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    Continuum Audio

    Continuum Audio features conversations with the guest editors and authors of Continuum: Lifelong Learning in Neurology, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. AAN members can earn CME for listening to interviews for review articles and completing the evaluation on the AAN’s Online Learning Center.

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    Latest Episodes:
    Treatment of Alzheimer Disease With Dr. David Geldmacher Jan 15, 2025
    Show notes

    Anti-amyloid therapies provide the first FDA-approved option to alter AD pathology, but an understanding of overall utility and value to patients remains in its infancy. In this episode, Teshamae Monteith, MD, FAAN, speaks with David S. Geldmacher, MD, FACP, FANA, author of the article "Treatment of Alzheimer Disease" in the Continuum® December 2024 Dementia issue. Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida. Dr. Geldmacher is a professor and Warren Family Endowed Chair in Neurology and the director of the Division of Cognitive and Behavioral Neurology, Department of Neurology, Marnix E. Heersink School of Medicine at the University of Alabama at Birmingham in Birmingham, Alabama. Additional Resources Read the article: Treatment of Alzheimer Disease Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @headacheMD Transcript Full interview transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Monteith: This is Dr Teshamae Monteith. Today, I'm interviewing Dr David Geldmacher about his article on treatment of Alzheimer's disease, which appears in the December 2024 Continuum issue on dementia. Welcome to our podcast, Dr Geldmacher. How are you? Dr Geldmacher: I'm very well, thank you. It's a pleasure to be here. Dr Monteith: Yeah. So, why don't you introduce yourself to our audience? Dr Geldmacher: Sure. I'm David Geldmacher. I'm a professor of neurology at the University of Alabama in Birmingham and I lead the division of Cognitive and Behavioral Neurology. Dr Monteith: So, I'm really excited about this, to personally learn, and I know that or neurology community is also really excited about this interview. So, why don't we start off with your main objective. Dr Geldmacher: So, my main goal in the article was to review the FDA-approved pharmacologic treatments for dementia. There's lots of ways of thinking about treatment of dementia; psychosocial, caregiver support, and so forth. But I really wanted to focus on the issues of drug treatment because that's what has been our backbone for a long time and now has recently expanded. Dr Monteith: Why don't we talk a little bit about, first of all, the boom in the field? What's that been like? Dr Geldmacher: So, the big change in the field is over the last several years, we've had treatments become available that actually attack the underlying Alzheimer pathology, and that's new and different. For decades, we've been able to treat the symptoms of the disease, but this is the first time we've really been able to get to the root of the pathology and look toward removing amyloid plaques from the brain. Dr Monteith: Let's step back a little bit and talk about the framework of diagnosis and how that leads into the therapeutic potential. I know you're going to dive into some of the biologics, but we should probably talk about the kind of holistic approach to considering the diagnosis. Dr Geldmacher: Sure. So, you know, when someone comes to the clinic with memory complaints, our question we have to ask is, is this neurologic origin, a structural origin like Alzheimer's disease or vascular dementia? Are there complicating factors, the software issues of mood disorders and sleep disorders and pain that can all magnify those symptoms? The clinical reasoning is a critical part of that, but in Alzheimer's disease, typically the problems revolve around difficulty forming new memories of events and activities, the episodic memory. And then it's often accompanied by changes in word finding and semantic knowledge. And those are the things that we look for in the clinic to really point toward an AD diagnosis. And then we support it with exclusion of other causes through blood work and identification of patterns of brain atrophy on MRI. And then most recently in the last couple of years, we've been able to add to that molecular imaging for amyloid with PET scans as well as, most recently, blood-based biomarkers for Alzheimer's pathology. So, it's really been a revolution in the diagnosis over these last several years. Dr Monteith: And when approaching patients or populations of individuals, there seems to be a real full spectrum with looking at the societal burden, the biological impact, of course, risk factors of primary prevention, and now this whole area of brain health and secondary prevention. How do you kind of tie all of this together when talking to patients and family members? Dr Geldmacher: Sure. So, the approaches for brain health apply to everyone. In basically every clinic visited, our brain aging and memory clinic, we reviewed lifestyle approaches to brain health like regular physical exercise, healthy diet, cognitive and social stimulation. And those are fundamental to the approach to everyone, whether they have cognitive impairments that are measurable or not. These are all things that are good for our brain health. And then, you know, focusing on the vascular risk factors in particular and working with the patient and their primary care team to ensure that lipids and blood sugar and blood pressure are all in good healthy ranges and being appropriately treated. Dr Monteith: You know, there's this kind of whole considerations of clinically meaningful endpoints and clinical trials, and even when we're talking to our patients. What would you say the field has kind of identified has the best endpoints in helping patients? Would you call it impaired daily function? Is that like the best hard endpoint? Obviously, there are other things such as caregiver burden, but you know, how do you approach assessing patients? Dr Geldmacher: Defining the endpoints is very difficult. Typically, if we talk to patients and their families, they would like to have better memory or improve memory. How that applies in everyday life actually is daily function. And so, we focus very much on daily function. And when I talk about our therapies, whether they're symptomatic therapies or the new disease-modifying therapies, I really talk about maintenance of function and delays and decline or slowing of decline, helping to foster the person's independence in the activities that they have and be able to sustain that over the longer term. Dr Monteith: And when thinking about diagnosis- and we're going to get into treatments, but when thinking about the diagnosis, and of course, it's full-spectrum from mild cognitive impairment to moderate and severe forms of dementia, but who should have CSF testing and PET imaging? Obviously, these are invasive, somewhat invasive and expensive tests. Should all people that walk in the door that have memory complaints? How do you stratify who should have tests? Dr Geldmacher: I think about this in a big funnel, basically, and the starting point of the funnel, of course, is the person with memory complaints. Then there's that neurologic reasoning. Are these memory complaints consistent with what we expect from the anatomy of Alzheimer's disease, with atrophy in in the hippocampus and temporal lobe? Do they have episodic memory loss or not? That first step is really trying to characterize, do the clinical patterns act like those of Alzheimer's disease or not? And then we follow the Academy of Neurology guidelines, looking for reversible sources of cognitive decline, things like B12 deficiency and depression, sleep disorders and the like, and try to exclude those. We start with structural imaging with everyone, and MRI, typically, that will help us understand vascular burden and patterns of atrophy, looking for things like mesial temporal atrophy or precuneus atrophy that are characteristic of Alzheimer's disease. If those things are all pointing in the direction of AD as opposed to something else, then typically before moving on to CSF or PET scan, we will use blood-based biomarkers, which are one of the big changes in the field in the last year or so, and there are now multiple panels of these available. The downside is they are typically not covered by insurance. On the other hand, they can really help us identify who is likely to have a positive PET scan or positive findings on CSF. We start to provide that counseling and information to the patient before they get to those more definitive tests. We can push people in the other direction. We can say, your blood-based biomarkers are negative or do not indicate AD as the most likely source of your condition now, so let's treat other things. Let's see what else we can focus on. The blood-based biomarkers are now, in our clinic at least, the critical choke point between the routine workout that we've always done on everyone and then the more advanced workup of proving amyloid pathology with CSF or a PET scan. Dr Monteith: How sensitive are those blood biomarkers and how early are they positive? Dr Geldmacher: The sensitivity is generally pretty good, in the ninety plus percent range on average and it depends on which panel. And as you point out, when in the course of symptoms that they're done, we know that they become positive and presymptomatic or asymptomatic people. We're using these kinds of markers to screen people for prevention trials. So, I think when someone is symptomatic, they're a good indicator of the presence or absence of AD pathology. Now that doesn't mean the AD pathology is the sole cause of their symptoms. And so, we still need to think about those other things like sleep and mood and so forth. But they do point us in the in the direction of Alzheimer's change. Dr Monteith: So why don't we talk about some of the more standard older treatments, and it's also important to leave with kind of some rational approach to when we start and what should we be counseling our patients on. So why don't we start with the older, you know, choline esterase inhibitors and then some of the MDA- I guess there's only one modulator, SEPTA modulator. Dr Geldmacher: So, I've been really fortunate in my career span, the time from the first of those symptomatic agents reaching the market in 1993 to seeing the disease modifying drugs enter the market now. I think most neurologists actually have entered practice after those clinical trials of the colon esterase inhibitors were published. So, one of my goals in this article was to review that primary data and what can we expect from those symptomatic drugs. We know that they are inconsistently effective in mild cognitive impairment, and the Academy of Neurology guidelines says there is not strong evidence to use them in mild cognitive impairment. But in mild AD and beyond, the cholinesterase inhibitors provide meaningful benefits. They delay decline, they can delay nursing home placement. They reduce overall costs of care. So, I think they provide real value. So, in the article I have reviewed what the data looked like on those. My approach is to start with oral Donepezil at five milligrams and increase it to ten in everyone who tolerates the five. If for whatever reason the oral Donepezil is not well tolerated, I'll switch to transdermal rivastigmine to help improve tolerability. There are very few head to head comparisons, but nothing suggests that one of the cholinesterase inhibitors is superior to the other for clinical outcomes, and there's no evidence to support conjoint use of more than one at a time. Should someone be showing decline then on typical cholinesterase inhibitor therapy - and people will, it's often delayed, but the decline will reemerge - then I will add the NMDA receptor, a modulator memantine and titrate that up to full dosing, either 10 mg twice a day for the conventional release or 22 mg extended release. And at that point we're sort of on maximal pharmacologic therapy for Alzheimer's disease. These agents can provide some benefit in other conditions, they're off-label except for Lewy body disease where rivastigmine is labeled. But they can provide benefit across different conditions. And there's some preliminary data, for instance, of acetylcholinesterase inhibitors being helpful in vascular cognitive impairment. So, I will use them, but I expect the greatest response when someone really does follow the patterns of Alzheimer's disease. Dr Monteith: And you have a great chart, by the way, and nice figures looking at some of the meta-analyses on cognitive outcomes as well as functional outcomes. So, thank you for that. Dr Geldmacher: In general, all of those tables favor treatment over placebo in the domains of cognition, daily function, neuropsychiatric symptoms. And it's that consistency of result that lets me know that we really are seeing a drug effect, that it's not a class effect with those, that we really are helping our patients. It's not like some studies are positive and some are negative. They are very consistently positive. Small magnitude, but consistently positive. Dr Monteith: And I know we have a lot of patients coming in where, at least, their caregivers are complaining about agitation, and sleep is also a problem for others. And so how do you help that patient? I know you have a good algorithm that also you included in your article, but why don't you summarize how we should approach these symptoms? Dr Geldmacher: Sure. So, for nonpsychotic agitation, you know, just restlessness, wandering, pacing and so forth, my first choice is an off-label use of citalopram. And there is good clinical trials evidence to support that. if someone has psychotic agitation that is with delusions or hallucinations and so forth, I think we do need to move to the antipsychotic drugs. And the one drug that is now approved for treatment of agitation and Alzheimer's disease does fall into that antipsychotic category, along with its various black box warnings - and that's brexpiprazole. For many of our patients, getting coverage for that agent is difficult. It's not on many formularies. So, it is something I progress toward rather than start with. Similarly, for sleep, there is one approved agent for sleep, that's a dual orexin agonist. And it shows effectiveness, but can have some negative cognitive effects, and so I tend not to start with that either. My first choice when sleep is the primary issue for our patients with dementia is trazodone, and there are some small, limited studies for it's off-label used to enhance sleep. It's safe, inexpensive, often effective, and therefore it's my first choice. Dr Monteith: So, now let's get into the big conversations that everyone is having. Let's talk about the newer disease modifying anti amyloid therapies. Give us a summary dating back 2021 probably, although we can hold the preclinical work, but let's talk about wha…

    Full show notes at the publisher

    Genetics and Neuropathology of Neurodegenerative Dementias With Dr. Sonja Scholz Jan 08, 2025
    Show notes

