Diagnostic Criteria for Multiple Sclerosis

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: October 1, 2024

Expiration Date: October 1, 2025

Estimated Time of Completion: 33 minutes

Diagnostic Criteria for Multiple Sclerosis

Daniel Ontaneda, MD, PhD

Description

Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

Target Audience

Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

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CREDIT DESIGNATION

• American Medical Association (AMA)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
  
  Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

• American Nurses Credentialing Center (ANCC)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 ANCC contact hours.

• Certificate of Participation
  A certificate of participation will be provided to other health care professionals for requesting credits in accordance with their professional boards and/or associations.

• American Board of Surgery (ABS)
  Successful completion of this CME activity enables the learner to earn credit toward the CME requirements of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Credit will be reported within 30 days of claiming credit.

Podcast Series Director

Imad Najm, MD
Epilepsy Center

Additional Planner/Reviewer

Cindy Willis, DNP

Faculty

Daniel Ontaneda, MD, PhD
Mellen Center

Host

Glen Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Diagnostic Criteria for Multiple Sclerosis

Daniel Ontaneda, MD, PhD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

The following faculty have indicated they have no relationship which, in the context of their presentation(s), could be perceived as a potential conflict of interest: Cindy Willis, DNP.

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

HOW TO OBTAIN AMA PRA Category 1 Credits™, ANCC Contact Hours, OR CERTIFICATE OF PARTICIPATION:

Go to: Neuro Pathways Podcast October 1, 2024 to log into myCME and begin the activity evaluation and print your certificate If you need assistance, contact the CME office at myCME@ccf.org

Copyright © 2024 The Cleveland Clinic Foundation. All Rights Reserved.

Introduction: Neuro Pathways, a Cleveland Clinic Podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neurorehab, and psychiatry.

Glen Stevens, DO, PhD: Multiple sclerosis can be challenging to diagnose due to its varied presentation and similarity to other neurologic conditions. As our ability to image the brain has improved, so is our understanding of the disease and its presentation. As such, the diagnostic criteria for multiple sclerosis continues to evolve, the latest iteration coming to light through the 2024 McDonald criteria.

In today's episode of Neuro Pathways, we're breaking down the components of the new diagnostic criteria for use by neurologists across the globe. I'm your host, Glen Stevens, DO, PhD, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute, and I'm very pleased to have Dr. Dan Ontaneda join me for today's conversation. Dr. Ontaneda is a staff neurologist in Cleveland Clinic's Mellen Center for Multiple Sclerosis and a co-author of the new diagnostic criteria for multiple sclerosis. Dan, welcome to Neuro Pathways.

Dan Ontaneda, MD, PhD: Thanks so much for having me, Glen.

Glen Stevens, DO, PhD: So Dan, before we start, tell us a little bit about yourself, your background, how you came to Cleveland and what you do on a daily basis at the Mellen Center.

Dan Ontaneda, MD, PhD: So originally, I'm from Ecuador, South America, that's where I was born. I'm a little bit of a mix. My mom is American, my dad's Ecuadorian. My dad was a career diplomat, so I spent my life traveling. I was in a different country every several years. And what attracted me to Cleveland, of course, was the Mellen Center and the excellent multiple sclerosis care that I knew about before coming here. And I made my career here at the Cleveland Clinic, did my residency, fellowship, and then I was on a K award followed by independent funding, always surrounded by amazing mentors and I couldn't have really dreamt up a more fruitful career or surrounded by people who really are passionate about multiple sclerosis.

Glen Stevens, DO, PhD: Great. Well, I'm really excited that you're here today because I love talking about multiple sclerosis. I'm not sure if you know, but my mother had multiple sclerosis diagnosed in the 60s, which is really in some ways a dark age. There really was not much that was available. And I remember our diagnostic biomarker for MS before MRI was a hot water bath.

Dan Ontaneda, MD, PhD: That's right.

