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The Neurotransmitters: Clinical Neurology Education
CAA-related TFNEs or Amyloid Spells with Dr. Andreas Charidimou
On popular demand, we invited Dr. Andreas Charidimou once again, to discuss amyloid spells or Cerebral Amyloid Angiopathy-related Transient Focal Neurological Episodes (CAA-TFNEs)
- What are CAA-TFNEs and its suggested pathophysiology?
- What are some of its differentials?
- Clinical features of TIA vs TFNE
- How many TIAs are really CAA-TFNEs?
- Who to start on anti-seizure meds and how long do you continue?
- Neuroimaging findings and when to repeat imaging?
- Possible relationship with Amyloid-related imaging abnormalities (ARIA)
All this and more! Tune in now!
You can find Dr. Charidimou on Twitter/X at @a_charidimou or email him at antreas.charidimou@bmc.org
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Hello and welcome back to the Neurotransmitters. I'm your host, Dr. Michael Kentris, and I'm really thrilled to be recording today's episode, as we are rejoined by a friend of the show, Dr. Andreas Charidimou, and today we are talking about a topic that I find very fascinating, very challenging, and that is amyloid spells. Thank you again for joining us today, Andreas.
Dr. Andreas Charidimou:Thank you so much for inviting me again and I'm thrilled to talk again about one of my favorite subtopics in CEA.
Dr. Michael Kentris:Yes, Just before we were hitting record, you were saying that, obviously, for those who know you, you are very well-published in the arena of amyloid angiopathy cerebral amyloid angiopathy and you were telling me that during some of the talks that you get, whether or not you mention it directly, one of the topics that comes up time after time is these amyloid spells. So could you just tell us a little bit about what is an amyloid spell and when should we be considering that on our differential diagnosis?
Dr. Andreas Charidimou:Yeah, sure. So historically and traditionally, the presentation that most people have linked with cerebral amyloid angiopathy, or CAA, is that of lobar intracerebral hemorrhage, and this has been known for at least 30 to 40 years with the advent of neuroimaging 40 years with the advent of neuroimaging. One least known presentation, at least as of 10 years ago, is these presentations with what used to be called amyloid spells or transient focal neurological episodes related to CAA. And, as the name implies, these are episodes that are transient, neurologic in nature and focal, and the prototypical descriptions of these episodes are basically positive symptoms, so paresthesias, pins and needles, feeling, which are migrating, and the syndrome that was first described and is more characteristically associated with symptoms is spreading positive sensory symptoms in the arm up to the mouth and then slowly going back to normal in the same fashion. However, there is a spectrum, essentially from a symptomatic point of view, it includes any transient symptoms that they might look similar to TIA. So there might be negative symptoms speech impairments, focal weakness, arm or leg or they can resemble auras visual auras typically that they might remind you the auras that you typically see with migraine.
Dr. Andreas Charidimou:And, as you can tell, it is a tough symptom to link directly, tough phenomenology and not specific to link directly to CAA, because the differential is broad.
Dr. Andreas Charidimou:When you see transient symptoms of any nature in neurology, but when you should be suspecting this, I think it's in any patient that is on the older spectrum of age, so any patient older than 55 or 60 years old coming with transient symptoms, you should be thinking. When you think about TIAs, essentially you should be thinking whether this is CA-related phenomenon and one of the characteristics which differentiates this from TIAs actually is that these episodes are multiple and stereotypical, whereas a TIA typically is going to, you know, you're going to have the episode once and then probably a different kind of focal phenomenology if the patient has a second TIA. So in that sense it resembles a bit focal seizure activity, because focal seizure is another differential when you see a patient with recurrent episodes and you think about TIAs, but it's too stereotypical, happened too many times, so you might consider that this is a focal seizure. So in that context I think you would consider seizure-related amyloid spells.
Dr. Michael Kentris:Yeah, I'm going to have to update my lecture that I give to trainees about the differential diagnosis for first-time seizure events to include amyloid spells. But that is one of the tricky things, right, we always talk about with migraine, with seizures, this kind of spreading cortical depression, all this kind of stuff, and it almost sounds kind of like that same kind of phenomenon in this situation. And I know it gets even hairier when we start talking about things in the epilepsy world like negative motor seizures and things of that, which are also stereotyped. So one other thing you had mentioned is that, whether these are focal dysfunction versus, is it actually edging into the territory of causing seizures and when do you start to consider one versus the other? Or how does that kind of affect how you approach these patients?
