A Case-Control Study of the Environmental Risk Factors for Narcolepsy

Picchioni, Dante; Hope, Chris; Harsh, John R.

doi:10.1159/000111581

Cited by 56 publications

(27 citation statements)

References 51 publications

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“…4 Diagnostic delay is less in those with cataplexy and in younger patients. 5 There is a strong association with human leucocyte antigen (HLA) DQB1*0602 and reported associations with environmental factors such as streptococcal infection, 6 seasonal influenza, 7 and more recently pandemic A/H1N1 2009 influenza. 8 In England, a monovalent pandemic strain vaccine containing the oil-in-water adjuvant AS03 (Pandemrix) was introduced in October 2009 during the second wave of infection, initially for people with high risk clinical conditions 9 10 and then in healthy children aged under 5 from mid-December 2009.…”

Section: Introductionmentioning

confidence: 99%

Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis

Miller¹,

Andrews²,

Stellitano

et al. 2013

BMJ

272

146

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Setting Sleep centres and paediatric neurology centres in England.Participants Children and young people aged 4-18 with onset of narcolepsy from January 2008. Main outcome measuresThe odds of vaccination in those with narcolepsy compared with the age matched English population after adjustment for clinical conditions that were indications for vaccination. The incidence of narcolepsy within six months of vaccination compared with the incidence outside this period measured with the self controlled cases series method.Results Case notes for 245 children and young people were reviewed; 75 had narcolepsy (56 with cataplexy) and onset after 1 January 2008. Eleven had been vaccinated before onset; seven within six months. In those with a diagnosis by July 2011 the odds ratio was 14.4 (95% confidence interval 4.3 to 48.5) for vaccination at any time before onset and 16.2 (3.1 to 84.5) for vaccination within six months before onset. The relative incidence from the self controlled cases series analysis in those with a diagnosis by July 2011 with onset from October 2008 to December 2010 was 9.9 (2.1 to 47.9). The attributable risk was estimated as between 1 in 57 500 and 1 in 52 000 doses. ConclusionThe increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland. Because of variable delay in diagnosis, however, the risk might be overestimated by more rapid referral of vaccinated children. IntroductionNarcolepsy is a chronic disorder presenting with excessive daytime sleepiness, often accompanied by a transient loss of muscle tone triggered by strong emotion (cataplexy). Diagnosis is based on clinical criteria and can be confirmed by polysomnography followed by a multiple sleep latency test. 1 Estimates of prevalence generally range between 25 and 50 per 100 000, though might be less in some populations, possibly because of differences in genetic susceptibility or exposure to aetiological risk factors.2 Information on incidence is more limited. Onset can occur at any age 2 but is commonest in those aged 10-19, in whom an incidence of 3.84 per 100 000 person years has been reported. 3 The interval between onset and diagnosis can be long, with a median of 10.5 years in one study. 4 Diagnostic delay is less in those with cataplexy and in younger patients. 5 There is a strong association with human leucocyte antigen (HLA) DQB1*0602 and reported associations with environmental factors such as streptococcal infection, 6 seasonal influenza, 7 and more recently pandemic A/H1N1 2009 influenza. 8 In England, a monovalent pandemic strain vaccine containing the oil-in-water adjuvant AS03 (Pandemrix) was introduced in October 2009 during the second wave of infection, initially for people with high risk clinical conditions 9 10 and then in healthy 12 A second pandemic vaccine was used (Celvepan) but accounted for less than 1% of the total.In August 2010 concerns were raised in Finland and Sweden about a possible associat...

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Section: Introductionmentioning

confidence: 99%

Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis

Miller¹,

Andrews²,

Stellitano

et al. 2013

BMJ

272

146

View full text Add to dashboard Cite

show abstract

“…Indeed, a study already in 2007 in USA had found an association between self-reported flu a year prior to narcolepsy and in 2009–2010 this was confirmed by an independent study in Chinese [13, 40]. The second study showed that narcolepsy onset is seasonal and preferentially occurs after the flu season [13, 40]. In 2009–2010 flu season it became clear that one of the strongest environmental triggers for narcolepsy was influenza-A as both infection and vaccination for H1N1 pandemic influenza-A [13].…”

Section: Epidemiology Of Narcolepsy – Role Of Influenza Vaccination Amentioning

confidence: 71%

“…Importantly, clinicians had long suspected that narcolepsy was related to seasonal infections such as influenza [40] and strep throat [41]. Indeed, a study already in 2007 in USA had found an association between self-reported flu a year prior to narcolepsy and in 2009–2010 this was confirmed by an independent study in Chinese [13, 40]. The second study showed that narcolepsy onset is seasonal and preferentially occurs after the flu season [13, 40].…”

Section: Epidemiology Of Narcolepsy – Role Of Influenza Vaccination Amentioning

confidence: 99%

Autoimmunity in narcolepsy

Bonvalet

Ollila

Ambati

et al. 2017

Current Opinion in Pulmonary Medicine

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Purpose Summarize the recent findings in narcolepsy focusing on the environmental and genetic risk factors in disease development. Recent findings Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Recent studies suggest both humoral and cellular immune responses in the disease development. Summary Narcolepsy is a severe sleep disorder, where neurons producing orexin/hypocretin in the hypothalamus are destroyed. The core symptoms of narcolepsy are debilitating, extreme sleepiness, cataplexy and abnormalities in the structure of sleep. Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Importantly, the highest environmental risk is seen with influenza-A (pH1N1) infection and immunization. However, how the cells are destroyed is currently unknown. In this review we summarize the disease symptoms, and focus on the immunological findings in narcolepsy. We also discuss the environmental and genetic risk factors as well as propose a model for disease development.

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“…This was mainly due to the lack of systematically collected data. However, some support for a role of influenza per se in the development of narcolepsy could be found in previous reports of a seasonal variation in narcolepsy incidence [42]. Furthermore, the role of environmental factors and comorbidities could not be satisfactorily investigated.…”

Section: Discussionmentioning

confidence: 97%

A coordinated cross‐disciplinary research initiative to address an increased incidence of narcolepsy following the 2009–2010 Pandemrix vaccination programme in Sweden

et al. 2015

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In response to the 2009-2010 influenza A(H1N1) pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three-to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferongamma production in response to streptococcusassociated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar situations in which a fast and effective task force may be required to evaluate vaccination-related adverse events.

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A Case-Control Study of the Environmental Risk Factors for Narcolepsy

Cited by 56 publications

References 51 publications

Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis

Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis

Autoimmunity in narcolepsy

A coordinated cross‐disciplinary research initiative to address an increased incidence of narcolepsy following the 2009–2010 Pandemrix vaccination programme in Sweden

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