Conversion from clinically isolated syndrome to multiple sclerosis: A large multicantre 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. Dalfonso, J. C. Alvarez-Cermeño, P. Kleinová, D. Horáková, 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. Martínez, A. Carra, M. Salvetti, A. Uccelli, 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, Yaldizli, L. Vécsei, B. C. Kieseier, H. P. Hartung, P. Villoslada, A. Siva, A. Saiz, H. Tumani, E. Havrdová, L. M. Villar, M. Leone, N. Barizzone, F. Deisenhammer, C. Teunissen, X. Montalban, M. Tintoré, 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

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

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
Volume21
Issue number8
DOIs
Publication statusPublished - Jul 11 2015

Fingerprint

Oligoclonal Bands
Multiple Sclerosis
Cerebrospinal Fluid
Nuclear Antigens
Immunoglobulin G
Calcifediol
Cotinine
Serum
Cytomegalovirus
Vitamin D
Cell Count
hydroxide ion

Keywords

  • Clinically definite multiple sclerosis (CDMS)
  • clinically isolated syndrome (CIS)
  • Epstein-Barr nuclear antigen 1 (EBNA-1)
  • oligoclonal bands (OCBs)
  • serum 25-hydroxyvitamin D3 (25-OH-D)

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Kuhle, J., Disanto, G., Dobson, R., Adiutori, R., Bianchi, L., Topping, J., ... Giovannoni, G. (2015). Conversion from clinically isolated syndrome to multiple sclerosis: A large multicantre study. Multiple Sclerosis, 21(8), 1013-1024. https://doi.org/10.1177/1352458514568827

Conversion from clinically isolated syndrome to multiple sclerosis : A large multicantre study. / Kuhle, J.; Disanto, G.; Dobson, R.; Adiutori, R.; Bianchi, L.; Topping, J.; Bestwick, J. P.; Meier, U. C.; Marta, M.; Dalla Costa, G.; Runia, T.; Evdoshenko, E.; Lazareva, N.; Thouvenot, E.; Iaffaldano, P.; Direnzo, V.; Khademi, M.; Piehl, F.; Comabella, M.; Sombekke, M.; Killestein, J.; Hegen, H.; Rauch, S.; Dalfonso, S.; Alvarez-Cermeño, J. C.; Kleinová, P.; Horáková, D.; Roesler, R.; Lauda, F.; Llufriu, S.; Avsar, T.; Uygunoglu, U.; Altintas, A.; Saip, S.; Menge, T.; Rajda, C.; Bergamaschi, R.; Moll, N.; Khalil, M.; Marignier, R.; Dujmovic, I.; Larsson, H.; Malmestrom, C.; Scarpini, E.; Fenoglio, C.; Wergeland, S.; Laroni, A.; Annibali, V.; Romano, S.; Martínez, A. D.; Carra, A.; Salvetti, M.; Uccelli, A.; Torkildsen; Myhr, K. M.; Galimberti, D.; Rejdak, K.; Lycke, J.; Frederiksen, J. L.; Drulovic, J.; Confavreux, C.; Brassat, D.; Enzinger, C.; Fuchs, S.; Bosca, I.; Pelletier, J.; Picard, C.; Colombo, E.; Franciotta, D.; Derfuss, T.; Lindberg, R. L P; Yaldizli, ; Vécsei, L.; Kieseier, B. C.; Hartung, H. P.; Villoslada, P.; Siva, A.; Saiz, A.; Tumani, H.; Havrdová, E.; Villar, L. M.; Leone, M.; Barizzone, N.; Deisenhammer, F.; Teunissen, C.; Montalban, X.; Tintoré, M.; Olsson, T.; Trojano, M.; Lehmann, S.; Castelnovo, G.; Lapin, S.; Hintzen, R.; Kappos, L.; Furlan, R.; Martinelli, V.; Comi, G.; Ramagopalan, S. V.; Giovannoni, G.

In: Multiple Sclerosis, Vol. 21, No. 8, 11.07.2015, p. 1013-1024.