Dr. Andreas Charidimou:Yeah, it's a tough question, I think, taking one step back. Essentially, the question is what is the pathophysiology of these symptoms? Yes, excellent, and the answer is that we don't really know, because we haven't studied this phenomenon from a pathophysiological point of view. What happens is that behind these symptoms there is typically superficial bleeding in the form of a convex subarachnoid hemorrhage in the acute phase, when this phenomenon first occurs, or cortical superficial sclerosis, which essentially reflects vessel wall cracking in the leptomeningeal space due to CAA, leading to even one drop of blood on the surface of the cortex, which it creates a lot of irritation. So what has been suggested as a mechanism based on how stereotypical these episodes are, the positive phenomenology and the spreading pattern, along with the timing of this spread, is this might resemble a mechanism similar to cortical spreading depression, because in cortical spreading depression you have a slow wave of excitation which then is followed by total inhibition of cortical neurons, and this might correlate in some of the symptoms with the spreading excitation creating the positive symptoms and then slowly for example, if you have pins and needles going from the arm up in the mouth and then slowly those symptoms going away. But this is like a theoretical assumption about the pathophysiology, now that we know that there is a huge spectrum of these symptoms, from positive to negative, I'm thinking that maybe the negative symptoms might be focal seizures, again, maybe initiated by the irritating aspect of having blood on the surface of the brain, or sometimes having acute microbleeds in cortical areas that are symptomatogenic, and there is some indirect evidence that we should be thinking about a seizure mechanism.
Dr. Andreas Charidimou:There was a recent study from Mayo Clinic and another one from Italy where they look at the prevalence of epilepsy in patients with CA specifically and they did EEGs and they found that the factors associated with epilepsy and focal seizures, specifically based on EEG captures in CA is the presence of cortical superficial sclerosis, which is very common and underpins these amyloid spells, and the patient having inflammatory CA. There is a different kind of mechanism because inflammatory CA is a very it's a different kind of disease with brain edema and inflammation. So I think the bottom line is, and the message that I want to send is that probably patients presenting with transient focal immunological episodes, they don't get enough EEGs and this is underutilized in many centers. Even when you do the brain MRI and you see an area of acute subarachnoid hemorrhage or siderosis, even when you ascribe this to being CA-related. I think an EEG would still be useful because it's going to change the symptomatic management of these patients.
Dr. Michael Kentris:That makes sense.
Dr. Andreas Charidimou:Yeah.
Dr. Michael Kentris:Now, again, I don't know the data well enough when we look at and maybe the data isn't there when we look at EEGs in patients with CAA or suspected CAA, plus or minus the transient focal neurologic events, is the sensitivity for, say, a routine EEG still that proposed around 50%, in which case a positive result is much more useful than a negative result and perhaps you might treat regardless if there is a clinical history of recurrent stereotyped events, particularly with positive symptoms.
Dr. Andreas Charidimou:Yeah, I don't think the data are there. I would assume that the sensitivity should be similar to the sensitivity in other focal seizures. So if you capture something, I think it's very useful and a positive indication. If you don't capture anything, you might consider repeating it if the symptoms recur, or use your clinical judgment on how to manage this. In most of these patients, the symptoms tend to resolve on their own, presumably as the blood gets resorbed.
Dr. Andreas Charidimou:However, I think it makes sense in patients with negative symptoms to look a bit deeper for a focal seizure focus, and also in patients even with positive symptoms, when they get too many of these I mean, I have had patients having 20 episodes per day. Too many of these, I mean, I have had patients having 20 episodes per day. So these are interfering with their life. So in those patients you might consider a low dose anti-epileptic which you would keep the patient on for three to six months, with the aim then to remove it as the symptoms subside. But this is, you know, know, this is just for the symptomatic aspect of things. The importance of these episodes are not the symptoms per se, but it's what they indicate, and they indicate bleeding on the surface of the brain which is is dangerous in the setting of CAA. So that's, you know, that's the second layer.
Dr. Michael Kentris:So hypothetically. So let's say we have a patient who you know. They come in with a kind of TIA like event, you know an episode of you know face weakness or numbness or what have you. That resolves spontaneously. We get the MRI done and it shows maybe a small microbleed that would localize appropriately. But they've only had one event and let's say they're following up in the neurology clinic three, six months later and when they come back now they're having these events recurrently, so kind of a change in frequency, if you will. Would it be appropriate in those patients to repeat imaging to see like, is there a recurrence of a microbleed at that point in time?
