Summary An increased incidence of narcolepsy was seen in many countries after the pandemic H1N1 influenza vaccination campaign in 2009-2010. The H1N1 vaccine - narcolepsy connection is based on ...observational studies that are prone to various biases, e.g. confounding by H1N1 infection, and ascertainment, recall and selection biases. A direct pathogenic link has, however, remained elusive. We conducted a systematic review and meta-analysis to analyze the magnitude of H1N1 vaccination related risk and to examine if there was any association with H1N1 infection itself. We searched all articles from PubMed, Web of Science and Scopus, and other relevant sources reporting the incidence and risk of post-vaccine narcolepsy. In our paper, we show that the risk appears to be limited to only one vaccine (Pandemrix® ). During the first year after vaccination, the relative risk of narcolepsy was increased 5-14-fold in children and adolescents and 2-7-fold in adults. The vaccine attributable risk in children and adolescents was around 1 per 18,400 vaccine doses. Studies from Finland and Sweden also appear to demonstrate an extended risk of narcolepsy into the second year following vaccination, but such conclusions should be interpreted with a word of caution due to possible biases. Benefits of immunization outweigh the risk of vaccination-associated narcolepsy, which remains a rare disease.
Long and short sleep have been associated with increased mortality. We assessed mortality and 3 aspects of sleep behavior in a large cohort with 22-year follow-up.
Prospective, population-based ...cohort study.
21,268 twins aged > or =18 years responding to questionnaires administered to the Finnish Twin Cohort in 1975 (response rate 89%), and 1981 (84%).
N/A.
Subjects were categorized as short (<7 h), average, or long (>8 h) sleepers; sleeping well, fairly well, or fairly poorly/poorly; no, infrequent, or frequent users of hypnotics and/or tranquilizers. Cox proportional hazard models were used to obtain hazard ratios (HR) for mortality during 1982-2003 by sleep variable categories and their combinations. Adjustments were done for 10 sociodemographic and lifestyle covariates known to affect risk of death.
Significantly increased risk of mortality was observed both for short sleep in men (+26%) and in women (+21%), and for long sleep (+24% and +17%), respectively, and also frequent use of hypnotics/tranquilizers (+31% in men and +39% in women). Snoring as a covariate did not change the results. The effect of sleep on mortality varied between age groups, with strongest effects in young men. Between 1975 and 1981, sleep length and sleep quality changed in one-third of subjects. In men there was a significant increase for stable short (1.34) and stable long (1.29) sleep for natural deaths, and for external causes in stable short sleepers (1.62).
Our results show complicated associations between sleep and mortality, with increased risk in short and long sleep.
Summary 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.
Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune ...loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide–specific CD4⁺ T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA273–287 (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17–31 and C-amidated but not native version of HCRT54–66 and HCRT86–97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA273–287-tetramers, suggesting molecular mimicry. This public CDR3β uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-α/β CDR3 motifs of HCRT54–66-NH2 and HCRT86–97-NH2 tetramers were extensively shared: notably public CDR3α, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-α/β CDR3 sequences found in pHA273–287, NP17–31, and HCRTNH2 tetramer-positive CD4⁺ cells were also retrieved in single INF-γ–secreting CD4⁺ sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
The COVID-19 pandemic has produced unprecedented changes in social, work, and leisure activities, which all have had major impact on sleep and psychological well-being. This study documented the ...prevalence of clinical cases of insomnia, anxiety, and depression and selected risk factors (COVID-19, confinement, financial burden, social isolation) during the first wave of the pandemic in 13 countries throughout the world.
International, multi-center, harmonized survey of 22 330 adults (mean age = 41.9 years old, range 18–95; 65.6% women) from the general population in 13 countries and four continents. Participants were invited to complete a standardized web-based survey about sleep and psychological symptoms during the first wave of the COVID-19 pandemic from May to August 2020.
