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Current Neurology and Neuroscience Reports
Published in: Current Neurology and Neuroscience Reports 7/2018

01-07-2018 | Sleep (M Thorpy and M Billiard, Section Editors)

Narcolepsy Associated with Pandemrix Vaccine

Authors: Tomi Sarkanen, Anniina Alakuijala, Ilkka Julkunen, Markku Partinen

Published in: Current Neurology and Neuroscience Reports | Issue 7/2018

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Abstract

Purpose of Review

After the connection between AS03-adjuvanted pandemic H1N1 vaccine Pandemrix and narcolepsy was recognized in 2010, research on narcolepsy has been more intensive than ever before. The purpose of this review is to provide the reader with current concepts and recent findings on the Pandemrix-associated narcolepsy.

Recent Findings

After the Pandemrix vaccination campaign in 2009–2010, the risk of narcolepsy was increased 5- to 14-fold in children and adolescents and 2- to 7-fold in adults. According to observational studies, the risk of narcolepsy was elevated for 2 years after the Pandemrix vaccination. Some confounding factors and potential diagnostic biases may influence the observed narcolepsy risk in some studies, but it is unlikely that they would explain the clearly increased incidence in all the countries where Pandemrix was used. An increased risk of narcolepsy after natural H1N1 infection was reported from China, where pandemic influenza vaccination was not used. There is more and more evidence that narcolepsy is an autoimmune disease. All Pandemrix-associated narcolepsy cases have been positive for HLA class II DQB1*06:02 and novel predisposing genetic factors directly linking to the immune system have been identified. Even though recent studies have identified autoantibodies against multiple neuronal structures and other host proteins and peptides, no specific autoantigens that would explain the disease mechanism in narcolepsy have been identified thus far.

