Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009-2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009-2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy.

AP HP Pediatric Sleep Center CHU Robert Debré Paris France

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

Center for Sleep Medicine Sleep Research and Epileptology Clinic Barmelweid AG Barmelweid Switzerland

Centre de Reference Nationale Maladies Rares Narcolepsie et Hypersomnie Idiopathique Service Neurologie Hôpital Gui de Chauliac INSERM U1061 Université de Montpellier Montpellier France

Department of Anatomy and Neurosciences Amsterdam UMC Amsterdam The Netherlands

Department of Biomedical and Neuromotor Sciences Alma Mater Studiorum University of Bologna Bologna 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 and University of Bern Bern Switzerland

Department of Neurology Sechenov University Moscow Russian Federation

Department of Sleep Medicine and Neuromuscular Disorders University of Münster Münster Germany

Eindhoven University of Technology Eindhoven The Netherlands

Fundació Institut d'Investigació Sanitària Illes Balears Hospital Universitari Son Espases Palma de Mallorca Spain

Helsinki Sleep Clinic Vitalmed Research Center Helsinki Finland

Institute of Molecular Medicine Portugal Medical Faculty Lisbon University Lisbon Portugal

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

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

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

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 Medical University of Innsbruck Innsbruck Austria

Neurology Department University Hospital Zurich Zurich Switzerland

Neurology Service Multidisciplinary Sleep Unit Hospital Clínic of Barcelona IDIBAPS CIBERNED Barcelona 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 Center Neurocenter of Southern Switzerland Lugano Switzerland

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

Unidad de Neurofisiología y Trastornos del Sueño Hospital Vithas Internacional Madrid Madrid Spain

Data-Driven Phenotyping of Central Disorders of Hypersomnolence With Unsupervised Clustering

Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis