear to be at increased risk for diabetes because they frequently exhibit obesity, hypertension and T2D, and they share genetic and environmental risk factors with T1D as well [ 43 , 117 , 118 ]. Hypocretin neurons are found primarily in the posterior and lateral hypothalamic nuclei, as well as in the anterior hypophysis, adrenal medulla and enteric nervous system and throughout the pancreatic neuro-enteric system [ 119 ]. Hypocretin neuropeptides function by interacting with two G-coupled hypocretin receptors, type 1 having a high affinity for hypocretin A and type 2 having the same affinity for both hypocretin A and B. The anterior pituitary gland, the adrenal medulla, the spinal ganglions, and a variety of other tissues such as adipose, gut, pancreatic, adrenal gland and testis tissues all contain hypocretin receptors [ 120 ]. Endogenous signaling pathways for hypocretin are as diverse as its expression sites. Gq-phospholipase C is an omnipresent hypocretin signaling mediator in a variety of cell types, followed by downstream cascades of DAG and IP3-Ca2+ release, and modulates excitation/inhibition balance as well as gene expression in a variety of cells. The activation of Gi-adenylyl cyclase and the phosphatidylinositol 3-kinase (PI3K)-protein kinase C (PKC), both of which result in a high Ca 2+ influx, are two of the most common pathways mediating hypocretin’s central effects, particularly in the hypothalamic nuclei [ 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ].

7.2. Narcolepsy and Ischemic Stroke

Ischemic stroke is a type of cerebrovascular disease with a high mortality and disability rate around the world [ 131 ]. Brain tissue apoptosis and necrosis are caused by insufficient blood supply and a lack of oxygen [ 132 , 133 , 134 ]. Diabetic ischemic stroke has a multifaceted and complex pathophysiologic mechanism that includes excitotoxicity, endothelial dysfunction, disrupted energy homeostasis, oxidative stress, inflammation, disruption of the blood–brain barrier, atherosclerosis and other factors [ 135 , 136 , 137 , 138 ]. Several studies have demonstrated that hypocretins are an effective neuroprotective agent in cerebral ischemic insult and ischemia-reperfusion injury. Hypocretin possesses antioxidant, anti-inflammatory and anti-apoptotic properties, allowing the hypocretinergic system to perform cytoprotective functions, activate proliferation and normalize metabolism [ 139 ]. Patients with cerebral infarction or ischemic injuries have low levels of CSF hypocretins [ 140 , 141 , 142 , 143 ]. Furthermore, CSF hypocretins are reduced in patients with subarachnoid hemorrhage (SAH) for 10 days after the triggering event. CSF hypocretin levels are higher in patients who do not develop DID from complications of delayed ischemic neuronal deficit (DID) caused by symptomatic vasospasm in SAH patients. It is hypothesized that decreased hypocretin production in SAH and DID patients is associated with altered hypocretin signaling in response to ischemia [ 144 ]. Several rodent studies have revealed that hypocretin A strongly induces type 1 hypocretin receptor not only in neurons but also in astrocytes and oligodendrocytes, implying that type 1 hypocretin receptor is primarily associated with a cerebral ischemic insult [ 145 ]. Furthermore, increased expression of type 1 hypocretin receptor expression correlates with decreased hypocretin concentration in ischemic animal models’ cerebrospinal fluid. Notably, Irving et al. [ 45 ] found an increase in mRNA and protein levels of type 1 hypocretin receptor but not type 2 hypocretin receptor, as well as dynamic changes in CSF hypocretin A levels in rat ischemic cortex after permanent middle cerebral artery occlusion (MCAO). These findings imply that significant changes in hypocretin A and type 1 hypocretin receptors may play functional roles in neuronal damage caused by ischemic injury [ 144 ]. Furthermore, intracerebroventricular injection of hypocretin A reduces cerebral infarct volume and improves neural deficits caused by MCAO in mice [ 146 ]. The mechanism underlying hypocretin’s neuroprotective potential is most likely associated with a decrease in apoptotic cells and activation of HIF-1. The administration of an HIF-1 inhibitor, on the other hand, suppresses the stroke-induced increase in HIF-1 and reverses the cytoprotective effect of hypocretin [ 147 ]. Surprisingly, hypocretin promotes neuron survival in the rat cerebral cortex in a concentration-dependent manner. Furthermore, hypocretins have pro-survival properties due to decreased caspase-3 activity [ 148 ]. Hypocretin, according to Harada et al. [ 146 ], promotes the expression of brain-derived neurotrophic factor (BDNF) to enable neuroprotective functions and prevents neural damage in ischemic subjects. Hypocretin treatment altered the cytokine profile in hypocretin/ataxin-3 transgenic ischemic mice, specifically altering the expression of IL-6 and TNF at the mRNA level, implying that a chronic inflammatory response is also involved in this process [ 149 ]. According to these findings, the hypocretinergic system protects nerve cells from cerebral ischemia and ischemic-reperfusion injury by regulating anti-apoptotic and inflammatory responses. As a result, hypocretin deficiency may be responsible for clinical manifestations in stroke patients and may result in narcolepsy disease [ 150 ]. Future advances in our understanding of the common pathological features of stroke, diabetes, and narcolepsy, as well as the mechanisms of hypocretin-associated protection, may point to the possibility of using hypocretins to treat these diseases [ 151 ] ( Figure 3 ).

