The incidence of narcolepsy in Europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns
Highlights
► We identified 2608 narcolepsy cases in 6 EU countries between 2000 and 2010. ► After pandemic vaccination, incidence rates increased in Finland, Sweden and Denmark. ► In Denmark, the increase did not follow high pandemic vaccination coverage. ► In Italy, the Netherlands and the United Kingdom no increased rates were seen.
Introduction
Narcolepsy is a disabling chronic sleep disorder that interferes severely with normal daily activities, interpersonal relations, education, and career opportunities [1], [2]. The classic clinical syndrome consists of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic hallucinations and disrupted nocturnal sleep. While cataplexy is considered pathognomonic for narcolepsy, it is not always part of the clinical presentation. In contrast to narcolepsy with cataplexy, narcolepsy without cataplexy is probably not a single disease entity. Regardless of the variety and extent of symptoms at presentation, further laboratory investigations to confirm the diagnosis are state of the art today. Nocturnal polysomnography and multiple sleep latency test (MSLT) are performed most frequently. However, the specificity of these investigations is limited [3]. Determining very low or undetectable levels of the neuropeptide hypocretin-1 (also called orexin A) in the cerebrospinal fluid levels is a novel diagnostic approach with high specificity for the diagnosis of narcolepsy with and without cataplexy, and high sensitivity for narcolepsy with cataplexy although less so for narcolepsy without cataplexy [4]. Hypocretin-1 testing is a recent development, however not yet standardized and not widely available. Furthermore, HLA DQB1*0602 is strongly associated with but not specific for the narcolepsy diagnosis, as it is present in 12–38% of the normal European population, depending on the genetic origin [5]. As a consequence, many patients are diagnosed long after onset of symptoms, with delays ranging from 1 to 60 years [6], [7].
The narcolepsy diagnosis is particularly challenging in children due to a wide range of daytime sleep requirements, which are often considered normal in this age group. In addition, cataplexy in children may present with atypical features (i.e. absence of triggering emotions, a semipermanent state of facial muscle weakness on which partial or complete cataplectic attacks are superimposed), first described in 2008 [8], [9] Moreover, there is currently a lack of objective diagnostic criteria specific to the paediatric phenotype [1]. As a result, narcolepsy in childhood is possibly an underdiagnosed disease [10].
The estimated prevalence of narcolepsy in Western countries is 20–50 per 100,000 [2], [11], [12]. It is thought to affect men and women equally, although a male predominance has been found in some studies [13]. More than 50% of narcolepsy cases appear to exhibit symptom onset before 18 years of age, beginning typically in adolescence [14], [15], [16]. Bimodal peaks of onset have been reported, with one peak around 15 years of age (range 10–19 years) and another around 35 years [14]. In the past, diagnoses were typically not established prior to early adulthood in the majority of cases [6].
Little is known about the aetiology of narcolepsy. The strong association between hypocretin-1 deficiency and the presence of the HLA subtype DQB1*0602 [17] has led to the hypothesis that an autoimmune process may lead to loss of hypocretin producing neurons. However, as only very few carriers of this allele develop narcolepsy, other factors must contribute to its development. Given the age at onset of symptoms it is thought that an exposure which could trigger narcolepsy would occur during or before adolescence [12]. Some studies have focused specifically on environmental factors and disease inducing or promoting health events preceding clinical manifestation of narcolepsy. These types of studies are typically hampered by the considerable uncertainties around aetiology and pathogenesis of narcolepsy as well as the associated methodological difficulties, such as underdiagnosis and recall-bias [12]. Recently, streptococcal infection markers and antibodies against the protein Tribbles homolog 2 have been found to be associated with narcolepsy [18], [19], [20]. In addition, a study from China reported an increase in narcolepsy in children following influenza A(H1N1)pdm09 infection [21]. To the best of our knowledge, no association between vaccination and narcolepsy has been described prior to 2010.
Eight influenza A(H1N1)pdm09 vaccines [Cantgrip (Cantacuzino), Celvapan (Baxter), Celltura (Novartis), Fluval P (Omnivest), Focetria (Novartis), Pandemrix (GSK), Panenza (Sanofi Pasteur) and PanvaxH1N1 (CSL)] were licensed within the EU/EEA area during the 2009 pandemic. International recommendations on which groups should be offered vaccination and in what order came from the Strategic Advisory Group of Experts (SAGE) Committee of the World Health Organization (WHO) and the EU Health Security Committee, which were taken into account in national decisions on priority groups. AS03-adjuvanted Pandemrix® was the most used vaccine in Europe [22].
Two EU Member States participating in this study (Finland and Sweden) recommended vaccines to their entire population while other Member States (Denmark, Italy, the Netherlands and the United Kingdom) recommended vaccines only to selected risk groups, notably individuals with chronic disorders and in case of the Netherlands also children younger than five years of age [22].
