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 L...
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.
Additional Resources
Read the article: Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis
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
Social Media
facebook.com/continuumcme
@ContinuumAAN
Host: @headacheMD
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.
