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      Radiologically Isolated Syndrome: 5-Year Risk for an Initial Clinical Event

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          Abstract

          Objective

          To report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria.

          Methods

          Retrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model.

          Results

          Data were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11–74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01–21.1 y). Clinical events were identified in 34% (standard error = 3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96–0.99); p = 0.03], sex (male) [HR: 1.93 (1.24–2.99); p = 0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06–4.62); p = <0.001] were identified as significant predictors for the development of a first clinical event.

          Interpretation

          These data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.

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          Most cited references13

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          Incidental findings on brain MRI in the general population.

          Meike Vernooij, M Arfan Ikram, Herve L. Tanghe … (2007)
          Magnetic resonance imaging (MRI) of the brain is increasingly used both in research and in clinical medicine, and scanner hardware and MRI sequences are continually being improved. These advances are likely to result in the detection of unexpected, asymptomatic brain abnormalities, such as brain tumors, aneurysms, and subclinical vascular pathologic changes. We conducted a study to determine the prevalence of such incidental brain findings in the general population. The subjects were 2000 persons (mean age, 63.3 years; range, 45.7 to 96.7) from the population-based Rotterdam Study in whom high-resolution, structural brain MRI (1.5 T) was performed according to a standardized protocol. Two trained reviewers recorded all brain abnormalities, including asymptomatic brain infarcts. The volume of white-matter lesions was quantified in milliliters with the use of automated postprocessing techniques. Two experienced neuroradiologists reviewed all incidental findings. All diagnoses were based on MRI findings, and additional histologic confirmation was not obtained. Asymptomatic brain infarcts were present in 145 persons (7.2%). Among findings other than infarcts, cerebral aneurysms (1.8%) and benign primary tumors (1.6%), mainly meningiomas, were the most frequent. The prevalence of asymptomatic brain infarcts and meningiomas increased with age, as did the volume of white-matter lesions, whereas aneurysms showed no age-related increase in prevalence. Incidental brain findings on MRI, including subclinical vascular pathologic changes, are common in the general population. The most frequent are brain infarcts, followed by cerebral aneurysms and benign primary tumors. Information on the natural course of these lesions is needed to inform clinical management. Copyright 2007 Massachusetts Medical Society.
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            Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis.

            B. Keegan, J H Noseworthy, Istvan Pirko … (2013)
            It is unclear if all patients with relapsing-remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration-dependent. Some forms of progressive MS (e.g. primary progressive MS (PPMS)) are uncommon in population-based studies. Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age at progression onset between secondary progressive MS (SPMS) and PPMS but may introduce unclear biases. Our aim is to confirm that onset of progressive disease course is more relevant to the patient's age than the presence or duration of a pre-progression relapsing disease course in MS. We studied a population-based MS cohort (n=210, RRMS n=109, progressive MS n=101) and a clinic-based progressive MS cohort (n=754). Progressive course was classified as primary (PPMS; n=322), single attack (SAPMS; n=112) and secondary progressive (SPMS; n=421). We studied demographics (chi(2) or t-test), age-of-progression-onset (t-test) and time to Expanded Disability Status Scale of 6 (EDSS6) (Kaplan-Meier analyses). Sex ratio (p=0.58), age at progression onset (p=0.37) and time to EDSS6 (p=0.16) did not differ between the cohorts. Progression had developed before age 75 in 99% of patients with known progressive disease course; 38% with RRMS did not develop progression by age 75. Age at progression onset did not differ between SPMS (44.9±9.6), SAPMS (45.5±9.6) and PPMS (45.7±10.8). In either cohort, only 2% of patients had reached EDSS6 before onset of progression. Patients with RRMS do not inevitably develop a progressive disease course. Onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course. Moderate disability is sustained predominantly after the onset of a progressive disease course in MS.
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              Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome.