Diagrammatic representation of the pathological linking between narcolepsy, diabetes and stroke. Hypocretin A and hypocretin B are two types of hypocretins that mediate narcolepsy’s functional role via G protein coupled receptor-hypocretin receptors type 1 and type 2. The downstream cascade activates various transcription factors and implicates in the regulation of several processes. The main common pathogenesis for narcolepsy, diabetes and stroke is hypocretin deficiency. There are numerous underlying pathophysiological mechanisms that are associated that link these diseases.

7.3. Narcolepsy and Alzheimer’s Disease (AD)

Alzheimer’s disease (AD) is a neurodegenerative disease that causes progressive cognitive decline and behavioral impairment. The neuropathological hallmarks of AD include extracellular-amyloidal deposition and the formation of neurofibrillary tangles caused by tau protein hyperphosphorylation, undermining neuronal and synaptic functions. Some studies have concluded that Alzheimer’s disease is associated with hypocretinergic neuronal loss as well as impaired hypocretin neurotransmission, implying that the hypocretin neuronal system plays an important role in the pathogenesis of Alzheimer’s disease [ 151 ]. Fronczek et al. [ 152 ] quantified hypocretin neurons and measured hypocretin levels in the cerebrospinal fluid (CSF) of post-mortem hypothalamus of AD patients and found a 40% decrease in hypocretin neurons and a 14% decrease in CSF hypocretin-1 levels. Increased CSF-hypocretin levels, on the other hand, have been reported in some Alzheimer’s disease patients [ 153 , 154 , 155 , 156 , 157 , 158 ]. As low hypocretin decreases amyloid release, NT1 patients who have lost most of their hypocretin-containing neurons, seem to have a lower risk of developing AD [ 40 , 41 ]. Scammell et al. [ 159 ] suggested that chronic loss of hypocretin signaling provides no protection against Alzheimer’s disease, implying that normal levels of hypocretin are not required in the pathogenesis of the disease [ 160 ].

