Neurology® Podcast

Dr. Matthew Barrett talks with Dr. Elan Louis about the incidence and prevalence of mild cognitive impairment and dementia in essential tremor and what these findings may mean for patient care and future research.

Read the related article in Neurology®.

Disclosures can be found at Neurology.org.

Dr. Katie Krulisky talks with Dr. Kelsey Smith about the impact of menopause on women with epilepsy, including therapeutics and clinical management during midlife.

Read the related article in Neurology®Clinical Practice.

Disclosures can be found at Neurology.org.

Podcast Transcript:

Dr. Jose Merino: This is Jose Merino, Editor-in-Chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.

Dr. Katie Krulisky: Hello, and welcome to this episode of the Neurology Podcast. This is Katie Kruliski from the VA and University of Utah in Salt Lake City, Utah. Today, I have the pleasure of talking with Kelsey Smith. She's a neurologist and epileptologist at Mayo Clinic in Rochester, Minnesota. We will be discussing her recent paper published in the Neurology Clinical Practice Journal titled The Menopause Transition and Epilepsy: A Focus on Therapeutics. Welcome, Kelsey, and thank you for joining us.

Dr. Kelsey Smith: Thank you so much for having me. I'm really excited to be here today to talk about this paper and this really important topic.

Dr. Katie Krulisky: Yes. Your paper highlighted a staggering statistic, that women spend approximately 40% of their lives post-menopause. That shook me when I was reading this for a presentation on management of women in epilepsy. Being a woman, I felt totally blindsided by the statistic. I've never thought about it this way. I feel like so much of the emphasis of our clinical practice in epilepsy is choosing the right medications for pregnancy. And there is a lack of information and focus on women in perimenopause and post-menopause, even though a much larger percentage of the lifespan is spent in this phase. Let's go ahead and start with the clinical scenario. A 45-year-old woman with focal epilepsy is having some symptoms attributed to perimenopause and is interested in pursuing hormonal treatments. As her epileptologist, what is your approach to counseling her based on the current available data?

Dr. Kelsey Smith: And when it comes to patients like this, it's a very important topic. And the first thing is that it really requires both an individualized and multidisciplinary approach. So I think first as an epileptologist, I want to understand all I can about her epilepsy, what the current seizure control is, what the current therapy is, what the epilepsy's been like over other life stages if she's had epilepsy no earlier, to understand how seizures may have been during menstrual cycles to know if there's kind of a hormonal driver of seizures that's been noticed through the lifespan. And then also I really want to understand about her menopause symptoms. What are the symptoms that are really bothering her that she's hoping to start the hormonal therapy for? And are those symptoms things like vasomotor symptoms or sleep disturbances? And are those actually also influencing her current seizure control? If the vasomotor symptoms are waking her up at night and she's not getting good rest, is this lowering the seizure threshold and actually driving worse seizure control? Understanding all of this background's really important. And then to discuss with her what the data is about menopausal hormonal therapy and how it's related to epilepsy, how that data is really limited. And so we don't have a lot of data to go off of to provide counseling in this scenario. And all the studies that have really looked at this topic are really quite old, over 20 years old and have not used the same formulations of menopause hormonal therapy we use nowadays. And a lot of these studies didn't even use the anti-seizure medicines that we use nowadays. It's important to work with a patient like this and really let her know that despite the limited data, that epilepsy itself should not be a strict contraindication to considering menopausal hormonal therapy, but there are special considerations that we would need to think about, especially interactions between the hormones and anti-seizure medications and that she would probably require close following throughout using menopause hormonal therapy. I would also collaborate closely with a women's health expert so they can help us decide what the best hormonal therapy may be if it's indicated to treat her symptoms.

Dr. Katie Krulisky: So a lot of these patients will ask, "When looking at hormones, I want to know where my hormonal levels are at now." Are you ordering their hormone levels?

Dr. Kelsey Smith: Yeah, this is a common question that patients ask and I've also been working some with the women's health experts here at Mayo. And as we've worked on papers and things, it's not standard of care to draw these levels even throughout perimenopause and into menopause because of the fact that menopause is a clinical diagnosis. And also during perimenopause, there can be such wide fluctuations in hormonal levels. And so it's difficult to know what to make of different values and how that would influence clinical care. So overall, I'm typically not ordering hormonal levels, but would work with a women's health expert and if they though it would be helpful in a specific scenario, then definitely would consider it.

Dr. Katie Krulisky: So on a very basic level, I've come to understand that in general, estrogen can make you more likely to have a seizure. Progesterone is protective. With that in mind, it sounds like you're not saying completely no to addition of estrogen in the hormone replacement therapy. Is that accurate?

Dr. Kelsey Smith: Yeah, that is accurate. One of the things I learned by putting this paper together is that although some direct comparison of estrogen levels is difficult, but overall, usually actually estrogen that's used in menopausal hormonal therapy, the estrogen is less than the estrogen in oral contraceptive pills. And we don't see epilepsy as a contraindication to considering oral contraceptive pills, although obviously we need to take into consideration interactions with anti-seizure medications and things like that. But I don't think overall it should be a broad contraindication to considering the hormonal therapy. During perimenopause, the endogenous hormonal levels can fluctuate very significantly and there could potentially be an influence of seizure control based on those fluctuations. At least in theory, even menopausal hormonal therapy could potentially help with some of those fluctuations and could potentially be helpful, especially if some of the symptoms associated with menopause, like the sleep disturbances, like the vasomotor symptoms are actually making seizure control worse by reducing the seizure threshold.

Dr. Katie Krulisky: That's a really good thing to keep in mind because there's a lot of fear-based decision-making surrounding women's health and seizure medications because a lot of that, we see a lot of that in pregnancy, right? We also see a lot of that in perimenopause and menopause. I think historically we've though, oh, estrogen is dangerous. You shouldn't have any exogenous estrogen. And then it seems like women are suffering the consequences from exactly like you've pointed out, very limited actual data. So just for review, what is the actual data that we're extrapolating this from?

Dr. Kelsey Smith: Yeah. So there's a few older studies from the late 1990s and then early 2000s that are mostly observational studies asking women with epilepsy how did their seizures change with menopause hormonal therapy and things like that. And then there's one randomized controlled trial. It was published I believe around 2006, but it had very limited numbers, less than 25 patients. And that study said that with menopausal hormonal therapy, with the higher doses, there was a dose dependent relationship where seizures worsened with that therapy, the menopausal hormonal therapy. However, this study was using formulations that aren't typically in clinical practice anymore for menopausal symptoms as they're using more like estrogen patches and things like that. And so we really don't have data that looks at our currently used treatments in women's health and how it influences seizure control.

Dr. Katie Krulisky: So I'll just say that the available data is extremely outdated and not even necessarily applicable to our current treatment standards in that area.

Dr. Kelsey Smith: I would agree with that statement. I think we need more research, more data. And that was one of the motivations of putting this paper together, is just highlighting some of the gaps, but also using some of what we know from other life stages to highlight some of those interactions with anti-seizure meds, some of those things that we can at least talk to our patients about and we can try and improve clinical care.

Dr. Katie Krulisky: And when you're selecting an anti-seizure medication for women, how heavily are you considering its association with osteoporosis?

Dr. Kelsey Smith: Yeah, this was another very important topic when we're thinking about epilepsy and the menopause transition is osteoporosis. It's never too early to consider this and what anti-seizure medications are better for bone health because we know that there's many anti-seizure medications like enzyme inducing anti-seizure medications that can negatively impact bone health. And then there's even data that epilepsy itself can negatively impact bone health. So I don't think there's ever a time where it's too early to consider it and we should probably be considering it over the lifespan because if you get someone on an anti-seizure medicine that's really controlling their seizures, it's more difficult to switch them off to something else. But I do think that as people are reaching perimenopause age 40 or so, really reconsidering looking at that anti-seizure medication and how it could impact bone health. And also just considering bone health in general is important for us epilepsy doctors. And so thinking about both recommending lifestyle modifications that are good for bones, but then also thinking about things like vitamin D calcium or when they should have screening. And really as they reach menopause and estrogen levels drop significantly, that's when we know that bone mineral density is really impacted and this is a time where we really need to be thinking about this and considering it.

Dr. Katie Krulisky: The medication that always sneaks up on me is clobazam because I always think of it as a newer medication, but it can make you more likely to have osteoporosis, right?

Dr. Kelsey Smith: Yeah. Some of the newer medicines, there's still less data out there, but most of the anti-seizure medicines or even some of the newer medicines suggest some newer data that they can negatively impact bone health. And then also interestingly, some newer studies that suggest even epilepsy itself, taking populations of patients with epilepsy that for different reasons may not be on anti-seizure medicines may have impacted bone health. And all these things are so important to consider when we have patients who are having seizures, who are at higher likelihood of having falls related to seizures, or as they're aging and they're on anti-seizure medicines that can make them dizzy and predisposed to falls as well.

Dr. Katie Krulisky: That's so true. It's in addition to the epilepsy that can make you more likely to fall, all these other factors, the seizure medication, the sodium channel side effects, we have to keep in mind. When it comes to the screening tests, are you yourself ordering the DEXA scans or are you partnering with primary care? I've done it a little bit of both ways depending on the patient situation.

Dr. Kelsey Smith: I've done it a few different ways. Sometimes it's easier if they have that close primary care and I'm going to rely on primary care to help me out if the DEXA is really abnormal anyway. So if I can, I'd probably collaborate with their primary care provider, but in some scenarios I have ordered the DEXA scans.

Dr. Katie Krulisky: Because I know we both had these patients where it's like, if you don't order it, you know it's not going to happen.

Dr. Kelsey Smith: Yeah. Yeah. And then, yeah, if I get the result and it's very abnormal, then I can work with other folks or even refer to endocrinology to consider treatment.

Dr. Katie Krulisky: And we've touched on this a tiny bit, but overall, how do sex hormones impact seizure control?

Dr. Kelsey Smith: Really simplifying a very complicated relationship we don't completely understand. So overall, it's felt that estrogen is to be pro-convulsive, can reduce the seizure threshold and make seizures more likely to occur. While progesterone, especially through its metabolite allopregnanolone, is more kind of anti-convulsant in nature. But like I said, it's simplifying something that we don't completely understand, but there's some basic science data that supports some of that.

Dr. Katie Krulisky: When I do my presentation on this topic, I say exactly that, is that this is a gross oversimplification of the available information, but something that I always find interesting is that those GnRH cell populations themselves are vulnerable to injury from seizures themselves. So I wonder if that ties into the whole... Anyways, there's a lot more to learn. We can-

Dr. Kelsey Smith: Yes, I totally agree with that statement. I think there's a lot more to learn.

Dr. Katie Krulisky: So what's a practical approach to balancing the lamotrigine and estrogen interaction in midlife women?

Dr. Kelsey Smith: It's just really something we need to anticipate the interaction as opposed to saying, "Oh, you're on lamotrigine, you can't be on anything with estrogen in it." And we need to be prepared for it. And so if menopause hormonal therapy is indicated and is being started, we need to know that baseline serum concentration of lamotrigine and need to recheck levels within two to four weeks of starting something with estrogen in it and adjust the dose as needed based on those serum concentration levels. So also if they've had epilepsy throughout their lifespan and have had changes in estrogen earlier in life, like during pregnancy, for example, or with oral contraceptives, we may have some idea by their history if they're more likely to have that drop in the lamotrigine level.

Dr. Katie Krulisky: And when you're ordering lamotrigine levels, are you really going for a trough or are you more trying to get a consistent time of day? What's your approach with that?

Dr. Kelsey Smith: Yeah, as much as possible, a trough. You need at least a consistent time of the day, but I do prefer trough levels, just because that's what a lot of the reference range is based on. And then if it's a true trough level, it will be a consistent time of the day.

Dr. Katie Krulisky: What inspired you to put this review together?

Dr. Kelsey Smith: This review was a lot of fun to put together and I really learned a lot about menopause and menopausal hormonal therapy. This was an effort though that was actually initiated through the Epilepsy from Childbearing Age to Menopause Consortium. This was from the menopause committee of this consortium, and so got to work with a lot of great co-authors on this paper to put it together, really learned a lot and really excited to see what this consortium can do over time to really advance care for women with epilepsy.

Dr. Katie Krulisky: That is so cool. Can you say the name of this consortium again?

Dr. Kelsey Smith: Yeah. So it's ECAM for short, and it's Epilepsy from Childbearing Age to Menopause Consortium. And it's only been around for a few years. I joined it a couple years ago, but it's really got a lot of wonderful people involved and different committees looking at care for women with epilepsy really across the lifespan.

Dr. Katie Krulisky: I want to be a part of this group. That's so exciting.

Dr. Kelsey Smith: Yeah, you should be. There's a website and everything. So yeah, if you Google it, you'll find it.

Dr. Katie Krulisky: I feel like I have been somewhat radicalized by the process of having a child because all of just the things that women go through with the hormone fluctuation and truly the lack of available information on the impact of those hormone fluctuations is crazy. It is such a wild experience and to be in such a modern society and have so many blind spots within women's health is incredible in not a good way.

Dr. Kelsey Smith: I totally agree with that statement and some of that sentiment as well, is that once I had children myself, then you really start looking at some of these things in different ways. And it's not something that us as epileptologists need to overlook or shy away from in clinic. Our patients a lot of times want to talk to us about these things, especially if they think it's influencing seizure control. And now trying to work on some research studies in the area and stuff, menopause is so hard to find in the chart. We're not always bringing it up. We're not addressing it. It's a topic that we really need to be thinking about because it definitely can impact our patients. And we do know some about the best ways to manage things over this life stage, especially based on some of the data we have from other life stages.

Dr. Katie Krulisky: In general, what age range is menopause usually happening?

Dr. Kelsey Smith: Yeah. So the average age of menopause in the United States is around 51 to 52. There's some earlier data from those other studies I already mentioned about menopause and epilepsy that suggests the age may even be younger for women with epilepsy, especially with uncontrolled seizures. We need to be thinking about this really between the ages of 40 to 55 or so.

Dr. Katie Krulisky: So maybe even, considering I'm always asking women about childbearing potential, but maybe even including it in that discussion of are you still having a menstrual cycle?

Dr. Kelsey Smith: Yeah, I think so. Are you still having a menstrual cycle? Is there association with your seizures? And if we get more comfortable with this topic, even understanding eventually menopause symptoms and how they could influence seizures. The other thing that's a little interesting in terms of epilepsy and menopause is vasomotor symptoms. People get these hot flashes. They just last a few minutes. They can happen any time of the day. And so I could even see how clinically it could be somewhat difficult for some patients to maybe differentiate from focal seizures and things. So it's just interesting in that scenario. They could not be clear, are those seizures, what are these new symptoms? So important for us as epileptologists to recognize.