In August 2010 reports of a possible association between exposure to AS03 adjuvanted influenza A(H1N1)pdm09 vaccine and occurrence of narcolepsy commonly with cataplexy in children and adolescents emerged in both Sweden and Finland. This led to the discontinuation of the general recommendation of this vaccine in these countries and a review of the vaccine by the European Medicines Agency (EMA). Subsequently, cases following influenza A(H1N1)pdm09 vaccination and infection were reported from France, Germany [23] and Norway [24], Canada and the US [25], [26]. Since then more cases have been identified, mostly in children and adolescents in the initial two signalling countries. A registry study in Finland detected a 12.7-fold increase in narcolepsy in association with the AS03 adjuvanted influenza A(H1N1)pdm09 vaccine [27], [28]. Two Swedish studies have detected a relative risks of 4.2 in a rapid cohort study [29] and 6.6 in a case series study [30]. More recently, a 13-fold increase in risk of narcolepsy was found associated with Pandemrix vaccination in a cohort study in Ireland [31] and a case control study in France found an increased risk of 4.6 [32]. The Irish and French studies both also identified an increased risk in persons over 19 years of age, while this has not been reported from Sweden and Finland. As of August 2012 more than 600 cases of narcolepsy following influenza A(H1N1)pdm09 vaccination have been reported to the Eudravigilance database, of which more than 100 are reported to have occurred in adults [33].
In response to the signal from Sweden and Finland, a study into the background rates of narcolepsy in Europe was started by the VAESCO (Vaccine Adverse Events Surveillance and Communication) consortium on request of and in collaboration with the European Centre for Disease Prevention and Control (ECDC). The aim of the study was to provide information to ECDC, the EMA and national agencies for signal verification and public health decision making. Here we present the main findings of this study.
Section snippets
Design and setting
A dynamic retrospective cohort study was used to assess the rates of narcolepsy diagnosis during the period 2000–2010 in six countries with large linked automated health care databases. Participating countries were: Denmark, Finland, Italy (Tuscany and Emilia Romagna regions), the Netherlands (NL), Sweden, and the United Kingdom (UK). Although Norway provided data, insufficient data history was available to exclude prevalent cases. Therefore incidence rates could not be calculated and the
Results
The seven participating databases from six countries provided just under 280 million person years (PY) of observation time. Denmark, Emilia Romagna region in Italy and Sweden provided data up until December 2010. Finland provided data up until December 2009 and age specific counts for 2010. The Tuscany region in Italy, the NL-IPCI database and the UK-GPRD database provided data up until June, July, and October 2010, respectively. The cumulative amount of person-time by centre and calendar year
Discussion
To the best of our knowledge, this is the largest published study on narcolepsy epidemiology to date. It was designed as a proof of principle study utilizing the described approach to inform public health decision-making during an emerging public vaccine safety concern.
Incidence rate data of narcolepsy were useful to quantify background diagnostic rates and to provide insight into changing epidemiologic patterns of diagnoses over time, by age, sex, and country [41]. We found the incidence of
Conflict of interest statement
Miriam CJM Sturkenboom is head of a research group that occasionally conducts research for pharmaceutical companies including Pfizer, EliLilly, Boehringer, AstraZeneca and Novartis. None was related to this topic.
Markku Partinen has been a member of the medical advisory board of UCB Pharma and Leiras-Nycomed. He has received honoraries for lecturing and travel grants from Cephalon, GSK, Leiras-Nycomed, MSD, and UCB.
All other authors do not have any potential conflicts of interest related to
Acknowledgements
Erasmus MC, Rotterdam, NL: A. Vanrolleghem. RIVM, Bilthoven, NL: H. de Melker.
Danish Center for Sleep Medicine, Copenhagen, DK: S. Knudsen. Karolinska Institutet, Stockholm, SE: J. Pege.
National Public Health Institute, Helsinki, FI: H. Nohynek, J. Jokinen, T. Kilpi, Norwegian Institute of Public Health, Oslo, NO: J. Storsaeter. University Hospital, Oslo, NO: K. Bronder. HPA, London, UK: N. Andrews. Brighton Collaboration, Basel, Switzerland: S. Faisst.
This study is based in part on data from
References (44)
- et al.
Narcolepsy: immunological aspects
Sleep Med Rev
(2008) - et al.
Narcolepsy
- et al.
Factors associated with a delay in the diagnosis of narcolepsy
Sleep Med Rev
(2004) Narcolepsy in childhood
Sleep Med Rev
(2009)- et al.
Clinical features, diagnosis and treatment of narcolepsy
Clin Chest Med
(2010) - et al.
Hypocretin/orexin disturbances in neurological disorders
Sleep Med Rev
(2009) - et al.
Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain
Curr Opin Neurobiol
(2011) - et al.
Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines
Lancet
(2009 Dec 19) - et al.
Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test
Sleep
(2005)