7.4. Narcolepsy and Parkinson’s Disease

Parkinson’s disease (PD) is characterized by motor-related symptoms such as tremors, rigidity, slowness of movement and difficulty with walking and balance. Comorbid conditions in PD individuals include narcolepsy-like sleep patterns. The intersecting sleep symptoms of both conditions include excessive daytime sleepiness, hallucinations, insomnia and falling into REM sleep more quickly than an average person [ 161 ]. These sleep symptoms are also described in patients suffering from the sleep–wake disorder, i.e., narcolepsy. The International Classification of Sleep Disorders (ICSD-2) narcolepsy criteria use a number of markers for diagnosis, of which the lack or deficiency of cerebrospinal fluid (CSF) hypocretin-1 levels is a key marker. Hypocretin neurons prominently located in the lateral hypothalamus and perifornical nucleus have been proposed to interact with mechanisms involving sleep and arousal [ 162 , 163 ]. Low hypocretin-1 levels in the CSF have been shown to correlate with hypothalamic hypocretin cell loss in narcolepsy and other forms of hypersomnia; therefore, it has been proposed that degenerative damage to hypocretin neurons (such as in PD) may be detected by low CSF hypocretin-1 concentrations and may also explain the sleep symptoms experienced by some PD patients [ 163 ]. The neuropathology of the hypothalamus in Parkinson’s disease indicates a massive hypocretin loss, probably underlying the narcolepsy phenotype [ 164 ]. The benefit of the new, 24 h long acting ropinirole and transdermal rotigotine on sleep and sleepiness is modest. Eventually, the dopamine release in the mesocorticolimbic pathway is increased during rapid eye movement sleep, supporting its role in dopaminergic-induced vivid dreams [ 164 , 165 , 166 ]. Various sleep-related problems, for example, insomnia and symptoms of rapid eye movement behavior disorder, are common in patients with Parkinson’s disease (PD) [ 165 ]. Symptoms of rapid eye movement behavior disorder were associated with symptoms of narcolepsy, including symptoms of cataplexy [ 167 , 168 ]. Chunduri and colleagues [ 161 ] identified genetic signatures that link PD with its comorbid disorders and narcolepsy, including the convergence and intersection of dopaminergic and immune system related signaling pathways. These findings may aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with narcolepsy.

8. Diagnosis and Treatment

The most likely causes of narcolepsy are an autoimmune response against hypocretin-secreting neurons and low CSF-hypocretin levels (110 pg/mL) [ 16 ]. Accurate diagnosis is required for effective treatment [ 169 ]. Cataplexy is a prominent feature of narcolepsy, but it is not a typical symptom limited to narcolepsy patients because it occurs in fainting, malingering and migraine patients as well. Multiple polysomnography or a mean latent sleep test (MLST) is commonly used to diagnose narcolepsy. While a person is sleeping, both tests use physiological measures such as EEG and an electrocardiogram. MSLT is a standard test that has a sensitivity of 78% and a specificity of 93% for narcolepsy diagnosis. According to the ICSD-3 criteria, an MSLT test result of less than 5 min indicates narcolepsy. Comorbidities can influence the MLST result: a decrease in sleep time can be caused by depression or stress, and tension can increase sleep time; therefore, it is critical to interpret MLST results carefully [ 169 ]. The quantification of low hypocretin levels in CSF is another narcolepsy diagnostic test with high sensitivity and specificity, but there is no standard method for it. Indeed, a decreased level of CSF hypocretin has been found in some diseases, including Prader–Willi syndrome [ 170 , 171 ] and multiple sclerosis [ 172 ]. Furthermore, some narcoleptic patients have a normal range of hypocretin [ 173 , 174 ]. Filardi and colleagues [ 175 ] proposed the use of actigraphy for the screening of narcolepsy, as actigraphy provided a reliable objective measurement of sleep quality and daytime napping behavior able to distinguish central disorders of hypersomnolence and in particular narcolepsy type 1.

