Ep. 176: Embolic Stroke of Undetermined Source: Diagnostic Challenges and Therapeutic Options

00:00:00: Welcome to EA

00:00:01: Uncast, your weekly source for education, research and updates from the European

00:00:06: Academy of Neurology.

00:00:15: Hello, everyone.

00:00:16: Welcome to this EA Uncast weekly neurology.

00:00:21: Today's topic is a symbolic stroke of a determined source, diagnostic challenges and therapeutic options.

00:00:28: My name is Theodor Smavridis.

00:00:29: I'm a consultant neurologist, stroke specialist.

00:00:32: at Hala University Hospital Dublin Ireland and have the pleasure to have with me a professor Miracatan chair of the Department of Neurology in Basel Switzerland and also a professor Diana Aguirre de Souza consultant neurologist Lisbon Central University Hospital and assistant professor at University of Lisbon.

00:00:54: We'll start with the first question.

00:00:57: I'm going to address it to Professor De Souza.

00:01:01: To begin with, could you briefly define what is an Isus and explain how it differs from the broader category of cryptogenic stroke?

00:01:11: Thank you for the question and for the introduction.

00:01:13: This is really a very interesting and important topic.

00:01:17: So, symbolic source of undetermined source or Isus was... proposed new category within cryptogenic stroke that was suggested more than ten years ago, has a subgroup of these patients.

00:01:32: So it was defined as a non-lecuner ischemic stroke with no more than fifty percent stenosis of the supplying extracranial or intracranial artery.

00:01:43: Also no other major high-risk cardiomyobolic source like non-AF, mechanical valves, recent MI.

00:01:51: ventricular trombosis.

00:01:53: So patients that had no other specific cause.

00:01:56: after a standardized workup, and this is a really important thing to have in mind, that these patients would have to have a full workup, including vascular imaging, echocardiography, and at least a short-term monitoring for rhythm disturbances.

00:02:13: And so if everything was negative and there was this kind of pattern that was maybe symbolic, then these patients were classified as isos.

00:02:22: Cryptogenic stroke, actually, it is a much broader category because it also includes patients with incomplete workup, multiple competing causes, and so it is different.

00:02:34: And the idea was to have a more homogeneous group within isos.

00:02:38: that was likely to be symbolic.

00:02:41: But actually, and we will discuss it, I'm sure, very deeply, this group still turned out to be very heterogeneous.

00:02:50: Okay, this is a very good introduction and thank you for letting us know about what is an Isis.

00:02:57: and I would address the second question to Professor Katan.

00:03:01: What are the main diagnostic challenges that clinicians face when trying to classify a stroke as an Isis?

00:03:09: Yeah, I think it was, you know, it was the idea to use this classification in the beginning also to mine to tailor secondary prevention and that didn't really didn't really happen in the past.

00:03:24: and the main problem or main challenge actually of the concept of visas.

00:03:29: it's that it is the etiology or underlying etiology is very heterogeneous.

00:03:34: it includes many mechanisms so you can have a pattern which looks symbolic.

00:03:41: but the source of the embolus can be very very across all what we have to give to see what's underlying an acute stroke.

00:03:50: So it could be arterial disease, atherosclerotis.

00:03:54: It could be coming from the aortic arch.

00:03:57: It could be an unstable plaque from the carotid.

00:03:59: It could be an atheroma somewhere else.

00:04:01: It could be even cancer related.

00:04:03: It can be an other source of cardiabolic, the unknown term factors.

00:04:12: So I think the problem is really heterogeneity.

00:04:16: And that makes it a bit complex in the diagnostic work up as well, because I think we can't really treat all those patients with which we call eases the same way.

00:04:30: And so the concept is shifting here.

00:04:33: And I think there was like a shift over the last decades towards the idea also that you don't just want to classify the underlying etiology of the ischemic event which has happened, but you want actually to prevent the next stroke.

00:04:52: And also the idea that the ischemic event which has happened is the same mechanism as the next stroke is maybe to be challenged as well.

00:05:05: Isis has been an idea to kind of narrow a bit the cryptogenic stroke category but it wasn't really very useful for then looking at treatment options of these patients because underlying Isis again you have all these mechanisms still there and you can't really distinguish them just by excluding those which are obvious or those underlying etiologies which are obvious.

00:05:31: Yes, this is very important to say that, so just looking from the images and trying to put something in Bollig doesn't say where the embolus came from, where the embolus originated.

00:05:44: And this was a common misinformation because many of physicians thought that Jesus means cadmium Bollig, which is, we know nowadays, it's not.

