Continuum Audio

Neuroimaging is a tool to classify and ascertain the etiology of epilepsy in people with first or recurrent unprovoked seizures. In addition, imaging may help predict the response to treatment. To maximize diagnostic power, it is essential to order the correct imaging sequences.

In this episode, Aaron Berkowitz, MD, PhD, FAAN speaks with Christopher T. Skidmore, MD, author of the article "Neuroimaging in Epilepsy," in the Continuum February 2025 Epilepsy issue.

Dr. Berkowitz is a Continuum® Audio interviewer and professor of clinical neurology at the University of California, San Francisco

Dr. Skidmore is an associate professor of neurology and vice-chair for clinical affairs at Thomas Jefferson University, Department of Neurology in Philadelphia, Pennsylvania.

Additional Resources

Read the article: Neuroimaging in Epilepsy

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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

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@ContinuumAAN

Host: @AaronLBerkowitz

Guest: @ctskidmore

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 Christopher Skidmore about his article on neuroimaging in epilepsy, which appears in the February 2025 Continuum issue on epilepsy. Welcome to the podcast, Dr Skidmore. Would you please introduce yourself to our audience?

Dr Skidmore: Thank you for having me today. I'm happy to talk to you, Dr Berkowitz. My name is Christopher Skidmore. I'm an associate professor of neurology at Thomas Jefferson University in Philadelphia. I'm a member of the Jefferson Comprehensive Epilepsy Center and also serve as the vice chair of clinical affairs for the department.

Dr Berkowitz: Thank you very much for joining us and for this fantastic article. It's very comprehensive, detailed, a very helpful review of the various types of brain pathology that can lead to epilepsy with very helpful images and descriptions of some of the more common findings like mesial temporal sclerosis and some of the less common ones such as cortical malformations, heterotopia, ganglioglioma, DNET. So, I encourage all of our listeners to read your article and take a close look at those images. So, hopefully you can recognize some of these findings on patients' neuroimaging studies, or if you're studying for the right or the boards, you can recognize some of these less common congenital malformations that can present in childhood or adulthood with epilepsy.

In our interview today, what I'd like to do is focus on some practical tips to approaching, ordering, and reviewing different neuroimaging studies in patients with epilepsy. So to start, what's your approach when you're reviewing an MRI for a patient with a first seizure or epilepsy? What sequence do you begin with and why, how do you proceed through the different sequences and planes? What exactly are you looking for?

Dr Skidmore: It's an important question. And I think to even take a step back, I think it's really important, when we're ordering the MRI, we really need to be specific and make sure that we're mentioning the words seizures and epilepsy because many radiology centers and many medical centers have different imaging protocols for seizure and epilepsy patients as compared to, like, a stroke patient or a brain tumor patient. I think first off, we really need to make sure that's in the order, so that way the radiologist can properly protocol it. Once I get an image, though, I treat an MRI just like I would a CAT scan approach with any patient, which is to always approach it in the same fashion. So, top down, if I'm looking at an axial image. If I'm looking at a coronal image, I might start at the front of the head and go to the back of the head. And I think taking that very organized approach and looking at the whole brain in total first and looking across the flare image, a T2-weighted image and a T1-weighted image in those different planes, I think it's important to look for as many lesions as you can find. And then using your clinical history. I mean, that's the value of being a neurologist, is that we have the clinical history, we have the neurological exam, we have the history of the seizure semiology that can might tell us, hey, this might be a temporal lobe seizure or hey, I'm thinking about a frontal lobe abnormality. And then that's the advantage that we often have over the radiologist that we can then take that history, that exam, and apply it to the imaging study that we're looking at and then really focus in on those areas. But I think it's important, and as I've illustrated in a few of the cases in the chapter, is that don't just focus on that one spot. You really still need to look at the whole brain to see if there's any other abnormalities as well.

Dr Berkowitz: Great, that's a very helpful approach. Lots of pearls there for how to look at the imaging in different planes with different sequences, comparing different structures to each other. Correspondent reminder, listeners, to look at your paper. That's certainly a case where a picture is worth a thousand words, isn't it, where we can describe these. But looking at some of the examples in your paper, I think, will be very helpful as well. So, you mentioned mentioning to the neuroradiologist that we're looking for a cause of seizures or epilepsy and epilepsy protocols or MRI. What is sort of the nature of those protocols if there's not a quote unquote "ready-made" one at someone 's center in their practice or in their local MRI center? What types of things can be communicated to the radiologist as far as particular sequences or types of images that are helpful in this scenario?

Dr Skidmore: I spent a fair amount of time in the article going over the specific MRI protocol that was designed by the International League Against Epilepsy. But what I look for in an epilepsy protocol is a high-resolution T2 coronal, a T2 flare weighted image that really traverses the entire temporal lobe from the temporal tip all the way back to the most posterior aspects of the temporal lobe, kind of extending into the occipital lobe a little bit. I also want to see a high resolution. In our center, it's usually a T1 coronal image that images the entire brain with a very, very thin slice, and usually around two millimeters with no gaps. As many of our neurology colleagues are aware, when you get a standard MRI of the brain for a stroke or a brain tumor, you're going to have a relatively thick slice, anywhere from five to eight millimeters, and you're actually typically going to have a gap that's about comparable, five to eight millimeters. That works well for large lesions, strokes, and big brain tumors, but for some of the tiny lesions that we're talking about that can cause intractable epilepsy, you can have a focal cortical dysplasia that's literally eight- under eight millimeters in size. And so, making sure you have that nice T1-weighted image, very thin slices with no gaps, I think is critical to make sure we don't miss these more subtle abnormalities.

Dr Berkowitz: Some of the entities you describe in your paper may be subtle and more familiar to pediatric neurologists or specialized pediatric neuroradiologists. It may be more challenging for adult neurologists and adult neuradiologists to recognize, such as some of the various congenital brain malformations that you mentioned. What's your approach to looking for these? Which sequences do you focus on, which planes? How do you use the patient 's clinical history and EEG findings to guide your review of the imaging?

Dr Skidmore: It's very important, and the reason we're always looking for a lesion---especially in patients that we're thinking about epilepsy surgery---is because we know if there is a lesion, it increases the likelihood that epilepsy surgery is going to be successful. The approach is basically, as I mentioned a little bit before, is take all the information you have available to you. Is the seizure semiology, is it a hyper motor semiology or hyperkinetic semiology suggestive of frontal lobe epilepsy? Or is it a classic abdominal rising aura with automatisms, whether they be manual or oral automatisms, suggesting mesial temporal lobe epilepsy? And so, take that clinical history that you have to help start to hone your eye into those individual locations. But then, once you're kind of looking in these nonlesional cases, you're also then looking at the EEG and where their temporal lobe spikes, where their frontal lobe spikes, you know, using that and pulling that information in. If they saw a neuropsychologist pulling in the information in from the neuropsychological evaluation; if they have severe reductions in verbal memory, you know, focusing on the dominant temporal lobe. So, in a right-handed individual, typically the left temporal lobe. And kind of then really spending a lot of time going slice at a time, very slowly, because in some of these vocal-cortical dysplasias it can be just the blurring of the gray-white margin. What I find easiest is to identify that gray-white margin and almost track it. Like, you use the mouse to kind of track it around and say, can I outline the exact border of the gray white margin in the frontal lobe that I'm interested in or the temporal lobe that I'm interested in, kind of looking for those subtle abnormalities.

Often as neurologists, we don't have the luxury of being able to immediately reformat. As I mentioned, our T1 volume acquisition study is done in the coronal plane, but sometimes you might want it in the axial plane. And so, I might reach out to the radiologist and say, hey, can you reformat this in the axial plane because I'm interested in the frontal lobe epilepsy and it's a little bit better at looking at it in that plane? And I'll have them reformat and put it back on the pack so I can look at it in that manner. And so that's a, kind of another strategy is to take what you have, but also then go back to the radiologist and say, I need to look at it this a different way. Can you reformat it for me? Looking for that gray-white matter junction is the nice way to pick up for kind of subtle cortical dysplasias. And then when you see an abnormality, to be able to put the T1, the T2, and the flare image all up next to each other and use the technology built into most of our browsers to put on what's called the localizer mode, where I can highlight a specific spot that I'm seeing on the T1 and then very easily quickly see, what does it look like on the T2? What does it look like on the flare? To kind of quickly decide, is it a true abnormality or am I only seeing it on one slice because of an artifact on that one imaging sequence? And I think that's the biggest kind of key is to make sure, is it an artifact or is it not an artifact? That's kind of the most common thing that we, I think, get confused with.

Dr Berkowitz: So, some very helpful pearls there in terms of reviewing the imaging, being in dialogue with our neuroradiology colleagues to think about potentially reacquiring certain images on certain planes or looking at the images with our neuroradiology colleagues to let them know more about the clinical history and where we're sort of zooming in about possible abnormalities.

Dr Skidmore: I would just add in there that when looking at especially the mesial temporal structures, because of a lot of artifacts that can be present in an individual MRI machine, it's not uncommon that the mesial temporal structure will appear brighter because of an MRI magnet artifact. And so, it's a good key to look at the hippocampus compared to the insula. And so, the hippocampus and the insula should have similar signal characteristics. You're seeing the hippocampus is bright, but the insula ipsilateral to it's normal intensity. That would suggest that that's probably a true hyperintensity on the flare-weighted image as opposed to if both are bright, unless you're suspecting a hemispheric abnormality, it's more likely to be a kind of artifact in the MRI machine.

Dr Berkowitz: Okay. Those are really helpful tips, not just to analyze the hippocampus and medial temporal lobe itself---let's remember our anatomy and the circuit of Papez---and to look at associated structures for supporting evidence of a possible abnormality in the hippocampus itself. It looks like there may be something subtle. We can use some additional information from the image to try to decide if that is real or artifactual, and of course correlating with the clinical picture and EEG. I'd like to talk briefly now about some other imaging modalities that you discuss in your paper, the use of functional imaging such as PET, SPECT and fMRI. Let's talk a bit about each of these. When would you order a PET scan for a patient with epilepsy? What would you be looking for and how would you be using that to make clinical decisions?

Dr Skidmore: Yeah, so these functional imaging modalities are really utilized when we're evaluating somebody that's not responding to medications. So, they're medically intractable, and we're wondering, could they be a candidate for epilepsy surgery? And so, most of these imaging modalities are really relegated to the world of epileptologists at surgical epilepsy centers. I wanted to include them, though, in the article because I do think it's important for general neurologists to understand kind of what they are, because invariably a patient sees me and then they go back to their general neurology and be like, hey, Doctor Skidmore said I had this PET scan abnormality. What do you think? So, I think it's a good idea for general neurologists to kind of understand them. So, probably the oldest that we've utilized is the FDG PET scan, basically looking at fluorodeoxyglucose and the brain's utilization of glucose. As we all remember, again, glucose is the primary molecule for energy and ATP production in the brain. And so basically, by injecting radioactive glucose in the interictal state--- so not during a seizure but in between seizures---areas of the brain that are not taking up the radiotracer will show as being hypometabolic. So, low metabolism. And hypometabolic regions in the interictal state have been associated with onset regions for epileptic seizures.

Let's say you have a patient clinical history, you think they have temporal of epilepsy, EEG suggests temporal of epilepsy, but the MRI is nonlesional, meaning there's no abnormality that anybody could appreciate even at a 3 Tesla scanner. We'll get an FDG PET scan and see, is there hypo metabolism in that temporal lobe of interest? And if there is, well, that's been shown through several published papers, that's just as valuable as having an abnormality on the MRI. And so, we often again use these PET scans, especially in nonlesional cases, to try to find that subtle cortical dysplasia. Now you have your nice epilepsy protocol MRI, it says it's nonlesional. You get your PET scan, it shows hypometabolism in a region of the frontal lobe, let's say, in a in a frontal lobe epilepsy case. And then often we go back, we kind of talked about strategy of how you find those subtle lesions. Then you go back and say, well, look, this gyrus specifically on the PET scan said it's abnormal. You end up looking for really subtle, very tiny abnormalities that, even with somebody that's skilled, often at first review gets missed. So, that's how we use the PET scan.

