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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 impac

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. Margarit

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 m

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

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 exa

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

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 ove

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

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Dr. John Ney talks with Dr. Daniele Piomelli about the evolving role of cannabis in neurology, exploring its history, current research, and potential future applications. Read the related article in The New England Journal of Medicine.  Disclosures can be found at Neurology.org.

In part two of this two-part series, recorded at this year's AAN Annual Meeting, Dr. Gregg Day talks with Drs. Joel Salinas and Sarah Song about imperfect but practical brain health metrics, patient-centered assessment strategies, and future directions in brain health assessment.  Visit the newly launched BrainHealth.com to access trusted brain health information and stay informed.  Disclosures can be found at Neurology.org.    Show 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. Stacey Clardy: Hi, this is your Podcast Editor, Stacey Clardy. Today we feature part two of the brain health discussion that took place at the AAN annual meeting a few months ago. If you have not yet, take a listen to part one from this past Thursday's podcast. For this episode, we pick up with the discussion focusing on plans for how to implement and measure effectiveness of brain health interventions, the sort we can all undertake easily in our clinic visits. And then, we wrap up the episode with comments and questions from the audience who were present at the Brain Health Talk. I hope you take away some inspiration and some ideas on how to encourage your patients to be proactive about protecting their brain. Thanks. Enjoy. Dr. Gregg Day: Hello, this is Gregg Day from Mayo Clinic, and welcome to this special conversation. Today's episode is recorded live at the Brain Health Hub during this year's AAN Annual Meeting in Chicago. Because it was recorded on site, the audio may sound a little different from our usual episodes, but bear with us because it's absolutely worth it. This panel discussion is totally aligned with AAN's mission of bringing brain health to all, and on point with the release of brainhealth.com, AAN's new website, bringing together our resources for clinical practice and for research in this space. We hope you enjoy this panel discussion as much as we enjoyed recording it. One thing that we acknowledge on the Brain Health Committee, one thing that the AAN is committed to fix as we move forward, there's a lack of validated brain health metrics and biomarkers when we talk about brain health. So what does it mean to be healthy? Or maybe a better question, what does it mean to be healthier than I was a year ago headed in the right direction or trending in the right direction? Joel, your thoughts, what should neurologists measure today, even if it's imperfect, that can help us move brain health from concept to more of an accountable practice? Dr. Joel Salinas: This point about imperfect is actually really critical. I think when we're thinking about measurements, there's a trap that we tend to fall into, which is trying to identify the perfect measurement. And I often see that as an excuse to not measure at all. And so, thinking about what is it that you can most practically take into account today. And there's so many different measures for so many different elements, and I would just encourage you to think about what's most relevant to the patient in that moment, and that would be the ideal tool. There's things like the PHQ-9. There's all these cognitive screening assessments. There's different measures related to cardiovascular risks that are out there. Even though none of those are perfect, right? None of those are perfect, we've been able to move healthcare forward quite a lot using these imperfect measures. So I would encourage you to find what is your toolkit of measures that are most helpful for you. Actually, one of my favorite measures, going back to sleep, is actually not metric itself. It's actually just asking, how are you sleeping? And getting that qualitative data because we forget that metrics don't have to be quantitative, they can be qualitative as well. We often will collect things like the GAD-7, the PHQ-9. There's a UCLA 3-item Loneliness Scale. But when I'm in clinic, I'll often just ask, "Have you been feeling lonely?" Or, "How often are you feeling lonely?" And that in and of itself gives you a lot of really valuable information. Dr. Gregg Day: Simply asking that question about physical, mental, social well-being and where do you think you are compared to last year? We've spent a lot of money, a lot of investment to try to develop a tool that performs better than asking someone directly, "Do you feel depressed?" It's hard to do that. So yeah, let's not forget our patients in the room as maybe the greatest arbitrators of that