Despite the lack of a standard measure, the low range for CSF hypocretin for narcolepsy diagnosis must be fixed in order to be correctly interpreted. Furthermore, because the age of narcolepsy onset has a bimodal distribution in terms of childhood and adolescence, age is another important criterion to be considered for the diagnosis and confirmation of the narcolepsy disease [ 34 , 65 , 176 ]. As a result, more dependable and precise methodologies for correct diagnosis and confirmation of narcolepsy are required [ 24 ]. Because no cure for narcolepsy has been discovered to date, almost all established treatments are primarily symptomatic. Nonpharmacological treatment may alleviate some of the symptoms of narcolepsy, taking scheduled naps reduces excessive daytime sleepiness both subjectively and objectively, and a low-carbohydrate, high-protein diet can improve wakefulness. However, no randomized controlled trial has been conducted to support the efficacy of nonpharmacological therapy. Furthermore, treating narcolepsy with nonpharmacological therapy alone is ineffective. According to a report published by the American Academy of Sleep Medicine, “scheduled naps can be beneficial in combating sleepiness but rarely suffice as primary therapy for narcolepsy” [ 167 ]. The primary treatment option for excessive daytime sleepiness is pharmacological therapy [ 16 ]. Current narcolepsy treatments provide some symptomatic relief at the expense of significant side effects. The exact nature of altered functions and effects in type 2 hypocretin receptor mutant dogs is still unknown. If the mutations result in a reduced functional response to hypocretin, the administration of the hypocretin receptor may alleviate narcolepsy symptoms. Similarly, hypocretin administration can reverse the disastrous effects of hypocretin deficiency in knockout mice. Similarly, if a similar pathogenesis occurs in humans, the same treatment for the aforementioned hypocretin agonists or hypocretin administration may be effective. Nonetheless, because hypocretin has been shown to regulate eating behavior, neuroendocrinology, arousal behavior, reward-seeking behavior and pain behavior, major brain systems are likely to be modulated when hypocretins are introduced. The potential effects on the immune system should also be considered [ 81 , 177 ].

8.1. Future Therapeutics

Hypocretin-1 intranasal administration and transplantation of neonatal hypothalamic stem cells into the brainstem are both promising therapeutic approaches. However, intracerebroventricular (ICV) administration of hypocretin-1 restores fragmented sleep patterns to normal levels, which improves wakefulness and reduces cataleptic episodes [ 178 ], but not in hypocretin-2-mutated dogs. Steroids, plasmapheresis and intravenous immunoglobulin are short-term immunomodulatory treatments used to treat autoimmune-induced narcolepsy with cataplexy. Clinical trials for histamine H3 receptor antagonists are currently underway for a variety of central nervous system disorders, including narcolepsy. Following acute administration, these agents can increase wakefulness in cats and rodents, but their effects after repeated dosing have not been reported. In addition, thyrotrophin-releasing hormone and the nicotine patch are both promising new treatments for narcolepsy. Future research is required to validate and establish future treatment options as effective therapeutic strategies for narcolepsy [ 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 ]. Table 1 contains a list of potential therapeutics that may help with narcolepsy symptoms.

Potential therapeutics that may improve narcolepsy symptoms.

8.2. Prospects for Future Research

To better understand the pathological mechanisms of hypocretin neuron loss in narcolepsy, it is necessary to expand our understanding of hypocretin nerve cell neurobiology. Because of significant breakthroughs in induced pluripotent stem cell (iPSCs) technology, in vitro neurological disease modeling for preclinical research has greatly improved. Adult differentiated somatic cells (i.e., human fibroblast cells) are reprogrammed using iPSC technology to generate pluripotent stem-cell-like cells [ 187 ]. In addition to autogenous cell replacement, iPSC technology allows for in vitro disease modeling and the discovery of either generalized or personalized drugs [ 188 ]. Researchers are unable to ensure that susceptibility genes of narcolepsy with cataplexy act cell-autonomously in hypocretin neurons or cell-non-autonomously in the immediate hypothalamic environment using current technology and knowledge. However, these mechanisms do not explain the actions of the immune-related predisposition genes DQB1*06:02 and TCRA. To identify these contributing factors, direct isolation of immune cells or iPSCs from narcolepsy patients, as well as a relevant cell-type differentiation protocol, will be required. Surprisingly, the interactions between hypocretin neurons and their general and immune environments are presumably genotype-dependent, and thus the iPSC approach can help to elucidate it. Nonetheless, the establishment of an in vitro narcolepsy model appears to be extremely difficult at the moment, but hypocretin neurons or hypothalamic cells from patients would be extremely important. A deep understanding of effector immune mechanisms associated with injury or lesion formation is critical for the development of demanding and significant immune therapies.

