Revised McDonald Diagnostic Criteria Signals New Era in Multiple Sclerosis Treatment

Daniel Ontaneda, MD, PhD

In the last 30 years, no subspecialty in neurology has seen greater advancements in treatment than multiple sclerosis (MS). With more than 20 disease-modifying therapies (DMTs) approved and more in the pipeline, we are now able to essentially freeze the disease in its course and reduce disability progression, when treatment is started early.

As the McDonald diagnostic criteria have evolved to meet the need for earlier detection, the field has faced challenges in increasing the sensitivity of the criteria without compromising specificity. This is, in part, due to the disease’s varied presentation and similarity to other neurological conditions, as well as a lack of specific diagnostic biomarkers. We know that on average, it takes 2 years from the onset of symptoms to receive a diagnosis, and of those diagnosed, 20% do not actually have MS.

Addressing the current limitations of the McDonald diagnostic criteria remains an ongoing process in our quest to improve diagnostic speed, accuracy, and long-term patient outcomes. The 2024 revisions presented at the 40th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis 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.

Jeffrey Cohen, MD

The addition of these biomarkers was driven by data, and we at Cleveland Clinic Mellen Center for Multiple Sclerosis Research and Treatment are proud to have contributed evidence needed to support the addition of the central vein sign (CVS), as well as paramagnetic rim lesions (PRLs), areas in which we have led through our CAVS-MS study.

Data shows that the majority of white matter lesions in MS have CVS detectable on MRI, so it is an ideal discriminator between individuals who have MS and those who do not. Similarly, 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 criteria incorporate kappa free light chains as an alternative to oligoclonal bands (OCBs) in cerebrospinal fluid. While OCBs remain a part of the criteria, kappa free light chains offer an easier-to-measure biomarker—an update that will be particularly helpful in regions where measuring OCBs is challenging.

The new criteria also expand the number of topographies used to establish dissemination in space. In addition to the historical topographies (juxtacortical, periventricular, infratentorial, spinal cord), the optic nerve now represents a 5th topography. Optic nerve involvement can be established on MRI, Optical coherence tomography, or visual evoked potentials.

The greater reliance on MRI and other biomarkers allows for 2 significant changes in rendering a diagnosis:

A Departure from Dissemination in Time: Building on changes started by the 2017 revisions, the 2024 criteria move away from the notion that you need evidence that MS is affecting areas of the central nervous system at different times to make a diagnosis. Historically, this required a new clinical relapse, new MRI lesions, or progression of disability. Now, when 4 to 5 topographies are identified, we no longer need to demonstrate dissemination in time.

Diagnosing Asymptomatic Individuals: When there is a presence of specific biomarkers, such as OCB, PRLs, and CVS, you can actually make a diagnosis of MS in individuals with no symptoms. This is a significant advancement in the way we approach diagnosis as previously, asymptomatic individuals were diagnosed with radiologically isolated syndrome and typically did not start treatment unless new lesions appeared over time and even then, could not be diagnosed until they developed clinical symptoms of MS. Now, clinicians can diagnose MS and begin treatment earlier, potentially improving long-term outcomes.

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.

A series of upcoming companion and peer-reviewed papers detailing guidelines, optic nerve and visual function, MRI techniques, biomarkers, etc, will help with the rollout of the criteria, but a concerted effort from the entire MS community—from clinicians to regulators and advocacy organizations—is critical to its success. Key considerations include:

• Early Intervention: This shift toward earlier detection raises a philosophical question: who needs to be treated and when? High-efficacy medications, while effective, come with potential side effects and long-term risks. Ensuring that the diagnosis is made with a high degree of certainty before initiating treatment will be crucial. While asymptomatic individuals have not been studied across all DMTs currently approved, regulators will have to guide us on whether all treatments can now be used in this population.
• Continued Education and Training: The dissemination of these criteria requires a multi-faceted approach and will take time. The development of ancillary materials, and comprehensive education programs will ensure that neurologists and other MS specialists are well-versed in the latest diagnostic techniques and criteria. Workshops, webinars, and training modules will be pivotal in fostering a deep understanding of the new guidelines, enabling clinicians to apply them accurately and consistently in their practice. Until there is widespread adaption, we should expect to see an increase in referrals to specialty neurologists, which may create challenges with patient volumes and wait times.
• Accessibility and Cost: The criteria utilize advanced imaging and diagnostic techniques, which may not be readily available in all healthcare settings. While the revisions to the criteria were purposely designed to be flexible, allowing for multiple ways to make a diagnosis, cost is an important factor in a large-scale adaption and underscores the importance of clinicians identifying an approach that works best for them and their current capabilities.

Continued validation and data aggregation in real-world practice will further enhance the updated criteria, but the 2024 revisions represent an exciting step forward in greater accuracy and earlier intervention.

Looking forward, we envision a future where we use a fully biomarker-based approach to diagnose MS. One where clinicians no longer need to wait for overt symptoms, and instead rely on advanced imaging and diagnostic tools to make an immediate and unequivocal identification of the disease. We have seen this happen in many fields of medicine already and we believe MS is headed down this path as well.

This shift toward precision diagnostics is made possible through ongoing research, education, and collaboration, and paves the way for more personalized treatment plans and, ultimately, better outcomes.