Glen Stevens, DO, PhD: Utilizing sort of the Utah's phenomena, which came about in the 1800s by an ophthalmologist with problems with nerve transmission, with people that got hot. So I think that we've moved a long ways from that, thank God. And of course, I also remember when interferon came out, Betaseron, and you know the excitement about it. But now you guys have leapt forward just incredibly. So with that background, tell us a little bit about the practice of MS as it's evolved over time and where we are.

Dan Ontaneda, MD, PhD: Yeah, so what you highlighted is true. One, we previously used mainly clinical characteristics to make a diagnosis of MS and there wasn't really an urgency to diagnose because for many years, we had no treatments for multiple sclerosis. That changed radically. So it started with the introduction of interferon medications and to the date right now, we have over 24 approved therapies for multiple sclerosis. And it makes the relapsing-remitting form of disease very treatable condition that if you have a patient with multiple sclerosis and you start these treatments early on, especially highly effective treatments, they go on to live normal lives.

They many times do not accumulate disability and they don't end up kind of what we consider secondary progressive MS people that we typically associate with being confined to a wheelchair for example, or lost the ability to walk. And so, concomitant with that push towards diagnosing early, we have to understand that if you have treatments available, you want to diagnose early and you have to be accurate about that diagnosis. And so, that I think has been the challenge for the multiple sclerosis field. That is we have evolved the criteria to make it easier to make a diagnosis and to make a diagnosis sooner, but that comes with some challenges. And I think those are challenges that specifically we can address.

Glen Stevens, DO, PhD: So, very exciting. But as you mentioned, we need some criteria. So the previous McDonald criteria came out in 2017. What did that look at?

Dan Ontaneda, MD, PhD: Yeah, so the criteria in 2017 were really an evolution of the structure that we have been using for years to make a diagnosis of MS. And that structure is that in order to make a diagnosis of multiple sclerosis, you need to meet criteria for something called dissemination in space and criteria for something called dissemination in time. And that is basically the evidence that multiple sclerosis is affecting multiple areas of the brain and is affecting different regions at different time as you follow a patient. And so, in the 2017 criteria, it was pretty clear that the conditions to make a diagnosis required dissemination in space, which really, the bar for that has decreased over time. So in the 2017 criteria, you needed lesions that are present, one or more lesion in two or more locations.

So basically, if you need lesions in the juxtacortical regions, which is very close to the cortex lesions touching the cortex, we always remind the residents this is not a lesion close to the cortex, it's touching the cortex, lesions that are periventricular, once again touching the surface of the ventricle, infratentorial lesions, which we know are more common in MS. And then finally, spinal cord lesions. And that had to be combined with some form of dissemination in time. And dissemination in time, of course, required either the presence of a new lesion showing up on an MRI or what we've evolved to thinking about is making a diagnosis of MS with a single scan, the presence of enhancing and non-enhancing lesions. On enhancing lesion, multiple sclerosis indicates that it probably developed within the last six weeks. And so, the idea was if you have an enhancing and a non-enhancing lesion, you could make a diagnosis.

And then the other thing that was relatively new in the 2017 criteria is we brought back cerebrospinal fluid. And the way we brought it back is we said, "If you can't meet dissemination in time because you haven't had a second attack or because you're not accumulating new lesions on MRI or you don't have enhancing and non-enhancing lesions, you can meet dissemination in time indirectly through the presence of CSF oligoclonal bands." And so, that was the first kind of departure of thinking of a measure that's a biomarker that doesn't truly reflect dissemination in time, but was used in the criteria as a replacement or instead of dissemination in time.

Glen Stevens, DO, PhD: So if we look at the 2017 criteria, globally, how many people are misdiagnosed with that criteria? Do we know what's the average time or delay to make the diagnosis? I'm sure it improved everything, but do we have an idea of that?