The SPECT scan is done typically in the ictal state. So, now somebody's in an epilepsy monitoring unit often, where you're injecting radio tracer at the exact moment that somebody starts having a seizure. And we know when there's increased seizure activity, the increased seizure activity---let's say it's from my right temporal lobe---is going to increase cerebral blood flow transiently to the right temporal lobe. And then if that seizure discharge spreads from the right temporal lobe maybe to the entire right hemisphere and eventually becomes a focal to bilateral tonic chronic seizure by spreading to the other side, the entire brain is going to be hypoperfused at that point. So, if you want to, as soon as the seizure starts, inject that radio tracer to see, where is the blood flow earliest in the seizure? And then we might do an interictal SPECT when you're not having a seizure. Look at, all right, what's the normal blood flow when somebody's not seizing? What's it like when they're having a seizure? And then the area that has increased activity would- might suggest that's where the seizure started from. But we have to be very careful because again, some seizures can spread very rapidly. So, if you delay injecting an injection ten, fifteen, twenty seconds, the seizure could have already propagated to another region of the brain, giving you a false positive in another location. So, you have to be very careful about that modality.

I think what's most exciting is the functional MRI because the functional MRI, for many, many centers, is replacing a very old technique called the WADA test. So, in the WADA test, typically you place a catheter angiogram into the internal carotid artery and transiently introduce a sedative medication to put, let's say, the left hemisphere to sleep because you wanted to see what functions were still active in the right hemisphere. And then the surgeon would move the catheter or the right internal carotid artery, and you inject a sedative on that side after the left hemisphere is recovered and see what the left hemisphere can do. And we used that for language dominance, we used that for memory dominance. And while most individuals did fine with angiograms, unfortunately complications do occur and there's injury to the artery, there could be strokes that can- that have happened, which can be quite devastating for the patient. And so, functional MRI is a nice, noninvasive way for us to map out language function, motor function, sensory function, visual function, and is starting to show some usefulness also for mapping out kind of memory function, dominant memory function, meaning verbal memory compared to visual memory. To be able to do those things noninvasively becomes really important because, if we're talking about epilepsy surgery, we want to make you seizure-free but neurologically intact. And so, we need to understand the relationship between where we think the seizures are coming from and where eloquent cortex is so we can properly counsel you and avoid those regions during any planned surgery. Those are the three most common functional imaging modalities that we're using now to supplement the rest of the presurgical work.

Dr Berkowitz: Very helpful. So, these are studies, PET, SPECT, and fMRI, that would really be obtained predominantly in patients in whom epilepsy surgery was being considered to have more precise lesion localization, as well as with the fMRI to get a better sense of how to provide the safest maximal resection of epileptogenic tissue while preserving functions.

Dr Skidmore: That's a perfect summary.

Dr Berkowitz: Fantastic. This has been a really helpful interview with Dr Skidmore and a really fantastic article. As I said, a picture is worth a thousand words, so I definitely encourage you to read the article and look at the images of some of the conditions we've been talking about and some of these findings that can be seen on interictal PET or ictal SPECT to get a sense of the visual aspects of what we've been discussing. So again, today I've been interviewing Dr Christopher Skidmore about his article on neuroimaging and epilepsy, which appears in the most recent issue of Continuum on Epilepsy. Be sure to check out Continuum audio episodes from this and other issues. And thank you so much to our listeners for joining us today.

Dr Skidmore: Thank you for having me.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

EEG is the single most useful ancillary test to support the clinical diagnosis of epilepsy, but if used incorrectly it can lead to misdiagnosis and long-term mental and physical health sequelae. Its application requires proper understanding of its limitations and variability of testing results.

In this episode, Katie Grouse, MD, FAAN, speaks with Daniel Weber, DO, author of the article "EEG in Epilepsy," in the Continuum® February 2025 Epilepsy 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. Weber is the director of adult epilepsy and vice chair of clinical affairs at the St. Louis University in St. Louis, Missouri.

Additional Resources

Read the article: EEG in Epilepsy

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

Guest: @drdanielweber

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 Daniel Weber about his article on EEG and epilepsy, which appears in the February 2025 Continuum issue on epilepsy. Welcome to the podcast and please introduce yourself to our audience.

Dr Weber: Hi, thanks for having me. My name is Dan Weber and I'm an epileptologist at Saint Louis University. I direct the adult epilepsy program here and also serve as the vice chair for Clinical Affairs. Been my pleasure to work on this article.

Dr Grouse: I'm so happy to have you today. I read your article. I found it to be incredibly useful as someone who often orders EEG in the general neurology clinic. So, I wanted to start with asking, what is the most clinically relevant message or takeaway from your article that you'd really like neurologists to know?

Dr Weber: Yes, when I was asked to write this article, I looked back at the previous Continuum on epilepsy and just the general literature. And there's a lot of good articles and books out there on EEG and epilepsy and sort of giving you a primer on what you might see and how to interpret it. So, we wanted to try to go a slightly different direction. This article gives you some of that gives you the background of EEG and some of the basic things that you may see, but the real thrust of it is more about the limitations of EEG in the clinical picture of epilepsy and common things you might avoid. There are some things that we get hammered into our brains in training that aren't always true and there's plenty of examples in the literature to review, and this article sort of tries to encapsulate as many of those as possible in a digestible format. The main takeaway would be that EEG is an extremely helpful tool in the diagnosis of epilepsy, is the best tool we have to help supplement your clinical acumen. But it does not make the diagnosis of epilepsy. And there are certain circumstances when it may not be as helpful as you may have been led to believe in residency.

Dr Grouse: Maybe not the most comforting of messages, but certainly an important one, very important to learn more about this. So, we appreciate that. Can you tell us your decision-making process when deciding whether to order a routine EEG, an extended EEG, prolonged ambulatory EEG, or inpatient video EEG?

Dr Weber: Sure. So, it's a multi-part question because each one, I think, has a different clinical scenario. In the current state, our best data for estimating risk of recurrence after an initial seizure comes with routine EEG abnormalities. So, often I will order routine EEGs in those scenarios. So new patient presentation, new patients coming in with an initial seizure who want to know what's their risk of recurrence. So, risk stratification, I use a lot of routine EEG for, often sleep deprived if possible to increase the sensitivity. If you'd like, the extended EEG does offer higher sensitivity, or you can repeat the routine EEG if the first routine EEG is nonconclusive.

For generally extended EEGs, I tend to order them in my practice if patients have come to see me with a suspected diagnosis of epilepsy but haven't yet had any electrographic confirmation.

Maybe they've already had routine EEGs done in the past, so we'll try to obtain just a little more data. The longer-term EEGs I tend to use in different clinical scenarios, in patients usually who already have established diagnosis or people who have become refractory and we haven't yet confirmed their diagnosis. I tend to do inpatient EEGs in those situations. Ambulatory EEGs I do more when there are certain characteristics of the patient or the patient 's presentation that may not fit well on the inpatient side. Patients who are reliant on substances who can't use while they're inpatient and may have withdrawal effects complicating the stay. Or people who have a strong activation component to their epilepsy where activity really draws it out, certain activities that they do at home that they might not do during the inpatient stay. Those are the sorts of people I'll do ambulatory EEGs on. There are a couple other scenarios as well that come up less commonly, but everything has its own little niche.

Dr Grouse: That's a really helpful review as we sort of think about which way we want to go as we're working up our patients in the inventory setting. Can you tell me a little more about the difference between sensitivity of, for instance, doing maybe two routine EEGS versus prolonged ambulatory EEG?

Dr Weber: Generally speaking, the longer you're recording someone's brain waves, the higher the sensitivity is going to be. So routine EEG is twenty to forty minutes at most places. One of those gives you a certain sensitivity. More of them will give you more sensitivity. And there was a recent study highlighted in the article that compared routine EEGs to initial multi-day ambulatory EEG, and the ambulatory EEG obviously, as would be expected, has a higher sensitivity than either of the routines. So, there may be some cases with that initial evaluation where an ambulatory EEG may be held and we get into that in more detail in the article. But with the caveat, a lot of this article is about limitations, and the data that we have to talk about increased risk of recurrence was based off seeing epileptic form discharges on routine EEG. So you could hypothesize that if you only have one epileptic form discharge in three days on an ambulatory EEG, that may not carry the same recurrent significance as catching one on a twenty minute EEG. But we don't have that knowledge.

Dr Grouse: Getting a little bit more into what you mentioned about the limitations, when is the scalp EEG less useful or limited in the evaluation of epilepsy?

Dr Weber: So, one thing I see a lot in my residence at here and other places where I've worked is, I get them very excited about EEG and they may order it a bit too much. So, if patients have a known, established diagnosis of epilepsy, electrographically confirmed, and they come in with a breakthrough seizure and they're back to their baseline, there's really not a strong reason to get an EEG. We often seem to in the emergency department as part of our evaluation, but we already know what happened to the patient. The patient's not doing poorly right now, so the EEG is not going to give you any additional information. Just like really any test, you should think, what are the possible outcomes of this test and how would those outcomes alter the care of this patient? And if no outcome is going to affect the care of the patient or give you any additional diagnostic information, then probably don't need to be doing that test.

Dr Grouse: This is probably a good segue into asking, what is an area of confusion or common pitfalls that you've seen in the clinical application of EEG and epilepsy?

Dr Weber: So, a lot of times on the inpatient service, we'll get longer-term EEGs for patients who are having spells that are occurrent while they're in the ICU or other places or altered in some way, encephalopathic. And these patients will have their spell, and in my report, I'll say that there is not any electrographic correlate. So, there's no EEG finding that goes along with the movement that they're doing that's concerning for a seizure. And that doesn't always mean that it's not an epileptic seizure. An EEG is not a one-hundred-percent tool. Epilepsy and seizures are a clinical diagnosis. The EEG is a helpful tool to guide that diagnosis, but it is not foolproof, so you need to take the whole clinical picture into account. Particularly focal seizures without impaired awareness often can be electrographically silent on surface EEG. If you see something that looks clinically like a seizure but doesn't show up on the EEG, there are circumstances that they get to in the paper a little bit where that can still be an epileptic seizure. And you just have to be aware of the limitations of the tests that you're ordering and always fall back on the clinical skills that you've learned.

Dr Grouse: Are there any tips or tricks you can suggest to improve the clinical utility of EEG for diagnosis of epilepsy? And also thinking about the example you just gave, but maybe other cases as well?

Dr Weber: Again, definitely need to incorporate EEG as part of a larger picture. The video component of EEG is incredibly helpful. You can't interpret EEG in isolation. Regardless of what the EEG shows, you can't make a diagnosis of epilepsy, but you certainly can be very suspicious of one. So, in those cases where you have a high suspicion for an epileptic seizure and the EEG has not given you any confirmatory evidence, it's really helpful to rely on any clinical expertise that you have access to. So, people who have seen lots of seizures may be helpful in that situation. Getting good recordings, good data to prove yourself one way or the other is helpful and continuing to evaluate. So usually, as I said, focal seizures that don't show up well on the EEG. People who have focal seizures will often have larger seizures if left untreated. So, you can try to admit them to an epilepsy monitoring unit where we try to provoke seizures and try to provoke a larger seizure to help confirm that diagnosis.

Dr Grouse: This kind of gets into what we've already reviewed to some degree, but what is the easiest mistake to make (and hopefully avoid) when using EEG to diagnose epilepsy or make other treatment decisions?

Dr Weber: I think the easiest, most common mistake I see is overreliance on the test. There's a lot of subjectivity to the interpretation of this test. There are a lot of studies out there on interrater reliability for epilepsy and intrarater reliability for epilepsy. We continue to try to make the findings more objective and get more quantified. The articles talk about our six criteria for epileptiform discharges and have reference to where that came from and the sorts of specificity that each of those criteria lead to. Just because an EEG report has said something, that does not diagnose or negate a clinical diagnosis of epilepsy. It is common for folks with non-epileptic seizures to have a history of reported epileptic form discharges on their EEG. Again, because there is some subjectivity to the test, some abnormal-looking normal variants will pop up and get interpreted as epileptiform discharges. It's important to review the whole patient, as much of the data as you can, and make the best clinical judgment you can of the overall case.

Dr Grouse: What is quantitative EEG and how can it be clinically useful?