Research output: Contribution to journalArticle

Kuhle, J, Disanto, G, Dobson, R, Adiutori, R, Bianchi, L, Topping, J, Bestwick, JP, Meier, UC, Marta, M, Dalla Costa, G, Runia, T, Evdoshenko, E, Lazareva, N, Thouvenot, E, Iaffaldano, P, Direnzo, V, Khademi, M, Piehl, F, Comabella, M, Sombekke, M, Killestein, J, Hegen, H, Rauch, S, Dalfonso, S, Alvarez-Cermeño, JC, Kleinová, P, Horáková, D, Roesler, R, Lauda, F, Llufriu, S, Avsar, T, Uygunoglu, U, Altintas, A, Saip, S, Menge, T, Rajda, C, Bergamaschi, R, Moll, N, Khalil, M, Marignier, R, Dujmovic, I, Larsson, H, Malmestrom, C, Scarpini, E, Fenoglio, C, Wergeland, S, Laroni, A, Annibali, V, Romano, S, Martínez, AD, Carra, A, Salvetti, M, Uccelli, A, Torkildsen, Myhr, KM, Galimberti, D, Rejdak, K, Lycke, J, Frederiksen, JL, Drulovic, J, Confavreux, C, Brassat, D, Enzinger, C, Fuchs, S, Bosca, I, Pelletier, J, Picard, C, Colombo, E, Franciotta, D, Derfuss, T, Lindberg, RLP, Yaldizli, , Vécsei, L, Kieseier, BC, Hartung, HP, Villoslada, P, Siva, A, Saiz, A, Tumani, H, Havrdová, E, Villar, LM, Leone, M, Barizzone, N, Deisenhammer, F, Teunissen, C, Montalban, X, Tintoré, M, Olsson, T, Trojano, M, Lehmann, S, Castelnovo, G, Lapin, S, Hintzen, R, Kappos, L, Furlan, R, Martinelli, V, Comi, G, Ramagopalan, SV & Giovannoni, G 2015, 'Conversion from clinically isolated syndrome to multiple sclerosis: A large multicantre study', Multiple Sclerosis, vol. 21, no. 8, pp. 1013-1024. https://doi.org/10.1177/1352458514568827
Kuhle J, Disanto G, Dobson R, Adiutori R, Bianchi L, Topping J et al. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicantre study. Multiple Sclerosis. 2015 Jul 11;21(8):1013-1024. https://doi.org/10.1177/1352458514568827
Kuhle, J. ; Disanto, G. ; Dobson, R. ; Adiutori, R. ; Bianchi, L. ; Topping, J. ; Bestwick, J. P. ; Meier, U. C. ; Marta, M. ; Dalla Costa, G. ; Runia, T. ; Evdoshenko, E. ; Lazareva, N. ; Thouvenot, E. ; Iaffaldano, P. ; Direnzo, V. ; Khademi, M. ; Piehl, F. ; Comabella, M. ; Sombekke, M. ; Killestein, J. ; Hegen, H. ; Rauch, S. ; Dalfonso, S. ; Alvarez-Cermeño, J. C. ; Kleinová, P. ; Horáková, D. ; Roesler, R. ; Lauda, F. ; Llufriu, S. ; Avsar, T. ; Uygunoglu, U. ; Altintas, A. ; Saip, S. ; Menge, T. ; Rajda, C. ; Bergamaschi, R. ; Moll, N. ; Khalil, M. ; Marignier, R. ; Dujmovic, I. ; Larsson, H. ; Malmestrom, C. ; Scarpini, E. ; Fenoglio, C. ; Wergeland, S. ; Laroni, A. ; Annibali, V. ; Romano, S. ; Martínez, A. D. ; Carra, A. ; Salvetti, M. ; Uccelli, A. ; Torkildsen ; Myhr, K. M. ; Galimberti, D. ; Rejdak, K. ; Lycke, J. ; Frederiksen, J. L. ; Drulovic, J. ; Confavreux, C. ; Brassat, D. ; Enzinger, C. ; Fuchs, S. ; Bosca, I. ; Pelletier, J. ; Picard, C. ; Colombo, E. ; Franciotta, D. ; Derfuss, T. ; Lindberg, R. L P ; Yaldizli, ; Vécsei, L. ; Kieseier, B. C. ; Hartung, H. P. ; Villoslada, P. ; Siva, A. ; Saiz, A. ; Tumani, H. ; Havrdová, E. ; Villar, L. M. ; Leone, M. ; Barizzone, N. ; Deisenhammer, F. ; Teunissen, C. ; Montalban, X. ; Tintoré, M. ; Olsson, T. ; Trojano, M. ; Lehmann, S. ; Castelnovo, G. ; Lapin, S. ; Hintzen, R. ; Kappos, L. ; Furlan, R. ; Martinelli, V. ; Comi, G. ; Ramagopalan, S. V. ; Giovannoni, G. / Conversion from clinically isolated syndrome to multiple sclerosis : A large multicantre study. In: Multiple Sclerosis. 2015 ; Vol. 21, No. 8. pp. 1013-1024.
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abstract = "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.",
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TY - JOUR

T1 - Conversion from clinically isolated syndrome to multiple sclerosis

T2 - A large multicantre study

AU - Kuhle, J.