Dan Ontaneda, MD, PhD: Yeah, I think the 2017 criteria were definitely an improvement. It's been an evolution. But I think what you're mentioning is true, which is our diagnostic criteria are far from perfect. We think that on average, it probably takes approximately two years from when a person has onset of symptoms until they get diagnosed and those delays are still present even with the 2017 criteria. And this push that we've had to make the criteria more sensitive and more sensitive, so that we can start medications earlier, has also resulted in a fair amount of misdiagnosis. We calculate that approximately 20%, which is 1 in 5 people who are diagnosed with MS, might actually have an incorrect diagnosis. And that's probably because of misapplication of MRI. So if you take a person who's in their 60s and you count microvascular lesions, chances are you're going to have one or two lesions that touches the cortex, one or two lesions that touches the ventricle, you might have some infratentorial lesions and that person by MRI criteria not applied in the correct scenario will be inaccurately diagnosed with multiple sclerosis.

Glen Stevens, DO, PhD: You look like you were looking right at me when you said in your 60s with white matter change.

Dan Ontaneda, MD, PhD: I'm predicting that due to your vascular risk factors, you have no white matter lesions, Glen.

Glen Stevens, DO, PhD: I do appreciate that. Obviously, there's reason to improve the criteria and there's reason to decrease the number of false positive patients. So evolution of criteria, clearly important. If we look at the evolution of the criteria six years, seven years later, what are the things that are incorporated into the new criteria that weren't in the previous criteria that will help with those numbers?

Dan Ontaneda, MD, PhD: Yeah, definitely. So the criteria have evolved in a substantial way I think. And I think that these new criteria are actually going to be the largest shift in terms of the diagnostic criteria that we've had in a long time. Some of the stuff that is going to be included in the criteria is somewhat incremental and some of that stuff we predicted was going to happen. And I think the first thing that probably most of us predicted and was already discussed at the previous meeting was the inclusion of the optic nerve as an additional topography to make a diagnosis of MS. As we highlighted before, it was juxtacortical, infratentorial, spinal cord or periventricular lesions. And what we're adding now is presence of lesions in the optic nerve. And those lesions in the optic nerve can be assessed in a variety of different ways. Certainly on MRI, if you use a dedicated orbital sequence, you can see a lesion in the optic nerve. If you do something called optical coherence tomography, you can see evidence that there's been optic neuritis in that eye. And then finally a technique that we've used for some years, which is visual evoked potential can demonstrate that there's slowing of transmission across that optic nerve.

And so, I think that addition of the optic nerve is something that we had all called for many, many years, people have been interested in the optic nerve. And actually, at the meeting, there was a ton of data presented that demonstrated that if you include the optic nerve as an additional area, it basically increases your sensitivity to make a diagnosis without much cost of specificity. Why? Because we know that optic neuritis is quite specific for MS already. And so, incorporating that, I think was natural.

Glen Stevens, DO, PhD: And the oligoclonal bands are still included in the new criteria?

Dan Ontaneda, MD, PhD: That is correct, oligoclonal bands are still in the criteria. Interestingly, one of the changes is that we now also include something called kappa free light chains. So that is something that we actually studied years ago here at the Cleveland Clinic. Rick Rudick had a robust program looking at kappa free light chains, but there were some methodological issues back then, but especially in Europe, kappa free light chains are being used to make a diagnosis of MS and they can be used interchangeably with oligoclonal bands. I think for the timing, that's probably going to apply more outside of Europe and currently in the United States, we don't have an approved way of getting kappa free light chains from a laboratory perspective, but I think that's something that's coming.

Glen Stevens, DO, PhD: Yeah, I remember I would see some patients at the Mellen Center in the '90s and I remember we would check the kappa free light chains at that time. So what's the buy-in with the criteria worldwide? Do people buy into this? Are there some countries that don't or they have their own criteria or this is a worldwide international criteria that everybody will buy into?