Dr Weber: Now that most EEG is obtained digitally through the use of computer software, we have been able to employ computers to do a lot of the work for us. There are many different ways of looking at the EEG data, but it's all frequency bands over time. The quantitative EEG goal is really to simplify and condense what you're seeing on your normal EEG page into a more digestible format. Lets you look at a larger amount of data faster, which becomes more and more important as we're doing more of these long-term recordings, particularly in the intensive care unit. Quantitative EEG can help you assess a lot of data at a snapshot and get a general sense of what's going on with the patient over the past several hours. It does require some extra training to become familiar with it, but it's training that can be done at all levels. Again, it can help you see more, faster. Obviously, like everything, it has its own limitations. Sometimes the sensitivity and specificity may be a little off from the raw data review, and you should always go back to the raw data anytime there are questions. But it can be helpful to make things faster.

Dr Grouse: Do you think you could give me a hypothetical example of a case where this would be something really nice to have?

Dr Weber: The most common example is folks with repetitive seizures in the ICU. If you're just looking at the raw data, you will get a sense of how often the seizures are happening. But if you look at the quantitative data, it sort of compresses that all down to a much smaller snapshot. So you can see much more readily, yes, these are how many seizures were happening. And here's where we gave our intervention; and look, there are fewer seizures after that intervention. So, it can help you assess response to treatment, help you assess just overall volume of seizures in a much more condensed fashion, and you can get through it much faster with the appropriate training.

Dr Grouse: Can you tell us about any new developments in EEG that are on the horizon we should be aware of?

Dr Weber: Yeah. So, I think my two favorites, which I highlight in the article, are longer-term recordings---so, there's some companies that are working on subcutaneous EEG. So, implanted EEG electrodes that can stay in your body for the short, long term on the order of year or years and constantly send some EEG data. Obviously, it's not a full montage in most of those cases, but some EEG data that can help you assess long-term trends in epilepsy and long-term response to therapies. I think that's going to be really cool. I think it's very exciting and I think it'll change how we do clinical trials in the future. I think we'll be able to rely less on seizure diaries from folks and more on objective seizure data for patients who have these implanted. But with that will come an ever-increasing amount of data to be reviewed, which leads into the other exciting future trend is AI in the use of interpretations. AI is becoming more and more advanced and there are very exciting articles out on how good AI is getting at interpreting our EEGs. I think soon, in the very near future, the AI platforms will be able to dramatically reduce the amount of time it takes the experts to review an EEG. They'll be able to do a lot of the screening for us and then we can go back, just like I was talking about the quantitative EEG, go back and review segments of the raw data rather than having to review every page of every file, which is quite time consuming.

Dr Grouse: Wow, that's really exciting. It certainly does seem like AI is making breakthroughs in just about every area of how we touch the practice of medicine. Exciting to hear that EEG is no exception.

Dr Weber: Yeah, I'm fully excited. I think it's going to revolutionize what we're doing and also just greatly expand people's ability to access that level of expertise that the AI will offer.

Dr Grouse: I wanted to transition to talking a little bit more about you and your career in neurology. How did you become interested in this area of neurology to begin with?

Dr Weber: Yeah, it's sort of a roundabout fashion. So, I started out planning to be a neurointerventionalist, and then I realized that I didn't want that sort of call. For a hot minute in my PGI 3 year. I was planning to be a neuro-ICU doctor. I think that's largely because medicine is all I had been exposed to at that point and the ICU seemed like a very comfortable place. Then as I transitioned into PGI 3 we started doing more electives and outpatient rotations in my residency. And then I was planning on being a movement disorder specialist or an epileptologist, couldn't make up my mind for the longest time. And then I started to like EEG more than I liked watching videos. So, tilted myself towards epilepsy and haven't looked back.

Dr Grouse: Well, I really appreciated you coming to talk with us today about your article. I can't recommend it enough to anyone out there, whoever treats patients with epilepsy or orders the EEGs, I just think it was just incredibly useful. And it was such a pleasure to have you.

Dr Weber: Thank you very much for having me, Katie.

Dr Grouse: Again, today I've been interviewing Dr Daniel Weber about his article on EEG and epilepsy, which appears in the most recent issue of Continuum on Epilepsy. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Epilepsy classification systems have evolved over the years, with improved categorization of seizure types and adoption of more widely accepted terminologies. A systematic approach to the classification of seizures and epilepsy is essential for the selection of appropriate diagnostic tests and treatment strategies.

In this episode, Aaron Berkowitz, MD, FAAN, speaks with Roohi Katyal, MD, author of the article "Classification and Diagnosis of Epilepsy," in the Continuum February 2025 Epilepsy issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a clinical professor of neurology at the University of California, San Francisco.

Dr. Katyal is an assistant professor of neurology and codirector of adult epilepsy at Louisiana State University Health Shreveport in Shreveport, Louisiana.

Additional Resources

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Host: @AaronLBerkowitz

Guest: @RoohiKatyal

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 Roohi Katyal about her article on classification and diagnosis of epilepsy, which appears in the February 2025 Continuum issue on epilepsy. Welcome to the podcast, Dr Katyal, and could you please introduce yourself to our audience?

Dr Katyal: Thank you for having me. I'm very excited to be here. I'm Dr Roohi Katyal. I currently work as Assistant Professor of Neurology at LSU Health Shreveport. Here I also direct our adult epilepsy division at LSU Health along with my colleague, Dr Hotait.

Dr Berkowitz: Fantastic. Well, happy to have you here. Your article is comprehensive, it's practical, and it focused on explaining the most recent International League Against Epilepsy (ILAE) classification of epilepsy and importantly, how to apply it to provide patients with a precise diagnosis of epilepsy and the particular subtype of epilepsy to guide the patient's treatment. There are so many helpful tables and figures that demonstrate all of the concepts and how to apply them at the bedside. So, I encourage our listeners to have a look at your article, even consider maybe screenshotting some of these helpful tables onto their phone or printing them out for handy reference at the bedside and when teaching residents. Your article begins with the current definition of epilepsy. So, I want to ask you about that definition and make sure we're on the same page and understand what it is and what it means, and then talk through a sort of hypothetical patient scenario with you to see how we might apply these in clinical practice. You talked about, in your article, how the new definition of epilepsy from the ILAE allows for the diagnosis of epilepsy in three different scenarios. So, could you tell us what these scenarios are?

Dr Katyal: So, epilepsy in general is a chronic condition where there is a recurrent predisposition to having seizures. As you mentioned, epilepsy can be diagnosed in one of three situations. One situation would be where an individual has had two or more unprovoked seizures separated by more than 24 hours. The second situation would be where somebody has had one unprovoked seizure and their risk of having recurrent seizures is high. And the third situation would be where somebody had---where the clinical features could be diagnosis of an epilepsy syndrome. An example of that would be a young child presenting with absence seizures and their EEG showing 3 Hz characteristic generalized spike in with discharges. So that child could be diagnosed with childhood absence epilepsy.

Dr Berkowitz: Perfect. Okay, so we have these three scenarios, and in two of those scenarios, we heard the word unprovoked. Just to make sure everyone's on the same page, let's unpack this word "unprovoked" a little bit. What does it mean for a seizure to be unprovoked versus provoked?

Dr Katyal: So unprovoked would be where we don't have any underlying provoking features. So underlying provoking features are usually reversible causes of epilepsy. These would be underlying electrolyte abnormality, such as hyperglycemia being a common one which can be reversed. And these individuals usually do not need long-term treatment with anti-seizure medications.

Dr Berkowitz: Fantastic. Tell me if I have this right, but when I'm teaching residents, I… did it provoked and unprovoked---there's a little confusing, right? Because we use those terms differently in common language than in this context. But a provoked seizure, the provoking factor has to be two things: acute and reversible. Because some people might say, well, the patient has a brain tumor. Didn't the brain tumor provoke the seizure? The brain tumor isn't acute and the brain tumor isn't reversible, so it would be an unprovoked seizure. I always found that confusing when I was learning it, so I try to remind learners I work with that provoked means acute and reversible, and unprovoked means it's not acute and not reversible. Do I have that right? Am I teaching that correctly?

Dr Katyal: That's correct.

Dr Berkowitz: Great. And then the other important point here. So, I think we were all familiar prior to this new guideline in 2017 that two unprovoked seizures more than twenty-four hours apart, that's epilepsy. That's pretty straightforward. But now, just like we can diagnose MS at the time of the first clinical attack with the right criteria predicting that patient is likely to have relapse, we can say the patient's had a single seizure and already at that time we think they have epilepsy if we think there's a high risk of recurrence, greater than or equal to sixty percent in this guideline, or an epilepsy syndrome. You told us what an epilepsy syndrome is; many of these are pediatric syndromes that we've studied for our boards. What hertz, spike, and wave goes with each one or what types of seizures. But what about this new idea that a person can have epilepsy after a single unprovoked seizure if the recurrence rate is greater than sixty percent? How would we know that the recurrence rate is going to be greater than sixty percent?

Dr Katyal: Absolutely. So, the recurrence rate over sixty percent is projected to be over a ten year period. So, more than sixty percent frequency rate in the next ten years. And in general, we usually assess that with a comprehensive analysis and test. So, one part of the comprehensive analysis would be, a very important part would be a careful history taking from the patient. So, a careful history should usually include all the features leading up to the episodes of all the prodromal symptoms and warning signs. And ideally you also want to get an account from a witness who saw the episode as to what the episode itself looked like. And in terms of risk assessment and comprehensive analysis, this should be further supplemented with tests such as EEG, which is really a supportive test, as well as neuroimaging. If you have an individual with a prior history of, let's say, left hemispheric ischemic stroke and now they're presenting with new onset focal aware seizures with right arm clonic activity, this would be a good example to state that their risk of having future seizures is going to be high.

Dr Berkowitz: Perfect. Yeah. So, if someone has a single seizure and has a lesion, as you said, most common in high-income countries would be a prior stroke or prior cerebrovascular event, prior head trauma, then we can presume that the risk is going to be high enough that we could call that epilepsy after the first unprovoked seizure. What if it's the first unprovoked seizure and the imaging is unremarkable? There's no explanatory lesion. How would we get to a diagnosis of epilepsy? How would we get to a risk of greater than sixty percent in a nonlesional unprovoked seizure? I should say, no lesion we can see on MRI.

Dr Katyal: You know, in those situations an EEG can be very helpful. An EEG may not always show abnormalities, but when it does show abnormalities, it can help us distinguish between focal and generalized epilepsy types, it can help us make the diagnosis of epilepsy in certain cases, and it can also help us diagnose epilepsy syndromes in certain cases.

Dr Berkowitz: Perfect. The teaching I remember from a resident that I'm passing on to my residents, so please let me know if it's correct, is that a routine EEG, a 20-minute EEG after a single unprovoked seizure, this sensitivity is not great, is that right? Around fifty percent is what I was told with a single EEG, is that right?

Dr Katyal: Yeah, the sensitivity is not that great. Again, you know, it may not show abnormality in all the situations. It's truly just helpful when we do see abnormalities. And that's what I always tell my patients as well when I see them in clinic. It may be abnormal or it may be normal. But if it does show up normal, that does not rule out the diagnosis of epilepsy. Really have to put all the pieces together and come to that finally diagnosis.

Dr Berkowitz: Perfect. Well, in that spirit of putting all the pieces together, let's walk through together a hypothetical case scenario of a 19-year-old patient who presents after a first event that is considered a possible seizure. First, how do you approach the history and exam in this scenario to try to determine if you think this was indeed an epileptic seizure?

Dr Katyal: So, if I'm seeing them in the clinic or in the outpatient setting and they're hopefully presenting with somebody who's already seen the seizure itself, my first question usually is if they had any warning signs or any triggers leading up to the episode. A lot of times, you know, patients may not remember what happened during the episode, but they may remember if they felt anything different just before or the day prior, something different may have happened around that time. Yeah, so they may report that. Then a very important aspect of that would be talking to somebody who has seen the episode, a witness of the episode; and ideally somebody who has seen the onset of the episode as well, because that can give us very important clues as to how the event or the episode started and how it progressed. And then another very important question would be, for the individual who has experienced it, is how they felt after the episode ended. So, you can get some clues as to if they had a clear postictal state. Other important questions would be if they had any tongue biting or if they lost control of their bladder or all those during the episode. This, all those pieces can guide us as to if the seizure was epileptic, or the episode was epileptic or not.

