Application of New McDonald MS Criteria Uncovers Portion of Atypical Individuals Potentially Eligible for Disease-Modifying Treatment

Late-breaking findings using data from the CAVS-MS study showed that nearly one-fifth of patients with atypical clinical symptoms or radiological-only presentation met the latest criteria for multiple sclerosis (MS) using the updated 2024 McDonald Criteria revisions. The study suggests that the central vein sign (CVS) is a valuable para-clinical tool for confirming MS diagnosis in individuals with atypical symptoms or radiological-only presentation, thus opening the door for initiating treatment earlier.¹

Presented at the 2025 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27-March 1, in West Palm Beach, Florida, the analysis included 420 participants who were undergoing evaluation for MS. Of these, 166 were adjudicated as having atypical onset and an additional 25 were adjudicated as having radiological-only presentation. Of this group (n = 191), 19% (n = 36) met diagnostic criteria when applying the 2024 McDonald Criteria, which ultimately will allow for earlier treatment and potentially altering of patients’ disease course.

Led by Daniel Ontaneda, MD, PhD, a neurologist at Cleveland Clinic’s Mellen Center for Multiple Sclerosis, this was the first application of the latest clinical criteria, which introduced several significant updates aimed at enhancing early and accurate diagnosis. These included the incorporation of biomarkers such as CVS and paramagnetic rim lesions, offering advanced imaging tools to differentiate MS from other conditions. Notably, the optic nerve was added as a fifth anatomical location for assessing dissemination in space, allowing for a more comprehensive evaluation of lesion distribution.

"We have positive trials in (patients with atypical symptoms) demonstrating that if you start disease-modifying therapy in radiologically isolated syndrome, they're less likely to develop MS," Ontaneda told NeurologyLive®. "So it was hard for the diagnostic criteria to remain silent on those folks, and thankfully, they were incorporated into the criteria."

In the combined subset of patients with atypical onset and those with radiological-only presentations, 27% (n = 51) fulfilled dissemination in space (DIS), 4% (n = 8) fulfilled dissemination in time (DIT), and 4% (n = 7) fulfilled DIT and DIS. Of the 51 participants meeting DIS only on MRI, 37% (n = 19) were Select-6 positive, 29% (n = 15) had oligoclonal bands (OCB), and 10% (n = 5) were Select-6 positive and had OCB.

Key changes in the new criteria, which were initially presented at the 2024 European Committee for Treatment & Research in Multiple Sclerosis (ECTRIMS) Congress, included recognition of radiological isolated syndrome (RIS) as MS in specific cases and removal of requiring for DIT. Updates to DIS were introduced alongside the inclusion of kappa free light chains as a diagnostic tool. In addition, the criteria provided specific recommendations for diagnosing MS in older individuals and those with vascular risk factors, addressing the challenges in differentiating MS from other age-related conditions.²

"It's very clear that a substantial portion of individuals–we're talking about 1 in every 5 individuals–were diagnosed with multiple sclerosis based on the new criteria, which is a huge change for our field. The diagnostic test that was most used to confirm a diagnosis in that 20% of patients was the central vein sign, which highlights why it's so important to have the central vein sign in the diagnosis. It's a noninvasive, easy way to confirm diagnosis of the disease in individuals with atypical symptoms and in individuals with radiological onset only," Ontaneda added.

Other updates to the criteria included the recommendation of optional tools, such as the CVS and PRLs, for specific cases, and myelin oligodendrocyte glycoprotein tests suggested for diagnosing children and adolescents. Several in the field noted that the incorporation of optic nerve as a fifth topology or classic location represented a significant change in the diagnostic criteria for MS. While optic neuropathy and optic neuritis had been long recognized as a common MS manifestation, it was not previously included in the criteria.

Top Clinical Takeaways

1. The 2024 McDonald Criteria revisions, applied in the CAVS-MS study, led to nearly 19% of patients with atypical or radiological-only symptoms meeting MS diagnostic criteria.

2. The inclusion of biomarkers like the central vein sign (CVS) and paramagnetic rim lesions (PRLs) enhances diagnostic accuracy for MS, particularly in atypical cases.

3. The CAVS-MS study demonstrated that combining CVS+ and PRL+ lesions resulted in 90% diagnostic accuracy, with a sensitivity of 86% and specificity of 93%.

Following the presentation of these revised criteria, Ontaneda wrote that these changes "mark a pivotal shift toward increased specificity through the addition of pathologically-specific biomarkers and expanding who can be diagnosed with MS. The 2024 revisions include some of the most substantial and paradigm-changing features since the inception of MS diagnostic criteria in 2001."

Regarding the diagnosis of asymptomatic individuals, he added that "While these revisions bring us closer to our goal of making an MS diagnosis easier and sooner, the broadening of the criteria is not without challenges. A primary concern is overdiagnosis. The increased sensitivity of the criteria means that more people may be diagnosed with MS. As clinicians, we must be vigilant in applying the criteria accurately and consider the full clinical picture before making a diagnosis."

The CAVS-MS study, a National Institutes of Health (NIH)-funded study, primarily tested whether CVS can serve as a reliable diagnostic marker for MS. Initiated in 2020, this 2-year, prospective, international study determined whether use of CVS criteria allows for an earlier diagnosis of MS in patients who do not meet the previous McDonald criteria at baseline.

At the 2024 ACTRIMS Forum, data from CAVS-MS highlighted the performance of combined neuroimaging biomarkers. Data showed that prevalence of CVS+ lesions and PRL+ lesions differed markedly at baseline between adults with MS (n = 37) and those with an alternative diagnosis (n = 41). Overall, the combined presence of at least 1 CVS+ lesion and at least 1 PRL+ lesion occurred in 32 participants with MS (86%) as opposed to 3 (7%) participants with an alternative diagnosis. Diagnosis accuracy for MS was 90%, with a sensitivity of 0.86 (95% CI, 0.71-0.95) and a specificity of 0.93 (95% CI, 0.80-0.98).³