Dr. Andreas Charidimou:Totally yes. So if you have the diagnosis of CA-related TFNEs, if there is a silent period over two, three months and then the patient presents again with even the same symptoms, I think it's a good indication to repeat imaging to see if there has been a new bleeding event In patients that you have diagnosed. You know they have been having recurrent similar symptoms. You don't necessarily need to repeat imaging. But if one of those patients presents with a totally different symptomatology, then again the question is have they had a small bleeding in another area? Because these symptoms are basically it's like a clinical marker of fragility of the leptomeningeal vessels in CAA and this is a patchy disease which means that there might be other small bleeding events in other areas. So yes, this is exactly the patient population that you're going to have. Low threshold to re-image, because it's the only way to see what has been the progression.
Dr. Michael Kentris:Gotcha. Now that makes complete sense and I think that's a great point to emphasize right that CAA is a progressive neurodegenerative condition.
Dr. Andreas Charidimou:So we should expect this to be kind of a moving target for a lot of patients. Also, the other relevance of this is that, let's say you have the patient you mentioned coming to the emergency department with some sort of stereotypical transient neurological symptoms. Most clinicians at the top of the differential we're going to have the TIA right and not all patients will get immediately a brain MRI, because to diagnose this as amyloid spells you need brain MRI with blood sensitive sequences. Now, the big clinical implications in this scenario is that if you think the patient has a TIA and you don't have a brain MRI, what's the treatment for? Typically a TIA? You start. You start antithrombotics, right, yeah, and then you do the workup. However, if this was indeed an episode of ca related tfnes due to a small acute subarachnoid hemorrhage, by prescribing antithrombotics you're pushing the patient to bleed.
Dr. Michael Kentris:More essentially, right, and would this be a common scenario? Because I've encountered this once or twice myself. Obviously, at a you know smaller institution, our volumes aren't going to be quite as high, but where we have someone who comes in, it sounds like a tia. And then you get the mri and you see like maybe, maybe they don't meet full criteria for caa, but they're kind of in that possible camp where you've got like a you know micro hemorrhage in. You know, maybe they came in with aphasia and it's kind of in that left temporal or frontal area and you're like was this, was this?
Dr. Michael Kentris:an amyloid event. I don't have enough, necessarily. I've got them on dual anti-platelet therapy right now. Maybe I should deescalate that to maybe just like a low-dose aspirin.
Dr. Andreas Charidimou:Yeah, we can discuss all sorts of different scenarios. But let me put it this way Even one such patient if you get a brain MRI, even if the patient fulfills criteria for probable CAA, it doesn't mean that the episode is due to CAA. I think the highest level of certainty is when you see siderosis or subarachnoid hemorrhage in an area corresponding to the symptoms. In that scenario you can basically say that probably it has something to do with that acute bleeding and we can discuss later. But there is a whole differential of convexal subarachnoid hemorrhage. It's not the message, should not be.
Dr. Andreas Charidimou:You see the CAA, it has a huge list of potential diagnosis.
Dr. Andreas Charidimou:Now, if you only see a microbleed but it's in the right spot, I think you should pause and think whether it's related to that and maybe look for other less sensitive markers of CA. If this is a microblit in the right spot and the patient has severe perivascular spaces in the centrum semiovale or they have these small subcortical white matter spots that are included in the BOSTON criteria, it kind of raises the pre-test probability of these being related to the symptoms. In any case, you would still need to do a full workup for a TIA because if on that site you have a carotid stenosis, then obviously, you know, the plot thickens but you need to address that as well. So in some patients it's very difficult to have the exact set diagnosis and there are cases that at 1.5 Tesla using GRE, you might see only a micro-bleeds. And then you repeat imaging on a 3 Tesla MRI with an SWI susceptibility-weighted imaging and then you see that oh, actually there is a tiny spot of sclerosis. So imaging is not you know.
Dr. Michael Kentris:Now I'll create a beautiful yeah.
Dr. Michael Kentris:No, that's a great point. And I know our institution just started using SWI sequences in some of their protocols, thankfully, so that has been helpful. So we're kind of finally coming into the 20th century a little bit. But yeah, no, I think that's a great point, and I've certainly had those patients, as you intimated, where you know, maybe you've got a little bit of hemorrhage, you've got a bad carotid, maybe they also have a history of epilepsy too and you're like well, which one of these is the culprit this time around? And it does become very, very challenging.