    Recent progress in neurogenetics and molecular pathology has improved our understanding of the complex pathogenetic changes associated with neurodegenerative dementias. In this episode, Katie Grouse, MD, FAAN, speaks with Sonja W. Scholz, MD, PhD, FAAN, an author of the article "Genetics and Neuropathology of Neurodegenerative Dementias," in the Continuum® December 2024 Dementia issue. Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California. Dr. Scholz is a senior investigator at the National Institutes of Health in Bethesda, Maryland and an adjunct professor of neurology at Johns Hopkins University in Baltimore, Maryland. Additional Resources Read the article: Genetics and Neuropathology of Neurodegenerative Dementias Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Full episode transcript available here: Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Sonia Scholz about her article on genetics and neuropathy of neurodegenerative dementias, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast, and please introduce yourself to our audience. Dr Scholz: Thank you so much for inviting me. My name is Sonia Scholz. I'm a neurologist working at the National Institutes of Health. My main focus of research and clinical work are neurodegenerative diseases, and I have a particular interest in using modern genomic tools to understand these diseases and potentially leverage it for new translational applications. Dr Grouse: Sonia, we're really excited to have you today and thanks for joining us. Dr Scholz: I'm pleased to be here. Dr Grouse: I'd like to start by asking what you think is the most important message or takeaway point from your article? Dr Scholz: So, this is an article that really captures a very broad and exciting field. So, one thing I wanted to really highlight is that there's a lot of heterogeneity, clinical, pathological, molecular heterogeneity in age-related neurodegenerative dementia syndromes. Our article was really aimed at providing a bird's eye view of the pertinent pathological characteristics, but also important genetic advances and insights and how we can leverage that, particularly in the new physician medicine era, hopefully come up with better treatments and better ways to counsel our patients. Dr Grouse: What do you think is the most challenging aspect of understanding the genetics and neuropathologic basis of neurodegenerative dementias? Dr. Scholz: That's a good question. There're many big and challenging questions, but I think one of the things we struggle the most with is really the heterogeneity. I see patients with one and the same Mendelian form of dementia. One patient is in their forties another patient is in their eighties, and the clinical manifestations can be very different from one patient to another. There's a lot of heterogeneity, also, on the pathological level. Not every patient has exactly the same distribution. And so, we're starting to slowly define what the underlying causes are, but it's still quite baffling and quite challenging to put them together and understand them. Dr Grouse: Do you feel that the genome-wide association studies has helped our understanding of these diseases, specifically the heterogeneity? And if so how? Dr Scholz: That's a great question, but you're talking to a geneticist here. And I definitely would say genome-wide association studies have helped us a lot in identifying what the underlying disease pathways are and what the relationships between neurodegenerative disease entities are. It really also gave us a better understanding of apparently sporadic diseases where genetic factors are still playing a role. And we can leverage that type of knowledge increasingly to highlight high-risk groups, but also, we can increasingly use it to stratify patients for clinical trials, for example. And that's really exciting and there's still a lot of knowledge that we have to garner very quickly, especially in the non-Alzheimer dementia space. Dr Grouse: You've mentioned, of course, the heterogeneity and these syndromes. And in your article, you go into a lot of the issue of the significant crossover between the genetic links and the neuropathological findings for the various types of neurodegenerative dementias. Do you think that this crossover has been more of a help or a hindrance in better understanding these diseases? Dr Scholz: Yeah, it can be a little bit, you know, challenging to wrap one 's mind around it. But by and large, I think it's actually good news because it highlights that there is a shared biology between many of the neurodegenerative disease entities. And by figuring out which the pathways are that are very often involved, we can prioritize certain targets for therapy development. But we can also be smarter about how we developed treatments. We could repurpose a drug that has been developed for Alzheimer's disease very easily for Lewy body dementia because we increasingly understand the overlap. And we can also leverage new clinical trials design, like basket trials. This is something that has been really transformative in the oncology sphere and now, increasingly, neurodegeneration. We're trying to apply that kind of thinking as well to our patient populations. Dr Grouse: What do you think our listeners will find to be most surprising when they read the article? Dr Scholz: We often present these diseases in our textbooks as these black-and-white entities, but the reality is that there's a lot of overlap. And we also see that co-pathologies are actually the norm and not the exception, and a lot of the molecular risk factors are shared. It's not really surprising. And I think that overlap and crosstalk between the various diseases is something that's a little bit strange to think about, but it actually makes increasingly sense now that we see the genetic risk profiles coming up. Dr Grouse: In reading your article, I was really struck by how many, or how much the prior studies have been lacking in inclusion of different ethno-racial backgrounds in the patients who've been studied. How can this be improved going forward? Dr Scholz: Yeah, thank you. That's a really important and crucial question, and I think it really takes the collective effort of everybody in the healthcare research community to improve upon that. We need to talk to our patients about genetic testing, about brain donation programs, about referrals to clinical trials, and don't feel shy about reaching out to our colleagues and academic centers, even if you don't have the resources in a smaller institution. We also not only need to engage with the communities, we also need to build up a healthcare research community that has representatives from these various communities. So, it's really a collective effort that we build up and are proactive about building a more equitable healthcare system and research system that works for all of us and that really is going to provide us with the precision medicines that work for everybody. Dr Grouse: What do you think is the biggest debate or controversy related to the genetics and neuropathology of neurodegenerative dementias? Dr Scholz: Yeah, there are loads of interesting debates, but I think in my field, in particular in the genetics is what to do with risk variance. What is it that I actually communicate to the patient? Obviously, I can learn a lot on the bench and I think I can use a lot of the genetic risk factors for molecular modeling, etc. But to which extent should I share that information? Because genetic information is something that we cannot alter and many of the risk factors are actually mild, that they may never result in disease. And so, communicating risk with patients is something that's very challenging and we used to just steer away from it. But now the discussion is starting to shift a little bit. You know, nowadays we are starting to offer, for example, testing for the APOE4 allele in individuals who are considering antiamyloid therapies. And this really, this is precision medicine in his earliest days because it allows us to stratify patients into those that are high-risk versus low-risk and those that need more frequent follow-up or may be advised not to pursue this treatment. And we're probably going to see more of those discussions and the ethics around it. And it's even harder in an aged population where you know, you may never manifest any of the symptoms despite carrying a lot of these risk deals. Dr Grouse: You mentioned, you know, that testing, APOE4 testing for certain populations when deciding to do the antiamyloid immunotherapies. Apart from that, which I think is a really good example of where genetic testing makes sense, what other scenarios do you think it makes sense at this point in time to recommend genetic testing for symptomatic patients who are concerned about neurodegenerative dementias? Dr Scholz: Yeah. So, I usually have a very frank discussion with patients in whom I suspect the genetic etiology. So those are individuals who have a strong family history, individuals from very early onset of the disease where genetic testing may allow us to establish a molecular diagnosis, individualize and refine our counseling, and potentially get them into targeted clinical trials that may be suitable for that. Those are always very nuanced discussions, but I usually start with those high-risk individuals. Increasingly patients are, even with the apparently sporadic forms, are asking me about it. And then I have a frank discussions about the pros and cons and offer it to the patients who really would like to pursue it. Dr Grouse: That makes a lot of sense. What about in the case of patients who are asymptomatic but might have high risks because of, well, family members with certain types of neurodegenerative dementias? When would it make sense, if ever, to do genetic testing for them? Dr Scholz: Yeah, that's a that's a tough situation, to be honest. By and large, I would say I would like to understand what the motivation is to learn about the genetic status. If the motivation is something like family planning, future care planning, etc, then it may be a reasonable thing. But I also want to make it very clear upfront that knowing a genetic status, at least aside from APOE status, at least for now, doesn't actually change the clinical management. And I want to make sure patients understand if they are trying to lower their risk, knowing that genetic status is not going to lower their risk. There are other things, brain health habits, that are really important, that patients should double down on: avoiding vascular disease, avoiding traumatic brain injury, excessive alcohol use, etcetera. It's a discussion that really tries to understand the motivations behind the testing. But some patients are very frank and they want to have it. They may want to contribute to the research community, and so in those instances we may offer it, but I also really want to make them understand that knowing a genetic diagnosis may be acceptable to them, but family members who are related to them may not wish to know. And they can really cause a lot of psychological stress that extends beyond the individual. And then that's something to really consider before actually pursuing testing. Dr Grouse: I think that's a really good reminder, especially about how this can even affect people outside of the patient themselves. I think a lot of us don't even think about that. And certainly, our patients may not either. Taking it a step further, thinking about newly available biomarkers, imaging modalities, how should we incorporate the use of these for our patients when we're suspicious of things like Alzheimer's disease or dementia with the Lewy bodies? Dr Scholz: So by and large these biomarkers are used in in the research area, but we can, in a given patient where maybe the clinical presentation is somewhat atypical, we can use it to help with our diagnostic impression. It doesn't get rid of the clinical evaluation, but at least it gives us a little bit more certainty. Here are the you know, the molecular features, the abnormal amyloid tau deposits, for example, that we're there we're detecting supports diagnosis. May also sometimes help in patients where we suspect there could be even the co-pathology going on where we get a mixture of features, where we can counsel the patients and you know, detecting copathologies is something that is certainly challenging. We know that patients who have more pathologies on average are not doing as well as the ones who have relatively pure disease forms. But this is also an area of intense research and as long as it's used judiciously to help with the diagnostic compression, to reduce a diagnostic odyssey, I think there's a lot of potential there to improve the clinical evaluations nowadays. Dr Grouse: It is really exciting to see the options that are opening up as the years go by, which brings me to my next question. There is certainly, as we know, this new category of disease modifying therapies that are available in the form of the anti-amyloid immunotherapies. What else do you think's on the horizon for treatment and prevention, neurodegenerative dementias, going down the road five, ten, fifteen years down the line? Dr Scholz: Yeah, I think we're entering the era of precision medicine already and we're, we're seeing it already with the anti-amyloid therapies. By and large, I think the standard of care is going to be a multidisciplinary individualized treatment plan that incorporates a more holistic view. It incorporates diet, lifestyle factors, symptomatic management, but also disease modification strategies and potentially even multitarget disease modifying strategies. I think there's a lot more work that we have to do, especially in in the non-Alzheimer's dementia field. But overall, we're becoming much better in refining our diagnostic impression and in treating some of the complications that arise in these very complex diseases. Dr Grouse: I'm curious, with the future of dementia care and diagnosis being more of a precision medicine model, how do you think this will be possible in an aging population with already, I think, probably a limited access to neurologists even in current state? Dr Scholz: Yeah, this is- these are these are very challenging societal questions. Increasingly, you know, we can use modern technologies such as televisits for follow up, but also, you know, remote monitoring devices. We have to educate the next generation, we need more neurologists, we can't do it alone; but we also need to empower primary ca…

    Full show notes at the publisher

    Fluid Biomarkers in Dementia Diagnosis With Dr. Joseph Quinn Jan 01, 2025
    Show notes

