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dc.contributor.authorMalpas, Charles B-
dc.contributor.authorManouchehrinia, Ali-
dc.contributor.authorSharmin, Sifat-
dc.contributor.authorRoos, Izanne-
dc.contributor.authorHorakova, Dana-
dc.contributor.authorHavrdova, Eva Kubala-
dc.contributor.authorTrojano, Maria-
dc.contributor.authorIzquierdo, Guillermo-
dc.contributor.authorEichau, Sara-
dc.contributor.authorBergamaschi, Roberto-
dc.contributor.authorSola, Patrizia-
dc.contributor.authorFerraro, Diana-
dc.contributor.authorLugaresi, Alessandra-
dc.contributor.authorPrat, Alexandre-
dc.contributor.authorGirard, Marc-
dc.contributor.authorDuquette, Pierre-
dc.contributor.authorGrammond, Pierre-
dc.contributor.authorGrand'Maison, Francois-
dc.contributor.authorOzakbas, Serkan-
dc.contributor.authorVan Pesch, Vincent-
dc.contributor.authorGranella, Franco-
dc.contributor.authorHupperts, Raymond-
dc.contributor.authorPucci, Eugenio-
dc.contributor.authorBoz, Cavit-
dc.contributor.authorSidhom, Youssef-
dc.contributor.authorGouider, Riadh-
dc.contributor.authorSpitaleri, Daniele-
dc.contributor.authorSoysal, Aysun-
dc.contributor.authorPetersen, Thor-
dc.contributor.authorVerheul, Freek-
dc.contributor.authorKarabudak, Rana-
dc.contributor.authorTurkoglu, Recai-
dc.contributor.authorRamo-Tello, Cristina-
dc.contributor.authorTerzi, Murat-
dc.contributor.authorCristiano, Edgardo-
dc.contributor.authorSlee, Mark-
dc.contributor.authorMcCombe, Pamela-
dc.contributor.authorMacdonell, Richard A L-
dc.contributor.authorFragoso, Yara-
dc.contributor.authorOlascoaga, Javier-
dc.contributor.authorAltintas, Ayse-
dc.contributor.authorOlsson, Tomas-
dc.contributor.authorButzkueven, Helmut-
dc.contributor.authorHillert, Jan-
dc.contributor.authorKalincik, Tomas-
dc.identifier.citationBrain : a journal of neurology 2020; online first: 9 May-
dc.description.abstractPatients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.-
dc.subjectaggressive disease-
dc.subjectmultiple sclerosis-
dc.subjectprecision medicine-
dc.titleEarly clinical markers of aggressive multiple sclerosis.-
dc.typeJournal Article-
dc.identifier.journaltitleBrain : a journal of neurology-
dc.identifier.affiliationUniversité Catholique de Louvain, Brussels, Belgiumen
dc.identifier.affiliationDepartment of Biomedical and Neuromotor Science, University of Bologna, Bologna, Italyen
dc.identifier.affiliationIRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italyen
dc.identifier.affiliationCliniques Universitaires Saint-Luc, Brussels, Belgiumen
dc.identifier.affiliationCORe Unit, Department of Medicine, University of Melbourne, Melbourne, Australiaen
dc.identifier.affiliationCentre for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden-
dc.identifier.affiliationFlinders University, Adelaide, Australiaen
dc.identifier.affiliationRoyal Brisbane and Women's Hospital, Brisbane, Australiaen
dc.identifier.affiliationUniversity of Queensland, Brisbane, Australiaen
dc.identifier.affiliationDepartment of Neurology, Box Hill Hospital, Monash University, Melbourne, Australiaen
dc.identifier.affiliationDepartment of Neurology, The Alfred Hospital, Melbourne, Australiaen
dc.identifier.affiliationCentral Clinical School, Monash University, Melbourne, Australiaen
dc.identifier.affiliationAustin Health, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationDepartment of Neurology, Royal Melbourne Hospital, Melbourne, Australiaen
dc.identifier.affiliationDepartment of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italyen
dc.identifier.affiliationDepartment of Biomedical, Metabolic and Neurosciences, University of Modena and Reggio Emilia, Modena, Italyen
dc.identifier.affiliationDepartment of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic-
dc.identifier.affiliationDepartment of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy-
dc.identifier.affiliationHospital Universitario Virgen Macarena, Sevilla, Spain-
dc.identifier.affiliationIRCCS Mondino Foundation, Pavia, Italy-
dc.identifier.affiliationDepartment of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy-
dc.identifier.affiliationCHUM and Universite de Montreal, Montreal, Canada-
dc.identifier.affiliationCISSS de Chaudière-Appalaches, Levis, Canada-
dc.identifier.affiliationNeuro Rive-Sud, Quebec, Canada-
dc.identifier.affiliationDokuz Eylul University, Konak/Izmir, Turkey-
dc.identifier.affiliationDepartment of Medicine and Surgery, University of Parma, Parma, Italy-
dc.identifier.affiliationZuyderland Ziekenhuis, Sittard, The Netherlands-
dc.identifier.affiliationUOC Neurologia, Azienda Sanitaria Unica Regionale Marche - AV3, Macerata, Italy-
dc.identifier.affiliationKTU Medical Faculty Farabi Hospital, Trabzon, Turkey-
dc.identifier.affiliationDepartment of Neurology, Razi Hospital, Manouba, Tunisia-
dc.identifier.affiliationDepartment of Neurology, Razi Hospital, LR 18SP03, Clinical Investigation Center Neurosciences and Mental Health, Faculty of Medicine University Tunis El Manar, Tunis, Tunisia-
dc.identifier.affiliationAzienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy-
dc.identifier.affiliationBakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey-
dc.identifier.affiliationKommunehospitalet, Arhus C, Denmark-
dc.identifier.affiliationGroene Hart Ziekenhuis, Gouda, The Netherlands-
dc.identifier.affiliationHacettepe University, Ankara, Turkey-
dc.identifier.affiliationHaydarpasa Numune Training and Research Hospital, Istanbul, Turkey-
dc.identifier.affiliationHospital Germans Trias i Pujol, Badalona, Spain-
dc.identifier.affiliationMedical Faculty, 19 Mayis University, Samsun, Turkey-
dc.identifier.affiliationHospital Italiano, Buenos Aires, Argentina-
dc.identifier.affiliationUniversidade Metropolitana de Santos, Santos, Brazil-
dc.identifier.affiliationInstituto de Investigación Sanitaria Biodonostia, Hospital Universitario Donostia, San Sebastián, Spain-
dc.identifier.affiliationKoc University, School of Medicine, Department of Neurology, Istanbul, Turkey-
dc.identifier.affiliationDepartment of Clinical Neuroscience, Karolinska Institutet, Sweden-
dc.type.austinJournal Article-
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