Clinical insomnia symptoms were reported by 36.7% (95% CI, 36.0–37.4) of respondents and 17.4% (95% CI, 16.9–17.9) met criteria for a probable insomnia disorder. There were 25.6% (95% CI, 25.0–26.2) with probable anxiety and 23.1% (95% CI, 22.5–23.6) with probable depression. Rates of insomnia symptoms (>40%) and insomnia disorder (>25%) were significantly higher in women, younger age groups, and in residents of Brazil, Canada, Norway, Poland, USA, and United Kingdom compared to residents from Asian countries (China and Japan, 8% for disorder and 22%–25% for symptoms) (all Ps < 0.01). Proportions of insomnia cases were significantly higher among participants who completed the survey earlier in the first wave of the pandemic relative to those who completed it later. Risks of insomnia were higher among participants who reported having had COVID-19, who reported greater financial burden, were in confinement for a period of four to five weeks, and living alone or with more than five people in same household. These associations remained significant after controlling for age, sex, and psychological symptoms.
Insomnia, anxiety, and depression were very prevalent during the first wave of the COVID-19 pandemic. Public health prevention programs are needed to prevent chronicity and reduce long-term adverse outcomes associated with chronic insomnia and mental health problems.
•High rates of insomnia symptoms (36.7%) and disorder (17.4%) associated with COVID-19.•High rates of anxiety (25.6%) and depression (23.1%) associated with COVID-19.•People in confinement, living alone or with five or more people, at higher risk for insomnia.•Sleep health education needed to prevent chronic insomnia and adverse health consequences.
This protocol paper describes the development of an international collaboration to survey several thousand adults from different countries around the world about their sleep during the coronavirus ...disease 2019 (COVID‐19) pandemic. It is based on the development of a harmonised survey with 50 questions (106 different items) on sleep habits and sleep symptoms that permit comparability of information. The harmonised questionnaire may be used in anonymous cross‐sectional surveys, and the instruments within the questionnaire may also be used in prospective studies and clinical studies. The aim was to develop a questionnaire to sample a variety of sleep–wake disorders and other symptoms likely to be caused by prolonged social confinement or by having had COVID‐19. The questionnaire was designed to be: (a) simple and, (b) free to use, for research purposes, (c) multilingual, and (d) comprehensive. It can be completed in <30 min. By the end of June 2020, the survey questionnaire had been administered in Austria, Canada, China, Finland, France, Germany, Hong Kong, Italy, Japan, Norway, Poland, Sweden, UK and USA. Research questions to be addressed by the pooled data derived from the participating sites focus on describing the nature and rates of various sleep and circadian rhythms symptoms, as well as their psychological and medical correlates, that arise at various points during the COVID‐19 pandemic.
According to a European task force, symptoms of insomnia could be related to psychosocial factors and to the confinements.2 In Italy, anxiety related to COVID-19 was highly associated with disturbed ...sleep. Furthermore, they did not include patients with mild (ESS 11–14), moderate (ESS 15–17), or severe (ESS ≥18) daytime sleepiness and untreated severe sleep apnoea. ...the results cannot be generalised to all patients with obstructive sleep apnoea, and certainly not to patients with moderate or severe (ESS >14) daytime sleepiness. Emerging evidence indicates that disturbed sleep might be among the strongest risk factors for development of neurodegenerative diseases. ...all physicians should incorporate questions about sleep hygiene and quality into their routine clinical practice.
Narcolepsy is a chronic sleep disorder with strong genetic predisposition causing excessive daytime sleepiness and cataplexy. A sudden increase in childhood narcolepsy was observed in Finland soon ...after pandemic influenza epidemic and vaccination with ASO3-adjuvanted Pandemrix. No increase was observed in other age groups.
Retrospective cohort study. From January 1, 2009 to December 31, 2010 we retrospectively followed the cohort of all children living in Finland and born from January 1991 through December 2005. Vaccination data of the whole population was obtained from primary health care databases. All new cases with assigned ICD-10 code of narcolepsy were identified and the medical records reviewed by two experts to classify the diagnosis of narcolepsy according to the Brighton collaboration criteria. Onset of narcolepsy was defined as the first documented contact to health care because of excessive daytime sleepiness. The primary follow-up period was restricted to August 15, 2010, the day before media attention on post-vaccination narcolepsy started.