Summary

There was a marked increase in the incidence of narcolepsy after Pandemrix vaccination, especially in adolescents, but also in young adults and younger children. All vaccine-related cases were of narcolepsy type 1 characterized by hypocretin deficiency in the central nervous system. The disease phenotype and the severity of symptoms varied considerably in children and adolescents suffering from Pandemrix-associated narcolepsy, but they were indistinguishable from the symptoms of idiopathic narcolepsy. Narcolepsy type 1 is most likely an autoimmune disease, but the mechanisms have remained elusive.
Literature
1.
American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien: American Academy of Sleep Medicine; 2014.
2.
•• Sarkanen T, Alakuijala A, Dauvilliers Y, Partinen M. Incidence of narcolepsy after H1N1 influenza and vaccinations: systematic review and meta-analysis. Sleep Med Rev. 2017; https://​doi.​org/​10.​1016/​j.​smrv.​2017.​06.​006. A comprehensive review and meta-analysis of the observational studies reporting an association with Pandemrix and narcolepsy. In addition, biases affecting the risk and lack of an association with other vaccines and narcolepsy are discussed.
3.
Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 2014;13(6):600–13.CrossRefPubMed
4.
Dominguez-Cherit G, Lapinsky SE, Macias AE, Pinto R, Espinosa-Perez L, de la Torre A, et al. Critically ill patients with 2009 influenza A(H1N1) in Mexico. JAMA. 2009;302(17):1880–7.CrossRefPubMed
5.
6.
7.
•• Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7(3):e33536. The first epidemiological study reporting an increased incidence of narcolepsy after vaccination with Pandemrix. CrossRefPubMedPubMedCentral
8.
9.
Dauvilliers Y, Arnulf I, Lecendreux M, Monaca Charley C, Franco P, Drouot X, et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain. 2013;136(Pt 8):2486–96.CrossRefPubMed
10.
Heier MS, Gautvik KM, Wannag E, Bronder KH, Midtlyng E, Kamaleri Y, et al. Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. Sleep Med. 2013;14(9):867–71.CrossRefPubMed
11.
Miller E, Andrews N, Stellitano L, Stowe J, Winstone AM, Shneerson J, et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ. 2013;346:f794.CrossRefPubMed
12.
O’Flanagan D, Barret AS, Foley M, Cotter S, Bonner C, Crowe C, et al. Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010. Euro Surveill. 2014;19(17):15–25.PubMedCrossRef
13.
Oberle D, Pavel J, Mayer G, Geisler P, Keller-Stanislawski B. Retrospective multicenter matched case-control study on the risk factors for narcolepsy with special focus on vaccinations (including pandemic influenza vaccination) and infections in Germany. Sleep Med. 2017;34:71–83.CrossRefPubMed
14.
15.
Persson I, Granath F, Askling J, Ludvigsson JF, Olsson T, Feltelius N. Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up. J Intern Med. 2014;275(2):172–90.CrossRefPubMed
16.
Stowe J, Miller E, Andrews N, Kosky C, Leschziner G, Shneerson JM, et al. Risk of narcolepsy after AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in adults: a case-coverage study in England. Sleep. 2016;39(5):1051–7.CrossRefPubMedPubMedCentral
17.
18.
•• Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, Hublin C, Linna M, Olsen P, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7(3):e33723. The first article reporting the clinical picture and increased incidence of narcolepsy after vaccination with Pandemrix in the Nordic countries. CrossRefPubMedPubMedCentral
19.
Verstraeten T, Cohet C, Santos GD, Ferreira GL, Bollaerts K, Bauchau V, et al. Pandemrix and narcolepsy: a critical appraisal of the observational studies. Hum Vaccin Immunother. 2016;12(1):187–93.CrossRefPubMed
20.
Bollaerts K, Shinde V, Dos Santos G, Ferreira G, Bauchau V, Cohet C, et al. Application of probabilistic multiple-bias analyses to a cohort- and a case-control study on the association between Pandemrix and narcolepsy. PLoS One. 2016;11(2):e0149289.CrossRefPubMedPubMedCentral
21.
Sturkenboom MCJM. The narcolepsy-pandemic influenza story: can the truth ever be unraveled? Vaccine. 2015;33(Supplement 2):B6–B13.CrossRefPubMed
22.
• Han F, Lin L, Warby SC, Faraco J, Li J, Dong SX, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70(3):410–7. The authors report a 3-fold increase of narcolepsy in the Beijing area in China where no pandemic vaccines were used. A similar finding was seen in the Shanghai area, but not in any other country. CrossRefPubMed
23.
Han F, Lin L, Li J, Dong XS, Mignot E. Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic. Ann Neurol. 2013;73(4):560.CrossRefPubMed
24.
Wu H, Zhuang J, Stone WS, Zhang L, Zhao Z, Wang Z, et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in eastern China. Sleep Med. 2014;15(6):607–13.CrossRefPubMed
25.
Choe YJ, Bae GR, Lee DH. No association between influenza A(H1N1)pdm09 vaccination and narcolepsy in South Korea: an ecological study. Vaccine. 2012;30(52):7439–42.CrossRefPubMed
26.
27.
