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Familiarity with the clinical, MRI, CSF, and serologic features of MOGAD can help neurologists recognize this condition in clinical practice. Awareness of the utility and pitfalls of the MOG antibody test is critical. The current therapeutic approach is guided by retrospective studies and the application of immunotherapies used in other autoimmune neurologic disorders.
In this episode, Gordon Smith, MD, FAAN, speaks with Eoin P. Flanagan, MBBCh, coauthor of the article "Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease" in the Continuum® April 2026 Multiple Sclerosis and Related Disorders issue.
Dr. Smith is a Continuum® Audio interviewer and a professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.
Dr. Flanagan is a professor of neurology and the division chair of the Division of Multiple Sclerosis and Autoimmune Neurology in the Department of Neurology at Mayo Clinic in Rochester, Minnesota.
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Read the article: Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease
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Host: @GordonSmithMD
Full episode transcript available here
Dr Smith: So, what neurological disorder can cause bilateral optic neuritis, transverse myelitis, ADEM, or can mimic acute flaccid myelitis, intracranial hypertension, viral encephalitis, or cause seizures? Sounds like the great imitator, perhaps. If you want to know and learn more about this syndrome and how you can treat it---and it is very treatable---keep listening. My name is Gordon Smith, and today I have the great opportunity to talk with Dr Eoin Flanagan from the Mayo Clinic on his article on myelin oligodendrocyte glycoprotein antibody associated disease, or MOGAD, which is in the April 2026 issue of Continuum on Multiple Sclerosis and Related Disorders. 
Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.
Dr Smith: This is Dr Gordon Smith. Today I'm interviewing Dr Eoin Flanagan about his article on myelin oligodendrocyte glycoprotein associated disease, or MOGAD, which appears in the April 2026 Continuum issue on multiple sclerosis and related disorders. Eoin, welcome to the podcast, and please introduce yourself to our audience. 
Dr Flanagan: Yeah, thanks so much. I'm Eoin Flanagan. I'm a neurologist at the Mayo Clinic. I'm originally from Ireland. I work in the neuroimmunology lab at the Mayo Clinic, and work and see patients with MS, MOG, and autoimmune disorders here in Rochester, Minnesota. 
Dr Smith: Your article is super interesting, I think, and this has been a really rapidly evolving area over the last, you know, many years. We have many more antibodies, and MOG is something that's been around for a while, but we've certainly learned a lot more about it. This is a topic that I think will be familiar to most of our listeners, but I wonder if maybe you can just begin by laying the foundation. Like, what is MOG? What's its typical presentation?
 
Dr Flanagan: So, MOG is a protein on the surface of the oligodendrocyte or its CNS myelin, and it was always of interest as a potential antibody target, and initially it was investigated in multiple sclerosis. But subsequently, we recognized that the antibodies to MOG have a specific syndrome, of which about a quarter of patients are pediatric and then the remainder are adults. And they can present with a variety of syndromes, probably most commonly optic neuritis, but also acute disseminated encephalomyelitis, or ADEM. Transverse myelitis can also occur, and then some other unusual brain and brainstem cerebellar syndromes can also occur.
 
Dr Smith: I was really impressed in the very broad phenotypic spectrum of MOG. We'll talk more about that, of course. But I wonder if maybe you can tell us when we should be ordering MOG antibody? Given this broad variability, does anyone who has a CNS demyelinating disease need a MOG assay, only specific phenotypes? What guidance do you have for our listeners?
 
Dr Flanagan: Yeah. It's a great question. So, I think you have to be a little bit careful because the MOG antibody test is a little bit sticky. So sometimes we can see some low-positive false positives. So, we don't wanna order it in every single patient with classical MS. So, I suppose we'll start with who not to order it in. I think it's also a very optic nerve- and optic neuritis-central disease, so I think you really need to be considering this in a patient with optic neuritis who does not have lesions in the brain suggestive of multiple sclerosis. And then we think about some of the features: if the lesion, the enhancement along the optic nerve is long, if it's bilateral, if there's a lot of optic disc edema accompanying that, we tend to think about MOG antibodies. And then children with demyelinating disease, MOG is over-represented in that cohort, so it accounts for about a third of those. So, if you have a child with CNS demyelinating disease, particularly if they're under twelve, with ADEM presentations or other presentations, you probably want to be ordering the MOG antibody test. And then a longitudinally extensive transverse myelitis in adults, certain types of cerebral phenotypes that we can get into, you would want to consider ordering MOG antibodies too.
 
Dr Smith: Now, you point out in the article that it's really important that laboratories use the cell-based assay for MOG as opposed to an ELISA, for instance. Is this something folks need to be very attentive to, or are all of the commercial laboratories now using a cell-based assay?
 
Dr Flanagan: Yeah. I think all of the commercial labs are using cell-based assays, so we don't really get into much of an issue. There are some differences between serum and CSF, so really, serum is the optimal sample to order. There is also some differences between the live cell-based assay and the fixed cell-based assay, where the live cell-based assay may have some advantages in terms of sensitivity. And then CSF is kind of still under evaluation about its role in the condition. So in general, it's a serum test. And then we have to remember that the antibody tends to be highest at the onset, and then it goes down over time. So, if you delay your testing or you're testing a patient long after the condition, it can go negative, for example. So it tends to be highest both around the relapses and particularly at the onset of the condition.
 
Dr Smith: You mentioned earlier that the test is sticky, which I take to mean that there is some risk for low-titer false positives. How do you navigate that situation? When should we be suspicious about a false positive?
 
Dr Flanagan: Yeah. I think there's some very useful features that can help you. You know, the main differential diagnosis is going to be multiple sclerosis, particularly in the US, in regions of the northern US where MS is particularly common. So, you really wanna be making sure that if you get a positive result, low positive, that it's not multiple sclerosis. And some of the best discriminating features are CSF oligoclonal bands. They're about 85% in MS and about 15% in MOG, so an easy number to remember, 85 and 15. And then the lesions in MOG, the brain lesions, tend to disappear over time. So, if you have the advantage of that follow-up MRI a year down the line, about 70% of lesions in MOGAD will resolve, while in MS, as we know, the term means multiple scars, so the MS lesions tend to persist over time. So, they are two quite useful features that can help discriminate.
 
Dr Smith: And how about specific phenotypes or areas of involvement or imaging abnormalities that suggest MOG? One of the things I found really interesting in your article is there are a host of different syndromes that I think had largely been previously described, many of them, that became clear later that these were really tied to MOG antibodies. Presumably, that's helpful in interpreting the antibody assay in that patients who have, perhaps, a borderline low titer, for instance, but have a very typical phenotype are more likely to have MOG than those who have a more clearly MS-type phenotype.
 
Dr Flanagan: Yeah, absolutely right. Yes. So, there's certain phenotypes that we don't tend to see with MS. The acute disseminated encephalomyelitis, or ADEM, is one that's particularly common in children. And about half of people that have ADEM will be positive for the MOG antibody. So that's a syndrome you need to look out for, which would be often in children, encephalopathy, and they would have multifocal white matter lesions, sometimes involving the gray matter. A second syndrome that was an interesting discovery from a Japanese group was this unilateral cerebral cortical encephalitis, where patients can have this swelling and T2 hyperintensity, often just on one side of the brain. And it's in the cortex, and some of those patients won't have any white matter lesions. And in that situation, it's important to order the MOG antibody, and that seems to be a specific phenotype of MOGAD. But sometimes people don't think about it because the white matter is not involved. So, if you see these patients, they often present with seizures, sometimes they even have fever accompanied by it. And if you see those patients and see this radiological feature, then you really want to consider ordering the MOG antibody too.
 
Dr Smith: Yeah, I found that really interesting. And I- actually, my next question is perhaps a good follow-up on that, is, what are the diagnostic pitfalls? You give a lot of examples of situations and I think some cases where it's easy to get tripped up and misdiagnose someone who has MOG with another fairly common neurological problem.
 
Dr Flanagan: Yeah, I think some of the things that can help you when you're determining if the MOG is a true positive or false positive is the level of the antibodies. The super high titers, if it's a clear positive or very strong positive, the likelihood is that that is much more likely to be MOGAD than those low positives just above the cutoff. So that can be useful to help you discriminate from false positives. Those lesions, again, if all the lesions persist over time, that's going to be more suggestive of multiple sclerosis. Other diagnostic pitfalls, I suppose, if it's a syndrome that's not really associated with MOG, like peripheral neuropathy or other syndromes where we'll see some case reports, but usually I would be very cautious about those kind of presentations. So usually, having the antibody at a high level, and then also if they've had other symptoms suggestive of MOGAD, like if a patient has had recurrent optic neuritis and then they have an unusual brain syndrome, or they start out with an unusual brain syndrome and then have recurrent optic neuritis. You know, there are situations that make it more likely if they're having other typical phenotypes of the MOGAD where we can kind of expand the spectrum, but we have to be careful.
 
Dr Smith: I was really curious about the dynamic imaging findings. And you point this out both in terms of the resolution of imaging findings, but also in that patients who have an acute MOG syndrome often have very rapid evolution of the imaging abnormalities. I'm just curious, you know, why is that, and what do you make of it? Does it have a mechanistic implication, do you think?
 
Dr Flanagan: I don't think we know for sure. I think there's probably a lot more happening than we see on MRIs sometimes. What sometimes can happen in about 10% of patients is the initial MRI can be normal. We don't tend to see that with multiple sclerosis or NMOSD. Then what we see is it evolving over time. So, at that time, if you do a CSF, you'll often see inflammation, but we don't see the lesions. Now, that might be because the MRI is not very good at picking up cortical involvement. That can be difficult to see in MRI. Or there could be other factors. It could be a functional effect on the MOG but without frank demyelination yet, for example. Or there could be edema that you- myelin edema that you can't see as a lesion yet on MRI. But we do see that if you repeat the MRI, sometimes it'll change a lot. So, you may go from one or two lesions on the first MRI to twenty lesions on the second MRI a week later. So, it does tend to change a lot. And then over time, those lesions also resolve. So, what I say is if it's a very suspicious situation---like a child comes in with new-onset encephalitis, has inflammatory CSF---you might wanna consider repeating that MRI down the line and seeing if it's changing. And then over time, you know, a repeat MRI a year after the onset when there's brain or spinal cord lesions can be very helpful just to make sure you're on the right track, because lots of those lesions will then disappear, and that's a very clear discriminator from multiple sclerosis.
 