Dr. Katie Krulisky: It's important in epilepsy and I also think it's important, because I do some general neurology. I do general neurology and epilepsy as my practice, and I see it actually pervasively in neurology. I've had people come to me with symptoms of difficulty swallowing and just really broad symptoms. And then I remember one case specifically that they came back to me and said, "Oh, I was just going through menopause. I feel much better now."

Dr. Kelsey Smith: Yeah. And the brain fog and other things that can come with menopause obviously can span different potential neurologic diagnoses.

Dr. Katie Krulisky: Totally. And I have to say somewhat embarrassingly that I feel like I myself am not the most comfortable with discussing vasomotor symptoms associated with menopause. What topics are you screening for or what symptoms are you screening for?

Dr. Kelsey Smith: When you see someone in this midlife stage just asking, "Are you still having menstrual cycles? Do you feel like you've gone through menopause?" Because it's difficult to get that information or impossible to get that information without just asking about it. And then just asking if they're having symptoms they think that have changed with fluctuations in menstrual cycles as well to suggest they're in perimenopause and if they're having vasomotor symptoms or new sleep disturbances, what those could be like.

Dr. Katie Krulisky: I know the sleep thing comes up a lot with our patients. Do you have a first step of approaching that with the sleep issues or are you referring, trying to manage it yourself?

Dr. Kelsey Smith: I try and understand what the sleep disturbance is. Is it falling asleep? Is it frequently waking up? If there's any chance there could be potential sleep apnea playing a role, then I usually do an overnight oximetry and consider referral to look for that because sleep disturbance from sleep apnea, which can obviously start at any age, but mostly in older adults, if they're having problems with sleep apnea, then that needs to be managed first.

Dr. Katie Krulisky: Thank you so much, Kelsey, for taking the time to discuss your review on management of epilepsy in midlife women. The paper is titled The Menopause Transition in Epilepsy: A Focus on Therapeutics, and you can read all the details in the Neurology Clinical Practice Journal.

Dr. Stacey Clardy: This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword in your podcast app for any neurology specific topics.

Dr. Margarita Fedorova talks with Dr. Pascal Geldsetzer about how the herpes zoster vaccination may have neuroprotective effects, potentially delaying or preventing dementia.

Read the related article in The Lancet Neurology.

Disclosures can be found at Neurology.org.

Podcast Transcript:

Dr. José Merino: This is José Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.

Dr. Margarita Fedorova: Hi, this is Margarita Fedorova and I'm a neurology resident at the Cleveland Clinic. Today, we're exploring a study that speaks to an idea that's been building for a few years now, that vaccination itself might be neuroprotective. I'm here with Pascal Geldsetzer, a physician and epidemiologist at Stanford University. Pascal is the author on a paper published in the February 2026 issue of Lancet Neurology titled "Herpes Zoster Vaccination and Incident Dementia in Canada: An Analysis of Natural Experiments." What makes the study different is how they got at the question. When Ontario started publicly funding the shingles vaccine, eligibility came down almost entirely to date of birth. People born a few weeks on one side of a cutoff could get the vaccine for free, and people born a few weeks on the other side could not. That left Pascal and his colleagues with two groups of older adults who should be alike in essentially every way, except their access to the vaccine. And they asked whether those groups went on to develop dementia in different rates. We wanted to bring Pascal to the podcast because this is a question our patients are already asking us in clinic, and because vaccination is one of the few things we can offer an older adult that might actually protect the brain. Pascal, welcome to the podcast.

Dr. Pascal Geldsetzer: Thank you very much for having me.

Dr. Margarita Fedorova: Let's start with a take-home message. If I'm rounding with a team tomorrow and I get to teach them one thing from your paper, one thing I want them to still remember six months from now, what should that be?

Dr. Pascal Geldsetzer: I think it is that for shingles vaccination and dementia, we now have a body of evidence from observational data that we're usually never able to obtain in terms of the fact that we are able to get at cause and effect in a much more plausible way than we are usually able to. And we can say here now that shingles vaccination may well have a delaying or preventing effect on the dementia disease process.

Dr. Margarita Fedorova: Before we get into your study, give us the background. We tend to think about dementia in terms of amyloid, tau, vascular risk, and lifestyle. Where do vaccines come into it? And is this really a shingles story or is it something broader about vaccination and brain health in older adults?

Dr. Pascal Geldsetzer: Yeah, so unfortunately we don't know exactly. And so of course, broadly speaking, it could be either through reducing reactivations of the chickenpox virus or varicella zoster virus, which we know is a neurotropic virus, which we know reactivates throughout life. And so reducing these reactivations and probably accompanying neuroinflammatory processes may well have benefits. But there may also be a broader potentially virus-independent immune mechanism at play here that may also apply to other vaccines than just shingles vaccination. So we don't really understand the mechanism yet. It's a very interesting and fascinating area of research and hopefully we'll learn more in the future.

Dr. Margarita Fedorova: We already knew from a lot of prior work that shingles vaccine was associated with a lower risk of dementia, but in the paper you were direct that those earlier studies can't really speak to cause and effect, and that's a really big part of why this one matters. What goes wrong when we simply compare vaccinated people to unvaccinated people and how does your design get around it?

Dr. Pascal Geldsetzer: So this gets to the fundamental problem that we usually have in observational data analysis in epidemiology, right? It's that those who get a certain intervention, who get a certain medication or who decide to adopt a certain lifestyle regimen, certain diet, or who decide to get vaccinated are just very different to those who don't. And especially in the case of vaccination, we know there's this healthy vaccinee bias whereby those who have better preventive health behavior, health motivations, et cetera, are the ones who go get vaccinated and they have a lower risk of dementia in any case regardless of vaccination. And we can try to adjust for these differences between these groups. And that's what we do in epidemiology with all sorts of fancy methods. But at the end of the day, what we're restricted to is the information that we have in the data sources that we're analyzing. And I just don't have very much information at all in electronic health record data, medical claims data, et cetera, on all these various health behaviors, health motivations, dietary behaviors, et cetera, et cetera. So it becomes really hard to know whether we are really truly able to adjust for all of these differences. What we are doing instead in these shingles vaccination natural experiment analyses is we're changing the comparison group to something that's much more close to what we have in a clinical trial. And of course the clinical trial is what we need to ensure that the comparison groups are comparable because we know all that's different about them is whether a coin landed on heads or tails. And here in our natural experiments, we know that all that's different about the groups that we're comparing is whether they happen to be born essentially by random chance a few days earlier or a few days later because our natural experiments are exploiting these date-of-birth-based eligibility rules for shingles vaccination. For instance, in Wales, in our first paper that we published in this series, we know that those who had their 80th birthday just prior to the start date of the shingles vaccination program, which just so happened to be September 1st, 2013, were ineligible and remained ineligible for life. Well, if you had your 80th birthday just after, you were eligible and we see a jump in your probability of ever getting the vaccine by just a week's difference in birth from 0% to 50%. So we have now this really sharp contrast just by the fact that you were born a few days earlier or a few days later. And that's what makes our comparison groups different and the effects that we're seeing much more likely to reflect true cause and effect rather than just a correlation.

Dr. Margarita Fedorova: And for this current natural experiment, what exactly did you find? Without talking too much about the numbers, can you tell us whether we think we're preventing dementia or delaying it with the vaccination?

Dr. Pascal Geldsetzer: We don't know exactly if we are preventing or delaying dementia. That's an active research area in my group to truly understand this. But what we're seeing is that these groups of people were born just on either side of this eligibility cutoff. Those who happen to be eligible because they were born just a little bit later have a lower probability of receiving a new dementia diagnosis in the future. It's hard to pinpoint the exact magnitude of the effect because our method really zooms in on people born just around this cutoff. And of course also various data limitations that we usually run into such as having knowledge on your exact vaccination uptake levels in these two groups dementia and ascertainment, et cetera. But what we can say is that there seems to be a large, certainly clinically meaningful protective effect for dementia in the future. We always have to bear in mind the intervention here is a simple one-off inexpensive safe intervention that's already recommended in any case for shingles prevention. So the bar that this intervention has to pass in terms of showing efficacy is much lower because the downsides are so low. This is a really exciting, for me at least, it's a really exciting area of research.

Dr. Margarita Fedorova: I wanted to circle back to you talking about randomized trials. So is a trial potentially the right next step here and what would one have to look like to settle this question?

Dr. Pascal Geldsetzer: Yes. So that is the dream that I'm currently pursuing, trying to see if we can get the funding together for a clinical trial of the shingles vaccine that we have been studying in all our natural experiments, which is an off-patent shingles vaccine. It's the old live attenuated vaccine and may well be specific the effects that we're seeing to that vaccine. So just to reduce uncertainty using that vaccine is important. But that also means for funding, we really have to try to see if we can get philanthropic funding, private foundations. So yeah, that's what we're hoping for somehow. But yes, really to conclusively test this question, this link, what we need at the end of the day is a clinical trial and also to convince the medical and public health community. And also because it offers just really important opportunities to learn more about this link that we can't in observational data analysis. So it's a trial that would be ambitious in terms of its sample size because we do need here, we have the evidence for dementia prevention and that means we need a large sample size to be able to have enough events. However, we already start seeing survival curves for dementia incidence separating after about a year and a half or so, a year and three months. So a four-year follow-up period, for instance, would be reasonable. And so it's not a trial that would need to take decades. And yes, that's what I'm pursuing at the moment.

Dr. Margarita Fedorova: I do want to briefly talk about any important caveats that we have in this project. I'm thinking in particular about the sex difference since the effect looked stronger in women, and I suspect that this is one piece that people will latch onto. How much weight should we be putting on that?

Dr. Pascal Geldsetzer: Yeah, it's something that we tend to be seeing in our data sets that there are stronger effects, stronger protective effects among women than among men, but it doesn't mean that men do not benefit. And there's also still some uncertainty as to really how large or important this difference is between the sexes. It was particularly marked in our first analysis, but that was a bit of an outlier in terms of that relationship.

Dr. Margarita Fedorova: I also wanted to talk about what to do with this in terms of clinical practice and specifically patient counseling. Most of us in neurology don't think of ourselves as the people responsible for patients' vaccination. Should we be? And is there a case for a neurologist asking an older patient or patient with cognitive complaints whether they're up to date on their shingles vaccine?

Dr. Pascal Geldsetzer: It is a recommended vaccine for adults 50 years and older in the US. We know it prevents shingles. We know shingles can have a variety of complications. There's also some evidence that shingles vaccination potentially has benefits for cardiovascular and cerebrovascular disease risk reduction. So putting all of this together, I know clinicians are busy and that is probably the downside, having the bandwidth and taking the time to do this, but I certainly think it can't hurt to check on vaccination status, to recommend vaccination in those who are eligible for the vaccine. And for dementia, we can say now that there may well be benefits also for dementia, for cognitive health in older age.

Dr. Margarita Fedorova: And in terms of the underlying mechanism of the vaccine, there was a paper last year on the AS01 adjuvant that raised the possibility that the benefit isn't entirely about the virus, but more about what the vaccine does to an aging immune system. If that turns out to be right, it would say something much bigger about vaccination in older adults. Where does your instinct land?

Dr. Pascal Geldsetzer: It's hard to say. I'm probably the wrong researcher to ask about this because I don't look at basic science so much. I'm really more of a data cruncher, but certainly it's a possibility. We know these broader immune mechanisms are important for vaccines and seem to vary by particular types of vaccines. We just don't know yet to what degree they impact on chronic diseases, these broader mechanisms, including dementia. There's a strong case to be made as well, of course, for something specific to the varicella zoster virus, given that we know these neurotropic herpes viruses are in this constant interplay with the immune system, cause these neuroinflammatory processes, and that this poses some sort of chronic immune stress that drives inflammation in the body is something that, and that could be particularly important in older age as the immune system weakens. It's certainly something that seems to me at least very plausible as well from a biological perspective.

Dr. Margarita Fedorova: So let's say I have a 72-year-old in clinic next week. She's read a headline about the shingles vaccine and dementia, or maybe she's hesitant about vaccines in general. What is a fair and honest thing for me to tell her? How would you use this evidence in that conversation without overselling it?

Dr. Pascal Geldsetzer: Yeah, so of course I'm a researcher. I try to shy away from making vaccination recommendations, but practically speaking, I would certainly say it's safe to say that the shingles vaccine is a recommended vaccine for older adults. We know it prevents shingles and its complications. And we now have an additional body of evidence that suggests that the vaccine may also have benefits for dementia for cognitive health in older age. That is a very fair thing to say.

Dr. Margarita Fedorova: Thank you so much. I've been speaking with Pascal Geldsetzer from Stanford University, who's a senior author on a paper published in the February 2026 issue of Lancet Neurology titled "Herpes Zoster Vaccination and Incident Dementia in Canada: An Analysis of Natural Experiments." Thank you for your time and insight today.

Dr. Pascal Geldsetzer: Thank you. Thank you so much for having me.

Dr. Stacey Clardy: This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for a full list of past episodes, or you can also search by keyword in your podcast app for any neurology-specific topics you want to learn about.

Dr. Jason Crowell talks with Dr. John McDonough about the historical and economic factors shaping the US healthcare system and why understanding these systemic forces matters for neurologists and patient care.

Read the related article in The Harvard Gazette.

Disclosures can be found at Neurology.org.

Podcast Transcript:

Dr. Jose Merino: This is Jose Merino, Editor-in-Chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.

Dr. Jason Crowell: Hey, this is Jason Crowell from Norton Neuroscience Institute in Louisville, Kentucky. Thanks for listening to today's Neurology Podcast. Most of our audience members are practicing neurologists, you're in training or you're in an academic setting or in private practice. And for those of us who are in practice, we are well aware of the challenges of helping our patients access drugs, getting prior authorizations approved, the other areas of friction that exist in our healthcare system. And I would say that whether we realize it or not, these areas of friction are symptoms of larger choices about how our hospitals and clinics operate. And so to help us think about these things, today we've invited John McDonough to join us. John is a professor of public health practice at the Harvard T.H. Chan School of Public Health. We recently read an article about John's work published August 18th, 2026 in the Harvard Gazette and wanted to invite him to join us today. So John, thank you so much for your time.

Dr. John McDonough: Pleasure to be here with you, Jason. Thanks for inviting me.

