title: 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.
  
  
  RESULTS
  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%.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Canadian Multiple Sclerosis Scientific Research Foundation.
authors: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. brenda.banwell@sickkids.ca
authors: Brenda
authors: B
authors: Banwell
authors: Amit
authors: A
authors: Bar-Or
authors: Douglas L
authors: DL
authors: Arnold
authors: Dessa
authors: D
authors: Sadovnick
authors: Sridar
authors: S
authors: Narayanan
authors: Melissa
authors: M
authors: McGowan
authors: Julia
authors: J
authors: O'Mahony
authors: Sandra
authors: S
authors: Magalhaes
authors: Heather
authors: H
authors: Hanwell
authors: Reinhold
authors: R
authors: Vieth
authors: Raymond
authors: R
authors: Tellier
authors: Thierry
authors: T
authors: Vincent
authors: Giulio
authors: G
authors: Disanto
authors: George
authors: G
authors: Ebers
authors: Katherine
authors: K
authors: Wambera
authors: Mary B
authors: MB
authors: Connolly
authors: Jerome
authors: J
authors: Yager
authors: Jean K
authors: JK
authors: Mah
authors: Fran
authors: F
authors: Booth
authors: Guillaume
authors: G
authors: Sebire
authors: David
authors: D
authors: Callen
authors: Brandon
authors: B
authors: Meaney
authors: Marie-Emmanuelle
authors: ME
authors: Dilenge
authors: Anne
authors: A
authors: Lortie
authors: Daniela
authors: D
authors: Pohl
authors: Asif
authors: A
authors: Doja
authors: Sunita
authors: S
authors: Venketaswaran
authors: Simon
authors: S
authors: Levin
authors: E Athen
authors: EA
authors: Macdonald
authors: David
authors: D
authors: Meek
authors: Ellen
authors: E
authors: Wood
authors: Noel
authors: N
authors: Lowry
authors: David
authors: D
authors: Buckley
authors: Conrad
authors: C
authors: Yim
authors: Mark
authors: M
authors: Awuku
authors: Pamela
authors: P
authors: Cooper
authors: François
authors: F
authors: Grand'maison
authors: J Burke
authors: JB
authors: Baird
authors: Virender
authors: V
authors: Bhan
authors: Ruth Ann
authors: RA
authors: Marrie
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000367:Age Factors; D002170:Canada / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003711:Demyelinating Diseases / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D004781:Environmental Exposure / Q000009:adverse effects*; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D005819:Genetic Markers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C507799:HLA-DRB1*15 antigen