Dr. Andreas Charidimou:Yeah, yeah, it is very challenging and we don't know what's the size of the problem. In other words, how many of these patients are missed. How many are they diagnosed as TIAs or as focal seizures? The only study that I'm aware of is a study from Calgary where they actually went retrospectively and they looked at their TIA registry. I think they had around 400 patients and they reviewed the MRIs to see how many patients fulfilled BOSTON criteria for CAA and in how many of those there was an area of bleeding anatomically corresponding potentially to the symptoms. And I think they reported that in about 1% of their total population. Actually retrospectively, they thought that those were actually not TIAs but they were transient focal neurological episodes due to CAA, which it doesn't sound like a huge number. But if you put into perspective on how common TIAs are, the absolute number of patients getting misdiagnosed, especially in centers or countries that MRI is not part of the initial workup, then this number is pretty high.
Dr. Michael Kentris:No, that's a great point, especially, like you said, in rural areas. I know that there's different protocols, like where you get the CTAs to make sure there's not a hot carotid or anything like that, and you kind of work them up over the next two weeks as an outpatient, yeah. But yeah, that's a great point, there are certainly things that will not be captured, kind of doing that low resource triage.
Dr. Andreas Charidimou:And actually my involvement in CAA started by seeing one of these patients. There was a patient that came to the emergency department of University College London at the time when I was starting my PhD, with a lobar hemorrhage and when we looked back a few days before, the patient presented to his PCP a primary care physician with some sort of transient episodes positive in nature I think the left arm was affected and up the mouth, and at the time I don't know if it's still the case in the UK the protocol was that the patient gets a CT, you initiate antiplatelet therapy and then they go to a TIA clinic at some point and this is what they have done. When we saw the brain MRI, close to the area of the hemorrhage there was an area of acute subarachnoid hemorrhage and some chronic sclerosis, also in remote areas. And when we went back to the CT we actually saw that there was a tiny, tiny bit of blood in the right sulcus and at the time I had no idea what that was.
Dr. Andreas Charidimou:And my PhD supervisor, david Waring, he says, oh yeah, this is probably amyloid spells. And looking in the literature we realized that there were just some case reports of this phenomenon and this is how we started assembling a multicenter cohort to see, indeed, if this is a common phenomenon, what are the symptoms and what is the risk of bleeding. And this is how siderosis actually gained validity in the CA field as a good imaging predictor of the disease and the risk of bleeding through these TFNEs or amyloid spells.
Dr. Michael Kentris:Fascinating, yeah, and I was telling you before we started recording. You know, I've only really had these in my consciousness for about three to four years myself, which, you know, going through epilepsy and things like that I would expect to have. You know, transient neurologic events are kind of our thing, so I would have really expected to have heard more about them. But it is one of those things where it's, you know, kind of the most common disorder you've never heard of is how it feels.
Dr. Andreas Charidimou:Yeah, yeah, yeah. I wonder if some patients they might have a very brief episodes they don't even seek uh uh, you know medical care and some of them they then, you know, develop a hemorrhage or they might not have any other symptoms for good periods of time. So those are totally missed.
Dr. Michael Kentris:No, it makes complete sense. Those are totally missed. No, it makes complete sense. And so one thing that I've been kind of curious about, if you're willing to speculate wildly with me we know that there's a lot of anti-amyloid therapies kind of coming into the public consciousness these days, like aducanumab, lacanumab, all those kinds of things that are these anti-amyloid types of treatments, and we know that there is this inflammatory subtype of CAA. How, or if, do you think there is any pathophysiologic relatedness between the aria, these inflammatory adverse effects that we're seeing with some of these anti-amyloid therapies, as opposed to these like transient focal neurologic events that we see in the context of CIA, versus like Alzheimer's disease in general? I know it's a very broad question for which there's not a huge amount of literature, but I'm just curious what your perspective may be.
Dr. Andreas Charidimou:Why are you asking this question? Have you seen a patient that makes you wonder about inflammation in the setting of transient spells? Because your question is very at the point, I have to say.