Given that an autoimmune response is an obvious pathogenesis of narcolepsy, iPSC technology is emerging as a therapeutic intervention; however, using transplantation of differentiated iPSCs can result in anamnestic autoimmune destruction of the therapeutic cells, as seen with islet cell transplantation for autoimmune type 1 diabetes. As a result, the development and application of patient-derived induced pluripotent stem cell systems can ensure the identification of novel potential targets for narcolepsy therapeutic intervention. Immunosuppressive therapies may become necessary in the case of autologous cell transplantation [ 55 ].

More research is needed to develop potential therapeutic strategies for narcolepsy and its incapacitating symptoms. Several large, randomized, placebo-controlled trials have demonstrated that modafinil and sodium oxybate are effective treatments for EDS associated with narcolepsy [ 19 ]. Traditional stimulants such as amphetamine, methamphetamine, dextroamphetamine and methylphenidate are cheap in generic form and widely used in clinical practice, but there is little high-level evidence from published studies. There is an urgent need for randomized trials that compare traditional stimulants to novel somnolytic agents in order to determine the relative efficacy and safety of these agents so that clinicians can appropriately choose between them and rationally prescribe them to individual patients. Furthermore, future research should focus on the development of new, more effective and well-tolerated therapies, as well as EDS primary prevention. Furthermore, despite extensive clinical experience, antidepressants are recommended to treat cataplexy, but they have been poorly validated in clinical trials. Randomized controlled trials of a wide range of antidepressants, particularly in comparison to the expensive but effective sodium oxybate, are desperately needed to assist clinicians in medication selection. Having said that, narcolepsy clinical trials must include children, the elderly, pregnant and nursing women, and other vulnerable populations [ 173 ].

9. Conclusions

Narcolepsy is a rare disease that has a negative impact on a person’s physical, emotional and social well-being. Symptoms of dysregulated REM sleep include cataplexy, sleep paralysis and hypnagogic hallucinations. The exact pathophysiology of narcolepsy is still unknown, despite decades of research. The selective destruction of hypocretin neurons is the most likely cause of narcolepsy with cataplexy. As the downstream cascade activates various transcription factors and is implicated in the regulation of several processes, it seems that the main common pathogenesis for narcolepsy, diabetes and stroke is hypocretin deficiency with a great number of pathophysiological mechanisms that are associated with those diseases. There have been significant advances in highlighting the pathogenesis of narcolepsy, with substantial evidence for an autoimmune response against hypocretin neurons; however, there are some gaps that need to be filled. To treat narcolepsy, more research should be focused on identifying molecular targets and novel autoantigens. In addition to therapeutic advances, standardized criteria for narcolepsy and diagnostic measures are widely accepted, but they may be reviewed and updated in the future with comprehension. Tailored treatment to the patient’s symptoms and clinical diagnosis and future treatment modalities with hypocretin agonists, GABA agonists, histamine receptor antagonists and immunomodulatory drugs should be aimed at addressing the underlying cause of narcolepsy.

Funding Statement

This research received no external funding.

Author Contributions

Conceptualization, V.C., G.E.U., S.O.T., B.L. and N.M.; methodology, V.C., B.C., G.E.U., S.O.T., B.L. and N.M.; validation, V.C., B.C., B.L. and N.M.; formal analysis, V.C., B.L. and N.M.; investigation, V.C., B.L. and N.M.; data curation, V.C., B.C., S.O.T., B.L. and N.M.; writing—original draft preparation, V.C., B.L. and N.M.; writing—review and editing, V.C., B.L. and N.M.; visualization, V.C. and N.M.; supervision, V.C., B.L. and N.M. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Become a member today, It's free!