Dr. Jason Crowell: So John, in this piece that I read in the Harvard Gazette that was describing some of the work you've done, you point to a specific historical pivot around 1980 when US healthcare spending grew at a pace that's disconnected from the rest of the industrialized world. And that was 40 to 50 years ago, so most of our audience does not have experience with the practice of medicine prior to that time. The title of your upcoming book is America's Wrong Turn: US Healthcare in the Neoliberal Era. Can you help summarize what you mean by this wrong turn that happened? And also, can you just give us some background about what you mean by this neoliberal era?

Dr. John McDonough: So I've been influenced by a Yale political scientist, Stephen Skowronek, who suggests that there's a helpful way to look at American political economic history, not through the lens of individual presidential terms like say the Nixon era or the Reagan era or the Obama era, but to look at larger multi-decade politico economic eras where there are dominant political strains. And Skowronek says we've had five of these eras over the 250 years. But just to talk about the two most modern ones that are most relevant to our discussion here. The first one started in 1933 with Franklin Delano Roosevelt's inauguration as president in the midst of the Great Depression. And inaugurating an era that became known as the New Deal era, which was an era of muscular federal and state governmental leadership and guidance in terms of steering the economy toward greater productivity, toward higher wages, toward all different kinds of innovations like social security and Medicare and Medicaid. That era didn't end when FDR died. It went on until 1980 when it collapsed in the end of the Jimmy Carter presidency with upset and anger over what was then called stagflation, the Iran hostage crisis, the gas crisis from the Middle East with OPEC. So it was succeeded in 1980 with the inauguration of Ronald Reagan. And Ronald Reagan came in openly talking about let's move away from the New Deal era. It's not working anymore. We have to go forward. And that era was in some ways, people call it the neoliberal era because it was an era defined by a set of economists like Milton Friedman, Friedrich Hayek, other folks, Robert Bork, James Buchanan and others. And it represented a move toward let's have a much more muscular free market defining all manner of sectors of American economy and American society. Let's de-emphasize government to the maximum extent possible and just allow the free market to run. We have a professor at Harvard in the college, Naomi Oreskes, who refers to the era as the free market fundamentalist era. That's her label. I prefer neoliberal just because neoliberalism was actually a global movement in the '70s, '80s and beyond. It still lives on today in many places and in many ways. And it was not aimed at trying to transform American medical care or our healthcare system, but healthcare and medical care in the US is so huge and so important that it's really impossible to imagine that we would go through this societal revolution and medical care would go untouched. So my premise is that it did get touched quite a bit in a series of ways that I look at and say it created a lot more harm than benefit. And so inviting people to look at the neoliberal phenomenon in terms of its impact on health and medicine in the United States.

Dr. Jason Crowell: One of the key shifts that you highlight is the massive market consolidation that has occurred here in the healthcare system. And we've seen this in our own neurology practices. Small independent subspecialty practices are very rare these days. Many of them have been bought up by health systems or private equity firms. And we understand that when healthcare merges occur, the claimed value is in regards to more efficiency, less overhead, but you cite research that shows prices actually increase following hospital mergers. So has this consolidation in healthcare, how has it affected the delivery of healthcare?

Dr. John McDonough: So antitrust, anti-monopoly, anti-oligopoly began in earnest in the United States in the 1890s after the passage of the Sherman Antitrust Act. And over the succeeding 90 years, we had a belief that big corporate concentration in any sector, whether it's a humongous sector like steel or railroads or even relatively minor sectors that mattered in the economy, had to be confronted and addressed when you had companies that were growing by consolidating, swallowing up hostile takeovers that created then market dominance for one or several firms. And in the 1970s, and this came straight out of the neoliberal era, it was led by a man by the name of Robert Bork, who many people have probably heard of, former Solicitor General under President Richard Nixon, failed candidate for the Supreme Court in the mid-1980s. But in the 1970s, he took on the antitrust consensus that had governed the nation for 80 to 90 years. And he said, "We've got it all wrong. Big is not bad. If companies get big, it's because they deserve to be big and we should just let that happen. And if they get beaten up by the market, that'll take care of it, the discipline of the market." And he put these ideas together into a book and the book was called in 1978, The Antitrust Paradox. And he proposed what he called the consumer welfare theory of antitrust, which says that if two companies want to come together and they can demonstrate that consumers will benefit from lower prices, then it should be a green light. Do what you want, go ahead. And in the early 1980s, they rewrote fundamentally the federal antitrust guidelines, which provide the consensus to federal judges, federal prosecutors, states, everybody. Here's how we see it. And they rewrote them in 1981 and '82 to bring the consumer welfare hypothesis of Robert Bork into the mainstream in terms of this is how we look at antitrust. And so we had about 40 years of diminished antitrust enforcement kind of going into hibernation that affected the medical and healthcare community. So by the year 2020, in US counties, about 95% of US counties had what's called highest levels of corporate concentration. And with medical specialization at that point, it was about 65%. It's more now. For insurance companies, it was 75% highly concentrated markets all over the country. And there's a lot of newer economic research over the past several years that says that if we really want to understand why medical care, healthcare prices, insurance premiums, everything else is going up so much, they're looking at it. They're saying the extraordinary degree of corporate concentration over these decades has to be considered one of the prime, if not the most important culprit in terms of explaining what went on and how we got so consolidated relative to today versus where we were in the late 1970s.

Dr. Jason Crowell: Let's turn to drug costs for a second. We have talked about drug costs on this podcast for several years. We have closely followed the work of ICER, the Institute for Clinical and Economic Review, and the work that they've done in helping us understand the value of drugs. Our multiple sclerosis colleagues are very familiar with the high cost of drugs. We now have these anti-amyloid therapies available for patients with certain neurodegenerative disorders that our cognitive neurologists are using. And of course we celebrate these new drugs for our patients with neurological diseases, but the price tags that come with some of these drugs can be staggering and are often associated with significant friction in terms of accessing them. So whether it's step therapy or prior authorizations or large out-of-pocket copays. Would you say that these administrative frictions are a deficiency of our current system, or a necessary feature to contain the cost?

Dr. John McDonough: They are to some extent signs of dysfunction in the system in the sense that they've led to outcomes that have significantly diminished the level of competition and competitiveness. Just one data point for you, between 1985 and 2002, the market share of the top 10 firms in the pharmaceutical industry more than doubled from 20% in 1985 to 48% in 2002 in global sales, and it's gone up even more today. So we've seen the same story of heavy corporate consolidation. We see that far more than the money that pharmaceutical companies spend on research and development, which is the claim of what they need all this money, is substantially greater amounts of money sent out to their shareholders in terms of dividends and financing stock buybacks to an extraordinary extent that we've never seen before. Stock buybacks are when a company basically just buys back shares from stock owners just to shrink the share so that everybody's price then rises. Prior to the 1980s, since the 1930s, the New Deal era, buybacks were illegal. They were outlawed. They were considered to be corporate exploitation and manipulation that should not be permitted. And now it is just a regular feature that is part of another related growing phenomenon that we've seen over these past 40 to 50 years, which is the term financialization. That across the medical care sector, more and more of what is done is not being done with the prime purpose of creating products, improving care, improving people's health. It's being done to increase the financial wealth of the holders of capital to an extent that we have never really seen since way early in the 20th century, a long time ago. And so we see it in pharmaceuticals, we see it in medical devices, we see it across the board, we see it in hospitals. We even see it to a significant extent in the nonprofit hospital sector where we have had the creation of what we call mega providers who are now no longer just care delivery organizations, but they are major research institutes. And that has advantages and that has a role, but it is like everything else there's sometimes something called too much of a good thing. Or too much of the magic of the market in a way that then has harmful side effects and harmful results in terms of what people most want. We've had 40 years of tremendous growth in the size of our healthcare system in the United States as we have seen life expectancy still continue to grow, but grow way, way behind all of the other leading advanced industrial nations. And if we're not here about improving life expectancy, what are we here for?

Dr. Jason Crowell: To quote you, you said it's going to take radical action, quote, "Radical action to make changes that fix the system." So I would ask if you were advising healthcare policymakers today, what's the top two or three things, the top interventions that you would provide to improve the lives of our patients? Or by proxy to help us as neurologists and physicians who are trying to help these patients?

Dr. John McDonough: I would say right now that we are in an incredibly vital and dynamic period right now in 2026. In some ways it reminds me of 2005 and '06 when people were thinking about the next wave of health reform in the United States, which ended up resulting in the Affordable Care Act. But the people were looking three and four and five years ahead and starting to ask the questions, what's most important? What would have the greatest impact? I see us in a similar phase right now, and so there are loads of individual ideas. I put them into categories. We really need to re-empower patients and consumers in this system who have been turned into widgets for the financialization of the whole sector. We need a brand new patient bill of rights in the United States that gives patients protections around prior approvals, around excessive cost sharing, around various forms of manipulation by the market. Signing non-disclosure agreements and mandatory arbitration, rather than being able to take grievances to court, for example, that is now almost universal. We need a new set of protections for physicians, nurses, and other parts of the healthcare workforce to be able to exercise their rights and protect their professional values and identities in the face of a corporate takeover of so many parts of American medicine. We're dealing so much with moral injury to providers who find themselves at the wrong end of the stick of private equity, for example, and other kinds of corporate irresponsibility. We need a new code of conduct for corporations. We need a much more aggressive attitude toward market consolidation, whether it's monopoly or oligopoly or whatever. And we saw that, we started to see that in the first four years of this decade when President Biden put in a woman named Lina Khan in charge of the Federal Trade Commission and Jonathan Cantor in charge of the Justice Department's anti-monopoly division. We saw over those four years, and it was too brief a time to take full hold, but an extraordinary turning of the tide in terms of the ability of the large companies to take over at will anything that they wanted and to be able to merge and consolidate in ways that has been harmful, particularly looking at the vertical integration of major companies such as, for example, United Health Group or CVS. We've seen no longer just growing in their own spaces, but so United Health taking over providers, taking over pharmacy benefit management, taking over health data in ways that are just, it's too much power in one entity. And it has the tail wagging the dog and probably at this point, the tail is larger than the dog itself in many ways. Lots of categories also. We need to really rethink access to care in the United States, how people obtain it. And so a lot of not just individual interventions, we're going to need whole categories. We didn't get to this place through one or two or three or four policy changes. We saw 40 years of policy changes inside and adjacent to the medical care sector, and that needs to be addressed, but it's not going to happen overnight. It's a long-term project. And it's not about moving backwards to where we used to be 50 years ago. It's about a new vision of where we have to move forward in this age, in this era right now.

Dr. Jason Crowell: And John, as we wrap up here, I started by saying most of our audience members are busy in clinical care, maybe some do research, but we see a lot of patients, inpatient hospital duties. It can be easy to hear about these massive, very large scale policy issues and feel ill-equipped to make any difference. And so for the neurologist who's listening to this podcast on her commute home, who wants to provide great care, but she feels overwhelmed by the surrounding systems of care, do you have any recommendations about what she and all of us can be doing to meaningfully engage with or push back against some of these issues we face?

Dr. John McDonough: I know people in your specialization, Jason, are incredibly challenged keeping up with the fast pace of innovation in terms of research and innovation and discovery, and find it hard to keep up with that in many ways because of how fast things are moving in this new environment. I would suggest that it's also important to pay attention to the political and economic factors that surround your specialization. To understand and think about how changes going on in these areas that are adjacent to medical care practice and to surgical practice today are having real impacts in terms of how people are able to deliver care in ways that they think is most effective and efficient for their patients. And so I'd say that paying attention to some of these economic and political factors, weighing in with members of Congress who are considering perhaps changes to the rules around monopoly and consolidation or private equity, or other manifestations of the financialization and corporatization of American medical care, it's very important to do some education. For example, if you want to understand where we are or where we've come from in terms of market concentration and monopoly, I just recommend a single book called Goliath by a guy named Matt Stoller, S-T-O-L-L-E-R. Which is a 140 year history of monopoly and antitrust in American society. A different explanation, one that I find quite compelling and quite important.

Dr. Jason Crowell: Terrific. We really appreciate you joining us today, John. Again, I've been speaking with John McDonough. He's a professor of public health practice at the Harvard T.H. Chan School of Public Health. We came across his work that was described in the Harvard Gazette published back on August the 18th. John, thank you again for your time and your expertise. We really appreciate it.

Dr. Stacey Clardy: This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword on your podcast app for any neurology specific topics you want to learn about.

Dr. Shuvro Roy talks with Dr. Daniel Daneshvar about the prevalence of CTE at death among NFL players and the association between CTE severity and the risk of dementia.

Read the related article in the BMJ.

Disclosures can be found at Neurology.org.

Podcast Transcript:

Dr. Jose Merino: This is Jose Merino, Editor-in-Chief of the Neurology family of journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening, and have a great week.

Dr. Shuvro Roy: Hi, this is Shuvro Roy from the University of Washington, and welcome to today's Neurology Podcast. We'll be covering a study titled Prevalence of Chronic Traumatic Encephalopathy and Death in National Football League Players: A Retrospective Population-Based Cohort Study from 2008 to 2001, published in BMJ. We're joined by lead author Daniel Daneshvar, Chair of Spaulding Rehabilitation at Harvard Medical School. Dan, thanks for joining us.

Dr. Daniel Daneshvar: Great to be here. Thanks for having me.

Dr. Shuvro Roy: So Dan, this study has already received widespread national attention, but please give us the headline. What did you find and what's the number one thing that you want listeners to remember?

Dr. Daniel Daneshvar: So this was a study looking at how commonly this specific neurodegenerative disease called chronic traumatic encephalopathy or CTE, how commonly this occurs in a cohort with a lot of repeated traumatic brain injury exposure, namely former National Football League professional football players. And what we found was that between the years of 2016 and 2021, so for that five-year period, the absolute minimum prevalence of CTE at death in this group was 25%. The absolute maximum was 98%, and the true rate is somewhere in that range. Now, for context, in the general population in community cohort studies, the prevalence of this pathology is somewhere south of 1%.

Dr. Shuvro Roy: And what does this study add to our current understanding of CTE and neurologic disease associated with head trauma?

Dr. Daniel Daneshvar: So we've long known that individuals who have experienced repeated traumatic brain injury exposure, whether through sports like NFL, NHL players, professional soccer players, whether through occupational exposures like in the military or as in individuals who experience intimate partner violence, we've long known that these individuals have higher rates of neurodegenerative disease. But what we haven't known is just how much higher that rate is. And what this study has shown us is first off that this is alarmingly high in former professional football players at death. And then the second thing that this study shows us is that this pathology is unsurprisingly very linked to clinical symptoms, including with more severe disease, cognitive impairment that's so severe it results in dementia, meaning impairment in someone's ability to perform activities of daily living, including feeding, bathing, dressing, grooming, toileting, those kinds of things.

