PURPOSE: Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990-2018) and the factors associated with the delay in Europe. PATIENTS AND METHODS: We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. RESULTS: The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7-13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. CONCLUSION: Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.

Center for Investigation and Research in Sleep Lausanne University Hospital Lausanne Vaud Switzerland

Center for Sleep Medicine Sleep Research and Epileptology Klinik Barmelweid AG Barmelweid Aargau Switzerland

Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Department of Biomedical Metabolic and Neural Sciences University of Modena and Reggio Emilia Modena Italy

Department of Clinical Neurophysiology Institute of Psychiatry and Neurology Warsaw Poland

Department of Neurology and Clinical Neurophysiology Leiden University Medical Center Leiden the Netherlands

Department of Neurology Inselspital Bern University Hospital University of Bern Bern Switzerland

Department of Neurology Sechenov 1st Moscow State University Moscow Russia

Department of Sleep Medicine National Institute of Mental Health Klecany Czech Republic

Eindhoven University of Technology Eindhoven the Netherlands

Helsinki Sleep Clinic Vitalmed Research Center Helsinki Finland

Institute for Neurosciences of Montpellier INM Univ Montpellier INSERM Montpellier France

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

National Reference Centre for Orphan Diseases Narcolepsy Idiopathic Hypersomnia and Kleine Levin Syndrome Montpellier France

Neurology Department and Centre of Clinical Neurosciences 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Neurology Department EOC Ospedale Regionale di Lugano Lugano Ticino Switzerland

Neurology Department Hephata Klinik Schwalmstadt Germany

Neurology Department Medical Faculty of P J Safarik University University Hospital of L Pasteur Kosice Kosice Slovak Republic

Neurology Department Sleep Disorders Clinic Innsbruck Medical University Innsbruck Austria

Neurology Service Institut de Neurociències Hospital Clínic University of Barcelona Barcelona Spain

Neurophysiology and Sleep Disorders Unit Hospital Vithas Nuestra Señora de América Madrid Spain

Serviço de Neurofisiologia Hospital Santo António Centro Hospitalar Universitário do Porto and UMIB Instituto Ciências Biomédicas Abel Salazar Universidade do Porto Porto Portugal

Sleep and Epilepsy Unit Clinical Neurophysiology Service University General Hospital Gregorio Marañón Research Institute Gregorio Marañón University Complutense of Madrid Madrid Spain

Sleep Medicine Center Kempenhaeghe Heeze the Netherlands

Sleep Wake Center SEIN Heemstede Stichting Epilepsie Instellingen Nederland Heemstede the Netherlands

Sleep Wake Disorders Unit Department of Neurology Gui de Chauliac Hospital CHU Montpellier Montpellier France

Zobrazit více v PubMed

Bassetti CLA, Adamantidis A, Burdakov D, et al. Narcolepsy - clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol. 2019;15:519–539. doi:10.1038/s41582-019-0226-9 PubMed DOI

Ohayon MM. Epidemiology of narcolepsy. In: Bassetti C, Billiard M, Mignot E, editors. Narcolepsy and Hypersomnia. New York: Informa Healthcare; 2007:125–132.

Khatami R, Luca G, Baumann CR, et al. The European Narcolepsy Network (EU-NN) database. J Sleep Res. 2016;25(3):356–364. doi:10.1111/jsr.12374 PubMed DOI

American Academy of Sleep Medicine. The International Classification of Sleep Disorders. Third ed. Darien, IL: American Academy of Sleep Medicine; 2014.

Dauvilliers Y, Arnulf I, Lecendreux M, et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain. 2013;136(Pt 8):2486–2496. doi:10.1093/brain/awt187 PubMed DOI

Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7(3):e33723. doi:10.1371/journal.pone.0033723 PubMed DOI PMC

Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med. 2014;15(5):502–507. doi:10.1016/j.sleep.2014.01.015 PubMed DOI

Jennum P, Ibsen R, Petersen ER, 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. 2012;13(8):1086–1093. doi:10.1016/j.sleep.2012.06.006 PubMed DOI

Broughton RJ, Fleming JA, George CF, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology. 1997;49(2):444–451. doi:10.1212/WNL.49.2.444 PubMed DOI

Dauvilliers Y, Molinari N, Espa F, et al. Delay of diagnosis of narcolepsy in a European and in a North American population. J Sleep Res. 1998;7(Suppl 2):56.