Dan Ontaneda, MD, PhD: I think mostly everybody buys into this criteria. The criteria are authored by an international panel. Includes individuals from all continents and really, a broad representation of neurologists who really understand the realities of making the diagnosis of multiple sclerosis across different geographies and regions. Of course, there's always going to be differences, access to MRI, access to tests. We just highlighted the differences between kappa free light chains. But I think what the diagnostic criteria tries to do is try to give you a variety of different methods with which you can make the diagnosis. The methods you have, you apply and you use. If you don't have a method, you can’t use it, you can’t apply it, but it doesn't restrict the ability to make a diagnosis without those, that is you can always just rely on the clinical characteristics of the disease. I would like to talk a little bit about central vein because…

Glen Stevens, DO, PhD: Yeah, that was actually going to be my next, because I know you have great imaging interest and have done a lot of work on the central vein, so great time to talk about that.

Dan Ontaneda, MD, PhD: Yeah, so I mean, I think one of the diagnostic biomarkers that has actually come to the fore is the central vein sign. And the central vein sign is a radiological sign that recapitulates the perivenular pathology of multiple sclerosis lesions. If you go back and you look at Charcot's original histological descriptions of multiple sclerosis, you can see that there are small vascular structures, venules, around which multiple sclerosis lesions are forming. And we kind of knew that, but we could never image it. Our MRI wasn't of the adequate resolution. The central vein sign was first described in the 2000s in an imaging paper and it was described as venography for multiple sclerosis and it kind of got forgotten after that single paper.

And then when we started using 7T MRI, which allowed us to get much higher resolution, we started to see that lesions actually occurred around the small veins. That led to further development of techniques to identify these veins on a type of sequence called susceptibility-based imaging. This basically allows us to image iron and, of course, the deoxyhemoglobin that we find in venous structures is something that we can image and we can find those veins. And so, now we've applied that technology in 3T MRIs and 1.5T MRIs. We, at the Cleveland Clinic have been at the forefront of the development of the central vein and there are multiple studies demonstrating that the central vein is a sensitive and specific imaging biomarker for multiple sclerosis. So we presented the data on the central vein to the diagnostic criteria panel and it was accepted. It was accepted as a way that one can use central vein to actually increase your specificity for a diagnosis.

And so, that is part of how the diagnostic criteria are going to change, which is a greater reliance on these very pathologically specific measures. Central vein is one of them. We've got probably the most data for that. And the nice thing about central vein is that in that 60-year-old patient who had lesions that was confused as MS, you'll clearly be able to demonstrate that the vast majority of lesions in vascular paths don't have a central vein. And so, it's an easy discriminator that clinicians can use, that radiologists can use. We're in the process of writing the updated MRI guidelines, which is going to be a companion paper to the diagnostic criteria. And we're including recommendations for imaging of the central vein in that paper as well.

Glen Stevens, DO, PhD: Very exciting. If you line up five neuroradiologists and ask them, "Is there a central vein there?" How's the concordance?

Dan Ontaneda, MD, PhD: The concordance is actually pretty good. And central vein has been at the lesion level, there might be some differences between one radiologist and another. But generally, what the studies show is that MS patients, more than 50% of their lesions will have a central vein, that is an ideal discriminator between individuals who have MS and individuals who don't. So although you might have some differences at the lesion level, overall at the scan level interpretation, what the central vein does is it adds. You see if you find more than 50% of the lesions have a central vein, the likelihood of MS is going to be higher. How it's going to be encoded into the diagnostic criteria is through the presence of six central vein positive lesions. So the presence of six lesions or more with the central vein essentially will give you higher specificity for a diagnosis of MS. And the agreement on that is relatively high.

Glen Stevens, DO, PhD: And does burden of the new criteria... And I know you're going to use highly effective therapy, so it becomes a little bit difficult. But does the burden of how many criteria you have as an example, you said if you have six of the retinal vein lesions, is that an affective prognosis or hard to know because you're giving treatment?

Dan Ontaneda, MD, PhD: Yeah, interestingly, the central vein we think is a marker that assures you that a lesion is a demyelinating lesion. Now, if you take an MS patient, the vast majority of spots in their brain are going to be demyelinating lesions. So the actual number of central vein lesions, although it might contribute statistically a little bit more information because you're more sure that is in a 50-year-old MS patient, they might have 40 lesions that are MS lesions and 10 lesions that are microvascular. So you can be a little bit more precise about that.

