Updated McDonald Criteria for MS Allow Earlier Dx and Tx

Medscape

22-05-2025

This transcript has been edited for clarity.
Andrew N. Wilner, MD: Welcome to Medscape. I'm Dr Andrew Wilner. Today, I have the pleasure of speaking with Dr Oliver Tobin. Dr Tobin is a specialist in multiple sclerosis (MS) at the Mayo Clinic in Rochester, Minnesota.
Our topic is the revised 2024 McDonald Diagnostic Criteria for MS presented at the most recent ECTRIMS meeting in Copenhagen. We're going to discuss the impact of these revisions and how they change the diagnosis of MS. Welcome, Dr Tobin.
W. Oliver Tobin, MB, BCh, BAO, PhD: Thanks very much, Andrew. It's great to talk to you today.
Wilner: Thanks for joining us. Dr Tobin, I remember learning the original McDonald MS Criteria, I think it was back in 2001. There have been several revisions since then, with the last one in 2017, I believe. Why do we need a new one? Can you give us some background?
Why Were the MS Diagnostic Criteria Updated?
Tobin: Absolutely. Thanks very much, Andrew. As you said, there have been multiple iterations of the MS diagnostic criteria. The diagnosis of MS was defined over 150 years ago by Charcot. The entity was really, properly defined radiologically from the 80s with the original MRI studies.
This new iteration of the MS diagnostic criteria really adds much of the new technology that's available to be able to be more sensitive and specific. If we think about diagnostic criteria, they're used for multiple different things. They're used for clinical trials, so we need to be very specific for patients entering clinical trials. Also, with the disease-modifying therapies that are available, we also want to intervene early.
Whereas older iterations of the diagnostic criteria required to show a dissemination in time, that requirement has essentially been removed in most cases so that now we can make the diagnosis of MS earlier. It is heavily reliant on technology and the availability of that technology.
For the practicing physician, I think a key thing that has changed is the inclusion of what was previously called radiologically isolated syndrome, which is a frustrating term for patients and for doctors alike. If you are asking, well, do I have MS or don't I, and they say, well, you have radiologically isolated syndrome, that's been changed now to asymptomatic multiple sclerosis.
These are patients who don't have any clinical findings of MS, so you look at the MRI and it looks typical of MS, but the patient is essentially asymptomatic. That's called asymptomatic MS. That, I think, is really important to identify because of the fact that there have been two clinical trials in the past few years that have shown that treatment of patients with radiologically isolated syndrome can prevent the onset of clinically definite MS. I think that's a key clinical point.
The other important clinical point that will come up in your daily practice will be the inclusion of the spinal fluid kappa free light chain. You can think of them essentially the same as oligoclonal bands and perform the same diagnostically. They're included because they're faster to do, so they require less manpower. You can automate the assessment so it's easier for labs to perform them. They perform the same as oligoclonal bands so you can use those interchangeably depending on what's available in your lab.
The other key point, I think, is the inclusion of the optic nerve. We all think about optic neuritis as being, essentially, a sentinel feature of MS, but it actually wasn't in the most recent diagnostic criteria for MS. The reason for that was because there are many things that can mimic optic neuritis, in particular, migraine-related visual changes.
Having an objective measure of optic neuritis has been shown to be much better than just relying on a history of vision loss in the past. Those objective measures are OCT (optical coherence tomography) and MRI showing enhancement of the optic nerve. Visual evoked potentials, I understand, are also going to be included, although I would say that most MS specialists are primarily using OCT and MRI of the orbits.
Kappa Free Light Chains, Oligoclonal Bands and CSF
Wilner: It's fun that you mention visual evoked potentials, because I actually did my neurology training before we had ready access to MRI. Any patient that was suspected of MS had visual evoked responses and somatosensory evoked potentials to try to look at these pathways that, in many cases, we can see. With the advent of MRI, the use of visual evoked potentials has decreased enormously. Maybe they're going to have a little bit of a comeback.
Could you talk a little bit about these kappa free light chains? I know in my practice and in the practice of many neurologists, getting CSF (cerebrospinal fluid) for making the diagnosis of MS has, in many cases, fallen by the wayside because oligoclonal bands are very nonspecific, patients don't like the lumbar puncture, and it's a large amount of trouble. Are these kappa free light chains more specific than oligos?
Tobin: No, they're not. The key thing about including the spinal fluid analysis is that the presence of oligoclonal bands or kappa free light chains means the same thing. It can be substituted for dissemination in time. Where previously you required dissemination in time, now, if you have positive oligoclonal bands or positive kappa free light chains, that can be substituted for it. That's important from the point of view of the decision about treatment initiation.
There are many technical aspects about how the kappa free light chains themselves are analyzed. The caveat here is that the diagnostic criteria, although they have been presented at ECTRIMS in Copenhagen, as you said, they've not been published after peer review, nor have the methodological papers of how to assess the kappa free light chains been published or the recommendation papers for the MRI features as well. That all needs to be defined, I would say, in greater detail.
For the kappa free light chains, you can assess an absolute value in the spinal fluid alone without matching to serum, or you can match with serum and get a ratio. In our lab, we've actually been using the absolute value in CSF for over a year now, and my experience has been that it actually performs really well. It's quite similar to the oligoclonal bands, although the final recommendation may require an index, which would require the blood to be drawn also.
