ECTRIMS 2025 | The use of the 2024 McDonald criteria for the diagnosis of prodromal MS

So, as you may know, the McDonald diagnostic criteria have progressively evolved over time with the dual aim of announcing diagnostic specificity and enabling earlier diagnosis. And in this context, the 2024 revision introduced important refinement, such as the introduction of advanced MRI biomarkers, the central vein sign and paramagnetic rim lesions, but also the optic nerve as a fifth location for the dissemination in space criterion, and the kappa-free light chains as an alternative or complementary diagnostic tool to the long-standing oligoclonal bands in the CSF analysis. And under the new 2024 McDonald criteria, early conditions such as the radiologically isolated syndrome and clinical isolated syndrome, which previously did not meet the threshold for an MS diagnosis under the 2017 criteria, can now be diagnosed as MS if certain conditions are fulfilled. So we decided from an MS natural cohort study to retrospectively select people presenting with radiologically isolated syndrome or with clinically isolated syndrome not fulfilling the 2017 McDonald diagnostic criteria to determine whether the new 2024 criteria can differentiate people with higher neurodegenerative and neuroinflammatory markers. To do so, all patients underwent 3-TESLA brain MRI, including advanced sequence for the assessment of the central vein sign, SELECT-6 algorithm, the paramagnetic rim lesion and the cortical lesion biomarkers, but also brain volumetrics and T2 lesion load. And the atelica immunoassay system was used in a matched serum sample to determine the concentration of neurofilament light chains in the serum. And clinical data were also retrospectively reviewed for the determination of the optic nerve involvement and for the CSF analysis when available for the oligoclonal bands and kappa-free light chains presence. With the aim of stratifying patients into McDonald 2024 positive and McDonald 2024 negative groups and comparing pathological changes in MRI and soluble biomarkers. So we identified 81 suspected RIS and CIS cases from whom 38 fulfilled the new 2024 criteria, while 43 did not. And we also included, in order to contextualize the findings, an independent randomly selected cohort of age and sex matched patients with a diagnosis of MS as defined by the McDonald’s 2017 criteria for a total of 119 cases included. So when comparing the McDonald’s 2024 positive with the McDonald’s 2024 negative cases, we found a significantly higher NFL level in the serum in the first group, which persisted after age correction, and which was consistent with the brain volumetrics showing a reduced normalized thalamic volume and increased T2 lesion loads, and a greater cortical lesion and paramagnetic rim lesion counts. While when we compared the McDonald 2024 positive with the McDonald 2017 positive group, we did not find any differences except for a higher T2 lesion load and cortical lesion count in the second group. The differences found between the McDonald 2024 positive and McDonald 2024 negative groups persisted after age and sex correction except for the T2 lesion load, no longer significant between the two groups. And we finally also performed the sub-analysis in a complete case data set with only patients with all the variables available. And we identified the SELECT6 positivity as a best predictor for the 2024 positive McDonald’s status, which was confirmed in both ROC curve analysis and random forest analysis. So to conclude, the 2024 McDonald’s criteria seem to effectively identify CIS and RIS individuals with earlier inflammatory and degenerative changes, including elevated NFL in the serum, thalamic atrophy, and an increased cortical lesion and paramagnetic rim lesion burden. The overlap observed with the MS cases according to McDonald’s 2017 suggests that the revised criteria can capture patients earlier along the disease continuum, findings that support the diagnostic and potential prognostic utility of the new 2024 McDonald criteria. And given its importance, the inclusion of the central vein sign in the diagnostic workup is strongly recommended, although our results also suggest that PRL might deserve a greater consideration in future criteria revision. Here, prospective future longitudinal studies are needed to confirm the clinical relevance. Prompt diagnosis and management are essential to prevent the accumulation of neurological disability occurring since the earliest stage of the disease. And the differences that we found in cortical lesion and PRL burden reflect inflammatory changes present from the earliest stage of MS. Given that both biomarkers are highly specific for MS and that higher cortical lesion and paramagnetic rim lesion burden identify patients with a poorer prognosis, I think that our findings underscore the clinical utility of the new 2024 criteria because this may help identify high-risk individuals who could benefit from a closer monitoring and potentially early therapeutic intervention. We are currently working on the longitudinal follow-up of those early cases, including this study, in order to see if indeed the new 2024 criteria can identify indeed people maybe showing early disease activity or clinical progression in order to confirm in a longitudinal setting the results found in this current study.

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