00:05:57: This also has many implications to our treatment strategies and therapeutic options.

00:06:02: We know recently from the recent trials like Navigate Isis, Respect Isis and Aticus have saved the view of antithrombotic therapy in Isis.

00:06:12: Diana, could you summarize the key findings and what those mean in clinical practice?

00:06:18: How they have transformed our knowledge in terms of that category that we call Isis?

00:06:26: Yes, that's very important.

00:06:29: So we had quite a few trials, large trials showing us that this concept of having it using the same therapy as AF in these patients does not work.

00:06:41: First, we had the Navigate Isus trial.

00:06:43: It compared Rivaroxaban, fifteen milligrams, which is important to have in mind as well, to aspirin and more than seven thousand patients, Isus patients.

00:06:53: And this trial was stopped early because Rivaroxaban did not reduce recurrent stroke and actually there was an increase in major bleeding.

00:07:02: And so this was the first trial.

00:07:04: Then we had respect Isus.

00:07:06: also randomizing more than five thousand patients to the bigger trend compared with aspirin.

00:07:13: And again, no significant reduction in recurrent stroke, similar rates of major bleeding.

00:07:18: And then we have Atticus.

00:07:20: Atticus tested at Pixaban versus aspirin.

00:07:23: The difference was there was a mandatory prolonged cardiac monitoring and there were also MRI based endpoints.

00:07:30: So it was already a bit in reach, let's say.

00:07:33: in terms of easels patients with high risk but still a pxaban was not superior to aspirin again.

00:07:41: and so overall these trials give a very clear message that routine anticoagulation with DOAX, any of those, is not indicated an unselected easel's patient.

00:07:53: So aspirin is the standard for these patients and anticoagulation should be reserved for patients in whom we actually find AF or that have another clear indication.

00:08:05: And these trials really show us, again, as we were discussing, that Jesus is probably too heterogeneous, because if the response to anticoagulation is not seen in the trials, this means that probably there's no cardiomboleic mechanism, at least not one that we can treat with anticoagulation.

00:08:22: And so the benefit that we may have for some AF patients that are, that is uncovered AF, is very diluted in this large mixed population.

00:08:33: Probably the event rates are also lower than expected.

00:08:36: And of course, the follow-up of these trials can be also discussed.

00:08:39: But this overall means that we really have to consider other etiologies, non-stonotic, atroscorrhosis, small vessel disease, miscalcification of these patients.

00:08:50: So there are a lot of takes that we should really consider from these trials has a strong message.

00:08:58: This

00:08:59: is very interesting.

00:09:00: So the basic take-home message from those trials is do not change our current practice in terms of changing anti-platelets to anti-coagulation before we find the cause.

00:09:09: Don't just treat it as a cardio-embolic because it is completely different.

00:09:14: We have only the imaging, but it doesn't say anything about the underlying etiology.

00:09:18: And now I'm going to jump to my next question.

00:09:21: Mira, what can you say about when you have a patient with either the broader term of cryptogenic stroke or even the Isis classification, what would you do in terms of evaluating and try to find what is the underlying cause?

00:09:36: How would you assess diagnostically a patient that presents with an Isis?

00:09:42: Yeah, so I think actually to be very straightforward, I would do it the same as in all others and I'm explaining why this is.

00:09:52: So again, I think Isis or you know the term eases has been labeled for a therapeutic option.

00:10:00: but I think it is important that all underlying potential causes and they can be there at the same time they can be concurring and so on.

00:10:09: they should all be evaluated in all patients so not just in cryptogenic stroke patients or eases patients.

00:10:16: it makes sense even for example if you have a patient who had a lacuna stroke in terms of morphology, location, clinical presentation.

00:10:27: It doesn't mean that in this patient you shouldn't look also for carotid stenosis.

00:10:32: It doesn't mean that in this patient you shouldn't also look for atrial fibrillation.

00:10:38: Because we all know for example atrial fibrillation underlying has been detected in trials where they were implanted with loop recorders in the same rate as cryptogenic strokes.

00:10:50: So it's about twelve percent per year.

00:10:52: It's the same for small vessel strokes, incident strokes.

00:10:55: It's the same for large vessel strokes.

00:10:58: So meaning the diagnostic workup should not only depend on the assumed etiology of the first stroke.

00:11:08: Because if you find in your patient who had initially a laconic stroke.

00:11:14: You find in this patient clear signs in your first, let's say ECG you do, a FIB, what would you do?

