Cerebral Small Vessel Disease with Dr. Andreas Charidimou

Discover the intricacies of small vessel ischemic disease and cerebral amyloid angiopathy (CAA) with expert neurologist Dr. Andreas Charidimou. 

We dive into the everyday challenges faced by primary care physicians interpreting MRI results, offering expertise on distinguishing small vessel disease from migraine and demyelinating conditions, all while emphasizing the importance of correlating clinical symptoms with imaging for accurate diagnoses.

Navigating cerebral amyloid angiopathy (CAA) diagnosis, this episode sheds light on the inadequacies of the Boston criteria and the quest for reliable biomarkers. As we explore the importance of accurate CAA identification in the era of anti-amyloid therapies, we also offer insights into managing the blurred lines between transient neurological episodes, TIAs, seizures, and amyloid spells, with a special focus on the role of imaging and the nuanced prescription of anti-epileptic drugs.

Dr. Andreas Charidimou is the recipient of the 2024 Michael S. Pessin Stroke Leadership Prize.

You can find him on X at @a_charidimou

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Transcript

Dr. Michael Kentris: 0:31

Hello and welcome back to the Neurotransmitters. I am your host, Dr. Michael Kentris, and I'm joined today for a very special treat with Dr Andreas Charidimou, a neurologist and researcher at Boston University Medical Center and Boston Veteran Center. Andreas, thank you so much for joining me today. I am really excited to pick your brain about a number of topics.

Dr. Andreas Charidimou: 0:54

Thank you so much, Michael, for the invitation. I'm also very excited talking with you this morning about small vessel disease, CAA and whatever else.

Dr. Michael Kentris: 1:03

Yes, now for those who aren't familiar, we've known each other for a while on X, formerly known as Twitter, and had the chance to meet in real life, as the older millennials say, at the Academy meeting this last year, but this is our first time to have a longer conversation about what I consider. You're the guy for cerebral amyloid angiopathy and do a lot of teaching online about different types of ischemic disease to the brain. So if you could just kind of for those who might be less familiar, when we're talking about small vessel ischemic disease and how that relates to kind of the development of brain pathology, if you had to give just the 50,000 foot view, how would you characterize it?

Dr. Andreas Charidimou: 1:47

Yeah, yeah, yeah, that's a good question actually. So I think we're all familiar with the large vessel disease ischemic strokes, for example, cortical infarcts, these kinds of things. However, there are small vessels in the brain and they're affected by different pathologies and the definition of how small a small vessel needs to be in order to be considered a small vessel is kind of a moving target. But in general we're talking about arterials and smaller, so 500 microns and smaller, and these small vessels that are affected by some pathologies were particularly prevalent. The first one is kind of vascular risk factors driven Diabetes. Have retention. The same way they can cause atherosclerosis In smaller vessels they call arterial sclerosis or lipolylosis.

Dr. Andreas Charidimou: 2:44

So it's kind of a vascular risk factor driven pathology. And the other pathology is what is called cerebral amyloid angiopathy, which is entirely different in a way, because its characteristics is amyloid beta deposition in these small vessels, especially in the cortex and the leptominages. So when we say small vessel disease, we kind of mean at the basic level these two pathologies. However, with all the advances on imaging, the term small vessel disease now applies to also imaging manifestations, Microbleeds, white matter, higher intensities, or it might apply to clinical syndromes, for example, like QNAR infarcts. So, yeah, the disease can be approached at three different intersecting levels which kind of reflect how the knowledge and technology progressed from pathology to imaging and then integration.

Dr. Michael Kentris: 3:42

Excellent, Thank you. And as we were talking about just before, we started recording my knowledge thanks to you and other kind of vascular neurologists in the last few years has really put cerebral amyloid kind of on the map for me. But before we get to that, I know a lot of times in a lot of parts of the country we have primary care physicians who maybe don't have neurologists immediately available. Maybe they've gotten MRI of the brain and it shows some bright spots or these T2 hyperintensities on the images and you get this report back from radiologist and it's like could be seen with migraines, stroke, demyelinating disease. So for those who aren't as familiar, how would you go about kind of differentiating these? Let's say that they're a particularly ambitious person and they open up the actual films themselves and they're looking at kind of the T2 flare. What are the characteristics that help us differentiate sort of small vessel disease from, say, like the typical migraine hyperintensities or kind of the UBOs or unidentified bright objects that we sometimes talk about?

Dr. Andreas Charidimou: 4:52

Yeah, that's a very pertinent question and this scenario often leads to many downstream extra tests which might be harmful for the patient. Absolutely. And I would say the first piece of information, even before opening the actual MRI, is the clinical context. It's different if you see these spots on a 20-year-old female patient versus a 75-year-old patient with hypertension. So the clinical context is very helpful in terms of the pre-test probability. For example, white matter spots in a 75-year-old, the probability of that being a demyelinating disease is very low, just based on that.

Dr. Andreas Charidimou: 5:34

So there are a few things that you can use in addition to the clinical context. I think the first one is the pattern Typically small vessel disease-associated bright spots on flare. They're often preventricular, they're just around the ventricles, which basically the reason is that those are very vulnerable regions in terms of perfusion. Or, in addition to that, they might have some small subcortical spots which are kind of widespread in the brain, but you don't really see the subcortical spots in isolation. That's the one thing. The second thing is basically, if you see white matter spots in areas you wouldn't typically expect, for example corpus callosum, typically in small vessel disease you don't get, at least in initial stages, white matter lesions there. If you see a predominant pattern affecting the temporal lobe for example, or around the basal ganglia. It should make you think of catacel. So they're all sort of information regarding the pattern of this and how they look on the MRI.