Dr Berkowitz: Fantastic. That's very helpful guidance. All right. So, let's say that based on the history, you're relatively convinced that this patient had a generalized tonic clonic seizure and after recovering from the event, you do a detailed neurologic exam. That's completely normal. What's your approach at this point to determining if you think the seizure was provoked or unprovoked, since that's, as you said, a key component of defining whether this patient simply had a seizure, or had a seizure and has epilepsy?

Dr Katyal: The important findings would be from the laboratory test that may have been done at the time when the patient first presented with the seizure. So, we want to rule out features like hypoglycemia or other electrolyte abnormalities such as changes in sodium levels or big, big fluctuations there. We also want to rule out any other metabolic causes or other reasons such as alcohol withdrawal, which can be a provoking factor. Because these would be very important to rule out is if we find a provoking reason, then this individual may not need to be on long term anti-seizure medication. So very important to rule that out first.

Dr Berkowitz: Great. So, let's say you get all of your labs and history and toxicology screen and no provoking factors there. We would obtain neuroimaging to see if there's either an acute provoking factor or some type of lesion as we discussed earlier. Let's say in this theoretical case, the labs are normal, the neuroimaging normal. There is no apparent provoking factor, there's no lesion. So, this patient has simply had a single unprovoked seizure. How do we go about now deciding if this patient has epilepsy? How do we try to get ourselves to either an above sixty percent risk and tell this patient they have epilepsy and probably need to be on a medicine, or they have a less than sixty percent risk and that becomes a little more tricky? And we'll talk about that more as well.

Dr Katyal: For in a young patient, especially in a young patient as a nineteen year old as you present, one very important aspect if I get this history would be to ask them about absolutely prior history of similar episodes, which a lot of times they may not have had similar episodes.

But then with this age group, you also want to ask about episodes of brief lapses in awareness or episodes of sudden jerking or myoclonic jerking episodes. Because if you have brief lapses of awareness, that could signify an absence seizure in this particular age group. And brief, sudden episodes of myoclonic jerking could be brief myoclonic seizures in this age group. And if we put together, just based on the clinical history, you could diagnose this patient with a very specific epileptic syndrome, which could be juvenile myoclonic epilepsy in the best case. Let's say if you ask about episodes of staring or relapses of awareness, that's not the case, and there's no history of myoclonic jerking episodes or myoclonic seizures, then the next step would be proceeding to more of our supplemental tests, which would be an EEG and neuroimaging. In all cases of new-onset seizure especially should have comprehensive assessment with EEG and neuroimaging to begin with, and we can supplement that with additional tests wherever we need, such as genetic testing and some other more advanced testing.

Dr Berkowitz: That's very helpful. OK, so let's say this particular patient, you talk to them, you talk to their family, no prior history of any types of events like this. No concerns for spells that could---unlike absence, no concern for movements that could sound like myoclonus. So, as you said, we would be looking for those and we could get to part one of the definition. There is more than one spell, even though we're being consulted for one particular event. But let's say this was the only event, we think it's unprovoked, the neuroimaging is normal. So, you said we proceed to an EEG and as you mentioned earlier, if the EEG is abnormal, that's going to tell us if the risk is probably this more than sixty percent and the patient should probably be on a medicine.

But common scenario, right, that the patient has an event, they have a full work up, we don't find anything. We're convinced it was a seizure. We get our routine EEG as we said, very good, an affirmative test, but not a perfectly sensitive test. And let's say this person's routine EEG turns out to be normal. So how would you discuss with the patient their risk of a future seizure and the considerations around whether to start an anti-seizure medicine if their work-up has been normal, they've had a single unprovoked seizure, and their EEG is unrevealing?

Dr Katyal: And I'm assuming neuroimaging is normal as well in this case?

Dr Berkowitz: Correct. Yeah.

Dr Katyal: We have a normal EEG; we have normal neuroimaging as well. So, in this case, you know, it's more of a discussion with the patient. I tell them of that, you know, the risk of seizure may not be higher than sixty percent in this case with all the tests being normal so far and there's no other prior history of similar episodes. So, we have a discussion with them about the risks that can come with future seizures and decide where the medication should be started or not.

Dr Berkowitz: And so how do you approach this discussion? The patient will say, Doctor Katyal, I had one seizure, it was very frightening. I got injured. You told me I can't drive for however many months. One cannot drive in that particular state. But I don't really like taking medicines. What is my risk and what do you think? Should I take a medicine?

Dr Katyal: I'll tell you this because normally I would just have a direct conversation with them, discuss all the facts that we have. We go over the seizure one more time just to make sure we have not missed any similar episodes or any other episodes that may be concerning seizure, which ruled out all the provoking factors, any triggers that may be seen inseizures like this in a young age. And another thing would be to basically have a discussion with them, you know, these are the medication options that we can try. And if there is another seizure, you know, these are the these are the restrictions that would come with it. And it's a very individualized decision, to be honest. That, you know, not everyone may want to start the medication. And you'll also find that some patients who, you know, some individuals are like no, I want to go back to driving. I don't want to be in this situation again. I would like to try a medication and don't want to ever have a seizure. So, I think it's a very individualized decision and we have a discussion with the patient based on all of these tests. And I would definitely maintain follow-up with them to make sure that, you know, things have not changed and things have---no seizures have recurred in those cases.

Dr Berkowitz: Yeah, great to hear your approach. And similar experience to you, right, where some patients say, I definitely don't want to take the medication, I'll roll the dice and I hope I don't have another seizure. And we say, we hope so also. As you said, let's keep a close eye. And certainly, if you have another seizure, it's going to be a lifelong seizure medicine at that point. And some patients who, as you said, say, wait, I can't drive for months. And if I don't take a medicine and I have a seizure in the last month, I would have to have another period of no driving. Maybe in that case, they would want to start a medicine. That said, we would present that either of these are reasonable options with risks and benefits and these are the medications we would offer and the possible side effects and risk of those, and make a joint decision with the patient.

Dr Katyal: Absolutely correct. Mentioned it perfectly well that this is a very individualized decision and a joint decision that we make with the patient.

Dr Berkowitz: Fantastic. Another topic you touch on in your article is the definition of resolved epilepsy. How is that defined in the guidelines?

Dr Katyal: Yes. So, an epilepsy can be considered resolved if an individual has been seizure-free for at least ten years and has been off of IV seizure medications for at least five of those years. Another situation where epilepsy can be considered resolved would be if they have an age-defined epilepsy syndrome and now they are beyond the relevant age group for the syndrome.

Dr Berkowitz: That's very helpful. So again, a very clear definition that's helpful in these guidelines. And yet, as I'm sure you experience your practice, as I do in mine, sometimes a little challenging to apply. So, continuing with our made-up hypothetical patient here, let's say at some point in the subsequent years, they have a second unprovoked seizure, still have a normal EEG but they do go on an anti-seizure medicine. And maybe four or five years later, they're seizure-free on a low dose of an anti-seizure medicine. And they say, you know, do I really still need this medicine? I'd really like to come off of it. What do you think? Is that safe? How do you talk about that with the patient? This definition of ten years and five years off medicine seems to be---and maybe unless someone's seeing a lot of children and young adults, a relatively uncommon scenario. It's we've had a first unprovoked seizure. We never figured out why. We don't really know why they had the seizure. We can't really gauge their subsequent risk. They're on medicines, they don't want to be on them and it's only been a few years, let's say three, four, or five years. How do you frame discussion with the patient?

Dr Katyal: Yeah, so that's the definition of being resolved. But in terms of tapering off medications, we can usually consider tapering off medications earlier as well, especially if they've been seizure-free for two or more years. Then again, as we mentioned earlier, it would be a very individualized decision and discussion with the patient, that we could consider tapering off of medication. And we would also want to definitely discuss the risk of breakthrough seizures as we taper off and the risks or the lifestyle modifications that would come with it if they have another breakthrough seizure. So, all those things will go into careful concentration when we decide to taper off, because especially driving restriction may be a big, you know, hard stop for a lot of patients that, you know, now is not a time to taper off medication. So, all of these factors will go into consideration and we could consider tapering off earlier as well.

Dr Berkowitz: That's very helpful. Yeah, as you said, when we're tapering off medications, if that's the direction the patient wants to go during that period, obviously we wouldn't want them to drive, or be up on a ladder, or swimming alone. You said that some patients might say, actually, I'll keep the medicine, whereas some might say, OK, I'll hold off on all these activities and hope that I can be off this medication. I remember epilepsy colleagues quoting to me at one point that all comers, when a patient's been seizure-free for two years, they estimate the risk of relapse, of having another seizure, somewhere around thirty to forty percent. In your expert opinion, is that about what you would quote to a patient as well,. about a thirty to forty percent, all comers? Obviously not someone who's had a history of status epilepticus and has a lesion or a syndrome, but in the sort of common situation of some unprovoked seizures in an adult, we don't have a clear ideology. Is that thirty to forty percent figure, more or less, you would place the risk when you talk to the patient? Or?

Dr Katyal: Yeah, absolutely, especially if the neuroimaging is completely normal, all their EE GS have been normal. They have been in this situation---you have a young patient with two seizures separated by so many years. After three or four years of being on the medication and, you know, the patient has been adhering. There are no more seizures. Thirty to forty percent seems reasonable, and this is what I usually tell them that the risk of, as we taper off medications, that risk is not zero but it's low. And around thirty percent is relatively where we would place the risk at.

Dr Berkowitz: We've said in this theoretical case that the EEG is normal. But last question, I've heard some practitioners say that, well, let's say the patient did have an abnormal EEG early on. Not a syndrome, but had maybe a few focal spike wave discharges or sharps and that made you convinced that this patient had epilepsy. But still becomes seizure free for several years. I've heard of some practitioners repeating the EEG before tapering the anti-seizure medicines and I always wonder, would it change anything? It's a brief twenty-minute period. They still have one spike, but I tell them they can't come off. If the spikes are gone, it may be because of the medication, and maybe when I take them off they would have a spike. And how do you use---do you use or how do you use EEG in that decision of whether to taper a medicine?

Dr Katyal: Yeah. In general, I would not always use an EEG for considering tapering off medication. Again, it's very individualized decision. I can give you a hypothetical example, but it's a fairly common one, is that if an individual with let's say focal seizures with impaired awareness, they live alone, they live by themselves. Oftentimes they'll say that, I'm not sure if I'm missing any seizures because nobody has seen them. I may or may not be losing awareness, but I'm not too certain. They have not had any definite seizures for history in the last couple of years and are now considering tapering off medication. So, this may be a situation where I may repeat an EEG, and perhaps even considering the longer EEG for them to understand their seizure burden before we decide to taper off medication. But in most situations, especially if we consider the hypothetical situation you had mentioned for the young patient who had to witness seizures separated by several years and then several years without any seizures, that may be a good example to consider tapering off medication, especially considering all the tests that had been normal before then.

Dr Berkowitz: That's very helpful to hear. And of course, this is your expert opinion. As you said, no guidelines and different people practice in different ways, but helpful to hear how you approach this common and challenging scenario for practitioners. Well, I want to thank you again, Dr Katyal. This has been a great opportunity to pick your brain on a theoretical case, but one that I think presents a number of scenarios that a lot of us---myself as a general neurologist, as well as you and your colleagues as epileptologists, we all see in general practice patients with unprovoked seizures and a revealing workup, and how to approach this challenging scenario based on the guidelines and on your expert opinion. I learned a lot from your article. Encourage our readers again to take a look. A lot of very helpful tables, figures, and explanations, some of the concepts we've been discussing. So again, today I've been interviewing Dr Roohi Katyal about her article on classification and diagnosis of epilepsy, which appears in the most recent issue of Continuum on Epilepsy. Be sure to check out Continuum audio episodes from this and other issues. And thank you again so much to our listeners for joining us.

Dr Katyal: Thank you for having me.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Jennifer L. Hopp, MD, FAAN, FAES, FACNS, who served as the guest editor of the Continuum® February 2025 Epilepsy issue. They provide a preview of the issue, which publishes on February 3, 2025.

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. Hopp is a professor in the department of neurology at the University of Maryland School of Medicine in Baltimore, Maryland.

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Host: @LyellJ

Guest: @JenHopp71

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 Jennifer Hopp, who recently served as Continuum's guest editor for our latest issue on epilepsy. Dr Hopp is a professor and executive vice chair in the Department of Neurology at the University of Maryland School of Medicine, where she's also director of the Epilepsy Center. Dr Hopp, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners?