00:11:22: That would change your management.

00:11:23: No, you would start to anticoagulate this patient.

00:11:26: But if you don't look for it, you just also don't find it.

00:11:29: So it's important that the diagnostic workup of all underlying etiologies is not dependent on the classification of the etiology of the first stroke.

00:11:40: Meaning, if you can't find, after all workup, an underlying disease, an underlying etiology, then you have to look in all those patients, of course, for underlying amphibes, because that's always not so easy to find, but also in patients... the other way around with initial lacuna stroke or initial carotid, a large vessel stroke, you need to look for the other causes as well.

00:12:08: Great.

00:12:10: This is very, very important.

00:12:11: So it's not what we are thinking that it is that we need to search only for that, but for all causes.

00:12:18: basically what you're telling us is that we need to do that in all strokes that we have in front of us and this is very important.

00:12:25: So I will take one of your sentences and then I will move forward.

00:12:29: You told us that if we find a patient that had basically a latrine stroke and you had an ECG that pointed out that had a clear AFib, you will anticoagulate because it is an actual cause.

00:12:41: But let's go the other way around.

00:12:43: So you have a patient who has a stroke that we don't know where it came from, a bollock pattern, and then we need to do, for example, prolonged cardiac monitoring.

00:12:55: Then it comes the question of the egg and the hen.

00:12:59: For how long?

00:13:00: and if we pinpoint an AFib later on, let's say three, five, ten years later, would we assume that this stroke three, five or ten years earlier happened to this AFib and will change our management?

00:13:15: And this is a very... trying to make a discussion here with... we'll start with Diana and then we will have Mira in the conversation as well.

00:13:26: Yes, that's an important question and that has been highlighted also by recent studies.

00:13:31: It is not completely clear that if you find the Navy long time after it is... it is not clear that it has been the cause.

00:13:41: it is never clear.

00:13:42: actually we cannot never be sure about causality.

00:13:45: we can only you know and know about the associations and some some some groups have even question if we should do anticoagulation and you know what is really the risk and burden of disease in patients that have very.

00:14:00: short periods of AFib.

00:14:03: But overall, of course, we should do the monitoring.

00:14:07: And that's clinical practice to do at least the twenty-four hours monitoring during admission, preferably a bit more using the telemetry.

00:14:18: And then to do the external monitoring for Maltesers patients and patients that we feel are high risk or have strong atrial embolic features.

00:14:28: also should consider even an insertable cardiac monitor and test for it because it is important for us to know and then to make the decision of what's the risk of stroke, what's the the hemorrhagic risk as well and take a decision for that specific patient.

00:14:44: So what we do in our clinical practice in our hospital and what's on the guidelines is that it's just to do the monitoring to test for AFib and then to discuss, has a team, what is the burden of IEF and what should be the decision in terms of secondary prevention for each specific patient.

00:15:05: And I think that's what we should do.

00:15:08: But I also would like to hear Mira.

00:15:12: Thank you.

00:15:14: Yeah, I think you're totally right.

00:15:16: So the question is, when we go back to the initial questions of Theodoros was if you find a FIP, quite remote, so some months or years after the index stroke, if that has something to do with the index stroke, and we don't just don't know.

00:15:35: So it could, but it could not be.

00:15:37: But I think that's not the real question here.

00:15:39: I'm trying to shift again that concept.

00:15:41: So what we don't want to, it's an academic, it's really very interesting to know what the etiology of the index stroke is.

00:15:48: But what we actually as physicians want to do is we want to prevent the next stroke.

00:15:54: And if you find real AFIP, even if it's remote, we do know that those patients, if it's really AFIP over a long term, let's say in a halter or in a spot ECG, where you can assume that AFIP burden is high, this patient benefits.

00:16:12: And we know this data from also the primary prevention, even if that person hadn't had the stroke.

00:16:19: before but has a high chest vascular score and they benefit from oral anticoagulation to prevent the next stroke or the first stroke.

00:16:29: But patients who have very soon after the stroke, a very short episode, maybe just thirty seconds of atrial fibrillation, this is like this grey zone where we don't really know what we do with these patients.

00:16:46: because you know all our data on atrial fibrillation and anticoagulation regime is based actually on twelve lead ECG and maybe whole third ECG but not on ECG detected by for example loop recorders and very short timeframes and we don't really know in the stroke population.

00:17:05: if that is enough burden of a fifth to be anticoagulated.

00:17:10: So that's like the other topic.