Remember me

Send my password

Alkermes announces positive topline results from phase 1b study of alks 2680 demonstrating improved wakefulness in patients with narcolepsy type 2 and idiopathic hypersomnia.

— Orexin 2 Receptor Agonist ALKS 2680 Demonstrated Clinically Meaningful and Statistically Significant Improvements from Baseline in Mean Sleep Latency Compared to Placebo at All Doses Tested in Both Narcolepsy Type 2 and Idiopathic Hypersomnia —

— ALKS 2680 Was Generally Well Tolerated at All Doses Tested —

— Dose-Dependent Effects and Pharmacodynamic Profile Support Advancement Into Planned Phase 2 Study —

DUBLIN , April 9, 2024 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today announced positive topline results from the narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) cohorts of a phase 1b , proof-of-concept study evaluating ALKS 2680, the company's novel, investigational, oral orexin 2 receptor (OX2R) agonist in development as a once-daily treatment for narcolepsy. ALKS 2680 data demonstrated clinically meaningful and statistically significant improvements from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT) compared to placebo at all doses tested. ALKS 2680 was generally well tolerated in both patient populations at all doses tested.

The phase 1b NT2 (n=9) and IH (n=8) study cohorts evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of ALKS 2680 via once-daily, single, oral administration. Participants were randomized to a four-way crossover study in which each participant received 5 mg, 12 mg and 25 mg of ALKS 2680, and placebo, with washout periods between each treatment. Topline results from each cohort are as follows:

Narcolepsy Type 2:

• In the nine patients with NT2, treatment with ALKS 2680 demonstrated improved wakefulness compared to placebo at all doses tested, with a clear dose response. Prior to treatment with ALKS 2680, these patients had baseline sleep latencies ranging from 3 to 33 minutes, with a mean sleep latency of 14 minutes at baseline. Treatment with ALKS 2680 resulted in statistically significant and clinically meaningful improvements in sleep latency in these patients with NT2, with a mean change from baseline versus placebo of 12 minutes at the 5 mg dose (p<0.05), 19 minutes at the 12 mg dose (p<0.001), and 21 minutes at the 25 mg dose (p<0.001) (least squares mean difference). Placebo treatment in this cohort resulted in no change in mean sleep latency. At the 12 mg and 25 mg doses, the observed mean MWT scores over an eight-hour period post-dose were within the reported normal range for healthy individuals. 1
• ALKS 2680 was generally well tolerated across all doses tested in participants with NT2. All treatment-emergent adverse events (TEAEs) were transient and self-resolving. TEAEs were mild in severity, with the exception of one moderate case of pollakiuria at the highest dose (25 mg). AEs observed in >1 participant with NT2 and deemed to be related to study drug were pollakiuria, insomnia and dizziness. One mild, transient occurrence of photophobia was reported in a single patient at the 25 mg dose, which self-resolved within two hours of onset.
• There were no serious AEs or AEs leading to discontinuation in patients with NT2. Additionally, there were no clinically meaningful, treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram (ECG) parameters.
• The company plans to initiate a phase 2 study in patients with NT2 in the second half of 2024.