Dr. Michael Kentris:So I have had a couple inflammatory CAA-type patients come in. They kind of almost have that tumor-factive or neoplastic look on the initial MRI and you repeat it again three to six months later and it's quieted down a bit some residual hemorrhage there. But they will come in sometimes. Sometimes they will come in like maybe in focal status or maybe have had a seizure at onset, things like that. And then we've got these ARIA episodes with the anti-amyloid therapies and there's, you know, again, right, these kind of various neurologic phenomena that tend to occur, whether those are visual sensory kind of disturbances and it's, you know, it just seems too close to be coincidence. Uh, just from an observation yeah, you're totally right.
Dr. Andreas Charidimou:I think if we put it simply a bit simplistic, but I think it works for our discussion is that, uh, aria is basically iatrogenic. Ca related inflammation, the the two are, you know, mirror images. One is caused by a treatment that we do, the other one occurs spontaneously. So we can learn a lot from CA-related inflammation, because many of those things probably apply to ARIA, including the spectrum of the disease. So CA-related inflammation typically it was considered a condition during which the patient will be very severely affected, an encephalitis kind of picture, with changes in the level of consciousness, seizures, commonly with status epilepticus, and basically these patients will end up in the neuro ICU and on the MRI CSF. All the workup and on the MRI CSF, you know, all the workup you will and often a brain biopsy you will land on the correct diagnosis. Now I think, with greater awareness and more widespread use of brain MRI and blood sensitive sequences, we're realizing that this is only the tip of the iceberg. There are patients with CRN inflammation that they present with minimal symptoms, at the milder end of the spectrum, I think, our patients with CRN inflammation that they present with amyloid spells. I have no idea how common this presentation is, but for the past year I have encountered three patients. These patients they presented with positive or negative symptoms, transient, stereotypical. On the brain MRI there was evidence of bleeding in the right area. And these patients, they kept coming to the hospital with more episodes and more acute bleeding in that same area, which makes you wonder. This is not the typical, you know wild variety of amyloid spells that they will have one episode and then things are going to go silent. There was evidence of something going on locally. Vessels keep bleeding. I think in these patients, completely anecdotally, a contrast study will be useful because in these patients that I mentioned, a contrast study showed leptomeningeal enhancement in the very area that was bleeding, which makes you think if there was an inflammatory element. And in fact two of those patients we treated empirically with corticosteroids and there is no control group. But the patients are doing well and they haven't had any bleeding since. So, translating this to ARIA ARIA is also a spectrum from asymptomatic, so just imaging manifestation, which, by the way, I think is the only case that should be called ARIA.
Dr. Andreas Charidimou:Asymptomatic is the only scenario that you should be calling this amyloid-related imaging abnormalities. When the patients are having symptoms, there are no imaging abnormalities alone any longer. It's like they come with a symptom. We should have a better name to maybe sulcal hemorrhage or maybe fluid extravasation or edema focally. Now we might not encounter those patients very often, because when a patient is on leucanumab, let's say, these patients are monitored pretty closely with serial brain MRIs, typically after the fourth infusion, after the seventh infusion, and this is when ARIA has higher likelihood of happening. In other words, you might capture ARIA on imaging before it started manifesting with symptoms, aria on imaging before it started manifesting with symptoms. But I think it is possible that some of these amyloid spells, especially recurrent and different types, or even the same types, sometimes they might have an inflammatory basis, with or without anti-amyloid treatments. This is something that is a completely new realization. There are only a couple of case reports, I believe, interesting.
Dr. Michael Kentris:Because I have wondered in the past because, if I remember correctly, a history of intracranial hemorrhage of various types is kind of a contraindication to starting these anti-amyloid therapies. So are we causing this or are we unmasking it with some of these anti-amyloid therapies? I don't know if there's a good answer to that.
Dr. Andreas Charidimou:It's a very good question. First of all, I think in some patients the anti-amyloid drug is like a crash test to reveal if there is underlying CAA, because it's going to push the patient to express the cerebrovascular amyloid pathology. And for ARIA, I mean, we don't really know what's the cause. Right, there are two predominant hypotheses. The first one is that either the anti-amyloid antibody binds directly to the vascular amyloid, with different affinity but still binds there, inducing inflammation and vessel wall breakdown, or alternatively, as the amyloid plaques and the antibody and the inflammation kind of gets broken down, some of that needs to be removed from the brain via the perivascular space and the perivascular space is the scene where amyloid angiopathy also manifests.