Dr Hopp: Hi, Dr Jones. Thank you so much for having me on this podcast. I really had so much fun working with you and other authors of this issue and serving as editor. I feel like it was yesterday that I was author of an article in the past. And so, it's really a pleasure to take on this new role and create the content for the issue of Continuum for Epilepsy and really particularly to work with the stellar group of experts and authors that we were able to have us join this year.

Dr Jones: I want to thank you for, really, it's a remarkable issue. And we usually don't get into this a lot with our guest editors, but our last issue on epilepsy came out in 2022. Fantastic issue, guest edited by Dr Natalie Jette. When you were designing the table of contents and article topics for this issue, you had some great ideas. Walk us through your thought process on what was most important to convey in this issue.

Dr Hopp: Sure, I'm happy to do so. I think one of the things about Continuum that is so accessible to everybody is that it really is, to me, preeminent format of updating and educating, whether it's epileptologist, neurologist, trainees in every area of epilepsy, which is obviously an enormous task to really pull together all of these data to make updates and then to make it accessible to all of these different levels of learners as well as people like myself. I really read and always look forward to all the Continuum issues outside of my field. I use it to update my knowledge base, get ready for boards. I also read it as an educator because I want to know what my trainees are reading during their rotations and I want to be able to share materials with them. So, I really tried to go back and look at other issues and think about how we could make it fresh. So, I think one of the first challenges is just making sure that we're updating the content of each article based on the literature and the data we have. That really becomes the task of the authors. And so first of all, selecting the authors was both fun but also really important to me. But the second aspect of it to me was really the question of, how could we make this fresh this year? I think Continuum is always fresh and that it has new data, but I wanted to really think outside the box and I appreciate being able to take a few risks. One of them was really headed by Dave Clarke, who provides this incredibly thoughtful and comprehensive review of access to care and epilepsy. I think for anyone who wants a primer on the issues and language used in discussions of diversity or social determinants of health---you first of all do not have to be in the field of epilepsy to read this. So, you should check that out. But I also thought it was really critical to shed more light on these issues. So, we tried to be mindful of this in threading that through as best as we could each article, but also have a stand-alone section that he headed.

And so, he addresses issues of how to think about access to care for people with epilepsy, but actually, interestingly, also thinking about the investigators, providers, and researchers, and how we think about diversity in those viewpoints as well. I think we can always do better. Dave concludes with a wonderful focus on hope in this area with next steps for our community. So, I think that that was certainly one area that I wanted to take a risk and I think it was quite successful.

Dr Jones: Totally agree. I very much enjoyed that article. We have an article on implementation of guidelines and quality measures by Dr Christina Baca. I thought that was a great choice from your perspective, not only because Dr Baca is an expert on this, but it felt very practical, right?

Dr Hopp: Exactly. Exactly. And that was the other area that I thought really is always covered so well by the Academy of Neurology. There's so much work in updating the guidelines, whether it's the guideline that just was updated on people with epilepsy of childbearing potential or others outside of the field of epilepsy. And I thought that we could use Continuum to help educate all of the readers on how to take those guidelines and measures and then really bring them into practice. I think there's a whole field of implementation science that I think shines a light on the gap between the guidelines and the measures and then really what we do with them in practice. And that's actually what's most important for our patients and for the providers. And so Christine does just an amazing job as an expert, not only walking us through the guidelines that are relevant for epilepsy, but then helping us and providing, essentially, a toolkit to take those measures and guidelines and use them in a very feasible, accessible way in day-to-day practice. And I would suggest that it's relevant for anyone from a student level resident to an epileptologist who's been in practice, like me, for many years. And so I hope that's relatable and useful to the reader.

Dr Jones: I think it will be. And let's get right into it. So, I always enjoy talking to the guest editor. You're already an expert and now you've just read a bunch of articles and edited a bunch of articles from people who are really the premier experts in their area of the field, right? They're niche within epilepsy. So, as you've read these articles across the issue, if there were one biggest practice-changing recommendation that you would want to convey to our listeners, what would that be?

Dr Hopp: I think that's a fabulous question because again, each of these articles, I think, is designed and written by the author to stand alone. But ideally, they need to all be incorporated in practice. And I think what each author was able to really successfully do is not only review the data, but really take us to the next level with practice of epilepsy. For example, I think as we embark on the next couple of decades, clearly increased technology, AI, personalized medicine are all buzzwords and taking the lead. In reality, with advances, we still have to make sure our care is personalized. And we have to remember seizures are really the symptom, but epilepsy is the disease. What I think our authors do well is make sure that our care is personalized to the patients. You could take that from the first article that Roohi Katyall writes about how to approach the patient with epilepsy, which is still, I think, the seminal way to start to think about these patients. But we need to ask issues pertaining to people with epilepsy of childbearing potential; screen for mood, other comorbidities. Mark Keezer does a great job talking about these. And then as we discussed, Christine Baca, PCU, talks about how to then incorporate those practical considerations into practice. Each author also, I think, emphasizes the need to utilize technology and testing and evaluation to make sure that our care is personalized for our patient. For example, we have a focus on certain special populations. Some patients who we see from the diagnosis of epilepsy end up not having seizures. They may have nonepileptic events. And so, Adriana Bermeo-Ovalle and her co-author talk about how to address those patients. Well, Meriem Bensalem-Owen talks about gender based issues in epilepsy as well. And, and that particular article also was updated and refreshed to really address gender and sex-based issues beyond treating the woman with epilepsy. So, I think in summary, each of them really helps us make sure that we're personalizing the care for patients by emphasizing a very thorough and individualized approach to each of our patients that we see with seizures.

Dr Jones: Now that you put it that way, that really did come across as a consistent theme essentially in every article, right? All the way from the evaluation of the patient suspected of having epilepsy to the treatment options to the context of care. Personalization is really kind of a continuous thread throughout the issue. So, I think that's a great one.

Dr Hopp: I think it's still aspirational in some sense, but hopefully practical in another. For example, we certainly are going to make a medication selection when we see each individual patient based on their comorbidities, perhaps genetic considerations, and how they may respond to medications or have risks of rash. But there are certainly still guidelines that we need to approach and think about when thinking about populations of people who have epilepsy as a whole. I think that what's interesting in the field of epilepsy is that we still don't have as much consensus as I think we could on the best way to treat, for example, a drug-resistant patient with epilepsy. One of, I think, the biggest areas of opportunity in terms of personalized medicine as we move forward is that there's such variability on patient care based on the epilepsy center, the tools that we have on how to treat these patients. And I think an aspiration is for us to, in the future, be able to see a patient who has seizures or a person who has seizures, maybe put an FDA-approved device, as Dan Friedman talks about in his article, to help detect the seizures.

Use AI with EEG to detect abnormalities in their studies. And then use imaging processing and genetic or metabolic markers to really end up stratifying the risk and creating a treatment plan much akin to what's done in the world of cancer care. I think what's so exciting in epilepsy is that we have made so many advances in terms of our treatments, but I think there's so much to do to really stratify and personalize care for our patients that we really could take a lot of lessons from the world of cancer and in other fields of medicine to really be able to apply to our area of specialization.

Dr Jones: And I guess that's one of the common tensions in neurology---and medicine, really---is the pull between standardizing and protocolizing. And usually we do better when we're standardized in our care versus that personalization, doing the right thing for that individual person. And I guess expertise lies in the middle, which is why we want people to read these articles, right?

Dr Hopp: Exactly. I think you've hit the nail on the head, and I think the takeaway here is really that we need to do both. There's no question that we can't reinvent the wheel for every person who we see in the office who has epilepsy and not apply the knowledge that we've gained based on all of the research and work that's been done in the field of epilepsy. So, for example, we know that if someone is almost 25 years old, Quantum Brody published that shows that if someone does not respond to a few drugs, anti-seizure medicines, the likelihood that they're not going to respond, it is quite high. So, we need to apply data that we have to patients as a whole. But then, I think, what has changed and evolved over the past twenty-five years is our ability to potentially personalize some of that decision making. And that's where I think the field of epilepsy is right now, and hopefully where it's going to go in the next decade or so.

Dr Jones: So, what do you think the next big thing in epilepsy diagnosis or management will be?

Dr Hopp: I think that technology is really going to play a role. Technology, I think, will take many forms. We hear a little bit about some of the new advances in technology in several articles in this issue. One, for example, is in the ability to manage even emergent seizures or clusters of seizures in patients. The ability to provide a nasal spray that works very quickly is so different than the tools that we had to treat seizures even 10 years ago. I think that technology will likely thread through many different areas of epilepsy care, whether it's in the treatment and availability of different medications or in the ascertainment of epilepsy itself. I think that one of the very exciting areas in technology is in pharmacogenomics and genetics, which hopefully will allow us to close the gap in selecting one of the better medications or best medication for a patient earlier in their diagnosis and in their treatment plan. If we are able to get patients treated more quickly, whether it's with medication or in selection of the best surgical treatment, hopefully we will close the gap in reducing the possibility of drug resistant epilepsy, but also have impact in quality of life and getting patients and people with epilepsy and doing that, doing the things that they want to do such as driving, going to work, getting engaged in the things that make them happy. And so, I think our ability to use technology, whether it's in using a watch to make a diagnosis of seizures or pharmacogenomics to make a good medication selection, hopefully this will allow us to speed up our algorithm in making a diagnosis and getting an effective treatment plan for patients earlier. And ultimately that's our goal. Our goal for patients is ideally to have no seizures and no side effects with a good quality of life.

Dr Jones: Yeah, the technology has really been breathtaking. You know, one of the commonalities between your practice and my practice is electrophysiology. I do neuromuscular electrophysiology, which is much simpler than what you do with cerebral electrophysiology.

And whenever I sit down next to a colleague who is about to review forty-eight hours' worth of EEG recordings, I always think what a massive amount of data and I always feel sympathy for them. What, about AI? What about automated processing tools? Is that something that our listeners should look forward to in the future?

Dr Hopp: I think so. And I hope it's a blend. I hope that---and I always actually talk about this with trainees because I love EEG so much and I love translating the principles of physics and neurophysiology when we're sitting in front of an EEG with our trainees. I am excited about AI and technology. I will admit that I hope that it doesn't replace human readers because I do think that there is an importance in threading history and semiology and thoughtfulness in a human way with the interpretation of EEG. However, you're absolutely right that the amount of data is just becoming overwhelming for epileptologists and for EEG-ers to be able to synthesize in a reasonable and feasible amount of time. So, we already are seeing the applicability of the AI to, for example, prescreen large, large amounts of EEG data and try to at least give us tools for the ability to screen EEG in a more efficient way. I think some of the more exciting areas of EEG that are coming are in the background, which is in the network analysis in high-density EEG. There are very, very smart mathematicians that currently I'm collaborating with in utilizing network analysis of EEG that will hopefully allow us to apply these algorithms to EEGs that even look normal to the naked eye, but actually may have signals that help us predict who may or may not have seizures. I agree with you wholeheartedly. I think there's so much to come and our collaboration and integration with engineers and mathematicians, I think, is going to be paramount.

Dr Jones: Dr Hopp, what was your path to epilepsy?

Dr Hopp: Dr Jones, that is a great question. It was not linear and it really evolved over time, but basically went something like this. I majored in behavioral biology in college, and I was fascinated by the brain and how behavior was controlled by either physiology or anatomy or abnormalities in brain function. And as I moved along in my career and education, I really had a passion for neurology and for behavioral science. But I went to medical school and absolutely loved most of the rotations I did. And in fact, I loved OBGYN so much that I changed my entire career path with the goal of becoming an OBGYN and delivering babies. And I was really torn between two specialties of going into neurology or OB. And I went to a very sage advisor, Greg Kane up at Jefferson. And I said, I really don't know what field to go into. I love aspects of both. I like doing testing. I like making immediate impact. But I also love neurology. And he gave me some of the best advice, I think, that I have ever heard. And I try to share with our trainees all the time. He said, Jenny, I think you'll be successful at either, but which do you like reading about? And I had a relative epiphany at the time, and it was no question that I loved reading about neurology. It was very clear to me that reading about neurology and learning about the brain was just fascinating and led me to do a neurology residency where I was exposed to patients with epilepsy. And it really just continued to pique my interest to read about a field that I felt I could have such an impact. I really could help patients make a diagnosis relatively quickly and have a significant impact, maybe as I would in OBGYN but in a little bit different way. And it really has been, to me, the best choice that I could have made. And on a day-to-day basis, I still love reading about neurology. So, it was some of the best advice that I was given and I try to share that with others.