Dr. Andreas Charidimou: 6:53

The other thing I would add is how extensive they are. For example, many inflammatory or autoimmune conditions of the brain. They can cause edema and white matter spots. There are other ways to differentiate them, but to the eyes of a general practitioner they would look the same. So the extent, the symmetry, and when it comes to small vessel disease, sporadic small vessel disease the extent is often hard to judge because we don't have any normative data.

Dr. Andreas Charidimou: 7:28

When is white matter's hyperintensity too much for any given age? We don't have any normative data from healthy controls to compare. So yeah, the combination of clinical context makes you think the malenetic diseases or just associations with migraine that we typically see in these patients if they get a brain MRI, their pattern, their extent. And then you can also use other brain MRI sequences to characterize what travels along those white matter damage. For example, is it an area of gliosis actually, because the patient had an infarct? Is it a tumor with edema? So all of these they come into play. That's why usually the radiologists they give a huge list of differential. The CMOS manifestation does have a huge list of differential but taking into account the clinical context, the pattern and other sequences, you can nail down to maybe two or three differentials, which is already a great start.

Dr. Michael Kentris: 8:34

Excellent. No, that's super helpful. So kind of going from this small vessel. Ischemic disease and we touched on it just briefly earlier related to cerebral amyloid, which is, again, I consider you to be the person who's probably taught me the most about CAA in my short career, but we talked about the deposition and a lot of times tell me if this is wrong, how I characterize it when I'm talking to patients is it's almost like Alzheimer's of the blood vessels in the brain. Is that too simplistic? Am I being too simple? How would you say?

Dr. Andreas Charidimou: 9:17

No, actually, because I use the same kind of analogy when I explain this to patients. That is the Alzheimer's equivalent of the vessel. The only problem when using this equivalent is that the term Alzheimer's has a huge emotional load. True, true.

Dr. Michael Kentris: 9:38

That is a good point.

Dr. Andreas Charidimou: 9:40

But both conditions are like cousins in a way, because they're both characterized by amyloid deposition of different forms, one in the vessel, one in the parankima. But it is a good analogy to start.

Dr. Michael Kentris: 9:56

And so how would you like if you have someone? So, first of all, when should we start thinking about CAA as a potential diagnosis? What are the clinical events that bring it to the forefront of mind?

Dr. Andreas Charidimou: 10:11

Yeah. So first of all, caa is a very common pathology as we're growing older If we're lucky enough to live in our 80s or 90s most of us will have some degree of CAA and in most people probably doesn't cause any problem because it's very mild. Now when patients come to the hospital, the clinical syndrome associated with CA I think of them as stroke syndromes and memory clinic or cognitive syndromes. Among the stroke syndromes, the first one that was really characterized and is very well known is presentations with Lopar intracerebral hemorrhages, which in many elderly patients is due to CA plus or minus other exacerbating risk factors, blood pressure elevations and this sort of stuff. The second stroke syndrome is with acute convexal subarachnoid hemorrhage. You have an isolated subarachnoid hemorrhage in one of the cerebral convexities, in one or two of the sulci in the brain. Often these patients present with what is used to be called amyloid spells or transient focal neurological episodes. That we can discuss later if you want. What are their characteristics and how you should think about them. In my mind, acute convexal subarachnoid hemorrhage and amyloid spells are linked. The one is the acute imaging manifestation, the other is a clinical syndrome. Then, in terms of memory clinic presentations, ca can either present as a pure vascular cognitive impairment syndrome in patients that are very severely affected. But most often it presents as a co-pathology in patients with presumed Alzheimer's disease, louis-body dementia. You see stigmata of the disease on the brain MRI. In those patients that is a co-pathology.

Dr. Andreas Charidimou: 12:19

It's hard to characterize the contribution to specific cognitive domains. In those that is the primarily driving pathology. The cognitive syndrome is exactly that of the vascular type of cognitive impairment frontal, executive, visual, spatial would be like early affected. Then we have presentations, again acute, which do not fit with either. They fit with acute neurology and this is the CA related inflammation which is basically. It has a huge range but at its core is a syndrome of encephalitis type of presentation with a lot of confusion, seizures, cognitive impairment, and it can't be either very acute or it can be subtle and sub-acute. Within this context I consider ARIA amyloid related imaging abnormalities as one emerging clinical scenario where CA might be relevant. Basically, aria is the atrogenic CA related inflammation. It's in an oversimplification. This is what it is.

Dr. Michael Kentris: 13:26

Right, I know, with the advent of all of these anti-amyloid therapies that are coming to market for better or worse, I know there's still a lot of contested questions about how they're implemented and so forth. What role do you think there's like, perhaps undiagnosed or lurking in the background? This CAA aspect of Alzheimer's, potentially, or this co-pathology with Alzheimer's, is the driving force for why some patients develop ARIA and others do not.

Dr. Andreas Charidimou: 14:03

Yeah, I think that's the million dollar question. It's the core of the issue. As was discussing before, in the behavioral neurology world the CAA was neglected or it didn't have a primary role, but now it does have because it affects treatment decisions. We have limited pathological data. That's the problem with anti-amyloid treatment. But even with those limited data from three or four patients that actually died from ARIA, it seems like the primary pathology was destruction of the vessels, which vessels were heavily affected by amyloid deposition. It's some sort of autoimmune not autoimmune, sorry inflammatory reaction triggered by the anti-amyloid antibody within the vessel wall which has amyloid. So this makes me think that, probably underlying CAA in the brains of this patient, it is a real risk factor for developing ARIA. This is what all the trials and now the guidance that we have from FDA is trying to select.

