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

被引：231

作者：

Banwell, Brenda ^{[1
,2
]}

Bar-Or, Amit ^{[3
,4
]}

Arnold, Douglas L. ^{[5
]}

Sadovnick, Dessa ^{[6
,7
]}

Narayanan, Sridar ^{[5
]}

McGowan, Melissa ^{[1
]}

O'Mahony, Julia ^{[1
]}

Magalhaes, Sandra ^{[3
,4
]}

Hanwell, Heather ^{[1
,8
,9
]}

Vieth, Reinhold ^{[8
,9
]}

Tellier, Raymond ^{[10
]}

Vincent, Thierry ^{[11
]}

Disanto, Giulio ^{[12
]}

Ebers, George ^{[12
]}

Wambera, Katherine ^{[13
]}

Connolly, Mary B. ^{[14
]}

Yager, Jerome ^{[15
]}

Mah, Jean K. ^{[16
]}

Booth, Fran ^{[17
]}

Sebire, Guillaume ^{[18
]}

Callen, David ^{[19
]}

Meaney, Brandon ^{[19
]}

Dilenge, Marie-Emmanuelle ^{[20
]}

Lortie, Anne ^{[21
]}

Pohl, Daniela ^{[22
]}

Doja, Asif ^{[22
]}

Venketaswaran, Sunita ^{[22
]}

Levin, Simon ^{[23
]}

MacDonald, E. Athen ^{[24
]}

Meek, David ^{[25
]}

Wood, Ellen ^{[26
]}

Lowry, Noel ^{[27
]}

Buckley, David ^{[28
]}

Yim, Conrad ^{[29
]}

Awuku, Mark ^{[30
]}

Cooper, Pamela ^{[31
]}

Grand'Maison, Francois ^{[32
]}

Baird, J. Burke ^{[33
]}

Bhan, Virender ^{[34
]}

Marrie, Ruth Ann ^{[35
]}

机构：

[1] Univ Toronto, Hosp Sick Children, Res Inst, Toronto, ON M5G 1X8, Canada

[2] Univ Toronto, Dept Paediat, Div Neurol, Toronto, ON M5G 1X8, Canada

[3] McGill Univ, Neuroimmunol Unit, Montreal, PQ, Canada

[4] McGill Univ, Expt Therapeut Program, Montreal, PQ, Canada

[5] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada

[6] Univ British Columbia, Dept Neurol, Vancouver, BC V5Z 1M9, Canada

[7] Univ British Columbia, Div Med Genet, Vancouver, BC V5Z 1M9, Canada

[8] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada

[9] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada

[10] Univ Calgary, Dept Microbiol Immunol & Infect Dis, Calgary, AB, Canada

[11] CHU Montpellier, Hop St Eloi, Dept Immunol, Montpellier, France

[12] Univ Oxford, Dept Clin Neurol, Wellcome Trust Ctr Human Genet, Oxford, England

[13] Victoria Gen Hosp, Victoria, BC, Canada

[14] British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada

[15] Stollery Childrens Hosp, Edmonton, AB, Canada

[16] Alberta Childrens Prov Gen Hosp, Calgary, AB T2T 5C7, Canada

[17] Childrens Hosp Winnipeg, Winnipeg, MB, Canada

[18] Univ Sherbrooke, Ctr Hosp, Sherbrooke, PQ J1K 2R1, Canada

[19] McMaster Childrens Hosp, Hamilton, ON, Canada

[20] Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada

[21] Univ St Justine, Ctr Hosp, Montreal, PQ, Canada

[22] Childrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, Canada

[23] Childrens Hosp Western Ontario, London, ON, Canada

[24] Queens Univ, Kingston, ON, Canada

[25] St Johns Hosp, St John, NB, Canada

[26] IWK Hlth Ctr, Halifax, NS, Canada

[27] Royal Univ Hosp, Saskatoon, SK S7N 0W8, Canada

[28] Janeway Childrens Hlth & Rehabil Ctr, St John, NF, Canada

[29] Trillium Hlth Ctr, Mississauga, ON, Canada

[30] Windsor Reg Hosp, Windsor, ON, Canada

[31] Rouge Valley Centenary Hosp, Scarborough, ON, Canada

[32] Hop Charles LeMoyne, Montreal, PQ, Canada

[33] Sudbury Reg Hosp, Sudbury, ON, Canada

[34] Dalhousie MS Res Unit, Halifax, NS, Canada

[35] Univ Manitoba, Dept Internal Med, Winnipeg Hlth Sci Ctr, Winnipeg, MB, Canada

来源：

LANCET NEUROLOGY | 2011年 / 10卷 / 05期

基金：

加拿大健康研究院;

关键词：

EPSTEIN-BARR-VIRUS; DIAGNOSTIC-CRITERIA; MCDONALD CRITERIA; RISK-FACTORS; ANTIBODIES; CHILDHOOD; FEATURES;

D O I：

10.1016/S1474-4422(11)70045-X

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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, Mill 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 [FIR] 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 (FIR 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 C SF oligoclonal bands (6.33, 3.35-11.96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal Mill 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 Mill 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.

引用

页码：436 / 445

页数：10

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