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

Abstract

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.

• Authors: Brenda Banwell, Amit Bar-Or, Douglas L Arnold, Dessa Sadovnick, Sridar Narayanan, Melissa McGowan, Julia O'Mahony, Sandra Magalhaes, Heather Hanwell, Reinhold Vieth, Raymond Tellier, Thierry Vincent, Giulio Disanto, George Ebers, Katherine Wambera, Mary B Connolly, Jerome Yager, Jean K Mah, Fran Booth, Guillaume Sebire, David Callen, Brandon Meaney, Marie-Emmanuelle Dilenge, Anne Lortie, Daniela Pohl, Asif Doja, Sunita Venketaswaran, Simon Levin, E Athen Macdonald, David Meek, Ellen Wood, Noel Lowry, David Buckley, Conrad Yim, Mark Awuku, Pamela Cooper, François Grand'maison, J Burke Baird, Virender Bhan, Ruth Ann Marrie
• Journal: The Lancet. Neurology (Lancet Neurol) Vol. 10 Issue 5 Pg. 436-45 (May 2011) ISSN: 1474-4465 [Electronic] England
• PMID: 21459044 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Genetic Markers
• HLA-DR Antigens
• HLA-DRB1 Chains
• HLA-DRB1*15 antigen

Topics

• Acute Disease
• Adolescent
• Age Factors
• Canada (epidemiology)
• Child
• Child, Preschool
• Cohort Studies
• Demyelinating Diseases (diagnosis, epidemiology, genetics)
• Environmental Exposure (adverse effects)
• Epstein-Barr Virus Infections (diagnosis, epidemiology, genetics)
• Female
• Follow-Up Studies
• Genetic Markers (genetics)
• Genetic Predisposition to Disease
• HLA-DR Antigens (genetics)
• HLA-DRB1 Chains
• Humans
• Male
• Multiple Sclerosis (diagnosis, epidemiology, genetics)
• Prospective Studies
• Risk Factors