Idiopathic Hypersomnia:

• In the eight patients with IH, treatment with ALKS 2680 demonstrated improved wakefulness compared to placebo at all doses tested, with a clear dose response. Prior to treatment with ALKS 2680, these patients had baseline sleep latencies ranging from 6 to 34 minutes, with a mean sleep latency of 23 minutes at baseline. Treatment with ALKS 2680 resulted in statistically significant and clinically meaningful improvements in sleep latency in these patients with IH, with a mean change from baseline versus placebo of 8 minutes at the 5 mg dose (p<0.05), 11 minutes at the 12 mg dose (p<0.01), and 18 minutes at the 25 mg dose (p<0.001) (least squares mean difference). Placebo treatment in this cohort resulted in a two-minute reduction in mean sleep latency. At the 12 mg and 25 mg doses, the observed mean MWT scores over an eight-hour period post-dose were within the reported normal range for healthy individuals. 1
• ALKS 2680 was generally well tolerated across all doses tested in participants with IH. All TEAEs were transient and self-resolving. TEAEs were mild in severity, with the exception of one moderate case of pollakiuria at the highest dose (25 mg). AEs observed in >1 participant and deemed to be related to study drug were pollakiuria, insomnia and dizziness. One mild, transient occurrence of visual disturbance was reported in a single patient at the 25 mg dose, which self-resolved approximately one hour after onset.
• There were no serious AEs or AEs leading to discontinuation. Additionally, there were no clinically meaningful, treatment-emergent changes in hepatic and renal parameters, vital signs, or ECG parameters.

"The magnitude and durability of effect of ALKS 2680 seen in this proof-of-concept study in patients with narcolepsy type 2 and idiopathic hypersomnia is exciting. These data support further clinical evaluation of ALKS 2680 and demonstrate that orexin 2 receptor agonists such as ALKS 2680 may have utility in treating sleep disorders in patients without known orexin deficiency," said Ron Grunstein , M.D., Ph.D., Head of Sleep and Circadian Research at the Woolcock Institute of Medical Research. "New treatment options are needed, and orexin agonists have the potential to transform the current treatment landscape for people living with narcolepsy."

"We're pleased to share these topline results in patients with narcolepsy type 2 and idiopathic hypersomnia, which build upon our previously disclosed phase 1b data in narcolepsy type 1. These data further validate our hypothesis that an orexin agonist with appropriate pharmaceutical properties has potential to provide significant clinical benefits for both narcolepsy type 1 and type 2 patient populations," said Craig Hopkinson , M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes. "With these data now in hand, we are moving quickly to select doses for a phase 2 study in narcolepsy type 2, which we plan to initiate in the second half of this year."

Alkermes expects to submit results from this phase 1b , proof-of-concept study to a peer-reviewed journal for publication and to present additional ALKS 2680 study results at upcoming scientific meetings.

About the ALKS 2680 Phase 1 Study The phase 1 study for ALKS 2680 included single-ascending dose and multiple-ascending dose evaluations in healthy volunteers, and double-blind, cross-over treatment in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH).

In the healthy volunteer phase of the study, each cohort included eight participants, six of whom were randomized to receive ALKS 2680 and two of whom received placebo. In the single-dose portion, ALKS 2680 was dosed from 1 mg to 50 mg. In the multiple-dose portion, participants received single daily doses of ALKS 2680 ranging from 3 mg to 25 mg strengths for up to 10 days. The objectives of this part of the study were to assess ALKS 2680's safety, tolerability, pharmacokinetics and pharmacodynamics.

The phase 1b proof-of-concept part of the study enrolled patients with NT1 (n=10), NT2 (n=9) or IH (n=8). Following an initial two-week washout period of existing medications, patients received single doses of three active dose levels of ALKS 2680 (1 mg, 3 mg and 8 mg for NT1; 5 mg, 12 mg and 25 mg for NT2 and IH) and placebo in a randomized sequence in a four-way crossover design, with washout periods between each treatment in the sequence. The objectives were to assess safety and tolerability, and changes from baseline in average sleep latency, as measured through the Maintenance of Wakefulness Test (MWT) at each cross-over, along with plasma PK, biomarkers such as quantitative electroencephalogram (qEEG) and event-related potential (ERP), and a cognitive test, the Sustained Attention to Response Task (SART).

