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PLoS One. 2014 Mar 5;9(3):e90509. doi: 10.1371/journal.pone.0090509. eCollection 2014.

Radiologically isolated syndrome: 5-year risk for an initial clinical event.

Author information

  • 1University of Texas Southwestern Medical Center, Department of Neurology & Neurotherapeutics, Clinical Center for Multiple Sclerosis, Dallas, Texas, United States of America.
  • 2University of Istanbul, Department of Neurology, Cerrahpasa School of Medicine, Istanbul, Turkey.
  • 3Mayo Clinic College of Medicine, Department of Neurology, Rochester, Minnesota, United States of America.
  • 4Mt. Sinai School of Medicine, Department of Neurology, Radiology and Neuroscience, New York, New York, United States of America.
  • 5Barrow Neurological Institute, Department of Neurology, Phoenix, Arizona, United States of America.
  • 6Cleveland Clinic Lou Ruvo Center for Brain Health, Department of Neurology, Las Vegas, Nevada, United States of America.
  • 7MS Center of Catalunya Cemcat and Magnetic Resonance Unit, Vall d'Hebron Hospital, Barcelona, Spain.
  • 8University of Florence, Department of Neurology, Florence, Italy.
  • 9Centre Hospitalo Universitaire Bordeaux, Bordeaux, France.
  • 10Centre Hospitalo Universitaire Strasbourg, Strasbourg, France.
  • 11Centre Hospitalo Universitaire Purpan, Toulouse, France.
  • 12Centre Hospitalo Universitaire Salengro, Lille, France.
  • 13University of Siena, Department of Medicine, Surgery & Neuroscience, Siena, Italy.
  • 14University of Genoa, Department of Health Sciences (DISSAL), Genoa, Italy.
  • 15Yale University, Departments of Neurology and Diagnostic Radiology, New Haven, Connecticut, United States of America.
  • 16Hôpital Pasteur, Service de Neurologie, Nice, France.



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.


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.


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.


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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