2025 Brings Real-World Use of Clinical Biomarkers in Updated Multiple Sclerosis Diagnostic Criteria

The latest diagnostic criteria for multiple sclerosis (MS) were initially presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress and were finalized in late September 2025 in The Lancet Neurology.1-3 Throughout this year, clinicians have had the opportunity to incorporate the updated criteria into their clinical practice to support the care of patients with MS.

As part of This Year in Medicine, an annual series reviewing the most impactful developments in health care, NeurologyLive® invited MS experts to discuss the clinical application of the updated criteria, including the use of the central vein sign (CVS), paramagnetic rim lesions (PRL), and kappa free-light chain (kFLC) concentrations in cerebrospinal fluid (CSF).

Central Vein Sign

Based on the new criteria, the CVS visualized on MRI may be used to support the diagnosis of MS in selected clinical scenarios and can increase diagnostic specificity. However, the guidance stated that the demonstration of the CVS might not be required to establish a diagnosis. In patients with typical clinical presentations and dissemination in space, the criteria noted that the presence of CVS as defined by the Select 6 criteria may be sufficient for diagnosis. Similarly, in patients with typical clinical presentations and lesions in a single region, the combination of Select 6 CVS findings with either dissemination in time or positive CSF findings may be sufficient to establish a diagnosis.

To better understand the role of the CVS in MS diagnosis in the clinic, NeurologyLive spoke with Daniel Ontaneda, MD, PhD, a staff neurologist at Cleveland Clinic’s Mellen Center for Multiple Sclerosis. "We now use CVS routinely in clinical practice. It is particularly helpful in cases where there may be other reasons for white matter brain lesions (headache, vascular disease, rheumatological disease). It also helps us to confirm a diagnosis when we do not have documentation of dissemination in time, so we avoid waiting for new lesions or conducting a spinal tap,” Ontaneda told NeurologyLive.

“The strength is that CVS is a specific marker for MS, and therefore really helpful when you see an MRI where the majority of lesions have a CVS,” Ontaneda added. “The limitation is that you do need specialized sequences which are detailed in our companion paper,3 but the good news is these are available on almost all scanners.”

"I think the new diagnostic criteria incorporate specific biomarkers including the CVS and PRL, which ensure not only a timely diagnosis but also an accurate diagnosis. The goal is to start highly effective medication early to ensure optimal outcomes and these biomarkers allow us to be confident about a diagnosis of MS,” Ontaneda said.

Paramagnetic Rim Lesions

The presence of 1 or more PRLs on MRI can support the diagnosis of MS in selected clinical scenarios and may increase diagnostic specificity, according to the updated criteria for MS. However, the criteria stated that the detection of PRLs is not required to establish a diagnosis. In patients presenting with typical clinical symptoms and characteristic lesions in a single region, the guidance noted that the identification of 1 or more PRLs in combination with either evidence of dissemination in time or a positive CSF profile is sufficient to confirm the diagnosis.

“Paramagnetic rim lesions have influenced my thinking around MS diagnosis by reinforcing a shift from purely counting lesions to understanding underlying disease biology. However, in my own clinical setting, where 3-Tesla MRI is not available on site and imaging is largely performed at 1.5-Tesla, PRLs currently play a limited role in routine diagnostic decision-making,” Agne Straukiene, MD, consultant neurologist at Torbay and Southern Devon Healthcare NHS Foundation Trust and host of the BeeWellWithMS podcast, told NeurologyLive.

“Most evidence supporting PRLs comes from 3-Tesla susceptibility-based imaging, where sensitivity is significantly higher. At 1.5-Tesla, PRLs are often not detectable, meaning their absence cannot be interpreted as biological absence of chronic active inflammation. As a result, I use PRLs conceptually as a framework for understanding chronic, compartmentalised inflammation and progression risk rather than as a practical diagnostic marker in everyday practice,” Straukiene added. “This reinforces the importance of interpreting emerging biomarkers within the technical realities of clinical services, and of avoiding over-reliance on markers that are not yet equitably accessible.”

Straukiene told NeurologyLive, “The main strength of PRLs lies in their relative specificity for MS-related chronic active lesions, especially when interpreted alongside other features such as lesion morphology, distribution, and clinical context. They provide insight into smouldering inflammation that conventional MRI may miss. However, limitations remain significant: PRL detection depends heavily on MRI field strength, acquisition protocols, and expert interpretation, which limits generalisability. In addition, PRLs are not universally present in MS and are uncommon in early disease, so absence does not exclude MS nor reliably distinguish it from mimics.”

“Emerging biomarkers are moving MS diagnosis and management toward a more biologically and functionally informed model. Imaging markers such as PRLs and the central vein sign, alongside fluid biomarkers like kappa free light chains, are improving diagnostic confidence earlier in the disease course without relying solely on waiting for clinical or radiological dissemination in time,” Straukiene said. “Alongside these, digital technologies are increasingly acting as functional biomarkers. Remote assessments, digital motor and cognitive testing, patient-reported outcomes, eye tracking activity and sensor-based measures can capture subtle changes in function that conventional clinical assessments and MRI may miss. Used longitudinally, these tools offer a way to detect early progression, incomplete recovery, or smouldering disease activity in real-world settings.”

