<scp>Multiple Sclerosis</scp> Is Rare in Epstein–Barr Virus–Seronegative Children with <scp>Central Nervous System</scp> Inflammatory Demyelination

Nourbakhsh, Bardia; Cordano, Christian; Asteggiano, Carlo; Ruprecht, Klemens; Otto, Carolin; Rutatangwa, Alice; Lui, Allysa; Hart, Janace; Flanagan, Eoin P.; James, Judith A.; Waubant, Emmanuelle

doi:10.1002/ana.26062

Cited by 18 publications

(11 citation statements)

References 15 publications

(35 reference statements)

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“…These features were significant in univariate analysis and remained significant in multivariate analysis. These results are similar to those of prior studies, 35 including a recent study that found that EBV seronegativity in children with an MS‐like presentation may suggest an alternate diagnosis, particularly MOGAD 36 …”

Section: Discussionsupporting

confidence: 91%

“…These results are similar to those of prior studies, 35 including a recent study that found that EBV seronegativity in children with an MS-like presentation may suggest an alternate diagnosis, particularly MOGAD. 36 Additional features that may suggest a MOGAD diagnosis over MS include: lack of new MRI T2 brain lesions around the 12-month timepoint and resolution of most or all T2-lesions with follow-up (Fig ), as shown in recent studies, 37,38 as well as female sex (significant in the multivariable model only), initial optic nerve localization (significant in the univariable model only), and lack of CSF OCBs and initial spinal cord localization (both significant in the univariable model only). Although MOGAD cases were less likely to have CSF OCBs, OCBs were present in one-fifth of these patients; therefore, the presence of CSF OCBs should not exclude a MOGAD diagnosis.…”

Section: Discussionmentioning

confidence: 99%

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MOGandAQP4Antibodies among Children with Multiple Sclerosis and Controls

Gaudioso

Mar

Casper

et al. 2022

Annals of Neurology

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Objective The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)‐IgG and aquaporin‐4 (AQP4)‐IgG among patients with pediatric‐onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG‐IgG‐associated disease (MOGAD), and identify clinical features associated with final diagnosis. Methods Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case–control study on POMS risk factors. Serum AQP4‐IgG and MOG‐IgG were assessed using live cell‐based assays. Results AQP4‐IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG‐IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty‐five of 30 patients positive with MOG‐IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re‐review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein–Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). Interpretation MOG‐IgG and AQP4‐IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4‐IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271–284

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

MOGandAQP4Antibodies among Children with Multiple Sclerosis and Controls

Gaudioso

Mar

Casper

et al. 2022

Annals of Neurology

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“…While our research protocol did not direct the timing or selection of DMTs, we did not feel that therapy affected our ability to identify the atypical clinical features of MOG-IgG positive patients, as 9/12 never received DMT. Other features, such as serology evidence of prior Epstein–Barr virus (EBV) infection, 35 could contribute in differentiating pediatric MS from MOGAD, 36 and should be object of future studies.…”

Section: Discussionmentioning

confidence: 99%

Serum MOG-IgG in children meeting multiple sclerosis diagnostic criteria

et al. 2022

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Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is now recognized as distinct from multiple sclerosis (MS). Objective: To evaluate the importance of considering myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin-G (IgG) serology when applying MS diagnostic criteria in children. Methods: Within a prospective cohort of children meeting MS criteria (median follow-up = 6 years, interquartile range (IQR) = 4–9), we measured MOG-IgG in serial archived serum obtained from presentation, and compared imaging and clinical features between seropositive and seronegative participants. Results: Of 65 children meeting MS criteria (median age = 14.0 years, IQR = 10.9–15.1), 12 (18%) had MOG-IgG at disease onset. Seropositive participants were younger, had brain magnetic resonance imaging (MRI) features atypical for MS, rarely had cerebrospinal fluid (CSF) oligoclonal bands (2/8, 25%), and accumulated fewer T2 lesions over time. On serial samples, 5/12 (42%) were persistently seropositive, 5/12 (42%) became seronegative, and 2/12 (17%) had fluctuating results. All 12 children experienced a disease course different from typical MS. Conclusion: While children with MOG-IgG can have clinical, CSF, and MRI features conforming to MS criteria, the presence of MOG-IgG is associated with atypical features and predicts a non-MS disease course. Given MOG-IgG seropositivity can wane over time, testing at first attack is of considerable importance for the diagnosis of MOGAD.

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“…Therefore, EBV infection alone is not sufficient to cause the disease and other factors such as genetic traits may contribute substantially to EBV-associated MS risk. As a lower frequency of EBV seropositivity has been reported in POMS, 11,[13][14][15] it makes this age group ideal for assessing genetic susceptibility to EBV-associated MS.…”

Section: Gene-environment Interactions: Epstein-barr Virus Infection ...mentioning

confidence: 99%

Gene–environment interactions: Epstein–Barr virus infection and risk of pediatric-onset multiple sclerosis

Ziaei,

Solomon,

Casper

et al. 2024

Mult Scler

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Background and Objective: Prior Epstein–Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother’s education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). Results: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction ( p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction ( p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). Conclusion: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.

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Multiple Sclerosis Is Rare in Epstein–Barr Virus–Seronegative Children with Central Nervous System Inflammatory Demyelination

Cited by 18 publications

References 15 publications

MOGandAQP4Antibodies among Children with Multiple Sclerosis and Controls

MOGandAQP4Antibodies among Children with Multiple Sclerosis and Controls

Serum MOG-IgG in children meeting multiple sclerosis diagnostic criteria

Gene–environment interactions: Epstein–Barr virus infection and risk of pediatric-onset multiple sclerosis

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