Dr. Shuvro Roy: As you pointed out, your primary finding was that there was this maximum versus minimum prevalence, which ranged from anywhere from 98% to 25%, so obviously a wide range. But to help us understand this study, can you walk us through that methodology, the minimum and maximum prevalence approach? Why a range rather than a single estimate? And you mentioned that the number is likely somewhere in between. Where do you think that true number sits, if we even can estimate?

Dr. Daniel Daneshvar: So to understand why there's a range, it's helpful to understand how we got to these numbers. And so when we looked at the individuals who had CTE who played in the NFL across three brain banks, mostly the BU CTE Center, but also the Mount Sinai Brain Bank and the UCSF Alzheimer's Disease Center Brain Bank, when we combined all NFL players across these brain banks, we found that NFL players had a 93% prevalence of CTE at death, but that 93% represents a selected cohort. These individuals who chose to donate their brains more often than not chose to donate because they or a loved one had some concerns about them, not always, but many times. And so we don't believe that the true prevalence in NFL players is 93%, but what we wanted to get at is what could that true prevalence look like? And so we took advantage of the fact that amongst the NFL community, brain donation is something that has been less stigmatized over the past couple decades and is something that is very common. And so we said for the lowest, the conservative minimum prevalence of CTE, let's say that everybody who was not studied by one of our brain banks, that every single professional footballer who died during that time period had no CTE at all in their brain. If we make that assumption, then the absolute minimum over those last six years of the study is that 25%. Now, it's important to note what that assumption entails. That assumption assumes that, for example, the people who were diagnosed with CTE at other brain banks that were not included in this study, it assumes that they did not have CTE, even though they were diagnosed with CTE at other brain banks. That conservative minimum assumes that the 16% of people with dementia so severe, it was listed as the actual cause of death on their death certificates, the 16% who didn't donate, that they did not have CTE either. Now, of the people who did donate, for the folks who had dementia, 96% of them had CTE. So that's quite an assumption. We're assuming that they were all clean too. Despite those assumptions, the conservative minimum of CTE prevalence amongst these NFL players is one in four. Now, the maximum on the other side assumes that the only individuals who played in the NFL who died during that time period that didn't have CTE were the ones that we laid eyes on, and so that everybody else, they did have CTE. That's how we get the upper bound. And so when I say that range is somewhere in the middle, based on those assumptions, it's almost certainly higher than that 25% and likely substantially higher.

Dr. Shuvro Roy: So essentially trying to maybe correct for the possibility that maybe there's a "sick bias" or selection bias of the brains that were donated, but even the 25% is almost certainly too conservative, considering it is likely that those folks with dementia, at least some of them had some degree of CTE. To that point, beyond prevalence, you showed that stage four CTE was strongly tied to dementia with 90 plus percent of those donors affected. What does that add to the argument about CTE pathology mattering clinically? Can you speak a little bit more to that?

Dr. Daniel Daneshvar: It's pretty clear at this point that CTE pathology is associated with a substantial cognitive impairment, especially as it gets severe. In a different study, we took a look at individuals who had CTE in the absence of any other neurodegenerative disease, and we found in that study that individuals with more severe pathology were more likely to have dementia and specifically with stage three and stage four CTE. In this study, similarly, we also found that in individuals with CTE in the absence of other neurodegenerative pathology, which represented 53% of donors who had CTE that had no other neurodegenerative disease had dementia too. So CTE clearly can result in dementia when the pathology is severe. But that's, again, not surprising for anybody in the neurodegenerative disease space because the pathologic marker that's most closely linked to cognitive impairment in a disease like Alzheimer's disease, it's not the amyloid pathology, it's the tauopathy, it's the phosphorylated tau, the same neurofibrillary tangle pathology that we see in Alzheimer's. When that disease occurs in a different pattern, but also in CTE, it's not surprising that we see individuals with cognitive impairment.

Dr. Shuvro Roy: You also looked at the death certificates of the donors in these cases, and death certificates missed roughly 70% of the dementia that your clinicians identified. I think about CTE in the news and how many prior players who have since been found to have CTE posthumously were not necessarily identified to have dementia at the time. What does this finding mean for some of the earlier NFL mortality studies that relied on these numbers of the percentage of players who had dementia?

Dr. Daniel Daneshvar: Again, it's not particularly surprising for anybody in the neurodegenerative disease space that death certificates under-report the prevalence of dementia, because many individuals die with dementia but may die of say an MI or something else. But we've both been the beleaguered intern in the ICU in the middle of the night that has unfortunately had to write a death certificate for a patient of ours. And oftentimes what we're writing is the most proximal cause of death. So we might write that sepsis or pneumonia was the cause of death, but might not include on the death certificate that the sepsis was due to urosepsis related to dysphagia related to dementia. Those factors aren't typically what we are including in the death certificates. And so we know that death certificates are under-counting the rate of neurodegenerative disease. But what this study allowed us to do was put a number to it to let us know that we're missing the vast majority of individuals who are dying with dementia but of other processes if we only look at the death certificates. And so when we look at death certificates and we try to ascertain the causes of death for individuals, we might erroneously think that something like a heart attack is a bigger issue for NFL players than something like dementia, but that's why it's so important to take a look at what the population averages are. And so when we look at something like MI for NFL players, they die with MI, as we showed in a paper we published in Lani City Clinical Medicine last month. They die at a lower rate than the general population of MI, unlike dementia where neurodegenerative disease causes of death occur at a substantially over four times higher rate than the general population.

Dr. Shuvro Roy: Understood. Dan, I want to change tracks slightly. There's some really interesting findings in these studies that build off of prior work, as you mentioned. In this study, for example, career length predicted how severe CTE was, but not whether it was actually present. Back a few years ago, we had the opportunity to interview Anne McKee, one of your co-authors on this study on the same topic. And one of the major takeaways, at least at that time, was that duration of career did predict CTE presence in those studies. How should we think about these newer data in that context of those prior studies?

Dr. Daniel Daneshvar: Yeah, so great question. In this study, 93% of the decedents who donated had CTE pathology. And so we're looking at a profound ceiling effect rather than our previous work, which has looked at individuals across the entire range of exposure. To put it differently, what we effectively found in this study is that if you had 90 plus pack-years of smoking, that smoking 90 versus 95 pack-years didn't really play as big a role in whether or not you got lung cancer. It played a bigger role in how severe that lung cancer was for the people who got it. But there are some people who for genetic or other reasons, they just didn't get the disease. That's what we found effectively in these analyses. When you restrict it to the most extreme outliers in exposure, the people who had the most exposure to repeated traumatic brain injuries, the relatively small differences between that extreme end, it didn't predict CTE status, but it did predict the severity of the pathology. So if you had 16 years of American football versus 18 years of American football, that extra 10,000 Gs or so of head impact exposure, that didn't predict CTE status. But for those who unfortunately did have CTE pathology, it very strongly linked to how severe that pathology was.

Dr. Shuvro Roy: Understood. That makes a lot of sense. So essentially, that signal may still exist. It's more just with this particular population, given the sheer prevalence of CTE, we likely would not have the granularity to dig out the presence or lack thereof of CTE and how much that played into it, really just the severity. So that makes sense.

Dr. Daniel Daneshvar: It's also just important to note that the majority of the people that were included in this cohort, they were part of the previous studies that included the full range of donors. For example, there were 338 people in this study that donated that played in the NFL. Now, in our previous work, we looked at not just the NFL players, but we looked at over 600, I think it was 636 or so people who played football across the entire range from one year of football all the way up to 30 years of football. And in that study, we found a very clear dose response relationship between both the duration of play and the cumulative force to the head that these individuals experienced, and both the likelihood of CTE and for those that got it, the severity of CTE. So the best predictor that we have right now for whether or not someone's going to develop CTE, it appears to be the cumulative force to the head that someone experiences over their entire life. Of note, concussion did not predict CTE status. Of note, position played at the highest level did not predict CTE status. It really appears to be that cumulative force to the head.

Dr. Shuvro Roy: It's those cumulative sub-concussive hits that seem to be the most predictive for the body of work that we've seen thus far. Now, in prior work in this space, as you just mentioned, there has seemingly not been a correlate between CTE and football position played. That was always surprising to me. You might think that positions, there is that repeated trauma, offensive line, defensive line, linebackers, running backs, et cetera, would seemingly be at higher risk. In this study, you had some newer findings. Could you take us through those findings related to position played and the implications there?

Dr. Daniel Daneshvar: In this study and in previous work, we found that there isn't really a great link between position played at the highest level and CTE status. Now, of note, part of the issue is that we think of these repeated head impacts in terms of the number of hits, but what appears to matter more is the number times the force of those hits. And so folks like the linemen who are getting a lot of hits tend to be getting lower G-force hits. And in fact, actually, when you look at the cumulative force to the head, the relative difference between positions, they aren't that high. They exist, but they aren't that high. But it's actually the running backs who get the highest combination of force and number of hits versus the lineman. Now, another thing that we note is we think of these other hits that don't result in concussion. We often refer to them as sub-concuss, and that terminology is actually problematic because it masks the fact that so many of these head impacts are actually really substantial. For example, based on helmet sensor data, for a given offensive lineman in college who gets a concussion, going back and looking at all of the head impacts that that person experienced, for every head impact that resulted in a concussion, on average, that offensive lineman experienced 41 hits to the head of equal or greater force than the head impact that resulted in that concussion. And for that reason, we don't think that the term sub-concussive is really the best name for those impacts that don't result in concussions because sub implies that it's less than, when in fact, very many of these head impacts are technically, if you had to give it a name, supra, they're greater than the force of a concussion. And we published this in BJSM a couple years ago. We think the terminology should actually be non-concussive so that there are impacts that result in symptoms or signs, that's a concussive injury, but that there are impacts that don't result in signs or symptoms of concussion. Those are separate, those are non-concussive, and many of them can accumulate and cause subclinical traumatic brain injuries.

Dr. Shuvro Roy: I have certainly been guilty of using the term sub-concussive, so I will be correcting my terminology as well, and that's quite helpful. One thing actually you mentioned with the running backs, while there was no difference in the rate of CT presence, was there any difference that we saw with the presence of stage four CTE by position?

Dr. Daniel Daneshvar: One of the issues when we're looking at NFL players is that most NFL players, they didn't stick with one position. Most players, if you are a wide receiver at the NFL, many of them were the best player in their high school and were pretty much playing every position, but most often quarterback because you wanted your best player in the position that had the most touches. And so that's one of the problems when we look at the highest levels of play. But when we did look at highest level of play, what we found is that individuals who had stage four CTE were actually most likely to be running backs and least likely to be defensive linemen. So these data lined up really well with our 2023 Nature Communications paper where we similarly found that it appeared that the running backs were the ones that got that highest cumulative G-force. These data support those.

Dr. Shuvro Roy: That is really helpful context. And actually to your point of players over the course of their careers, when we look at this cohort, obviously a cohort of professional athletes that develop CTE, the burning question for those listening is how should we counsel younger players, youth, high school, college football players from these data? Is there anything new to counsel them on based on these results?

Dr. Daniel Daneshvar: This was a study of NFL players, and so the data only explicitly applied to NFL players, but their cumulative head impact exposure didn't start at the pro level. They had exposure in college, in high school, and many at the youth level. And so all of those head impacts matter. The accumulation of all of those, that cumulative force is what increases one's risk of problems later in life. And so if the background prevalence of CTE is somewhere south of 1%, like 0.6, 0.8%, and the prevalence in NFL players was at an absolute minimum under the most conservative assumptions, 25%, that's disconcerting then for those lower levels of play. And so that's where we need to think about ways that we can be more intentional about that cumulative force to the head that athletes are experiencing. And what I mean by that is doing things that reduce that cumulative force.

Dr. Shuvro Roy: I just am curious, do you feel like we have made progress in that way? When I interviewed Dr. McKee three years ago, for example, we didn't necessarily have these new Guardian caps that are placed over the helmet for practice, and now we even see them in games. Do you feel like we've made progress in that way?

Dr. Daniel Daneshvar: People are very excited about equipment and technological changes and their ability to influence cumulative force to the head, but I'm not convinced. I haven't seen data that's particularly convincing. What I mean by that is the Guardian caps that are used at the professional level, first off, those are ones that are not available below the professional level. So those are different than the ones that are being sold at the college and high school level. But those Guardian caps in lab testing have been shown to attenuate the force associated with the impacts by something like 7%. And so you're taking on average a 27G impact and you're making that 27G impact on average about a 25G impact. Pretty substantial head impact still. Now, the Guardian caps that are available at below the professional level, in lab testing, those have been shown to attenuate the forces associated by linear impact by about 3%. So you're taking on average a 27G impact and you're making it a 26 and change G impact. So I'm not particularly convinced that's going to be where the bulk of the difference is. Now, on the other hand, we know that nearly 70% of head impacts occur in practice. We also know that at the professional level, there's fewer than one contact practice per week. So if the college and high school and youth players practiced like the pros practice, we would eliminate more than half of the head impacts. We'd be making those 27G impacts, zero G impacts for up to 70% of them. That seems like it's a lot more bang for our buck, so to speak. And when you're talking about a few percent here or the majority there, a change that wouldn't affect a single minute of game time can get us a lot more power.

Dr. Shuvro Roy: Those are eye-opening numbers. I was not aware, for example, that when we look at the guardian cap data, that it's only a 7% reduction. And to your point, the vast majority of contact being in practice does seem like a lower hanging fruit. Finally, I would like to close with this. This study has placed a spotlight on the prevalence of CTE being far more common amongst NFL players than previously thought. I think this is the first time we've done a neurology podcast where we actually saw a study published in an ESPN article before we've even seen it in the journal itself. Where do you hope we can go from here? What do we still need to learn about CTE?

Dr. Daniel Daneshvar: Right now, CTE can only be diagnosed with known accuracy after someone passes away. And so we need to move from understanding CTE, which is critically important, to diagnosing and treating CTE, but we're making incredible strides on that front. We are identifying factors that help us diagnose the disease both based on clinical markers and objective markers, and we're also improving the ability to identify potential treatments for this disease. We should not get to the point where we can say an athlete has CTE in life and then not be able to provide that athlete with a treatment that meaningfully affects their risk of progression of disease. And so that's where we really need to be focused.