But there is a second imaging biomarker that we think is a diagnostic biomarker and is a marker of prognosis, and that's something called the paramagnetic rim lesion. And so, it turns out that some lesions in MS are what we call chronic active lesions. These are lesions that have a central core of demyelination and they're surrounded by chronically inflamed cells, typically microglial cells. And these microglial cells we think are driving potentially an slow expansion of the lesion. And this microglia, guess what they have, they have iron. And therefore, if we use that same susceptibility-based sequence, we can actually find these lesions and they look like they have a small rim of iron around them. That's why we call them paramagnetic rim lesions. The paramagnetic rim lesion, which is now going to be also incorporated in the diagnostic criteria, presence of these lesions is helpful from a diagnostic standpoint because these lesions don't occur outside of multiple sclerosis. They are very specific for MS. And the other thing that's helpful is that when you have a greater number of these lesions, the majority of studies indicate that if you have four or more paramagnetic rim lesions, the likelihood that your MS is going to follow a more aggressive disease course is much higher. So I like paramagnetic rim lesions because it combines diagnosis and prognosis all into one.

Glen Stevens, DO, PhD: So you probably didn't realize you were going to be a neuroradiologist when you started doing MS.

Dan Ontaneda, MD, PhD: That's true.

Glen Stevens, DO, PhD: That's really what you're becoming, right.

Dan Ontaneda, MD, PhD: In a sense, I mean, the majority of my research is imaging-based. And I think one of the things that I've also found fascinating about the nervous system is understanding how the nervous system can be imaged and how can you look into the brain to make discoveries that actually can affect people with MS. And in my mind, MRI is a window into what's going on in MS. It's a window into what's going on in people's brains. And it's probably our most utilized biomarker in neurologic disease. Certainly in multiple sclerosis, but I think in what all of us do. You could say that you probably spend more time looking at MRIs than anything else as well in your field.

Glen Stevens, DO, PhD: True enough.

Dan Ontaneda, MD, PhD: So we're all a little bit of neuro imagers in a sense.

Glen Stevens, DO, PhD: So it sounds like neurologists better buckle up. I mean, this sounds like a pretty significant change that's going to be coming forward and people really need to pay attention to this. How are you going to disseminate this knowledge?

Dan Ontaneda, MD, PhD: Yeah, so I think it's a great point. One of the things that I think is one of the biggest changes in the diagnostic criteria, which is completely new and has never been part of the criteria, is that under certain circumstances, that is presence of specific biomarkers such as the paramagnetic grim lesions, presence of the central vein, positive cerebrospinal fluid, you can actually make a diagnosis of MS in an asymptomatic individual. And previously, this is something we called radiologically isolated syndrome, and we would diagnose radiologically isolated syndrome. We would counsel the patient. We think this is an early form of multiple sclerosis, but we typically are not treating it unless you're accumulating new lesions over time. Now, what we're going to say is that under certain conditions, you can diagnose multiple sclerosis in an asymptomatic individual and you could potentially start treatment. And I think that's important because radiologically-isolated syndrome has already been studied in clinical trials and medications that we use for relapsing-remitting multiple sclerosis have already been demonstrated to actually reduce the time to a diagnosis of multiple sclerosis.

So that change is going to be really something big for providers to think about, and it's going to be a challenge, I think, not only from the providers. So making a diagnosis and asymptomatic individual is something that I think for many neurologists, it's going to be a little bit difficult to swallow and so, we have to get used to it. And the second thing is, well, how are we going to handle medications that are currently approved to treat multiple sclerosis? Are all those medications now approved to treat individuals who are asymptomatic and diagnosed with MS? Although they haven't been studied across all the medications, the FDA will have to make a decision on whether these populations are included or not.

