Episode 75 - Diagnostic Criteria for Multiple Sclerosis

Interactive Transcript

spk_0 Hi everybody and welcome to the neurology exam prep podcast.

spk_0 My name is William and Senior E-Lay, an incoming neuromospular fellow at Columbia Presbyterian.

spk_0 And today I'm joined by two fantastic former Yale neurology residents and now outgoing

spk_0 fellows in their respective fields.

spk_0 We have Dr. Kevin Yan finishing up neuroophthalmology in Emory in Atlanta and then we are also

spk_0 joined by Dr. Dinesh, a civic allandu who is finishing up neuro-menology at Cornell in

spk_0 New York City.

spk_0 Pleasure to have both of you guys here today to talk about a very cool topic.

spk_0 Thanks Philly.

spk_0 Good to be back.

spk_0 Thanks Philly for having me.

spk_0 So just to start off today we're going to be discussing the 2024 McDonald criteria update.

spk_0 We're going to have some stories by both Dr. Yan and a civic allandu and so we want

spk_0 to start off with a disclaimer for everyone.

spk_0 So the disclaimer is that the 2024 McDonald criteria has not been formally published and

spk_0 that our discussion will mainly be based on the guidelines discussed at the 2024 ECT

spk_0 RIMS, otherwise known as the European Committee for Treatment Research in MS, meeting that

spk_0 has been subsequently disseminated at various conferences, mainly the 2025 AAN annual meeting.

spk_0 And so to start off, I think we should go ahead and maybe go into the history of multiple

spk_0 sclerosis.

spk_0 I think Kevin, you want to take that away?

spk_0 Yeah, a long time.

spk_0 Listeners will know that I am the history buff up the group.

spk_0 So symptoms of unusual neurologic syndromes, transient neurologic symptoms have been noted

spk_0 as far back as medieval times.

spk_0 This was really first identified as a disease though by the illustrious neurologist John

spk_0 Marie Charco who you will probably recognize from his appearance in many in eponym in 1868

spk_0 in a series of lectures that he gave at Lobitall, Pitti, Salpettrier in Paris, France, and

spk_0 long time listeners will also remember at my inability to pronounce other languages.

spk_0 So I apologize to any French viewers.

spk_0 This was identified as a new disease entity that he called sclerosis on plaque or sclerotic

spk_0 plaques literally based on examination of several brains post mortem and several spinal

spk_0 cords post mortem in which he saw that there were several unusual appearing plaques in the

spk_0 white matter.

spk_0 When translated into English, this is what gave rise to the name multiple sclerosis.

spk_0 Over the next several decades, various treatments were tried really without success and without

spk_0 any evidence basis were still in the pre-evidence based medicine period at this point.

spk_0 According to the multiple sclerosis association of America, these treatments were quote-unquote

spk_0 treatments, included deadly nightshade, arsenic, mercury, and even the injection of malaria

spk_0 parasites.

spk_0 In 1951, that was when cortical steroids were first used to treat multiple sclerosis

spk_0 relapses when cortisone was described as working to improve symptoms and more rapidly resolve

spk_0 symptoms.

spk_0 But still, we're still in the quote-unquote diagnosis and audio space of multiple sclerosis

spk_0 where as neurologists, we could now diagnose it as a separate disease entity.

spk_0 But there were still very few effective treatments for the underlying disease.

spk_0 The diagnosis has also been a little controversial because it really has not been well characterized,

spk_0 so there were several different diagnostic criteria flowing around out there.

spk_0 And there really was not a true unifying diagnostic criteria that's been universally accepted

spk_0 until 2001 when Dr. Ian McDonald, who was a New Zealand neurologist, published the first

spk_0 diagnostic criteria for multiple sclerosis that has been widely accepted and used.

spk_0 And we now call these the McDonald criteria for the diagnosis of multiple sclerosis.

spk_0 The reason that this was not published until 2001 is because just before that, in the 1990s,

spk_0 the first disease modifying therapies were finally approved by the FDA, the US Food and Drug

spk_0 Administration, for the treatment of multiple sclerosis.

spk_0 These were avinex, which is interferon beta and capaxone, which is glutereomer acetate.

spk_0 So now that we actually have something that we can treat these patients with, it became

spk_0 more incumbent to actually have a formal diagnostic criteria.

spk_0 The initial diagnostic criteria were relatively bare-bills.

spk_0 They just boiled down to, do you have dissemination in time and do you have dissemination in space?