00:17:13: But for the question of Theo in terms of if we should consider this, the etiology or in connection with the etiology of the first stroke, we don't know.

00:17:24: And I think it's maybe not the main question we should ask.

00:17:29: Yeah, this is very interesting and intriguing because as you know, the chat vascor also has an event and if you pinpoint the event as to be related then you increase the score.

00:17:39: But let's move forward in terms of beyond atrial fibrillation, in terms of atrial cardiomyopathy and as an independent embolic source.

00:17:50: Mira, what are your thoughts on that, on the patients who have specific features of under cardiomyopathy.

00:17:59: Tell me about a very specific group that is unrelated completely to AFib.

00:18:06: So I think the concept of atrial cardiopathy has emerged maybe in the last ten years, more or less.

00:18:12: And the idea behind it just maybe to explain is that an underlying atrial cardiopathy, so a diseased atrium, can be an independent risk factor of stroke.

00:18:23: Independent?

00:18:25: from detected or overt atrial fibrillation.

00:18:31: Now, potentially this is just a continuum, meaning that atrial fibrillation could be the peak of the iceberg, just the electrical manifestation of this underlying atrial cardiopathy.

00:18:42: It could go also the way that this presentation of AFIP doesn't even have to you know, pop out anytime so it doesn't even have to come, even if you have a very diseased atrium, you might not even catch atrial fibulae as an electrical phenomenon.

00:18:59: But what epidemiological data suggested?

00:19:01: that in the case where atrial fibulation was not yet detected or yet diagnosed and patients had feature of an underlying atrial cardiopathy that they had a high risk of having an incident stroke.

00:19:14: And what was also shown?

00:19:15: that in the stroke population, patients with these features have also a high risk of recurrent stroke.

00:19:21: So there was an association adjusted for the fact that there is not known AFIP in this population.

00:19:28: So in addition, so it could be an independent risk factor, an independent entity or at least a sub entity.

00:19:38: Now, how can you define atrial cardiopathy?

00:19:41: This is also not totally clear yet.

00:19:45: But there are features which seem to be associated.

00:19:48: That's like imaging features, for example, on the echocardiography, you have left atrial enlargement, you have things in the ECG, such as P-wave terminal forests, and you have also blood-based biomarkers, which are related to atrial stretch.

00:20:05: And these are the natratic peptides, for example, measured by the atrial natratic peptide with an assay which targets the mid-regional part, which is called MR-PRO-ANP, or brain natratic peptide with an assay which targets the NTIP terminal part of the precursor, which is NTIP-PRO-BNP.

00:20:27: And both of these natratic peptides have been associated with... the occurrence of AFIP or the diagnosis of AFIP also with enlarged atriose in echo and and I think that's again really important because we're talking here about the stroke population and what we actually want to reduce is stroke recurrence.

00:20:51: so it's really important that these markers also have an association with stroke recurrence.

00:20:56: Otherwise, to guide clinical decision making, it wouldn't make really much sense to look for them.

00:21:03: Great.

00:21:04: Thank you for this valuable insight about the atrial cardiopathy.

00:21:09: And now we're going to move forward to another interesting topic that we are used to search nowadays more and more specifically in young patients, the pattern for amenovale, which remains a key discussion point.

00:21:24: How would you approach Diana, the PFO detection enclosure in patients meeting the cryptogenic or ease criteria?

00:21:34: That's a very important topic, also in clinical practice, very common question, because PFO is actually very common.

00:21:42: And that's also because of that, that we should really do a very complete etiological work with vascular imaging, with a written monitoring.

00:21:52: If there's an alternative clear cause like large artery disease, AF, left ventricular dysfunction, that having a BFO is of course an incident of finding.

00:22:04: So it is very important that we consider that we have a complete etiological workup and there's no other cause.

00:22:11: Also we can, you know... search for some suggestive features that can, from the clinical history and from the patient's population for being young, less than sixty years and having, you know, sources of venous trembolism, of course.

00:22:28: So there are some suggestive features and we can use scores like the rope score.

00:22:34: And this is actually now included in the ESO guidelines as well on PFO management and treatment.

00:22:42: So, overall, patients that have non-lecunorimbalic infections, no competing cause, especially if they have a high-risk PFO, some other way to large shins, a triceptal aneurysm, rope score that is high, and we have no other cause.

00:22:57: Of course, according to the guidelines, this is fully supported.

00:23:01: We should do percutaneous closure in these patients.

00:23:04: And of course, there's always the question of what to do between having before the treatment while we wait for the closure itself.