Dr Smith: Yeah, thanks. I mean, I was wondering the same thing about whether that particular feature might imply, you know, a functional abnormality as opposed to more of a structural abnormality. So probably a lot more to learn as we move forward. There are now consensus diagnostic criteria that were published a couple of years ago. I think you've already touched on kind of the general approach, but do you want to speak to those? I found your summary pretty helpful.
 
Dr Flanagan: Yeah, I think that those criteria are quite useful. They have three main parts to them. The first part is having a characteristic clinical syndrome. So, we talked about ADEM, we talked about cerebral cortical encephalitis, transverse myelitis that's often longitudinally extensive, and optic neuritis being the main syndromes, but sometimes other brainstem or cerebellar involvement can be seen. And then the second part is having a positive MOG antibody. And then there's some caveats there. So, if you have a high positive, then you don't really need any additional supportive criteria. On the other hand, if you're low positive, to get at those sticky antibodies that make sure it's not a false positive, you need some additional supportive clinical or MRI criteria. Or if you're only positive in CSF, you need that additional criteria. You also need to be negative for the aquaporin-4 antibody, because they can overlap clinically. And some of those supportive criteria are things that we talked about a little bit earlier, longer lesions within the optic nerve, bilateral involvement, involvement of the nerve sheath or optic disc edema. This is a situation, MOG antibody disease, where your fundoscope is useful and looking in the back of the eye and seeing swelling, because we don't tend to see that quite as often. It's less common in multiple sclerosis, but we often see prominent edema in MOGAD. And then in the spinal cord, the lesions tend to be central in the cord. Sometimes they form this H sign where it's restricted to the gray matter, and they tend to be longer, sometimes involving the conus. Patients will often have neurogenic bowel or bladder. And then in the brain, deep gray involvement, those large lesions along the cortex with swelling are some of the typical features. And then the final step is exclusion of another diagnosis. Just like with any test that we do in neurology, our final step is going to be to put that into context. So that's just a normal thing that we will always do when we get a group of test results back that we don't know what it means. We have to put it into context. So, make sure it's not multiple sclerosis, everything else does not look like multiple sclerosis, and then you can be on your way to make a diagnosis.
 
Dr Smith: Definitely encourage listeners to read your article. I guess I say that with every time I- or with everyone I talk to for Continuum Audio, but the images are really fantastic and the cases are fantastic. So, everything you've described is well-illustrated, including really nice schematic sort of diagrams that help differentiate NMO from MOG and MS. So, if you like MRI scans and good imaging frameworks, then this is the article for you.
 
Dr Flanagan: I think that's true, and the other thing is that the imaging is quite helpful because it takes a while for that antibody to come back. We're lucky at Mayo Clinic, if you work here, it, it comes back faster for you. But for many places, that time of sending it in, so a lot of times you don't know right away. So, looking at scrutinizing that MRI can be very helpful to guide you on your way and to know what you're dealing with and how to approach both the acute treatment and plans to have potentially a steroid taper after the acute treatment and those kind of things that can help guide you in that regard.
 
Dr Smith: Yeah. So, let's talk about treatment. You know, what's your approach to treating a patient who has an acute demyelinating syndrome related to MOG?
 
Dr Flanagan: So similar to other things, MOG is very steroid responsive. So, we use high-dose IV methylprednisolone in adults. That would be one gram IV for five days. And then we also will sometimes use oral steroids, twelve hundred and fifty milligrams. That's a bit of a hassle because it's twenty-five fifty-milligram tablets, it doesn't come in a larger tablet version. But it's very helpful to patients because they can get started on it right away. You don't have to set up an infusion center. So, we have used those oral steroids often in people who don't have access to an infusion center, are not in the hospital. And particularly as it's often optic neuritis, some of those patients are seen in the outpatient setting, so we can get in with treatment quickly. In patients where it's more severe, it doesn't recover quickly with steroids, then we would consider escalating to plasma exchange as our second-line treatment, and there's some retrospective data that suggests that plasma exchange can be useful. That's gonna be particularly for those people who don't have that quick response to steroids, or maybe more severe phenotypes like that brain involvement with ADEM or cerebral cortical encephalitis, where those patients might be in the hospital and quite unwell. I will say, we might get on to this, that sometimes MOG can be very, very severe and even fulminant, where there can be increased intracranial pressure, and these patients can be in the ICU, and it can be life-threatening. And so, it's really important to treat those patients aggressively, and some patients have even required hemicraniectomy or additional treatment. Sometimes IL-6 blocking medications have been used in that situation. So, monitoring and treating increased intracranial pressure in those rare patients, probably 2 or 3% that have the very severe attack, is important.
 
Dr Smith: I think one of the things I found interesting, and then I'd love to get your feedback on this, is that most patients with MOG seem to have a very readily treatable disorder that's monophasic, right? You treat them with steroids, and they do well. On the other extreme, there are these patients that have a much more malignant presentation, and there are some that sound like they benefit from prophylactic or some chronic therapy. What's your approach, right? In MS, we do serial scans to monitor, and obviously, our patients are on, you know, chronic disease-modifying therapy. How do you decide when you're going to provide some sort of prophylactic therapy? How do you monitor it? How long do you continue it?
 
Dr Flanagan: That's a great point. We don't know for sure yet, but I think for the most part, our approach has been if the patient has a single episode, they recover well from that episode. So, if that's optic neuritis, they're back to twenty/twenty vision. They have recovered well. We don't tend to use chronic maintenance immunotherapy. Sometimes after the first attack, we'll do a little bit of a slow taper, maybe over four, six weeks. We have done longer than that. And then we won't place them on any long-term treatment, because it's about 50% of patients that may have a monophasic disease, so we don't want to treat all those people who are destined never to have another relapse. On the other hand, if a patient had a very severe episode, they're in the ICU, they're intubated, some of those patients then afterwards we will start them at least temporarily on an attack prevention medication for at least a few years to get them through. Some patients will be very fearful of future relapses in that situation. Or if they don't recover well, if they're blind in one eye after an episode and then their other eye is vulnerable, or they're left with some residual deficits neurologically from a myelitis, then we would often sometimes put those patients after the first attack. But most of the time, we're gonna wait and see if they get that second attack, and then once they have the second attack, that is when we would consider a steroid-sparing medication. But I will say that there's no proven medications. We don't have any clinical trial data available yet. So some of those patients with relapsing disease, we'll either try to enroll them in a clinical trial, or we'll use an off-label treatment to try and manage their disease based on what we've learned from neuromyelitis optica or from multiple sclerosis. A few different options seem to be better, and we can maybe get into that too.
 
Dr Smith: Yeah, let's go there. So, what options are there? You mentioned in more fulminant disease IL-6 inhibitors, and by that I assume you mean tocilizumab, but what are the options when you want to use prophylactic therapy?
 
Dr Flanagan: So, that tocilizumab can be beneficial in the very acute situation, in that malignant situation. But also as an attack prevention treatment, the IL-6 blockers seem to- some of the retrospective data seems to look like it works reasonably well, so we work and see if we can get that approved. Another medication that can work well is IVIG or subcutaneous immunoglobulin as a maintenance treatment, so we would sometimes give that, like, at least one gram per kilogram once a month. The benefit of that is it doesn't lower your immune system, so there's some advantages there, particularly in people who may be more prone to infections, older people. So, we'll sometimes use that. But we do get into a lot of challenges with insurance coverage, and it can be difficult to get these approved by insurance because we only have retrospective data out there. So then for some patients, if they're in a region where there's a clinical trial available, we might try to enroll them in a clinical trial. And there are some clinical trials underway now, so hopefully in the future we'll be able to have some FDA-approved medications that can have some Class 1 data that we can follow. Because it's hard when you're just following retrospective data or anecdotal reports, it's a little bit difficult to know exactly how well you're doing with your treatments.
 
Dr Smith: Well, Eoin, I wonder if we could finish up by just looking into the future, right? I mean, it sounds like a fun patient population to take care of because you've got lots of great therapies and can have a durable impact. But sure would be nice to have more evidence-based therapies and an FDA approval. What trials are going on? What's the future look like?
 
Dr Flanagan: Yep. So, there's some trials going on in the- a couple of worldwide trials. One is on an FCRN blocker called rozanolixizumab, which is kind of like a plasma exchange-type treatment which removes your antibodies, and it's a weekly subcutaneous treatment where adults are enrolled. And the second one is called satralizumab, which is another IL-6 blocking medication. And again, that one's given once monthly under the skin. And the trial for that also includes children down to age eighteen, so for adolescents, too, that can be an option. There are trials, I believe, in Asia for tocilizumab too, and there's one starting in Australia for rituximab. So, the good news is that we're going to have some really good data down the line for lots of different agents, and we'll be able to figure out which treatments work. And this will be really of great benefit to our patients when we get that Class 1 data to kind of guide us on what we should be using and really build on the success of some of the other conditions like neuromyelitis optica spectrum disorder, where we now have four or five approved, medications that work very well.
 
Dr Smith: Well, Eoin, thank you. This is a great conversation. I will say that it... the topic that I was a little intimidated about. I'm a simple peripheral nerve guy, as you know. But I think moreso than any other Continuum article I've read recently, I'm, like, loaded for bear. I can't wait to go back on the inpatient service and look for some MOG patients, because your article really left me feeling kind of prepared to think through this in a clinical setting. So, thank you for the conversation, and congratulations on a really wonderful piece for Continuum.
 
Dr Flanagan: Yeah, thanks so much. Always a great honor to be involved in the Continuum, and thanks to all the readers out there.
 
Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Adult‑onset leukodystrophies, though rare, can closely mimic MS on both clinical presentation and neuroimaging, posing a significant diagnostic challenge. This episode highlights key clinical and radiologic red flags that can help distinguish these disorders from MS, preventing misdiagnosis and avoiding inappropriate treatment while enabling timely genetic counseling and targeted therapies.
In this episode, Teshamae Monteith, MD, FAAN, speaks with Roberta La Piana, MD, PhD, coauthor of the article "Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis" in the Continuum® April 2026 Multiple Sclerosis and Related Disorders issue.
Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida.
Dr. La Piana is an associate professor in the Department of Neurology and Neurosurgery at the Montreal Neurological Institute, McGill University, and an associate member of the Department of Diagnostic Radiology at McGill University in Montreal, Quebec, Canada.
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Read the article: Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis
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Full episode transcript available here
Dr Monteith: You just saw a patient in clinic. And you're clear, the diagnosis is multiple sclerosis. Not everything fits, but it kind of looks like multiple sclerosis. You see the patient back years later. There're some treatment issues, the patient's not responding to treatment, and things look different. Have you thought about a genetic inherited problem like leukodystrophy or a genetic white matter disorder? Listen to this podcast. We're going to help you figure it out.
Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.
Dr Monteith: This is Dr Teshamae Monteith. Today I'm interviewing Dr Roberta La Piana about her article on adult-onset leukodystrophies mimicking multiple sclerosis, which she wrote with Dr Gabrielle Macaron. This article appears in the April 2026 Continuum issue on multiple sclerosis. Welcome to our podcast. 
Dr La Piana: Thank you. Thank you for having me. 
Dr Monteith: Absolutely. Why don't we start off with you introducing yourself?
Dr La Piana: So, my name is Roberta La Piana. I'm a pediatric neurologist. I trained in Italy, I did my medical school, I did my residency in pediatric neurology there. And then I moved here to Montreal, to the Montreal Neurological Institute, to do a PhD in neuroscience. And that's where I specialized in adult-onset genetic white matter diseases. And after my PhD, I was recruited as an assistant professor here. So, that's where I got into this field. 
Dr Monteith: This big field, highly specialized; lots of disorders, but highly specialized. And what got you into this? Neuroscience is huge. So, was it a mentor, or…? 
Dr La Piana: No, actually, it was because of my background, because I trained as a pediatric neurologist and I loved the genetic white matter disorders in the pediatric population. So, when I came to the Montreal Neurological Institute, initially it was mainly to have a better expertise in imaging. And being at an adult neurology institute, I started seeing patients with adult genetic white matter diseases, and I was immediately fascinated by how different they were from their pediatric counterparts. Because in pediatric genetic white matter diseases, pediatric leukodystrophies look very diffuse, look very confluentous, so it's difficult to mistake them. But in adults, in the adult forms, I was initially driven by how often they can be misdiagnosed as multiple sclerosis or as other acquired white matter disorders. So that's why I got really interested in in this field. 
Dr Monteith: You're, like, literally the perfect person for this discussion. 
Dr La Piana: I'm not sure- *laughs*
Dr Monteith: Why don't we start off with what your objectives were when writing this article?
Dr La Piana: With writing this article, the goal is what I have been, actually, doing for the past ten years or so. So, really try to get more attention into the field because of the high rate of potential misdiagnosis of patients. So, that's exactly the reason why I really would like to raise the interest of neurologists for these disorders, because they are not considered enough in the differential diagnosis of patients, of adult patients presenting with white matter disorders. They are considered rare---which are, they are rare, definitely. But collectively, while each single form is rare, collectively they are not as rare. So- and thus, the risk of misdiagnosis and the potential impact of misdiagnosis on them with, you know, you can imagine giving patients inappropriate treatment or missing the possibility of a prenatal genetic diagnosis is so high that I really would like people to keep these disorders in the differential. 
Dr Monteith: And it sounds like more than ever, this is really important because some of the newer developments in the field.
Dr La Piana: Yes. Specifically, we have now tools that will allow to diagnose these patients quite quickly. All the genetic techniques that are available nowadays can really, with one single shot, we can now sequence hundreds of genes so we can have a quicker diagnosis. And this thing was impossible up until ten years ago. So that's definitely the first huge improvement that makes these disorders now easily diagnosed.
Dr Monteith: Yeah. So why don't we talk a little bit about how common is this misdiagnosis for these rare subtypes?
Dr La Piana: Yeah, the misdiagnosis, it depends on the cohorts. Generally speaking, I would say that the rate of that misdiagnosis for these forms is up to 25% or even more in some other cohorts. And it really depends on the forms. Like, there are clearly some forms, especially those that present with multifocal white matter diseases, that present with nonspecific clinical presentations like migraines, image---and especially for female patients, and for which migraine is so common, having multifocal with other abnormalities is so common, the rate of diagnosis increases even further. So, these are all things that we need to keep in mind. I know these are rare, but still, we need to always have them on the back of our minds. 
Dr Monteith: Are there any particular disorders that are more often misdiagnosed? And you spoke about progressive forms of multiple sclerosis being a common kind of misdiagnosis. 
Dr La Piana: Yeah. So, there are definitely forms that are more commonly misdiagnosed. And these are those that, as I probably repeated already too many times, is the word multifocal, which is key. So, all those genetic white matter disorders that present with multifocal white matter abnormalities are not initially considered as genetic. So, I'm thinking about all of the leukovasculopathies, so, the small vessel diseases which are genetic in origin. For example, CADASIL; for example, the disorders related to collagen-4; so, the COL4 A1 or A2-related disorders. Those are clearly more commonly misdiagnosed initially. Another big group, unfortunately, is the CSF1R-related disorders. I know I'm saying a lot of gene names, but due to the fact that they start with multifocal abnormalities and they start with quite nonspecific, slowly progressive symptoms, the rate of misdiagnosis is definitely higher.
Dr Monteith: And can you discuss some of the clinical challenges when seeing patients that might lead to this misdiagnosis? 
Dr La Piana: There are multiple clinical challenges. One is definitely the presence of nonspecific or initially mild clinical symptoms that sometimes don't raise initially the red flag of something, degenerative or progressive or genetic. One category that I would mention are psychiatric disturbances, especially in the form of depression, anxiety, or apathy. This is quite common in patients with some forms of genetic white matter disorders, and they are initially misdirected to psychiatrists and taken care in that domain. But it's only when some even mild neurological symptoms like a gait disturbance or hyperreflexia, or we had patients with, like, a urinary incontinence. It's only at that time, but maybe years have passed meanwhile, that these patients are finally referred to the neurologist
Dr Monteith: You spoke about some of these clinical symptoms. Can you give us some other clinical red flags? 
Dr La Piana: Well, some other clinical red flags can be, for example, the extraneurological involvement. So, we have patients where- and there's a reason immediately to some specific disorders. For example, infertility. The presence of infertility in a female patient with white matter disorders should immediately form the consideration of the specific genetic white matter diseases that are associated with these forms. And this is not something that neurologists tend to ask about in the collection of the clinical history. And this is something that can make the difference and can accelerate the diagnosis. 
Dr Monteith: What are some other things? I mean, I know we can think about treatment, lack of a common treatment response, maybe, to steroids. You gave a great example of optic neuritis, for example. Give us some other things that we should say, hey, this doesn't fit the picture. Red flag. 
Dr La Piana: In this case, I think we want to talk more about the specific misdiagnosis of MS. Because these patients are often misdiagnosed with MS, but they might sometimes be misdiagnosed with other forms of acquired white matter diseases. When we consider MS, definitely the presence of being treatment resistant: so, patients that are not responsive to the common MS-targeting treatment should be always a red flag. The evolution as well. So, for example, the presence of a more slowly progressive course is another red flag. The presence of optic neuritis. Sometimes it's tricky because it's not common in the genetic white matter disorders, it's used as a criterion to orient correctly towards a multiple sclerosis. But we need to keep in mind that there are forms, genetic forms, especially the mitochondrial forms, that can present with optic neuritis and are really at the overlap with the multiple sclerosis spectrum. Then, if we want to move forward beyond the clinical side and go into the laboratory, of course a negative lumbar puncture with no oligoclonal bands should be a major red flag.
Dr Monteith: What about some of the radiographic features? 
Dr La Piana: So, the radiographic features is something we are really working on in the field, especially with the new criteria used in MS. So, for example the paramagnetic rim lesions or the central vein sign, they are considered the specific forms. But it's true- and don't have an answer for that. I want to be clear, but it's true that they haven't been assessed yet extensively in patients with genetic white matter disorders. Anecdotally, I can say, because I have already reported this at conferences, that we have seen patients with genetic white matter conditions reaching a threshold for a central vein sign that can be considered diagnostic for MS. And we have seen that in some patients. Again, no study has been carried out extensively to date, but I think we should consider that with a grain of salt. But yeah, the paramagnetic rim in lesions is probably more accurate to distinguish between genetic and acquired white matter disorders. 
Dr Monteith: And what about some of the genetic white matter disorders that mimic MS? You spoke about things like CADASIL; what are other things that we should keep in the back of our mind? And you have great charts, to our listeners, and they're going to have to review those charts, because they're excellent. I think maybe they need to find a way to make that a little bookmark you walk around with on the ward. But what are some other conditions that kind of commonly mischaracterized? 
Dr La Piana: Two of the main groups are the one that you mentioned. So, leukovasculopathy is- so, CADASIL, is definitely one of the most common misdiagnoses of MS. And the presence, as we said, of some clinical features like migraine, especially when it's complicated migraine with visual aura, we all know that. But especially in the context of a positive family history for either a psychiatry condition or migraine as well, or strokes, these are all factors that should prompt the consideration of these disorders in the differential of a patient with white matter disorders. Another category are definitely mitochondrial disorders, which I think are more neglected than others because we don't think about mitochondrial disorders when we see white matter disease; we tend to consider that mitochondrial disorders are a problem of the gray matter, but they are not. There are white matter diseases that have definitely mitochondrial. And the third category are probably microgliocytes, which are represented by the CSF1R-related disorder. And this is also something that is clearly quite prevalent, relatively prevalent, in the field of genetic white matter disorders misdiagnosed as MS. 
Dr Monteith: Yeah. Why don't we go through some of the, kind of, key history, you know, some of the key questions you would ask in the history to try and differentiate? You mentioned kind of subtle symptoms, longstanding progressive symptoms. I know things that we look at like relapsing/remitting and some trigger factors can actually be associated with some of these genetic disorders. So how do you approach a patient? What are some of the key questions? You talked about family history and you talked about medical history, but why don't you kind of give us a nice way to kind of hone in on to the patient?
