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Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study

https://doi.org/10.1016/S1474-4422(11)70045-XGet rights and content

Summary

Background

HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children.

Methods

In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15, Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use.

Findings

Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61–4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99–222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25–4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00–1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99–4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26–273·85) or CSF oligoclonal bands (6·33, 3·35–11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%.

Interpretation

Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness.

Funding

Canadian Multiple Sclerosis Scientific Research Foundation.

Introduction

HLA-DRB1*15 genotype, remote infection with Epstein-Barr virus, and vitamin D insufficiency are possible predisposing factors to multiple sclerosis,1, 2 but have not previously been assessed in one cohort. Such an investigation would allow their interrelations and relative contributions to be established. Because risk of multiple sclerosis is strongly affected by country of residence during childhood,3 the contribution of environmental factors to development of this disease can be uniquely explored in children living in an area of high prevalence who have incident demyelination during the time of risk factor acquisition. In addition to consideration of these predisposing factors, clinical, MRI, and laboratory findings at presentation provide predictive information about the likelihood of subsequent disease—although the relative contribution of these features in prediction of multiple sclerosis outcomes in the paediatric population is less well defined than it is for the adult population. Improved identification of children who are very likely to be diagnosed with multiple sclerosis would justify clinical and MRI monitoring for diagnostic confirmation and would enable prompt initiation of targeted treatment. Conversely, identification of children in whom multiple sclerosis is unlikely would substantially reduce concern for the patients, parents, and care providers. We aimed to assess the contribution of predisposing environmental factors and clinical and laboratory findings on development of multiple sclerosis in a national cohort of children in Canada.

Section snippets

Participants and study design

In our prospective national cohort study of incident demyelination in children, we obtained comprehensive clinical, laboratory, and MRI data to examine the contribution and interrelations of HLA-DRB1*15, remote Epstein-Barr-virus infection, and vitamin D status as predisposing factors and clinical features, MRI images, and oligoclonal bands as predictors of multiple sclerosis. We developed a decision tree to aid in counselling regarding multiple sclerosis risk.

All 16 Canadian paediatric

Results

Between Sept 1, 2004, and June 30, 2010, we enrolled 332 children (figure 1), of whom 302 were eligible and followed up for more than 3 years (table 1). Six (2%) participants withdrew from the study after a median of 93 days (IQR 85–187) of follow-up, and data were censored at time of withdrawal.

Of 302 eligible patients with acute demyelinating syndrome, 63 (21%) were diagnosed with multiple sclerosis (24 by MRI evidence of dissemination in time only). Median time to a second clinical event or

Discussion

In our nationwide prospective cohort study of children with incident demyelination, the presence of HLA-DRB1*15 alleles, remote Epstein-Barr-virus infection, and low 25-hydroxyvitamin D concentrations predisposed to multiple sclerosis. Our findings add to those of previous studies5, 15, 16, 17, 18 comparing the frequency of these exposures between paediatric and adult patients with established multiple sclerosis with healthy controls (panel). We show that the three exposures are present in

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