Dr. Andreas Charidimou: 15:18

By saying that you shouldn't give any of these treatments in patients having four microblitz or more, the underlying idea is that you're trying to exclude patients that I mean. Why do they have microblitz? I'm talking about lower microblitz. Most likely is because of CAA. I don't believe hyper-tensive arteriopathy with deep microblitz poses any significant risk for ARIA. So you're trying to exclude patients who have very obvious and probably significant CAA, manifested as microblitz. But this is not enough, because that's only the tip of the iceberg.

Dr. Michael Kentris: 15:56

Right, I think back to the Boston 2.0 criteria, which you're one of the authors, I know. It's broken down into the definitive, probable possible so forth, but the definitive camp requires biopsy. You have to have tissue, which I imagine most people aren't lining up to have done.

Dr. Andreas Charidimou: 16:18

Yeah, I agree.

Dr. Michael Kentris: 16:22

So, in terms of the probable camp, how sensitive are these criteria in someone who maybe hasn't had a clinical that they're coming into the, let's say, the cognitive clinic, and maybe they have one or two low bar micro hemorrhages? They don't really meet the full criteria perhaps. How does our current understanding of making a diagnosis in someone who maybe just has a cognitive subtype and then risk stratifying them, or is that something that's still in flux?

Dr. Andreas Charidimou: 16:52

It's very much in flux but this gives a good opportunity to discuss about the structure of the Boston criteria and for important historical context. These criteria were drafted in the mid nineties as an effort to diagnose to diagnose CA related hemorrhage. They were never designed initially to capture CA pathology. They wanted to assign the probability of a low bar hemorrhage being due to CAA. So that's one thing. So they're very heavily drifted towards hemorrhagic presentations with micro bleeds and hemorrhages being the core of defining the categories in previous versions. Now the structure, as you alluded to the definite requiring pathology, probable and possible it reflects how all the criteria in the field of cognitive neurology was defined in the same time. Like you have definite, probable and possible for Louisbody dementia, for temporal dementia. So it was like a familiar way for clinicians maybe to think about the criteria.

Dr. Andreas Charidimou: 18:04

I personally think that this is outdated, at least for CA, because definite, you almost never have pathology. You wouldn't get a biopsy in any of these patients. Possible category is a very shaky category. The way I explained that is that it's a possible category for CA and a possible category for non-CA. I see that as like 50-50. The probable category is the one that we typically use. What we have done in the criteria is that we have expanded that category to include not only presentations with at least two hemorrhagic imaging markers, two micro bleeds or Ciderosis micro bleeds, but to be allowed to make the diagnosis when you have one of these hemorrhagic biomarkers plus one of the non-hemorrhagic biomarkers White matter, hyper intensity spots or peri vascular spaces in the cerebral white matter. In this way we try to expand the catch, especially for non-hemorrhagic presentations.

Dr. Andreas Charidimou: 19:07

Now, how good are they in the setting of memory clinic? The answer is that we don't know. We don't know how sensitive or how specific they are. We have some indirect data and some data that are under publication looking at different cohorts within the memory clinic or the general population, and the overarching conclusion is that the Boston criteria are not very good in diagnosing probable CA in the context of the memory clinic. They have low sensitivity and a bit higher specificity. So we're missing a lot of these patients Of note. I don't remember which conference was, but there was an abstract that they compare in a memory clinic how many patients can be diagnosed with possible or probable CA based on the old criteria and based on the new ones. And, if I remember correctly, based on the old criteria, they could make the diagnosis in around 15 or 20% of the patients, whereas with the new criteria they can diagnose possible or probable CA in up to 45% of the patients.

Dr. Michael Kentris: 20:27

Oh, that's quite high.

Dr. Andreas Charidimou: 20:29

Yeah, but it's more in line with what we know from pathological studies that in a memory clinic setting up to 40% of patients might have mild or moderate CA. So to wrap it up, is that just by saying it's an active field of research and we don't really know how good the Boston criteria are in this setting. Probably they're not as good as in a patient presenting with lower hemorrhages or convexel subarachnoid hemorrhage and I believe we need other markers and probably in some of what's different set of criteria. When we're publishing the paper, the focus and the material we had was primarily from hemorrhage presentations rather than memory clinics.

Dr. Michael Kentris: 21:20

I know to what you said earlier, these are obviously the small vessels that aren't imaged well on most of our conventional studies. Are there any either biomarkers or imaging markers that are currently being investigated that you think have promise?

Dr. Andreas Charidimou: 21:34

Yeah, in terms of non MRI markers, the two avenues of research that I have to say they have been stagnant for a long time, is amyloid PET and CSF biomarkers. Amyloid PET is a bit tricky because the amyloid, the radio tracers, they label both parenchymal and vascular amyloid. So a positive amyloid PET scan in the setting of a memory clinic, who knows? It's going to be parenchymal plugs plus or minus CAA, so you cannot really use it. There was the idea that maybe posterior predominance of amyloid pet binding might be more specific for CAA, Given that we know from pathology that CAA affects more posterior cortical regions. But the effect size of that association is very small and I'm not sure you can reliably detect that by negative eye on an amyloid pet.

Dr. Michael Kentris: 22:38

I wonder and maybe you know more about this, I think it back to my own training in epilepsy Do they ever do amyloid pet co-registration to MRI to see if it superimposes on areas with really confluence, white matter disease or anything like that? Does that have any correlation? I imagine someone has to have had to look into that in the past.

