Paramagnetic Rim Lesions Are Highly Accurate for MS Diagnosis at First Presentation

Finding at least one paramagnetic rim lesion (PRL) on brain MRI has 90% specificity and 86% sensitivity for diagnosing multiple sclerosis (MS) in adults first presenting to a specialty center for evaluation of suspected MS. These findings, from a multicenter study of 78 individuals, were recently published online ahead of print in Neurology (2025;105[6]:e213912).

“PRLs are highly prevalent in people with MS initially presenting to MS clinics, and their presence differentiates early MS from other conditions with high accuracy,” says Daniel Ontaneda, MD, PhD, of Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research, who served as co-senior author of the study along with Pascal Sati, PhD, of Cedars-Sinai Medical Center. “We used MRI sequences noninvasively acquired in a short time and employed different MRI scanners and multiple readers to detect PRLs, supporting the feasibility of using PRLs as a biomarker in clinical practice.”

MS misdiagnosis is still an issue

MRI is highly sensitive in diagnosing MS at first presentation, and it has become an essential tool for fulfilling MS diagnostic criteria. However, specificity continues to bea problem, leading to misdiagnosis in up to 20% of cases.

PRLs are emerging as a biomarker of interest in MS, as they indicate unresolved inflammation at the periphery of some demyelinated white matter lesions. PRLs appear as dark, ring-like structures on susceptibility weighted MRI sequences, reflecting iron accumulation in microglia.

Is PRL utility tied to disease stage?

Although associated with disease severity, PRLs have not consistently demonstrated value as a diagnostic biomarker, being detectable in only 25% to 50% of people with MS in previous multicenter diagnostic studies. However, recent research indicates that PRLs are more likely to be found in early stages of MS, including in clinically isolated or radiologically isolated syndromes and in pediatric MS. The cohorts in the earlier studies included patients with an already established diagnosis and longstanding disease, which might explain the low PRL detection rates.

This prospective study was designed to evaluate PRLs as a diagnostic tool in patients referred to an MS center for initial evaluation, presumably capturing a population relatively early in their disease course.

Design and results

Study participants were part of the Central Vein Sign in MS (CAVS-MS) pilot study. All were adults referred to one of 10 North American Imaging in MS Cooperative (NAIMS) centers, including Cleveland Clinic and Cedars-Sinai Medical Center, for new clinical or radiologic suspicion of MS. Patients with recent use of disease-modifying treatments or systemic corticosteroids were excluded.

The study cohort consisted of 78 participants (mean age of 45 years [range, 18-64]; 71% female) with a mean duration of 3.1 years since symptom onset. Of these, 37 (47%) were found to meet 2017 McDonald criteria for either relapsing-remitting MS (n = 35) or primary progressive MS (n = 2).

The presence of PRLs was evaluated from high-resolution 3D echo-planar imaging acquired on 3T brain MRI. Three independent readers were used, all blinded to diagnosis, with adjudication from a fourth. The 2017 McDonald criteria were used to determine each patient’s diagnosis, which was compared to PRL thresholds of at least one or at least two lesions positive for PRL.

A total of 124 PRLs were found in 36 (46%) of the 78 patients. Overall, there was a median of 3 PRLs per patient (range, 1-9). Among the 36 PRL-positive individuals, 32 (89%) fulfilled the McDonald criteria.

The threshold of at least one PRL had a diagnostic specificity of 0.90 (95% CI, 0.77-0.97) and a sensitivity of 0.86 (95% CI, 0.71-0.95).

The threshold of at least two PRLs increased specificity to 0.95 (95% CI, 0.83-0.99) but reduced sensitivity to 0.59 (95% CI, 0.42-0.75).

PRL presence linked to time from symptom onset

More time from symptom onset was associated with less likelihood of having a PRL (odds increased by 28% for each one-year reduction in symptom duration; P = 0.03). Such an association was not found in patients who did not have MS. No significant association was found between patient age and presence of PRLs.

“Our findings support our hypothesis that PRLs are a better indicator of MS in patients with more recent symptom onset, possibly explaining the differences in diagnostic prediction compared with earlier studies,” Dr. Ontaneda notes. “This knowledge can help inform and support recommendations for the use of PRLs as a diagnostic biomarker in the next update of the McDonald criteria. In fact, the data published here actually informed revisions of the 2024 criteria with respect to PRLs.”

Limitations and further investigations

This study is believed to be the first to report an association between PRL positivity and symptom duration in patients with MS. According to the authors, study limitations include the following issues:

• The cross-sectional design precluded reassessing the diagnosis over time, potentially missing an eventual diagnosis of MS in some patients who did not meet 2017 McDonald criteria.
• Only two patients had primary progressive MS, limiting generalizability of conclusions.

“Larger and long-term studies are needed to confirm and extend our findings,” Dr. Ontaneda says. “Longitudinal data also can help evaluate whether PRLs are associated with MS relapses and clinical progression.”

Such issues are being evaluated by the ongoing CAVS-MS prospective observational study (NCT04495556), for which Dr. Ontaneda serves as the Cleveland Clinic principal investigator. It is studying MRI biomarkers in 420 patients with typical and atypical MS and outcomes over two years.

An additional hurdle to possible broad clinical adoption of PRLs as a biomarker is limited availability of imaging that can detect these lesions. “Overcoming some technical barriers and standardization of protocols is needed,” Dr. Ontaneda concludes.