spk_0 The McDonald criteria were updated in 2005 and again in 2010, as we discovered more things about

spk_0 the disease and as we recognized additional qualities about multiple sclerosis.

spk_0 I should note that concurrently around the same time, we really have the proliferation of multiple

spk_0 disease modifying therapies, both injected, infused, taken orally, that have become a lot more

spk_0 effective than the initial capaxone and avinex world that people were living in in the 1990s.

spk_0 If you want to refresher on disease modifying therapy for multiple sclerosis,

spk_0 we do have a prior episode, episode 30 of this podcast, which was done with one of our prior

spk_0 residents, Dr. Safa Abdel-Hakeem and our neuro-imminologist Dr. Aaron Longbreak, where they discussed

spk_0 the multiple sclerosis drugs that were out at the time. Though, of course, since that episodes come

spk_0 out, there have been a lot more drugs out there. I always love to start with a little bit of

spk_0 history and see kind of how the diagnosis and treatment of these very important neurological

spk_0 pathologies began. So we'll take it from our man, Sharko in 1868 and let's fast forward to

spk_0 the current world of MS in 2025. Do you want to take that away?

spk_0 Now let's dive into an important update in the field of multiple sclerosis that proposed 2024

spk_0 revisions to the McDonald criteria. Before we get into the changes, I want to set the stage by reviewing

spk_0 where we are now and why these updates matter. Let's start with the fundamental principle of MS

spk_0 diagnosis. MS is a diagnosis of exclusion. That means before we can confidently say,

spk_0 someone has MS, we must rule out all other possible mimics, things like neuromyalitis optical,

spk_0 small vessel disease, infections and metabolic conditions. This is critical because the diagnosis

spk_0 carries lifelong implications and we don't want to mislabel someone without being absolutely sure

spk_0 that they have MS or not. Once we've excluded other conditions, then the current gold standard we

spk_0 use to make the diagnosis is the 2017 McDonald criteria. So what do the 2017 criteria require?

spk_0 But someone to be diagnosed with relaxing remitting MS or RRMS, they need to have three important

spk_0 things. One is dissemination in space. So when I say dissemination in space, they need to have

spk_0 lesions that are present in different parts of the central nervous system. Two is dissemination

spk_0 time. When I say dissemination in time, there needs to be evidence that new lesions have developed

spk_0 at different time points. And more importantly, they must have had at least one clinical attack,

spk_0 what we call a clinically isolated syndrome. So a clinical attack or relapse is when someone develops

spk_0 a focal neurologic symptom that localizes to the central nervous system. You can be anything

spk_0 like the optic neuritis or a spinal cord syndrome like partial transphys myelitis. And the symptom

spk_0 should last for more than 24 hours. Ideally, we can see a corresponding lesion on MRI.

spk_0 Once someone has had their first clinical episode, we then look for radiologic or clinical evidence

spk_0 of dissemination space and time. What counts as dissemination in space? As of 2017, there are four

spk_0 key anatomical regions that qualify. One is peribentricular. Peribentricular lesions are those that

spk_0 literally touch the ventricle. Two, juxtacarticle, these are white metal lesions that abut the cortex

spk_0 often involving u-fibers. Three, infertentorial, which include the brainstem and the cerebellum.

spk_0 And four, would be the spinal cord. To meet dissemination and time, we can either wait for a second

spk_0 clinical attack to occur at a different time point or use MRI to show both and enhancing

spk_0 and non-enhancing lesion, indicating lesions are of different stages. Or alternatively,

spk_0 we could identify oligoconal bands in the CSF that are not present in the serum. This suggests

spk_0 there's ongoing CNS restricted inflammation. OCBs or oligoconal bands are helpful because they

spk_0 tend to persist in MS, whereas in conditions like NMO, they may come and go. But here's the issue.

spk_0 So this approach requires us to wait this dissemination and time, sometimes for a second attack

spk_0 or for multiple MRI changes to occur. So as many of us in the MS field know, this can delay

spk_0 diagnosis and importantly delay treatment. So research by my former mentor at UCSF showed that

spk_0 radiographic events often outnumber clinical attacks but about 10 to 1. And he coined the term

spk_0 radiologic isolated syndrome or RIS to describe patients who have MS-like lesions but no symptoms yet.

spk_0 The data suggests that about 75% of RIS patients go on to develop MS within 10 years.