              D Goodin, E Waubant, B Cree … (2011)
              Technological advancements in neuroimaging and the increased use of these diagnostic modalities are responsible for the discovery of incidentally identified anomalies within the CNS. In addition to the identification of unanticipated brain MRI abnormalities suggestive of demyelinating disease in patients undergoing neuroimaging for a medical reason other than evaluation for multiple sclerosis (MS), asymptomatic spinal cord lesions are periodically identified. To determine if asymptomatic spinal cord lesions are associated with clinical progression in subjects with radiologically isolated syndrome (RIS). A retrospective review of RIS cases at the University of California, San Francisco Multiple Sclerosis Center was performed. The presence of asymptomatic cervical spinal cord MRI lesions was analyzed as a potential predictor for clinical progression. Twenty-five of 71 subjects with RIS possessed findings within the cervical spine that were highly suggestive of demyelinating disease. Of these subjects, 21 (84%) progressed clinically to clinically isolated syndrome (n = 19) or primary progressive multiple sclerosis (n = 2) over a median time of 1.6 years from the date of RIS identification (interquartile range 0.8-3.8). The sensitivity, specificity, and positive predictive value of an asymptomatic spinal cord lesion for subsequent development of either a first demyelinating attack or primary progressive MS were 87.5%, 91.5%, and 84%, respectively. The odds ratio of clinical progression was 75.3 (95% confidence interval 16.1-350.0, p < 0.0001). This association remained significant after adjusting for potential confounders. These findings suggest that the presence of asymptomatic spinal cord lesions place subjects with RIS at substantial risk for clinical conversion to either an acute or progressive event, a risk that is independent of brain lesions on MRI.
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                Author and article information

                Contributors
                Steven Jacobson: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 5 March 2014
                Volume: 9
                Issue: 3
                Electronic Location Identifier: e90509
                Affiliations
                [1 ]University of Texas Southwestern Medical Center, Department of Neurology & Neurotherapeutics, Clinical Center for Multiple Sclerosis, Dallas, Texas, United States of America
                [2 ]University of Istanbul, Department of Neurology, Cerrahpasa School of Medicine, Istanbul, Turkey
                [3 ]Mayo Clinic College of Medicine, Department of Neurology, Rochester, Minnesota, United States of America
                [4 ]Mt. Sinai School of Medicine, Department of Neurology, Radiology and Neuroscience, New York, New York, United States of America
                [5 ]Barrow Neurological Institute, Department of Neurology, Phoenix, Arizona, United States of America
                [6 ]Cleveland Clinic Lou Ruvo Center for Brain Health, Department of Neurology, Las Vegas, Nevada, United States of America
                [7 ]MS Center of Catalunya Cemcat and Magnetic Resonance Unit, Vall d′Hebron Hospital, Barcelona, Spain
                [8 ]University of Florence, Department of Neurology, Florence, Italy
                [9 ]Centre Hospitalo Universitaire Bordeaux, Bordeaux, France
                [10 ]Centre Hospitalo Universitaire Strasbourg, Strasbourg, France
                [11 ]Centre Hospitalo Universitaire Purpan, Toulouse, France
                [12 ]Centre Hospitalo Universitaire Salengro, Lille, France
                [13 ]University of Siena, Department of Medicine, Surgery & Neuroscience, Siena, Italy
                [14 ]University of Genoa, Department of Health Sciences (DISSAL), Genoa, Italy
                [15 ]Yale University, Departments of Neurology and Diagnostic Radiology, New Haven, Connecticut, United States of America
                [16 ]Hôpital Pasteur, Service de Neurologie, Nice, France
                National Institutes of Health, United States of America
                Author notes

                Membership of the Radiologically Isolated Syndrome Consortium (RISC) and Club Francophone de la Sclérose en Plaques (CFSEP) is provided in the Acknowledgments.

