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

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$a 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.

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