Dr La Piana: There are a couple of questions that we usually ask. I should make a disclaimer, though, that I work very closely with the MS clinics, so we are ready to receive patients that are prescreened. So, these are already patients that people working on acquired white matter disorders feel like they are atypical, so they want our opinion. But usually, there are two groups of questions that we always ask. One is about the family history. And by saying family history, I really dig into the family history. I don't just want to know whether there are family members with neurological disorders. I ask specifically about migraine. I ask specifically about infertility issues. I ask specifically about psychiatric issues. These three things are always on the top of my mind when asking about family history. The other thing is a family history for neurodevelopmental disorder, because you know that some people might not remember that some genetic white matter diseases can present at different ages. So, in the same family, there might be cases with a pediatric-onset leukodystrophy, and that can manifest at a later age in other family members. So, this is something that we always explore. In terms of the clinical history, one question that I recommend always to ask is really about more subtle symptoms. So, for example, many of our patients present with progressive balance problems or progressive mobility issues that have been going on for a while. So, we always ask how they were when they were in their teenage years, for instance. And it's frequent that they say, actually, I was a bit clumsy. Actually, I was not the first being picked in school at phys-ed sports. And these are all interesting aspects. Maybe they are totally incidental, and sometimes they suggest that there was probably something going on for a long time. The other thing is the presence, for example, of learning difficulties. Again, these are things that are subtle but testify that there was probably a process that was more longstanding.
Dr Monteith:  You talked about things like rim lesions. Are there other types of sequences that might be useful to better characterize demyelinating diseases that are genetic in origin? I assume higher levels of MRI might be better at differentiating. 
Dr La Piana: Yeah. So, in the clinical setting, there are a couple of sequences that are very useful. One is the diffusion, because as opposed to multiple sclerosis, the presence of persistently restricted areas of diffusion can point immediately towards some genetic white matter diseases. One is CSF1R-related disorders. But there are also some other, more rare tremor and ataxia syndrome that present with persistent areas of restricted diffusion as well as others. The presence of calcification. So, adding an SWI, susceptibility weighted imaging, to check not just for calcifications that can immediately orient towards some disorders, but can also identify areas of microhemorrhages that, if we are going back to the leukovasculopathies, to the genetic leukovasculopathies, can tell us that we are on the right track for excluding those type of diseases. Basically, these are the two that are available in every scanner without even going into fancy, more advanced techniques.
Dr Monteith: I was going to ask you that question, how often should we think about this next-generation sequencing when you're kind of on the fence, allowing for some negative results to come back in the abundance of caution? 
Dr La Piana: The problem with the panel, of course, is that you run a panel and you don't know what's coming back. So, then having to deal with variants of unknown significance in genes, then you have to deal with them, and then you have to deal with results that maybe are not as black or white as you would expect initially. So, I'll answer to your question when to do that, our recommendation would be to do that every time you are presented with a patient that presents those atypical features that we summarized in the paper, and that basically raise multiple red flags for an atypical white matter disease that is not multiple sclerosis. And then what to do when you have results? I still believe that having access, of course, to genetic counselors, to neurogeneticists, is critical, but also having access and being in contact with the network of people working on this. Because we are a network; we put the website address on the paper of the white matter rounds because this is an international network that we built over the years, and we connect monthly, on a monthly basis, with meetings to discuss exactly this type of patient. So, we are all learning together, and it's very frequent that people ask us to present cases at the white matter rounds because they have a presented with unusual or atypical genetic findings and they want the opinion of experts. 
Dr Monteith: Great. Well, I'm really glad that resource is available. And I'm also really glad that you wrote that article with your colleague. Thank you so much.
Dr La Piana: Thank you so much, Tesha.  
Dr Monteith: Today I have been interviewing Dr Roberta La Piana about her article on adult-onset leukodystrophies mimicking multiple sclerosis, which she wrote with Dr Gabrielle Macaron. This article appears in the April 2026 Continuum issue on multiple sclerosis. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today. 
Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Novel MRI biomarkers, including cortical lesions, the central vein sign, and paramagnetic rim lesions, are highly specific for MS and can aid diagnosis in select clinical scenarios, particularly early in the disease course or in atypical presentations. When used with appropriate MRI sequences, these markers can improve diagnostic sensitivity while helping prevent misdiagnosis.
In this episode, Casey Albin, MD, speaks with Jiwon Oh, MD, PhD, FRCPC, FAAN, author of the article "Diagnostic Neuroimaging Biomarkers for Multiple Sclerosis" in the Continuum® April 2026 Multiple Sclerosis and Related Disorders issue.
Dr. Albin is a Continuum® Audio interviewer, associate editor of media engagement, and an assistant professor of neurology and neurosurgery at Emory University School of Medicine in Atlanta, Georgia.
Dr. Oh is the medical director of the Barlo Multiple Sclerosis Program at St. Michael's Hospital and an associate professor at the University of Toronto in Toronto, Ontario, Canada.
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Host: @caseyalbin
Full episode transcript available here
Dr Albin: Spend any time in a neurology conference, and you are certain to hear about the new central vein sign, which, as I learn, is not actually all that new. But have you heard about cortical lesions or these paramagnetic rim lesions? Because today I have the privilege of talking to Dr Jiwon Oh about her article, and we're going to unpack all these new biomarkers in MS.
Dr Jones: This is Dr Lyell Jones, editor in chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.
Dr Albin: Hello, this is Dr Casey Albin. Today I'm interviewing Dr Jiwon Oh about her article on diagnostic neuroimaging biomarkers for Multiple Sclerosis, which appears in the April 2026 Continuum issue on multiple sclerosis. Welcome to the podcast. Thank you so much for being here. I'd love to start by having you introduce yourself to our listeners. 
Dr Oh: Thanks, Casey. Hi, everybody. My name is Jiwon Oh and I'm a neurologist, mainly an MS specialist at Saint Michael's Hospital at the University of Toronto, and I'm the medical director of our MS program.
Dr Albin: And you have written a really fantastic article that dives deep into some of the nitty gritty about these new diagnostic biomarkers that we find on the MRI that we're getting for our patients with multiple sclerosis. And I think we are going to get into a lot of that nitty gritty. How do we look for them? How do they improve our diagnostic specificity? This is really come a long way in shaping the advances for multiple sclerosis. And I'd kind of like to just start with the big picture. Like why do we need these more specific biomarkers? 
Dr Oh: This set of diagnostic criteria in MS, it's actually a huge change in the field, and particularly for people like me who are really interested in developing new MRI measures, we're really, really excited because it's actually the first time since MRI was officially incorporated into the MS Diagnostic criteria, which was way back in 2001. It's the first time that we've actually been able to get newer, more advanced imaging measures beyond just simply detecting, new T2 lesions in the MS diagnostic criteria. So, it's a big moment in the field, and many of us are really excited about it in terms of why we need some of these newer, more specific imaging measures. Well, you know, diagnostic criteria always evolve over time for any disease state, and MS is one that we've recognized over the years. By the time someone actually presents with typical clinical symptoms and has diagnosed, whatever has been happening from a patho-biological standpoint has been happening probably for almost 5 to 10 years before that individual actually presents. And so, because of this recognition in the field and the fact that we're recognizing how important it is to first diagnose MS and then treat MS earlier and earlier, because we know that early treatment helps prevent more clinical outcomes. Diagnostic criteria over time have become much more permissive, meaning that we're doing everything that we can to try to facilitate a diagnosis of MS when we know that someone biologically has MS. But the problem with making diagnostic criteria more permissive, and it's obviously a good thing because you want to capture as many people with MS as early on as possible. The problem with making it permissive is there is this terrible risk of misdiagnosis. As clinicians, we all think we never make mistakes. But it turns out when you actually do studies, you do. And even at MS specialty centers, when studies have been done, 10% to 20% of people with MS are misdiagnosed. So, this is exactly why we need in diagnostic criteria that really help to facilitate a diagnosis. We need things that help us prevent misdiagnosis as well. And these are these specific imaging measures that have now been incorporated into the diagnostic criteria in many settings that will help to facilitate a diagnosis. But the really big perk is if you use them, you can help to prevent misdiagnosis as well. 
Dr Albin: Yeah, that really shone through in your article that this was such a big step in towards being more specific about who were diagnosing. Also capturing more people, right? Trying to get those people that we, we don't want to miss because of all the things you say, you know, that allows them to accumulate more disability, have worse outcomes. Early diagnosis is so important. But I really did take away from your article just how critical these are and sharping our diagnostic acumen. And so just to jump right in, and you describe these three new biomarkers, these cortical lesions the central vein sign and paramagnetic rim lesions. And so just to kick things off let's start with cortical lesions I sort of conceptualize multiple sclerosis a disease of white matter. So, what's going on here? 
Dr Oh: Yes. MS classically has always been described as a white matter disease. But it turns out when you look at brain and spinal cord tissue, as well as when you use kind of better sequences to actually look for lesions in the gray matter, it actually turns out there's a ton of lesions in the gray matter as well. And in fact, what's interesting is that regardless of whether it's the cortex or the deep gray matter, it's lesions within these areas that seem to have the highest relevance for clinical disability in MS. So, all this to say, of course, MS is a lesion that does affect white matter, but it also affects gray matter a lot. And maybe pathology within the gray matter is even more relevant to clinical disability. So, this is why we're really interested in being able to develop methods using MRI to more accurately visualize the gray matter, particularly the cortex, as well as deep gray matter structures like the thalamus. I should add the caveat that cortical lesions were actually included in the 2017 diagnostic criteria revisions, but they were included together with juxtacortical lesions, which are a typical area that MS lesions form. And so, this imaging measure, despite the fact that it is relatively novel and we consider it advanced, it hasn't been used that much only because it's not that easy to detect lesions within the cortex. And reasons for this include that you usually need higher field magnet platforms. And so, the typical clinical MRI scanners that are available kind of widely, regardless of whether you're at an academic center or a community center, are 1.5 Tesla magnets. And cortical lesions are actually really difficult to detect on those typical scanners. But when you get to like, say, three Tesla or seven Tesla, they're a lot easier to detect. But obviously that's a big hindrance to widespread use. And then you actually need very specialized sequences to adequately visualize cortical lesions. And these are not sequences that are usually collected for clinical purposes. So, it kind of requires convincing your radiologists that you need this additional sequence. And then it actually takes a lot of time and training to be able to adequately, accurately detect cortical lesions. So, despite the fact that it's actually very useful when you do have the appropriate MRI sequences and scanners to detect cortical lesions, even though they were incorporated into the 2017 criteria outside of specialty centers, they're not actually widely used. But when you do have the appropriate sequences, cortical lesions are actually pretty specific for MS. So, very helpful for a diagnosis in certain settings. But there's all these practical limitations that have really limited its widespread use.
Dr Albin: That is a beautiful summary. So, it sounds like once we kind of get up to speed in terms of like the protocols for this, having the magnet strength for this, this will be really a game changer in terms of increasing the specificity and also maybe finding things that impact patient's clinical presentation and therefore quite meaningful. But it sounds like for most of us, this is probably not something that they're going to be adopting right away. Is that a fair assessment? 
Dr Oh: Yes. And you know, they were included in the last diagnostic criteria revisions. And it really hasn't changed things very much, only because of these difficulties with, you know, requiring higher field magnet strengths and these specialized sequences and then needing training to kind of figure out how you can adequately detect cortical lesions.
Dr Albin: Totally. So, the other thing we've heard a lot about, and I have to say, I was in the AAN fall conference not too long ago, and this came up quite a bit, was the central vein sign and the fascination with that, because it tells us a lot about the MS pathophysiology and again, increasing that specificity. And it seems like maybe this is one that we can more easily adopt in clinical practice. So, tell our listeners about what that is, how they detect it. How many do you need to find? 