    Blood-based biomarkers for dementia diagnosis are emerging and rapidly evolving. These fluid biomarkers should be used when the results will impact management decisions, including patient and family counseling, symptomatic therapies, and disease-modifying therapies. In this episode, Allison Weathers, MD, FAAN, speaks with Joseph F. Quinn, MD, FAAN, an author of the article "Fluid Biomarkers in Dementia Diagnosis," in the Continuum® December 2024 Dementia issue. Dr. Weathers is a Continuum® Audio interviewer and associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Quinn is a professor in the Department of Neurology at Oregon Health & Science University in Portland, Oregon. Additional Resources Read the article: Fluid Biomarkers in Dementia Diagnosis Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Transcript Full interview transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Weathers: This is Dr Allison Weathers. Today, I'm interviewing Dr Joseph Quinn, author along with Dr Nora Gray, of Fluid Biomarkers in Dementia Diagnosis from the December 2024 Continuum issue on dementia. Welcome to the podcast and please introduce yourself to our audience. Dr Quinn: Sure. I'm Joe Quinn. I'm a neurologist at the medical school in Oregon, Oregon Health Science University, and I work in neurodegenerative disease, Alzheimer's disease, and Parkinson's disease. Dr Weathers: Certainly some really weighty topics. But again, as I said, today we want to focus on a really fascinating one, the concept of fluid biomarkers in dementia diagnosis. And we'll perhaps get into monitoring of treatment as well. So, this search for reliable biomarkers in the diagnosis of dementia, certainly not a new topic, but you and your co-author Dr Nora Gray did a really fantastic job in the article right from the get-go, laying out the urgency around this now that there are FDA of treatments that depend on pathologic diagnosis. And it feels like they're more and more announced by the day. Even as I was preparing for this interview a few days ago, the FDA approval for donanemab was announced, with the news making every major media outlet. Well, there are several really critical points made by you both in the article. What do you feel is the most important clinical message of your article? What do you want our listeners to walk away with as their one key takeaway? Dr Quinn: I think we still have the best evidence for CSF biomarkers, cerebrospinal fluid biomarkers, really making a diagnosis with some confidence. PET scans are available for visualizing amyloid and Tau now, but they're so expensive and they're not covered. So, the spinal tap information is what most of us around here really rely on when we want to be sure about what's going on. The blood tests are very promising, very exciting, but as you probably know, there's a lot of different opinions about this out there. Some people are sure that it's a done deal and that we now have a blood test for Alzheimer's disease. After I sent the article off, I opened up my issue of Neurology and there was an editorial saying these blood tests will never work. So, there's different ends of the spectrum on this and we tried to strike a balance with that. So they're very promising. I think before the article is due for revision, things are going to be different. But right now, spinal fluid is probably where we have the most confidence. Dr Weathers: I think that's a really solid takeaway to start our discussion with. And then, I think you both did really strike that very delicate balance in what is right now an area where, as I said, you know, things still are changing by the day. I know for our listeners who do subscribe, and I hope that most of them do, Table 9.1, clinically useful CSF biomarkers for the differential diagnosis of dementia, is one that I personally think I will frequently return to. You and Doctor Gray did just a wonderful job organizing these very complex concepts into an easy read and really powerful tool, especially for use at the bedside. Along the lines of knowing which biomarker to use, how frequently routine care are you ordering these tests on your patients? And do you anticipate this changing the media future? Is this another one of those things that by next week, we'll have a different kind of answer in how we use these tests? Dr Quinn: Yeah, as you said in your preliminary comments, the whole picture has been changed by the approval of these antibody therapies for Alzheimer's disease, lecanumab and just last week, donanemab. Prior to the approval of those two medications, I didn't use spinal fluid tests routinely, but I relied on them when I really needed to make a diagnosis with certainty of something really important hung in the balance. If we were trying to rule out some other treatable, more treatable problem. You know, for example, if it was a question of whether somebody primarily had a psychiatric problem or a neurodegenerative disease, this is something that would really allow me to objectify things. And- but that was a minority of people that I would see for dementia evaluation. You know, now that the two therapies are approved, I'm not actively engaged in administering those therapies very frequently but I can see already that the, the patients that I am discussing this with that spinal fluid is where we're probably going to rely for making a diagnosis of the amyloid burden in the in the living patient until PET scans are approved. If amyloid PET scans are- not approved, but covered by insurance, then those will probably replace the spinal fluid. So those tests in that table, A beta 42, tau, p-tau, one of them that's relatively new is this test for aggregated alpha-synuclein. Those I order with some frequency when I'm in those circumstances. Dr Weathers: That's really helpful for our listeners to hear from an expert such as yourself and to think about as they encounter similar patients. Whenever discussing complex topics such as this one, I'm always curious about, what is the most common misconception or pitfall regarding the use of biomarkers for the diagnosis of Alzheimer's and other dementia that you encounter? Dr Quinn: With respect to the blood biomarkers, you know, we were saying a moment ago that there's a lot of evidence available, but the jury is still out to some degree as to how reliable they are. And I think an important message with respect to those blood biomarkers is that they really are confounded by comorbidities. Remember, we're dealing with an elderly population, so comorbidities like hypertension and renal insufficiency and those kinds of things are relatively common and they can really throw off the blood biomarkers in a more dramatic way than cerebrospinal fluid biomarkers. The other fact, and I can't remember how well we cited this in the article, was that the blood biomarkers don't perform as well in underrepresented minorities. And you know, all of us are appropriately paying more attention to that problem in our practice of medicine. And for these blood biomarkers, that's a real issue. And whether the inferior performance in underrepresented groups is due to more comorbidity or just due to genetic differences is unclear at this time. So those are really important cautions. We mentioned the renal insufficiency and, I think, some of the other comorbidities, but it's a reason to really be careful with the blood biomarkers. Dr Weathers: I think a really important point, especially again, kind of going back to what we were talking about at the beginning of our discussion, there's so much excitement around them. There's so much potential. People think we finally have that kind of silver bullet of diagnosis. So, I think really something to keep in mind. What about in the use of their- in monitoring the efficacy of treatments? Dr Quinn: So that's I think a little earlier in its history in terms of what biomarkers would be useful for monitoring. But the donanemab trial really relied on blood biomarkers as outcome measures and really showed some interesting phenomena. One of them was that plasma neurofilament light, which is all the rage now and all over neurology, people are measuring plasma neurofilament light. It's a nonspecific marker of neuronal damage that makes it out into the serum. So, you can measure it in serum and detect CNS damage in the serum. And intuitively, you would think that would be a good measure of efficacy, but in terms of detecting a treatment effect with donanemab, it didn't perform very well. Conversely, GFAP, which is a marker of astrocyte activation, which I would not have predicted was going to be a sensitive marker for treatment efficacy, performed well in at least the donanemab trial. So, I think it's early in the history of using these markers as outcome measures in clinical trials. And I think we're going to continue to learn as each therapy comes along and as these things come to pass. Dr Weathers: Don't make any assumptions yet? Would that be a good way to sum that up? Dr Quinn: I think that's, yes. I think that's very fair that that we have to be careful about these things. Dr Weathers: OK. So, in summary, I think, does it sound like it's fair to say that the pitfall might be to say it's too early to make any assumptions or any conclusions quite yet? Dr Quinn: That's right. And, and I think, you know, we're going to need to monitor these therapies. I think all of us in neurology have become very accustomed to how you do that in multiple sclerosis, right? We've got MRI scans to be used to monitor therapy, maybe NFL is going to be an appropriate assay there as well. But, you know, there we've all had the experience of a chronic disease and seeing how well your therapy is doing, changing therapy if it fails. So, we're absolutely going to need those things in in Alzheimer's disease and other neurodegenerative diseases, but it's a little early for us to be sure exactly what the right measures are to make those important decisions. Dr Weathers: And a lot more work to be done for sure. As I mentioned, this is a topic of such great interest and I know, you know, certainly most of our listeners are neurologists or people in our world, medical students and trainees. I know I have one regular nonneurologist listener, my father. He really gets a kick out of listening to my interviews. Even though he is a retired sales manager from IBM and most of the time the topics of discussion are pretty different from his usual favorite podcasts. But this one he will be particularly interested in and I'm sure I will get a list of questions about, particularly because my grandfather unfortunately had Alzheimer's disease. So, I'm sure one of his questions will be about the use of these biomarkers in asymptomatic patients. How do you counsel family members of patients when they inquire about the use of biomarkers for that youth case? What is their utility in presymptomatic testing? Dr Quinn: We know from studies like the Alzheimer's disease neuroimaging initiative and other biomarker studies that some of these markers will be sensitive to pathology. Even in asymptomatic people, that pathology appears long before people develop symptoms. Despite that, I don't recommend that asymptomatic people get any of the testing right now because we do not have evidence that early intervention at the completely asymptomatic stage is valuable. And those clinical trials are underway. There are trials underway right now for people who don't even meet the memory deficit required to have a diagnosis of mild cognitive impairment, people who are entirely cognitively intact, but who on one biomarker study or another have evidence of pathology burden. And the interventions are being started early. And in a few years, we'll know the answer to that. Right now, for somebody to find out that they have pathology without any ability to act on it, I think is not valuable. So, I discourage people from pursuing that. Dr Weathers: And that is really important guidance. Thank you. I know you have, as you mentioned, a beginning in a really diverse neurologic background with expertise, as you said, not only in dementia, but also in Parkinson's disease. And you didn't even mention this, but I know expertise in stroke as well, but your research has been primarily in Alzheimer's. What drew you to dementia and to this specific the aspect of it? How did you become an expert in biomarkers? Dr Quinn: Well, I'll start with the dementia part. So, you know, I was always just interested intuitively in trying to understand how, you know, the brain mediates the mind. So as an undergraduate, I got started working in a lab that was working on the cholinergic system in the brain, which was still being sorted out at that time. It is important in Alzheimer's disease, but it was really where the focus was. And that's what got me interested in Alzheimer's disease, which incidentally is what got Alzheimer interested in Alzheimer's disease. You know, he was very interested in trying to find the biological footprints of all these different neurological and psychiatric diseases. And he usually came up empty-handed until he came across the patient with Alzheimer's disease where there were actual footprints in the brain that he thought was pointing towards what was going on. And we're still wondering about that a hundred years later, I guess that's how I got interested in dementia and Alzheimer's disease. I think I have always spent part of my time as a clinician. I think that's what got me interested in biomarkers, that this problem has always been there that, you know, we've got quite, you know, research criteria for making diagnosis and all that sort of thing. But we've really needed some biological evidence to help us firm this up even before the availability of the therapies. And that's what got me interested in- I'm making another point. I thought that computer research biomarkers are going to help point me towards the causes of the disease, and unfortunately that part hasn't entirely panned out. We've got some research in that area on micro-RNA biomarkers that maybe will bear some fruit down the road, but that's been a tougher, tougher nut to crack. Dr Weathers: But it's so incredibly important work. Well, this has been wonderful. I really enjoyed our conversation, and I always like to end on a hopeful note. What developments in the biomarker space are coming on the horizon are you most excited about? Dr Quinn: I'm hoping that these biomarkers that allow us to evaluate disease efficacy, blood biomarkers that don't require extraspinal t…

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    LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy With Dr. Vijay Ramanan Dec 25, 2024
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    Although Alzheimer disease (AD) is the most common neurodegenerative cause of dementia, other etiologies can mimic the typical amnestic-predominant syndrome and medial temporal brain involvement. Neurologists should recognize potential mimics of AD for clinical decision-making and patient counseling. In this episode, Kait Nevel, MD, speaks with Vijay K. Ramanan, MD, PhD, an author of the article "LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy," in the Continuum December 2024 Dementia issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Ramanan is a consultant and assistant professor of neurology in the Division of Behavioral Neurology at Mayo Clinic College of Medicine and Science in Rochester, Minnesota. Additional Resources Read the article: LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: IUneurodocmom Guest: @vijaykramanan Full episode transcript available here Dr Jones: This is Dr Lyle Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum 's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Nevel: This is Dr Kait Nevel. Today I'm interviewing Dr Vijay Ramanan about his article he wrote with Dr Jonathan Graff-Radford on LATE hippocampal sclerosis and primary age-related tauopathy, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast. Vijay, can you please introduce yourself to the audience? Dr Ramanan: Thanks so much, Kait. I'm delighted to be here. So, I am a cognitive neurologist and neuroscientist at the Mayo Clinic in Rochester, Minnesota. I have roles in practice, education and research, but amongst those I see patients with cognitive disorders in the clinic. I help direct our Alzheimer's disease treatment clinic and also do research, including clinical trial involvement and some observational research on genetics and biomarkers related to Alzheimer's and similar disorders. Dr Nevel: Great, thanks for that. So, I'd like to start off by talking about why is LATE hippocampal sclerosis, why is this important for the neurologist practicing in clinic to know about these things? Dr Ramanan: That's a great question. So, if we take a step back, we know that degenerative diseases of the brain are really, really common, and they get more and more common as we get older. I think all neurologists, and in fact most clinicians and large swaths of the general public, are well aware of Alzheimer's disease, which is the most common degenerative cause of cognitive impairment in the population. But there are non-Alzheimer's degenerative diseases which can produce cognitive difficulties as well. And it's important to be aware of those disorders, of their specific presentations and their implications, in part because it's always a healthy thing when we can be as precise and confident about diagnosis and expectation with our patients as possible. I'll look to the analogy of a patient presenting with a myelopathy. As neurologists, we would all find it critical to clarify, is that myelopathy the result of a compressive spondylotic change? The result of an inflammatory disorder, of a neoplastic disorder, of an infectious disorder? It's critical to guide the patient and choose appropriate management options based on the cause of their syndrome. It would potentially harm the patient if you treated an infectious myelopathy with steroids or other immune-suppressant drugs. So, a similar principle holds in cognitive neurology. I accept with humility that we can never be 100% crystal clear certain about things in medicine, just because when you think you got it all figured out there's a curveball. But I want to get as close to that 100% as possible. And recognizing that disorders like LATE or PART can mimic the symptoms, sometimes even the imaging features of Alzheimer's disease. I think it's critical to have heightened awareness of those disorders, how they look, to be able to apply appropriate counseling and management options to patients. I think this becomes particularly critical as we move into an era of disease-specific, and sometimes disease-modifying, therapies, where applying a choice of a treatment option could have significant consequences to a patient if the thing you're treating isn't the thing that the drug is trying to accomplish. So, having awareness and spreading awareness about some of these non-AD causes of cognitive difficulty, I think, is a big mission in the field. Dr Nevel: Yeah, that makes total sense. And kind of leaning into this, you know, trying to differentiate between these different causes of late-life amnestic cognitive impairment. You know, I'll point out to the listeners today to please read your article, but in addition to reading your article, I'd like to note that there's a really nice table in your article, Table 6-1, where you kind of go through the different causes of amnestic cognitive impairment and the different features that better fit with diagnosis X, Y, or Z, because I think it's a really nice table to reference and really easy to look at and reference back to. But on that note, what is your typical approach when you're seeing a patient in clinic, have a new referral for an older patient presenting with a predominantly progressive amnestic-type features? Dr Ramanan: Excellent question. And this is one that I think has relevance not just in a subspecialty memory clinic, but to all the clinicians who help to diagnose and manage cognitive disorders, including in primary care and general neurology and others. One principle that I think it's helpful to keep in our minds is that in cognitive neurology, no one data point takes precedence over all the others. We have a variety of information that we can gather from history, from exam, from imaging, from fluid biomarkers. And really the fun, the challenge, the reward is in piercing together that information. It's almost like being a lawyer and compiling the evidence, having possibilities on your list and raising and lowering those possibilities to get as close to the truth as you can. So, for patients with a cognitive syndrome, I think the first plank is in defining that syndrome. As you mentioned, if I'm seeing someone with a progressive amnestic-predominant syndrome, I first want to make sure, are we talking about the same thing, the patient, the care partner, and I? Can often be helpful to ask them for some examples of what they see, because sometimes what patients may report as memory troubles may in fact reflect cognitive difficult in other parts of our mental functioning. For example, executive functioning or naming of objects. And so helpful to clarify that in the history to get a sense of the intensity and the pace of change over time, and then to pair that with a good general neurologic exam and some type of standardized assessment of their cognitive functioning. At the Mayo Clinic, where partial to the short test of mental status. There are other ways to accomplish that, such as with an MMSE or a MoCA. If I understand that the syndrome is a progressive amnestic disorder, Alzheimer's disease is the most common cause of that presentation in older adults, it deserves to be on my differential diagnosis. But there might be some other features in the story that could raise or lower those mimics on my list. So, in patients who are, say, older than the age of seventy five, disorders like LATE or PART start to rise higher on the likelihood for me, in particular if I know that their clinical course has been more slow brewing, gradually evolving. And again, most degenerative disorders we expect to evolve not over days or weeks, but over many months to many years. But in comparison with Alzheimer's disease, patients with LATE or with PART would be expected to have a little more slow change where maybe year over year they or their care partners really aren't noticing big declines. Their daily function is relatively spare. There might not be as much involvement into other non-memory cognitive domains. So, these are some of the pieces of the story that can help to perhaps isolate those other non-AD disorders on the list as being more likely and then integrating, as a next level, diagnostic testing, which helps you to rule in and rule out or support those different causes. So, for example, with LATE there can be often out of proportion to the clinical picture, out of proportion to what you see on the rest of their imaging or other profiles, very predominant hippocampal and medial temporal volume loss. And so that can be a clue in the right setting that you may not be dealing with Alzheimer's disease or pure Alzheimer's disease, but that this other entity is there. So, in the big picture, I would say being systematic, recognizing that multiple data points being put together helps you get to that confident cause or etiology of the syndrome. And in particular, taking a step back and thinking about big picture factors like age and course to help you order those elements of the differential, whether AD or otherwise. Dr Nevel: Great, thanks. In your article, you talk about different imaging modalities that can be used, as you mentioned, you know, just another piece of the puzzle, if you will, to try and put together what may be going on with the patient, and recognizing that some of these imaging techniques are imaging is special imaging, not available in a lot of places. You know, and maybe other diagnostic type tests that could be helpful in differentiating between these different disorders may not be available, you know, for the general neurologist practicing in the community. So, what do you suggest to the general neurologist maybe practicing somewhere where they don't have access to some of these ancillary tests that could assist with a diagnosis? Dr Ramanan: Critical question. And here I think there's not likely to be one single answer. As with most things, awareness and recognition is a good place to start. So, some of those clues that I mentioned earlier about the clinical course, about the age, the- we're talking about clinical setting there. So, comfort with and understanding that the clinical setting can help you to be more confident about, for example, LATE or PART being present in contrast to AD. That's important information. It deserves to be part of the discussion. It doesn't necessarily need other tests to have value on its own. A second piece is that tests help, in some cases, to rule in and rule out causes for cognitive difficulty. As part of a standard cognitive evaluation, we would all be interested in getting some blood tests to look for thyroid dysfunction or vitamin deficiencies. Some type of structural head imaging to rule out big strokes, tumors, bleeds. Head CT can accomplish some of that perspective. It's ideal if a brain MRI can be obtained, but again, keeping in mind, what's the primary goal of that assessment? It's to assess structure. Occasionally you can get even deeper clues into a syndrome from the MRI. For example, that very profound hippocampal or medial temporal atrophy. So, increasing awareness amongst clinicians throughout our communities to be able to recognize that change and put it in the context of what they see in other brain regions that can be affected by Alzheimer's or related disorders. For example, the parietal regions can be helpful. And recall that MRI can also be helpful in assessing for chronic cerebrovascular disease changes. This is another mimic that shows up in that table that you mentioned. And so multiple purposes can be satisfied by single tests. Now, you're absolutely right that there are additional test modalities that, perhaps in a subspecialty clinic at an academic medical center, we're very used to relying on and finding great value on; for example, glucose PET scans or sometimes fluid biomarkers from the blood or from the spinal fluid. And these are not always as widely available throughout our communities. Part of the challenge for all of us as a field is therefore to take the expertise that we have gathered in more subspecialty settings and tertiary care settings and translate and disseminate that out into our communities where we need to take care of patients. That's part of the challenge. The other challenge is in continued tool and technological development. There's a lot of optimism in our field that the availability of blood-based biomarkers relevant for Alzheimer's disease may play a part in helping to address some of the disparities in resource and access to care. You can imagine that doing a blood test to give you some high-quality information, there are going to be less barriers to doing that in many settings compared to thinking about a lumbar puncture or a PET scan, both in terms of cost to the patient as well as infrastructure to the clinicians and the care team. So I'm optimistic about a lot of those changes. In the meantime, I think there are, through both clinical evaluation and some basic testing including structural head imaging, there are clues that can help navigate these possibilities. Dr Nevel: So, let's say you have your patient in clinic, you've done your evaluation, maybe gotten some ancillary testing, and you highly suspect either LATE or PART. How do you counsel those patients and their families? How do you manage those patients moving forward who you really suspect don't have, you know, some sort of co-pathology? Dr Ramanan: So, it's- I think it's helpful to remember when patients are coming to see us, either they or the people around them have noticed an issue. And very likely it's an issue that's been brewing for a little while. I think it can be very valuable, very helpful for patients to have answers. What's the cause for the issue? Once you have answers, even if sometimes those answers are not the most welcome things or the things that you'd be looking forward to, answers give you an opportunity to grab hold of what's going on, to define a game plan. So, understanding there is a degenerative disease there, it sheds light on why that individual had had memory symptoms over the years. And it gives them a general expectation that over time on an individualized basis, but generally expecting gradually over many months to many years, there may be some worsening in some of those symptoms helps them to plan and helps them to make the adaptations that are a-ok and great to make to just help you to do the things you want to do. As much as I can, I try to put the focus here closer to how we would view things like high blood pressure or high cholesterol. Those are also chronic issues that tend to be more common as we get older, tend to get more troublesome as we get older. The goal is, know what you're dealing with and take the combination of lifestyle m…

