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.
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.
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%.
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.
Canadian Multiple Sclerosis Scientific Research Foundation.
Copyright © 2011 Elsevier Ltd. All rights reserved.