Dr. Shuvro Roy: Dan, you've been generous with your time. Thank you so much. Again, the article is titled Prevalence of Chronic Traumatic Encephalopathy and Death in National Football League Players: A Retrospective Population-Based Cohort Study published in BMJ. That has been today's Neurology Podcast. Thanks for tuning in.

Dr. Daniel Daneshvar: Real pleasure to be here. Thank you.

Dr. Stacey Clardy: This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword on your podcast app for any neurology-specific topics you want to learn about.

Dr. Kait Nevel talks with Dr. Katharina Schmidbauer about primary CNS T-cell lymphoma, highlighting diagnostic challenges, imaging characteristics, and treatment approaches for this rare disease.

Read the related article in Neurology®.

Disclosures can be found at Neurology.org.

Podcast Transcript:

Dr. José Merino: This is José Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.

Dr. Kait Nevel: Hello, my name is Kait Nevel. Today, I am interviewing Katharina Schmidbauer on her article, "Clinical Manifestations of Primary CNS T-Cell Lymphoma." Welcome to the Neurology Podcast. And Katharina, I would love to hear a little bit about you.

Dr. Katharina Schmidbauer: Thank you, Kait. Thank you for having me. It's a pleasure. I am a neurologist with a great research interest in neuro-oncology, working at the University Hospital of Munich.

Dr. Kait Nevel: Wonderful. Thank you for that. What do you think the most important takeaway is from your article for the practicing neurologist?

Dr. Katharina Schmidbauer: Primary CNS T-cell lymphoma is very rare and the diagnosis is often really difficult to establish. In this study, we present hallmarks of the disease that could help with the diagnosis in the future. And our case series really illustrates many diagnostic challenges. The first important message would be how to deal with diagnostic uncertainty. If you have a progressive tumefactive CNS lesion and the clinical course, the imaging, and pathology don't quite fit together, CNS lymphoma and also T-cell CNS lymphoma need to remain on the differential, even if the first biopsy is inconclusive. And in this context, it's also important to avoid, of course, steroids before biopsy because they could cause regression of the lesion and therefore make the biopsy non-diagnostic, which is not the same as a negative biopsy.

Dr. Kait Nevel: Thank you for that. And before we get into some more of the details of the findings of your study, could you give us a brief overview of the background and methods of your study?

Dr. Katharina Schmidbauer: Sure. Primary CNS T-cell lymphoma is very rare and an aggressive subtype of CNS lymphoma. Most primary CNS lymphomas are B-cell lymphomas, but for T-cell lymphoma, we have very little systematic data. In fact, there are only three case series so far, and therefore we performed a multicenter retrospective study across three centers in Munich, Heidelberg, and Boston. And there we identified 16 adult patients with histologically confirmed primary CNS T-cell lymphoma without systemic disease treated between 2008 and '24. We looked at several levels of the disease, the clinical presentation, of course, histopathology, immunophenotype, T-cell receptor gene rearrangement testing, and if available, next-generation sequencing. And we also gathered MRI and PET imaging, treatment regimes, and of course outcome data. We also centrally reviewed the imaging and histopathology results in a multidisciplinary setting. And the study is mainly of course descriptive. However, we also tried to find associations that are relevant for outcome.

Dr. Kait Nevel: Getting into some of the things that you found or discovered through this study, what's one thing that surprised you?

Dr. Katharina Schmidbauer: One surprising finding of the study was the heterogeneous presentation on MRI and the high number of misdiagnosis on MRI in more than half of the patients. If you look into the imaging figures in the paper, these tumors can present as like any other disease. They can mimic neuroinflammatory disease, high-grade glioma, small vessel disease, and even meningioma or leptomeningeal disease. So the most common misdiagnosis was high-grade glioma, and indeed these lesions often showed very infiltrative growth patterns and almost streaky or perivascular patterns of contrast enhancement. And another interesting finding was the PET imaging. You might expect an aggressive tumor to show very high metabolic activity on FET PET, such as in high-grade glioma. But in our small subgroup of patients who underwent FET PET imaging, uptake was often relatively low to moderate or also completely photopenic, especially on FDG PET.

Dr. Kait Nevel: Yeah. I found that part of your findings fascinating that the imaging is so unlike what we see in the much more common diffuse large B-cell lymphoma that we see in the CNS. It's much more common than T-cell lymphoma. Was there any understanding of why the imaging looks so different, particularly on the PET and FET imaging, as you mentioned?

Dr. Katharina Schmidbauer: CNS lymphoma is a very heterogeneous entity itself. And we also know that from other PET imaging studies and CNS lymphoma that it can present heterogeneously with low or moderate, but also high uptake. And on MRI, we also know that in the CNS lymphoma, it's not always the common picture and the involvement of subcortical or deep brain structures. So it's a mimicking disease also in other studies, but in this rare subtype of T-cell lymphoma, this was pretty striking. Yeah.

Dr. Kait Nevel: One thing that you've already mentioned that stood out to me was the number of initial misdiagnoses before reaching a diagnosis of primary CNS T-cell lymphoma. How do we work as a team, do you think, when we're evaluating these patients to reach the correct diagnosis more quickly? Is there anything that we should be doing differently?

Dr. Katharina Schmidbauer: I feel the solution is early multidisciplinary discussion. We need to involve all disciplines pretty early, neuroradiology, neuropathology, and neurosurgery of course, and plan the diagnostic steps together, especially the biopsy. In some cases, we also used FET PET imaging to look for potential hotspots within the lesion that might provide a more representative biopsy target. Interestingly, of course, the uptake was only moderate in our cases, but I would potentially give it a try to have additional information when to plan and where to plan the biopsy. Of course, also histopathology needs to be regarded when we talk about misdiagnosis. I don't have a good explanation for why even when we obtain enough tissue, some characteristic findings we would expect such as T-cell receptor clonality were simply not detected. Yeah, this is not solved so far.

Dr. Kait Nevel: Has anything you discovered in your results changed the way that you evaluate patients with brain lesions that have yet to be diagnosed or maybe the patient who has an unusual imaging or unusual clinical history coupled with imaging that maybe isn't totally typical for anything?

Dr. Katharina Schmidbauer: Yeah, there are several things. I would be cautious about the diagnostic approach and sometimes especially the imaging or also the histopathology creates some uncertainty. If CNS T-cell lymphoma or CNS lymphoma in general is suspected, I would try very hard to obtain tissue before the application of steroids. This is maybe the first point. And next is how I deal with an apparently negative biopsy. I would distinguish between a truly negative biopsy and a non-diagnostic biopsy. So the histopathology findings show non-specific inflammation. For example, I would ask, was the patient exposed to steroids? Was enough viable tissue obtained? Was the right part of the lesion sampled? Was there necrosis? And also what you mentioned, how is the imaging pattern and does it fit also the clinical course? Is it relevant like the lesion behaves? Is it like an inflammatory disease? Does it regress and recur or progressively enlarge? If these questions leave you uncertain, then I would plan to reperform another biopsy. But what sometimes happens in the retrospective of the study, in some cases you jump to the next plausible diagnosis and of course, such as an inflammatory tumefactive CNS lesion that may also have responded to steroid treatment in the beginning, you could also go with another plausible diagnosis. So we need to be careful to reassure is it really a negative biopsy or is it a non-diagnostic one and how to proceed?

Dr. Kait Nevel: What did you learn about outcomes in your patient cohort and do you think that we can use your results to guide treatment decisions for patients with primary CNS T-cell lymphoma?

Dr. Katharina Schmidbauer: Yeah, of course we looked also at associations with outcome based on the treatment regimens that we found in our study. However, in my view, our results provide somehow supportive evidence, but I would be careful about using the small retrospective series to recommend specific treatment regimes. In our cohort, MTX-based treatment was commonly used and patients who received high-dose MTX-based treatment with autologous stem cell transplantation had longer overall survival, which is of course consistent with general treatment principles we know from primary CNS B-cell lymphoma. But of course we have only 16 patients and there is obviously substantial selection bias. Younger and fitter patients are more likely to receive intensive treatment and transplantation. So overall, I would say that our results support MTX-based treatment, including stem cell transplantation in selected patients as an important therapeutic strategy.

Dr. Kait Nevel: Do you think that it is important or helpful to get next-generation sequencing on the samples of patients who have established primary CNS T-cell lymphoma?

Dr. Katharina Schmidbauer: I would say molecular characterization is really important, but I would not say that every patient needs broad NGS. In my view, it's extremely valuable when you have an unusual histological phenotype, diagnostically difficult case, disease relapse, or when the result could potentially change treatment. And of course our ALK1-positive case is a good example. She had a fast progressive subtype and of course knowing about the mutation that changed the treatment algorithm, but in other cases we look at our small NGS subgroup. We also found variants of uncertain significance and we cannot term them as pathogenic mutations. So I would go for it if you have the facility to do it, but maybe not in every case.

Dr. Kait Nevel: That makes sense. And it sounds like important to consider because as you highlight in our conversation and in your paper, you can uncover something that could be potentially pretty impactful to treatment for some patients. What do you think that we could do to learn more about this very rare oncologic condition? I mean, in your study, this was a multicenter. There were three different centers involved over a decade, almost 14-year timeframe, I think it was, or 16 years.

Dr. Katharina Schmidbauer: Yeah, exactly.

Dr. Kait Nevel: And you identified 16 patients, so about one patient per year over three academic centers, so pretty rare. What can we do or what do you think we should do as a neuro-oncologic community maybe to understand this group of heterogeneous, somewhat heterogeneous diseases better?

Dr. Katharina Schmidbauer: The biggest challenge is of course the rarity of the disease and to gain any evidence that is useful. So as a single center, we would have never had enough patients and international collaboration of course is key for gaining any evidence. Yeah, I'm also really thankful for the great work and collaboration with the centers in Heidelberg and Boston. But yeah, we need larger registries for rare CNS tumors and ideally prospective standardized data sets to gather all the relevant information. And of course, I believe there are many distinct molecular subgroups of primary CNS lymphoma. They may behave differently or respond differently to treatment. And the next step in my view would be to really focus on the molecular subtypes and also aim for biology-driven treatment. But still the first steps, the number of misdiagnosed cases is maybe also not that low and should in the first place aim for not to miss any diagnosis of primary CNS T-cell lymphoma and to remember to keep it on the differential.

Dr. Kait Nevel: Yeah, that sounds like a good goal. And your article and this podcast hopefully is a call out to people to remember this in the differential diagnosis for patients who have brain lesions, that it's not really clear what they are and diagnosis has been elusive to keep this in the list of possibilities.

Dr. Katharina Schmidbauer: That would be great. Yeah.

Dr. Kait Nevel: Great. Thank you so much for talking with me today, Katharina, and thank you for sharing more information about your study with us and educating all of us about primary CNS T-cell lymphoma.

Dr. Katharina Schmidbauer: Thank you so much for having me.

Dr. Kait Nevel: So again, I've been talking with Katharina Schmidbauer about her article, "Clinical Manifestations of Primary CNS T-Cell Lymphoma."

Dr. Stacey Clardy: This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword on your podcast app for any neurology-specific topics you want to learn about.

The October Recall features four previously posted episodes on immune‑based therapies for neurologic disease. In the first episode, Dr. Bhaskar Roy reviews the latest treatments, comparing their efficacy and safety. The second episode, with Dr. Michael Levy, focuses on satralizumab for treating relapsing MOGAD, current management challenges, and the encouraging results of this new therapy. That conversation leads into an episode with Dr. Amanda L. Piquet, who discusses the efficacy and safety of miv-cel in patients with stiff person syndrome. The episode concludes with Dr. Irene Cortese highlighting recent advances in the treatment of PML.

Podcast links:

Comparison of the Efficacy and Safety of Myasthenia Gravis Treatments

Safety and Efficacy of Satralizumab in Patients with Relapsing MOGAD

Miv-cel CD19 CAR T-Cell Therapy Shows Efficacy and Safety in Stiff Person Syndrome

Resolution of PML after Treatment with Virus-Specific T Cells and HCT

Article links:

Comparison of the Efficacy and Safety of Myasthenia Gravis Treatments

Safety and Efficacy of Satralizumab in Patients with Relapsing Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease

Miv-cel CD19 CAR T-Cell Therapy Shows Efficacy and Safety in Stiff Person Syndrome in a Pivotal, Multicenter, Phase 2 Study (KYSA-8)

Resolution of PML after Treatment with Virus-Specific T Cells and HCT

Disclosures can be found at Neurology.org.

Dr. Dara Albert talks with Dr. Bruce Cohen about the future of child neurology residency training, exploring current models, consensus areas, and challenges in evolving the curriculum to meet future healthcare needs.

Read the related article in Neurology® Education.

Disclosures can be found at Neurology.org.

Podcast Transcript:

Dr. Jose Merino: This is Jose Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.

Dr. Dara Albert talks with Dr. Bruce Cohen: Hi, this is Dara Albert from Nationwide Children's Hospital and Ohio State University. I am delighted to be joined today by fellow Ohioan, Bruce Cohen, a child neurologist at Akron Children's Hospital and an expert in the care of children and adults with mitochondrial disorders. Bruce is the lead author of a paper published in June 2026 called Education Research: The Future of Child Neurology Residency Training: The Perspective of a Child Neurology Society Task Force. Child neurology occupies this unique space at the intersection between pediatrics and adult neurology and pediatric neurology. And really there are a few topics in our field that generate as much discussion amongst child neurologists as how we should train the next generation. You get 10 child neurologists in the room, maybe there's 15 different opinions on how we should do this. Recognizing that there's a lot of evolution in our field, the Child Neurology Society, or CNS as I'm going to refer to it, assembled a task force to explore whether the current training models continue to meet the needs of our trainees, practicing physicians, and the patients that they serve. And we're going to talk about the results of that task force and what was published in the paper. Before we dive into that though, I do want to note that Bruce is joining us today as a representative of the task force and its findings. And while he contributed to this work, the perspectives and recommendations outlined in the paper are going to reflect the collective views of the task force and may not always fully align with his individual opinions. So Bruce, welcome to the podcast.

Dr. Bruce Cohen: Thanks. It's great to be here.

Dr. Dara Albert talks with Dr. Bruce Cohen: Absolutely. Let's start with a little history. Many may not be as familiar with how child neurology training developed in the United States. Can you tell us a little bit more about the current training model, how it came to be, and how it has evolved over the decades?