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    Vascular Cognitive Impairment With Dr. Lisa C. Silbert Dec 18, 2024
    Show notes

    Vascular cognitive impairment is a common and often underrecognized contributor to cognitive impairment in older individuals, with heterogeneous etiologies requiring individualized treatment strategies. In this episode, Katie Grouse, MD, FAAN speaks with Lisa C. Silbert, MD, MCR, FAAN, an author of the article "Vascular Cognitive Impairment," in the Continuum December 2024 Dementia issue. Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California. Dr. Silbert is is co-director at Oregon Alzheimer's Disease Research Center, a Gibbs Family Endowed professor of neurology, a professor of neurology at Oregon Health & Science University, a staff neurologist, director of Cognitive Care Clinic, and director of the Geriatric Neurology Fellowship Program at Portland Veterans Affairs Health Care System in Portland, Oregon. Additional Resources Read the article: Vascular Cognitive Impairment Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Full transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Lisa Silbert about her article on vascular cognitive impairment, which is part of the December 2024 Continuum issue on dementia. Welcome to the podcast and please introduce yourself to our audience. Dr Silbert: Hi Katie. Thanks for having me here today. Like you mentioned, my name is Lisa Silbert. I am a behavioral neurologist at Oregon Health and Science University and my research focus is in the area of vascular contributions to cognitive impairment and dementia. Dr Grouse: It's such a pleasure to have you and I really enjoyed reading your article. Just incredibly relevant, I think, to most practicing general neurologists, and really to any subspecialty. I'd like to start by asking, what do you think is the main takeaway point of your article for our listeners? Dr Silbert: Yeah. I think, you know, the field of vascular cognitive impairment has changed and evolved over the last several decades. And I would say the main take-home message is that vascular cognitive impairment or vascular dementia is no longer a diagnosis that is only considered in someone who's had acute decline following a clinical stroke. That we have to expand our awareness of vascular contributions to cognitive impairment and consider other forms of the disease that can cause a more subacute or slowly progressive form of cognitive impairment. And there are many, many forms of vascular cognitive impairment that present in a more slowly progressive manner. The other thing I would say as a major take-home message is that we know that cerebrovascular disease is a very common copathology with other forms of dementia and that it lowers one 's threshold for manifesting cognitive impairment in the context of multiple pathologies. And so, in this way, vascular cognitive impairment should be considered as a contributing and potentially modifiable factor in any dementia. Dr Grouse: I found that last point just really, really fascinating. And also, you know, the reminder that a combination of pathologies are more common than any one. To your initial point, I'm actually curious, could you kind of outline for us how you approach diagnosing vascular cognitive impairment? Dr Silbert: Yeah. So with everything in neurology, a lot of it comes down to the initial history taking. And so part of the work up always includes a very detailed history of the presentation of cognitive impairment. Any time there is an acute change in cognition, vascular contribution should be considered, particularly if it's in the context of a clinical stroke or some kind of event that might have lowered cerebral blood flow to the brain. And then having said that, I already mentioned there are many forms of vascular cognitive impairment that can mimic neurodegenerative disease in terms of its course. So being more slowly progressive. And so because of that neuroimaging, and in particular MRI, has become an extremely valuable tool in the workup of anyone who presents with cognitive impairment in order to evaluate contributions from cerebral vascular disease. And so, MRI is a really helpful tool when it comes to teasing out what may be contributing to a patient's clinical syndrome, as well as their other comorbid medical issues, including stroke risk factors and other kind of medical conditions that might contribute to reduce cerebral blood flow. Dr Grouse: I'd love to talk a little bit more about that. You know, as is often the case with neurologic disease associated with vascular pathology, the importance of prevention, you know, focusing on prevention of vascular diseases is so important. What are some things that we can make sure to focus on with our patients and, you know, particularly anything new to be aware of in counseling them? Dr Silbert: Yeah, I'm really glad you asked me that question because like I mentioned, you know, cerebral vascular disease is so common, it lowers one's threshold for cognitive impairment in the face of other age-related brain pathologies. And so, it's really important for all of us to focus on preserving our cognitive health, even starting in midlife. And so, there are a number of areas that I counsel my patients on when it comes to preserving cerebral health and maximizing cerebrovascular health. And so, these stem from the American Heart Association's Life's Essential 8 because we know that preserving cardiovascular health is likely going to also preserve cerebral vascular health. And so, some of the things that I'm very commonly discussing with my patients are controlling stroke risk factors such as blood pressure, blood sugars and cholesterol, maintaining a healthy weight, and then also working towards a lifestyle that includes a healthy diet, no smoking, regular exercise. And then new within the last couple years is also the recommendation that people get adequate sleep, which is something that hasn't been focused on previously. Dr Grouse: I was really interested in reading your article to learn about enlarged perivascular spaces and the role as a mediating factor in the interaction between through a vascular dysfunction and development and progression of neurodegenerative pathology. Can you elaborate on this further? Dr Silbert: So, this is an area that's still largely unknown in the field, and it's an area where there's a lot of emerging work being done. The short answer is, we really don't know with great certainty how it directly connects with accumulating Alzheimer's pathology. But there is some evidence to suggest that the perivascular space is involved in the clearance of toxic solutes from the brain, including Alzheimer's disease pathology. And so there's a lot of work looking at how potentially cerebrovascular risk factors might affect the clearance of those toxic solutes through the perivascular space, including pulse pressure changes that might occur with accumulating cerebrovascular disease and other potential contributors. But one thing I can say with more certainty is that the, you know, location of perivascular spaces is thought to help distinguish those who might have cognitive symptoms due to cerebrovascular disease versus due to cerebral amyloid angiopathy. Or I guess I should say location is helpful in terms of recognizing vascular contributions to cognitive impairment that's due to arteriolosclerosis versus that due to cerebral amyloid angiopathy. In so much that… when we see a lot of perivascular spaces in the basal ganglia in the subcortical structures, that is thought to be more associated with arteriolosclerosis and hypertension type related vascular cognitive impairment. Whereas when we see multiple perivascular spaces within the centrum semiovale, that tends to be more associated with cerebral amyloid angiopathy. Dr Grouse: That's so interesting. And on the topic ofcerebral amyloid angiopathy, you did go into this a good deal. And you know, I think I encourage everybody to revisit the article to remind themselves about, you know, the findings that can increase the suspicion of tribal amyloid angiopathy. However, you also talked about transient focal neurologic episodes, which I think is just a great reminder that, you know, these can occur in this setting and definitely not to miss. Tell us more about what to look for with these types of episodes. Dr Silbert: Transit focal neurologic episodes can be very difficult to tease apart from a transient ischemic attack. And these transient focal neurologic episodes due to CAA can present in a number of different ways. And I think the important take home message for that is that in people who have neuroimaging evidence of CAA to inform them that they are at increased risk for having these focal neurologic episodes and that if they do present to a hospital or an emergency department with any kind of neurologic event, that those treating them are aware that they have evidence of CAA on their neuroimaging because the treatment of course is quite different. So, it's someone presenting with ATIA who has transient neurologic symptoms might be considered urgently to get a thrombolytic or, you know, TPA, whereas someone who has known cerebral amyloid angiopathy or suspected CAA, they likely already have microbleeds on their neuroimaging and in those cases thrombolytics and TPA would be contraindicated and not helpful in terms of the etiology of their neurologic symptoms. Dr Grouse: That's a really good point to make. And I think also in your article you mentioned the use of aspirin if you're suspecting ATIA versus a, you know, a transient amyloid related focal neurologic episode. You know, one you would treat with aspirin and the other one you wouldn't. Dr Silbert: That's right. Dr Grouse: Another sort of interesting topic you delved into was cerebral microinfarct and how this can also contribute to vascular impairment. Could you elaborate a little more on that? Dr Silbert: Yeah. So cerebral microinfarcts are kind of the hidden cause of or a hidden cause of vascular cognitive impairment. And it's extremely challenging because by definition they are not visible on routine clinical neuroimaging. It's something that we are more aware of based on pathological studies and neuroimaging studies that have been done at ultra-high field strength like 7T MRI. And so, we are just learning more about how prevalent they are in certain conditions and how we can only look at these after death when we're looking at brain tissue and then go back and realize that these play a significant role in cognitive decline when someone is alive. It's important to understand that we're probably only appreciating kind of the tip of the iceberg when we're evaluating a patient and looking at their neuroimaging. That what we're actually seeing on MRI are only the things that are actually quite relatively big and obvious. And that a lot of these neuroimaging features of vascular cognitive impairment are actually associated with pathologic features that we're missing such as microinfarcts. But the hope is that by treating all individuals, particularly those who already have signs of vascular cognitive impairment, by modulating their stroke risk factors and focusing on maintaining brain health, that those will, interventions will also reduce the incidence of microinfarcts. Dr Grouse: What do you think is the greatest inequity or disparity you see in treating patients with vascular cognitive impairment? Dr Silbert: I think the greatest disparity is- really starts way before I treat a patient. That relates to really focusing on healthy lifestyle factors early in life and being able to, you know, afford fruits and vegetables, and having the advantages of being able to exercise regularly, and just being aware that all of these things are extremely important before older age. So, these are things that, you know, I think more education and awareness and greater access to healthcare will definitely improve access to. Even preventative healthcare is a disparity and not available across all of the population and geographic locations. So, I think of the- all the dementias, vascular cognitive impairment probably has the greatest association with health and social disparities in terms of primary prevention and access to care. Dr Grouse: All really important things to consider. I have to say when, you know, reading your article, dare I say I came away with a little bit of hope thinking, you know, even with, you know, how little we still, you know, or how much we still need to do to really learn how to fight Alzheimer's and, you know, prevent it and, and, you know, help with its progression. The idea that in so many cases, even just doing what we can to prevent the vascular or cognitive impairment can really help any type of dementia. That was really a strong message for me. Do you mind elaborating on that a little more? Dr Silbert: No, not at all. I agree. I really am hopeful about the prevention and treatment of dementias and through the treatment and prevention of cerebrovascular disease. I think that is a true reality, just like, you know, as we were discussing before, the treatment and prevention of cerebrovascular disease really should be a part of the treatment of any type of cognitive impairment and recommendations for prevention of cognitive impairment. This is the, you know, one thing we know is largely modifiable and preventable in most cases. I think the, really the key thing is just education and making sure that people understand that these are things that really need to be, they need to be engaged in in midlife and that it's much harder to reverse these- the damages once you have them in later life. Having said that, I do think that there's greater awareness of maintaining healthy lifestyle and maintaining awareness of stroke risk factors. And I think we're already starting to see a reduction in dementia worldwide in several large population-based studies, and probably that is due to more attention to the modifying stroke risk factors. So, I agree with you, it's very encouraging. Dr Grouse: Is there anything exciting on the horizon that you can tell us about that we should all be keeping our eyes out for? Dr Silbert: Yeah. So, you know, I'm really interested in this connection between vascular cognitive impairment and Alzheimer's disease. And it's a real area of exciting new research. And so I think we're going to have more answers as to how, whether and how, cerebrovascular disease is directly linked to accumulating neurodegenerative disease or neurodegenerative pathologies. The other area that's, I think, really exciting, that's moving forward, is the in the area of blood-based biomarkers for vascular cogniti…