Dr Jones: What a great question for a mentor to ask. And I wonder if he was really thinking, if she likes to read, she probably should be a neurologist to begin with. You like to read, don't we?

Dr Hopp: I think so. I think he was spot on. I think he knew the answer before he asked the question.

Dr Jones: Dr Hopp, thank you for joining us today. Thank you for such a thorough and fantastic discussion on caring for patients with epilepsy and our recent issue on epilepsy for Continuum.

Dr Hopp: My pleasure. Thank you for having me.

Dr Jones: Again, we've been speaking with Dr Jennifer Hopp, guest editor of Continuum 's most recent issue on epilepsy. Please check it out. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.

Informal care partners are essential to the care of people living with dementia, but they often experience significant burden and receive minimal training, support, and resources. Multicomponent interventions can mitigate burden and other negative consequences of caregiving.

In this episode, Gordon Smith, MD, FAAN speaks with Angelina J. Polsinelli, PhD, ABPP-CN, author of the article "Care Partner Burden and Support Services in Dementia" in the Continuum® December 2024 Dementia issue.

Dr. Smith is a Continuum® Audio interviewer and professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.

Dr. Polsinelli is an assistant professor of clinical neurology at the Indiana University School of Medicine in Indianapolis, Indiana.

Additional Resources

Read the article: Care Partner Burden and Support Services in Dementia

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Host: @gordonsmithMD

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 Smith: This is Dr Gordon Smith. Today, I've got the great pleasure of interviewing Dr Angelina Polsinelli about her article on care partner burden and support services in dementia. This article appears in the December 2024 Continuum issue, which is on dementia. Ange, welcome to the podcast. And maybe you can begin by just introducing yourself to our audience?

Dr Polsinelli: Yeah. Well, thank you for having me. I'm very excited to be here. I'm Ange Polsinelli. I'm a neuropsychologist at Indiana University School of Medicine, where I work in the Department of Neurology. I also work with the Longitudinal Early Onset Alzheimer's Disease study that's led by Liana Apostolova. And I also do some work with the Outreach, Recruitment and Engagement Core of the Indiana Alzheimer's Disease Research Center. This topic that we're going to talk about today is extremely near and dear to my heart.

Dr Smith: Well, thanks for joining me. And of course, IU is a powerhouse for Alzheimer's and basketball, in that order. So, we're really excited to have you. I'd like to get right into it. I'll emphasize, we were chatting a little bit about this, Ange, before we started recording, that your topic today is so important for all of us. And I think, you know, this is a podcast that not only neurologists listen to, but students and, and I think increasingly members of the lay public. And this conversation is going to be very important for neurologists and our neurology learners. But I lost my grandmother to Alzheimer's disease. I lost my uncle just in the last week. So, this touches all of us. So, I'm really excited. And then with that in mind, I wanted to begin with a statistic that- you can correct me if I misunderstood it, but it really blew my mind. And that is across the world, as I understand it, care partners provide one hundred and thirty three billion hours of care for people living with dementia yearly, which is pretty staggering. But what's really amazing is that by 2030 that number is expected to go to one point four trillion hours, which I couldn't grab my mind around it. So, I figured I'd try and determine how many years of person work is that and if my math is right, that's almost a hundred and sixty million person years of worth caring for people with dementia yearly across the world. One, are those numbers right? Did I get it right? And then, assuming so, can you put a human face or experience to these numbers?

Dr Polsinelli: Yeah, unfortunately those numbers are correct. And with our increasing aging population across the world, that's why you're getting that, you know, exponential increase in care per hours, compounded by the fact that the majority of the caregiving that happens is not done by doctors, physicians, but it's done by these informal care partners, these family members, these friends, these siblings, children, who are providing these really important services and unfortunately not being trained to do this, doing it largely on their own in a lot of respect. But again, these are people who are loved ones of the person living with dementia. There are a variety of kinships, as I mentioned, siblings, children, spouses, friends; and all sorts of age ranges as well. A large majority of them being spouses, and then the second largest majority being children. So, kind of a sandwich generation of people who are caring for parents with Alzheimer's or dementia and then caring for children as well.

Dr Smith: Yeah, I was actually struck by the statistic that a quarter of caregivers or so called sandwich caregivers; in other words, they're taking care of a parent and a child. But listen to what you said. But just to call it out, two-thirds of care partners are women, which is a striking statistic.

Dr Polsinelli: Absolutely. Women are not only more likely to have dementia, but they are also more likely to be the care partners of somebody who has dementia. And so, the research shows, too, that if you're a care partner, you're at higher risk of developing dementia yourself. So, there's a lot of risk for women when it comes to dementia, development of dementia, but also that the burden and the majority of care needs that are that are supported by women as well.

Dr Smith: Right. And there's a lot to unpack in that observation, and maybe we can come back to that. But I wonder if you might talk to us a little bit about the risk of dementia in women caregivers. That's really striking. Is there any thought regarding mechanism for that? Why is that the case? Is it a shared risk factor? Is it cause and effect? What's the story?

Dr Polsinelli: So, there are - this is kind of a dissociable or different - kind of two aspects to this, this question. There's the fact that women are at higher risk for developing dementia in general. I think the researchers feel sort of out about why exactly that is. It's not just that women are at higher risk or more likely to develop dementia because they're living longer than men, but there's probably some hormonal aspects of their higher risk factor for dementia. But then there's the other aspect of it too, is that as caregivers, caregivers are at higher risk of developing dementia. And because caregivers tend to be women, that increases or compounds the risk for women as well. We know with caregiving, particularly with someone who's living with dementia, there's more risk of developing things like depression, high stress, health problems, psychological distress, and all of these things increase somebody 's risk for developing dementia as well.

Dr Smith: So, I wonder if you might talk a little more, Ange, about what you mean by burden? I think we have in our mind what that is. But in reading your article, there's a lot of- a lot more to it than may meet the eye.

Dr Polsinelli: Yeah, it is a more complicated, I guess, topic or terminology that's gone through several iterations over the course of doing research into burden. But when we think about burden, it's really a kind of a combination of both objective experiences and subjective experiences. And these objective, subjective experiences fall into the categories of physical burden, emotional burden, psychological burden. So, there's a lot of different areas of life in which someone can experience burden. But really, it's a combination of factors of both the objective experience, lived experience, and the person 's perception of that experience or what they're dealing with. I should also mention that it appears to be more of that subjective experience or that perception that people have of their objective experience of stressors or burden. That really does determine the person's response to that, if whether they actually perceive their lived experience as being burdensome.

Dr Smith: One of the things I found really interesting was the societal and cultural context surrounding this, that there are different cultural expectations and societal dynamics, both in the nature of the burden care partners may feel and how they're viewed. I wonder if you could talk about that? I think it's something that it would seem all of us need to be attuned to as we're working with our patients and their families.

Dr Polsinelli: Yeah, this is a topic we could talk for a very long time on. I will try and- I will try not to kind of provide too much of a, or too lengthy of a response. But what we know now is basically that our models of stress and burden that we have typically used or historically used do not incorporate a lot of factors of cultural identity of social and structural determinants of health factors. And so, what we understand now is that stress and the way that people perceive burden is influenced by so many other factors than just kind of an experience and a perception. Because that perception is influenced by so many factors, including, as you mentioned, cultural factors that include how society's familial expectations for us, cultural expectations for us, as well as what our resources are that are determined by, again, structural and social determinants of health, what our community resources are. They're just a lot of different factors that go into how somebody perceives their ability to cope with, again, this kind of life-altering diagnosis that their loved one has received and them being the person who is caring for them through that.

Dr Smith: Your article actually goes through in some detail the types of burdens and what drives the burden. And that changes over time. And so I wonder if maybe you can talk a little bit about what the specific natures of the burden are from the caregiver perspective. I mean, what sort of tasks there are, you know, from the many of us who take care of patients, we still don't know unless we've been in the room or in the home watching this happen. So maybe you can describe that for those of our listeners who maybe haven't lived through this?

Dr Polsinelli: Yeah, absolutely. I will say upfront that the caregiving experience is going to be different for every single person. And again, kind of dependent on some of those factors that I mentioned before. So, it's going to look different for most people. It's also going to look different through the dementia journeys. The experiences and the requirements earlier on in dementia are going to be a vastly different than what occurs later on when dementia is in the more late stage, moderate or severe stages of the disease. Those care responsibilities absolutely change over the spectrum of that time as well. We know that early on the stage of disease, primary care partner might be spending forty plus hours a day. So, a full-time- or not a day. I'm sorry, a week. So, a full time job carrying it. But that number increases up to a hundred and fifty or so hours per week once the person is more advanced in their disease. So, I say that because the number of hours, I think, make all, like- putting that into perspective of somebody having a full time, multiple full time jobs, basically providing care, I think is really important. But the responsibilities of the care partner are going to range from everything from just helping the person early on in terms of managing finances or managing them, making sure they're reminding them to take their medications, scheduling their medical appointments for them, maybe taking over all of the driving to get them to their appointments or to get them to family outings and things like that. They're going to be the ones that's going to be the most responsible for reminding people to do something: to eat, to maybe stay on track for a recipe or something that they are making. So, kind of being the eyes and ears for this person right away, basically right at the beginning, even early stages. And then that progresses over time to the person who is caregiving, who is doing potentially everything for this person. So that means helping them use the restroom when they need to, helping them shower. So, there's a physical component to the caregiving as well as that- sort of what we call instrumental support in terms of organizing medical appointments and things like that. They're just basically doing it all for that person.

Dr Smith: So, what about a busy clinician who has half an hour to see a dementia patient follow up? Kind of hard to- in these days, you know, we've got, you know, these new therapies to think about as well. What advice do you have to neurologists and other professionals caring for patients?

Dr Polsinelli: Yeah. And I think neurologists, I mean, we all have limited time. And I know neurology in particular is like primary care, has even more constrained time. I think one of the biggest things that neurologists can do is really check in with the care partner. So, take a moment to check in with the care partner who's there with the person with dementia to see how are they doing. You're looking for signs of burden or stress, so things like physical complaints like headaches or stomach ache, mentioning feeling burnt out or overwhelmed, maybe feeling depressed or something like that. There's also some short kind of questionnaires that you could give care partners prior to an appointment that they could fill out. You could kind of get a sense of where is this person at this point and then help connect them potentially to some resources that might be available. And I would refer people to that article that has a list of resources in there that you could just basically print out and give to somebody.

Dr Smith: Yeah, I was going to make the same point, Ange. Your article is a treasure trove of information. And you know, I'm certainly, I keep all of these on file, as you might imagine, but I'm keeping it in hand for future use. One of the things you talk about that really hit home for me among many is the idea of self-care, and I think sometimes the best care partners are susceptible to burnout because they they're so dedicated. You made the airplane oxygen mask metaphor, which I love. So maybe you can talk about what airplane oxygen masks have to do with dementia care and what advice you have for us and helping our patient's care partners take care of themselves?

Dr Polsinelli: Yeah, absolutely. Self-care is the number one thing I tell care partners to do. It's also one of the hardest things for care partners to do. Like you mentioned, there is a deep, generally speaking, a deep love and caring for the person with who is living with dementia. And the focus becomes on them. And understandably so, the care partners sort of loses focus on themselves and making sure that they're doing okay. So I oftentimes use this oxygen airplane metaphor for people, which is basically, you know, when you're in an airplane and if there's some kind of pressure change in an airplane, they always tell you, put your oxygen mask on first before you help somebody else because you're not going to be any good to anybody if you're passed out. In the airplanes, the pressure changes, you know. You need to be available. you need to be getting what you need in order to help somebody else. So, I think that metaphor, that analogy really works well in dementia care is you need to be- the care partner needs to be caring for themselves and replenishing themselves in order to be the best care partner they can be for their loved one.

Dr Smith: Another challenge that, it strikes me as shared between people living with dementia and their care partner is that of social isolation and loneliness, right? If you're working a hundred and fifty hours a week doing anything, you don't have time to care for yourself or very hard to engage in social connections. And one of the loud messages I think I heard from your article is the power of social connectedness, both in terms of resilience and in many different ways. I wonder if you can talk a little bit about loneliness? And I just reflect that in a postpandemic world, this is probably a bigger issue than it was four years ago or four years and three months ago.

