Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

J. Kuhle, G. Disanto, R. Dobson, R. Adiutori, L. Bianchi, J. Topping, J. P. Bestwick, U-C Meier, M. Marta, G. Dalla Costa, T. Runia, E. Evdoshenko, N. Lazareva, E. Thouvenot, P. Iaffaldano, V. Direnzo, M. Khademi, F. Piehl, M. Comabella, M. SombekkeJ. Killestein, H. Hegen, S. Rauch, S. D'Alfonso, J. C. Alvarez-Cermeno, P. Kleinova, D. Horakova, R. Roesler, F. Lauda, S. Llufriu, T. Avsar, U. Uygunoglu, A. Altintas, S. Saip, T. Menge, C. Rajda, R. Bergamaschi, N. Moll, M. Khalil, R. Marignier, I. Dujmovic, H. Larsson, C. Malmestrom, E. Scarpini, C. Fenoglio, S. Wergeland, A. Laroni, V. Annibali, S. Romano, A. D. Martinez, A. Carra, M. Salvetti, A. Uccelli, O. Torkildsen, K. M. Myhr, D. Galimberti, K. Rejdak, J. Lycke, J. L. Frederiksen, J. Drulovic, C. Confavreux, D. Brassat, C. Enzinger, S. Fuchs, I. Bosca, J. Pelletier, C. Picard, E. Colombo, D. Franciotta, T. Derfuss, R. L. P. Lindberg, Oe Yaldizli, L. Vecsei, B. C. Kieseier, H. P. Hartung, P. Villoslada, A. Siva, A. Saiz, H. Tumani, E. Havrdova, L. M. Villar, M. Leone, N. Barizzone, F. Deisenhammer, C. Teunissen, X. Montalban, M. Tintore, T. Olsson, M. Trojano, S. Lehmann, G. Castelnovo, S. Lapin, R. Hintzen, L. Kappos, R. Furlan, V. Martinelli, G. Comi, S. V. Ramagopalan, G. Giovannoni

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244 Citations (Scopus)


Background and 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.
Original languageEnglish
Pages (from-to)1013-1024
Number of pages12
JournalMultiple Sclerosis Journal
Issue number8
Early online date13 Feb 2015
Publication statusPublished - Jul 2015


  • 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)


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