Dr. Bruce Cohen: The current training model is about 50 years old. 50 years ago, there was no CAT scans or MRI scans or genetic testing. We had pneumoencephalograms. So there really have been major changes in the last 50 years in how we take care of children with neurological problems and how we treat them. And one would expect that the training needs would change as well over that timeframe. So here we are today to discuss the differences of opinions among my colleagues.

Dr. Dara Albert talks with Dr. Bruce Cohen: It's hard to imagine doing an encephalogram these days. We've come a long way from that.

Dr. Bruce Cohen: Well, it just shows my age. I remember taking tours of medical school, seeing the pneumoencephalogram suite. It was still up and running when I was in training. It doesn't seem that long ago. It was in the 1980s, but they still had the chair.

Dr. Dara Albert talks with Dr. Bruce Cohen: Wow. Why did the Child Neurology Society or CNS feel that this task force was needed at this particular moment? What questions or challenges were you hoping to address?

Dr. Bruce Cohen: So we know the ACGME is going to go on their 10-year cycle and look into the training requirements of child neurology in 2027. They're getting set up to do that. And it was just seemingly an appropriate time at the end of my term as president of the Child Neurology Society, which ended in 2023 to set up this task force just to see what we could contribute to the body of knowledge and the differences of opinions. I didn't really expect us to reach a consensus when we set up this task force, but I just wanted to lay out the differences of opinions that are out there.

Dr. Dara Albert talks with Dr. Bruce Cohen: Yes. And we will definitely get into the opinions that came up as part of this task force. But before we talk about that, one of the strengths of this effort was the attempt to bring together a variety of perspectives. Can you walk us through how the task force was assembled, how you approached building consensus around these complex issues during discussions?

Dr. Bruce Cohen: So the task force was assembled over a period of a month or so. I don't think I lost any friends by not asking them to join the task force, but I certainly got a lot of calls asking me why I didn't appoint them to the task force. But we started out with nine task force members that were mainly people that have dedicated their lives to education of child neurologists or have been some authoritative positions in the field of child neurology. But we needed to balance those appointed members of the task force with younger and more diverse group of individuals, some right out of training. We also tried to get people who practice mainly in a private practice environment. We didn't really succeed on that in terms of balancing that aspect of the membership, but we basically asked for volunteers and we got 65 applications or four additional members of the task force. We did have some diversity. Nine were female, 10 were white, 12 had US board certifications through the American Board of Psychiatry and Neurology. And initial certification ranging from 1988 to 2022, one was certified through the Royal College of Physicians and Surgeons of Canada. In the meantime, since the initial certification was 14 years with a range of two to 36 years, 12 members were currently clinically active in academic or hospital-based practices. So we did have a bit of diversity. We didn't get the private practice applicants that we hoped to have gotten. And so we may have missed a bit in terms of what those opinions may have been. We also had some diversity among the sub-subspecialty education of the members. We had one person trained in developmental disabilities, three trained in epilepsy neurophysiology, one in neuromuscular neurology. And again, the majority having held positions of authority within the child neurology, either child neurology training or child neurology national administration as officers in the CNS or AAN child neurology section. Eight of the members either currently or formally were residency program directors.

Dr. Dara Albert talks with Dr. Bruce Cohen: Seems like a nice slice through a lot of different aspects of our field, although as you mentioned, not as much in private practice, but otherwise a good diversity of experience and time out from training and all of that. That's awesome. So it seems from reading the paper that the task force met and had discussions around these topics and tried to form consensus, identify lack of consensus around a lot of topics related to child neurology training. So I'm curious, where did the task force find the strongest consensus or areas of agreement and where were the opinions most divided?

Dr. Bruce Cohen: Going back a little bit to maybe your first question is how are child neurologists trained in the first place? The majority of child neurologists enter a two and sometimes three year pediatric training program, but currently the majority have two years of general pediatrics followed by a three-year neurology residency. We sometimes refer to this as our neurology fellowship, but it's really a residency. That neurology residency is classically one year of adult neurology and two years of child neurology with the electives divvied up between both specialties. And at the end of this five-year training track, which majority of people go through, we call it the two plus three program, allows one to sit for the general pediatric boards as well as their neurology boards. And the certificate awarded to a child neurologist trained in this fashion is neurology with special qualifications in child neurology. And that ostensibly allows us to take care of patients of any age with neurologic problems. Of course, one shouldn't venture into taking care of patients that one doesn't have experience taking care of. And certainly child neurology has changed over the course of the years. 50 years ago, neonatal neurology was pretty much non-existent and probably consisted of children born 26 to 28 weeks gestation and older. And of course now neonatal neurology is blended into topics that are covered in fetal neurology, something that I have no training in doing. I didn't do it when I trained 40 some odd years ago and I certainly haven't picked that up any time along the way. I would also say that I would never take on patients with adult onset multiple sclerosis. The training I had back when I was in residency was intrathecal steroids and we've come a long way since then. So there's a constant learning curve on what we should be doing and what we're boarded to do. There's two issues of non-consensus. One is how long the training program should be in the first place. And the second is do we really need that whole year of adult neurology? So the strongest consensus has to do with the definition of what a neurologist is. We're on solid footing in that regard. We need structured programs both in terms of didactic activities and the residents must be provided protected time to participate in these core didactic activities. So issues like that we all agreed upon with almost unanimity as we discuss these areas. We also agree that residents must attend a longitudinal continuity clinic at least one half day a week throughout the duration of the program. Something that really didn't exist 50 years ago was a topic of neurogenetics and that we needed to have a ramped up education in neurogenetics and it be mandatory part of our training. And although not available at all training sites, new therapies including molecular therapies that would include but not limited to gene therapy should be at least part of the didactic training, if not part of the actual hands-on training. So we really had a lot of areas of consensus.

Dr. Dara Albert talks with Dr. Bruce Cohen: So one of the biggest takeaways for me in reading the paper is that the task force could not really reach consensus on what to do with the adult neurology and the general pediatrics components of training. Why do you think these questions remain so difficult for our field to answer?

Dr. Bruce Cohen: When I look back at my old textbooks of pediatrics and my old textbooks of neurology, they were thin. There wasn't a whole lot in them and now they're thick and two volumes, some of them. The last edition of Swaiman's weighs about as much as a bowling ball. I'm referring to Swaiman's Textbook of Pediatric Neurology. There's a lot more to learn in these two plus three years or one plus three years or however we're going to do it. And one of the questions being raised, is it time to give up that full year of adult neurology so we can squeeze more into our 36-month training program of neurology? And again, that's been an area of non-consensus ever since I started having this discussion back probably about 15 years ago.

Dr. Dara Albert talks with Dr. Bruce Cohen: Yes. I likewise have had many conversations with colleagues over the few years I've been a child neurologist and that seems to be an area of a lot of disagreement. So a challenging question to answer, but it is quite remarkable how much we have grown and expanded and learned as a field such that like you gave the example of the textbook being really small when you were in training and now we're in these big giant multi-volume textbooks. That's so true. I'm curious, was there a perspective or argument raised during the discussion that changed your thinking or at least maybe challenged some of your assumptions about this topic?

Dr. Bruce Cohen: It certainly opened up my mind. Again, some of the people I chose to be on this task force I knew would disagree with my own personal opinions about this. And I chose them because the purpose of the task force is to lay all the issues out on the table so that the RRC can deliberate and come up with what's going to be best for the field. 50 years ago, we really didn't think about how much debt a resident would land themselves into after four years of college and four years of medical school and being paid a salary that would likely be considered a poverty salary if that resident had a small family. And one of the questions is that if you can train an adult neurologist in four years, one year of adult general medicine, three years of neurology, can you train a pediatric neurologist in four years, one year of pediatrics, three years of pediatric neurology? So that was one issue that came up. And just the finances of that is daunting. The other question is would we improve our labor force of child neurologists if we cut a year of training out? And then of course, no one's really done that and the question that arises, is it safe to do this? And we talked about that as well.

Dr. Dara Albert talks with Dr. Bruce Cohen: Like safe for our patients.

Dr. Bruce Cohen: Safe for our patients. Safe for us too. There were some members of the task force thought that it really took five years of post-graduate maturity and training to become a fully trained child neurologist, the two plus three model, but you could also tiptoe into what about a one plus four model if you're going to do that? And of course, I don't think once we create a one plus three model, my own personal opinion is that there's no stepping back on going back to a two plus three model if we chose to go to the one plus four.

Dr. Dara Albert talks with Dr. Bruce Cohen: Yeah, sure. If we shorten training, it's going to be hard to lengthen it again after that change has been made for sure. Yeah, lots to consider. And yeah, the student debt is not an insignificant factor at this point in time, unfortunately. What do you see as the most important next step for our field? Who else needs to be involved in this conversation and what other perspectives might we be missing?

Dr. Bruce Cohen: We need the perspective of the American Board of Pediatrics and the RRC of general pediatrics because we've been part of their first two years of training for a half a century and to pull back unilaterally saying we're changing our training to a one plus three model or a one plus four model or whatever without consulting the pediatricians would be not taken well. About half of us work in departments of neurology and half of us work in departments of pediatrics. And it varies between hospital and university, the university as to where pediatric neurology lands. And it's not an insignificant portion of the patients either that are being cared for. And so if you're in the department of pediatrics and all of a sudden you're changing the training of the labor force that will be taking care of these children, we may have something to say about it.

Dr. Dara Albert talks with Dr. Bruce Cohen: Yeah. Gosh, there are just so many perspectives to think about. This is such a complex issue and lots of potential downstream consequences to any decision that might come out of this review, even if that decision is to keep things the way they are. Throughout this process, the task force spent considerable amount of time thinking about the future of our specialty. So looking ahead 10 years, what do you think the task force would consider an ideal outcome for child neurology training and how would we know if we've achieved it?

Dr. Bruce Cohen: The most important thing is that we have a labor force that can take care of the children, the newborns, the pre-borns, and be able to do so not only in big cities like Northeast Ohio or Columbus, Ohio, but in the tiny towns. Ohio's an interesting state because it's really got a lot of pediatric neurology going on in it, but there are lots of states without pediatric neurologists. There are certainly not enough pediatric neurologists to take care of the kids. So how do we make sure that those children get taken care of? So anything that we do, we really need to think about putting boots on the ground so that we can deliver the care that we need to be able to deliver. So that would be one measure of success for sure. Being able to build our numbers up, I think would be another measure of success. Child neurology has done a great job, especially compared with what's going on in some of the subspecialty fields of pediatrics that are really having difficulty with creating a stable labor force. So we've done a really nice job, but we certainly could do better. And being able to attract more students into the residency programs I think would be another measure of success.

Dr. Dara Albert talks with Dr. Bruce Cohen: Another thing that I've heard in talking with colleagues about this topic, about what the future of residency could look like is maybe allowing some flexibility for individual programs to tailor training to what makes the most sense at their institution or for their trainees. Did the task force address this question? And if not, do you have an opinion on this question?

Dr. Bruce Cohen: In some respects, programs are already doing this. At our hospital, for example, we're now defining pediatrics up to the age of 26. Where pediatrics ends and adults begin is now becoming more of an economic and political debate more than we think about adulthood beginning at 16 or at 18. To some extent, training programs are already taking some leeway, the program requirements. I don't think the programs are overstepping their bounds. For a program to differ or make themselves different, there would have to be agreement amongst the child neurology core of trainers and the adult neurology core of trainers. You'd have to get the programs to agree internally to make any changes. There are some members of the task force that are pushing for this within their own programs. And so that's one possible solution is to let the programs have a little more flexibility on how much adult training would be required. The bigger issue about how many years does it take to train a child neurologist, that's going to have to be something decided on a national level.

Dr. Dara Albert talks with Dr. Bruce Cohen: To some extent, the flexibility also needs to be decided on a national level, just in the sense that we don't want to give programs the opportunity to change their training such that their graduates would not be board eligible, for example. So we need the boards and the governing body, the ACGME, to allow for that flexibility with retained board eligibility at the end of it.

Dr. Bruce Cohen: I personally think the most important or if not one of the most important aspects is the training certificate that says I'm boarded in neurology with special qualifications in child neurology. I really personally would not want to see that certificate type disappear.

Dr. Dara Albert talks with Dr. Bruce Cohen: Yeah. So if program A decided they wanted to do less than 12 months of adult neurology, but the ABPN, the American Board of Psychiatry and Neurology said, "Nope, you wouldn't get that certificate at the end of it," then that flexibility isn't really supported. So there needs to be that conversation with the governing bodies as well.

Dr. Bruce Cohen: Yeah. And I guess one of the questions would be, could we define how you spend your month? If you're going to do, let's say a two-month stroke rotation, can you get both adult and pediatric credit if the ratio of patients, adults and kids fits the bill?

Dr. Dara Albert talks with Dr. Bruce Cohen: Sure. Yeah.

Dr. Bruce Cohen: Same thing with neurophysiology. How many adult EEGs versus child EEGs do you interpret over the course of that one to three month training period?

Dr. Dara Albert talks with Dr. Bruce Cohen: Yes. There are so many facets. It's so complicated to think about all of the things that go into training and where are the areas where we can be flexible and where are the areas where we can't? It's just interesting to think about, but I am optimistic for the future that we're having this conversation, that the CNS is behind that you assembled this task force to have these discussions, and hopefully we can move forward as a field together with something that makes sense.

Dr. Bruce Cohen: I think what we both would agree upon is that this is the best time to be a child neurologist.

Dr. Dara Albert talks with Dr. Bruce Cohen: Absolutely. It's a great field. Thank you so much, Bruce. I've been speaking with Bruce Cohen from Akron Children's Hospital and lead author on a paper published in June 2026 in neurology education titled Education Research: The Future of Child Neurology Residency Training: The Perspectives of a Child Neurology Society Task Force. Thank you, Bruce, so much for your time and your insights into this important topic.

Dr. Bruce Cohen: Thank you.

Dr. Stacey Clardy: This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword on the podcast app for any neurology-specific topics you want to learn about.

Dr. Tesha Monteith talks with Dr. Tamara Pringsheim about the updated American Academy of Neurology (AAN) and American Headache Society (AHS) guidelines on pharmacologic treatment for migraine prevention in adults.

Read the related article in Neurology®.

Disclosures can be found at Neurology.org.

Show transcript:

Dr. Jose Merino (00:08): This is Jose Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.