spk_0 So under the current criteria, we might be waiting years or sometimes even a decade before

spk_0 intervening. But we also know that early treatment is key. Once information sets in, the damage to

spk_0 axons can be irreversible. The immune systems attack may be quiet on the surface, but it is causing a

spk_0 lot of harm underneath and we want to shut down the disease as early as we can. And this is the gap

spk_0 that the proposed 2024 McDonald criteria are trying to close. And before I get into what's changed,

spk_0 a quick caveat is that these updates have not been formally published. They are still proposed

spk_0 and might be revised further. So what are the proposed 2024 changes? One is the inclusion of

spk_0 the optic nerve as the fifth region. Kevin will be talking more about this later but I'm just going

spk_0 to give you a brief overview here. So optic neuritis is often the first presiding sign of MS.

spk_0 About 30% of patients start this way. Yet in the 2017 criteria, the optic nerve was encountered

spk_0 towards dissemination in space and that's changing. The optic nerve is heavily malinated and a

spk_0 logical addition. Evidence of involvement can be seen via MRI, visually above potential or

spk_0 optical coherence tomography. But a critical note here is that the optic nerve lesion should not be

spk_0 explained by other conditions. Kevin will talk more about this in detail later. So I'll leave it at

spk_0 that. The second thing that is changing is radiologically I said is syndrome or RIS is now

spk_0 considered MS. So if a patient has no clinical symptoms but has lesions fulfilling both dissemination

spk_0 space and dissemination in time, they're now diagnosed with MS, not just RIS.

spk_0 And even if they don't have dissemination in time but they have dissemination space,

spk_0 plus if they have six or more lesions with a central vein sign, they can still meet criteria for MS.

spk_0 So what is central vein sign? Central vein sign was developed by Danny Reich and esteem of the NIH.

spk_0 It is rooted in Sharko's 19th century observation that Kevin was talking about earlier

spk_0 that MS lesions often form around veins. By combining the T2 weighted images on MRI and the

spk_0 susceptibility weighted images where we can see veins, we can detect a hypointense vein running

spk_0 through the center of lesion. And that is what is a central vein sign. And for lesion to count as

spk_0 having a central vein sign, the vein must be literally at the center of the lesion and must be

spk_0 visible at least in two orthogonal planes. So it can be viewed as a dot in two planes and

spk_0 a linear vein in one plane. And if six or more lesions show the central vein sign and other criteria

spk_0 met, that can support a diagnosis of MS. And the fourth thing that is changing is CSF

spk_0 copper-free light chain as an Oligoclonal band substitute. This in labs where OCP testing is

spk_0 in standardized, now copper-free light chain can now be used. The sensitivity is comparable and it's

spk_0 easier to quantify. This opens up diagnosis in more global setting. And fifth thing that is

spk_0 changing is there's no need for dissemination time but in very specific situation. So

spk_0 dissemination time may be waived if the patient has symptoms and fulfills dissemination in space,

spk_0 but not in time. And in the dissemination space, if they have more than six lesions that have

spk_0 central vein sign, then there's no need for DID they have MS. Two, if they have symptoms,

spk_0 but no dissemination space they only have one topographic lesion, but they do meet the criteria

spk_0 for dissemination and time and have six or more lesions with central vein sign. Third, if they have

spk_0 symptoms, no dissemination space like the last time they have only one topographic lesion, but that

spk_0 lesion has one or more paramagnetic rim, then they have MS and they don't need to fulfill

spk_0 the submission time criteria. So I introduce the word paramagnetic rim lesions. So what are they?

spk_0 These are lesions that have chronic active inflammation often surrounded by ion-laden microglia

spk_0 macrophages. These can be seen on SWI as high-pointense rim surrounding lesion or on quantitative

spk_0 susceptibility mapping as a hyperintense rim. So these are the changes of the 2024 McDonald

spk_0 criteria. Before I conclude, I want to say a quick word about progressive MS while the McDonald

spk_0 criteria are mostly discussed in the context of relapsing MS, we are also evolving in how we

spk_0 define progressive MS. We now recognize MS as a spectrum, not just categories. Early disease

spk_0 tend to be inflammatory and leading to relapses. Later disease becomes more degenerative with fewer

spk_0 relapses and more steady progression. So in progressive MS, you must show at least one year of

spk_0 clinical progression, usually a slow worsening progressive myelopathy and in the scenario of evidence

spk_0 of dissemination in space, it can be fulfilled with two or more spinal cord lesions alone and they

spk_0 don't need to have all the topographical lesions. So the key takeaways that the field is moving towards

spk_0 earlier and a more accurate diagnosis using advanced imaging and CSR biomarkers to get ahead of the