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    Lewy Body Dementia With Dr. James E. Galvin Dec 11, 2024
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    Lewy body dementia is a common cause of cognitive impairment in older adults but is often subject to significant delays in diagnosis and treatment, increasing the burden on patients and family caregivers. Understanding key features of the disease and use of biomarkers will improve recognition. In this episode, Allison Weathers, MD, FAAN, speaks with James E. Galvin, MD, MPH, author of the article "Lewy Body Dementia," in the Continuum December 2024 Dementia issue. Dr. Weathers is a Continuum® Audio interviewer associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Galvin is a professor of neurology at the University of Miami Miller School of Medicine in Miami, Florida. Additional Resources Read the article: Lewy Body Dementia Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Weathers: This is Dr Allison Weathers. Today I'm interviewing Dr James Galvin, author of Lewy body dementias from the December 2024 Continuum issue on dementia. Welcome to the podcast, Dr Galvin. Please introduce yourself to our audience. Dr Galvin: Thank you, Allison. My name is Jim Galvin. I'm a neurologist, a professor of neurology at the University of Miami Miller School of Medicine. Dr Weathers: We're so happy to have you with me today. Thanks, Jim, for your time. And as you highlight right from the start in your really outstanding and comprehensive overview of this really complex topic, even though Lewy body dementia is the second most common cause of neurodegenerative dementia, it often goes unrecognized in clinical practice, resulting in really potentially lengthy diagnostic delays. So, this is a really important article for a neurologist and an important topic for our listeners. So, I'm thrilled we're having this conversation today. While I traditionally start by asking the authors what they feel is the most important clinical message of their article, I would love to actually start a step earlier in this conversation with you. Can you start us off by explaining what's actually meant when we say Lewy body dementia? Dr Galvin: Great. So, you know, I think this is a, this is an interesting concept. So, we're really talking about two diseases that have a shared common pathology. So, Parkinson's sees dementia and dementia with Lewy bodies. So, their shared pathology is a Lewy body and that's why they're often grouped together as the Lewy body dementias. And then there's arguments back and forth as to whether these are distinct diseases or sort of two ends of the same candle burning in different directions. So, Parkinson's dementia is a lot like what it sounds like. So, if someone has Parkinson's disease, then at some point later they develop a dementia. And so back in the 1800's when Parkinson's disease was like first described as an entity, we basically felt that cognition wasn't affected. But we now know that's not true. And so most patients with Parkinson's do have some cognitive symptoms and a large proportion of them will eventually develop dementia. Perhaps up to 80% of Parkinson's patients will develop a dementia. The flip side is the dementia with Lewy body picture. And these are people who present primarily with a cognitive behavioral syndrome that may or may not have parkinsonism. So, they will sometimes have bradykinesia. They rarely have a rest tremor. And so, these are the people that are very much in the delayed diagnosis group. The Parkinson's dementia is more whether the clinician is checking their cognition as part of their annual visit. The flip side is that the people with DLB are often misdiagnosed early on, but together, this is Lewy body dementia, which is the most common disease that many people have never heard of. Dr Weathers: That's a great tagline, I think, for the whole article and for this concept. So now that that we're all on the same page about what's meant when we use that the term, what would you want our listeners to walk away with as their one key takeaway from our conversation today? Dr Galvin: Well, I think the article makes several key points, but I think if I put those all together into a single key point, it would really be that the Lewy body dementias are underrecognized, they're underdiagnosed, yet it is very possible to make the diagnosis using the standardized clinical criteria. They're very, very, very specific. They lack a little bit in sensitivity. So, because other diseases sometimes can look like this, but they're really quite specific. So, if you're confident clinically that the person has Lewy body dementia, you're probably going to be right. And in today's world, we have tests available to help confirm our diagnosis. The world is changing. We can make these diagnosed with much more confidence and we have confirmatory diagnosis laboratory tests that can help us. Dr Weathers: I want to talk more about the diagnosis in one minute, but first, how common actually are dementia with Lewy bodies and Parkinson's disease dementia? Dr Galvin: That's a great question. I think one of the challenges, of course, we really don't know how many people have any disease because it's going to largely rely on how well people code the diseases in the medical record. So, if you look at the most common cause of dementia in the United States, it's really dementia not otherwise specified, right? But we believe it to be the second most common cause of dementia. The Lewy Body Dementia Association, about a decade ago, started to try to develop some estimates. So, we have an estimate about how many people roughly have Parkinson's disease and that about 80% of those individuals would go on to develop dementia. And we know from the dementia population that about 40% of those individuals coming to autopsy have Lewy bodies. So, when you start to put that all together, you can get a reasonable estimate of how many people likely have the disease. And then that can be expanded on an annual basis, just like the Alzheimer's Association uses, by extrapolating those estimates onto the census data. So, we estimate right now there are about 1.4 to 1.6 million Americans who are living with Lewy body dementia. That's less than the 6.8 million people who have Alzheimer's disease, but more than a lot of other common diseases. So, if you think about, again, I said before, it's the most common disease no one's ever heard of. You know, there are about a million people who have multiple sclerosis. There are about eight hundred thousand people who have a stroke. There are about seven hundred thousand people who have a brain tumor. There are two hundred and fifty thousand people who have muscular dystrophy. There are twelve thousand people who have ALS. But I think if you stopped clinicians or people in the street and say have you ever heard of ALS or muscular dystrophy, they would say yes. If you ask them if they've heard of Lewy body dementia, they would say no. Dr Weathers: That's an excellent point. And I know over the years I think there's been some increased awareness. I think sadly with some of the celebrities that have been impacted, I think that did a lot to raise awareness. But I think you're right that it's still so less commonly recognized by the lay public, by non-neurologists, than so many other diseases that you mentioned. And I think that leads back well into my next question into something that we've already mentioned just a few times already in our short conversation, this unfortunate and very common delay in the diagnosis. Why? And you mentioned earlier that there are these, you know, clinical criteria, these now ancillary tests. So, what makes the diagnosis so challenging? What aspects in particular do you think that neurologists find to be the most challenging in diagnosing patients? What trips us up? Dr Galvin: So, there's an old analogy, right, that, you know, if you'll be three blind men to an elephant and each of them are touching a different part of the elephant, they'll each think it's something different. So because Lewy body dementia has so many different diverse kind of symptoms, it would really depend on who's seeing the patient first. So, if a person presents predominantly with a memory cognitive disorder and they go see someone who specializes in memory disorders, they're highly likely to be called Alzheimer's disease. If they present predominantly with the movement problem, they're going to see a movement disorder person and be called Parkinson's disease. If they present with a behavioral disorder, they're going to go see a psychiatrist. Then they'll get diagnoses like, you know, geriatric schizophrenia or bipolar disease or major depressive disorder. If they present with the constitutional symptoms, which are very common and drive patients absolutely batty. So chronic constipation, REM sleep disorder, runny nose, you know, heat intolerance, urinary frequency, obstipation, and you know, they're going to be called all sorts of things. So, if you start thinking about this, who do you show up with first is going to guide how fast you can get a diagnosis. So, we interviewed at point over a thousand caregivers and what we found was there was about an eighteen month delay after seeing five to six doctors for the majority of patients, of which Lewy body dementia was misdiagnosed about 75% of the time for the initial diagnosis. Dr Weathers: Wow, what a sobering statistic. And you spoke about the criteria and some of the ancillary tests. What can really help, do you think, kind of mitigate or prevent this misdiagnosis? What is your approach in your own patients? Dr Galvin: Well, I think like every good clinician, not starting off with a preconceived notion of what the person has and trying to collect all the valuable information. So, one of the things I highlighted in the article was, while there are diagnostic criteria and people can follow diagnostic criteria, the truth is at your fingertips. You don't always sit and think about whether someone meets diagnostic criteria. So, in the first table in the article, we tried to really then put all the different common symptoms into buckets, right? Because people present like that. They say, well, I have this and I have this and I have this and I have this. Well, then you can start to think about, well, they have a cognitive symptom that's predominantly executive attention or visual perceptual in nature. And gee, they have constipation and heat intolerance and they say they can't smell quite as well as they once did, right, and they're having some disturbance in their sleep with excessive daytime sleepiness. Now you can start to say, well, even though that didn't fit the core and suggestive criteria, the fact is that spectrum of symptoms makes it much easier to begin to make a diagnosis. And so, it's investigative work. A lot of neurology is still investigative work. The old days, they used to say, we knew everything but could do nothing, but now we know everything and can do something about it. And so, I think it's really important that we try to apply this information in clinically useful ways. That was part of the gist of putting this Continuum article together was to try to present it not just as listing the diagnostic criteria, because you can get that anywhere, but how do you actually apply it in clinical practice? Dr Weathers: That's a great point. And that table that you referenced was really fantastic. And I know I say this a lot, but they're true. So, you know, many of the tables, the reference to Continuum, one I will certainly kind of come back to again, again, as an excellent point of care tool. So, I know in, in preparing for today and reading more about, about you and your areas of research that one of your particular areas of focus and expertise is in healthcare disparities, especially in the early detection of neurodegenerative dementias. What is the greatest inequity or disparity that you see in the diagnosis and treatment of patients with Lewy body dementia? Dr Galvin: So, there's a couple things that are that are really interesting. So first, unlike Alzheimer's disease, which tends to be a little bit more female predominant, the Lewy body dementias are male predominant. It's about 1.6 men for everyone woman. So, it's going to be a different presentation. It's going to be largely men and their caregivers are largely going to be their spouses. So, you're going to see sort of a different person looking, you know, staring on the other side of the table to you. It's going to be largely a male. And the other thing that's really interesting is that almost all of the series, case series, case reports, clinical papers are in predominantly white populations. So, this lends to some interesting things. So, you know, is the disease less common in African Americans and other minority populations or are we just really bad at ascertaining the disease? You know, many of the case reports in Alzheimer's disease include African Americans. In fact, we know that African Americans may be at a twofold increased risk of developing Alzheimer's disease compared to nonHispanic whites, probably due to vascular risk factors. But in case series of Lewy body dementia, almost all the patients are non-Hispanic white. There also seems to be a higher risk in Asian populations, and in fact, some of the very earliest case reports were from Japan. Is this a case ascertainment problem or is this really a disparity in how the disease presents? And I think those are really important questions that still need to be asked. I know as researchers, we struggle to try to develop cohorts that could help us understand that. I would say in my twenty five years of seeing these patients, I would say the large percentage of them, and I've seen a lot of them, have been no-Hispanic white. Dr Weathers: So, so definitely more research needed in this very important area. So, moving on to somewhat of a personal question, I always, this is such an honor. I always talk about that I get to have this time to sit down with the authors of these outstanding articles and learn not only more about their subjects, but about them as people. I had shared during my last interview that my paternal grandmother had Alzheimer's disease, and unfortunately also my maternal grandmother actually did as well. In preparing for this, I had listened to one of your previous interviews and learned that you also have a personal connection that led you to this subspecialty with several family members impacted. How has this connection inspired your research and your interactions with your patients? Dr Galvin: Yeah, I…

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    Diagnosing Alzheimer Disease With Dr. Gregory S. Day Dec 04, 2024
    Show notes