Dr. Andreas Charidimou:So there is a problem with the perivascular drainage in patients with CAA. So those again simplistic hypothesis is that these breakdown products, they get clogged in there again, inducing inflammation. So essentially one of the primary risk factors for developing ARIA is having underlying amyloid angiopathy recommendations. When they say you shouldn't be giving these treatments to patients who have four or more microblades or to patients who have sclerosis, essentially indirectly you're saying you shouldn't be giving these patients when it's very obvious they might have evidence of advanced CAA. But many patients have either fewer microblades or more silent CAA and then you do the crash test. So essentially, these patients need to be very carefully selected and obviously very closely monitored.
Dr. Michael Kentris:That makes good sense. Something you mentioned earlier is you know, it seems like a lot of the emphasis on kind of these transient, focal neurologic events is related to more of the superficial siderosis, so the kind of that cortical surface. But we need to not anchor on that too much. So you mentioned that you have a differential diagnosis that you kind of work through when you see these cortical bleeds. What kind of things also go through your mind as far as potential underlying etiology.
Dr. Andreas Charidimou:Yes. So I think we can approach this. First, obviously you have a differential diagnosis of the episodes, of the episodes themselves, and we mentioned TIAs especially for a first comer with these episodes. First comer with these episodes, so TIAs, focal seizures, migraine with aura, sometimes metabolic abnormalities. I mean I'm sure you have seen patients with hypoglycemia who have focal symptoms, functional urological disorders. So there is a whole differential just based on the clinical symptoms and the context and then based on imaging.
Dr. Andreas Charidimou:If you see acute subarachnoid hemorrhage, there is a whole different differential diagnosis which includes things like small AVM, any sort of vascular malformation causing the bleed in that area, sometimes small aneurysm. You can have endocarditis causing an aneurysm there, inflammatory again in nature, or septic embolism causing the bleeding. You might have RCVS which can cause convex subarachnoid hemorrhage. There the age is a good indicator. For example, the most common cause of convex subarachnoid hemorrhage in someone younger than 50 years old is typically RCVS, whereas the most common cause in someone older than 60 years it's amyloid angiopathy. Then you can have IV drug use cocaine, heroin can cause, via a similar mechanism to RCVS, convexal subarachnoid hemorrhage.
Dr. Andreas Charidimou:So for that again, the clinical history and what are the other imaging findings are going to guide you on what might be the underlying diagnosis. Do you see other areas of chronic superficial bleeding, any other areas of sclerosis? Do you see lower micron bleeds? In other words, is there evidence that there have been similar bleeding events in an elderly individual, evidence that there have been similar bleeding events in an elderly individual, solidifying your differential that this might be CAA? But again, you keep an open mind because you still need to do a workup for the rest of the patients, including vessel imaging.
Dr. Michael Kentris:No, that makes complete sense. Now, something you mentioned about some of these people with recurrent, sometimes disabling or very frequent episodes that are disturbing to them. Potentially, you mentioned you'll put them on an anti-seizure medication for sometimes a dedicated period of time, like three to six months. Is it likely that after the acute hemorrhage, that when you wean them off the anti-seizure medication, that these spells will not recur, or do you find that this is more of a lifelong anti-seizure medication for some patients?
Dr. Andreas Charidimou:Yeah, so this is kind of different with patients with focal seizures in that the idea.
Dr. Andreas Charidimou:So the idea is that these episodes, unless there is more bleeding, they will tend to subside because the blood will get absorbed into hemocytogen and it's going to be less irritating.
Dr. Andreas Charidimou:So the majority of these patients will have resolution of the symptoms over a period of the next three to six months. The idea of putting someone on an anti-epileptic patient I mean with a CRLTFN is twofold. First, if you have identified a focal seizure on EEG as the mechanism and you believe this is just CAA, then you would put the patient on anti-epileptics. If you haven't identified that mechanism which I guess is your question if there are multiple episodes, you're going to put this patient on an anti-epileptic with the hope that it might help with quicker resolution and with the idea that as soon as the episodes get resolved which might relate to the natural history of the condition, which might relate to the natural history of the condition, then you try to get off the patient from the anti-epileptic. It's not going to be for life, so typically the longest I have used anti-epileptic in one of these patients is up to a year.
Dr. Andreas Charidimou:Okay, no, that's good to know. So then you take them off. I'm not even sure if the anti-epileptics were doing something or the symptoms were deemed to get resolved.
Dr. Michael Kentris:Their natural history, taking care of itself. Yeah, that's a good point.
Dr. Andreas Charidimou:There are some people that try to use anti-epileptic medications that there are ex vivo data that they actually might affect cortical spreading depression.
