title: Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study.
abstract: OBJECTIVE
  We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort.
  
  
  METHODS
  Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS.
  
  
  RESULTS
  At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres.
  
  
  CONCLUSIONS
  We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
authors: Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, UK/ Departments of Neurology and Biomedicine, University Hospital Basel, University of Basel, Switzerland.
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authors: Kuhle
authors: Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, UK.
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authors: Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, UK.
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authors: Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, UK.
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authors: Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, UK.
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authors: Department of Neurology and INSPE, Vita-Salute San Raffaele University, Scientific Institute San Raffaele, Italy.
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authors: Department of Neurology, Erasmus MC University Medical Center, The Netherlands.
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authors: Institut de Génomique Fonctionelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, Université Montpellier, France, and Hôpital Carémeau, France.
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authors: Salvetti
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authors: Myhr
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authors: Fuchs
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authors: Siva
authors: Center for Neuroimmunology and Department of Neurology. Institut d'investigacions Biomèdiques August Pi Sunyer (IDIBAPS) - Hospital Clinic of Barcelona, Spain.
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authors: Saiz
authors: Department of Neurology, CSF Laboratory and MS Outpatient Unit, University of Ulm, Germany.
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authors: Department of Neurology, Charles University in Prague, Czech Republic.
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authors: M
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authors: Tintoré
authors: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Sweden.
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authors: Olsson
authors: Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Italy.
authors: M
authors: M
authors: Trojano
authors: Institut de Génomique Fonctionelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, Université Montpellier, France, and Hôpital Carémeau, France.
authors: S
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authors: Lehmann
authors: Institut de Génomique Fonctionelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, Université Montpellier, France, and Hôpital Carémeau, France.
authors: G
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authors: Castelnovo
authors: Centre of Multiple Sclerosis, City Clinical Hospital#31, Russia.
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authors: Lapin
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authors: Hintzen
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authors: L
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authors: Kappos
authors: Department of Neurology and INSPE, Vita-Salute San Raffaele University, Scientific Institute San Raffaele, Italy.
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authors: Furlan
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authors: Martinelli
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authors: G
authors: G
authors: Comi
authors: Department of Physiology, Anatomy and Genetics and Medical Research Council Functional Genomics Unit, University of Oxford, UK.
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authors: SV
authors: Ramagopalan
authors: Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, UK g.giovannoni@qmul.ac.uk.
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authors: Giovannoni
mesh_terms: D000328:Adult; D015331:Cohort Studies; D018450:Disease Progression; D004720:Endonucleases; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000473:pathology*; D009687:Nuclear Proteins / Q000032:analysis; D043025:Oligoclonal Bands / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D018570:Risk Assessment; D016019:Survival Analysis; D014807:Vitamin D / Q000097:blood
chemical_list: D007074:Immunoglobulin G; D009687:Nuclear Proteins; D043025:Oligoclonal Bands; D014807:Vitamin D; D004720:Endonucleases; C095221:SND1 protein, human
keywords: Clinically definite multiple sclerosis (CDMS); Epstein-Barr nuclear antigen 1 (EBNA-1); clinically isolated syndrome (CIS); oligoclonal bands (OCBs); serum 25-hydroxyvitamin D3 (25-OH-D)