So there's going to be a little bit of a learning curve here. And our dogma of treat everybody who has MS as early as possible and with as potent medications as possible has to be thought of also in the presence of an asymptomatic patient. That is, you're probably more likely to take some risks with some high-efficacy treatment if somebody's already had at least one attack. The moment somebody hasn't had any symptoms, selling them on a medication that they have to take for many years that is highly effective might be a little bit more difficult.

But to answer your question about how we're going to disseminate the results, that's an important point because the criteria are one, making major changes in how we make the diagnosis. That is we're relying less on a second clinical attack. This whole concept of having dissemination in time is not as important anymore. We already saw in the previous criteria that if you had oligoclonal bands, you don't need a second attack or you don't need accumulation of new lesions. Now we're taking it a step further. That is if you have a very large number of topographies, you don't even need to think about dissemination in time. That is, there is sufficient specificity just with finding lesions in several locations that can make you have a diagnosis of MS. So that, I think we have to adapt to.

Then we're using these imaging biomarkers that we've been looking at here at the Cleveland Clinic for years, but there are places that hasn't been done. And so, certainly there has to be some education around how do you interpret these MRI findings, getting used to reading MRIs with multiple sclerosis patients on the susceptibility-based contrast. All that is going to be a little bit of a change. Thankfully, this is an international effort. The National Multiple Sclerosis Society, the European Committee Treatment for Research in MS are heavily invested in a very robust dissemination plan.

The criteria paper is going to be published with several ancillary papers, one paper focused on optic nerve and visual function, how you integrate that into the diagnostic criteria. One paper on biomarkers, specifically CSF biomarkers, how do you interpret the technical considerations? One paper on MRI guidelines, which I'm participating in. And then finally, one paper that talks about differential diagnosis. So how do we put all these things, all these tools we now have for a diagnosis together when we're considering alternative diagnosis? So I think across these papers and using a robust teaching module methodology that the National Multiple Sclerosis Society is going to be implementing, I think we stand a really good chance of making sure that neurologists are kept up to date on these new criteria.

Glen Stevens, DO, PhD: Well, what an exciting problem to have, right?

Dan Ontaneda, MD, PhD: Yes.

Glen Stevens, DO, PhD: So every year, I run a neurology update meeting, and next year it'll be in DC. I'm thinking you probably need to come and talk at that. I'm going to put that out there right now, that I think this is really important stuff. And it'll all be out by then. There'll be some water underneath the bridge. People will start to utilize the criteria, it'll probably be a great time to look at it. So look for me to hit you up because this is very exciting stuff and…

Dan Ontaneda, MD, PhD: I'll be there.

Glen Stevens, DO, PhD: I think it needs to get out. I also remember a lot of work done many years ago. When I was going through and being taught MS is a white matter disorder, but I know that there was work that came out of the Mellen Center looking at effects on grey matter as well. What's the status on that today? Is that involved with the criteria? Do you see these MRI findings just in white matter? Can you see them in grey matter? Is it just sort of an area of interest that affects a bigger part of the brain than we think, or what's the thinking there?

Dan Ontaneda, MD, PhD: Yeah, absolutely right. Multiple sclerosis now is considered a central nervous system disorder that broadly affects white and grey matter. The 2017 criteria already included the presence of these juxtacortical lesions. You can also count cortical lesions. So it's interesting because these juxtacortical lesions, although we think of them as white matter lesions, because we say they touch the cortex. When you look at them pathologically, those lesions are actually in the cortex. And the issue is that the MRI can pick them up very easily in the white matter, not as easily in the grey matter. But the previous criteria already made a consideration that if you use techniques that are specifically sensitive to cortical lesions, if you find a cortical lesion that counts as an additional topography. So it already kind of was embedded into the juxtacortical cortical lesions. And in our new MRI paper guidelines, of course, we include recommendations on how to image those grey matter lesions. We think it's a big part of MS.

