Chapters Transcript MS, MOG and NMO: What Should We Do? Course: Neurology Updates 2023: Case by Case Well it's a pleasure to be here this morning uh talking to you all, and I wanna thank our directors for giving me the opportunity to share some thoughts with you about the MS Prodrome. So you know I don't like the concept of people having lesions in their brains and in fact of course when we diagnose MS we usually do it with the help of an MRI which shows just that. And so the concept here is, are there things going on in people with MS possibly before those lesions begin. So my disclosures I've helped some of the pharmaceutical companies in getting their medications approved, particularly for pediatric MS uh, most of those I've asked not to be financially reimbursed, but I have given them help and assistance and I think it's important to disclose that. So we're gonna start out with a 19 year old who has very severe depression and loses interest in work and then about 2 years later he develops right hand numbness that gets worse over the next couple of days to involve his face, his neck, his arm, and his leg. He feels his basketball, which he loves, is not quite right. He presents to the ER where some weakness is noted and sure enough on his MRI he has multiple lesions. And he started on a high efficacy disease modifying therapy and he does well and so the question here here is you know when did his MS begin? And this notion that there might be changes including things as nonspecific as mood um occurring before the classic diagnostic symptoms is a concept that's been uh appreciated in other conditions including Parkinson's disease or rheumatoid arthritis and in MS for a number of years it's been reported in. Clinical series usually small case reports of individuals who have mood changes before they develop neurologic symptoms but in the past few years some large uh population based studies has looked into this issue a little bit more closely. And what they've found is that for example mood changes are occurring uh quite a bit in a variety of ways in people before the symptoms of MS so in a population based study where they looked at all the medical records from people in Canada who ultimately had MS and they compared them to people of a similar age and gender who did not have. they found that hospitalizations for psychiatric problems, physician visits for mood related problems and the use of medications um that affect mood or antidepressants were all significantly higher in those group of people who later presented with MS and this increased rate in went higher and higher the closer you got to the MS diagnosis. And if you just look even more broadly, not just at psychiatric related medical problems, but all visits to primary care doctors, you pretty much see the same thing and this is in large numbers of individuals, so 14,000 people who eventually became diagnosed with MS compared to 72. T1,000 people who did not have MS and then they looked into a clinic, an MS clinic and sort of did the same thing, those people who presented with MS versus people who didn't have the MS diagnosis and they found these uh increased visits to primary care doctors and um getting increased hospitalizations and and being on medications. So, um, another study from the United Kingdom found the same thing and you know basically in um in in the blue as you can see the closer you get to the index neurologic presentation, the more frequent very non-specific things bladder symptoms, neck and head pain, fatigue, anxiety, insomnia, eating problems. So we thought this was specific to MS it turns out it isn't so in looking just recently this came out um earlier this month prior to Crohn's disease and prior to lupus you can also see increased numbers of um physician visits. And which problem or symptom is going on more frequently might vary a little bit and so in fact in the MS patients the use of antidepressants was higher compared to those other neurologic disorders but or medical disorders but the concept applies so there's uh changes probably in the immune system that are occurring even before the ting tingling numbness or physical other physical impairments begin. And then I have had an interest in children with MS of course MS typically occurs in young adults, but rarely people under the age of 18 can can get MS also and in this study what they looked at was the mothers of the kids with MS and what they found. Was that the mothers before the kid was diagnosed were seeking psychiatric care they were having more depression more anxiety they were going to psychiatrists uh for their care they were going into the hospital they were taking medications. All prior to the kid being diagnosed with MS, so there's different ways of interpreting that where the parents was the moms picking up on subtle stuff that wasn't going quite right with their child or was there a certain amount of sort of psychological distress in the family. That preceded the onset of MS symptoms we don't know um I have some thoughts that may be one of the things that contributes to an earlier age of MS onset may be some environmental stressors, but, um, in any case this is another piece of information that supports this notion of a MS prodrome. Now we've talked mostly about large databases with thousands of patients and the problem there is that you never know well maybe they were really presenting with neurological symptoms and it was just being missed by the primary care doctor. So in another study where people were hospitalized for their first MS attack, all the uh patients were given extensive questionnaires about their symptoms and it turned out that in fact about a third of the symptoms were really neurologic. But 2/3 were not at least we don't think of them as representing focal deficits, so things like sleep disturbance, fatigue, headache, we're all seen um as problems that they experienced before the MS onset. Well this is great except you know how are we going to um deal with this right? These are non nonspecific symptoms by definition and you know you can't do an MRI on everybody who has uh fatigue I wouldn't recommend it actually but where are we going with this, you know, as a field and I think the answer to that is we're looking for more sensitive biomarkers we still have a huge. Challenge in front of us these biomarkers are insufficiently specific they're they're not diagnostic for sure, but nonetheless they do support the concept that there's something going on before the neurologic symptoms present. So one of the ones that has gained a lot of interest is circulating serum neurofilament light change. And this neurofilament can be found in the blood. It's also present in the spinal fluid, but from a screening perspective, you know, you really wanna focus on on a blood test and um what we saw in uh in this particular study was that looking at people who develop MS. And comparing them to people who do not serum levels of neurofilament light chain, uh, were higher as far back as 6 years before the person developed their symptoms and like their non-specific prodromal symptoms, the levels