                Competing Interests: Dr. Okuda reports personal fees for consulting, advisory board, and speaking activities from Acorda Therapeutics, Biogen IDEC, Genzyme, Ipsen Pharmaceuticals, and Teva Neuroscience, outside the submitted work. Professor Siva reports personal fees for consulting and serving on a scientific advisory board from Bayer-Schering AG, Novartis, Biogen IDEC and Allergan within the last year, and travel and registration coverage for congresses or symposia from Bayer-Schering AG, Merck-Serono, Gen Ilac, and Allergan. Professor Siva received research support from Bayer-Schering AG, outside the submitted work. Dr. Kantarci has nothing to disclose. Dr. Inglese reports personal fees from Celgene, and Vaccinex. Dr. Katz reports grants from Acorda Therapeutics and from the National MS Society, outside the submitted work. Dr. Tutuncu has nothing to disclose. Dr. Keegan reports personal fees from eMedicine, Bristol Meyers Squibb, Novartis, Bionest, and grants from Terumo BCT, outside the submitted work. Dr. Donlon has nothing to disclose. Dr. Hua has nothing to disclose. Dr. Vidal-Jordana reports personal fees from EMD Serono, outside the submitted work. Dr. Montalban reports personal fees from Almirall, Bayer, Biogen IDEC, EMD Serono, Merck, Genentech, GeNeuro, Genzyme, Neurotec, Novartis, Sanofi-Aventis, and Teva Neuroscience, outside the submitted work. Dr. Rovira reports personal fees from AdvanceCell Bayer-Schering Pharma, Novartis, OLEA Medical, Sanofi-Aventis, Teva Neuroscience, Biogen IDEC, grants from Siemens AG, outside the submitted work. Dr. Tintoré reports personal fees from Genzyme, Biogen IDEC, Teva Neuroscience, Novartis, Sanofi-Aventis, Bayer, and Merck Serono, outside the submitted work. Dr. Amato reports grants and personal fees from Biogen IDEC, Merck Serono, Bayer-Schering, Teva Neuroscience, Sanofi-Aventis, and Novartis, outside the submitted work. Dr. Brochet reports personal fees from Novartis, Genzyme, and Bayer, grants from Bayer and Teva Neuroscience, Merck-Serono, and Caridian, outside the submitted work. Dr. de Seze has nothing to disclose. Dr. Brassat reports personal fees from Bayer-Schering, Biogen IDEC, Merck-Serono, Novartis, Sanofi-Aventis, and Teva Neuroscience, outside the submitted work. Dr. Vermersch reports grants and personal fees from Biogen IDEC, Sanofi-Aventis, Bayer, Merck-Serono, personal fees from Novartis, GSK, and Almirall, outside the submitted work. Dr. De Stefano reports personal fees from Merck-Serono, Novartis Pharma AG, Teva Neuroscience, Sanofi-Aventis, Bayer-Schering AG, and Biogen IDEC, outside the submitted work. Dr. Sormani reports personal fees from Biogen IDEC, Merck-Serono, Actelion, Synthon, and Allozyne, outside the submitted work. Dr. Pelletier reports personal fees from Teva Neuroscience, Biogen IDEC, and Roche, grants from Biogen IDEC, outside the submitted work. Dr. Lebrun has nothing to disclose. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: DO AS OK MI NDS MPS DP CL. Performed the experiments: DO AS OK NDS MPS DP CL. Analyzed the data: DO AS OK MI IK M. Tutuncu BK SD LH AVJ XM AR M. Tintoré MPA BB JdS DB PV NDS MPS DP CL. Contributed reagents/materials/analysis tools: DO AS OK MI IK M. Tutuncu BK SD LH AVJ XM AR M. Tintoré MPA BB JdS DB PV NDS MPS DP CL. Wrote the paper: DO AS OK NDS MPS DP CL. Managed the data collection, assisted with the design of study Figures and Tables: DO AS OK MI IK M. Tutuncu BK SD LH AVJ XM AR M. Tintoré MPA BB JdS DB PV NDS MPS DP CL.

                Article
                Publisher ID: PONE-D-13-39088
                DOI: 10.1371/journal.pone.0090509
                PMC ID: 3943959
                PubMed ID: 24598783
                SO-VID: 12337e9c-3f39-48bd-973f-a1d9456118b1
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 23 September 2013
                Date accepted : 19 December 2013
                Page count
                Pages: 9
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Neuroscience
                Subject: Neuroimaging
                Subject: Medicine
                Subject: Clinical Immunology
                Subject: Autoimmune Diseases
                Subject: Multiple Sclerosis
                Subject: Neurology
                Subject: Demyelinating Disorders
                Subject: Multiple Sclerosis
                Subject: Neuroimaging
                Subject: Radiology
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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