Dr Polsinelli: Yeah, absolutely. Loneliness and social isolation was a big problem before, and it's even worse now is when I'm hearing from my patients. What I'm seeing in the literature is this postpandemic time is even more has been even more isolating and more problematic for people, but this social network cannot be, as you said, it cannot be overstated in terms of the importance for people. So that social network is important for not only providing potential instrumental care - so that practically care that care partners can use can lean on other people to come into the home to do things for the person living with dementia so the care partner can go practice self-care or go do those errands that need to be done - but also the emotional support as well that social networks can provide for people. And also, you know, social networks for not just the person, the care partner, but for the person living with dementia as well. We know that social engagement in particular is really good for brain health. I mean, we don't think about it, but social engagement is a very cognitive activity. And so, it helps give the brain a bit of a workout. So that social network is important for a lot of different reasons, and understandably a lot harder to maintain in this sort of postpandemic world as well.

Dr Smith: As our time starts to come to- close to a close, we're not done yet, but I think we're probably going to have to start winding up. I wonder if we could pivot to something positive and then talk about the joy in this. And by that, I mean you describe and I think we've witnessed relationships and caring, caregiving situations that, as challenging as they are, provides fulfillment and the connection one has with a loved one or sort of that social aspect. Are there things that- predictive of that kind of positivity, and are there ways that we as professional caregivers for patients and their families can facilitate that?

Dr Polsinelli: Yeah, there are. There are a couple of things. So, one of which is basically the quality of relationship between the care partner and the person living with dementia already. So that's the quality of that relationship. The better the quality of that relationship, the more likely it is that the care partner will experience more meaning and fulfillment and joy associated with caregiving, kind of outweighing that burden. But the additional piece of that is the more resources, the more mastery they feel about their caregiving or care partnering abilities, the more competent they feel and their ability to do good by the person, their loved one, the person living with dementia, the more likely they are to find that role fulfilling and meaningful. And I think that's where neurologists and other providers can kind of come in as helping people make sure that they have those resources that they are connecting to places where they can learn skills for giving appropriate care so that they can feel confident in what they're doing. There's the preexisting relationship piece that matters a lot. But I think that there's a lot of modifiability that neurologists have, too, in making a positive impact on the care partner and the person living with dementia.

Dr Smith: That's really great advice, Ange. And I definitely will refer our listeners yet again to your article, which is a compendium of useful advice about this, both in terms of the text itself and in tables that provide lists of resources, websites, books, organizations, good case examples. It's a home run and I hope all of our listeners check it out. I'd like to wind up by talking a little bit about your work. And as I understand it, you obviously are very passionate about this topic, but you have specific interests in caregiver burden and underserved and marginalized communities. And then, we've touched on this, but this is a huge percentage of our population. And when you look out globally, it's even bigger than that. Tell us about what you're working on. And then maybe following that, what's the future look like? Where are we going to see advances in this in the coming years?

Dr Polsinelli: So just a really quick kind of brief history is that I've worked in dementia for almost twenty years or so now. And what I've consistently seen is when you give care partners good supports and education and resources, there are better outcomes for them and their families. The unfortunate thing is, a lot of these really great interventions and things that we have are not necessarily really accessible by a lot of people, but particularly not accessible by those living in underserved communities. The last few years in particular, I've really shifted into wanting to better understand that and better understand how do we provide culturally and socially appropriate interventions and education for these care partners and their families. With the current research project that I'm working on, we're looking at better understanding the needs of care partners of people who have early onset Alzheimer's disease, specifically from Black and African American individuals and other underrepresented groups. Again, the idea of this is to understand the needs before building an intervention for these groups, and I'm very excited about it. I know that there are lots of really great people who are working in this area, including Dr Dilworth Anderson and Kalisha Bonds Johnson, doing really fabulous work in this area. So, and building on what they're doing as well. In terms of what the future holds, one, I think we absolutely need to, we have lots of really great care partner interventions out there that have been lots of research going on, but it's not really transitioning into the clinical sphere. It's really kind of staying in that research sphere. So, I think it's really important that we get some implementation scientists who are taking those interventions and moving them into the clinical sphere, into the sort of like everyday, how do these actually work for people sphere. And then similar to some of this conversation we're having in terms of serving, making sure our interventions and making sure that our resources are appropriate and accessible for underserved communities, we really need to be taking a look at what these communities need rather than kind of saying, this is what's available. Kind of, hopefully this works for you. Speaking with these communities, engaging stakeholders and understanding what are the needs in these groups so that we can provide the appropriate resources, the appropriate interventions, the appropriate supports for care partners and people living with dementia.

Dr Smith: And I'm just thinking, imagine what this looks like with effective treatments for Alzheimer's disease, that slow progression. And you know, that's going to make the caregiving even more important, it seems to me. But there's an opportunity to make it a better rewarding and a better-supported system as we develop these new therapies. So, this is a, like a Clarion call for learners listening that they should all become dementia neurologists and neuropsychologists like here. Thank you. That was outstanding. Say, Ange, I want to thank you a lot for a really engaging conversation. This fulfilled every hope I had coming into it. I was really excited to talk to you. I always love talking to neuropsychologists, but I think again, this is really useful for neurologists, learners, people who are nonneurologists everyone. And so, thank you very much. I've learned a lot and I really would encourage everyone to check out the article.

Dr Polsinelli: Well, thank you so much for having me on and giving me the opportunity to talk about the stuff that is really important to me and, I think, to most of us out there. So, hopefully people find the article and the resources in there useful and, and thanks again for having me.

Dr Smith: I'm sure they will. Again, today I've been interviewing Dr Angelina Polsinelli, whose article on care partner burden and support service in dementia appears in the most recent issue of Continuum, which is on dementia. Be sure to check out Continuum audio episodes from this and other issues. And thanks to you, our listeners, for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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

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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 what is available to our patients.

Dr Geldmacher: Sure. And the development of anti-amyloid therapies goes all the way back to 1999. So, it's a pretty long course to get us to where we are today.

Dr Monteith: Yeah, that's why we limited that.

Dr Geldmacher: With that first approved agent with aducanumab in 2021, it received a limited or accelerated approval in FDA parlance. These agents, the aducanumab, lecanemab and donanemab, all approved, are known to remove amyloid pathology from the brain as measured by CSF and/or BIPET. They are amyloid lowering therapies, often called disease-modifying therapies. And across the agents there's some variable results. But if we look at the two with full approval, lecanemab and donanemab, they slow clinical progression by 25% to 35% on average. And that's measured by either cognitive measures or global measures or composite measures, but it's pretty consistent in that range of about one-third slowing. That makes it really difficult to discern in an individual patient, though, because there's so much variability in the progression of the disease already that it can be difficult to tell in one person that these drugs are working. They're also complex to use, so there's a qualification process that involves MRI to exclude things like a high tendency toward hemorrhage. It includes genetic testing for papal E4 status to help us understand the risk for complication, and then once-monthly or twice-monthly infusions with standardized schedule for MRI scanning. So, there's a lot that goes into managing these agents. And they are expensive, and we don't yet know their cost effectiveness. The cost effectiveness of the cholinesterase inhibitors was questioned when they first came out back in the 1990s, and it took five or ten years to really understand that they provided benefit to society and to individuals in those domains of quality of life and return on investment. And we're still learning about that with the disease modifying therapies.

Dr Monteith: So, two questions. One, the case that you presented was an individual having symptoms and kind of voiced their desire to be on these therapies. So, people are going to be asking, coming to clinic asking and then of course, they're going to be people that you select out. So, how do you make that decision to recommend this treatment for patients given the potential risk?

Dr Geldmacher: We've got some really good guidance from appropriate use recommendation papers for aducanumab and lecanemab, and I'm expecting one from donanemab fairly soon. But the key is to identify individualized risks, and that involves knowing their APOE4 status, knowing their- whether they've had microhemorrhages in the brain previously, and then documenting that they really do have amyloid pathology with something like PET scan to establish those baselines. I talk to people about the burden of twice-monthly infusions or, now with donanemab, once-monthly infusions. And for instance, for someone who's got a working caregiver, getting to an infusion center twice a month can be a significant burden. And then if there are complications, frequent MRI scans and so forth. So, we talk about the burden of entering into this therapeutic pathway. The reality is that people who are qualified generally want it. I have relatively few folks who have said, no, these risks are more than I'm willing to accept. For decades my patients have said, anything you can do to slow this down, I'm willing to try. And now we're seeing that translated to reality with people willing to accept high-risk, high-cost treatments with the chance of slowing their individual progression.

Dr Monteith: And how do you select between the two treatments?

Dr Geldmacher: So far that's been easy because donanemab's not readily available.

Dr Monteith: Outside of clinical trials, right?

Dr Geldmacher: Exactly. For prescription use, it's coming in - the first cases have now been infused - but it's not generally available. Nonetheless, what I will do for patients in this is look at the risk tables. So donanemab appears to have in general some higher rates of the Aria complications, amyloid-related imaging anomalies, and some people are going to be more risk tolerant of that for the payoff of potentially faster response. The donanemab trials restructured that. They did their first assessment of effectiveness. I had amyloid removal at six months and a significant proportion of people were eligible to discontinue treatment at six months because their amyloid was below treatable thresholds. So higher risk, perhaps faster action and fewer infusions for donanemab. Lecanemab we have more direct experience with, and between the two of them, the eighteen month outcomes are pretty much the same and indistinguishable. So are we in it for a quick hit, or are we in it for the long race? And different patients and different families will have differing opinions on where they want to accept that risk and burden and so forth. But so far, the data don't indicate a lot of difference in their longer-term outcomes. We still have plenty to learn.

Dr Monteith: And so, it sounds like, as you mentioned, we're looking at eighteen months out for kind of a hard outcome, and that there is a lot of variability in response rate. How are you tracking patients- you know about the imaging, so just in terms of clinical outcomes and efficacy?

Dr Geldmacher: Sure. So, for Medicare to reimburse on these treatments, people need to be enrolled in a registry program - and there are several of these, CMS runs one of their own. But the requirement for that is, every six months, to do cognitive and functional outcomes through the first two years. Cognitive outcomes are up to the clinician, but things like the mini mental state exam, the MoCA, are appropriate. In our own program, we use something we developed locally called the Alabama Brief Cognitive Screener. As for the cognitive outcomes and then for functional, we use an instrument called the General Activities of Daily Living Scale, but there are many other ADL scales that could be used as well. CMS does not mandate specific tests. Since the progression of the disease is variable to begin with, we don't really know how to interpret these results in reference to whether the drug is working, but I can tell a patient or a family member, your scores are stable, or, you have a decline of three points in this test. That's typical for this duration of illness. But there isn't a good way to know whether the drug is working in this person at this time, at least with our current levels of data.

Dr Monteith: So, I think we have to talk about health equity, and it sounds like Medicare is reimbursing for some of us. We look at different socioeconomic backgrounds, educational backgrounds, race, ethnicity. Not everyone is aware of these treatments. So, how do we get more patients to become aware of these treatments? And how do we get them to more people to help people?

Dr Geldmacher: Yeah, I mean, that's- it's a major, major issue of inequity in our population. We've done some work at UAB looking at the flow of members of minority communities into memory clinics. So, we know that the overall population of, and I'll choose, for an example, blacks and African Americans, that they are represented a much higher rate in our overall UAB treatment population than they are in our memory clinic population. So, they're not even getting to us in the specialty clinic at the same rates as other segments of our population. We also know that blacks and African Americans in our population are not receiving PET scans as often as the overall treatment population. So yes, there are real, real problems with access. There are cultural issues behind this as well. And in many communities, a change in cognition, a loss of memory is an expected part of the aging process rather than recognized as a disease. So, people who come to us from minority communities are often further along in the course of cognitive and functional decline and beyond the point where they might qualify for the disease-modifying therapies, where early AD is the sort of defining boundary. So, I think more awareness and more screening in primary care settings, perhaps more community outreach to let people know that changes in memory that affect daily function are not normal as part of the aging process and should be evaluated for intervention. So, there's lots of places in our healthcare community where we could foster better outreach, better knowledge to get more folks access to the medicines. And this is before we even get to cost.

Dr Monteith: Yeah, yeah. And obviously, there's some stigma as well.