Dr Oh: Sure. And so, this is one of the imaging measures I'm really excited about. So, the central vein sign heard about it recently. And probably in the last ten years particularly in the MS field we're talking about it all the time. But just wanted to emphasize that the central vein sign is not something that is new. Even back in the 1800s, when Charcot described MS lesions in these ancient textbooks, he actually very clearly described that MS lesions form around the central vein. And that makes sense, because we know that these waves of peripherally mediated inflammation somehow get through the blood-brain barrier and cause this cascade of events leading to inflammation in the brain and spinal cord, which is what MS is. But we know that B cells in T cells require veins to get into the central nervous system. And so, it's no surprise, really, that MS lesions form around veins. And so, this is something that's been known pathologically. But the reason we're so excited about it now is because we actually have good enough iron-sensitive MRI sequences that allow us to see a central vein when it is present within a white matter lesion. As a neurologist, we know that there's probably hundreds and hundreds of different things that can cause white matter lesions in the brain. But when you use an appropriate iron-sensitive sequence and you see that many of them, if not most of them, actually have visible central veins, that tells you that this person very likely has MS. And so that's why we're so excited about it, because there have been many studies done in the last ten years. In fact, so much evidence generated in the last ten years that there have been I think it's now four systematic reviews and meta analyzes. Looking at the diagnostic properties of the central vein sign. And, you know, it turns out that when you look at people with MS, most of them have a pretty high proportion of white matter lesions that have visible central veins. And there's a lot of questions about, you know, how to best use the central vein sign. But when 40% or more of the white matter lesions that you see have visible central veins, then the likelihood of a diagnosis of MS is very high. So, this is why we're so excited about it in the MS field because it's a really useful diagnostic tool. You know, again when you have appropriate ion sensitive sequences, if you see someone with white matter lesions and you see that 40% or more of them have visible central veins, this tells you that this person very likely has MS. 
Dr Albin: So, Dr Oh, I hear you say, you know, 40% of the lesions. Does that mean the neuro radiologist needs to look at every single lesion and then count how many have the central veins, or is there an easier way to do this?
Dr Oh: Great question. Casey, there is definitely an easier way because our neuro radiologists would not be our friends anymore if we made them look at every white matter lesion and make sure that 40% of them had the central vein sign. So, because it's so time-consuming to use that 40% threshold, there's an easier criterion that has actually made it into the diagnostic criteria. And it's called Select Six. And what this means is when you have more than ten lesions, as long as you show that six of them have a visible central vein, you just have to count six with the central vein. Then you're done. So that means you're Select Six positive or central veins nine positive. However, if you have ten or fewer lesions, as long as you show that more than 50% of them show a visible central vein, then you are select six positive, and then you're done. So, as you can see, it's a much simpler criterion to apply, and it seems to perform almost as well as that 40% threshold, which is why that is the criterion that's made it into the new diagnostic criteria. 
Dr Albin: Perfect. I love that we definitely do not want to make enemies with our neuro radiology colleagues, but yet they do so much for us. So perfect. I'm glad that we can, make their jobs a little easier without losing any specificity there, or just losing a touch of specificity there. All right. If I am working with a, you know, in a center that maybe doesn't do this all the time, am I just getting a run of the mill SWI sequence? Do I need to ask my radiologist for a special sequence? Or is this just, you know, you can get it from the typical array of what our patients are getting. 
Dr Oh: You know, SWI is a widely available commercial sequence that's iron-sensitive, the ones that are typically commercially available, they can detect central veins, but there actually are little tweaks that you can do to make it a little more optimal. With the recent diagnostic criteria publication, which was, led by Xavier Montalban and recently published in Lancet Neurology. There's actually a companion MRI paper that was led by Frederick Barkov and Danny Wright. And the reason I'm specifically citing those papers is in that companion MRI paper, there's a table that has kind of optimal sequence parameters that you can use even with a conventional SWI sequence, to try to best detect the central vein sign. And then there's a wide range of different iron-sensitive sequences, and SWI is one of them, but the one that seems to have emerged as most sensitive to detect the central vein sign is something called the 3D T2*-EPI sequence. But the bottom line is there's a whole bunch of different iron-sensitive sequences that you can use, little tweaks that you can do to make them optimal, to be able to visualize central veins when they're present within white matter lesions.
Dr Albin: Incredible. So like partner with your neuro radiologist, there is a great sounds like a field guide almost to this. So, it makes it easy to pick up in your standard of care so that you can make sure that you are detecting them at the optimal level to see that more specific diagnostic biomarker. 
Dr Oh: Yes. And you know, in contrast to what we were talking about with cortical lesions, you can actually detect central veins when you use these iron-sensitive sequences at any field magnet. So even at 1.5 Tesla, particularly when you use contrast, which is often given with the diagnostic scan anyway, you can very easily detect a central vein. So that's a huge benefit because it allows for widespread use. As long as you work with your radiologist to get the right iron-sensitive sequences in. 
Dr Albin: Yeah, that's incredible. I mean, I think that it really will be practice-changing. And then the last one that I think was honestly new to me, I feel like I had heard a lot about the central vein sign, but the whole new to me term was this paramagnetic rim lesion. So, what does that tell us about the underlying biology of MS? And are there any other things that might also have this finding that we should sort of be aware of? And how specific is it? 
Dr Oh: You know, the central vein sign is kind of the main, really new imaging measure that's made it into every part of the MS diagnostic criteria. And then together with that paramagnetic rim lesions or we call them PRL or pearls for short, they've made it as well, but in a much more limited way only because there's not as much evidence that has accumulated over time to support the diagnostic utility of pearls. But first of all, what are pearls? So, people in the MS field are really excited about pearls, because we know that they capture a subset of what we call chronic active lesions. So, MS lesions will form acutely and over time, some of them will become inactive. And then some of them are chronic active lesions, meaning that they have this rim of activated microglia around them. Over time, they continue to slowly expand. And it's almost like this slow burn. And the reason why we focus a lot on chronic active lesions is because we know that they're a driver of progressive disease biology and MS, meaning that in people who have progressive MS or who have pretty severe disability, global disability or cognitive disability, we know that they have a high burden of pearls. And so that's why there's so much excitement in MS about being able to image chronic active lesions. It's because we're always looking for an imaging measure that allows us to accurately predict progression or to, measure progression over time. So that's why there's so much excitement in MS about pearls. But as kind of an added bonus, it turns out pearls are also really specific for MS. And so, when you use the same iron-sensitive sequences, by the way, that's used to detect the central vein sign when you use appropriate iron‑sensitive sequence. And if you see that someone has a pearl, the likelihood of a diagnosis of MS is very high. The one exception to that is Susac syndrome, where pearls have been observed. But other than that, with many other white matter diseases like neuro rheumatology disease, NMOSD, MOGAD, you really don't see pearls. And so, this is why it's made it into the new diagnostic criteria. In contrast to the central vein sign, though, not everybody with MS has a pearl, so the sensitivity isn't as high. However, it's really, really specific in the range of, you know, 90 to 95%. So, this is why it's been added as, an imaging measure in certain settings. It can help facilitate a diagnosis. But the real utility, again, is when you use it, it helps you to prevent misdiagnosis. 
Dr Albin: It's fantastic. And hearing you talk about that, this one stands out to me as a biomarker that not only helps increase our diagnostic specificity, but also may really inform if the patient has having progression despite the treatment they're on, that this could play a role in helping you say, look, there probably is something that we need to switch because we can still see this ongoing progression.
Dr Oh: Yes. And especially in this new era of treatment in MS. I think, you know, MS as a field, we've been so fortunate to have so many treatments emerge over the years that mainly target relapsing disease. But we hopefully, in the next little while, in short order, I hope we'll have treatments that target these progressive disease biologies. And so, not only is it helpful as a diagnostic marker, but there's a lot of evidence accumulating, showing that it may have a lot of prognostic value and will also help guide treatment decisions, exactly as you said. 
Dr Albin: It truly does sound like it's a great time to be an MS doctor there. So, so many new advances in the field. There is so much more that we can do for these patients in our limited time left. I'd love to ask you, what is it that you're most excited about now with the change in the biomarkers, the change in the treatment, what makes you really excited to be a doctor specializing in MS right now?
Dr Oh: I feel like we're on the brink of a new era of treatment. I think, you know, in the last two decades, MS care has changed so dramatically. I remember, you know, way back when, as a medical student, when I did my first neurology elective, this was when the first treatments for MS were emerging. And the prognosis that we were talking to patients about at that time is like night and day compared to what we talk to them about now. But we're going to do even better in the next couple of years. And so, there's a number of new treatments that hopefully will be approved soon that, for the first time, have shown an effect in clinical trials where it seems to be decreasing progression that is independent of relapsing activity. And that's really the greatest unmet treatment need that we have. And it seems like we might have some therapies on the horizon that can actually target that aspect of progression. It's really exciting, and even more that we're going to be able to do for our patients to completely change the way, we look at and the way we treat MS in the years to come. 
Dr Albin: Dr Oh, this has just been fantastic. To all of our listeners, I really want to point you to the article because obviously, as an imaging biomarker article, there are so many beautiful images. There are great examples. There are some fantastic cases that show how applying these new biomarkers can help get you to the right diagnosis. This is truly a tour de force of how imaging has really shifted the care that we provide patients with MS, and so please go and check it out. It is one that you do not want to miss. And again, today I've been interviewing Dr Jiwon Oh about her article on diagnostic neuroimaging biomarkers for multiple sclerosis, which appears in the April 2026 Continuum issue on multiple sclerosis. Thank you again, Dr Oh, this has just been such a delight. 
Dr Oh: Thank you for having me on the show, Casey, and look forward to people reading the article.
Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Andrew J. Solomon, MD, FAAN, who served as the guest editor of the April 2026 Multiple Sclerosis and Related Disorders issue. They provide a preview of the issue, which publishes on April 2, 2026.
Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.
Dr. Solomon is the Division Chief of Multiple Sclerosis and a Professor in the Larner College of Medicine at the University of Vermont in Burlington, Vermont.
Additional Resources
Read the issue: continuum.aan.com
Subscribe to Continuum®: shop.lww.com/Continuum
Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud
More about the American Academy of Neurology: aan.com
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facebook.com/continuumcme
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Host: @LyellJ
Full episode transcript available here
Dr Jones: It's been more than 150 years since Jean-Martin Charcot first described the disease that we now know as multiple sclerosis. Since then, the tools we have to diagnose and treat this disorder have expanded enormously. So why are the diagnostic criteria for MS. still evolving? Today we're speaking with Dr Andrew Solomon, guest editor of our latest issue of Continuum on MS and related disorders. To learn more about this question and much more.
Dr Jones: This is Dr Lyell Jones, editor in chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about subscribing to the journal, listening to verbatim recordings of the articles, and exclusive access to interviews not featured on the podcast.
