Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study

Banwell, Brenda; Krupp, Lauren; Kennedy, J. S.; Tellier, Raymond; Tenembaum, Sílvia; Ness, Jayne; Belman, Anita; Бойко, А. Н.; Ov, Bykova; Waubant, Emmanuelle; Mah, Jean K.; Stoian, Cristina; Kremenchutzky, Marcelo; Bardini, Maria Rita; Ruggieri, Martino; Rensel, Mary; Hahn, Jin S.; Weinstock‐Guttman, Bianca; Yeh, E. Ann; Farrell, Kevin; Freedman, Mark S.; Iivanainen, Matti; Sevon, Meri; Bhan, Virender; Dilenge, Marie-Emmanuelle; Stephens, Derek; Bar‐Or, Amit

doi:10.1016/s1474-4422(07)70196-5

Cited by 298 publications

(257 citation statements)

References 56 publications

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“…Prior EBV infection is thus far the strongest and most consistent environmental factor associated with pediatric and adult‐onset MS 9, 10, 11, 12, 13, 20, 21. We observed that this association with pediatric MS is seen regardless of race and ethnicity, although the association is stronger in whites, as recently reported in adult‐onset MS 14.…”

Section: Discussionsupporting

confidence: 82%

“…Although several other studies investigated the association of prior viral infections and pediatric MS risk,9, 10, 11, 12, 13 very few studies examining the risk of MS in relation to previous viral exposures and the possible interactions with age, race and ethnicity have been conducted 14. Using a large case–control study, we aimed to assess the heterogeneity of association between remote infections with common herpesviruses and the risk of pediatric MS in children with a diverse racial and ethnic background.…”

Section: Introductionmentioning

confidence: 99%

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Heterogeneity in association of remote herpesvirus infections and pediatric MS

Nourbakhsh

Rutatangwa

Waltz

et al. 2018

Ann Clin Transl Neurol

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ObjectiveWhile prior Epstein–Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections.MethodsCases with pediatric‐onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses‐1 (HSV‐1) and ‐2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA‐DRB1:1501 status.ResultsA total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV‐viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5–12.0, P < 0.001). Seropositivity for HSV‐1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06–2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35–3.52, P < 0.001) and those negative for HLA‐DRB1*1501 (OR = 1.89, 95% CI 1.17–3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA‐DRB1*15:01 status.Interpretation EBV seropositivity is strongly associated with pediatric MS, as is HSV‐1 seropositivity in subjects negative for HLA‐DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Nourbakhsh

Rutatangwa

Waltz

et al. 2018

Ann Clin Transl Neurol

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“…The percentage of cases positive for this determination (99-100%) was greater than among controls (81-98%), except in the study of Bray et al [23]. In work performed among paediatric subjects, there was also a higher percentage of positive cases, but with differences more accentuated than in adults [17][18][19]. The study performed by Zivadinov et al [43] was the only one in which the proportion of positive results was higher in controls than in cases.…”

Section: Anti-vca Igg Determinationmentioning

confidence: 85%

“…In addition, its weight was the highest among the set. All remaining studies used serum samples [4,10,19,31,42] and the proportion of seropositive patients was also higher in cases than in controls, except for the study by Banwell et al [18], which was carried out in children, and with an OR that failed to indicate any association between the virus and MS. The article with the highest OR was that by Haahr et al [4].…”

Section: Anti-ebna-1 Igg Determinationmentioning

confidence: 99%

Relation between Epstein-Barr virus and multiple sclerosis: analytic study of scientific production

Santiago

Gutiérrez

Sorlózano

et al. 2010

Eur J Clin Microbiol Infect Dis

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Numerous studies have been carried out to determine whether infection by the Epstein-Barr virus (EBV) can be considered as a risk factor for multiple sclerosis (MS). This work is a meta-analysis of casecontrol observational studies published before January 2009 aimed at assessing the degree of association between EBV and MS infections. A Medline electronic database search was carried out using "Epstein-Barr virus" and "multiple sclerosis" as keywords, from which we selected 30 published studies that met our methodology criteria. We found an association between MS and an exposure to EBV, studied by determining the anti-VCA IgG antibodies (odds ratio [OR]=5.5; 95% confidence interval [CI]=3.37-8.81; p<0.0001), anti-complex EBNA IgG (OR=5.4; 95% CI= 2.94-9.76; p<0.0001) and anti-EBNA-1 IgG (OR=12.1; 95% CI=3. 13-46.89; p<0.0001). No significant association could be found when studying anti-EA IgG (OR=1.3; 95% CI=0.68-2.35; p=0.457), EBV DNA in serum (OR= 1.8; p=0.051) and DNA in brain tissues and in cerebrospinal fluid (CSF) (OR=0.9; 95% CI=0.38-2.01; p=0.768). This meta-analysis detected an association between infection by EBV and MS through the investigation of antibodies, mainly anti-EBNA-1, anticomplex EBNA and anti-VCA IgG.

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“…In accordance with these findings, Waubant et al [30] found that EBNA-1 seropositivity was associated with an almost fourfold risk of MS in patients with early paediatric MS. Interestingly, in a further study children with MS did not differ from age-matched healthy controls in seroprevalence of further childhood viruses [31].…”

Section: Discussionmentioning

confidence: 72%

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

Csuka

Simon

Hóbor

et al. 2013

Clinical and Experimental Immunology

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SummarySeveral studies suggest that infection by Epstein-Barr virus (EBV) might be one of the environmental factors which facilitates the development of autoimmune disorders in genetically susceptible individuals. Recent data indicate that high anti-Epstein-Barr nuclear antigen 1 (EBNA)-1 immunoglobulin (Ig)G titre is a strong risk factor for multiple sclerosis (MS) in patients both with and without the main genetic predisposing trait, human leucocyte antigen (HLA)-DRB1*15:01. Because no similar studies have been published in systemic lupus erythematosus (SLE) patients, we determined the HLA-DRB1*15:01 carrier state and the serum titres against the whole EBNA-1 and its small fragments aa35-58 and aa398-404 in 301 SLE patients, 135 MS patients and in 345 healthy controls. The carrier state of the HLA-DRB1*15:01 allele was deduced from genotyping of a tagSNP (rs3135388) by applying a Taqman-based assay. The serum concentrations of antibodies to EBNA-1 and its aa35-58 or aa398-404 fragments were determined using a commercial assay (ETI-EBNA-G) and home-made enzyme-linked immunosorbent assays, respectively. The serum concentration of anti-EBNA-1 antibodies was significantly (P < 0·001) higher both in MS and SLE patients than in controls. Similar significant differences were found both in HLA-DRB1*15:01 carriers and non-carriers. Furthermore, titres of antibodies against the aa35-58 EBNA-1 fragment were elevated both in MS and SLE patients. By contrast, the levels of aa398-404 EBNA-1 antibodies were elevated significantly only in the SLE patients. These findings indicate that high anti-EBNA-1 IgG titres are HLA-DRB1*15:01-independent risk factors not only for MS, but also for SLE, while high antibody titres against the aa398-404 fragment are characteristic for SLE.

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Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study

Cited by 298 publications

References 56 publications

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Relation between Epstein-Barr virus and multiple sclerosis: analytic study of scientific production

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

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