    A pragmatic and organized approach is needed to recognize patients with symptomatic Alzheimer Disease in clinical practice, stage the level of impairment, confirm the clinical diagnosis, and apply this information to advance therapeutic decision making. In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Gregory S. Day, MD, MSc, MSCI, FAAN, author of the article "Diagnosing Alzheimer Disease," in the Continuum December 2024 Dementia issue. Dr. Berkowitz is a Continuum® Audio interviewer and professor of clinical neurology at the University of California, San Francisco Dr. Day is an associate professor in the Department of Neurology at Mayo Clinic Florida in Jacksonville, Florida. Additional Resources Read the article: Diagnosing Alzheimer Disease Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @GDay_Neuro Full episode transcript available here Dr Jones: This is Doctor Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Berkowitz: This is Dr Aaron Berkowitz, and today I have the pleasure of interviewing Dr Gregory Day about his article on Alzheimer disease, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast, Dr Day. Would you mind introducing yourself to our audience? Dr Day: Thanks very much, Aaron. I'm Gregg Day. I'm a behavioral neurologist at Mayo Clinic in Jacksonville, Florida, which means that my primary clinical focus is in the assessment of patients presenting typically with memory concerns and dementia in particular. Dr Berkowitz: Fantastic. Well, as we were talking about before the interview, I've heard your voice many times over the Neurology podcast and Continuum podcast. I've always learned a lot from you in this rapidly changing field over the past couple of years, and very excited to have the opportunity to talk to you today and pick your brain a little bit on this very common issue of evaluating patients presenting with memory loss who may have concerns that they have dementia and specifically Alzheimer disease. So, in your article, you provide a comprehensive and practical approach to a patient presenting for evaluation for possible dementia and the question of whether they have Alzheimer disease. The article is really packed with clinical pearls, practical advice. I encourage all of our listeners to read it. In our interview today, I'd like to talk through a theoretical clinical encounter and evaluation so that I and our listeners can learn from your approach to a patient like this. Let's say we have a theoretical patient in their seventies who comes in for evaluation of memory loss and they and/or their family are concerned that this could be Alzheimer disease. How do you approach the history in a patient like that? Dr Day: It's a great way to approach this problem. And if you're reading the article, know that I wrote it really with this question in mind. What would I be doing, what do we typically do, when we're seeing patients coming with new complaints that concern the patient and typically also concern those that know the best? So be that a family member, close friend, adult child. And in your scenario here, this seventy year old individual, we're going to use all the information that we have on hand. First off, really key, if we can, we want to start that visit with someone else in the room. I often say when talking to individuals who come alone that there's a little bit of irony in somebody coming to a memory assessment alone to tell me all the things they forgot. Some patients get the joke, others not so much, but bringing someone with them really enhances the quality of the interview. Very important for us to get reliable information and a collateral source is going to provide that in most scenarios. The other thing that I'm going to start with, I'm going to make sure that I have appropriate time to address this question. We've all had that experience. We're wrapping up a clinical interview, maybe one that's already ran a little bit late and there's that one more thing that's mentioned on the way out the door: I'm really concerned about my memory or I'm concerned about mom 's memory. That's not the opportunity to begin a memory assessment. That's the opportunity to schedule a dedicated visit. So, assuming that we've got someone else in the room with us, we've got our patient of interest, I'm going to approach the history really at the beginning. Seems like an easy thing to say, but so often patients in the room and their caregivers, they've been waiting for this appointment for weeks or months. They want to get it out all out on the table. They're worried we're going to rush them through and not take time to piece it together. And so, they're going to tell you what's going on right now. But the secret to a memory assessment, and particularly getting and arriving at an accurate diagnosis that reflects on and thinks about cause of memory problems, is actually knowing how symptoms began. And so, the usual opening statement for me is going to be: Tell me why you're here, and tell me about the first time or the first symptoms that indicated there was an ongoing problem. And so, going back to the beginning can be very helpful. This article is focused on Alzheimer disease and our clinical approach to the diagnosis of Alzheimer disease. And so, what I'm going to expect in a patient who has a typical presentation of Alzheimer disease is that there may be some disagreement between the patient and the spouse or other partners sitting in the room with me about when symptoms began. If you've got two partners sitting in the room, maybe an adult child and a spouse, there may be disagreement between them. What that tells me is at the onset, those first symptoms, they're hard to pin down. Symptoms typically emerge gradually in patients with symptomatic Alzheimer disease. They may be missed early on, or attributed or contributed to other things going on in the patient's time of life, phase of life. It's okay to let them sort of duke it out a little bit to determine, but really what I'm figuring out here is, are we talking about something that's happened across weeks, months or more likely years? And then I'm going to want to listen to, how did symptoms evolve? What's been the change over time? With Alzheimer disease and most neurodegenerative diseases, we expect gradual onset and gradual progression, things becoming more apparent. And at some point, everyone in the room is going to agree that, well, as of this state, there clearly was a problem. And then we can get into talking about specific symptoms and really begin to pick that apart the way that we traditionally do in any standard neurological assessment. Dr Berkowitz: Fantastic. And so, what are some of the things you're listening for in that history that would clue you in to thinking this patient may indeed be someone who could have Alzheimer's disease and going to require a workup for that diagnosis? Dr Day: It's pretty common when I have new trainees that come to clinic, they just head into the exam room and they sort of try to approach it the way that we would any patient in the emergency department or any other clinical scenario. The challenge with that is that, you know, we're taught to let the patient speak and we're going to let the patient speak - open-ended questions are great - but there's only so many questions you need to sort out if someone has a memory problem. And memory is really only one part, one component, of a thorough cognitive evaluation. And so, I'm going to help by asking specific questions about memory. I'm going to make sure that there is memory challenges there. And whenever possible, I'm going to solicit some examples to back that up, add credibility and sort of structure to the deficits. I'm also going to choose examples that help me to understand how does this concern, or this complaint, how does that actually affect the patient in their day-to-day life? Is it simply something that they're aware of but yet hasn't manifested in a way that their partner knows about? Is it to a level where their partner's actually had to take over their responsibility? It's causing some difficulties, disability even, associated with that. That's going to be important for me as I try to understand that. So, I'll ask questions when it comes to memory, not just, you know, do you forget things, but do you manage your own medications? You remember to take those in the morning? Do you need reminders from your partner? What about appointments; health appointments, social appointments? Are you managing that on your own? Sometimes we need a little bit of imagination here. Partnerships, and particularly those who have been together for a long time, it's natural that different people are going to assume different responsibilities. And so, might have to say, Imagine that you went away for the weekend. Would you worry about your partner remembering to take their medications over that time frame? That can help to really solidify how much of an impact are these challenges having on a day-to-day basis. I may ask questions about events, something that they maybe did a couple of weeks ago. Is the patient likely to remember that event? Are they going to forget details? Maybe the most important of all, with each of these, when there's a yes or an affirmation of a problem, we want to be clear that this represents a change from before. We all have forgetfulness. Happens on a day-to-day basis, and we all pay attention to different details, but what we're concerned about and typically the reasons patients want to come and see us as neurologists is because they've noticed a change. And so, I'm going to focus in on the things that represent a change from before. After I've discussed memory, I think it's really important to talk about the other domains. So, how is judgment affected? Decision-making? In a practical way, we often see that borne out in financial management, paying the bills. Not just paying them on time and consistently, but making wise choices when it comes to decisions that need to be made. You're out at a restaurant. Can you pay the bill? Can you calculate a tip? Can you do that as quickly and as efficiently as before? Are we starting to see a breakdown in decision-making abilities there? We can sometimes lump in changes in behavior along with judgment as well. The patient that you know, maybe isn't making wise choices, they've picked up the phone and given their social security number out to someone that was calling, seeming to be well-meaning. Or maybe they've made donations to a few more institutions than they would have otherwise? Again, out of- out of order. Again, something that could be atypical for any individual. Looking for behavioral changes along with that as well. And then I'm going to talk about orientation. What's their ability to recognize days of the week, date of the month? Do they get lost? Is there concerns about wayfinding? Thinking about that, which is really a complex integration of some memory, visuospatial processing, judgment, problem solving, as we look to navigate our complex world and find our way from point A to B. And then I like to know, you know, what are they doing outside of the home? What are they doing in the community? How are they maintaining their engagement? Do they go to the store? Do they drive? An important topic that we may need to think about later on in this patient 's assessment. And inside the home? What responsibilities do they maintain there? Are the changes in decision making, memory problems, are they manifesting in any lost abilities inside the home? Cooking being a potentially high-risk activity, but also using typical appliances and interacting with technology, in a way that we are all increasingly, increasingly doing and increasingly reliant on. And last but not least, you know, maybe the one that everyone wants to think about, well, I can still manage all of my own personal care. Well, good news that many of our patients who have early symptoms can manage their own personal care. Their activities of daily living are not the big problem. But we do want to ask about that specifically. And it's not just about getting in the shower, getting clean, getting out, getting your teeth brushed. Do you need reminders to do that? Do you hop in the shower twice because you forgot that you'd already been in there once during the day? And so, asking some more of those probing questions there can give us a little bit more depth to the interview and really does sort of round out the overall comprehensive history taking in a patient with a memory or cognitive concern. Dr Berkowitz: Fantastic. That was a comprehensive master class on how to both sort of ask the general questions, have you noticed problems in fill in the blank memory, judgment, behavior, orientation, navigation and to sort of drill down on what might be specific examples if they're not offered by the patient or partner to try to say, well, in this domain, tell me how this is going or have you noticed any changes because the everyone's starting from a different level cognitively based on many factors. Right? So, to get a sense of really what the change is in any of these functions and how those have impacted the patient's daily life. So, let's say based on the history, the comprehensive history you've just discussed with us, you do find a number of concerning features in the history that do raise concern for dementia, specifically Alzheimer's disease. How do you approach the examination? We have the MoCA, the mini-mental. We have all of these tools that we use. How do you decide the best way to evaluate based on your history to try to get some objective measure to go along with the more subjective aspects of the history that you've ascertained? Dr Day: And you're honing in on a really good point here, that the history is one part of the interview or the assessment. We really want to build a story and potentially and hopefully a consistent story. If there are memory complaints, cognitive complaints from history, from reliable- that are supported by reliable collateral sources, we're going to expect to see deficits on tests that measure those same things. And so, I think that question about what neuropsychological measures or particular bedside tests can we integrate in our assessment is a good one. But I'll say that it's not the end-all-be-all. And so, if you've got a spouse, someone that lives with an individual for twenty or thirty years, and they're telling you that they notice a change in daily activity and it's impairing their day to day function, or…

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    December 2024 Dementia Issue With Dr. Lisa Silbert Nov 27, 2024
    Show notes

