title: Radiologically isolated syndrome: 5-year risk for an initial clinical event.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Texas Southwestern Medical Center, Department of Neurology & Neurotherapeutics, Clinical Center for Multiple Sclerosis, Dallas, Texas, United States of America.
authors.forename: Darin T
authors.initials: DT
authors.lastname: Okuda
authors.affiliation: University of Istanbul, Department of Neurology, Cerrahpasa School of Medicine, Istanbul, Turkey.
authors.forename: Aksel
authors.initials: A
authors.lastname: Siva
authors.affiliation: Mayo Clinic College of Medicine, Department of Neurology, Rochester, Minnesota, United States of America.
authors.forename: Orhun
authors.initials: O
authors.lastname: Kantarci
authors.affiliation: Mt. Sinai School of Medicine, Department of Neurology, Radiology and Neuroscience, New York, New York, United States of America.
authors.forename: Matilde
authors.initials: M
authors.lastname: Inglese
authors.affiliation: Mt. Sinai School of Medicine, Department of Neurology, Radiology and Neuroscience, New York, New York, United States of America.
authors.forename: Ilana
authors.initials: I
authors.lastname: Katz
authors.affiliation: University of Istanbul, Department of Neurology, Cerrahpasa School of Medicine, Istanbul, Turkey.
authors.forename: Melih
authors.initials: M
authors.lastname: Tutuncu
authors.affiliation: Mayo Clinic College of Medicine, Department of Neurology, Rochester, Minnesota, United States of America.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Keegan
authors.affiliation: Barrow Neurological Institute, Department of Neurology, Phoenix, Arizona, United States of America.
authors.forename: Stacy
authors.initials: S
authors.lastname: Donlon
authors.affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, Department of Neurology, Las Vegas, Nevada, United States of America.
authors.forename: Le H
authors.initials: le H
authors.lastname: Hua
authors.affiliation: MS Center of Catalunya Cemcat and Magnetic Resonance Unit, Vall d'Hebron Hospital, Barcelona, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Vidal-Jordana
authors.affiliation: MS Center of Catalunya Cemcat and Magnetic Resonance Unit, Vall d'Hebron Hospital, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: MS Center of Catalunya Cemcat and Magnetic Resonance Unit, Vall d'Hebron Hospital, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Rovira
authors.affiliation: MS Center of Catalunya Cemcat and Magnetic Resonance Unit, Vall d'Hebron Hospital, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Tintoré
authors.affiliation: University of Florence, Department of Neurology, Florence, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Amato
authors.affiliation: Centre Hospitalo Universitaire Bordeaux, Bordeaux, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Brochet
authors.affiliation: Centre Hospitalo Universitaire Strasbourg, Strasbourg, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: de Seze
authors.affiliation: Centre Hospitalo Universitaire Purpan, Toulouse, France.
authors.forename: David
authors.initials: D
authors.lastname: Brassat
authors.affiliation: Centre Hospitalo Universitaire Salengro, Lille, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vermersch
authors.affiliation: University of Siena, Department of Medicine, Surgery & Neuroscience, Siena, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Stefano
authors.affiliation: University of Genoa, Department of Health Sciences (DISSAL), Genoa, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Sormani
authors.affiliation: Yale University, Departments of Neurology and Diagnostic Radiology, New Haven, Connecticut, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pelletier
authors.affiliation: Hôpital Pasteur, Service de Neurologie, Nice, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lebrun
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D003711:Demyelinating Diseases / Q000175:diagnosis; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D033162:Incidental Findings; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000401:mortality / Q000473:pathology*; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013116:Spinal Cord / Q000473:pathology; D055815:Young Adult