Dr. Andreas Charidimou: 23:00

Yeah, they have looked at that in relation to Loper microblitz and it was found that there is a shell of amyloid pet binding around microblitz of higher uptake For white matter damage. I don't think so. I don't think it was tested, but it's a good idea. The core registration.

Dr. Michael Kentris: 23:23

Yeah, I don't know it's really challenging. As far as the CSF biomarkers, is that fun to that neurofilament light chain family of investigation or something unique?

Dr. Andreas Charidimou: 23:37

Exactly. We need something unique CSF biomarkers. They offer the possibility of something unique. Of course you can measure T-Tau and P-Tau and all of those neurodegenerative biomarkers. But what might he support CA from other pathologies is the amyloid beta species. You can measure the CSF and characterize how high or lower the amyloid beta species In CA. Amyloid beta 40 is the species that presumably gets deposited in the vessel wall More than amyloid beta 42, which is the predominant amyloid beta species in amyloid plaques. On CSF, low levels of amyloid beta 40 and other amyloid beta species with less than 40 amino acids, so amyloid beta 38. They seem to have a great promise and a great discriminatory value in teasing apart CA versus Alzheimer disease.

Dr. Michael Kentris: 24:42

Interesting, yeah, yeah.

Dr. Andreas Charidimou: 24:46

Serum biomarkers. The Alzheimer disease field is moving into the serum biomarkers.

Dr. Michael Kentris: 24:55

Right? Yeah, because it goes back into that thing where, if we look at the incidence of Alzheimer's and, by association, the suspected co-incidence of things like CIA, how many of these people won just in terms of societal costs, getting lumbar punctures? The invasiveness of the tests A lot of these people are probably on antithrombotic therapies, maybe even anticoagulation. What's the risk of holding these for invasive procedure? It becomes this mounting, a logistical barrier to getting to a definitive diagnosis in people, a vast majority of people, yeah.

Dr. Andreas Charidimou: 25:34

I don't think you need to get a definite diagnosis in the overwhelming majority of people because the idea of diagnosis is only when it's going to change management, Right. Sometimes Good point you don't need to know all the definite co-pathologies in any given patient if it's not going to change the management or if it doesn't have any huge clinical relevance. Cas becoming very relevant because an accurate diagnosis in the memory clinic or in Alzheimer's disease it might actually be the decision point for patients getting anti-ameloid disease modifying treatments or not. Those are not the overwhelming majority of patients. There was a study from the Mayo Clinic memory service and they analyzed all their patients and they found out that about 5-10% would be eligible, using current eligibility criteria, to get anti-ameloid treatments In that fraction of patients. If we want to make anti-ameloid treatment safer, we need to improve our accuracy in diagnosing CA. Maybe in those patients a lumbar puncture might make sense and the risks and benefits.

Dr. Michael Kentris: 26:52

You probably know the numbers better than I do. If I remember right, it's around 20-ish percent of people who are qualified candidates for this have the risk for ARIA. Is that correct?

Dr. Andreas Charidimou: 27:04

So asymptomatic ARIA, just based on imaging, is about right between 15 and 20%, and then symptomatic ARIA is much lower, in the range of maybe 3-5%, but the asymptomatic ARIA the one. The little asterisk is that we don't really know what are the long-term consequences, because having more microblitz in the brain or more areas of white matter damage is not a good thing intuitively.

Dr. Michael Kentris: 27:35

Right, and I know I've seen some cognitive neurologists out there talking about like, at the end of these trials, total brain volume is diminished and all these other things you had mentioned, and it's like we really don't have the longitudinal data to say. What does that mean from a clinical perspective? And that's always a little nerve-wracking when we're talking about the risks and the cost and all those sorts of things.

Dr. Andreas Charidimou: 28:02

It is. It is Plus, we don't have long-term data to see if the curves, if the curves of benefits in those getting the treatment versus placebo they continue to diverge, or maybe after three, four years they have the exact same path, irrelevant of whether they got the drug or not. That's also a bit it's not satisfying.

Dr. Michael Kentris: 28:31

Right Right, I know there's, yeah, lots of debate, lots of hot takes out there online, and I'm certainly not an expert in that particular field, but it's always good to see that there is a robust discussion from both sides.

Dr. Andreas Charidimou: 28:47

Yeah, I think there is a robust discussion between people that they focus a lot on the benefit and people who focus a lot on the risk. In any case, at least LeCanema got FDA license. So you cannot take the clock back, but the debate is still relevant to make the treatment safer.

Dr. Michael Kentris: 29:09

Yeah, and just more of an opinion from you. If I remember right, I think the UK did not approve. I don't know if it was Adjoucanamab or one of the other anti-amyloid therapies, but I know in Europe there's been a lot more hesitancy towards the approval from the regulatory boards as far as these go. Yeah, does that speak to anything? Just maybe a difference in philosophy, or maybe a more stringent criteria in terms of showing benefit.

Dr. Andreas Charidimou: 29:41

It's pro, I'm not. I don't have inside information so I don't know for sure, absolutely I'm not going to hold you to it.

Dr. Andreas Charidimou: 29:48

But I think it's a combination of those two things. Maybe they're a bit more strict compared to the FDA and how they review all of these new treatments. Plus, maybe there is indeed a different philosophy In general. I notice in the US there is a tendency of having a pill or a drug for everything to fix everything. But when it comes to dementia, even in patients getting anti-amyloid treatments, there's a lot more that goes into the dementia care and how. At the end of the day, the question is is not how to remove the amyloid effectively, but the question for this patient is that how can they live a fruitful and a nice life despite having Alzheimer's? And maybe part of the story is removing the amyloid, but there are a lot more elements into it. So I'm not sure, and I think European boards are even more hesitant based on what happened with the AduGanum app. It was a big failure, I believe, in how the story evolved.