spk_0 disease, but we still emphasize that MS remains a diagnosis of exclusion. You don't want to label

spk_0 someone with MS unless you've ruled out other explanations because the consequences of the label

spk_0 are profound, emotionally, medically and financially. Excellent update from Denesh. Now we are caught

spk_0 up on the entire history of MS from 1800s to the most recent 2024 criteria, but as Denesh briefly

spk_0 alluded to, there is a little bit of controversy and no better to talk about optic neuritis in MS than

spk_0 our upcoming neuroophthalmologist, Kevin yet. Billy calls this a talk. It's more of me ranting about

spk_0 eyes for 10 minutes. And as a reminder to our listeners about other conditions that can look like MS

spk_0 that evolved the optic nerves air and power. And I did do an episode on deweaks syndrome or neuro myelitis

spk_0 optic, expect from disorders and myelinolidodidocyte, like a protein antibody associated disease,

spk_0 which is episode 61 of this podcast that you can go back and listen to if you want.

spk_0 The reason that the optic nerve is included is because it makes sense for it to be included.

spk_0 It is a white matter track. If you remember from your neuro anatomy class,

spk_0 cranial nerves one and two are not true cranial nerves. They're not peripheral nerves.

spk_0 They're what matter tracked. The optic nerve is myelinated like the white matter of the brain.

spk_0 It's not myelinated with shwan cells like a peripheral nerve. It's not treated as a

spk_0 peripheral nerve. It's not susceptible to the things that peripheral nerves are susceptible to.

spk_0 It is basically a little bit of brain that's poking out from your eyeballs.

spk_0 So the same things that affect the white matter track in the brain can affect the white

spk_0 matter tracks in the optic nerve. So it makes sense that they're included in the new

spk_0 McDonald criteria. And this is not even an entirely new thing. Prior iterations of the

spk_0 McDonald criteria have included the optic nerve as a potential modality. The 2024, though at this

spk_0 point, it's going to be the 2025 or even 2026 McDonald criteria, have discussed ways that the

spk_0 diagnosis of optic neuritis can be made. And they suggest things such as MRI orbits,

spk_0 usually fat suppresses the modality that you want, visual evoked potentials, and optical coherence

spk_0 tomography. This part is going to be important to all of our listeners for the purposes of

spk_0 certification examinations such as the right, but practically in real life, you're not going to

spk_0 be using all of these modalities. Part of the goal of the 2024 McDonald criteria was to have a

spk_0 worldwide single set of diagnostic criteria that can be packaged up and used anywhere, regardless

spk_0 of the resource setting. So that's why things like visual evoked potentials are included,

spk_0 because it's relatively inexpensive to have someone do visual evoked potentials, while more

spk_0 accurate modalities might be harder and less common. That being said, in real life, at least in

spk_0 the United States, you're not going to be seeing people use visual evoked potentials that often.

spk_0 Practically speaking, it's hard to do visual evoked potentials well. They're very susceptible to

spk_0 operator error and artifact. That being said, you do have to know it for the board examinations,

spk_0 those who do study it up. Basically, what it boils down to is they want to show some evidence

spk_0 of optic nerve dysfunction on one of those modalities. So MRI, that can be enhancement of the

spk_0 optic nerve and the active phase or T2 hyperintensity to suggest chronic nerve damage.

spk_0 For visual evoked potentials, it's going to be of the delayed or decreased peak at the level

spk_0 of the optic nerve. And for optical coherence tomography, it's going to be thinning of a retinal

spk_0 nerve fiber layer or thinning of the ganglion cell complex if you're doing an OCT of the macula.

spk_0 The problem with these criteria and why you really have to be careful in using them is they

spk_0 will not differentiate optic neuritis from any other cause of optic neuropathy.

spk_0 Anything that damages the optic nerve will cause T2 hyperintensity on the MRI if it's severe enough,

spk_0 will cause delayed visual evoked potentials and will cause thinning of retinal nerve fiber layer

spk_0 on optical coherence tomography. So you really, really, really do have to be careful.

spk_0 Optic neuritis is not easy to diagnose. Technically, it's a clinical diagnosis. Vision loss

spk_0 with a relative effort, puberty effect, and either decreased visual acuity or decreased color

spk_0 vision and pain with eye movements. Technically, you can diagnose someone of optic neuritis just

spk_0 based on those criteria, but you really, really, really have to be careful because there's a lot of

spk_0 other conditions that can mimic optic neuritis. One of the more recent papers on the diagnosis of

spk_0 optic neuritis was published in 2022 in the Lancet's Neurology. It's called Diagnosis and

spk_0 Classification of Optic Neuritis, published by a cohort of authors led by Dr. Axel Petzelt.

