600 www.thelancet.com/neurology Vol 13 June 2014 Review Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination Markku Partinen, Birgitte Rahbek Kornum, Giuseppe Plazzi, Poul Jennum, Ilkka Julkunen, Outi Vaarala Narcolepsy is a sleep disorder characterised by loss of hypothalamic hypocretin (orexin) neurons. The prevalence of narcolepsy is about 30 per 100 000 people, and typical age at onset is 12–16 years. Narcolepsy is strongly associated with the HLA-DQB1*06:02 genotype, and has been thought of as an immune-mediated disease. Other risk genes, such as T-cell-receptor α chain and purinergic receptor subtype 2Y11, are also implicated. Interest in narcolepsy has increased since the epidemiological observations that H1N1 infection and vaccination are potential triggering factors, and an increase in the incidence of narcolepsy after the pandemic AS03 adjuvanted H1N1 vaccination in 2010 from Sweden and Finland supports the immune-mediated pathogenesis. Epidemiological observations from studies in China also suggest a role for H1N1 virus infections as a trigger for narcolepsy. Although the pathological mechanisms are unknown, an H1N1 virus-derived antigen might be the trigger. Introduction Narcolepsy is a rare hypersomnia of central origin, characterised by a dissociate state of the sleep–wake system with rapid eye movement (REM) sleep intrusions into wakefulness (hypersomnia). In the first descriptions of this disease, 1,2 it was defined as a combination of daytime sleep attacks and cataplexy (sudden episodes of striated muscle weakness that are usually triggered by emotions). In the diagnostic classification of sleep and arousal disorders published in 1979, 3 and in the first International Classification of Sleep Disorders (ICSD), 4 idiopathic hypersomnia (but never cataplexy and not related to REM sleep abnormality) was discriminated from narcolepsy. In ICSD (2001) and ICSD-2 5 (2005) narcolepsy was classified into two main types: narcolepsy with cataplexy, and narcolepsy without cataplexy. Two new terms—type 1 narcolepsy and type 2 narcolepsy— were introduced in 2014, in the ICSD-3. 6 The most common symptom of both clinical forms is excessive daytime sleepiness with unintentional lapses into sleep. Disrupted nocturnal sleep with frequent awakenings is also common, mainly in narcolepsy with cataplexy. Additionally, some patients experience hypnagogic (at sleep onset) or hypnopompic (at awakening) hallucinations, sleep paralyses, and nightmares. The presence and frequency of these additional symptoms vary depending on the age at onset and duration of the disease. 7 Common terms used in narcolepsy are defined in panel 1. Type 1 narcolepsy, as classified in the new ICSD-3 of the American Academy of Sleep Medicine, 6 is caused by the loss of hypothalamic hypocretin (orexin)-producing neurons. 9,10 Decreased concentrations of cerebrospinal fluid hypocretin (orexin) are characteristic of narcolepsy, and especially narcolepsy with cataplexy. 14 Genetic risk of narcolepsy is strongly associated with the HLA- DQB1*06:02 allele, providing evidence of narcolepsy as a T-cell-mediated autoimmune disease similar to other HLA-associated diseases such as type 1 diabetes or coeliac disease. The exact mechanisms of autoimmunity are, however, poorly understood. Streptococcal and influenza infections have been proposed as environmental triggers of the autoimmune process leading to narcolepsy. However, the evidence of these infections being the causative agents for narcolepsy has been indirect and relatively weak. After the H1N1 vaccination campaign during the pandemic in 2009–10, a rapid increase in the incidence of narcolepsy was reported, especially in children and adolescents who were vaccinated with AS03 adjuvanted Pandemrix vaccine. Importantly, in controlled epidemio- logical studies, when individuals who had and who had not been vaccinated with Pandemrix were compared, an increased risk of narcolepsy was noted in vaccinated individuals in many European countries. 15–22 At the same time an increase in incidence was reported from northern China, where the vaccine was not used, 23 which suggests that H1N1 virus infection could be an environmental trigger for narcolepsy. In this Review we outline the epidemiological, clinical, genetic, and pathophysiological features of narcolepsy. We discuss the possible role of the H1N1 virus infection and vaccination. We also discuss the potential benefits of immunomodulatory treatment, together with data on the evolution of the disease and effect of treatment and suggest future directions for pathophysiological studies and treatment options. Epidemiology Prevalence of narcolepsy According to most epidemiological studies, the geometric mean prevalence of narcolepsy is about 30 (95% CI 15–60) per 100 000 people (table 1). 24–34 The highest reported prevalence is from Japan 24 (160 per 100 000), and the lowest figures are from Israel (0·23 per 100 000) and Saudi Arabia (4·00 per 100 000). 25,26 Some rare hereditary forms have also been described, 35–37 such as autosomal dominant cerebellar ataxia, deafness, and narcolepsy. 35 Differences in the frequency of the HLA-DQB1*06:02 risk haplotype in different ethnic groups and countries is a possible explanation for the global differences in the Lancet Neurol 2014; 13: 600–13 Helsinki Sleep Clinic, Vitalmed Research Centre, Helsinki, Finland (Prof M Partinen MD); Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland (M Partinen); Molecular Sleep Laboratory, Department of Diagnostics, Glostrup Hospital, Glostrup, Denmark (B R Kornum PhD); Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy (G Plazzi MD); IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy (G Plazzi); Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark (Prof P Jennum MD); Department of Virology, University of Turku, Turku, Finland (Prof I Julkunen MD); Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland (I Julkunen); and Department of Vaccines and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland (Prof O Vaarala MD) Correspondence to: Markku Partinen, Helsinki Sleep Clinic, Vitalmed Research Centre, Sitratori 3, 00420 Helsinki, Finland markku.partinen@helsinki.fi