title: Defining secondary progressive multiple sclerosis.
abstract: A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden [median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0)] versus non-progressive patients [1.8 (1.2, 1.9)]. This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Johannes
authors.initials: J
authors.lastname: Lorscheider
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia 3 Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Buzzard
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Vilija
authors.initials: V
authors.lastname: Jokubaitis
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Spelman
authors.affiliation: 4 Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdova
authors.affiliation: 4 Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Horakova
authors.affiliation: 5 Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Trojano
authors.affiliation: 6 Hospital Universitario Virgen Macarena, Seville, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
authors.affiliation: 7 Hôpital Notre Dame, Montreal, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Girard
authors.affiliation: 7 Hôpital Notre Dame, Montreal, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Duquette
authors.affiliation: 7 Hôpital Notre Dame, Montreal, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: 8 Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater Studiorum - Università di Bologna, Bologna, Italy 9 IRCCS Istituto delle Scienze Neurologiche - "UOSI Riabilitazione Sclerosi Multipla" Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lugaresi
authors.affiliation: 10 Neuro Rive-Sud, Hôpital Charles LeMoyne, Greenfield Park, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Grand'Maison
authors.affiliation: 11 Hôtel-Dieu de Lévis, Lévis, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Grammond
authors.affiliation: 12 Orbis Medical Center, Sittard, The Netherlands.
authors.forename: Raymond
authors.initials: R
authors.lastname: Hupperts
authors.affiliation: 13 Amiri Hospital, Kuwait, Kuwait.
authors.forename: Raed
authors.initials: R
authors.lastname: Alroughani
authors.affiliation: 14 Nuovo Ospedale Civile S.Agostino/Estense, Modena, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sola
authors.affiliation: 15 Karadeniz Technical University, Trabzon, Turkey.
authors.forename: Cavit
authors.initials: C
authors.lastname: Boz
authors.affiliation: 16 Neurology Unit, ASUR Marche, AV3, Macerata, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Pucci
authors.affiliation: 17 Department of Neurology, John Hunter Hospital, Newcastle, Australia 18 School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Lechner-Scott
authors.affiliation: 19 Mondino National Neurological Institute of Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bergamaschi
authors.affiliation: 20 University Hospital San Carlos, Madrid, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Oreja-Guevara
authors.affiliation: 21 Ospedali Riuniti di Salerno, Salerno, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Iuliano
authors.affiliation: 22 Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Van Pesch
authors.affiliation: 23 University of Parma, Parma, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Granella
authors.affiliation: 24 Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ramo-Tello
authors.affiliation: 25 AORN San Giuseppe Moscati, Avellino, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Spitaleri
authors.affiliation: 26 Kommunehospitalet, Aarhus, Denmark.
authors.forename: Thor
authors.initials: T
authors.lastname: Petersen
authors.affiliation: 27 Flinders University and Flinders Medical Centre, Adelaide, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Slee
authors.affiliation: 28 Groene Hart Ziekenhuis, Gouda, The Netherlands.
authors.forename: Freek
authors.initials: F
authors.lastname: Verheul
authors.affiliation: 29 Nemocnice Jihlava, Jihlava, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Ampapa
authors.affiliation: 30 University of Florence, Florence, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Amato
authors.affiliation: 31 The University of Queensland, Brisbane, Australia.
authors.forename: Pamela
authors.initials: P
authors.lastname: McCombe
authors.affiliation: 32 Westmead Hospital, Sydney, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Vucic
authors.affiliation: 33 Hospital de Galdakao-Usansolo, Galdakao, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Sánchez Menoyo
authors.affiliation: 34 Hospital Italiano, Buenos Aires, Argentina.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Cristiano
authors.affiliation: 35 Department of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Barnett
authors.affiliation: 36 Liverpool Hospital, Liverpool, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Hodgkinson
authors.affiliation: 37 Hospital Universitario Donostia, San Sebastian, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Olascoaga
authors.affiliation: 38 Instituto de Neurosciencias INEBA, Buenos Aires, Argentina.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Saladino
authors.affiliation: 39 South Eastern Trust, Belfast, Northern Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Gray
authors.affiliation: 40 Geelong Hospital, Geelong, Australia.
authors.forename: Cameron
authors.initials: C
authors.lastname: Shaw
authors.affiliation: 41 Jewish General Hospital, Montreal, Canada.
authors.forename: Fraser
authors.initials: F
authors.lastname: Moore
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia 3 Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia butz@unimelb.edu.au.
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kalincik
mesh_terms: D000328:Adult; D015331:Cohort Studies; D032921:Consensus; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis* / Q000503:physiopathology; D012720:Severity of Illness Index
keywords: MSBase; definition; disability; secondary progressive multiple sclerosis; study design