Dr Jones: This is Dr Lyell Jones, editor in chief of Continuum, Lifelong Learning in Neurology. Today I'm interviewing Dr Andrew Solomon, who is Continuums guest editor for our latest issue of Continuum on multiple sclerosis and related disorders. Dr Solomon is a professor of neurological sciences at the University of Vermont, where he also serves as the division chief of multiple sclerosis. Dr Solomon is an internationally recognized authority on MS, particularly on the diagnostic approach to this complex disorder. Dr Solomon, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners? 
Dr Solomon: Hi, everyone. This is Andy Solomon. It's a pleasure to be here with you. And I feel honored to have helped this collaborative effort that created this important tool for trainees and clinicians in practice, the Continuum issue on multiple sclerosis and related disorders. 
Dr Jones: Obviously, we're grateful that you've taken us on. A lot has happened in the world of MS and other neuroinflammatory disorders in the last few years, so lots to update. But as we've done over the last few podcasts, I'm going to start off the interview today, Dr Solomon, with a trivia question. And then we'll come back at the end of the podcast and give the answer. So, the trivia question is this. There are now more than 20 drugs approved by the FDA for the treatment of MS. What was the first disease-modifying therapy approved for MS? And when was it approved? So, don't answer because I know you know the answer. But we'll come back to it at the end of the interview. And our listeners can think about that question. So, let's get right to it. As many of our listeners know, the diagnostic criteria for MS. were recently revised. And you were involved with that revision. So, you're the perfect person to ask what were the major changes in the 2024 McDonald criteria, and why did we need to update them in the first place?
Dr Solomon: I'm very excited about the 2024 McDonald criteria, and it was an honor to be part of that process that resulted in that manuscript. When we revise the diagnostic criteria for MS usually it's driven by accumulating data that suggests some changes or revisions might help us diagnose patients either earlier or with more accuracy. And that's certainly the case with this criteria. There was accumulating data that suggested some particular changes were important. You know, there's a lot of expert opinion involved as well. You know, there's many experts who are involved in the collaborative decisions that go into these revisions. And some of the changes in our field also pushed some of the revisions to where maybe there's not as much evidence, but where we felt it would improve care for patients with MS. This criteria, I would argue, is probably one of the most substantial revisions in over 20 years. There's multiple changes that are potentially impactful for the diagnosis of MS. Some very important changes involve the incorporation of new paraclinical tools that we can use to assess the visual pathway, as well as, imaging tools that provide high specificity for MS that we can use to substitute or dissemination in time, for instance, as well as other tools that may allow us to diagnose patients earlier than we would have in prior criteria.  There's also some opportunities with the new criteria to potentially provide access in regions where some tools are more available than others. For instance, the incorporation of Kappa Free Light Chains as a substitute for oligoclonal bands may open up opportunities in regions where expertise for oligoclonal band testing are not available. That's a very qualitative test, whereas Kappa Free Light Chain index is more quantitative, less expensive and may allow CSF testing to be performed to aid the diagnosis of MS in some regions where it wasn't available previously. This criteria provides multiple pathways to the diagnosis of MS, many more than we've had in prior criteria. So, it's important to emphasize that while there's all these new tools and changes that have been incorporated, not every pathway needs to be available where you practice. What it incorporates as flexibility. It is a bit more complex looking at all of these different possibilities, but the point is this flexibility allows clinicians or providers to diagnose MS early with high accuracy based on the tools they have available.
Dr Jones: I think it will be a learning curve, right? I think any time we make a change in how clinicians get accustomed to approaching a diagnosis of a disorder, it will take some time for folks to incorporate it. And I see what you mean about the complexity, but I think that's a really great point, that emphasizing the different pathways to the diagnosis is really a strength of the revision, right?
Dr Solomon: I agree, I think, you know, in other disorders, particularly if you think about rheumatologic disorders, systemic rheumatologic disorders or inflammatory disorders, where over time we've not had very highly specific and sensitive biomarkers. And we've incorporated a variety of clinical and prior clinical findings, testing, laboratory testing and biopsy and other things to confirm a diagnosis. These approaches to these disorders are sort of a checklist. And I think that clinicians became familiar with that approach and were able to make diagnoses accurately this way. And I think of the new criteria in a similar way. It's not quite amenable to a checklist, but the pathways are sort of simplified with multiple options. Hopefully, using the figures, clinicians can look at the paper and see what tools they have available to help them confirm a diagnosis of MS. I think it's really important to emphasize that the diagnostic criteria for MS still does not discriminate MS from other disorders. Everyone who's listening here, you do, the clinicians do. So, to enter the diagnostic criteria and these pathways, we first have to feel confident that the patient has a clinical presentation and an MRI presentation or MRI findings that are highly suggestive of MS. That aspect of the criteria hasn't changed since, the Schumacher criteria in the 1960s. This concept of no better explanation. So, we still need to know what's typical for MS. And we need to know what signs or symptoms or findings are that might suggest another disorder, because the criteria are really only validated and tested in patients who have these presentations to start with that are typical for MS. A major change in this particular criteria is that we can now diagnose patients who are asymptomatic. Previously just called radiological isolated syndrome. Not every patient with an MRI finding concerning for MS and now being diagnosed with MS. There's other features that, must be present, but even more than before, knowing what the typical appearance of MRI lesions suggestive of MS, it is even more critical now than it was before, because in those patients who have either no symptoms or a nonspecific presentation, if we have an MRI that's highly convincing for MS and some other prior clinical findings, we can make the diagnosis. But we first need to know with some confidence what that MRI should look like. 
Dr Jones: So, there is a little circularity when we do these diagnostic criteria. I think our listeners who see patients will be reassured that the clinician is still in the loop. We haven't been automated out of the process yet. 
Dr Solomon: We need a highly sensitive and specific biomarker or a set of biomarkers for MS.  We're getting closer with some of these advanced imaging findings like central vein sign and paramagnetic rim lesions. But not every patient can be diagnosed with those. And they're not required for the diagnostic criteria. In lieu of a highly sensitive and specific test. Our clinical acumen, for what we find a neurologic exam. And what we see on imaging in particular, is quite critical for ensuring that the criteria perform as well as we hope they will.
Dr Jones: So, you've had the opportunity, the vantage point, to review all of these articles covering a wide variety of topics, MS, other neuroinflammatory disorders like aquaporin‑4–positive neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease, MOGAD. Anything that surprised you in these articles as you were reading through them? 
Dr Solomon: I think maybe for listeners, what may be surprising to some of them is that despite guidelines surrounding the use of some of our disease modifying therapies in pregnancy and breastfeeding that are published by regulatory authorities in the United States or Europe or other places, we are making other decisions for patients based on the data we have, the best data we have. Thinking about family planning is really important for us with patients who are newly diagnosed with MS, as well as through the course of their disease. This is a conversation we should be having shortly after diagnosis, because there are strategies we can take to minimize the risk of exposure of DMT around conception and to make plans for how we're going to think about DMT surrounding breastfeeding, to ensure the health of mom and the baby, and reduce risks as much as we can with the knowledge we have. I think in medicine it's quite common for us to use medications off label, right? I mean, so medications are often FDA approved for one indication. And in neurology, for instance, we find a lot of medications after their approval were quite effective for migraine prophylaxis for instance. Right? And so, it's not unusual for us to prescribe medications beyond the label. And I'm not suggesting that we necessarily ignore the advice of our regulatory authorities. But sometimes the data is accumulating really fast around some of these therapies after they're approved. Sometimes we can look towards experts and how we can navigate pregnancy and breastfeeding in MS.
Dr Jones: I think that's a great point about the importance of family planning and having to use judgment. I do want to highlight to our listeners and our subscribers a fantastic article in the issue on family planning and MS and other neuroinflammatory disorders. This was written by Dr Ruth Dobson and Dr Kersten Hellwig, and I think it covers a lot of that gray area where we have to use our clinical judgment to manage these diseases in the absence of a regulatory approval. And I think, again, that's an important gap that the issue fills. And really, that's just a wonderfully written article that I think is a must-read. So, we cover lots of topics in this issue. And one of them is again a relatively newly characterized disorder, MOGAD. What's the latest in the world of MOGAD, what should our listeners be aware of?
Dr Solomon: I agree, I think we're in an exciting time in CNS inflammatory disease. And this is a recently described disorder. You know, and the diagnostic criteria now is only a few years old. So, I think importantly, readers should be aware of the diagnostic criteria. This is something that, really will help us distinguish this disorder from NO spectrum disorder and MS. There's a key overlap between the MS diagnostic criteria and MOGAD. Two decades ago we saw a pediatric MS included somewhat atypical presentations like bilateral optic neuritis or acute disseminated encephalomyelitis. And we had caveats in our approaches to pediatric presentations of presumed MS, suggesting that there could be something very different than adult MS. Subsequently, we've realized that pediatric MS presents quite similarly to adult MS in terms of its clinical syndromes and MRI appearance, and many of those pediatric patients who had initially been diagnosed with MS and MOGAD. MOGAD is actually probably more common demyelinating syndrome in patients who are under 12 years old. So, the MS diagnostic criteria requires testing for MOG-IgG with a good assay, a cell-based assay, any patient being evaluated under the age of 12 or with a demyelinating syndrome to avoid misdiagnosis. 
Dr Jones: Thanks for that. Obviously, MOGAD is one of several disorders that have been more recently characterized and, something that our readers need to be familiar with, and there's plenty of updates within the issue on that and other topics. Okay. So now back to our Continuum audio trivia question. And just to remind our listeners, there are now more than 20 drugs approved by the FDA for the treatment of MS. What was the first disease-modifying therapy approved for MS? And when was it approved? Dr Solomon, do you want to take the honors and answer the question? 
Dr Solomon: Sure. It was way back in 1993. You had to get on a wait list, I believe, initially to get on it. There was some sort of lottery, and it was Betaseron. 
Dr Jones: Betaseron in 1993, was the first disease-modifying therapy approved by the FDA for the treatment of MS. It just shows how much water under the bridge we've had since then. 1993 was also the first year of the Jurassic Park series of movies. It was the biggest movie of the year, the song of the year in 1993 was "I Will Always Love You" by Whitney Houston. It was also the year you can tell that I look back into 1993 to see what else happened. It was also the first year the World Wide Web became publicly available, which is it kind of puts brackets on the era or the epoch of MS disease modifying therapy. And finally, the Super Bowl champs that year were the Dallas Cowboys, who unfortunately, have not had much luck in Super Bowls since the 1990s. Maybe they will have more opportunities like we've seen with MS therapeutics. So, Dr Solomon, I want to thank you for joining us today. I want to thank you for such a wonderful discussion of the latest in MS. I think the updated diagnostic criteria are really going to be critical for our listeners to understand and incorporate into their practice. Really grateful for your leadership of the issue, putting together a really stellar group of experts for all of our articles and grateful for your time today. Thank you for joining us. 
Dr Solomon: Thanks so much for having me. Thank all the other listeners out there for joining us as well. I'm really excited about this issue of Continuum. 
Dr Jones: Again, we've been speaking with Dr Andrew Solomon, guest editor of Continuums most recent issue on multiple sclerosis and related disorders. Please check it out. And thank you to our listeners for joining today.
Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the Journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.