Thorpy M, Cronin S, Temple H. Age of onset and time to diagnosis of narcolepsy. Neurology. 1999;52:6.

Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med. 2004;5(1):37–41. doi:10.1016/j.sleep.2003.06.002 PubMed DOI

BaHammam AS, Alenezi AM. Narcolepsy in Saudi Arabia. Demographic and clinical perspective of an under-recognized disorder. Saudi Med J. 2006;27(9):1352–1357. PubMed

Ingravallo F, Gnucci V, Pizza F, et al. The burden of narcolepsy with cataplexy: how disease history and clinical features influence socio-economic outcomes. Sleep Med. 2012;13(10):1293–1300. doi:10.1016/j.sleep.2012.08.002 PubMed DOI

Frauscher B, Ehrmann L, Mitterling T, et al. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the innsbruck narcolepsy cohort. J Clin Sleep Med. 2013;9(8):805–812. doi:10.5664/jcsm.2926 PubMed DOI PMC

Ueki Y, Hayashida K, Komada Y, et al. Factors associated with duration before receiving definitive diagnosis of narcolepsy among Japanese patients affected with the disorder. Int J Behav Med. 2014;21(6):966–970. doi:10.1007/s12529-013-9371-5 PubMed DOI

Taddei RN, Werth E, Poryazova R, Baumann CR, Valko PO. Diagnostic delay in narcolepsy type 1: combining the patients’ and the doctors’ perspectives. J Sleep Res. 2016;25(6):709–715. doi:10.1111/jsr.12420 PubMed DOI

Maski K, Steinhart E, Williams D, et al. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden, and treatment efficacy. J Clin Sleep Med. 2017;13(3):419–425. doi:10.5664/jcsm.6494 PubMed DOI PMC

Luca G, Haba-Rubio J, Dauvilliers Y, et al. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J Sleep Res. 2013;22(5):482–495. doi:10.1111/jsr.12044 PubMed DOI

Ohayon MM, Thorpy MJ, Carls G, et al. The nexus narcolepsy registry: methodology, study population characteristics, and patterns and predictors of narcolepsy diagnosis. Sleep Med. 2021;84:405–414. doi:10.1016/j.sleep.2021.06.008 PubMed DOI

Tio E, Gaig C, Giner-Soriano M, et al. The prevalence of narcolepsy in Catalunya (Spain). J Sleep Res. 2018;27(5):e12640. doi:10.1111/jsr.12640 PubMed DOI

Zhang Z, Mayer G, Dauvilliers Y, et al. Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European narcolepsy network database with machine learning. Sci Rep. 2018;8(1):10628. doi:10.1038/s41598-018-28840-w PubMed DOI PMC

Zhang Z, Gool JK, Fronczek R, et al. New 2013 incidence peak in childhood narcolepsy: more than vaccination? Sleep. 2021;44:2. doi:10.1093/sleep/zsaa172 PubMed DOI

Nadarajah S, Haghighi F. An extension of the exponential distribution. Statistics. 2011;45(6):543–558. doi:10.1080/02331881003678678 DOI

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;38:177–186. doi:10.1016/j.smrv.2017.06.006 PubMed DOI

Roenneberg T, Kuehnle T, Pramstaller PP, et al. A marker for the end of adolescence. Curr Biol. 2004;14(24):R1038–1039. doi:10.1016/j.cub.2004.11.039 PubMed DOI

Obremski TE. Practical nonparametric statistics. Technometrics. 1981;23(4):415–416.

Hastie T, Tibshirani R, Friedman J. Boosting and Additive Trees the Elements of Statistical Learning: data Mining, Inference, and Prediction. New York, NY: Springer New York; 2009.