Van Effelterre T, Dos Santos G, Shinde V. Twin peaks: A/H1N1 pandemic influenza virus infection and vaccination in Norway, 2009-2010. PLoS One. 2016;11(3):e0151575.CrossRefPubMedPubMedCentral
28.
Melen K, Partinen M, Tynell J, Sillanpaa M, Himanen SL, Saarenpaa-Heikkila O, et al. No serological evidence of influenza A H1N1pdm09 virus infection as a contributing factor in childhood narcolepsy after Pandemrix vaccination campaign in Finland. PLoS One. 2013;8(8):e68402.CrossRefPubMedPubMedCentral
29.
30.
•• Vaarala O, Vuorela A, Partinen M, Baumann M, Freitag TL, Meri S, et al. Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for Pandemrix-associated narcolepsy risk. PLoS One. 2014;9(12):e114361. A study reporting differences in nucleoprotein (NP) of the viral component in Pandemrix and Arepanrix. Furthermore, increased antibody response against NP was seen in subjects with the HLA DQB1*06:02 narcolepsy risk allele. CrossRefPubMedPubMedCentral
31.
Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A, et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med. 2015;7(294):294ra105.CrossRefPubMed
32.
Tesoriero C, Codita A, Zhang MD, Cherninsky A, Karlsson H, Grassi-Zucconi G, et al. H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice. Proc Natl Acad Sci U S A. 2016;113(3):E368–77.CrossRefPubMed
33.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and g protein-coupled receptors that regulate feeding behavior. Cell. 1998;92:573–85.CrossRefPubMed
34.
de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A. 1998;95(1):322–7.CrossRefPubMedPubMedCentral
35.
Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 2000;6(9):991–7.CrossRefPubMed
36.
Julkunen I, Partinen M. Neuroimmunology: disease mechanisms in narcolepsy remain elusive. Nat Rev Neurol. 2014;10(11):616–7.CrossRefPubMed
37.
Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev. 2005;9(4):269–310.CrossRefPubMed
38.
• Tafti M, Hor H, Dauvilliers Y, Lammers GJ, Overeem S, Mayer G, et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep. 2014;37(1):19–25. A large genome-wide association (GWAS) study with over 1200 narcolepsy patients and 3500 controls. It was shown that the majority of the genetic risk of narcolepsy is explained by the HLA DQB1 locus only. HLA DQB1*06:02 positive individuals carry a 251-fold increased risk of developing narcolepsy. CrossRefPubMedPubMedCentral
39.
Hor H, Bartesaghi L, Kutalik Z, Vicario JL, de Andres C, Pfister C, et al. A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. Am J Hum Gen. 2011;89(3):474–9.CrossRef
40.
Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Gen. 2001;68(3):686–99.CrossRef
41.
• Ollila HM, Ravel JM, Han F, et al. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet. 2015;96:136–46. One of the first reports to find HLA class I associations in narcolepsy. CrossRefPubMedPubMedCentral
42.
• Tafti M, Lammers GJ, Dauvilliers Y, et al. Narcolepsy-associated HLA class I alleles implicate cell-mediated cytotoxicity. Sleep. 2016;39:581–7. One of the first reports to find HLA class I associations in narcolepsy. CrossRefPubMedPubMedCentral
43.
Aran A, Lin L, Nevsimalova S, Plazzi G, Hong SC, Weiner K, et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep. 2009;32(8):979–83.CrossRefPubMedPubMedCentral
44.
Haggmark-Manberg A, Zandian A, Forsstrom B, Khademi M, Lima Bomfim I, Hellstrom C, et al. Autoantibody targets in vaccine-associated narcolepsy. Autoimmunity. 2016;49(6):421–33.CrossRefPubMed
45.
Saariaho AH, Vuorela A, Freitag TL, Pizza F, Plazzi G, Partinen M, et al. Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus. J Autoimmun. 2015;63:68–75.CrossRefPubMed
46.
Cvetkovic-Lopes V, Bayer L, Dorsaz S, Maret S, Pradervand S, Dauvilliers Y, et al. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. J Clin Invest. 2010;120(3):713–9.CrossRefPubMedPubMedCentral
47.
Kawashima M, Lin L, Tanaka S, Jennum P, Knudsen S, Nevsimalova S, et al. Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy. Sleep. 2010;33(7):869–74.CrossRefPubMedPubMedCentral
48.
Katzav A, Arango MT, Kivity S, Tanaka S, Givaty G, Agmon-Levin N, et al. Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice. J Autoimmun. 2013;45:24–30.CrossRefPubMed
49.
Lind A, Ramelius A, Olsson T, Arnheim-Dahlstrom L, Lamb F, Khademi M, et al. A/H1N1 antibodies and TRIB2 autoantibodies in narcolepsy patients diagnosed in conjunction with the Pandemrix vaccination campaign in Sweden 2009-2010. J Autoimmun. 2014;50:99–106.CrossRefPubMed
50.
51.
Goodfellow JA, Willison HJ. Antiganglioside, antiganglioside-complex, and antiglycolipid-complex antibodies in immune-mediated neuropathies. Curr Opin Neurol. 2016;29(5):572–80.CrossRefPubMed
52.
Overeem S, Geleijns K, Garssen MP, Jacobs BC, van Doorn PA, Lammers GJ. Screening for anti-ganglioside antibodies in hypocretin-deficient human narcolepsy. Neurosci Lett. 2003;341(1):13–6.CrossRefPubMed
53.