progress. Sarah, any other things that you're thinking of along these lines? Dr. Sarah Song: I still go back to what Joel was saying earlier about individualizing it to the patient and getting more details on something that they happen to mention about if they're feeling lonely or if they mention their sleep, and then delving further into that. As a stroke neurologist, what's really easy for me is I always ask how they're sleeping, I ask how their mood is, and I just go into the markers of depression that we all learn about that are not necessarily just mood. But I ask, obviously, how they're sleeping, how they're eating, do they have energy, what exercise are they doing, what therapy are they doing? And those for me are natural as part of the conversation of post-stroke, but that they touch upon a lot of the elements of brain health already. That's what's really key. Brain health isn't something new, it's actually something that we're already measuring and we're already looking for and we're already asking. Being able to put any sort of, I know it's not qualitative, but putting any sort of number to it or any sort of marker that we can use to measure it and even asking, "Last year you mentioned that you weren't sleeping very well. Do you think that you're sleeping better now or is it worse?" or, "What changed?" Right? Dr. Gregg Day: I think we're talking about setting goals with our patients that we can then ask, "Are we attaining those goals? Are we maintaining those goals?" We can begin that process together. That's really important, very practical. Thank you, guys. We talk about brain health, we talk about quality, and quality of evidence here, and we can appreciate that really matters and is challenged by the multitude of sources of evidence and various levels of quality that we have. Joel, you hit the nail on the head with this encouragement to not let perfect become the enemy of good. And so recognizing that, how do we navigate some of these challenges when we're talking about interventions that patients are bringing forward or maybe that we're interested in trying out? We think there might be some role for those, albeit imperfect. So how do we navigate the uncertainty while maintaining credibility and building trust with our patients about making these recommendations towards brain health? Dr. Joel Salinas: Neurology, in particular, we all develop an expertise in navigating uncertainty. When it comes to brain health, it's just bringing some of those tools and perspectives into that space as well, right? Because we're always talking about prognosis and what to expect and building trust with patients. They're not really looking for you to be certain. Right? They're looking for you to be honest about that uncertainty. The more you're able to actually very clearly articulate to them, "This is what we know about this, this is what we don't know, and this is directionally what we think is helpful." And that applies within the brain health space as well. Right? We don't have huge randomized clinical trials around all the different intervention. The U.S. POINTER study from last year was really helpful in pointing in that direction. From all the literature that we have, we do have a sense of direction. Maybe we don't know the magnitude of effect quite yet, but we can at least point people in the right direction towards things that can be most helpful for them. And then, couch it within how certain we are based off of the evidence. And I will say, most of the time that I bring up issues of uncertainty, patients will respect and trust more me as a clinician than I'm being honest about what I know and what I don't know, and how we're navigating things together. Dr. Gregg Day: Excellent advice. Do you want to add anything to that? Dr. Sarah Song: Neurology is a field that inherently has a lot of uncertainty. We have to be honest and truthful, and we have to listen to our patients. And ideally, we want to be able to promise just good things. Right? I always do caveat with strokes. I'm like, "We're going to do everything we can to help prevent another stroke. Nothing brings the risk down to zero, but we're going to do everything we can to move that needle in your favor." And being honest and truthful does go a long way, but you should never assume that you're God, and that you can fix everything. Nobody can. Dr. Gregg Day: There's that element of humility that we're all expressing here, which is very important. This is a great opportunity to hear from you guys. It can be a question for the panel, that's totally fine. It can be a story that you want to share, your own experience to brain health. Maybe it's the challenges that you're dealing with in clinic. Or maybe it's a success and just an incremental move in the right direction, something that you've already seen. So if you would like to share something, you just put up your hand, and be prepared to catch because this square is coming your way. That's the goal. So we're really hoping we get to see somebody actually catch this. Oh, here we go. Our first candidate, Dr. Lazar. Yes. Dr. Lazar: Hi, everyone. So PGY-3, neurology resident. And I recently did my rotation in Generative Psychiatry, and it was a very important case. We have a demented