Dr Geldmacher: That's right.

Dr Monteith: Really recognizing what the issues are and diving and asking those questions and funding research that asks those questions, as you mentioned, is really important. And then you have also a nice area where, you know, looking on the impact of treatments on caregiver-related outcomes, and of course ultimately want to keep patients out of nursing homes and prevent death. And so, can you talk a little bit about that? And, you know, mainly the caregiver burden.

Dr Geldmacher: So, my research in that area goes back a long way now. But I learned early in the course of therapy that many times the outcome that the family is noticing for symptomatic therapies is not a change in the patient's memory per se, but that there is less work involved in the caregiving. Less time is spent in direct caregiving roles. The patient may shadow less and because they have better independent cognition. I remember one family member once told me, the medicine you started is a godsend because now I can go to the bathroom by myself and he's not pounding on the door saying where are you, where are you. He's able to recall long enough that I'm in the bathroom that I have that moment of privacy. That was very meaningful to me to hear that. So.

Dr Monteith: Cool. So why don't you just help us wrap this up and just give us, like, three main takeaway points that we should be getting out of your article?

Dr Geldmacher: The three points that I would emphasize from my article is that the symptomatic therapies provide meaningful benefits and measurable, consistent, meaningful benefits. The second is that those benefits extend beyond things like cognitive test scores and into things like caregiver well-being and maintenance of independence in the home environment. And the third is that the disease-modifying therapies are an exciting opportunity to modify the pathology, but we still are learning about their cost effectiveness and their long-term benefit both to individuals and to society. But the only way we're going to learn that is by using them. And that was the experience that we gained from the symptomatic therapies that took use in the community for years before we really began to understand their true value.

Dr Monteith: Thank you. That was excellent. And I put you on the spot, too.

Dr Geldmacher: No problem.

Dr Monteith: Again, today I've been interviewing Dr David Geldmacher, whose article on treatment of Alzheimer's disease appears in the most recent issue of Continuum on Dementia. Be sure to check out Continuum audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at contentpub.com/AudioCME. Thank you for listening to Continuum Audio.

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 care doctors who are usually the first go-to person. And perhaps biomarker testing will become much more common even in the primary care setting. I think overall, you know, we can tackle it by educating the community, empowering participants in various clinical trials, and being flexible of embracing certain new technologies.

Dr Grouse: Absolutely. I think that makes a lot of sense and hopefully this will be another call to arms to try to get the word out, get more access to neurology and more people interested and like you said, getting our other colleagues involved and being able to manage it as well.

Dr Scholz: Yeah.

Dr Grouse: I wanted to transition a little bit into learning more about you. How did you become interested in genetics of neurodegenerative dementias?

Dr Scholz: Yeah, it's something, it's an interest that has grown gradually. I started out as a neuroscientist in in Austria, where I was fortunate to work with a group that was very strongly involved in Parkinson's disease care. And I was so thrilled to see patients, you know, treated with deep brain stimulation. But yet in the same clinic, I also saw the patients who were not eligible because they had atypical neurodegenerative diseases. And it's the realization that there is such a broad spectrum of diseases that we frankly don't understand very well, that we really need to work with, understand and hopefully develop the treatments with. That's really has resonated with me. And I've since then really built my entire career around it through different countries at the United Kingdom and the United States. And I'm very fortunate to work at the National Institutes of Health, where I can pursue a lot of these research passions and work with interesting patients and colleagues.

Dr Grouse: Well, I've learned a lot today, and I'm sure our listeners would agree. Thank you so much for joining us. It's really been a pleasure speaking with you.

Dr Scholz: Well, thank you so much for allowing me to contribute. And, you know, I hope the review article conveys a lot of the exciting developments in this really challenging field. But there's loads of hope that we will eventually get to the point to tackle these conditions.

Dr Grouse: I encourage all of our listeners to check out Dr Scholz 's article. It is a great overview of these conditions and the genetics and neuropathology underlining them. Again, thank you so much.

Dr Scholz: Thank you for having me.

Dr Grouse: Again, today I've been interviewing Dr Sonia Scholz, whose article on genetics and neuropathology of neurodegenerative dementias appears in the most recent issue of Continuum on dementia. Be sure to check out Continuum audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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

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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 taps and that sort of thing. I hope that all comes to pass. And I do think that there is a lot of research underway looking at biomarkers in a novel way that I think could help point us to new targets for therapy, things that you and I haven't even thought of yet. Those are the two things. I guess you asked me for one, I gave you two.

Dr Weathers: Oh I think very fair. I agree. Both of those would certainly be wonderful and, and I'm excited as well. Well, thank you, Dr Quinn, for taking the time to speak with me this evening.

Dr Quinn: A pleasure. Thank you for having me. Thank you for inviting me to do the piece. It was really a great experience.

Dr Weathers: Again, today I've been interviewing Dr Joseph Quinn, who's written with Doctor Nora Gray on fluid biomarkers and dementia diagnosis. This article appears in the December 2024 Continuum issue on Dementia. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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

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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 modifications, adaptations in your day-to-day and maybe medications to keep them as mild and as slow-changing as possible. With something like LATE, we don't have specific medication therapies to help support cognitive functioning at this time. There's a lot of hope that with additional research we will have those therapies. But even so, I think it's an important moment to emphasize some of those good healthy lifestyle habits. Staying mentally, socially and physically active, getting a good night's sleep, eating a healthy, balanced diet, keeping good control of vascular risk factors, all of that is critical to keeping the brain healthy, keeping the degenerative disease as mild and slow-brewing as possible. And understanding what some of the symptoms to expect could be. So, with LATE the syndrome tends to be very memory-predominant. There may be some trouble with maybe naming of objects or perhaps recall of emotionally salient historical knowledge, world events, but you're not expecting, at least over the short to medium term, huge intervening on other cognitive functioning. And so that can be helpful for patients to understand. So, the hope is once you know what what you're dealing with, you understand that the disease can look different from person to person. Having a general map of what to expect and what you can do to keep it in check, I think, is the goal.

Dr Nevel: I agree with you 100% that it really can be helpful even if we can't, quote unquote, fix it, that for people, family, the patient have a name for what they have and kind of have some sort of idea of what to expect in the future. And they may come in thinking that they have Alzheimer's or something like that. And then, so, to get that information that this is going to be a little different, we expect this to go a little bit differently then it would if you had a diagnosis of Alzheimer's, I can see how that would be really helpful for people.

Dr Ramanan: I completely agree. And here's another challenge for us in the field when most patients have heard about Alzheimer's disease and many have perhaps even heard of dementia with Lewy bodies or frontotemporal dementia, but may not have heard of things like LATE. And they're not always easy to go online or find books that talk about these things. Having a name for it and being able to pair that with patient-friendly information is really critical. I see our appointments where we're sharing those diagnosis and making initial game plans as an initial foray into that process.

Dr Nevel: Yeah, absolutely. What is the greatest inequity or disparity that you see in taking care of patients with progressive amnestic cognitive impairment?

Dr Ramanan: Yeah, great question. I think two big things come to mind. The first, you hinted at very well earlier that there are disparities in access to care, access to diagnostic testing, access to specialists and expertise throughout our communities. If we want diagnostics and therapeutics to be broadly applicable, they do need to be broadly available. And that's a big challenge for us as a field to work to address those disparities. There's not going to be one single cause or contributor to those iniquities, but as a field, I'm heartened to see thought and investment into trying to better address those. Another big weakness, and this is not just limited to cognitive neurology, it's a challenge throughout neurology, is that too many of our research studies are lacking in diversity. And that impacts our biological and pathophysiological understanding of these disorders. It also impacts our counseling and management. Again, if we want a new drug treatment to be broadly applicable throughout all of the patients that we take care of, we need to have data which guides how we apply those treatments. And so again, I'm heartened. This is a big challenge. It's a long standing challenge. It will take deep and long standing committed efforts to reverse. But I'm heartened that there are efforts in the field to broaden clinical trial enrollment, broaden observational research enrollment, and again, broaden access to tools and expertise. As a neurologist, I got into this field because I want to help people, use my expertise and my training to help people. These are steps that we can take to make sure that that help is broadly applicable throughout everybody in our communities.

Dr Nevel: Yeah, absolutely. So, kind of segueing from you mentioning research and how we can better include patients in research. What do you think the next breakthrough is going to be? What do you think the next big thing is going to be in these disorders? What do we still need to learn?

Dr Ramanan: There's a lot. I think for LATE and PART, the development of specific biomarkers would be top of the agenda. Now, biomarkers are by their nature imperfect. Even with Alzheimer's disease, where in comparison, we know quite a lot. We have a variety of imaging and fluid biomarkers that we can use to support or rule out a diagnosis. There are nuances in how you interpret those biomarkers. Patients can have signs of amyloid plaques in their brain and have completely normal cognition. They may be at risk for developing cognitive trouble due to Alzheimer's disease in the future, but it's one piece of the puzzle. Patients can have the changes of Alzheimer's disease amyloid plaques and tau tangles in the brain. We can confirm that through biomarkers. But at the end of the day, their cognitive syndrome might be driven by something else. Maybe it's Lewy body disease, maybe it's LATE, maybe it's a combination of factors. So, integrating and interpreting those biomarkers is challenging. But I do think, again, from the standpoint of giving patients answers with a diagnosis, having those biomarkers is really critical to just kind of closing the loop. It will also be critical to have those biomarkers as we're assessing for treatment response. So, for example, patients who may have coexistent Alzheimer's disease and LATE, I don't think we know the answer fully as to how likely they are to benefit from, say, newer antiamyloid monoclonal antibodies for Alzheimer's disease in the setting of that second pathology. So, wouldn't it be great if, similar to an oncologic setting where you engage in a treatment and then you're tracking two or three or four plasma measures and you're tracking tumor size with imaging, if we had this multimodal ability to track neurodegenerative pathology through biomarkers? I think that'll be a critical next step. And so, filling out that for non-Alzheimer's diseases, including LATE and PART, I think is item number one on the agenda.

Dr Nevel: Wonderful, thank you so much. I really appreciate you taking the time to chat with me today about your article. I really enjoyed our conversation, certainly learned a lot.

Dr Ramanan: Thank you so much, Kait. Love talking with you. And again, it was an honor to write this article. I hope it's helpful to many out in the field who take care of patients with cognitive issues.

Dr Nevel: Yeah, I think it will be. So again, today I'm interviewing Dr Vijay Ramanan about his article that he wrote with Dr Jonathan Graff-Radford on LATE hippocampal sclerosis and primary age-related tauopathy, which appears in the most recent issue of Continuum on dementia. Be sure to check out Continuum audio episodes from this and other issues. And thank you, Vijay, and thank you to our listeners for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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.

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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 cognitive impairment. As these emerge, we'll be able to really identify those at greatest risk for vascular cognitive impairment, but also identify novel mechanisms that lead to VCI that can be targeted for therapeutic intervention.

Dr Grouse: Well, I'm really excited to see what's coming down the pipeline and what more we'll learn in this area. So, thank you so much for everything you've done to contribute to this field.

Dr Silbert: Yeah.

Dr Grouse: I wanted to ask a little bit more about you. What drew you to this work?

Dr Silbert: Well, actually, so my very first published manuscript in medical school was a case report and review on MELAS, which is mitochondrial encephalopathy with lactic acidosis and strokelike syndrome. And so, I was really fortunate to have Dr Jose Biller, who is a renowned expert in stroke and cerebrovascular disorders, as my mentor for that paper. And so, that got me really interested in neuroimaging findings of cerebral vascular disease. And so when I was a fellow at Oregon Health and Science University, I was then really fortunate to be able to work with Jeffrey Kaye's oldest old population. And in working with that population, I really became interested in their neuroimaging findings of these white matter lesions and just realizing how prevalent they were in that population, you know, it just led me to start investigating their clinical significance and etiology, which kind of led me along this path.

Dr Grouse: You know, Lisa, thank you so much. I really learned a lot from your article, and I think our listeners will definitely find that it was very helpful for their practice. Thank you so much for joining us.

Dr Silbert: Thank you so much, Katie. It's been really fun.

Dr Grouse: Again, today I've been interviewing Dr Lisa Silbert, whose article on vascular cognitive impairment appears in the most recent issue of Continuum on dementia. Be sure to check out Continuum audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.