The real benefit of the kappa free light chain is primarily from the manpower side in the lab. They're faster to do, and they require less humans to do the test.
Optic Neuritis vs MS
Wilner: I'm going to ask you to help the clinicians out there. You have a 27-year-old woman who comes in with blurry and painful vision in the right eye. You suspect optic neuritis. You do the MRI, and her optic nerve is swollen. Is this MS?
Tobin: That's optic neuritis. Optic neuritis has a differential diagnosis, as you're alluding to. To evaluate that, we get the typical evaluation of MS, which in my mind requires an MRI of brain, cervical and thoracic spine, a spinal fluid analysis, and an ophthalmologic evaluation.
For optic neuritis itself, you'd want to consider neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) testing. Now, there are some features of the optic neuritis that might push you toward testing those more strongly and certainly some people would advocate testing both in everyone. The performance of the NMO-IgG test by live cell assay is very good. I don't have a problem with testing NMO in everybody with an optic neuritis.
For MOG, the performance of the assay is not as good. There are definitely some patients with low positive MOG assays in the 1-20 to 1-100 range who don't have myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). It's fine to test it, but it's important to interpret that in the clinical context if you have a low positive MOGAD.
Wilner: If a patient comes in with suspected optic neuritis, they should certainly have an MRI of the brain. No one would argue that. The spine as well because we're looking for lesions outside of the optic nerve that would steer us to a more diffuse demyelinating disease like MS. Should they also have a CSF exam in your view?
Tobin: I would. If you had a brain MRI that demonstrated clear findings of MS with enhancing lesions, and it was all very clear that was MS, then you can make a diagnosis of MS without the spinal fluid. If you just have a patient in clinic and you don't have the imaging, and the patient is presenting as optic neuritis, then I would do all the tests. Then you have the information when they come back, and you can move forward with treatment without any major delay.
PPMS vs RRMS
Wilner: There was some fine print about the same criteria for primary progressive MS and relapsing MS. Could you expound on that?
Tobin: This gets to the edge cases of MS, essentially. There are some patients with single spinal cord lesions who have a progressive course, who have positive oligoclonal bands, and clearly have progressive MS but don't fulfill the multiple parts of MS. These are solitary sclerosis patients. These patients were not included in the current diagnostic criteria. What was included was patients with two spinal cord lesions. This is on the edge of where the diagnosis is.
My understanding of how the criteria are going to be published is that patients with two spinal cord lesions who have a progressive disease course can be classified as MS, whereas patients with a single spinal cord lesion will not.
Obviously, there are challenges there with respect to MRI imaging, the quality of the imaging, and whether you actually get the imaging. Often patients just have cervical spine imaging. If you don't image the thoracic cord, you're going to miss the lesions there. I am curious to see the final, published document, but that's my understanding as to where the recommendations will fall.
Wilner: Another practical question is when we look at these patients, we often order MRI with and without contrast, using the contrast to show perhaps active inflammation. Is that what you would do as well?
Tobin: Absolutely. The presence of contrast-enhancing lesions is going to give you a better sense about the disease activity. If we're trying to diagnose patients early and risk stratify with respect to treatment, then that information is very useful. Certainly at initial evaluation, a contrast-enhanced MRI is very useful.
Also from the point of view of the optic nerve, just going back to your question about optic neuritis, a gadolinium-enhancing lesion within the optic nerve is very helpful. T2 hyperintensity within the optic nerve is very nonspecific, and I'd be very cautious about making any decisions based on that alone.
The question that arises in follow-up is, when you have a patient on treatment, should you get a contrast-enhanced MRI subsequently? That's less clear. My experience has been, with the highly efficacious treatments, that they tend to be highly efficacious and so the breakthrough rate is very low. If they do have breakthrough, it's usually a small enhancing lesion, which is asymptomatic.
It's unclear whether patients definitely need gadolinium going forward on an ongoing basis. I think it's definitely reasonable to get it at the first follow-up MRI because that's where you're more likely to get the disease breakthrough. Obviously, there are going to be resource issues, such as the time of scanning and the cost of the gadolinium, depending on where somebody is being scanned. There's definitely a greater sensitivity to breakthrough disease activity if you get a contrast-enhanced MRI.
The other thing to note is that, although our technology has developed amazingly as it has in epilepsy from an imaging perspective, if we look at imaging sequences that are dedicated for cortical lesions and get two specialist-trained neuroradiologists to review them, they identify about 10% of the cortical lesions that are identified on pathology. There is a floor to our MRI sensitivity, which is going to be challenging to get around.
Wilner: Dr Tobin, we're just about out of time. Is there anything you'd like to say to give us a wrap up? What's the most important update here?
Tobin: I think the key features are the change of radiologically isolated syndrome to asymptomatic MS. I think that's going to be really helpful to all of us, providers and the patients, and the fact that these patients are likely to benefit from treatment.
The inclusion of the kappa free light chain. I would just see that as analogous to your oligoclonal bands, so to use it in the same way. Then the inclusion of the optic nerve as a fifth anatomical site, but to ensure that is associated with an objective measure, preferably OCT or contrast-enhanced MRI.
Wilner: Dr Oliver Tobin, this has been a terrifically informative discussion for me, and there are many practical take-home points. Thanks for joining me on Medscape.
Tobin: Thanks so much, Andrew.
Wilner: I'm Dr Andrew Wilner. See you next time.