Friedman JH. Stochastic gradient boosting. Comput Stat Data Anal. 2002;38(4):367–378. doi:10.1016/S0167-9473(01)00065-2 DOI

Nakagawa S, Schielzeth H. A general and simple method for obtaining R2 from generalized linear mixed-effects models. Methods Ecol Evol. 2013;4(2):133–142. doi:10.1111/j.2041-210x.2012.00261.x DOI

Xu R. Measuring explained variation in linear mixed effects models. Stat Med. 2003;22(22):3527–3541. doi:10.1002/sim.1572 PubMed DOI

Kuhn M. Building predictive models in R using the caret package. J Stat Softw. 2008;28(5):26. doi:10.18637/jss.v028.i05 DOI

Okun ML, Lin L, Pelin Z, Hong S, Mignot E. Clinical aspects of narcolepsy-cataplexy across ethnic groups. Sleep. 2002;25(1):27–35. doi:10.1093/sleep/25.1.27 PubMed DOI

Ohayon MM, Ferini-Strambi L, Plazzi G, Smirne S, Castronovo V. How age influences the expression of narcolepsy. J Psychosom Res. 2005;59(6):399–405. doi:10.1016/j.jpsychores.2005.06.065 PubMed DOI

Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology. 2001;57(11):2029–2033. doi:10.1212/WNL.57.11.2029 PubMed DOI

Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70(3):410–417. doi:10.1002/ana.22587 PubMed DOI

Latorre D, Kallweit U, Armentani E, et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature. 2018;562(7725):63–68. doi:10.1038/s41586-018-0540-1 PubMed DOI

Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 2014;13(6):600–613. doi:10.1016/S1474-4422(14)70075-4 PubMed DOI

Pedersen NW, Holm A, Kristensen NP, et al. CD8(+) T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens. Nat Commun. 2019;10(1):837. doi:10.1038/s41467-019-08774-1 PubMed DOI PMC

Bernard-Valnet R, Yshii L, Queriault C, et al. CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice. Proc Natl Acad Sci U S A. 2016;113(39):10956–10961. doi:10.1073/pnas.1603325113 PubMed DOI PMC

Won C, Mahmoudi M, Qin L, Purvis T, Mathur A, Mohsenin V. The impact of gender on timeliness of narcolepsy diagnosis. J Clin Sleep Med. 2014;10(1):89–95. doi:10.5664/jcsm.3370 PubMed DOI PMC

Coffey AA, Joyal AA, Yamanaka A, Scammell TE. The impacts of age and sex in a mouse model of childhood narcolepsy. Front Neurosci. 2021;15:644757. doi:10.3389/fnins.2021.644757 PubMed DOI PMC

Piilgaard L, Rose L, Hviid CG, Kohlmeier KA, Kornum BR. Sex-related differences within sleep-wake dynamics, cataplexy, and EEG fast-delta power in a narcolepsy mouse model. Sleep. 2022. doi:10.1093/sleep/zsac058 PubMed DOI

Macleod S, Ferrie C, Zuberi SM. Symptoms of narcolepsy in children misinterpreted as epilepsy. Epileptic Disord. 2005;7(1):13–17. PubMed

Rocca FL, Finotti E, Pizza F, et al. Psychosocial profile and quality of life in children with type 1 narcolepsy: a case-control study. Sleep. 2016;39(7):1389–1398. doi:10.5665/sleep.5970 PubMed DOI PMC

Oosterloo M, Lammers GJ, Overeem S, de Noord I, Kooij JJ. Possible confusion between primary hypersomnia and adult attention-deficit/hyperactivity disorder. Psychiatry Res. 2006;143(2–3):293–297. doi:10.1016/j.psychres.2006.02.009 PubMed DOI

Plazzi G, Pizza F, Palaia V, et al. Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain. 2011;134(Pt 12):3477–3489. doi:10.1093/brain/awr244 PubMed DOI PMC