    In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Lisa C. Silbert, MD, MCR, FAAN, who served as a guest editor of the Continuum® December 2024 Dementia issue. They provide a preview of the issue, which publishes on December 2, 2024. Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Dr. Silbert is co-director at Oregon Alzheimer's Disease Research Center, a Gibbs Family Endowed professor of neurology, a professor of neurology at Oregon Health & Science University, a staff neurologist, director of Cognitive Care Clinic, and director of the Geriatric Neurology Fellowship Program at Portland Veterans Affairs Health Care System in Portland, Oregon. Additional Resources Continuum website: ContinuumJournal.com Subscribe to Continuum: shop.lww.com/Continuum More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @LyellJ Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology, clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum who are the leading experts in their fields. Subscribers to the Continuum Journal have access to exclusive audio content not featured on the podcast. If you're not already a subscriber, we encourage you to become one. For more information, please visit the link in the show notes. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr Lisa Silbert, who recently served as Continuum's co-guest editor for our latest issue on dementia alongside Dr Lianna Apostolova. Dr Silbert is a professor in the Department of Neurology at Oregon Health and Science University of the School of Medicine in Portland, Oregon, where she's also the director of the Neuroimaging Core and now the co-director of the Alzheimer's Disease Research Center. She also serves as director of the dementia clinic at the VA Portland Healthcare System. Which, Dr Silbert, sounds like a lot of work? Anyway, welcome. I really appreciate you taking the time to join us today and co-guest editing this issue. Why don't you introduce yourself a little bit to our listeners? Dr Silbert: Well, thank you so much for interviewing with me today and for inviting me to be the guest, co-guest editor of this issue. It's a really exciting time for dementia care and dementia research. As you already said, my name is Lisa Silbert. I'm in Oregon Health and Science University in Portland, Oregon. I've been involved in caring for dementia patients and their families for over twenty years now and been involved in a lot of really exciting research during that time. But I would say now is probably the most dynamic time in dementia research and care that I've seen. So, it's really, really exciting to be here. Dr Jones: It really is an interesting time. So, I look back in our last issue of Continuum focusing on dementia came out in 2022, which doesn't sound like that long ago, but a lot has changed, right? With the anti-amyloid monoclonals for Alzheimer's disease, new biomarkers and so on. And as the guest editor, you have this unique view, Dr Silbert, of the issue and the whole topic of dementia. As you were reading these really outstanding articles, what was the biggest "aha" moment for you or the biggest change in practice that you saw that's come up over the last couple of years? Dr Silbert: I think, you know, in reading through the different manuscripts or chapters in this issue, it really struck home the advances that have been made throughout all the different areas of dementia. Not just- so, we hear a lot about Alzheimer's biomarkers and Alzheimer's treatments on the horizon, which is really exciting, but this is happening across other dementias as well. There's biomarkers on the horizon for a Lewy body disease and potentially for some of the frontaotemporal dementias. And so that to me really struck home as this is really, across the board, a change in the entire field that we're looking at. Dr Jones: That is exciting. And I'd like to come back to some of those biomarker developments because I think that's an area where we've really been lacking in neurology as a specific way to diagnose those disorders. I think a topic which you just alluded to that a lot of our listeners and readers are thinking about are those antiamyloid monoclonal therapies for Alzheimer's disease. So, addicanumab, lecanumab and most recently the approval of donanemab. For these drugs specifically, how are you using them in your practice and how should our listeners be thinking about these drugs? Dr Silbert: These are, you know, relatively new, really exciting new and emerging therapies for Alzheimer's disease. They are shown to remove amyloid from the brain. Patients who have clinical manifestations of Alzheimer's disease, and that is those in the stages of mild cognitive impairment or mild dementia. We are using lecanemab at Oregon Health and Science University through our therapeutics and clinical units. It's a really exciting time and it's a time where we have to be, also, cautious about who undergoes these therapies. So being really informed about the use, who's appropriate to undergo these therapies, what kind of safety tests need to be undergone, how do you assess risk in individual patients so that you can counsel them. So, all of these factors need to be weighed in when you're making a decision about whether or not to treat a patient with a monoclonal antibody therapy. And specifically, we do neuroimaging to assess whether there are already the presence of microhemorrhages in the brain. We do genetic testing to look for APOE 4 genotypes that can increase the risk of Aria, which is amyloid-related imaging abnormalities. And all of these factors go into how we counsel patients and discuss whether or not to pursue treatment with monoclonal antibodies. Dr Jones: So certainly a complex patient selection process and drug administration and monitoring of therapy for those patients. And that- it brings to mind for me how we already have too few neurologists in the US. And now for a really prevalent disorder, Alzheimer's disease, we're making it a lot more complicated to deliver these new disease-modifying therapies. What do you think or what do you see as the role of the neurologists in caring for patients with dementia? And do these developments change that role? Dr Silbert: For now, I think these developments make it even more important in a way that neurologists are involved in making a very specific clinical diagnosis of which dementia is playing a factor in the patient 's clinical presentation. I think one thing to note is with these emerging biomarkers, a lot of them can be positive before there are clinical symptoms and multiple etiologies are also very prevalent. And so just having one positive biomarker, it doesn't necessarily tell you what's going on with an individual patient. You need to take the whole picture into consideration. So, I think a really detailed evaluation by the neurologist, especially with these emerging therapies that have potential risks, is extremely important right now. Just getting a test is really not sufficient. You really have to take the entire clinical picture into account and know the ins and outs of the risks involved in these disease-modifying therapies. Dr Jones: Which brings us back to something you mentioned earlier, right? Which is good news. We have on the horizon new potential biomarkers for other neurodegenerative causes of dementia. I can foresee and maybe I'm, you know, being an alarmist here, Dr Silbert, but if we have sensitive biomarkers for other neurodegenerative conditions, we know patients often have copathologies. Is that going to help clarify things? Is it going to confuse us? How is that going to work? Dr Silbert: Well, I think ultimately, it's going to help clarify things. Because there are multiple pathologies that are common in age related cognitive impairment, any kind of additional specific input that we can get with different biomarkers is going to be helpful in putting the pieces together to come up with what's happening clinically with each individual patient. Ultimately, I think these biomarkers, they're not- any one biomarker isn't going to be a solution to diagnosis, but putting them together to help improve early and accurate diagnosis is really the goal here. Having a very early diagnosis, having a very accurate diagnosis will improve our ability to give prognosis and also improve effective treatment strategies moving forward. I think that these biomarkers have the promise in facilitating that for us. Dr Jones: And progress is always a good thing. We just have to learn how to adapt and use the evidence appropriately. There have been and I think most of our listeners will be familiar with some of the controversies related to these, these new disease-modifying drugs for Alzheimer's disease. Do you want to walk us through a couple of those, and what are your thoughts about those controversies? Dr Silbert: Yeah, these new therapies, they're very exciting for everyone in the field, but they, like you mentioned, they're not without their controversies. I think one controversy or one potential downside to these therapies is access to them. Like you already mentioned there, there's really not enough neurologists out there. There's not enough behavioral neurologists out there. There's limitations to infusion centers, sites and prescribers. Access to these therapies is is significantly limited. They are requiring infusions quite frequently. So, if you're not living near specialty care, you're not really able to feasibly undergo these kinds of treatments. Another controversy is the fact that the treatment effects are considered by some to be fairly modest when looking at the clinical data and in association with that, there are risks involved. Like I already mentioned, there's the amyloid-related imaging abnormalities, which sounds kind of like a benign thing, but they really consist of microhemorrhages that can lead to bigger hemorrhages and edema in the brain. These risks are relatively small - they are seeing more commonly in those who have a specific genotype, an APOE E 4 genotype - but they're risks nonetheless. And so, there's controversy about the risk-benefit ratio and access to care with these new therapies. Dr Jones: It's very exciting, but we should be cautious, right? I recall a few years ago as a program director, a neurology residency program director, interest in different areas of neurology would often follow developments in those areas, right? Lots of interest in autoimmune neurology when those developments would proceed in neuro oncology, etc. And I wonder if the therapeutic advances in in behavioral neurology and neurodegenerative cognitive disorders, I wonder if that's going to stimulate interest among our trainees to pursue behavioral neurology? Do you have a view on that or have you seen much change in interest in in this field? Dr Silbert: You know, we are seeing a lot more interest in our trainees. The residents are very interested in these new therapies and how to apply them. And I'm really excited about that. I'm hopeful that this will stimulate interest in the field. And we need those specialists, we need those sub specialists to undergo fellowship training in behavioral neurology and geriatric neurology so that we have more access to the subspecialty care and delivering these new therapies. So, I agree with you, I'm hopeful about it and I am seeing new interest in our trainees about these new therapies. Dr Jones: We can hope so. And all the other fellowship directors will be anxious if neurology residents start leaving to go into behavioral neurology. But there's certainly demand. And I know that under the best of circumstances, dementia is so common. It's something that we have to care for in partnership with primary care and community resources. And these disease-modifying therapies capture a lot of attention, but it's really a small part of the continuum of care of these patients. And Dr Silbert as an expert, you know, if we put that disease-modifying therapy to the side for a second and just said, well, what are the biggest gaps in the care for patients with dementia? What do you see as those biggest gaps and, and what can we do to fix them at not just a neurology level, but at a societal level? Dr Silbert: That's a big question. And you know, what I see almost every day are gaps in the support mechanisms for families who are caring for patients with dementia. These caregivers are under a lot of stress and oftentimes they just don't have the resources to take care of somebody who at some point will often need twenty-four hour care and supervision. Caregivers are older, usually of older age themselves and have their medical issues as well. And then we're just not doing a good job as a nation in in supporting patients and their families with like supportive care and respite care that's really needed. So, you know, I'm not just seeing and treating patients with dementia, but I'm seeing and I'm really trying to support and care for those who are taking care of patients with dementia. To me, that's the biggest gap in our system. Dr Jones: Yeah. And as I look through this issue of Continuum, we touched on not only the conventional topics in dementia and behavioral neurology. I'm really happy in hindsight that we have invited some discussion of the psychiatric symptoms in dementia, which I think are really important and often underrecognized and maybe undermanaged or mismanaged, and really also focusing on the caregiver burden and support services. We do have an article dedicated to that as well, and I think that'll be useful to our readers and listeners when we when we publish those podcasts. We we've heard this year especially a lot of public conversation about cognitive impairment and dementia. I sometimes wonder if that public attention is helpful and constructive for the population of patients with dementia. Sometimes I wonder if that conversation is counterproductive. What's your take on that? Dr Silbert: You know, I think it's- it can be a mixed bag, but ultimately, it's in the conversation. We're talking about it. And I think that's only a good thing. There's more public awareness of it. There is more interest in therapies. So, I think at the end of the day, talking about it, making it more prevalent in the ether, it stimulates the conversation and discussion. And even if there's controversies about it, we're talking about it. And I think that's kind of the first step in acknowledging that we need more support, we need more therapies. Dr Jones: Yeah, I agree. And I think often patients with neurologic disorders and their caregivers and families often appreciate being seen. Dr Silbert: Yeah, no, absolutely true. So, I'd say in regards to the monoclonal antibody treatments, you know, despite the controversies with these new treatments, I think there's a real promise and a real hope and a real excitement across a lot of behavioral neurologists, including myself, that this is just the beginning. That even if these first line, first generation therapies maybe have downsides, that…

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    Neuromodulation for Neuropathic Pain Syndromes With Dr. Prasad Shirvalkar Nov 20, 2024
    Show notes

    For certain diagnoses and patients who meet clinical criteria, neuromodulation can provide profound, long-lasting relief that significantly improves quality of life. In this episode, Aaron Berkowitz, MD, PhD, FAAN speaks with Prasad Shirvalkar, MD, PhD, author of the article "Neuromodulation for Neuropathic Pain Syndromes," in the Continuum® October 2024 Pain Management in Neurology issue. Dr. Berkowitz is a Continuum® Audio interviewer and a professor of clinical neurology at the University of California, San Francisco Dr. Shirvalkar is an associate professor in the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology at Weill Institute for Neurosciences at the University of California, San Francisco in San Francisco, California. Additional Resources Read the article: Neuromodulation for Neuropathic Pain Syndromes Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @PrasadShirvalka Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor in Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors, who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Prasad Shirvalkar about his article on neuromodulation for painful neuropathic diseases, which appears in the October 2024 Continuum issue on pain management in neurology. Welcome to the podcast, and if you wouldn't mind, please introducing yourself to our listeners. Dr Shirvalkar: Thanks, Aaron. Yes, of course. So, my name is Prasad Shirvalkar. I'm an associate professor in anesthesiology, neurology and neurological surgery at UCSF. I am one of those rare neurologists that's actually a pain physician. Dr Berkowitz: Fantastic. And we're excited to have you here and talk to you more about being a neurologist in in the field of pain. So, you wrote a fascinating article here about current and emerging neuromodulation devices and techniques being used to treat chronic pain. And in our interview today, I'm hoping to learn and for our listeners to learn about these devices and techniques and how to determine which patients may benefit from them. But before we get into some of the clinical aspects here, can you first just give our listeners an overview of the basic principles of how neuromodulation of various regions of the nervous system is thought to reduce pain? Dr Shirvalkar: Yeah, I would love to try. But I will promise you that I will not succeed because I think to a large extent, we don't understand how neuromodulation works to treat pain, to describe or to define neuromodulation. Neuromodulation is often described as using electrical stimuli or a chemical stimuli to alter nervous system activity to really influence local activity, but also kind of distant network activity that might be producing pain. On one level, we don't fully understand how pain arises, specifically how chronic pain arises in the nervous system. It's a huge focus of study from the NIH Heal Initiative and many labs around the world. But acute pain, which is kind of when you stub your toe or you burn your finger, is thought to be quite different from the changes over time and the kind of plasticity that produces emotional, cognitive and sensory dimensions. Really what I think is its own disease, chronic pain, of which there are multiple syndromes when we use neuromodulation, either peripheral nerve stimulation or electrical spinal cord stimulation. One common or predominant theory actually comes from a paper in science from 1967 and people still use it, foundational theory and it's called the gate control theory. Two authors, Melzack and Wall, postulated that at the spinal level, there are, there's a local inhibitory circuit or, you know, there's a local circuit where if you provide input to either peripheral nerves or either spinal cord ascending fibers that to kind of summarize it, there's only so much bandwidth, you know, that nerves can carry. And so that if you literally pass through artificial signals electrically, that you will help gate out or block natural pathological but natural pain signals that might be arising from the periphery or spinal cord. So, you know, one idea is that you are kind of interfering with activity that's arising for chemical neuromodulation. The most common is something known as intrathecal drug infusion drug delivery ITTD for that we quite literally put a catheter in the spinal fluid, you know, at the level of the dorsal horn neurons that we think are responsible for perpetuating or creating the pain. Where's the pain generator? And you really, you can infuse local anesthetic, you can infuse opioids. And what's nice is you avoid a lot of systemic side effects and toxicity because it goes right to the spinal cord, you know, by infusing in the fluid. So there's a couple of modalities, but I will say just, like maybe all of our living experience, pain is in the brain. And so, we don't really understand, I would say, what neuromodulation is doing to the higher spinal or brain levels. Dr Berkowitz: Fascinating topic. And yeah, very interesting to hear both what our current understanding is that some of our current understanding is based on data that's 60 years old and that we're actually probably learning about pain by using these modulation techniques, even though we don't really understand how they might be working. So interesting feedback loop there as well as in as in the as in this land. So, your article very nicely organizes the neuromodulation techniques from peripheral to central. So, encourage our listeners to check out your article. And first before we get into some of the clinical applications, just to give the listeners the lay of the land, can you sort of lay out the devices and techniques available for treating pain at each level of the neuroaxis? We'll get into some of the indications in patient selection in a moment, but just sort of to lay out the landscape. What's available that you and your colleagues can use or implant at different levels when we're thinking of referring patients too? Dr Shirvalkar: Absolutely. So, starting from the least invasive or you know, over the counter patients can purchase themselves a TENS machine. Many folks listening to this have probably tried a TENS machine in the past. And the idea is that you put a couple of pads, at least two. So you have like a dipole or you have a positive and a negative lead and you basically inject some current. So, the pads are attached to a battery and you can put these pads over muscle. If you have areas where myofascial pain or sore muscles, you can put them, frankly, over nerves as well and stimulate nerves that are deeper. Most TENS machines kind of use electrical pulses that occur at different rates. You change the rates, you can change the amplitude and patient can kind of have control for what works best. Then getting slightly more invasive, we can often stimulate electrically peripheral nerves. To do this we implant through a needle, a small wire that consists of anywhere from one electrical contact to four or even eight electrical contact. What I think is particularly cool, like TENS, which is transcutaneous electrical nerve stimulation that goes through the skin. Peripheral nerve stimulation aims to stimulate nerves, but you don't have to be right up against the nerve. So, yeah. We typically do this under an ultrasound and you can visualize a nerve like the sciatic nerve, peroneal nerve, or you know, even if someone has an ulnar or a neuropathy, you know, that's the compression. There's a role obviously for surgery and release, but if they have predominantly pain, it's not related to a mechanical problem per se, you could prevent a wire from a peripheral nerve stimulator as far as one centimeter from a nerve and it'll actually stimulate that that modulated and then, you know, kind of progressing even more deeply. The spinal cord stimulation, SCS, it's probably the most ubiquitous or popular form of neuromodulation for pain. People use it for all kinds of diseases. But what it roughly involves is a trial period, which is a placement of either two cylindrical wires, not directly over the spinal cord, but actually in the epidural space, right? So, it's kind of like when you get an epidural injection or doing labor and delivery, when women get epidural catheters, placing spinal cord stimulator leads in that same potential space outside the dura, and you're stimulating through the dura to actually target the ascending dorsal column fibers. And so, you do a trial period or a test drive where the patients get these wires put in. They're coming out of the skin, they're connected to a battery, and they walk around at home for about a week, take careful notes, check in with them, and they keep a diary or a log about how much it helps. Separately. I will say it's hard to distinguish this, the placebo effect often, but you know, sometimes we want to use the placebo effect in clinical practice, but it is a concern, you know, with such invasive things. But you know, if the trial works well, right, you basically can either keep the leads where they are and place a battery internally. And it's for neurologists. You're familiar with deep brain stimulation. These devices are very similar to DVS devices, but they're specifically made for spinal cord stimulation. And there's now like seven companies that offer manufacturers that offer it, each with their own proprietary algorithm or workflow. But going yet more invasive, there is intrathecal drug delivery, which I mentioned, which involves placement of the spinal catheter and infusion of drug into spinal fluid. You could do a trial for that as well. Keep a patient in the hospital for a few days. You've all probably had experience with lumbar drains. It's something real similar. It just goes the other way. You know, you're infusing drugs, and it could also target peripheral nerves or nerve roots with catheters, and that's often done. And last but not least, there's brain stimulation. Right now, it's all experimental except for some forms of TMS or transcranial magnetic stimulation, which is FDA approved for migraine with aura. There are tens machine type devices, cutaneous like stimulators where you can wear on your head like a crown or with stickers for various sorts of migraines. I don't really talk about them too much in in the article, but if there's a fast field out there for adjunctive therapy as well, Dr Berkowitz: Fantastic. That's a phenomenal overview. Just so we have the lay on the land of these devices. So, from peripheral essentially have peripheral nerve stimulators, spinal cord stimulators, intrathecal drug delivery devices and then techniques we use in other areas of neurology emerging for pain DBS deep brain stimulation and TMS transcranial magnetic stimulation. OK let's get into some clinical applications now. Let's start with spinal cord stimulators, which - correct me if I'm wrong - seem to be probably the most commonly seen in practice. Which patients can benefit from spinal cord stimulators? When should we think about referring a patient to you and your colleagues for consideration of implantation of one of these spinal cord stimulator devices? Dr Shirvalkar: So, you know, it's a great question. I would say it's interesting how to define which patients or diagnosis might be appropriate. Technically, spinal cord stimulators are approved for the treatment of most recently diabetic peripheral neuropathy. And so, I think that's a really great category if you have patients who have been failed by more conservative treatments, physical therapy, etcetera, but more commonly even going back, neuropathic low back pain and neuropathic leg pain. And so, you think about it and it's like, how do you define neuropathic pain. Neuropathic pain is kind of broadly defined as any pain that's caused by injury or some kind of lesion in the somatosensory nervous system. We now broaden that to be more than just somatosensory nervous system, but still, what if you can't find a lesion, but the pain still feels or seems neuropathic. Clinically, if something is neuropathic, we often use certain qualitative descriptors to describe that type of pain burning, stabbing, electric light, shooting radiates. There's often hyperpathia, like it lingers and spreads in space and time as opposed to, you know, arthritis, throbbing dull pain or as opposed to muscle pain might be myofascial pain, but sometimes it's hard to tell. So, there aren't great decision tools, I would say to help decide. One of the most common syndromes that we use spinal cord stimulation for is what used to be called failed back surgery syndrome. We never like to, we now try to shy away from explicitly saying something is someone has failed in their clinical treatment. So, the euphemism is now, you know, post-laminectomy syndrome. But in any case, if someone has had back surgery and they still have a nervy or neuropathic type pain, either shooting down their legs and often there's no evidence on MRI or even EMG that that something is wrong, they might be a good candidate, especially if they're relying on long term medications that have side effects or things like full agonist opioids, you know that that might have side effects or contraindication. So, I would say one, it's not a first line treatment. It's usually after you've gone through physical therapy for sure. So, you've gone through tried some medications. Basically, if chronic pain is still impacting your life and your function in a meaningful way that's restricting the things you want to do, then it it's totally appropriate, I think, to think about spinal cord stimulation. And importantly, I will add a huge predictor of final court stimulation success is psychological composition, you know, making sure the person doesn't have any untreated psychological illness and, and actually making sure their expectations going in are realistic. You're not going to cure anyone's pain. You may and that's, you know, a win, but it's very unlikely. And so, give folks the expectation that we hope to reduce your pain by 50% or we want you to list personally, I like functional goals where you say what is your pain preventing you from doing? We want to see if you can do X,Y, and Z during the trial period. Pharmacostimulation right now. Yeah. Biggest indication low back leg pain, Diabetic peripheral neuropathy. There is also an indication for CRPS, complex regional pain syndrome, a lesser, I'd say less common but also very debilitating pain condition. For better or worse. Tertiary quaternary care centers. You often will see spinal cord stem used off label for neuropathic type pain syndromes that are not explicitly better. That may be for examp…