Dr. Michael Kentris: 31:02

Yeah, it definitely wasn't the thing that a lot of people were hoping for. I don't believe.

Dr. Andreas Charidimou: 31:07

Yeah, Having said that, I truly believe that, despite the failures in general in the Alzheimer's disease field, it's positive that we're moving towards more treatments, which means that the private sector and all the companies they have a very new interest in investigating a bit more in this disease and trying to find beneficial medications. Because when AduGanum app turned out to be very risky compared to the benefit, many people, especially companies, they started closing their neuroscience programs looking at dementia treatments. So in general, I think it's a positive step. The question is how we can make it safer and beneficial at the end of the day.

Dr. Michael Kentris: 31:59

Right? No, I think that's absolutely true. So I know we've kind of beaten the dementia horse for a while. But I work a lot in the hospital and something that always comes up we have these transient neurologic events or transient focal neurologic events, and I know the temptation for many of us, and maybe even more so for non-neurologists, is to call any transient neurologic event a TIA or a seizure. But it's probably accurate that there is something in between the two. Perhaps, and as we kind of hinted at earlier, they used to be called amyloid spells. A lot of my instructors are a little old-fashioned and so we would call anything that we weren't definitive was a seizure. It would be a spell which I know is not currently in vogue, but I have a certain historical fondness for it. But could you tell me a little bit about amyloid spells? When should we consider them? How do we go about proving them to the best of our ability?

Dr. Andreas Charidimou: 33:03

Yeah, this is when I came across patients with these symptoms. My PhD supervisor at the time, david Waring at UCL. He used these term amyloid spells. I'm like, oh, this sounds fascinating. It's a spell. Is it caused by amyloid? Why is it different to a TIA? So yeah, it's a very interesting question.

Dr. Andreas Charidimou: 33:28

The first step is to know, as you said, that not all transient episodes, transient symptoms in neurology are TIAs or focal seizures. They could be a number of things. They could be like a microenora, they could be functional symptoms, or they could be amyloid spells or CA related transient focal neurological episodes. So it's hard to make the diagnosis just clinically. The same way, it's hard to make the diagnosis of a TIA just clinically before you do brain imaging, I mean.

Dr. Andreas Charidimou: 34:04

But some of the indicators that maybe you're dealing with something that is not a TIA is, first of all, positive symptoms. Typically TIAs, they cause negative symptoms, so loss of function, upper extremity weakness or aphasia. The prototypical amyloid spell is a spell that involves migrating parashthesias from the arm up to the mouth, which resolves in a typical microdory fashion as well. So this is one indicator, although we now know that some amyloid spells, they have negative symptoms. So if you have this microdory positive nature. It should make you suspicious. But if you don't have it, it doesn't mean it's not an amyloid spell. Now, the other thing which is very atypical for a TIA is to have recurrent, stereotypical episodes of the exact same symptoms, exact same pattern. You don't get that with a TIA just because different areas are affected, depending on what's the mechanism of the TIA. You might have that with a focal seizure though. So again, none of these clinical indicators are very specific.

Dr. Andreas Charidimou: 35:24

The other indicator is when you have, let's say, transient neurological episodes in a patient without any vascular race factors, or in a patient that you have excluded carotid stenosis and any other sources of emboli. Let's put it this way, but it's not enough. All of these are just indicators when present. It should make you think more about amyloid spells. When they're absent, they don't mean patients do not have them. So the key, after having amyloid spells in your differential, is to get blood-sensitive sequences on the brain MRI, because that's the only way you can diagnose CA and that's the only way you might find the underlying cause of these amyloid spells, which in the overwhelming majority is acute subarachnoid hemorrhage in an area, in an eloquent area of the cortex, depending on where the symptoms are or depending if the patient came immediately to the hospital or after a few days. You might only see cortical superficial cirrhosis, which is the chronic form of subarachnoid hemorrhage.

Dr. Michael Kentris: 36:38

I think there's a second of course. Yeah, sorry, go ahead, go ahead.

Dr. Andreas Charidimou: 36:42

I was about to say with the brain MRI. Of course you have ruled out other causes of these symptoms.

Dr. Michael Kentris: 36:49

So that was the other thing I wanted to ask you about, because I know sometimes you'll get the MRI back and there will be this tiny little punk date area of restricted diffusion as well, like very superficial on the cortex, like literally just like one or two millimeters across, and maybe it correlates with the symptoms, maybe not. In what context? Or I should say, how far are we looking for some sort of like embolic source of stroke versus a tributary more to an amyloid etiology?

Dr. Andreas Charidimou: 37:22

Yeah, so are you referring to the scenario that you suspect that patients might be having amyloid spells?

Dr. Andreas Charidimou: 37:28

You do the brain MRI but you see no cirrhosis and no subarachnoid hemorrhage Correct In the area you expect, but instead you see a small punk date DWI lesion, right.