AU - Disanto, G.

AU - Dobson, R.

AU - Adiutori, R.

AU - Bianchi, L.

AU - Topping, J.

AU - Bestwick, J. P.

AU - Meier, U. C.

AU - Marta, M.

AU - Dalla Costa, G.

AU - Runia, T.

AU - Evdoshenko, E.

AU - Lazareva, N.

AU - Thouvenot, E.

AU - Iaffaldano, P.

AU - Direnzo, V.

AU - Khademi, M.

AU - Piehl, F.

AU - Comabella, M.

AU - Sombekke, M.

AU - Killestein, J.

AU - Hegen, H.

AU - Rauch, S.

AU - Dalfonso, S.

AU - Alvarez-Cermeño, J. C.

AU - Kleinová, P.

AU - Horáková, D.

AU - Roesler, R.

AU - Lauda, F.

AU - Llufriu, S.

AU - Avsar, T.

AU - Uygunoglu, U.

AU - Altintas, A.

AU - Saip, S.

AU - Menge, T.

AU - Rajda, C.

AU - Bergamaschi, R.

AU - Moll, N.

AU - Khalil, M.

AU - Marignier, R.

AU - Dujmovic, I.

AU - Larsson, H.

AU - Malmestrom, C.

AU - Scarpini, E.

AU - Fenoglio, C.

AU - Wergeland, S.

AU - Laroni, A.

AU - Annibali, V.

AU - Romano, S.

AU - Martínez, A. D.

AU - Carra, A.

AU - Salvetti, M.

AU - Uccelli, A.

AU - Torkildsen,

AU - Myhr, K. M.

AU - Galimberti, D.

AU - Rejdak, K.

AU - Lycke, J.

AU - Frederiksen, J. L.

AU - Drulovic, J.

AU - Confavreux, C.

AU - Brassat, D.

AU - Enzinger, C.

AU - Fuchs, S.

AU - Bosca, I.

AU - Pelletier, J.

AU - Picard, C.

AU - Colombo, E.

AU - Franciotta, D.

AU - Derfuss, T.

AU - Lindberg, R. L P

AU - Yaldizli,

AU - Vécsei, L.

AU - Kieseier, B. C.

AU - Hartung, H. P.

AU - Villoslada, P.

AU - Siva, A.

AU - Saiz, A.

AU - Tumani, H.

AU - Havrdová, E.

AU - Villar, L. M.

AU - Leone, M.

AU - Barizzone, N.

AU - Deisenhammer, F.

AU - Teunissen, C.

AU - Montalban, X.

AU - Tintoré, M.

AU - Olsson, T.

AU - Trojano, M.

AU - Lehmann, S.

AU - Castelnovo, G.

AU - Lapin, S.

AU - Hintzen, R.

AU - Kappos, L.

AU - Furlan, R.

AU - Martinelli, V.

AU - Comi, G.

AU - Ramagopalan, S. V.

AU - Giovannoni, G.

PY - 2015/7/11

Y1 - 2015/7/11

N2 - 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.

AB - 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.

KW - Clinically definite multiple sclerosis (CDMS)

KW - clinically isolated syndrome (CIS)

KW - Epstein-Barr nuclear antigen 1 (EBNA-1)

KW - oligoclonal bands (OCBs)

KW - serum 25-hydroxyvitamin D3 (25-OH-D)

UR - http://www.scopus.com/inward/record.url?scp=84929479105&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929479105&partnerID=8YFLogxK

U2 - 10.1177/1352458514568827

DO - 10.1177/1352458514568827

M3 - Article

C2 - 25680984

AN - SCOPUS:84929479105

VL - 21

SP - 1013

EP - 1024

JO - Multiple Sclerosis Journal

JF - Multiple Sclerosis Journal

SN - 1352-4585

IS - 8

ER -