It still is hard to find those lesions. And I would say that one of our big challenges with MRI is even in the best case scenario, when you use a 7T MRI and you use a dedicated sequence, you're only picking up a very small proportion of those cortical lesions. So we're still doing a lot of work. Bruce Trapp has identified a type of multiple sclerosis that just affects the cortex and the spinal cord, something we call myelocortical MS. We're furthering our studies in that sense because we think that that might be a demonstration of multiple sclerosis that predominantly affects the cortex. And so, I think we have to think about these variants. I think altogether how we think about the diagnostic criteria and how we think about treatment, we have to be careful because what we've done to date is make it more sensitive, but we have to balance it because I think the stakes are high. You need to start treatments early in MS. but you have to be sure that a person has MS before you ask them to start a treatment that many times will be a 20-year-long treatment with a highly effective medication.

So I think we're at a point where we've developed sufficiently specific pathological markers that allow us to make this diagnosis without relying on kind these old disseminations in space and dissemination in time. I imagine that in the future, we might be able to have a fully biomarker-based diagnosis of MS. And the example I always give is you think about cardiologists. A cardiologist doesn't wait for somebody to develop symptoms of congestive heart failure from tricuspid regurgitation, for example. They do an ultrasound, they find tricuspid regurgitation, and the diagnosis is made, no questions asked. Clinical doesn't even matter. Why? Because they have very specific diagnostic testing. And I think in multiple sclerosis, we're heading in that direction. That is you can interrogate used on an MRI sufficiently specific imaging biomarkers that allows you to make a spot diagnosis.

Glen Stevens, DO, PhD: Well, this is fascinating. So any closing thoughts, things that we haven't covered that you think are important or just a closing statement?

Dan Ontaneda, MD, PhD: Yeah, I mean, I think I would kind of recapitulate by saying that making a diagnosis of MS has always been considered to be something that requires some clinical experience and expertise and some careful considerations. And I think that continues to be the case. Although we rely more on biomarkers and although the tools we have at our disposal are more powerful to make this diagnosis early, I think the diagnosis has to be considered in a person who has neurological symptoms that are compatible with the disease. The diagnosis has to be confirmed, making sure that there's no other motive that a person might have white matter lesions or neurological symptoms. So those points I think we can't get away from.

One of the fascinating things for me is individuals who present with what we consider atypical symptoms. You have plenty of people who present with an optic neuritis and you can say, yes, this person probably has MS, but we have tons of people who present with vague symptoms, cognitive dysfunction, numbness and tingling, and that's not specific. And I think in those cases, we're going to have to rely even more on our biomarkers to make a diagnosis.

Glen Stevens, DO, PhD: Well, I mean, it's clearly a revolutionary time and groundbreaking time going on, and I love the fact that the criteria continually update that we use biomarkers as we move forward. And we didn't even get into all the medications and development and certainly can get into that at a different time. But I appreciate all the work that you're doing. I love hearing all of this. I love reading the various articles with the developments that you guys are doing at the Mellen Center. So keep up the good work and I'm proud of you.

Dan Ontaneda, MD, PhD: Thanks so much, Glen, and thanks also for sharing your personal history with MS. And it always means a lot when we talk to people who've had MS for a while and family members of people with MS because the reality is that people were really invested in this disease, people with multiple sclerosis have contributed to the research, to the mission of making it better. And I think we always end with a shout-out to all our patients who participate in our research and who have helped us really develop these treatments and changing what multiple sclerosis looks like in an individual today is based on the work of a lot of people and also the collaboration of a lot of patients.

Glen Stevens, DO, PhD: And just as a last shout-out, I would say that with diseases where we need a lot more work going on, patient advocacy cannot be understated. And I think that patient advocacy will help drive clinical care. So if you have a disease out there and you feel it's not getting its due, you need to find a way to get clinically advocacy in your patient population to talk to people that can make the change as it moves forward. So I wish you well, and I'm sure you got to get back and read some more MRI scans. So thanks a lot.

Dan Ontaneda, MD, PhD: Thanks so much, Glen.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's @CleClinicMD, all one word. And thank you for listening.