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    Opioids and Cannabinoids in Neurology Practice With Dr. Friedhelm Sandbrink Nov 13, 2024
    Show notes

    Opioids may be considered for temporary use in patients with severe pain related to selected neuropathic pain conditions and only as part of a multimodal treatment regimen. Close follow-up when initiating or adjusting opioid therapy and frequent reevaluation during long-term opioid therapy is required. In this episode, Allison Weathers, MD, FAAN speaks with Friedhelm Sandbrink, MD, FAAN, an author of the article "Opioids and Cannabinoids in Neurology Practice," in the Continuum® October 2024 Pain Management in Neurology issue. Dr. Weathers is a Continuum Audio interviewer and the associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Sandbrink is the national program director of Pain Management, Opioid Safety and Prescription Drug Monitoring Programs at the Veterans Health Administration, Uniformed Services University in Bethesda, Maryland. Additional Resources Read the article: Opioids and Cannabinoids in Neurology Practice Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media @ContinuumAAN facebook.com/continuumcme Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal and how to get CME. Dr Weathers: I'm Dr Allison Weathers. Today I'm interviewing Dr Friedhelm Sandbrink, who is one of the authors of the article Opioids and Cannabinoids for the Practicing Neurologist from the October 2024 Continuum issue on pain management Neurology. Welcome to the podcast and please introduce yourself to our audience. Dr Sandbrink: Yeah, hi. So, I'm Friedhelm Sandbrink. I'm a neurologist and pain physician. I work at the Washington DC VA Medical Center, where I lead our intercessory pain management team, and I have a role also in the VA central office for pain management. I'm also associate professor, clinical associate professor at George Washington University and at the Uniformed Services University in Bethesda. Dr Weathers: A lot of expertise, which you obviously brought to this article. And I do want to emphasize before we get started, although the article discusses both opioids and cannabinoids, as I said in the introduction, you worked in specifically on opioids. And so that's the part of the article where we'll focus our conversation today. Of course, I think all of our Continuum Audio topics are really fascinating. I know that some may not resonate as much, especially with our non-neurology listeners as others. Clearly not the case with your articles. I was reading it and preparing for a conversation today. I was really struck by how broadly applicable this topic is, not only to all neurologists but, really, all physicians, and even it should be to all of our listeners. Especially with what happened been going on over the last several years, what's been in the news about the opioid epidemic. And while usually like to start with this question, it feels even more pertinent in your case, what is the most important clinical message of your article? Dr Sandbrink: So, the role of the opioid, the role of opioid therapy, really, for pain care has changed dramatically over the last many years right? I mean, it's we, we still consider opioids like the most potent analgesic medication for treatment of acute pain. The benefit for chronic pain really has changed right I mean, you know, we- the understanding in that regard and they're controversial. So, they're generally not recommended for chronic treatment for neuropathic pain conditions or for headache, but there are probably situations when opioids are still indicated and may be considered especially for temporary use. So, one example is probably the patient who has severe acute post hepatic neuralgia and we know that we use other medications for that, you know, the gabapentinoids and duloxetine and but they may take several days or weeks to work, right? And we have to titrate them up. And when more acute pain relief is needed, the opioid medication may be may be an option for temporary use. But I think what we need to keep in mind is that when we use it, we need to be informed about how to mitigate the risks, right? What, what are our best ways to reduce harms? And we need to also know the regulatory, you know, situation right I mean, what is that that we have to do nowadays to stay within the frameworks, right? And so, one of the main emphasis on this article is really go through what the clinical that the CDC has now established as the standards for opiate therapy when we use opioids I think we all need to know the rules right I mean, we know what to do to mitigate risks. What is expected from us in regard to use it as safely as possible, right? And that's important for the patient. That's also important for us in our practice. Dr Weathers: I think very important advice. And this seems so obvious, but at the same time, I think it's worth very clearly stating why is it so important for neurology clinicians and again, really all clinicians, to read this article? Dr Sandbrink: Yeah. We need to know the words regarding opiate prescribing right in the clinic. You know, the CDC has now issued their opiate practice guide, the Opiate Therapy Guideline. Really, it's a guideline for pain care in 2022. It's an update from 2016 that made some major changes in that regard. And I think we need to know really where we are nowadays in regard to expectations. I think we need to place the opiate therapy appropriately in our armamentarium regarding the many options that we have for pain care. But then when we use them, we need to know what we need to do to make it safe. Right? So, I'm thinking about the prescription drug monitoring programs and the patient education that's expected. We use in our practice an informed consent process even for patients on chronic pain, When and how to interpret urine drug screens, right? And how to issue, and maybe when to issue a naloxone comedication in order to have a rescue medication in case the patient is in a terrible situation. So, these are just things that have become nowadays standards of care and part of our practice. And we need to be familiar with it and use them as we take care of the patients. And for instance, in regard to opiate medication, we need to know about the specific rules regarding telehealth, prescribing of controlled substances, controlled Substances Act and the Ryan Hate Act that mandates in person evaluations for patients when we prescribe controlled substances. That obviously has been somewhat amended or changed or temporarily put on hold during the COVID crisis. And many states now have started developing their own guidance in regard to what's available and what's possible during telehealth. And we need to be familiar about that also. Dr Weathers: I think those are such important and thoughtful points. I, I've mentioned it several times on this podcast before. I am a clinical informaticist and this is a topic that really lends itself to the EHR being able to help support. So, a lot of the things that you just mentioned, the consents for patients, the prescribing of naloxone, some of the support, clinical decision support can really be done in the electronic health record to help support providers. However, it's also one of those things where if people don't understand what's behind it, it can become a little bit of a crutch. And so, as I was reading the article, I was really struck by how helpful it is to really have that background. I think people can become very dependent and it becomes almost just doing it all for them and, and they lose the- then you can make this argument about probably a lot of the other clinical decision supports in there, but really understanding the why behind a lot of the support that's there around all of the, the tools that are in there to, to support safe opioid prescribing. I think it's so important for that people have that background that the article provides. Dr Sandbrink: I think often it feels like you're going through a checklist of things to do right and, and, and you do right. But at the same time, as you said, you need to know why you're doing it right And, and I think it's very important for us to know what the rules are and the expectations in regard to standards of care. So, we also know what is the framework that we have to follow, but where can we make modifications? Where can we individualize based on the patient's need? What is really that that is still within our ability to do and how to modify that? Because in the very end, it really is about good care of the patient. We need to know what we are allowed to do, but we also need to know where the limits are right And I hope that that article provides really some information about that, especially as it outlines what the CDC expects. But then also, I think it gives - hopefully, and this is a message that the CDC also has – it really emphasizes that it's about good communication with the patient, truly informing them and about what are the range of options and the limits that we have, but also at the same time never to abandon the patient. You know, I think this is something that we need to understand. It's not really about us. The rules are there to make the care of the patients safer. The rules are not the primary goal itself. It is still patient care. So, in that regard, we need to make sure to never abandon the patient, even if the patient for instance, may come to us and maybe they took more opiates and prescribed or you know, and they ran out early and figure out what exactly was that drove the patient for that, right? I mean, you know, so that we know maybe it is actually worse than pain. Maybe there was something that happened that caused the patient to have a significant increase of it. You know, I think one of the biggest misconceptions is really also that patients who make sure some misuse of medication, that everybody has opioid abuse disorder, addiction. Common, far too common, right? And I think we've learned over the years how common it is. Clearly pain itself, intractable pain is a very strong driver of behavior. If you're in pain, if a patient is in pain, they are desperate often to seek some kind of relief. And taking extra medication in itself, while it's not at all something that we can endorse and tolerate, obviously in many ways, right, we have to still take it as a possible sign of pain control rather than opiate use disorder in itself. So, we need to be very careful of how to assess such a patient and that we guide them into the right direction in regard to the next. Dr Weathers: That, again, is very important advice, and thinking about how chronic pain on a very different level than acute pain, right? Understanding how these patients are processing pain in a very different way than patients with acute pain. And again, also, I think a very important point that the pendulum has swung kind of back and forth over the years. You know, that they were in pain was another vital sign and it was make sure you're asking your patient about pain. And then all of a sudden it was, oh, we have to be really careful and people should not, nobody should be on these medications, which you- to your point, led to sudden abandonment. And that's not the point. That's not what we should be doing as providers. I know, though, there's very sensitive and challenging situations when you find out a patient though, perhaps taking more than expected because of chronic pain, but perhaps diversion. How have you handled those challenging cases? Dr Sandbrink: I think diversion needs to be taken obviously very, very seriously. And you know, if a patient is truly diverting medication and there are obviously multiple variations of that, right? I mean, it's like giving it to a family member, for instance. That's one thing. It's on the other hand actually selling it. I think a patient who diverts is such a situation where opioid prescribing has to stop immediately, right? I mean, this is not a patient that we would take off at this point. I mean, so I think it's one of the very, very few occasions where you'd say that you have to just stop it immediately. I think there are other situations really in general, I think the patients who have been on opioids long term, especially in higher doses, I mean the majority of patients are not different. We have to be aware of it. We have to always look out for it. That's part of our risk mitigation. But we also have to make sure that patients on long term opioid therapy, right, that we guide them appropriately. I think the guidance probably in many ways is that we want to make sure whether opioids, the opioid medications still have helps them to achieve their functional goal. Are they truly helpful for the patients in achieving what they aspire to do in regard to their work life, in regard to the family situation. I think a lot of times for patients who have been on opioids long term, it's probably not that it really helps them that much for pain anymore, but they've often made that experience and they try to stop it. Pain gets worse, which is the effect obviously, that that happens with opiates right I mean, the moment you stop them, the opposite of the effect happens right I mean, they become irritable, right? The sleep gets worse, the pain gets worse, right? And it's a temporary phenomenon. And so, when we try to talk to a patient about possibly reducing the medication, I think this is one of the most challenging aspects that we have, that we really look at the patient and try to motivate them to be part of that plan. It's not something that we want to impose on the patient, but rather that we motivate the patient to look towards in the long term, probably more efficient pain care, which is really much more comprehensive pain care using all modalities. And I think one of the things that we learned over the last years is that when we make opiate medication reductions, we have to go very slowly. I think in the past we've talked about a matter of weeks and now the guidance including from the CDC guideline is probably more- closer to 10% per month to reducing it. So, you make reductions that may take many months to a year even, right. And the patient is allowed to help us, guide us how fast we can go. And you're allowed to make pauses if needed for the patient to adjust physiologically to reduction. And we want to go slowly enough that we don't run into an acute withdrawal situation right If you do it very gradually, it's much more manageable for the patient to do that. Then they'll be much more motivated to work with you. But still, it's a challenge right I think that we do. And I think at the very end, it's really providing good patient care that allows us to build that rapport with the patient that they trust us and that they say, Hey, you know, yes, I'm, I'm willing to work with you, doc, to maybe reduce my relia…

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