Dr. Tesha Monteith (00:23): Hi, this is Tesha Monteith with the Neurology Podcast. I'm excited to talk to you today about the update in Migraine Guideline: Pharmacologic Treatment for Migraine Prevention in Adults: Practice Guideline Recommendations, a report of the American Academy Neurology Guidelines Subcommittee, and the American Headache Society. Since the last guideline in 2012, there's been a lot of new advances, including the introduction of CGRP inhibitors for acute and preventive treatment.

(00:53): With me to discuss is the lead author, Tamara Pringsheim, a neurologist at the Department of Clinical Neurosciences, Psychiatry, Pediatrics, and Community Health Sciences at the University of Calgary. How are you, Tamara?

Dr. Tamara Pringsheim (01:06): Great. Thank you for asking me to talk to you about this.

Dr. Tesha Monteith (01:09): Why don't you tell me a little bit about yourself and how you got involved in this work?

Dr. Tamara Pringsheim (01:14): Sure. I've been working as a methodologist for the American Academy of Neurology Guidelines Subcommittee for a number of years, since 2015. Prior to that, I was a member of the guideline development subcommittee from 2011. I've worked on a number of different guidelines across neurological conditions.

Dr. Tesha Monteith (01:36): Great. So how do these new guidelines compare, just broadly speaking, with the older guidelines?

Dr. Tamara Pringsheim (01:43): I guess since the last guidelines were published more than 10 years ago, we've had changes to our methodological process. We had a major update to our guideline process manual in 2017, and guideline methodology has continued to evolve over that time period. And as well, a number of targeted treatments for migraine have come out. So there's been an explosion of evidence, particularly in the last five to seven years. And so we have a whole new class of medications available for migraine prevention, which really target our underlying understanding of the condition, whereas most of the other medications were discovered through serendipity.

Dr. Tesha Monteith (02:33): So I know that you reviewed over 200 randomized controlled trials. And so how was the quality or confidence of the evidence determined?

Dr. Tamara Pringsheim (02:47): With our process, we start by rating risk of bias for every article. This basically gets at a number of different features related to the clinical trial methodology and reporting, and it helps us determine how confident we are in the evidence. In order for us to be highly confident that the results that we are seeing reflect the truth, we typically need to have at least two Class 1 studies for any intervention outcome pair. The effect size estimate also has to meet a certain threshold in terms of the effect size and the precision surrounding that estimate. So if we feel that based on what the panel decides in terms of what is the minimal clinically important difference between an intervention and placebo, that will help us determine our confidence in the evidence.

(03:51): So there's this critical coming together of the number of studies, the quality of studies, the effect size, and the precision of the evidence that helps us determine our confidence in the evidence. And all of this is done behind the scenes using a very algorithmic approach so that these rules are faithfully applied across the different interventions we're looking at. This complexity makes it hard for people to understand why certain drugs land in a certain area, but it's one of the things that we do to make this process standardized and rigorous.

Dr. Tesha Monteith (04:37): So I do want to talk to you about that, where drugs have landed. One newer thing was that the review was not just episodic migraine, but also chronic migraine.

Dr. Tamara Pringsheim (04:47): Yes.

Dr. Tesha Monteith (04:48): Were there important differences in the strength of evidence between these populations?

Dr. Tamara Pringsheim (04:53): One thing that's really important to remember is that the use of the term chronic migraine is fairly new. So a lot of the trials of the older headache preventive medications were done in the 80s and the 90s. And at this time, there wasn't a definition which distinguished chronic migraine in particular. So a lot of the trials for amitriptyline, for example, were not done in a purely episodic or chronic migraine population. And so this really contrasts with the newer studies where these populations were well-defined. And so we're going to have higher quality evidence or evidence specifically for chronic migraine with the new drugs, whereas for the old drugs, we won't have that.

Dr. Tesha Monteith (05:50): Let's get into the preventive treatments that had the strongest level of evidence for episodic migraine.

Dr. Tamara Pringsheim (05:57): We had high confidence in the evidence for two of the CGRP medications, erenumab and galcanezumab. Again, these high confidence in the evidence statements are based on the fact that for both these drugs, there were multiple Class 1 studies showing that they were efficacious. And the effect size was in the range that was pre-specified. So the lower level of the 95% confidence interval was clearly higher than what we decided was the minimal clinically important difference. Both these drugs, one had two Class 1 studies, one had three Class 1 studies, so we could be very highly confident that these two medications were efficacious.

(06:50): Now for the moderate confidence drugs, we have a longer list for episodic migraines. So it includes atogepant, eptinezumab, fremanezumab, propranolol, rimegepant, topiramate, and valproate, and then a slightly longer list for the low confidence drugs. So amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan.

(07:18): And for this outcome, I'm specifically talking about episodic migraine headache days. Now, one of the layers of complexity, again for this guideline, is that we had a few different outcomes that we were looking at. So the two main outcomes we were looking at were the headache frequency, the change in the number of headache days, but also the 50% responder rate. That's the proportion of people in the treatment group who had at least a 50% reduction in their headache frequency. And some drugs would make it for one endpoint, but not the other. And this is an important nuance that, again, adds complexity to our data synthesis.

Dr. Tesha Monteith (08:06): And what about for chronic migraine?

Dr. Tamara Pringsheim (08:08): So for chronic migraine, for the number of headache days, we had high confidence for fremanezumab, galcanezumab and onabotulinumtoxinA, and moderate confidence for atogepant, eptinezumab, erenumab, topiramate, rimegepant, and valproate. We didn't have any medications that were in the low confidence in the evidence category.

Dr. Tesha Monteith (08:33): Oftentimes in the newer clinical trials, we're looking at change in monthly migraine days, but interesting that you looked at headache days.

Dr. Tamara Pringsheim (08:42): Yeah. So another difficulty is that there's not always consistency in what's reported. So some trials would report headache days and some trials would report migraine days per month. Wherever possible, we use the change in the number of days with migraine. And where this was not present, we would use headache days.

Dr. Tesha Monteith (09:08): Now, a drug that we use very often in clinical practice is rimegepant, which has a dual benefit of acute attack treatment as well as prevention. And that was rated as low confidence, but in a recent International Headache Society, Italian guidelines, that was noted as moderate quality evidence, strongly in favor of. What do you think that discrepancy was about? Is that a matter of outcomes or?

Dr. Tamara Pringsheim (09:38): This guideline includes clinical trials that were published up until June of 2024. And so at that time, the only trial of rimegepant versus placebo that was published was in a population of patients that had episodic or chronic migraine. The population was combined. And so we only have one study. And as I was explaining at the beginning, in order for us to have high confidence in the evidence, we have to have at least two Class 1 studies and the minimal clinically important difference has to meet a certain threshold. So for rimegepant in June of 2024, there's only one study published versus placebo. So the highest possible confidence in the evidence we could have for rimegepant based on the fact that just one study would be moderate.

(10:38): The reason why it's not listed in recommendation 3A as high or moderate confidence is because while we had moderate confidence in the evidence for rimegepant on the number of headache days, we had low confidence in the evidence for the 50% responder rate. And that's because for the 50% responder rate, it did not meet the pre-specified cutoff with respect to the minimally clinically important difference.

(11:11): So again, it's a small nuance in the evidence, but for an evidence-based guideline, we really pay attention to these things. I know it makes it complex and hard for people who are not immersed in the evidence to understand. This is part of the rigor. There's a temptation to oversimplify things so that it's easy to understand, but that's really one of the strengths of the AAN process is that we take the evidence very seriously. We are truly evidence-based. We are going through every data point very carefully, and so that you should feel confident when you see that we've rated these medications as a higher moderate confidence, that we've really looked and evaluated these data points very carefully.

Dr. Tesha Monteith (12:01): We can say that different guidelines have different outcomes. And to your point, it's more than just the data. It's your pre-specified process that then led to those recommendations, right?

Dr. Tamara Pringsheim (12:14): Yeah. And I feel pretty confident that if we were to update the evidence, including the last two years, that rimegepant would move up, right? Because just looking even quickly now, we can see that since 2024, there have been several additional studies published. So now we wouldn't just be basing our evidence review on one placebo controlled study. There have been several more, the medications FDA approved.

Dr. Tesha Monteith (12:44): Right.

Dr. Tamara Pringsheim (12:45): I don't think anyone should change their practice based on this and people should be using rimegepant. That's not the message that we're trying to send.

Dr. Tesha Monteith (12:54): That's really important.

Dr. Tamara Pringsheim (12:55): Yes. We are not on a campaign to say that rimegepant is not a treatment option. As you can see, it is listed and it is in the guidelines. It's just based on the data we had available, we had low confidence in one of the outcomes, the 50% responder rate. So I hope that makes sense.

Dr. Tesha Monteith (13:14): Yeah, I think it makes sense. It's the processes, it's a 2017 guideline manual, and that does make sense. So thank you for that clarification because a lot of our clinicians will be asking questions about this.

Dr. Tamara Pringsheim (13:26): I mean, the same goes for another drug, candesartan is the other one.

Dr. Tesha Monteith (13:30): Yeah. Candesartan recently had a paper published in the Lancet.

Dr. Tamara Pringsheim (13:33): Yes.

Dr. Tesha Monteith (13:33): And it did well, and people are using candesartan.

Dr. Tamara Pringsheim (13:38): Yes. Yes, exactly. I prescribe candesartan for migraine prevention. At the time we did the evidence review, we had a couple of positive studies, a couple of negative studies. And when we put the data together, it came out as very low confidence because there's a discrepancy. And then we have a huge trial published that is a positive study, but it came out in 2026. It was not part of our evidence review. We don't say anywhere in the guideline, don't use candesartan, right? We don't say that. We highlight the drugs for which we have the confidence in the evidence and put them in there. But we need to remember that new drugs are coming out all the time and that they didn't factor into our decision making.

(14:26): So again, I hope that people don't read the guideline and say, "Oh my God, I can't use candesartan." That's not true.

Dr. Tesha Monteith (14:33): So one thing I want to look at is quality of life outcomes. That was something also not seen in the first or the 2012 guidelines. And so how did you look at quality of life outcomes and how should we consider them?

Dr. Tamara Pringsheim (14:47): Yeah, so we wanted to make sure that we incorporated patient reported quality of life outcomes in the guideline, recognizing that this is very important. And the newer trials of the more recent medications have been incorporating patient reported quality of life outcomes in their clinical trials. This adds overall credibility that we are incorporating into our decision-making evidence that not only are patients' number of headache days decreasing, but their quality of life is improving because that's important to patients and hence is important to us.

(15:31): So we used outcomes from validated measures of migraine related quality of life. So there's the MIDAS, there's the HIT-6, and there's something called the migraine specific questionnaire, which has three subscales. One is emotional function, one is role function preventive, and one is role function restriction. And then a few studies use something called the migraine physical function impact diary. So those were the main instruments that we looked at. And again, we had a pre-specified minimally clinically important difference on these instruments that we looked at.

(16:19): And we had a reasonable amount of data, not as much data as we had for headache days or the responder rate, but certainly again, for the CGRP antagonists, we had high confidence in the evidence for galcanezumab, for example, in episodic migraine. And for chronic migraine, we had moderate confidence in the evidence for a number of medications including topiramate and onabotulinumtoxinA. So these quality of life measurements seem to be increasingly used in our modern clinical trial era.

Dr. Tesha Monteith (17:07): Great. Another question is just thinking about some of the limitations of this work. There were very few high quality head-to-head trials. How does that limit your comparative effectiveness data?

Dr. Tamara Pringsheim (17:19): This is a major issue that most, but not all of the head-to-head trials were investigator-led. Many were done a very long time ago before the modern clinical trial era, and so the quality of these studies was low. And also they were not non-inferiority studies. So basically the only question they could answer is whether drug A is better than drug B based on their trial protocol and methodology. And for most of the comparisons, we have very low quality evidence, so we really cannot support or refute that drug A is better or worse than drug B. So we can't really say anything. There were a few instances where we could say that drug A is better than drug B, but it's low confidence evidence, very few comparisons.

(18:17): Some evidence is emerging so that some of the CGRP drugs are being compared to some of the older drugs now with the hope that we can prescribe these sooner to migraine patients. That evidence will probably emerge in the coming years.

Dr. Tesha Monteith (18:31): And another question is how should these guidelines be incorporated in clinical practice also while balancing tolerability, comorbidities, patient preference, reproductive considerations, access, and costs?

Dr. Tamara Pringsheim (18:47): So we have the evidence synthesis. So you can say, okay, this is the evidence. These are the effect sizes. This is the number of studies to support this outcome, that outcomes. You have the details in the systematic review, right? And then how do you take those details and apply them in the practice? And that's the art of medicine. And we don't make decisions without our patients. All of our decisions are collaborative. I say to my patients, "It's my job to tell you what your options are. It's your job to discuss these options with me and for us to make a decision together regarding which one is the best for you in your situation."

(19:30): And that's what we're trying to do in the recommendations. In the recommendation statements, you'll see that in this specific situation, this might be a better choice. We talk a lot about when you're going to decide to even start a preventive and the importance of shared decision making, that those are our first two sets of recommendations. Recommendations one and two are about those things.

(19:56): And then our recommendation three statements just tries to gently offer some advice on when you should think about which medication, where efficacy is the priority, tolerability is the priority, long-term harms, cost. Cost is a really tricky one because cost really depends on the person's specific pharmaceutical formulary plan and healthcare insurance. I know that for some patients, their insurance plans require a certain number of oral medications to be tried before an injectable like a botulinum toxin or a subcutaneous medication or one of the newer medications can be prescribed.

Dr. Tesha Monteith (20:41): So you put a lot of work in this, your team, the American Academy of Neurology, the American Headache Society, outstanding work. What should we take away from this?

Dr. Tamara Pringsheim (20:52): I think that we should take away that a lot of work is being done by headache neurologists and neuroscientists who are interested in headache to develop new treatments for people with migraine. I think that the CGRP drugs are a major advance and that now we have many new medications that are specifically designed for migraine treatment and these treatments are changing people's lives for the better. I think it's brought new hope to people with migraine and it's an exciting time to be a clinician who treats patients with migraine when you have several new medications where the companies have invested the time to do the research, do well-designed clinical studies, and that we can feel confident that these medications are helping our patients.

Dr. Tesha Monteith (21:51): Excellent. I couldn't have said that better. Thank you again for your work and your time and for being on our podcast.

Dr. Stacey Clardy (22:00): This is Stacey Clardy, your podcast editor. If you've enjoyed the podcast, please take a few moments to subscribe, rate, and review the Neurology Podcast through Apple Podcasts, Google Podcasts, Spotify, or wherever you listen. And remember, you can always head to neurology.org/podcast for our full list of past episodes, or you can also search by keyword on the podcast app for any neurology specific topics.