• Bergman P, Adori C, Vas S, Kai-Larsen Y, Sarkanen T, Cederlund A, et al. Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proc Natl Acad Sci U S A. 2014;111(35):E3735–44. In this study, 27% of narcolepsy patients showed autoantibodies against three different neuronal structures in immunohistochemical stainings on rat brain. Although staining against hypocretin neurons was not seen, autoantibodies against hypothalamic NEI/αMSH neurons were found. Passive transfer of sera from NEI/αMSH-positive subject into a rat brain produced disturbed REM and slow wave sleep patterns. CrossRefPubMedPubMedCentral
54.
Montplaisir J, Petit D, Quinn M-J, Ouakki M, Deceuninck G, Desautels A, et al. Risk of narcolepsy associated with inactivated adjuvanted (AS03) A/H1N1 (2009) pandemic influenza vaccine in Quebec. PLoS One. 2014;9(9):e108489.CrossRefPubMedPubMedCentral
55.
Jacob L, Leib R, Ollila HM, Bonvalet M, Adams CM, Mignot E. Comparison of Pandemrix and Arepanrix, two pH1N1 AS03-adjuvanted vaccines differentially associated with narcolepsy development. Brain Behav Immun. 2015;47:44–57.CrossRefPubMed
56.
57.
58.
• Zandian A, Forsstrom B, Haggmark-Manberg A, Schwenk JM, Uhlen M, Nilsson P, et al. Whole-proteome peptide microarrays for profiling autoantibody repertoires within multiple sclerosis and narcolepsy. J Proteome Res. 2017;16(3):1300–14. The authors presented a novel method for screening autoantibodies, namely high-density peptide arrays. They recognized a potential new autoantigen neurexin 1 in narcolepsy. CrossRefPubMed
59.
• Sadam H, Pihlak A, Kivil A, Pihelgas S, Jaago M, Adler P, et al. Prostaglandin D2 receptor DP1 antibodies predict vaccine-induced and spontaneous narcolepsy type 1: large-scale study of antibody profiling. EBioMedicine. 2018;29:47–59. The authors describe a potentially new autoantigen prostaglandin D2 receptor against which narcolepsy patient have developed autoantibodies. CrossRefPubMedPubMedCentral
60.
Ambati A, Poiret T, Svahn BM, Valentini D, Khademi M, Kockum I, et al. Increased beta-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases. J Intern Med. 2015;278(3):264–76.CrossRefPubMed
61.
Soriano A, Nesher G, Shoenfeld Y. Predicting post-vaccination autoimmunity: who might be at risk? Pharmacol Res. 2015;92:18–22.CrossRefPubMed
62.
Martinez-Orozco FJ, Vicario JL, Villalibre-Valderrey I, De Andres C, Fernandez-Arquero M, Peraita-Adrados R. Narcolepsy with cataplexy and comorbid immunopathological diseases. J Sleep Res. 2014;23(4):414–9.CrossRefPubMed
63.
Barateau L, Lopez R, Arnulf I, Lecendreux M, Franco P, Drouot X, et al. Comorbidity between central disorders of hypersomnolence and immune-based disorders. Neurology. 2017;88(1):93–100.CrossRefPubMed
64.
Pizza F, Peltola H, Sarkanen T, Moghadam KK, Plazzi G, Partinen M. Childhood narcolepsy with cataplexy: comparison between post-H1N1 vaccination and sporadic cases. Sleep Med. 2013;15(2):262–5.CrossRefPubMed
65.
• Sarkanen T, Alakuijala A, Partinen M. Clinical course of H1N1-vaccine-related narcolepsy. Sleep Med. 2016;19:17–22. The first longitudinal study of the clinical phenotype of Pandemrix-related narcolepsy. The symptoms of narcolepsy and severity of the disease seem very heterogeneous. CrossRefPubMed
66.
Szakacs A, Darin N, Hallbook T. Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology. 2013;80(14):1315–21.CrossRefPubMed
67.
68.
Winstone AM, Stellitano L, Verity C, Andrews N, Miller E, Stowe J, et al. Clinical features of narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in England. Dev Med Child Neurol. 2014;56(11):1117–23.CrossRefPubMedPubMedCentral
69.
70.
Alakuijala A, Sarkanen T, Partinen M. Polysomnographic and actigraphic characteristics of patients with H1N1-vaccine-related and sporadic narcolepsy. Sleep Med. 2015;16(1):39–44.CrossRefPubMed
71.
Knudsen S, Biering-Sorensen B, Kornum BR, Petersen ER, Petersen ER, Ibsen JD, et al. Early IVIg treatment has no effect on post-H1N1 narcolepsy phenotype or hypocretin deficiency. Neurology. 2012;79(1):102–3.CrossRefPubMed
72.
Viste R, Soosai J, Vikin T, Thorsby PM, Nilsen KB, Knudsen S. Long-term improvement after combined immunomodulation in early post-H1N1 vaccination narcolepsy. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e389.CrossRefPubMedPubMedCentral
73.
Dauvilliers Y, Abril B, Mas E, Michel F, Tafti M. Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. Neurology. 2009;73(16):1333–4.CrossRefPubMed
74.
Sarkanen T, Alen R, Partinen M. Transient impact of rituximab in H1N1 vaccination-associated narcolepsy with severe psychiatric symptoms. Neurologist. 2016;21(5):85–6.CrossRefPubMed
75.
Lecendreux M, Berthier J, Corny J, Bourdon O, Dossier C, Delclaux C. Intravenous immunoglobulin therapy in pediatric narcolepsy: a nonrandomized, open-label, controlled, longitudinal observational study. J Clin Sleep Med. 2017;13(3):441–53.CrossRefPubMedPubMedCentral
Metadata
Title
Narcolepsy Associated with Pandemrix Vaccine
Authors
Tomi Sarkanen
Anniina Alakuijala
Ilkka Julkunen
Markku Partinen
Publication date
01-07-2018
Publisher
Springer US
Published in
Current Neurology and Neuroscience Reports / Issue 7/2018
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-018-0851-5

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