CAVS-MS Analysis Adds Further Validation to Utility of Paramagnetic Rim Lesions in MS Diagnosis

Newly presented findings from the CAVS-MS trial demonstrated the diagnostic performance of paramagnetic rim lesions (PRLs) as a confirmatory biomarker during cases of suspected multiple sclerosis (MS). In the study, PRLs showed high diagnostic specificity and sensitivity, further supporting their inclusion to the recently published 2024 McDonald Criteria.¹

Considered the largest, prospective, international study examining PRL use in MS diagnosis, the trial featured 420 participants who were diagnosed using the 2017 McDonald Criteria by international panel members. Presented at the 2025 at the 2025 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 24-26, in Barcelona, Spain, 210 (50.0%) of the patients had atypical clinical attack at onset and 149 (35.5%) fulfilled criteria for MS diagnosis.

Led by a group of clinicians, including Cleveland Clinic’s Daniel Ontaneda, MD, PhD, findings revealed sensitivity of 69.7% (95% CI: 62.4-77.2), 52.3% (44.3-60.4), 44.3% (36.3-52.3), and 35.6% (27.9-43.3) for thresholds of at least 1, 2, 3, and 4 PRLs, respectively. Using those same thresholds, investigators reported specificity of 79.0% (95% CI, 74.1-83.8), 87.5% (83.5-91.4), 91.5% (88.2-94.8), and 94.8% (92.2-97.5), respectively. Notably, the data did not differ regardless of onset presentation.

The 2024 revisions to the McDonald Criteria, presented at ECTRIMS Congress 2024, marked a pivotal shift toward increased specificity of MS diagnosis through the addition of pathologically-specific and expanding the pool of patients who can be diagnosed. Among them included PRLs and the central vein sign (CVS), both brought out through data collected by the CAVS-MS study and others.²

In the late-breaking analysis, Youden’s index was optimized for at least 1 PRL. Following that, results showed that factors associated with the presence of meeting this mark included age (<40 years; OR, 2.12; 95% CI, 1.42-3.18; P <.001), sex (male; OR, 2.08; 95% CI, 1.30-3.32; P = .002), race (Black; OR, 1.92; 95% CI, 1.05-3.54; P = .034), and presence of brain lesions in at least 2 of 3 evaluable MS topographies (OR, 16.9; 95% CI, 10.0-28.4; P <.001).

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Following the original announcement of the 2024 Diagnostic Criteria, MS expert and study author Jeffrey Cohen, MD, wrote in an editorial, "PRLs are an imaging biomarker of chronic active lesions, which are characterized by a central demyelinated core surrounded by activated microglial cells. Iron within these microglial cells appears as a rim of susceptibility on MRI giving PRLs their unique features. Both are detectable through susceptibility-based imaging sequences, and the new criteria affirms them as sensitive and specific imaging biomarkers for the disease."

The greater reliance on MRI and other biomarkers in the criteria also allows for 2 significant changes in rendering a diagnosis: a departure from dissemination in time (DIT) and diagnosing asymptomatic individuals. A late-breaking study from CAVS-MS presented earlier this year at the 2025 ACTRIMS Forum highlighted the use of CVS as a diagnostic tool in suspected cases of MS.³

Of 420 participants undergoing evaluation for MS, 191 had either atypical onset (n=166) or radiological-only presentation (n=25), and among them, 19% (n=36) met diagnostic criteria using the 2024 McDonald 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 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.

At the time, Ontaneda told NeurologyLive, "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."

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REFERENCES
1. Lee J, Renner B, Amin M, et al. Diagnostic Performance of Paramagnetic Rim Lesions in Multiple Sclerosis in a Large, Prospective, Multicenter Cohort: Insights from the CAVS-MS Study. Presented at: 2025 ECTRIMS Congress. September 24-26; Barcelona, Spain. Abstract P916.
2. Montalban X. 2024 Revisions of the McDonald Criteria. Presented at ECTRIMS Congress; September 18-20, 2024; Copenhagen, Denmark. Scientific Session 1: New diagnostic criteria.
3. Scharf A, Gombos E, Alvarez E, et al. LB1.3. Application of 2024 McDonald Criteria to individuals with atypical and radiological only presentations in a multicenter diagnostic biomarker study. Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. ABSTRACT LB1.