Dr. Michael Kentris:I think lamotrigine is one of them more in the sodium channel? Yeah, I would imagine.
Dr. Andreas Charidimou:Yeah so that's another rationale. That may be with the with some antiepileptics, where you're targeting cortical spreading depression in addition to epileptogenicity. So but Keppra, I think, as in many other areas of urology, is often to go to medication 500 milligrams. Right, just plug and play Twice per day, which is a low dose but still a good dose in an elderly individual. Lacosamide is the one I used as well.
Dr. Michael Kentris:Again, completely non-evidence based, right. Well, I gotta start somewhere.
Dr. Andreas Charidimou:Yeah, and this is not this is a rare scenario to start on to have so many episodes that you're gonna start an anti-epileptic. It's like maybe 10% of all the CA-related TFNs You're going to need to do that.
Dr. Michael Kentris:Gotcha, yeah. So my takeaway as far as anti-seizure meds would be recurrent stereotyped episodes, maybe more of a preponderance of positive symptoms, and if they're disabling, obviously, and you find no evidence of Like, in the absence of recurrent bleeding, would you say or plus or minus.
Dr. Andreas Charidimou:So I would go purely by the recurrence of clinical symptoms. Okay now, if there was a recurrent bleed without any evidence of either a new seizure or a new episode, there is no indication to continue anti-epileptics.
Dr. Michael Kentris:You wouldn't do it prophylactically okay because I know we still there's a little bit of debate out there for like some of the you know intraparenchymal hemorrhages, about uh, prophylactic anti-seizure medications, but I see a lot of, because sometimes these these consults will come more to the neurosurgeon than to the neurology team as far as like a, a small subarachnoid hemorrhage, so everyone gets put on you know capra or something like that for seven days.
Dr. Andreas Charidimou:You know kind of like the traumatic brain injury type uh, yeah, I guess it varies between institutions.
Dr. Michael Kentris:So right, right yeah but no, those, those are all very helpful points. I really love the the tip about using the contrast at mri. It's not something I think about with um, with these types of patients, with when I'm kind of doing the tia or caa kind of evaluation, but I'm going to definitely keep that one in my back pocket going forward yeah, especially when you see a patient that is a bit different or atypical to the patients you have seen before, with these episodes.
Dr. Michael Kentris:Any other questions that you find come up a lot from people asking you about amyloid spells or the TFNEs that you think would be useful for people to know about or would help them identify these patients.
Dr. Andreas Charidimou:I think there are two questions that they have been coming up a lot. The first one is okay, the patient comes to the ED with these symptoms. You do a brain MRI or even a CT initially and you see there is an acute subarachnoid hemorrhage. Is an acute subarachnoid hemorrhage, how do you treat this patient? And my answer is that it's reasonable to send this patient to the new ICU with the aim of, essentially, you should treat it as a hemorrhage, as a brain hemorrhage, intraparenchymal hemorrhage in terms of lowering the blood pressure, having a very strict target closely monitoring these patients for any recurrence of the bleeding. And it might be a short stay it might be just one day just to control the blood pressure if it was high and have a more definite diagnosis. So this again depends on availability in each individual center, but I think the blood pressure in the acute setting, in the first 24 hours, is a reasonable target to have in the management of these patients. So this is in the acute setting. The second question that comes up very often is what is the risk of these patients having a lower hemorrhage and what do you do when you find out that they have AFib or they have another indication for anticoagulation, which is something that we discussed in the previous podcast. But I think the overall approach is that these patients again they should be treated similarly to a patient who had a lower hemorrhage due to CAA in terms of the future risk of hemorrhage, because it's not that the amyloid spells increase the risk of future hemorrhage. The reason that these patients have high risk of hemorrhage is that they have a lot of cortical superficial sclerosis. So the imaging manifestation is a biomarker of severe or advanced CAA. So it's likely that you know, very stochastically, one of these small vessels will pop and the hemostatic mechanism might not be enough to seal the crack and these patients might end up with a lower hemorrhage. So we know from observational studies that these patients they might have risk of future hemorrhage from 15 to 20 percent per year, risk of future hemorrhage from 15% to 20% per year. And the risk you can kind of quantify it based on what are the imaging manifestations of CA on the rest of the brain? Do they have multiple areas of siderosis? Did they come with a second episode of acute subarachnoid hemorrhage? Both of those scenarios increase the risk of hemorrhage. We also know that they have considerably high risk of an ischemic stroke, just based on how common vascular risk factors are in these elderly patients.
