Conversion from clinically isolated syndrome to multiple sclerosis: a large multicentre study
Open accessAbstract
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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Multiple studies provide evidence that in adult patients with CIS, CSF OCBs are an independent predictor of the risk of a second attack when controlling for demographic, clinical, treatment, and MRI variables.
“Multiple studies provide evidence that in adult patients with CIS, CSF OCBs are an independent predictor of the risk of a second attack when controlling for demographic, clinical, treatment, and MRI variables. 61-69”
From Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria (2018) · cites this paper as [69]
The available indexed passages are bibliographic records for Kuhle et al. (2015), with no Results or other study-text passage reporting the predictors of a second attack. Searches for OCBs, oligoclonal bands, and second attack found no passage addressing whether the association remained after adjustment for demographic, clinical, treatment, and MRI variables. (LLM, conf=0.70)
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Cites
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Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria
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- Authors
- Kuhle, J., Disanto, G., Dobson, R., Adiutori, R., Bianchi, L., Topping, J., Bestwick, J., Meier, U.-C., Marta, M., Costa, G. D., 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., D’Alfonso, S., Alvarez-Cermeño, J., 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., Carra, A., Salvetti, M., Uccelli, A., Torkildsen, Ø., Myhr, K., Galimberti, D., Rejdak, K., Lycke, J., Frederiksen, J., Drulovic, J., Confavreux, C., Brassat, D., Enzinger, C., Fuchs, S., Bosca, I., Pelletier, J., Picard, C., Colombo, E., Franciotta, D., Derfuss, T., Lindberg, R., Yaldizli, Ö., Vécsei, L., Kieseier, B., Hartung, H., Villoslada, P., Siva, A., Saiz, A., Tumani, H., Havrdová, E., Villar, L., 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., & Giovannoni, G.
- Affiliations
- 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
- Queen Mary University of London (GB)
- Vita-Salute San Raffaele University (IT)
- Erasmus MC (NL)
- City Clinical Hospital No 31 (RU)
- Institut de Génomique Fonctionelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, Université Montpellier, France, and Hôpital Carémeau, France
- University of Bari Aldo Moro (IT)
- Karolinska Institutet (SE)
- Universitat Autònoma de Barcelona (ES)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Innsbruck Medical University (AT)
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Department of Neurology and Immunology, Hospital Ramón y Cajal, Spain
- Charles University (CZ)
- Universität Ulm (DE)
- Center for Neuroimmunology and Department of Neurology. Institut d’investigacions Biomèdiques August Pi Sunyer (IDIBAPS) – Hospital Clinic of Barcelona, Spain
- Dr Orhan Öcalgiray Molecular Biology-Biotechnology and Genetics Research Centre, Istanbul Technical University, Turkey
- Department of Neurology, Istanbul University, Turkey
- Istanbul University (TR)
- Heinrich Heine University Düsseldorf (DE)
- University of Szeged (HU)
- Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT)
- Aix-Marseille Université (FR)
- Medical University of Graz (AT)
- Lyon 1 Université (FR)
- Clinic of Neurology, Belgrade University School of Medicine, Serbia
- University of Copenhagen (DK)
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden
- University of Milan (IT)
- Haukeland University Hospital (NO)
- University of Genoa (IT)
- Azienda Ospedaliera Sant'Andrea (IT)
- Department of Neurology of Hospital Británico of Buenos Aires, Argentina
- Medical University of Lublin (PL)
- University of Gothenburg (SE)
- Department of Neurology, Glostrup Hospital, University of Copenhagen, Denmark
- University of Belgrade (RS)
- Université de Toulouse (FR)
- MS Unit, Neurology Department, La Fe University and Polytechnic Hospital, Instituto de investigación Sanitaria La Fe, Spain
- University of Basel (CH)
- Hospital Clínic de Barcelona (ES)
- Azienda Ospedaliero Universitaria Maggiore della Carita (IT)
- Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Receca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Spain
- Centre National de la Recherche Scientifique (FR)
- University of Oxford (GB)
- ORCID
- Disanto, G
- Dobson, R
- Adiutori, R
- Bianchi, L
- Meier, U-C
- Marta, M
- Costa, G Dalla
- Evdoshenko, E
- Iaffaldano, P
- Khademi, M
- Piehl, F
- Comabella, M
- Killestein, J
- Hegen, H
- Rauch, S
- D’Alfonso, S
- Kleinová, P
- Horáková, D
- Saip, S
- Menge, T
- Rajda, C
- Bergamaschi, R
- Khalil, M
- Marignier, R
- Larsson, H
- Scarpini, E
- Fenoglio, C
- Wergeland, S
- Laroni, A
- Annibali, V
- Romano, S
- Salvetti, M
- Uccelli, A
- Torkildsen, Ø
- Galimberti, D
- Rejdak, K
- Lycke, J
- Drulovic, J
- Brassat, D
- Enzinger, C
- Pelletier, J
- Picard, C
- Colombo, E
- Franciotta, D
- Derfuss, T
- Yaldizli, Ö
- Vécsei, L
- Villoslada, P
- Saiz, A
- Tumani, H
- Havrdová, E
- Leone, M
- Barizzone, N
- Deisenhammer, F
- Teunissen, C
- Tintoré, M
- Olsson, T
- Trojano, M
- Lehmann, S
- Castelnovo, G
- Lapin, S
- Hintzen, R
- Kappos, L
- Furlan, R
- Martinelli, V
- Comi, G
- Giovannoni, G
- Venue
- Multiple Sclerosis Journal
- Publisher
- SAGE Publications
- Published
- 2015-02-13
- Volume
- 21
- Issue
- 8
- Pages
- 1013-1024
- ISSN
- 1352-4585 (ISSN-L)
- 1477-0970
- OpenAlex
- W1827868006
- Cited by
- 299
- References
- 5
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 21 · 2023: 20 · 2022: 25 · 2021: 30 · 2020: 30 · 2019: 36 · 2018: 33 · 2017: 32 · 2016: 26 · 2015: 17 · 2014: 2
- FWCI
- 28.52
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Locations
- Multiple Sclerosis Journal (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Istanbul Technical University Academic Open Archive (Istanbul Technical University) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Acorda Therapeutics
- Bayer Fund
- Bundesministerium für Bildung und Forschung
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Oncology › Polyomavirus and related diseases
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Keywords
- clinically isolated syndrome, conversion to multiple sclerosis, clinically definite multiple sclerosis, oligoclonal bands, cerebrospinal fluid biomarkers, T2 hyperintensity, MRI lesion burden, age of onset, vitamin D, 25-hydroxyvitamin D, Epstein-Barr virus, cytomegalovirus, risk factors
- MeSH terms
- Adult, Endonucleases, Female, Follow-Up Studies, Humans, Immunoglobulin G, Magnetic Resonance Imaging, Male, Multiple Sclerosis, Nuclear Proteins, Predictive Value of Tests, Prognosis, Vitamin D, Cohort Studies, Survival Analysis, Disease Progression, Risk Assessment, Oligoclonal Bands
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