Dr. Andreas Charidimou: 37:39

So in this scenario that you haven't found any sort of chronic or acute bleeding in an area that can explain the symptoms and you have a DWI lesion, in this scenario you need to look a bit hard for embolic sources, including long I mean in addition to cardiac echo, long term monitoring, and you go all the way towards that path of embolic stroke workup. However, if you have a patient that, in addition to those tiny DWI lesions just above the cortex, they have acute subarachnoid hemorrhage or cortical superficial cirrhosis, I don't think you should look very far for embolic sources, because we know that in these patients with CA and acute superficial bleeding, we often see small DWI lesions in that area just below where the bleeding has happened. And I'm not sure what's the exact mechanism. Maybe it's cortical spreading depression in patients that basically all their vessels, they lack auto-regulation so it's easier to get small DWI lesions, or I don't know if there's any other mechanism.

Dr. Michael Kentris: 38:56

Because I recall a few years ago I had this huge run when I was covering the epilepsy service of we're doing all these long term EEGs on these patients in the neuro ICU who were coming in with subarachnoid hemorrhages and obviously, depending on the size, it'll believe that diminishes your sensitivity on your recording, but you would watch them for 24, 48 hours, you'd capture the spells.

Dr. Michael Kentris: 39:25

There wouldn't be any electro-graphic changes. And it does make me wonder are we seeing? The best I could find were some theoretical papers at the time talking about that exact same thing, this spreading field of depression, which I feel is like this phrase that we as neurologists throw out for anything that we can't explain otherwise, like inflammation, right, and inflammation. But yeah, it does seem like all these same mechanisms do apply. It's not necessarily vascular, it's not electrical, it's kind of the combination of the two. And we see this with all of these disorders that are transient, migratory, migraine, seizures, other kinds of vascular events that aren't clearly TIAs or strokes, and it does make me wonder these are all kind of happening on this spectrum. Is there any role for amyloid spells assuming that we've ruled out TIAs and strokes to the best of our ability for any anti-seizure medication or anything of that nature?

Dr. Andreas Charidimou: 40:30

Yeah, yeah, that's also a good question that comes up very often. So the answer is that there is a role. Again, as in most areas of CA, we're in uncharted territory in terms of randomized control trials. There are zero randomized trials of what we're talking about, but the anecdotal clinical experience with these patients is that you know there's some sort of task in trying to figure out the episodes. They tend to diminish on their own.

Dr. Andreas Charidimou: 41:01

The reason being is that the acute blood gets absorbed and, you know, gets Decrated down the line, so it's not so irritating to the cortex. However, we have had patients that they have 10 or 20 of these episodes in a single day, so it's quite bothersome. If the patient thinks the episodes are bothersome, then prescribing a short course of anti-epileptic medication is not a bad idea. At least You're trying but I wouldn't keep them more than like a month or two because I would assume the episodes should subside it by then Interesting. So there is a role, but not in all patients and again, I'm not even sure if the anti-epileptics are working in this scenario or just time Right.

Dr. Michael Kentris: 41:49

Yeah, that's a good point.

Dr. Andreas Charidimou: 41:50

Yeah, maybe, so it's go away.

Dr. Michael Kentris: 41:52

I know that's one of the things that will will sometimes do was like basically like a In empiric, you know, therapeutic slash, diagnostic trial of meds, like I'm not sure what these spells are, yeah, try this for, come back in a month, tell me if they go away. And Especially in areas where you can't get folks into, like an epilepsy unit or something like that, for for closer monitoring you. You do kind of have to Try stuff sometimes which can be challenging.

Dr. Andreas Charidimou: 42:19

No, it is because most of these patients are elderly, so you wouldn't want to have them on an anti-epileptic without any reason.

Dr. Michael Kentris: 42:24

But right in some, in some of them, it's not unreasonable to try right, right, yeah, especially you know there's some that are relatively low risk as long as. I'm interact and you know, etc.

Dr. Andreas Charidimou: 42:35

etc but it's important for whoever makes a diagnosis or To continue following these patients because, as you probably know better than I do, as soon as there is a patient or an Anti-epileptic, if they go to their PC pure or else, how likely is it to ever stop that anti-epileptic?

Dr. Michael Kentris: 42:53

Oh, never, never. Oh, I should say, alright, I'm gonna, you know, complain for a minute. One thing that drives me crazy is Folks who are at nursing homes. They check especially levitar acetam levels on these patients. That's like, oh, your level is too high. Like they've been on the same dose for like two years. They drop the level down, the dose down, they have a breakthrough seizure. They wind up in the hospital like, why'd they change your meds? Oh, okay, so that's what I always tell all of my trainees like don't check capra levels Unless you're worried the patient isn't taking it or they're in renal failure. Otherwise it's probably a waste of your time.

Dr. Andreas Charidimou: 43:34

Yeah, that's a very good point actually. Yeah, why would you check levels and monitoring any patient that has been taking it without any problems?

Dr. Michael Kentris: 43:42

I think that's. I think it's just a reflexive thing. You do see older physicians out there where you would check, you know, like Valproate or fenitone levels, right, like that's appropriate, especially in someone who might be having auto metabolism as they age. But they start to cross-apply that to some of the more modern medications which don't really have the same indications. But yes, that's my own particular Soapbox that I have in my area, but I'm sure I'm not unique in that.

Dr. Andreas Charidimou: 44:09

Let me, since, since I have you here, let me ask this question if you have a patient, let's say on capra yeah, he had a breakthrough seizure. You measured levels. They're therapeutic. Does it make sense to increase the dose, to kind of boost the levels further up, or would just add another? On tp Leptic depending on, based on you think the patient needs more coverage. There was no precipitating factor. It's probably just a much providing something.