In part one of this two-part series, recorded at this year's AAN Annual Meeting, Dr. Gregg Day talks with Drs. Joel Salinas and Sarah Song about the evolving landscape of brain health, practical approaches to incorporating brain health assessments into routine care, and the importance of collaboration across specialties. Visit the newly launched BrainHealth.com to access trusted brain health information and stay informed.  Disclosures can be found at Neurology.org.    Show 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. Gregg Day: Hello, this is Gregg Day from Mayo Clinic, and welcome to this special conversation. Today's episode was recorded live at the Brain Health Hub during this year's AAN Annual Meeting in Chicago. Because it was recorded on site, the audio may sound a little different from our usual episodes, but bear with us because it's absolutely worth it. In this conversation, our panel explores the evolving landscape of brain health, including growing use of wearables, digital tools, direct to consumer tests, and artificial intelligence. We discuss how neurologists can help patients to navigate brain age scores, consumer health data, and emerging technologies while integrating brain health into everyday clinical care. This panel discussion is totally aligned with AAN's mission of bringing brain health to all, and on point with the release of brainhealth.com, AAN's new website, bringing together our resources for clinical practice and for research in this space. We hope you enjoy this panel discussion as much as we enjoyed recording it. We appreciate people joining this special session on integrating, educating, and implementing systems of care around brain health for the practicing neurologist. I've got a great team of practicing neurologists here as well. We're looking forward to sharing some of this discussion with lots of opportunities for questions as well. And we're going to kick into the contact right away. I'm Gregg Day. I'm a behavioral neurologist at Mayo Clinic in Florida. I'm joined by Joel Salinas and Sarah Song. I'm going to let them introduce themselves and then I'll provide a bit of scope for our discussion. Dr. Joel Salinas: Great. Thank you, Gregg. So I'm Joel Salinas. I'm a behavioral neurologist, and then I'm also a clinical associate professor of neurology at NYU Langone Health. Dr. Sarah Song: My name is Sarah Song. I'm a stroke neurologist here at Rush University in Chicago, and my favorite job is at the editor-in-chief of Brain and Life, soon to be brainhealth.com. Dr. Gregg Day: Over the past few years, the AAN has definitely taken a clear and very intentional position. Brain health is part of the central nervous system of our academy. It is not meant to be on the periphery, and it's going to become increasingly central to what we do in our practice. And so along with that call, we're really seeing this shift in our field being called to move beyond simply episodic disease management towards a launch of a comprehensive brain health platform and a development of a shared definition of brain health, which we want to conceptualize as this continuous state of attaining and maintaining optimal neurological function to meet the needs of our patients. So this vision raises some real questions in clinical practice. What does preventive neurology look like when we integrate it into our clinic visit? How do we integrate health screening into the clinic visit? We all have time constraints and we're going to be honest and open about that. And what's the future? How do we start educating people on how to actually do this in practice? And maybe even a little bit more challenging, how do we address some of those social structural problems that are often a bit beyond our immediate control, but we all know are critically important here? So today we're going to talk about some of these questions head on. We do want this to be a bit of a dialogue. We want to invite perspectives. We want to hear other perspectives from the audience as well. And we're not here to debate whether brain health is important. I'm going to argue if you're sitting here joining us, you already know why it's important. And if you don't think it's important, you're in the wrong place, but that's okay. Instead, we're going to focus on some of the realistic challenges and maybe strategies to address this. And this key question, what's the AAN going to look like if we're successful in this mission moving forward? So I've asked Joel and Sarah not just to share successes here, but we're going to be candid about the challenges. And so some of these things we just don't know yet about, but we do recognize what we need to be doing to move things forward. And we're going to begin by reframing the neurologist's role in brain health and what that shift means for the people that we care for. So as we've said, the AAN has a definition of brain health. It's changing our view on clinical practice on research and education. So love to hear from Sarah first on your perspective on how this definition has changed or maybe challenged your role as a neurologist in day-to-day practice. Dr. Sarah Song: So I think as a stroke neurologist, my biggest challenge was moving from a reactive to a proactive preventive situation. So I see people on their worst day when they're having a stroke in the hospital, in the ER. I show up and the effects of whatever they've been doing to their brain has ultimately reached some sort of conflict. I think in that sense I was always, okay, how do we prevent a recurrent stroke? But less so thinking on the front end, less so thinking about the lifespan. When we talk about brain health, it starts from prenatal all the way to senescent. It doesn't start when you're 75 and you show up in the ER and I meet you. It should really be starting before you have disease. What can we do upfront? What can we tell your mother before you're even born? So that was the biggest takeaway for me was thinking not just reactive, but proactive, preventive. Dr. Gregg Day: Expanding the scope for sure. Joel, what would you like to add to that? Dr. Joel Salinas: Yeah, with this definition of brain health, which bears repeating again, and it's like over here on one of the posters over here, it's a continuous state of attaining and maintaining the optimal neurologic function that best supports one's physical, mental, and social wellbeing through every stage of life. And as a neurologist, I'm coming from the lens of a behavioral neurologist, it can seem a little overwhelming to feel like you have to now tackle all these different elements of a person's care, but it's really just more than anything reframing something that we've already been doing in practice, which is really claiming responsibility over helping to prevent disease, prevent risks, managing those risks, really being much more proactive. And it's a little bit more of a public health framing, but it's helpful to really claim that responsibility of things that happen before the patient presents in the hospital in the acute state. And there's so much that we can do, which I know we'll get to, but it's an important framing for neurologists in particular to own. Dr. Gregg Day: And this emphasis on prevention, obviously very important. That's the best way to manage disease is going to be to prevent it, certainly best for our patients. But Sarah, as you pointed out, the lifespan perspective isn't within any one of our reaches. So of course the importance of working as a team. Thankfully, we have amazing representation of neurologists here at the AAN, and we all have our own contacts, people that we work with, and so can broaden this mission. Thinking about preventive neurology though, this implies this earlier, broader, sometimes non-traditional interventions to improve our patient's ability to maintain and attain the function that they need. So Sarah, what aspects of brain health promotion feel most natural for you in your clinical environment? Maybe which are some of the areas where you think as a field or as a neurologist, we're going to have more struggles or we're going to hesitate? Dr. Sarah Song: So think as a stroke neurologist, the first thing that really comes up is risk factor management. You both were essential in creating the safest brains, and I'll just refer to some of it. I'll let you guys talk more about that. But for me, it's blood pressure. Above and beyond anything, blood pressure causes strokes of hemorrhagic and ischemic strokes. So talking about risk factor control, especially blood pressure. And then the other one that among risk factor control, just there are so many other risk factors that contribute to stroke. More interesting to me though is the other end, the things that I don't think neurologists are comfortable with. So the addressing mental health, for example. Mental health is something that we learn about, of course, in neurology. We do psychiatry rotations, but we're not necessarily equipped with all of the medication wherewithal or the social strategies that we can use to help so with mental health. And I also think in that same sense, we're not necessarily given the tools to deal with the disparities in health, so socioeconomic disparities that really do affect brain health outcomes as we've learned. So approaching those sorts of situations that we're not comfortable and finding a solution upfront, whether in training or whether in CME or something like that, that we can become more proficient in will actually help us to become more of a well-rounded brain health practitioner. Dr. Gregg Day: And you referenced the safest brains. And Joel, thank you for joining the team in w

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