NeuroVoices: David A. Hafler, MD, FANA, on Evolving the MS Diagnostic Criteria to Enhance Precision for Earlier and More Effective Care

David A. Hafler, MD, FANA

(Credit: Yale School of Medicine)

The McDonald Diagnostic Criteria, initially developed in 2001 and last updated in 2017, provides neurologists with guidelines to improve the accuracy and timeliness of multiple sclerosis (MS) diagnoses. Since 2021, an expert committee has worked on further updates to reflect new knowledge about MS, aiming to help clinicians identify the disease earlier for better patient outcomes. The new update focuses on incorporating a deeper understanding of MS's biological mechanisms, supporting more precise assessments alongside symptom evaluation.¹

Presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held September 18-20 in Copenhagen, Denmark, key recommendations in the revision include advanced testing methods and tailored criteria for diagnosing MS in both younger and older patient populations. These changes aim to improve diagnostic clarity by examining deeper markers of MS-related damage beyond visible symptoms. The committee is preparing a peer-reviewed publication of the finalized updates, expected by early 2025. Following publication, the National MS Society and ECTRIMS will work to ensure that providers and patients are informed and equipped to apply the new criteria.²

In a new iteration of NeuroVoices, David A. Hafler, MD, FANA, the William S. and Lois Stiles Edgerly Professor of Neurology at Yale School of Medicine, offered an additional clinical perspective on how the evolving MS diagnostic criteria might influence early treatment decisions and patient outcomes. He also spoke about the role of advanced biomarkers, like kappa free light chains and paramagnetic rim lesions (PRLs), in enhancing diagnostic accuracy for MS. Moreover, Hafler, who also serves as the Neurologist-in-Chief at the Yale-New Haven Hospital, talked about how the use of spinal taps can contribute to reducing diagnostic errors in patients with symptoms resembling MS.

NeurologyLive: How do the new diagnostic criteria impact various specialties and aspects of care, like clinical care versus radiological care?

David A. Hafler, MD, FANA: It’s an interesting question about criteria because, in essence, the disease hasn’t changed. But every few years, new criteria are introduced. The question is, what are these criteria really for? I think they serve several purposes. One is for non-specialists who need help in defining what the disease might be. I believe some of the additions to the new criteria—partly based on new technologies—have genuinely improved the criteria. But ultimately, I should point out that the diagnosis of MS is a pathological diagnosis, and what we do clinically is add various measurements that increase the probability of making an accurate diagnosis.

I think the term "definitive" MS should be discarded, because if it's a probabilistic determination, then how could something be definitive? If the definitive diagnosis is pathological, my view—having watched the criteria evolve from Charles Marcel Poser, MD, FAAN, when I was a fellow many years ago to Ian McDonald, MB, ChB, PhD’s criteria and beyond—is that it’s been fascinating to watch this evolution, much of it driven by new technologies that help with diagnostic precision. It’s really about increasing the probability of a correct diagnosis. This is important because, as we’ve seen over the past two decades, the earlier we can treat someone likely to have MS, the better the outcome. So, the sooner we can make a presumed diagnosis, the better.

At the Yale MS center, my fellows and junior faculty know I haven’t necessarily been a great fan of these criteria—we use our own criteria, but we have a lot of experience. The question really comes down to whether we have enough confidence in the diagnosis to begin treatment. For instance, putting RIS (radiologically isolated syndrome) into the MS category—we did that years ago. I’m not going to wait for a committee to tell me that RIS is MS. Still, having certain defined criteria is helpful. In particular, we’ve adopted the central vein sign from the new criteria, which I think is very useful. Also, if someone is under 50—or even in their teens or 20s—and has lesions that look like MS, we feel more confident in making a diagnosis than if the person were 65 and had white matter lesions. Adding an age cutoff to make the criteria more stringent makes a lot of sense. So, indeed, these are all very important issues addressed by the new criteria.

One other point I feel strongly about—I'll say it outright—is that it borders on medical malpractice not to do a spinal tap on every patient. Not every center does this, but whether it’s required by diagnosis or not is irrelevant to me, because again, it’s about probability. After seeing enough MS patients over decades, you realize that MRI just looks at water density in the brain. The spinal fluid, however, provides an entirely different data set for inflammation. Occasionally, though rarely, you’ll find someone with high protein levels or many white cells, which might indicate sarcoidosis or another disease that resembles MS. So, before committing someone to what could be decades of therapy, not to perform a benign test like a spinal tap—if only to rule out other diseases—seems ill-advised. I strongly feel it should be part of every patient’s diagnostic workup.

How do you think these criteria could influence drug development and clinical trial studies?

Well, for clinical trials, they certainly have an influence. When conducting a trial across multiple centers—or even just at one center—you must have defined criteria for study inclusion. These criteria are as good as any. You also need criteria to define who is included in the disease category. Again, this is another useful application of these criteria, many of which are technology-based. For example, free light chains, specifically kappa free light chains, have been used for decades. However, recent findings show they’re about as effective as oligoclonal bands, but much easier and faster to measure. Including them in the criteria is a good move. Similarly, PRLs add considerable specificity to the diagnosis. Although the clinical significance of this isn’t entirely clear, it’s still closely associated with MS. So, technology-driven findings lead to a higher probability of diagnosis. I think we need to view the criteria as probabilistic, increasing the probability that, pathologically, the patient falls within the MS category.

Is there anything else you’d like to add regarding these criteria for a clinical audience?

My closing thoughts would be, first, that early treatment is critical. B-cell depletion, in whatever form—whether subcutaneous or intravenous—is, I think, a paradigm shift in neurology. Particularly in younger individuals, it’s proving to be a benign form of therapy, and initiating treatment as early as possible is essential. Another question is, what comes next? For instance, we’ve moved from using CIS (clinically isolated syndrome)—a term I’ve always questioned. It doesn’t make sense to me, so I refer to it as "singular sclerosis," though that term is likely as meaningless. But the concept is the same: the first attack. RIS, however, represents a significant step forward for the field. Finally, acknowledging that just because someone hasn’t had a clinical attack, if there’s inflammation in the central nervous system and clear MRI lesions, then it’s MS. We know that for every clinical event, there are ten MRI events. Why wait for a clinical event for a pathologic diagnosis?

For years, we’ve treated RIS, especially when we see inflammation in the spinal fluid, with B-cell depleting therapies. The next step, I believe, is diagnosing MS before there are parenchymal lesions. We’re beginning to study this by looking at first-degree relatives, especially young women with a high polygenic risk score, who are predisposed to MS. By tracking those who haven’t been exposed to Epstein-Barr virus and monitoring neurofilament light chains, which indicate central nervous system damage, we may gain predictive insights. Ultimately, being able to measure early autoreactivity to myelin antigens with tools like MHC class II tetramers could allow us to diagnose MS before any parenchymal damage occurs. That’s the next big step, which could significantly advance our understanding of disease biology and pathogenesis.

Transcript edited for clarity. Click here to view more NeuroVoices.

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. European Committee for Treatment and Research in MS. McDonald Diagnostic Criteria. Accessed November 12, 2024. https://ectrims.eu/mcdonald-diagnostic-criteria#