Neurologic complications of substance use may be the first symptoms that lead patients with substance use disorders to seek care. Neurologists have a key role in identifying patients with substance use disorders and connecting them to treatment.
In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Adeline L. Goss, MD, author of the article "Neurologic Complications of Drug and Alcohol Use" in the Continuum® February 2026 Neurology of Systemic Disease issue.
Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.
Dr. Goss is a neurohospitalist and associate chief of neurology for Highland Hospital in Oakland, California.
Additional Resources
Read the article: Neurologic Complications of Drug and Alcohol Use
Subscribe to Continuum®: shop.lww.com/Continuum
Earn CME (available only to AAN members): continpub.com/AudioCME
Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud
More about the American Academy of Neurology: aan.com
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Host: @LyellJ
Full episode transcript available here
Dr Jones: A big part of neurology is solving mysteries. Patients can show up with all kinds of mysterious symptoms. Sometimes the diagnosis comes from within, some internal disruption of neurophysiology. But sometimes the problem is a complication of drug or alcohol use. Today we have the pleasure of speaking with Dr Adeline Goss, who recently authored an article for Continuum on this exact problem, a topic all neurologists need to be familiar with.
Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.
Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr Adeline Goss, who recently authored an article on the neurologic complications of drug and alcohol use for our latest issue of Continuum on the neurology of systemic disease. Dr Goss is a neurohospitalist and the associate chief of neurology at Highland Hospital in Oakland, California. She's also an accomplished writer, broadcaster and podcaster. Dr Goss, welcome, and thank you for joining us today. Why don't you introduce yourself to our listeners?
Dr Goss: Great to speak with you, Dr Jones. Yes, I'm Adeline. I also go by Addie Goss.
Dr Jones: So, before we get into the discussion, we're going to start off today with something fairly new to the podcast, the Continuum Audio trivia question. So, we all know that alcohol and other substances have many potential complications in that use of these substances fluctuates over time. But this one stood out to me from your article, Dr Goss, just for the sheer size of the change. So, for our listeners, here's the question. Accidental exposures to what substance increased a whopping 1,375% between 2017 and 2021? I'll read that again. Accidental exposures to what substance increased 1,375% between 2017 and 2021? So, stick around to the end of our interview for the answer. And let's get right to it, Dr Goss. If you had a single most important message to our listeners from your article, what would it be?
Dr Goss: Well, I mean, many of us went into neurology because of the way that neurologic illnesses can be life-changing for patients. And I work as a neurohospitalist at a public hospital in Oakland, California. Many of my patients are admitted for neurologic conditions related to substance use. And when I see my patients later in the discharge clinic, many tell me that the last day that they used meth or the last day they used cocaine, the last day they smoked, was the day they had their stroke or whatever they came into the hospital for. I think the most important message is that hospitalization for a neurologic condition related to substance use can interrupt use patterns, can motivate change. And therefore, as neurologists, we really have an opportunity to connect to our patients and connect our patients to substance use treatment and make a dramatic difference in people's lives in this regard.
Dr Jones: I think that's a fantastic point. I enjoyed a point you made in your article---and I can't remember exactly how you phrased it, I won't say it as well---that you think of the syndromes through which alcohol and drug exposures can present. Those syndromes almost always could end up of other primary neurologic disorders. So, put a different way, when a patient presents with a neurologic problem, most of the time an exposure could be on the differential.  And so, we really do have a responsibility as neurologists to be familiar with these.
Dr Goss: To be familiar with these and to know how to connect patients to resources to try to get treatment.
Dr Jones: Totally agree. And you touched on the public health aspect of this. It's really hard to talk about drug or alcohol use without acknowledging the public health impact particularly of opioids, which has been a crisis for most of this century. Right? And I think most of our listeners will be familiar with the rapid rise in opioid-related deaths. But there might be a glimmer of optimism there. Is what I've seen true, that opioid-related deaths may have plateaued?
Dr Goss: So, yes, it's true that opioid-related deaths, overdose deaths in general, have begun to decline, actually, since 2023. And that's in part because overdose deaths really surged early on in the Covid-19 pandemic, in the setting of all of the social disruption, reduced access to services, and social isolation that occurred with the pandemic. But there were really multiple factors there. So, as you mentioned, there was this really rapid rise in illicitly manufactured fentanyl. Fentanyl became a major driver in overdose deaths starting in the mid-2010s. And by the late 2010s, it overtook heroin and prescription opioids as drivers of overdose deaths. And then this just collided with the pandemic in 2020, causing skyrocketing deaths. So, as we know as neurologists, fentanyl is more potent, it's shorter-acting, and it's also cheaper than heroin. It can cost as little as 50 cents or a dollar a pill. Thankfully, as services have rebooted and also as naloxone has become more widely distributed, there has begun to be a decline in opioid overdose-related deaths. So, we're relying on provisional data from the CDC for the most recent years, but that shows about a 24% decline in annual overdose deaths, comparing late 2023 to late 2024. And that's real. That comes out to 70 lives saved per day. Unfortunately, deaths still remain above prepandemic levels, and we're still talking about 87,000 drug overdoses per year. So, I would agree, a glimmer of hope. But we're still seeing overdose as the leading cause of death among young Americans aged 18 to 44. And there's a very long way to go.
Dr Jones: 23% is a big number, and that is certainly exciting to think about, but we're still above that long-term secular trend. So, hopefully whatever is happening to bring that down, hopefully it continues. And we talk a lot about- appropriately, we talk a lot about opioid exposures and some of the neurologic presentations of opioid use and toxicity, but alcohol use disorder is the most common substance use disorder, correct? I learned that from your article. And it has been for some time, and it has well-known acute and chronic toxicities. But I think many of us have been taught something of a myth in the acute treatment of patients who may have thiamin deficiency or Wernicke's encephalopathy. Can you tell us a little more about that?
Dr Goss: Yeah, sure. So, boy, what is my favorite vitamin? As a neurologist, I think thiamin is my favorite vitamin. Thiamin is a cofactor in- for several enzymes that are involved in glucose catabolism. And it's necessary to synthesize myelin and several neurotransmitters. And as we know, alcohol use disorder leads to reduced nutritional intake and impaired digestion and absorption of nutrients. And this can lead to deficiencies in water-soluble B vitamins, including thiamin, as well as trace elements. The thing about thiamin is that thiamin deficiency often appears first, because the body's stores of thiamin deplete in about 4 to 6 weeks. You know, we're traditionally taught if a patient presents with symptoms concerning for Wernicke's encephalopathy, that if they're also hypoglycemic or just in general, we have to get glucose into them first, because we don't want to tax these thiamin-dependent glucose catabolism pathways. But really, there's no reported case of a single glucose bolus precipitating some dramatic symptomatic thiamin deficiency. It's thought that harm would come potentially from prolonged carbohydrate administration without thiamin. And so, if a patient in front of you is both thiamin deficient and hypoglycemic, you just treat both. You treat both emergently. But it doesn't really matter in what order you do so.
Dr Jones: That's good to know that doing the right thing for the patient can involve using either of those in whatever order. And I agree with you, I don't think I've ever hurt anybody by giving them thiamin. It's an easy one to miss and an important one to remember in the right context. And speaking of, and I think a lot about in your article, Dr Goss, I can see a neurologist seeing a patient in the emergency department or in the hospital or even in the clinic thinking about the wonderful points in your article. But we know that when alcohol or substance use enters our mind on the differential, the next impulse is to test for it. And we also know there are pitfalls of drug screening, doing urine drug screens, etc. How do you approach testing when you think about a potential drug-related complication in their differential?
Dr Goss: So, like most people, I would start with a urine drug screen for any patient who's presenting with a possible toxidrome or some substance-related neurological presentation. These urine drug screens, they're rapid, they're inexpensive, they're immunoassays for traditional drugs and their metabolites. So, usually amphetamines, cocaine, opiates, plus/minus cannabis. But I think the first thing to note is that they miss entire categories of drugs, and not just drugs that are not in that list. They miss synthetic opioids, including fentanyl. One group is keeping track of this number. So, I have an update for mid-2025. And that's that 30% of U.S. ED overdose encounters as of mid-2025 included fentanyl testing. Only 30% for patients who are presenting with an overdose syndrome.
Dr Jones: And that's for one of the most widely used synthetic opioids. So that's really a striking number.