Dr. Michael Kentris: 44:41

Yeah, so, so typically I, I, I would typically Maximize monotherapy before adding in a second agent. Personally, assuming you know normal kidney function and you know they're tolerating it, okay, and if they are on a you know middling dose like 750 twice a day to a thousand twice a day, you know you got a little bit of room to go up. I Typically, if I'm up to 1500 twice a day, I Some people will go to 2000 twice daily. Personally, I tend to find the side effect incidence goes up and I don't really get that much benefit in most people. Now if you're seeing, like when you went from a thousand to 1500 you had a good reduction, maybe you can make an argument that they're a good responder and they just need a little bit more. But in my experience I would say those people are the exception rather than rule. But a lot of times I, I like I'm a big fan of optimizing monotherapy just because of, like, med compliance.

Dr. Michael Kentris: 45:43

Obviously, when you get to, as you know, polypharmacy is a a big independent risk factor for medication. Nonadherence, yeah, just do the complexity of some of our regimens. So I tend to To be a monotherapy advocates until you've kind of exhausted that yeah line and then I think it does become one of those questions Did the Kepra, as you were titrating it up, did it make any difference in terms of frequency or severity of the episodes? If not, then I tend to be someone who would Cross titrate to an entirely different agent, as opposed to adding on a second agent on top of it. So it really does depend on the clinical response to the initial monotherapy Whether or not I would keep it on board as I kind of progress down that pathway.

Dr. Andreas Charidimou: 46:29

Yeah, thank you. Thank you for that. It makes a little sense actually, and it's a common. It's a common scenario, right, right, we see them quite often in the emergency department with the breakthrough seizures.

Dr. Michael Kentris: 46:40

Yeah and that is right, that that is the knee jerk responses just to you know, oh, they're not maxed out, we'll just bump it up, don't be wrong, I do that, yeah, very often myself. You know it's like, but as, as you also know, right, the main reason why people do have breakthrough seizures, you know they, maybe they missed a couple doses and we don't don't really need to do anything in those patients. More often I'll have the conversation about either changing it to an extended release form or To a medication that has a longer half-life, if, if compliance is is a concern just because of missed doses on a repeat basis. So going to something long-acting like zenisomide, that would be an option. Or S Lea carbazopene, again, just depending on interactions and all that jazz.

Dr. Michael Kentris: 47:26

But, yeah, before I make this a seizure podcast episode, but yeah, yeah, you know, for me it is, but but as far as so, this is another situation, kind of going into that that complex, right, because it, like you said, it's rare that we get any one of these pathologies by themselves. When we have someone, we're thinking you know, they've got these micro hemorrhages in the low bar areas. But we also see on the MRI maybe they have had like a lacunar stroke, either acutely or in the past, and they've got some cardiovascular risk factors or cerebral vascular risk factors. What is the role of of antithrombotic therapy or you know, god forbid anti coagulation and some with atrial fibrillation? How do we navigate those waters?

Dr. Andreas Charidimou: 48:18

Yeah, those are difficult waters to navigate but we have some answers. The the way I think about CAA is that you can have symptomatic CAA, defined by the syndromes, primarily the hemorrhagic, but also in the setting of a memory clinic. And you might have CAA as an incidental finding just because you got a brain MRI. And we know again from your pathological studies that CAA again depending on the age is quite common. So having CAA incidentally In a patient who got a brain MRI because he had an ischemic stroke, it's a very common scenario. And the way you you might identify incidental, incidental CAA is by seeing, as you said, a couple of lower microblitz. So Before, partly because of the of the literature and the way they feel in small vessel disease and microblitz Focus so much on bleeding. Even the name micro blitz is a scary name. It involves bleeding in the brain. It's not a good thing. We now know that a lot of micro blitz they're not even bleeding events in nature Based on your pathology. So it's a range. It's a range of underlying pathologies that cause what we see as micro blitz on on brain MRI. So in those patients that have incidentally found micro blitz Without any lower hemorrhage, without cirrhosis, without clinical CAA events.

Dr. Andreas Charidimou: 49:53

It's probably very safe to prescribe antithrombotics for secondary stroke prevention. And I'm saying this because we have good observational data From the chromis study, from the hero study in Spain and then from a large meta analysis involving more than 13,000 people, who were all patients with ischemic stroke, with or without a fee, who had a brain hemorrhage baseline. They assess micro blitz and then they assessed for future events and they found that even in patients who had more than two lower micro blitz a pattern suggestive of CAA the risk of hemorrhage was always lower than the risk of ischemic stroke. So you need to look at the absolute number of events, not the relative numbers. Okay, so always in this particular scenario, the absolute number of events of ischemic stroke. They're much higher than in stress-free hemorrhage. In other words, you get more benefit than harm by prescribing antithrombotics.

Dr. Andreas Charidimou: 51:02

And this is yeah right.

Dr. Michael Kentris: 51:05

Oh, I was gonna say, is that that's typically for monotherapy?

Dr. Andreas Charidimou: 51:08

I see, yeah most of I mean, based on the data, most of those patients. They were on monotherapy, either Plavix or aspirin. There were some on dual anti-platelets, but very few and really the indications for Dual anti-platelets I mean they're not huge, they're very specific scenario that a patient needs to be on Dabbed and for specific time frame.

Dr. Michael Kentris: 51:32

Yeah, I don't know why, in the last few months I've seen a run of a run of people who have been on dual anti-platelets for for very long, like like years After a small stroke or something like that. I'm just like you must have gotten lost a follow-up at some point this.

Dr. Andreas Charidimou: 51:49

Yeah, I think that there was one of the stroke fellows at Boston Medical Center who did a quality improvement study Because we started noticing the same. But patients after a minor stroke put on doubt. They continue for months and that was the reason Lost that follow-up or continued follow-up with another provider and, yeah, they just Stayed on it and is did you find just my own curiosity?