spk_0 And if our listeners are interested, I'd encourage you to go find that paper and read it yourself.

spk_0 And it's a good guideline for sure, but you just really have to remember that all of these

spk_0 guidelines have the pitfall that you really have to know what you're looking for that you're not

spk_0 missing mimics. For example, T2 hyperintensity is a finding that can be seen in any severe

spk_0 optic neuropathy. There was a paper published in 2024, The Journal of Neuroophomology,

spk_0 by the Emory Group, by Fernando Lebella Alvarez, that showed that if you apply those 2022

spk_0 optic neuritis criteria to a group of patients that you know have non-inflammatory optic neuropathies,

spk_0 a good number of them will actually satisfy the diagnostic criteria. So that really shows that

spk_0 you really have to take the patient's clinical context and history into account when making this

spk_0 diagnosis. Also, Dr. Fernando Lebella Alvarez published another paper in 2024 that said that

spk_0 optic nerve T2 hyperintensity is entirely a non-specific marker of optic nerve damage. He looked at a

spk_0 lot of eyes that had various ideologies, including compressive inflammatory and even glaucoma

spk_0 dysoptic neuropathies, and a bunch of them had T2 hyperintensities. Again, T2 hyperintensity in the

spk_0 optic nerve is a very non-specific finding that you can think of just as a flare hyperintensity

spk_0 on the MRI in the brain. There have been a lot of patients who have been diagnosed with multiple

spk_0 sclerosis who really have something else. For example, someone with a lot of vascular risk

spk_0 factors, and this is a pretty common situation that we've seen, has several white matter lesions

spk_0 in the brain that are red as maybe perhaps a little more severe or a little out of proportion to

spk_0 what you'd expect for white matter disease. And they also have a non-arturitic anterior ischemic

spk_0 optic neuropathy. And then all of a sudden, you're saying, okay, you have white matter lesions, you have

spk_0 something affecting the optic nerve. It must be multiple sclerosis. Let's start you on disease

spk_0 modifying therapy. Don't do that. We've also seen patients who have white matter lesions, usually

spk_0 just one or two, that may be suspicious and maybe not who knows, who also have a coincident

spk_0 eye disease like severe glaucoma that causes T2 hyperintensity. And that gets treated as

spk_0 optic neuritis to satisfy the dissemination of the space criteria. There are a lot of patients

spk_0 out there who've been treated with disease modifying there before a punitive diagnosis of multiple

spk_0 sclerosis based purely on blindly following the criteria without really thinking about the bigger

spk_0 clinical context. So that's the one thing that I really want to encourage our listeners to think

spk_0 about as they take these guidelines out into the world and as they see patients. This is not the

spk_0 kind of stuff that you're going to see on certification examinations, but it's really the thing that

spk_0 you have to think about when you're seeing patients. Diagnosing optic neuritis is hard. Diagnosing

spk_0 multiple sclerosis is hard. As Dinesh said, it's a diagnosis of exclusion. So if you're going to

spk_0 say someone has multiple sclerosis based on something evolving the optic nerve, you really,

spk_0 really should be sure that it's optic neuritis. And if there's any doubt, ideally you can refer

spk_0 the patient to, for example, your local neuroophomologist who may be able to provide a little more

spk_0 guidance about what they think is going on. And I think that's enough of a rant about the optic nerve

spk_0 for now. So throw it back to Billy. Thank you, Kevin, for the well formulated rant from the

spk_0 neuropomology perspective. But nonetheless, very important when we discuss new updated criteria for

spk_0 any path of physiology within neurology that there may be pitfalls when they're first implemented.

spk_0 And just like Kevin said, it's really important to consider the entire clinical context of your

spk_0 patients. So we've now done a review history of MS from earlier stages to the most updated version.

spk_0 And now I think finished it up today. I really appreciate having both of you guys here on to

spk_0 the podcast. It's been a while since I've seen you both and lab were able to reconnect in this

spk_0 manner. I appreciate your time, Kevin, and to that. Yeah, thanks Billy, for having us.

spk_0 I was glad to come back and talk about something I enjoy. Hope you all enjoyed this episode.

spk_0 All right. Take care now. Bye.

Episode 75 - Diagnostic Criteria for Multiple Sclerosis

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