About ALKS 2680 ALKS 2680 is a novel, investigational, oral, selective orexin 2 receptor (OX2R) agonist in development as a once-daily treatment for narcolepsy. Orexin neuropeptides are important regulators of the sleep/wake cycle through OX2R activation, and loss of orexinergic neurons in the brain is associated with excessive daytime sleepiness and cataplexy in narcolepsy. 2 ALKS 2680 was designed to address the underlying pathology of narcolepsy with the goal of improving duration of wakefulness and providing cataplexy control. Once-daily oral administration of ALKS 2680 was evaluated in a phase 1 study in healthy volunteers and people living with narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia.

About Alkermes plc Alkermes plc is a global biopharmaceutical company that seeks to develop innovative medicines in the field of neuroscience. The company has a portfolio of proprietary commercial products for the treatment of alcohol dependence, opioid dependence, schizophrenia and bipolar I disorder, and a pipeline of clinical and preclinical candidates in development for neurological disorders. Headquartered in Dublin, Ireland , Alkermes has a research and development center in Waltham, Massachusetts ; a research and manufacturing facility in Athlone, Ireland ; and a manufacturing facility in Wilmington, Ohio . For more information, please visit Alkermes' website at www.alkermes.com .

Note Regarding Forward-Looking Statements Certain statements set forth in this press release constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: the potential therapeutic and commercial value of ALKS 2680; and the company's expectations regarding plans and timelines for further clinical development activities for ALKS 2680, including the phase 2 study and presentation of additional data from the phase 1 study. The company cautions that forward-looking statements are inherently uncertain. Although the company believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, the forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those expressed or implied in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: whether ALKS 2680 could be shown to be ineffective or unsafe; whether preclinical and initial clinical results for ALKS 2680 will be predictive of results of further clinical studies or real-world results; potential changes in the cost, scope and duration of the ALKS 2680 development program; whether future clinical trials or future stages of ongoing clinical trials for ALKS 2680 will be initiated or completed on time or at all; and those risks and uncertainties described under the heading "Risk Factors" in the company's Annual Report on Form 10-K for the year ended Dec. 31, 2023 and in subsequent filings made by the company with the U.S. Securities and Exchange Commission (SEC), which are available on the SEC's website at www.sec.gov . Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by law, the company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release.

1 Krahn LE, Arand DL, Avidan AY, et al. Recommended protocols for the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test in adults: guidance from the American Academy of Sleep Medicine. J Clin Sleep Med. 2021;17(12):2489–2498. 2 Nagahara T, Saitoh T, Kutsumura N, Irukayama-Tomobe Y, Ogawa Y, Kuroda D, Gouda H, Kumagai H, Fujii H, Yanagisawa M, Nagase H. Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists. J Med Chem. 2015 Oct 22;58(20):7931-7. doi: 10.1021/acs.jmedchem.5b00988. Epub 2015 Aug 26. PMID: 26267383.

Alkermes Contacts: For Investors: Sandy Coombs , +1 781 609 6377 For Media: Gretchen Murphy , +1 781 609 6419

SOURCE Alkermes plc

Related News

@ the bell: tsx slips on oil drop, @ the bell: tsx sinks after boc keeps rates firm, @ the bell: how will boc rate decision impact markets, recent u.s. press releases, deadline alert: faruqi & faruqi, llp investigates claims on behalf of investors of ocugen, investigation alert: the schall law firm announces it is investigating claims against globe life..., shareholder alert: levi & korsinsky, llp notifies investors of an investigation into the fairness..., featured news links, private placement: past production (25.7 g/t au, 2,880 g/t ag & 3.2% cu) with upcoming drill program, a buildable green steel project with after-tax irr of 25%, uranium mill takes significant step towards recommencing production, constructing the highest grade undeveloped copper project in the world, g mining ventures provides project update at brazilian gold property, company adds exciting gold property to exploration portfolio in saskatchewan.

Get the latest news and updates from Stockhouse on social media

Follow STOCKHOUSE Today