Dr. Michael Kentris: 52:19

Is it people who had kind of the the lower NIH's minor strokes who tended to be more lost to follow up? Yeah that makes. That makes more sense. They're not as fixated on their post stroke deficits, I imagine. Yeah yeah very interesting.

Dr. Andreas Charidimou: 52:34

Yeah, they were too good.

Dr. Michael Kentris: 52:38

Right, I mean, that is what happens right now. I want to go to the doctor.

Dr. Andreas Charidimou: 52:40

Yeah.

Dr. Michael Kentris: 52:42

I Need any final thoughts. I feel like I've learned a lot today and I very much appreciate it. Anything else that you think you know the the medical community at large Should be cognizant of, as they're out there treating patients with with neurologic disorders, transiently cognitive decline etc. That you think would kind of improve the care in their community.

Dr. Andreas Charidimou: 53:07

Yeah. So I think if we are to close with like a couple of take-home message is that To make a diagnosis of CA when you have a relevant scenario you need blood-sensitive sequences. Otherwise we're just talking theoretically and potentially harming the patient. And now we have very good blood-sensitive Sequences, especially the SW UI susceptibility with imaging. It's much better than the T2 star GRE in making in Visualizing Ciderosis micro bleeds. So these are better sequences to make a CA diagnosis. So you need that. If you assess a TI patient and you get a brain MRI without blood-sensitive sequences, then you're missing the opportunity to make alternative diagnosis.

Dr. Michael Kentris: 53:56

So, for those of us who only have GRE at our institution, how many do you think we're missing? A lot of patients, let me put it that way.

Dr. Andreas Charidimou: 54:06

I'm not sure how many are missed. I Would assume there are not many. It's just with SW UI versus GRE. You can see more Now. If at your institution you have on 1.5 Tesla GRE, then if you compare it with the three Tesla SW UI, they're maybe you're missing. I'm not sure. I'm not sure. Maybe 10, 15%, I'm not sure. We don't have the data I Got ya, no, no one's running that study.

Dr. Andreas Charidimou: 54:36

Yeah, we have the data from patients who were already diagnosed with CA or they had micro bleeds on GRE. When you look at the SW UI, you just see those, say micro bleeds better, and you see more Mm-hmm. Yeah, it makes sense. And in a few patients you see Micro bleeds or cedar roses that you didn't see in your GRE. Or if you go back to the GRE, an area that look a bit blurry Was actually cedar roses or a micro bleeds.

Dr. Andreas Charidimou: 55:07

So, yeah, I think SW UI is that should be the the standard of care Going forth. And the second, the second take home message is that we shouldn't be so afraid of micro bleeds, in the sense that Not all micro bleeds are due to CA. Not all micro bleeds are micro hemorrhages and Outside the clinical syndromes of CA, micro bleeds should not hold off from prescribing Antisrombotics in a patient with a real indication, especially when it comes to secondary stroke prevention or prevention of MIs, because I think the tendency is to be over conservative and Not prescribing these medications just because there were a bunch of micro bleeds, incidentally, on a brain MRI that makes sense and obviously that the emphasis being on the micro part of the micro bleeds right.

Dr. Andreas Charidimou: 56:05

Yeah, I, yeah. I mean just to clarify the micro bleeds. They're not small version of lower hemorrhages, right, it's an imaging construct in a way, and they appear Black and scary on SW UI and the T2 star sequences. They're real size is likely 10 to 30 times smaller In the brain than what they appear to be on the MRI. They just there is susceptibility artifact as it's called. So the, the distortion of the magnetic field is Is much higher than the actual size of the lesion. Just to give you like a congress example, you might have a microbleed and when you look at the pathology, there's three macrophages with hemocidurin. That's it.

Dr. Michael Kentris: 56:55

Oh, wow, that does put it in context. Yeah well, andreas, thank you so much. If people want to find you online, where should they track you down?

Dr. Andreas Charidimou: 57:06

so I'm pretty active on Twitter at a_charidimou my surname, so they can find me and they can also email me. I can share my email if you like sure go for it my email is Andreas with a D, dot, charidimou. My surname dot 09 at UCL, dot ac dot UK. Or, you know, you can send me a message on Twitter it's easier.

Dr. Michael Kentris: 57:37

Sure, I'll include a link to your your Twitter bio on the show notes today as well. Yeah, and thank you again. I think this was very educational, a lot of good information. I very much appreciate you taking the time to talk with me, talk with our listeners, and thank you, really appreciate it.

Dr. Andreas Charidimou: 57:54

The pleasure was all mine. I mean, it was very nice to get to spend some time with you after all this time that we have been interacting and I definitely learned a lot from your questions, and I learned a bit on epilepsy as well.

Dr. Michael Kentris: 58:08

So You're too kind, too kind.

Dr. Andreas Charidimou: 58:12

Thank you.

Dr. Michael Kentris: 58:13

Thank you again for listening. This episode was edited and produced by Rida Farhan. If you enjoyed this podcast, please leave a five-star review for us on Apple or Spotify or wherever else you might get your podcast. This really helps with giving a show noticed and spreading the word. You can find me on x formerly Twitter at Dr Kentress, dr KEN TRIS, and you can find the official neurotransmitters feed at Neuro underscore podcast. Lastly, you can find a lot of our content online and keep in touch with us through our website at the Neurotransmitterscom. Thank you again for listening and we'll see you next time.