Dr. Andreas Charidimou:So it is a good target group to try something other than anticoagulants. Probably they are at the high end of the spectrum in terms of future hemorrhage where probably many neurologists will feel uncomfortable putting the patient on an anticoagulant. So these are the patients that probably they might warrant a discussion with cardiology. If they have AFib, that is, to get a left atrial appendage occlusion device, and the idea behind it is that both CAA and atrial fibrillation are conditions that inevitably they're going to progress are conditions that inevitably they're going to progress. So by considering an occlusion device early, it's probably a good idea to reduce the long-term risk of both hemorrhagic and ischemic stroke. So, yeah, it comes back to one of the thorny dilemmas in CA, which is what do you do when you have tons of glycolate Right? Yeah, it comes back to one of the third-needle dilemmas in CA, which is what do you do when you have tons of glycolate Right?
Dr. Michael Kentris:Yeah, stroking versus bleeding, and I know the data is fairly equal poise. As far as, like you know, a low-dose aspirin or like mono antiplatelet agent, I don't think the risk, if I remember correctly, isn't particularly elevated in terms of the balance between ischemic versus hemorrhagic stroke. Is that correct?
Dr. Andreas Charidimou:I think this is fair to say that there are no randomized data just on this population. But based on this rationale you mentioned, in some centers instead of giving anticoagulation they might give low-dose aspirin to at least mitigate some of the bleeding risk while gaining something in terms of preventing ischemic strokes. So the ongoing trials in the field that they're randomizing patients with hemorrhage, intracerebral hemorrhage they don't explicitly include these patients that they present with just sulcal subarachnoid hemorrhage and they have CAA. Only one of the studies in Canada initially included these patients, but there was. They published a letter in last neurology saying that the interim review of their monitoring committee saw that these patients are at high risk of events when they're randomized to anticoagulation treatment. So they have stopped recruiting this patient in the trial.
Dr. Andreas Charidimou:This was a trial looking on oral anticoagulation versus I don't remember what was the other arm aspirin or standard of care in patients with intracerebral hemorrhage or CAA, and they had these amyloid spells patients potentially. My rating of this is that probably, even when multiple trials that are now ongoing are completed, we might not have a good answer for this subgroup of CA patients, either because they're not included or because the risk was too high to even randomize. So we might need to just go in the absence of evidence and discuss what would be the most rational and beneficial approach.
Dr. Michael Kentris:No, that makes sense. Definitely a very challenging clinical scenario that it comes up Not super duper rare, but yeah, no, I always appreciate every time we talk I feel like I learn so much every time, so I really do appreciate it. Any final thoughts? Anything you'd want to share with our listeners today? Projects you're working on Places. They can find you online.
Dr. Andreas Charidimou:Yeah, sure, so I'm pretty active on Twitter or X and I tend to post about these dilemmas or ideas about mechanisms, these dilemmas or ideas about mechanisms, and you can share my email as well in your webpage, and whoever I mean. If there are any questions, I'm happy to answer. I'm currently working on how to further improve diagnosis of CA in different patient populations, using cohorts of patients who had in vivo MRI plus neuropathology at some point when they died or when there was a biopsy. So I'm very open and seeking collaborations because we need numbers Awesome.
Dr. Michael Kentris:Now we'll make sure to include your X handle and your email in the show notes for today, but thank you so much. I always really appreciate it and I really did learn a lot today. It's definitely going to change some of the things I'm thinking about as I encounter these patients in the future. So thank you very much, thank you.
Dr. Andreas Charidimou:Thank you so much because your questions made me think a lot and you're asking, like the pertinent questions, about how to approach these patients and what might be the underlying mechanism. So, yeah, I really enjoyed meeting with you again.
Dr. Michael Kentris:Oh, you're too kind. And for anyone who wants to find more, you can obviously check out our past interview with Dr Charidimou about cerebral amyloid angiopathy and our other episodes. You can find us on all of your major platforms and you can also find more of our work at the neurotransmitterscom and you can find our podcast handle on X at neuro underscore podcast and myself at Dr Kentris D-R-K-E-N-T-R-I-S. Thank you again, andreas and myself at drkentris D-R-K-E-N-T-R-I-S. Thank you again, Andreas, it's always a pleasure.
Dr. Andreas Charidimou:Thank you Likewise.