steadily go up the closer you are to the onset of of the diagnosis. And can there be other diagnostic markers, and the answer is of course yes so this is the traditional view that we have the classical view of MS so we know that you can sometimes see a person who comes in with migraine. And you do an MRI and you see lesions all over the place that go along with the diagnosis of MS and you don't call that person having MS because they are symptoms of migraine or not we think related to those lesions but they have radiologically isolated syndrome and then that progresses to their first clinical attack which might be clinically isolated syndrome. And then they go on to a relapse remitting course and then if untreated that progresses to secondary progressive MS and that's about how 85% of people with MS present. But now we have this other concept, another vision of the different phases of MS, and that takes into account that there are certain people who are in incredibly at risk for MS. So who might that be? Um, well, for example, if you're, um, a monozygotic twin. And your sibling, your twin has MS you have a very high chance of getting MS too, so that's sort of the susceptibility idea that those people with certain genetic, um. Risk factors who've been exposed to certain environmental triggers are of great interest and at great risk and then we have these sort of subclinical changes that may not even be associated with any symptoms that then lead to uh prodromal symptoms. What we don't know is. Whether at the time of those projoal symptoms the person has lesions that you would identify as RIS, those studies haven't really been done yet, but presumably many of them do and then that is then followed pretty similarly to the other kind of phases that we discussed. So how might we uh think about this? Well, I mentioned that if you have a person with radiologically isolated syndrome they have of course a great risk of over time, you know, over 10 to 15 years at least half of those people will develop a clinical symptom that goes with MS, but then we have monozygotic twins and then we have all these other things. Things that you know are relatively low risk factors but do increase your risk compared to someone without those factors so a first degree relative with MS having high levels of EBV exposure early having a history of infectious mono, and then even things like a history of smoking, a history of mood disorder. Um, these are all things that, um, or positive clonal bands that may be present in somebody at risk but who doesn't yet have MS. So how can we screen? Well this is again a a a a an area that there's a lot going on uh as we speak to try to come up with better tools so specific questionnaires one approach polygenic risk scores. So this has been done with some other disorders and what one can imagine is that one day you'll be able to order a blood test very inexpensively as our technology gets better and better that will give you a uh score. That captures the degree to which you have any of those 234 genes that contribute to MS susceptibility certainly not there yet, but I think this type of approach is coming. Another difference in the blood is the immune response to EBV so we know that Epstein-Barr virus is is necessary but not sufficient to cause MS. And it turns out that people who are gonna develop MS have a much more robust and widespread immune response to this virus than people who do not have MS. Um, consistent with the importance of neuro ophthalmology, which you're gonna be hearing about later this morning is the idea of screening with OCT. So if you look at people who ultimately pass away and have MS, 99% have a lesion somewhere in their optic nerve, and, uh, even people with zero symptoms of MS have thinning of their retinal ganglion cell layer. So could we use OCT as a screening approach? Uh, perhaps another point is that, you know, a lot of times we get referrals for people. Could this be MS and they have some lesions that we would call non-specific maybe there's a perioventricular lesion but not that much else so can we come up with. More specific measures on MRI and one that's getting increased um application is the central vein sign which may distinguish better than some of our other tools these sort of nonspecific MRI patterns from people who have MS. So what do we do? As I said, we can't do an MRI on everyone, but we can think about those people with very high risk, uh, situations like the part person with RAS, the person with a monozygotic twin. I'm not saying there's a lot of people like that walking around, but you might think about doing a screening MRI and then what do you do if you find MS? What if the person has RAS? And um no symptoms well I I had actually talked a little bit about this last year and I think that we're beginning to consider intervening on some of those people I think not everybody. Um, I think what's the real question is what's the resilience of those individuals who have a brain full of lesions that look like MS but they have no symptoms, you know, what can we learn from their neurologic strength that enables them to move on and and carry on with zero symptoms, but really, um, those people who have. Spinal cord lesions are at very, very high risk for developing an MS attack and those people who continue to have enhancing lesions are at high risk so I think those are clearly situations where you need to think about intervening and there was a study showing that uh using one of the disease modifying therapies in RIS, not surprisingly will delay um or lower the risk of a subsequent MS presentation. So I mean I wanna wrap it up here and just emphasize that the notion that something's going on in people before that you see lesions on their brain is is potentially potentially an an opportunity, a window to intervene before those lesions occur. Um, the challenge is the lesions are very variable and we can see they're not specific. You can see the same thing or similar things in lupus and Crohn's disease, but if we can develop more specific and sensitive tools. Like incorporating gene scores or circulating neurofilaments, um, maybe, maybe we would have a way of intervening before the lesions ever developed you know that would be the thing that I would love to see, not that you know you have a few lesions of MS in your brain and you're devastated, absolutely not, but we do know that. Even on the best of therapies people with MS do show some subtle changes over time, and I have to believe that those lesions can lead to neurons that are more vulnerable because they're demyelinated neurons that begin to die off so that people develop atrophy and wouldn't it be nice if we could avoid all of that. So I wanna thank you for your in your uh paying attention. It's early in the morning and I think you're gonna find you're looking at a bunch of great additional talks coming your way and my understanding is we're gonna do questions at the end, so thank you. Published December 15, 2023 Created by Related Presenters Lauren Krupp, MD View full profile
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