Dr Goss: Yeah, one of the most widely used and one with the greatest rate of complications. So, states can make a difference here. In 2022, California passed a law requiring fentanyl testing on hospital urine drug screens and several states have followed. And so that number is rising, the rate of testing for fentanyl. But that's just a really key thing to know, that that one is often missed. Other just important pitfalls, the timing of the urine drug screen matters because for most substances, it only picks up the drug within 24 to 72 hours after the last use. With amphetamines and cocaine going out a couple more days after that, especially in patients who use repeatedly. And then also, notably, there's a risk of false positives. This is especially true with amphetamine use, and beta blockers are one of the drugs that can lead to false positives on an amphetamine test, on a urine drug screen. So, I'll share that I've had several patients who have presented with intracerebral hemorrhage and who tested positive on the emergency department's urine drug screen and who adamantly stated that they do not use amphetamines, they've never used amphetamines, and they didn't ingest anything that could have contained amphetamines. And when we did serum confirmatory testing, in fact, their amphetamine testing was negative, and all those patients had received esmelol or the labetalol in the ED to treat their blood pressure related to their ICH. So false positives can occur with, you know, other medications like decongestants and certain antidepressants. But beta blockers are a key one to know. And then finally, there are just a number of things outside of that short list of substances that I mentioned, including a huge range of novel psychoactive substances that would not be tested for on a standard urine drug screen. And for those, you'd require serum testing, or at some large academic centers or specialty toxicology labs, you can actually do liquid chromatography high-resolution mass spectrometry, with- which is basically unbiased testing for any substance that's present in the patient sample. So, I guess, you know, you asked about my approach. Start with the urine drug screen, but there's no substitute for good history-taking and close examination of your patient's general examination, not just their neurologic presentation. And if patients are presenting with a toxidrome that I would expect would show up on a urine drug screen but it's negative, there are other confirmatory tests that can be sent, although they're often send-out labs and come back in a very delayed fashion.
Dr Jones: So, in other words, it's complicated, which usually means it's humbling. And if I'm understanding it correctly, there's the risk of the false positive on the urine drug screen. And then there's the risk of the false negative if we think we're screening for something that might not even be on that initial screen. So, that's a wonderful reminder that these are clinical diagnoses and we have to keep our clinician hats on while we're thinking about how to establish these diagnoses or exclude them. So, back to opioids, Dr Gross. There are some really peculiar neurologic syndromes associated with opioid overdose. Tell us a little about those.
Dr Goss: Well, I mean, some of these were described first with heroin. So, we can start with the one that almost anybody has heard of, heroin-associated spongiform leukoencephalopathy, which we know is associated with a practice known as "chasing the dragon," which is inhaling vapors of heroin heated on foil. But we know now that this syndrome can occur with other opioids, including fentanyl. The clinical features are, you know, apathy, cerebellar signs, quadriparesis, parkinsonism, myoclonus, and some patients progress to coma or even death. But on MRI you're seeing, you know, these confluence symmetric white matter diffusion restriction and T2 hyperintensities in the cerebellar white matter and the posterior limb of the internal capsule that spare the subcortical U-fibers. So, you know, I think this is kind of the classic example of something that's symmetric, that has a very obvious and interesting MRI pattern. But as time is passing, we're seeing more and more similar types of syndromes of leukoencephalopathies, but with different clinical presentations and MRI characteristics. So, another of these is CHANTER syndrome. This is an opioid overdose-related presentation where people have stupor and coma. And on the MRI there, you see bilateral symmetric diffusion restriction in the cerebellar cortex, in the hippocampi, in the basal ganglia. And it spares the cerebral cortex. And notably in these cases, patients can progress to cerebellar edema, to obstructive hydrocephalus. And some require suboccipital craniotomy. I had a week recently at Highland Hospital, where I work, where we had two of these cases in the same week, in just a community hospital. And there's a similar syndrome in children known as POUNCE syndrome with profound cerebellar edema, and many patients require posterior decompression. So that's another different distribution of findings with a different outcome. Fortunately, there's a milder sort of phenotype of opioid-associated amnestic syndrome, is what it's been described, where there's primarily DWI changes in the hippocampi and the globus pallidus. So, patients primarily present with an amnestic syndrome, mostly anterograde amnesia. Seeing these in practice, I'm not sure that patients always fall into one bucket or another. But in general, you'll see some degree of symmetric diffusion restriction or symmetric white matter changes that clearly point to a toxic presentation, a toxic syndrome, as opposed to pure anoxia, for example. And it's important to know that because from a prognostic standpoint, anoxic brain injury, which can occur after cardiac arrest and after opioid overdose, can look different than some of these syndromes. Finally, heroin has been associated with myelopathy, but also that's been reported on with fentanyl. So, I think some of these conditions got their reputation from heroin. But as fentanyl has proliferated---and prior to that as prescription opioid, you know, misuse had proliferated---we're seeing similar syndromes with all of the opiates.
Dr Jones: And I think it's a good case in point that you can have multifocal disease and it be a manifestation of an intoxication, and I think that's a really good reminder that we have to have many of these syndromes in our differential, we have to be aware of them, otherwise we might miss them or attribute them to another mechanism. Dr Goss, our last issue of Continuum that was dedicated to the neurology of systemic disease came out in 2023, and here we are in 2026 publishing our latest issue, including your article and this podcast. Since 2023, have there been any emerging patterns or novel agents of abuse or misuse out there?
Dr Goss: The short answer is yes, and I would say the reason is just the supply is moving at more and more rapid speed. The relationship between the internet and drug supply has really informed what's out there at any given moment. So, the turnover in the market can change in weeks, not in years. And there's all of this distribution through social media and encrypted apps. And then manufacturers are kind of continuously tweaking chemical structures to evade law enforcement. In the process of researching this article, I came across some, I mean, really wild examples. To be clear, these are not- not all these are common substances, but I think the general phenomenon should be known that people can walk into a vape shop or walk into a gas station or meander around online and buy some really weird stuff. So, in 2024, there was this nationwide recall of a product called Diamond Shrooms that was sold online and in smoke and vape shops, and this was billed as, like, a hemp and mushroom mixture. But it led to multiple- I mean, over 100 cases of seizures and agitation and depressed consciousness and a few possible deaths. And when the contents were analyzed, they included psilocybin analogs and pregabalin. I mean, some weird stuff. And so, those have been pulled. But people are constantly inventing and marketing these different substances. I think another example… we all know about nitrous oxide and its association with B12 myopathy. But the use of nitrous oxide has really changed. Companies are selling large canisters online and in vape shops, and they're flavored, like, in blue raspberry flavor. And unfortunately, there's been a rise of nitrous among youth. So, we're seeing not just increased cases of myelopathy, but also a 2025 study in JAMA found a spike in deaths attributed to actual nitrous oxide overdose. And so nitrous, I think, had not been that commonly used a few years ago, but has become more common in the last couple of years.
A final one I'll just mention is ketamine. So, ketamine has certainly appeared in reviews of neurological syndromes related to substance use for a long time, and it's also been studied and used off-label for mood disorders in outpatient infusion clinics for some time. But in the pandemic, there was an expansion in telemedicine, as we know, and an associated proliferation of teleclinics that were prescribing very frequent, even daily oral and lozenge and nasal formulations of ketamine, which has led to increased rates of misuse. So, you know, acutely, the syndrome associated with ketamine intoxication is very brief. And often by the time people come to the emergency department, their symptoms have already worn off. But long-term, frequent use of ketamine is really still being studied. There seems to be an association with persistent neuropsychiatric effects like cognitive impairment, psychosis, persistent depressive symptoms. And so, you know, I think it's just important to realize that while the list of substances may look pretty similar to 2023, the use patterns, the distribution patterns are continuing to change. It's hard to keep up. And while alcohol and opioids and stimulants are by far the most common substances that a neurologist is going to encounter in daily practice, there's this ever-expanding range of possible substances that can trigger neurologic syndromes, both acute and chronic.
Dr Jones: And I think that might be the best possible plug to read your article, because it is evolving and we have to stay on top of it. And we really can't be complacent with it. So, thank you for that update. Okay, back to our trivia question. Accidental exposures to what substance increased a whopping 1,375% between 2017 and 2021? Dr Goss, what do you think?
Dr Goss: That was THC-infused edibles. Specifically, these would be THC-infused substances that are often marketed as looking like candy or snacks or cereal. Exactly what a kid might want to get their hands on. And unfortunately, accidental cannabis exposures in children under age five went up by 1,375% between 2017 and 2021, and 600 of those patients required critical care admission.
Dr Jones: Yeah. So, just a mind-blowing number, and obviously something for us to be on the lookout for, especially if you see children in your practice and someone comes in with CNS depression or stupor, it's one to not miss. So that was something I learned in reading your article, among many other things. And Dr Goss, I want to thank you for joining us. I want to thank you for such a great discussion. I learned a lot from reading your article, I learned a lot just from our conversation today, and I suspect our readers and our listeners will too.
Dr Goss: What a pleasure. Thank you so much, Dr Jones.
Dr Jones: Again, we've been speaking with Dr Adeline Gross, author of a fantastic article on neurologic complications of drug and alcohol use in our latest issue of Continuum on the neurology of systemic disease. Please check it out, and thank you to our listeners for joining us today.
Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.