Application of the 2024 McDonald Criteria in Individuals With Nonspecific Symptoms or Incidental Imaging Findings in a Multicenter Study.

BACKGROUND AND OBJECTIVES: The 2024 McDonald criteria allow diagnosis of multiple sclerosis (MS) in individuals presenting with symptoms not specific for MS or incidental imaging findings suggestive of demyelination when supported by biomarker evidence, reflecting a shift toward diagnostic definitions increasingly grounded in biological mechanisms of disease. The diagnostic yield of these criteria in such populations has not been evaluated in multicenter cohorts. We aimed to determine the proportion of individuals with nonspecific or incidental imaging presentations who meet the 2024 McDonald criteria and describe the contribution of central vein sign and CSF oligoclonal bands (OCBs) to diagnostic classification.

METHODS: This cross-sectional post hoc analysis used data from the Central Vein Sign in Multiple Sclerosis study, a multicenter observational cohort. Adults aged 18-65 years referred for diagnostic evaluation of possible MS were adjudicated by an expert panel. This analysis focused on participants with symptoms not specific for MS or incidental imaging findings suggestive of demyelination. Dissemination in space (DIS) and dissemination in time (DIT) were assessed using 2017 MRI criteria. Fulfillment of the 2024 McDonald criteria at baseline-the primary outcome-was determined using the Select-6 CVS and CSF OCBs. Select-6 assessment was available for all participants, whereas OCB data were available for a subset based on prior clinical evaluation.

RESULTS: Of 420 participants enrolled, 191 (45%) presented with either nonspecific symptoms (n = 166) or incidental imaging findings (n = 25). The mean age was 42 years, and 78% were female. Thirty-six (19%) met the 2024 McDonald criteria at baseline, including 28 (17%) in the nonspecific symptom cohort and 8 (32%) in the incidental imaging cohort. Among 51 participants meeting 2017 DIS, 22 (43%) were Select-6 positive, 17 (33%) had positive OCBs, and 4 (8%) met 2017 DIT. Nonspecific sensory symptoms, visual disturbances, and subacute cognitive decline were most associated with a diagnosis of MS.

DISCUSSION: Application of the 2024 McDonald criteria identified nearly one-fifth of individuals without typical presentations as meeting diagnostic criteria for MS at baseline. Biomarker incorporation-particularly the CVS-accounted for a substantial proportion of diagnostic yield. Interpretation is limited by availability of CSF data and absence of longitudinal follow-up.