Dr. Justin Abbatemarco talks with Dr. Irene Cortese about recent advances in the treatment of progressive multifocal leukoencephalopathy (PML), focusing on immune-based therapies like virus-specific T cells and immune checkpoint inhibitors.

Read the related article in The New England Journal of Medicine.

Disclosures can be found at Neurology.org.

Show transcript:

Dr. José Merino: This is José Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening, and have a great week.

Dr. Justin Abbatemarco: Hello and welcome. This is Justin Abbatemarco with the Cleveland Clinic here with Irene Cortese to discuss an update on progressive multifocal leukoencephalopathy treatment in light of a New England Journal of Medicine correspondence, Resolution of PML After Treatment with Virus-Specific T Cells and HCT. Irene directs the Experimental Immunotherapeutics Unit at NINDS. Hello and welcome.

Dr. Irene Cortese: Hi, thank you for the invitation to join you today.

Dr. Justin Abbatemarco: It's a pleasure to have you on and to talk about this expanding space in rare disease. And maybe if we could start off, can we just take an overview on how PML usually presents and why does it remain so difficult to treat?

Dr. Irene Cortese: PML, or progressive multifocal leukoencephalopathy, is an opportunistic infection of the brain that is caused by the JC virus. And most of us carry this virus lifelong and without any symptoms, and it really only causes disease when the immune system is significantly compromised and loses the ability to keep it in check. And so when that happens, the virus can gain the ability to infect oligodendrocytes, and this can lead to the rapidly progressive demyelinating infection called PML. These lesions that develop in PML are typically located in the white matter, and they are most often multifocal. And this leads to the clinical manifestation of a combination of cortical and subcortical symptoms that evolve over weeks to months. And, unfortunately, if immune competence can't be restored quickly, then the disease is fatal within just a few months. And so that's really the core of the problem here, is that there is no effective direct antiviral treatment. And the only thing that works is restoring the immune system ability to control it, but that's often very difficult to do. When it's even possible, it's frequently just not even fast enough. And so you can see this even in situations where you'd think that we'd have an advantage, for example, in HIV-associated PML, where we do have effective antiretroviral therapy. Even there, restoring immune competence can sometimes just take too long relative to how quickly PML progresses. And so on top of all that, PML is really quite rare and is also remarkably heterogeneous because it can occur in very different patient populations from HIV to hematological malignancy to genetic immune deficiencies. And this rarity and heterogeneity really make both the diagnosis difficult and also treatment development quite difficult.

Dr. Justin Abbatemarco: It's such a interesting story, and these different backgrounds really present different challenges. But at these last few years, this has been a success story in some way because we've seen so much effort and research into this rare disease space, which is encouraging. We mentioned this at the top, but there are immune checkpoint inhibitors that have at least been trialed for this T cell exhaustion to see if we can boost the immune system, and then more recently with your work around allogeneic-specific T cells to help clear the infection. What have you taken away from those updates?

Dr. Irene Cortese: The biggest takeaway is that these two approaches, checkpoint inhibitors and Virus-Specific T Cells, have really transformed the way that we think about PML. So for decades, our only option was really to try to reverse the underlying immune suppressive condition and just hope that the immune system caught up in time. And now we have these two active strategies to try to speed this process up. Importantly, both these strategies have validated the same core hypothesis that even without a direct antiviral agent, we can improve PML outcomes by restoring effective antiviral immunity. And that said, each of these approaches has real limitations. So first of all, they don't work in all patients. And we have best estimates of success rates somewhere in the 50 to 60% range overall. With checkpoint inhibitors, the fundamental issue is that you're trying to unleash an immune response that has to already be there in some latent or exhausted form. For example, in patients with very advanced immune compromise where the T-cell compartment is essentially absent, there's just nothing left to invigorate, and so checkpoint blockade is really unlikely to help. And even when they do work, there is a real risk of exacerbating underlying autoimmune disease as well as the risk of leading to immune reconstitution inflammatory syndrome, or IRIS, where inflammation in the central nervous system of this immune system waking up and attacking the infection can actually lead to severe morbidity and even death in some patients. Virus-Specific T Cells have a whole different set of limitations. These are mostly practical and logistical at this point. Access is really the big one because there are only a handful of centers worldwide that can manufacture Virus-Specific T Cells. And so this just isn't something you can easily do everywhere or quickly. And also, biologically, every virus-specific T-cell product which is made from a different donor is essentially a different drug. And so it's really hard to predict how any given cell product will actually behave in a given patient. I should also mention that for both these approaches, they truly are still experimental. We don't have any controlled studies, and so most of what we're working from is really retrospective series and case reports. And we definitely have no head-to-head data. And so while we apply general principles estimating residual immune capacity or weighing the risk of exacerbating immune-mediated adverse events, we're really making individualized judgment calls rather than following an evidence-based algorithm.

Dr. Justin Abbatemarco: And could you talk about those Virus-Specific T Cells? It's not something we use commonly in neurology. How do those work? And have they been used in other spaces successfully that we've been able to maybe apply some of those principles here?

Dr. Irene Cortese: Yeah. So Virus-Specific T Cells were really first developed in the transplant setting, and they were essentially a way to bridge patients immediately following myeloablation. And in the period of time it took them to fully immune reconstitute a brand new immune system, it was a way to protect them from the common viral infections mostly that can develop in this time period and that led to such high morbidity and even mortality. And so the way this is done is that you basically take healthy lymphocytes from a healthy donor, and you can train them in vitro by ex vivo expansion and stimulation to basically become professional killers of the particular virus of interest so that, at the end of this expansion period, you basically have a enriched antiviral product that can be adoptively transferred to the patient recipient. And they may not last for a very long time, however, they can, especially with repeated infusions, provide the necessary immunity to bridge until definitive immune reconstitution is achieved. And so the initial experience with Virus-Specific T Cells was really against the various viruses that are so common in the post-transplant setting, like CMV, EBV, adenovirus, and also BK virus, which is a cousin, let's say, of the JC virus. And over time, the process for manufacturing Virus-Specific T Cells has become more and more streamlined. And so back as in 2015, 2017, we started to realize that perhaps these types of cell products might even be used to treat an acute infection and not just to administer in the setting of a planned transplant. And so essentially we've done exactly this, basically copied these manufacturing methods from the transplant world to make Virus-Specific T Cells against the JC virus and can then use them to treat PML. I should mention that BK virus is very similar in structure to the JC virus. And for that reason, what we learned early on when we started to apply Virus-Specific T Cells to the treatment of PML was that we could actually use Virus-Specific T Cells that were made against BK virus and successfully treat PML. More recent years, groups have been manufacturing JC virus-specific BST, but those BK Virus-Specific T Cells can still be used to treat PML.

Dr. Justin Abbatemarco: That's really incredible. And it's so cool when we borrow things from these other fields to help inform rare diseases within neurology space. Maybe it's a perfect segue into the cases report in New England Journal of Medicine where you had two cases with inborn errors of immunity. You've utilized the strategy and then stem cell transplant. Walk us through those cases. What did you see? What did we learn from these that we can apply more broadly?

Dr. Irene Cortese: Our paper really told the story of our experience of treating these two young men. Both of them had developed PML in the setting of an inborn error of immunity. One of them had DOCK8 deficiency, and he also had Sézary syndrome as a comorbid condition. And the second patient had a CD40 ligand deficiency. And for both these patients, we basically adopted the same strategy, which was to first try to gain control of the JC viral infection. And once that infection was actually under control, then we went ahead and proceeded to definitive treatment of their underlying genetic immune deficiency, which was transplant in their setting to correct the real root problem that they had. And what I think was perhaps most instructive in this experience is what happened after transplant in both cases. So transplant obviously involves a period of renewed immune vulnerability, and that's exactly when we feared that the PML might come back, even though we had been able to gain control, at least temporarily, using this adoptive transfer Virus-Specific T Cells. Fortunately, in these two cases, that didn't happen. And in fact, patient one actually developed IRIS shortly after engrafting with worsening neurological symptoms and also imaging that showed active inflammation, which responded well to steroids. And he's now years out with no evidence of PML or his prior malignancy, which was also treated by the transplant. The second patient's course was complicated by cryptogenic organizing pneumonia, or COP, which can happen in the post-transplant setting, and did require steroids. And this did cause a transient uptick in the JC viral copy number in the spinal fluid, but this resolved once the steroids were tapered. And this patient also is now several years out with only mild residual neurological deficits. So it's important that for both these patients, the transplant donors, in addition to undergoing collection for the transplant itself, they also underwent a collection to make extra rescue Virus-Specific T-Cell products that we had on hand just in case the PML relapsed post-transplant, which of course was not, in the end, needed. And so basically, the overall strategy for both these patients was sequential and deliberate. First to establish virus-specific immune control, and only then proceeding to the definitive but higher risk step of transplant with the safety net available in case virus reactivated during that post-transplant period.

Dr. Justin Abbatemarco: The complexity of these cases, though, and the successful outcome is just incredible. And again, we don't always treat these level of patients, but most neurologists will see PML during their career. How do you think this helps inform this broader field of PML treatment in your mind?

Dr. Irene Cortese: For me, these two cases really crystallized the idea of immune facilitation as a bridge rather than as a standalone endpoint. For example, in these two patients, Virus-Specific T Cells could not have led to a definitive cure because the underlying immune defect was still there, but they could buy time and control the virus long enough to get to something that could actually fix the underlying problem, which in this case was the transplant. And I'll be honest, proceeding to transplant in a patient with active or recent PML was really frightening. And clearly that is not an option or appropriate at all for the majority of patients with PML. So I guess that the broader lesson here is that Virus-Specific T Cells or potentially other immune-facilitating strategies might serve as a bridge to get us to the point where we either have a way to address that root cause of immune suppression or just buy us the time needed to recover from immune suppressive exposures and perhaps opens up the question of how we might use sequential strategies and combinations of strategies to optimize the care of these patients.

Dr. Justin Abbatemarco: Really appreciate your paradigm of how you think about these cases in treatment, and yet you can have these short-term strategies to bridge patients to have an improved immune response to get this under control. Could we talk about other common examples? So we have natalizumab-induced PML cases, HIV-associated PML cases. How would you think about managing those, so outside of these inborn errors of immunity?

Dr. Irene Cortese: Each PML patient is somewhat unique, and definitely the underlying condition that is driving the immune suppressed state is really critical in mapping out what we need to do. I think of HIV-associated PML or even natalizumab-related PML as being somewhat unique. Because unlike most other causes of PML, we actually do have clear and reliable ways to restore immune competence, so basically antiretroviral therapy in HIV infection or simply discontinuing the non-immune-depleting drug natalizumab in the case of natalizumab-related PML. And so this is obviously a real advantage compared to many of the other underlying conditions where there really is no good way to reverse that immune suppression at all. That said, in some patients, for example, with advanced AIDS and very low CD4 counts, immune reconstitution can still be very slow even when the HIV replication itself is well controlled. And so in a subset of patients, the PML can still really pace the recovery. And so we do sometimes need strategies to bridge that gap. And basically. we would consider the same immune restoration approaches that we've been talking about right now. There is an added layer of complexity here that's a bit more, let's say, unique to HIV-related PML or to the setting of natalizumab-related PML, which is that in both these cases, immune reconstitution is going to happen eventually. And when it does, then many of those patients do experience PML IRIS where the constituting immune response paradoxically worsens the neurological injury by attacking the infected tissue. And so this really needs to be watched for and managed typically with steroids. And certainly this risk of developing PML IRIS needs to be really considered if we are going to use strategies to boost or facilitate immune reconstitution in the setting of HIV infection or natalizumab-related PML. And we just have to be particularly mindful because there's already a very high likelihood of developing PML IRIS independently of getting that extra boost. Comparatively, in the setting of non-HIV-related PML or not in the setting of natilizumab treatment, I think that strategies like checkpoint inhibition and Virus-Specific T Cells have really been game-changing because, historically, these patients had no equivalent to antiretroviral therapy with no reliable path to reconstituting immunity. And we're really hoping that these approaches will start to bring the outcomes that we've seen, for example, among HIV-related PML and in the setting of natalizumab and PML to these other underlying conditions and achieve the same immune control and survival rates that are achieved in at least a substantial portion of these patients.

Dr. Justin Abbatemarco: It's been so exciting. Again, the updates in this field when we really did... We had nothing to offer patients for so long and now to have conversations that are a little bit different. Can I ask you to peer around the corner? What does the future look like in your mind? Do you see other therapies that are potentially at play and maybe right now are there clinical trials that we could enroll patients so that we can help inform the field more broadly?

Dr. Irene Cortese: Yeah. So I think that ways to facilitate and accelerate immune reconstitution have clearly been shown to be a valid strategy. And so what I expect and hope is that in the years to come, we'll learn to harness that better and learn to identify which patients are most likely to respond to particular types of strategies to facilitate immune reconstitution. It's really important, I would say, that patients participate in trials because the field really does lack controlled data and it lacks head-to-head comparisons. And so every patient enrolled in a trial or a well-structured registry is really contributing to how the next patient gets treated. And given just how rare and heterogeneous PML is, we're just not going to advance this field through isolated case reports alone. And so we really do need patients and their physicians to be willing to participate in structured and collaborative research. The Holy Grail is, of course, a direct antiviral agent that would really broaden our ability to treat patients and potentially also continue to treat whatever that underlying condition was that led them to the risk of PML in the first place, so, for example, patients receiving treatment for cancer or patients having an autoimmune disease that requires immune suppression. And so I am hopeful that eventually the direct antiviral will be identified. And along that line, what I can mention is there are certainly clinical trials that are ongoing. At NIH, we have an active natural history study from where we can funnel patients into various experimental treatment strategies, including Virus-Specific T Cells or checkpoint inhibitors. Or right now, we actually do have an ongoing trial of intravenous brincidofovir as a possible direct antiviral strategy. What I hope for the future is that we will find ways to really collaborate and to form national as well as international consortia so that we can accelerate the development of these treatments.

Dr. Justin Abbatemarco: We have things we can do now, and then we can help inform care for our future patients as well. So these are great messages, and I can't thank you enough for coming on. Again, most of these developments have been under your guidance, and we appreciate your leadership in this space and helping to give us this insight into this really rare disease. For folks, they can check out the article. It's in the New England Journal of Medicine, Resolution of TML After Treatment with Virus-Specific T Cells and HCT. Irene, thank you for coming on.

Dr. Irene Cortese: Thank you so much.

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