Quaedackers L, Pillen S, Overeem S. Recognizing the symptom spectrum of narcolepsy to improve timely diagnosis: a narrative review. Nat Sci Sleep. 2021;13:1083–1096. doi:10.2147/NSS.S278046 PubMed DOI PMC

Lecendreux M, Lavault S, Lopez R, et al. Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms in pediatric narcolepsy: a cross-sectional study. Sleep. 2015;38(8):1285–1295. doi:10.5665/sleep.4910 PubMed DOI PMC

Dauvilliers Y, Beziat S, Pesenti C, et al. Measurement of narcolepsy symptoms: the narcolepsy severity scale. Neurology. 2017;88(14):1358–1365. doi:10.1212/WNL.0000000000003787 PubMed DOI

Barateau L, Lecendreux M, Chenini S, et al. Measurement of narcolepsy symptoms in school-aged children and adolescents: the pediatric narcolepsy severity scale. Neurology. 2021;97(5):e476–e488. doi:10.1212/WNL.0000000000012272 PubMed DOI

Lividini A, Pizza F, Filardi M, et al. Narcolepsy type 1 features across the life span: age impact on clinical and polysomnographic phenotype. J Clin Sleep Med. 2021;17(7):1363–1370. doi:10.5664/jcsm.9198 PubMed DOI PMC

Maski K, Mignot E, Plazzi G, Dauvilliers Y. Disrupted nighttime sleep and sleep instability in narcolepsy. J Clin Sleep Med. 2022;18(1):289–304. doi:10.5664/jcsm.9638 PubMed DOI PMC

Bassetti CLA, Kallweit U, Vignatelli L, et al. European guideline and expert statements on the management of narcolepsy in adults and children. Eur J Neurol. 2021;28(9):2815–2830. doi:10.1111/ene.14888 PubMed DOI

Barateau L, Lopez R, Chenini S, et al. Linking clinical complaints and objective measures of disrupted nighttime sleep in narcolepsy type 1. Sleep. 2022. doi:10.1093/sleep/zsac054 PubMed DOI

Schuld A, Hebebrand J, Geller F, Pollmacher T. Increased body-mass index in patients with narcolepsy. Lancet. 2000;355(9211):1274–1275. doi:10.1016/S0140-6736(05)74704-8 PubMed DOI

Nishino S, Ripley B, Overeem S, et al. Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol. 2001;50(3):381–388. doi:10.1002/ana.1130 PubMed DOI

Fortuyn HA, Swinkels S, Buitelaar J, et al. High prevalence of eating disorders in narcolepsy with cataplexy: a case-control study. Sleep. 2008;31(3):335–341. doi:10.1093/sleep/31.3.335 PubMed DOI PMC

van Holst RJ, van der Cruijsen L, van Mierlo P, et al. Aberrant food choices after satiation in human orexin-deficient narcolepsy type 1. Sleep. 2016;39(11):1951–1959. doi:10.5665/sleep.6222 PubMed DOI PMC

Dietmann A, Wenz E, van der Meer J, et al. The Swiss Primary Hypersomnolence and Narcolepsy Cohort study (SPHYNCS): study protocol for a prospective, multicentre cohort observational study. J Sleep Res Apr. 2021;30:e13296. PubMed PMC

Cook JD, Prairie ML, Plante DT. Ability of the multisensory jawbone UP3 to quantify and classify sleep in patients with suspected central disorders of hypersomnolence: a comparison against polysomnography and actigraphy. J Clin Sleep Med. 2018;14(5):841–848. doi:10.5664/jcsm.7120 PubMed DOI PMC

Quaedackers L, De Wit J, Pillen S, et al. A mobile app for longterm monitoring of narcolepsy symptoms: design, development, and evaluation. JMIR Mhealth Uhealth. 2020;8(1):e14939. doi:10.2196/14939 PubMed DOI PMC

Daytime sleepiness and BMI exhibit gender and age differences in patients with central disorders of hypersomnolence

Central Disorders of Hypersomnolence: Association with Fatigue, Depression and Sleep Inertia Prevailing in Women