Vaccination coverage in the cohort was 75%. Of the 67 confirmed cases of narcolepsy, 46 vaccinated and 7 unvaccinated were included in the primary analysis. The incidence of narcolepsy was 9.0 in the vaccinated as compared to 0.7/100,000 person years in the unvaccinated individuals, the rate ratio being 12.7 (95% confidence interval 6.1-30.8). The vaccine-attributable risk of developing narcolepsy was 1:16,000 vaccinated 4 to 19-year-olds (95% confidence interval 1:13,000-1:21,000).
Pandemrix vaccine contributed to the onset of narcolepsy among those 4 to 19 years old during the pandemic influenza in 2009-2010 in Finland. Further studies are needed to determine whether this observation exists in other populations and to elucidate potential underlying immunological mechanism. The role of the adjuvant in particular warrants further research before drawing conclusions about the use of adjuvanted pandemic vaccines in the future.
The aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on ...central disorders of hypersomnolence.
The ultimate goal for a sleep disorders classification is to be based on the underlying neurobiological causes of the disorders with clear implication for treatment or, ideally, prevention and or healing. The current ICSD classification, published in 2014, inevitably has important shortcomings, largely reflecting the lack of knowledge about the precise neurobiological mechanisms underlying the majority of sleep disorders we currently delineate. Despite a clear rationale for the present structure, there remain important limitations that make it difficult to apply in routine clinical practice. Moreover, there are indications that the current structure may even prevent us from gaining relevant new knowledge to better understand certain sleep disorders and their neurobiological causes.
We suggest the creation of a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence; containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity and sensitivity in the diagnostic context.
We propose and define three diagnostic categories (with levels of certainty):
1/“Narcolepsy” 2/“Idiopathic hypersomnia”, 3/“Idiopathic excessive sleepiness” (with subtypes).
Narcolepsy is a rare neurological sleep disorder especially in children who are younger than 10 years. In the beginning of 2010, an exceptionally large number of Finnish children suffered from an ...abrupt onset of excessive daytime sleepiness (EDS) and cataplexy. Therefore, we carried out a systematic analysis of the incidence of narcolepsy in Finland between the years 2002-2010.
All Finnish hospitals and sleep clinics were contacted to find out the incidence of narcolepsy in 2010. The national hospital discharge register from 2002 to 2009 was used as a reference.
Altogether 335 cases (all ages) of narcolepsy were diagnosed in Finland during 2002-2009 giving an annual incidence of 0.79 per 100,000 inhabitants (95% confidence interval 0.62-0.96). The average annual incidence among subjects under 17 years of age was 0.31 (0.12-0.51) per 100,000 inhabitants. In 2010, 54 children under age 17 were diagnosed with narcolepsy (5.3/100,000; 17-fold increase). Among adults ≥20 years of age the incidence rate in 2010 was 0.87/100,000, which equals that in 2002-2009. Thirty-four of the 54 children were HLA-typed, and they were all positive for narcolepsy risk allele DQB1*0602/DRB1*15. 50/54 children had received Pandemrix vaccination 0 to 242 days (median 42) before onset. All 50 had EDS with abnormal multiple sleep latency test (sleep latency <8 min and ≥2 sleep onset REM periods). The symptoms started abruptly. Forty-seven (94%) had cataplexy, which started at the same time or soon after the onset of EDS. Psychiatric symptoms were common. Otherwise the clinical picture was similar to that described in childhood narcolepsy.
A sudden increase in the incidence of abrupt childhood narcolepsy was observed in Finland in 2010. We consider it likely that Pandemrix vaccination contributed, perhaps together with other environmental factors, to this increase in genetically susceptible children.
PDF