“Together, biological and digital biomarkers have the potential to support earlier, more individualised treatment decisions and closer monitoring, particularly in settings where access to advanced imaging is limited,” Straukiene noted. “The key challenge will be integrating these tools into routine care in a standardised, equitable, and interpretable way, ensuring that increased data truly enhances clinical decision-making rather than adding complexity without clarity.”

Kappa Free-light Chain

In the latest guidance, the criteria stated that the kFLC index is considered an appropriate paraclinical test to support the diagnosis of MS. According to the published criteria, studies have indicated that the kFLC index is largely interchangeable with CSF oligoclonal bands and may be used as an alternative marker for intrathecal immunoglobulin synthesis in the diagnostic evaluation of MS.

“The integration of κ-FLC into the 2024 McDonald diagnostic criteria may meaningfully refine how MS clinicians make an early MS diagnosis. Until now, CSF oligoclonal IgG bands (OCBs) were a central marker of intrathecal immunoglobulin synthesis, but κ-FLC now offers a quantitative, automated measure of the same immunologic process,” Carrie Hersh, DO, MSc, FAAN, president-elect of the Consortium of Multiple Sclerosis Centers (CMSC), told NeurologyLive. “In practice, this empowers clinicians to confirm intrathecal inflammation in a more standardized and potentially more accessible way — particularly in settings where traditional OCB testing is less available or when OCB results are borderline. By aligning κ-FLC index positivity as an interchangeable marker with OCBs for ‘positive CSF,’ the criteria help support earlier and more confident identification of MS without reliance solely on radiologic dissemination in time.”

Hersh noted some of the strengths and limitations of the biomarker when distinguishing MS from other neurological conditions:

Strengths

Objectivity & accessibility: κ-FLC measurement uses automated immunoassays (e.g., turbidimetric or nephelometric platforms), which are typically easier and faster than OCB isoelectric focusing and interpretation.

Diagnostic performance: At optimal index cutoffs (e.g., ≥ 6.1), the κ-FLC index shows comparable sensitivity and specificity to OCBs in distinguishing MS from non-MS cases.

Prognostic signal: Higher κ-FLC index values may correlate with more active disease and a higher risk of subsequent events, adding clinical nuance beyond binary positive/negative results.

Limitations

Specificity caveat: Like OCBs, elevated κ-FLC reflects intrathecal immunoglobulin production, which can also be seen in other inflammatory CNS disorders (e.g., neuroinflammatory or infectious diseases), so it must be interpreted within the full clinical and MRI context.

Concordance not perfect: There are cases where κ-FLC and OCB status do not align (~90% concordance), suggesting value in complementary testing for diagnostically challenging cases.

“The 2024 McDonald criteria mark a shift toward integrating objective molecular and imaging biomarkers into routine diagnosis. κ-FLC’s inclusion alongside imaging metrics like the central vein sign (CVS) and paramagnetic rim lesions reflects this trend toward greater specificity and earlier certainty,” Hersh added.

Going forward, she shared a few ways she sees how emerging biomarkers will shape clinical decision-making:

Shortening diagnostic delay: Quantitative biomarkers like κ-FLC can confirm intrathecal inflammation even when classic MRI dissemination criteria are borderline, enabling earlier initiation of disease-modifying therapy.

Personalizing risk stratification: Biomarker levels that correlate with disease activity (e.g., higher κ-FLC index) may inform discussions around therapy intensity or monitoring frequency.

Refining differential diagnosis: As biomarker panels grow — with measures like neurofilament light for monitoring or other immune-signature assays — clinicians will have a richer profile to distinguish MS from mimics and tailor follow-up accordingly.

“Ultimately, the trajectory is toward biomarker-informed, earlier, and more precise diagnosis and management, improving outcomes while minimizing unnecessary treatments for those without MS,” Hersh said.

Conclusion

In summary, the updated diagnostic approaches for MS incorporate both imaging and CSF biomarkers to enhance diagnostic accuracy in the clinic. Overall, the guidance stated that the CVS and PRLs may be applied in selected clinical scenarios to help reduce the risk of misdiagnosis, whereas the kFLC index could offer a viable alternative to oligoclonal bands for supporting the diagnosis. Together, these biomarker tools provide clinicians with additional evidence-based strategies to improve diagnostic confidence in MS in their practice.

References:

1. Montalban X. 2024 Revisions of the McDonald Criteria. Presented at ECTRIMS Congress; September 18-20, 2024; Copenhagen, Denmark. Scientific Session 1: New diagnostic criteria.

2. Revisions to McDonald Diagnostic Criteria for Multiple Sclerosis published. News release. ECTRIMS. September 18, 2025. Accessed December 19, 2025. https://ectrims.eu/press/revisions-to-mcdonald-diagnostic-criteria-for-multiple-sclerosis-published/

3. Montalban X, LeBrun-Freney C, Oh J, et al. Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria. Lancet Neurol. 2024;24(10):850-865. doi:10.1016/S1474-4422(25)00270-4

4. Barkhof F, Reich DS, Oh J, et al. 2024 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI for the diagnosis of multiple sclerosis. Lancet Neurol. 2025;24(10):866-879. doi:10.1016/S1474-4422(25)00304-7