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In 85% of young adults with multiple sclerosis (MS), onset is a subacute clinically isolated syndrome (CIS) of the optic nerves, brainstem, or spinal cord. Methods of assessing the prognosis for patients who present with a CIS have been sought, because only 30–70% of patients with a CIS develop MS. When clinically silent brain lesions are seen on MRI, the likelihood of developing MS is high. MS can be diagnosed within 3 months of CIS presentation with certain MRI and CSF criteria. Disability from MS is less likely in patients with a CIS of optic neuritis or sensory symptoms only, few or no MRI lesions, a long period to the first relapse, and no disability after the first 5 years. Development of more reliable prognostic markers will enable new treatments to be targeted for those who are most likely to benefit. We encourage continued clinical and laboratory assessment of patients with a CIS.