00:23:14: Some people do anticoagulation, some do antiplatelets.

00:23:18: There's still a bit of discussion around this, but at least antiplatelet therapy and then to do the closure and then the management around that is usually guided by cardiology usually involves double antiplatelet therapy for a period and then long-term single-antiplated therapy.

00:23:37: So definitely this is supported by the guidelines and it is within already clinical practice.

00:23:46: Then in older patients there's a bit more, you know, between sixty, sixty-five.

00:23:52: Sometimes we have this question whether we should consider PFO or not.

00:23:59: Overall, It is more accepted to consider at least in some patients also closure over sixty years, but we should be cautious and really individualized decisions and usually prioritizing aggressive vascular risk factor, search for AF and not doing routine closure in this patient.

00:24:19: So it should be a very individualized decision.

00:24:23: This is a very very interesting topic and indeed we need to be careful when we are dealing with PFOs because we know in the general population around twenty five percent of the people.

00:24:34: do have a PFO, but it doesn't mean that it caused a shock.

00:24:38: And also we have some scores like the rope score or the Pascal score, who also assesses the type of the hole, if it is an aneurysmal, if it has multiple holes, and they can also figure out how to close it.

00:24:53: It's a very, very important thing.

00:24:56: Before starting the question with the discussion of future perspective on Isis, I would like also to mention and possibly We have a brief talk about the new categorization of plaques and that the fact that we don't, where clinicians were not used to pay attention to the carotid plaques if they weren't above a specific type of stenosis, but this is wrong.

00:25:20: We know that from the NACET and the ECST that those guidelines were made purely and mostly for surgical.

00:25:30: intervention of those patients.

00:25:31: that doesn't mean that the plaque is not responsible for a stroke or even an easis because we know that as both of you have mentioned that an embolic stroke can be also from the arteries or even the aortic arts.

00:25:45: and we need to know the new rat scale classification of plaques and to label a plaque high or low risk.

00:25:54: independent of the degree of stenosis.

00:25:57: I would like your brief discussion on that, and then I will move to the last question on future research directions.

00:26:05: Mira, can you elaborate on that?

00:26:08: Yeah,

00:26:08: of course.

00:26:08: So I think you pointed out a very important topic as well.

00:26:12: So not a word or cover it, or the sclerotic source of stroke is important, and it came as... say it can be an unstable non-stenotic plug of the carotid.

00:26:25: It can be a complex aortic arch plug.

00:26:28: And just to look at the definition or the grade of stenosis per se is not enough.

00:26:36: It helps in terms of... This is a category with a high risk of re-events.

00:26:43: I think that's where it also comes from at the end of the day.

00:26:47: But to identify those who, you know, might benefit in the first fourteen days after stroke for women intervention.

00:26:53: But it doesn't really help in better understanding what potentially could still be an etiology of a stroke.

00:27:03: And the problem rather is that if you have an unstable lonstenotic plaque, And that might be the cause.

00:27:09: We don't really know what the best treatment is.

00:27:12: I think it's important to do, of course, best treatments conservatively, but we don't know yet.

00:27:19: And it might be in the future that these patients might, if you select them very well on imaging parameters, maybe also on biomarkers, that they might benefit also from standing or in the rectorectomy.

00:27:34: But we don't know yet.

00:27:36: So I think it's important to look for that.

00:27:39: It's important to have then really a very good eye on the vascular risk factors, which we should treat anyway, but you should maybe look further and have really close guidance in terms of lipid management and also inflammatory.

00:27:55: parts within.

00:27:56: We now more and more about inflammation and maybe in some selective patients also colchicine could be an option.

00:28:04: We do have some first date of the convinced study with some subgroup analysis is where we see there is a trend.

00:28:11: We don't still know yet how best to select those patients who might benefit.

00:28:16: And currently it's not in the guidelines, but I think this is a whole avenue which will, you know, there will be lots of more information.

00:28:24: maybe also some biomarkers we could use to guide our decision-making, not just high-sensitive CRP, but maybe also other inflammatory markers, cytokines and so forth.

00:28:35: So I think there is much, much research to be done, but the important point you made, I think it's very important to look... deeply and more closely to the type and how the plaque looks like with MRI imaging, but also with ultrasounds, methods.

00:28:52: There are different ways to have a better look also.

00:28:54: For example, you can do symbolic monitoring, so how active a plaque is and so forth.

00:29:01: So there are many ways to look a bit closer into that area.

00:29:08: Thank you.

00:29:09: Thank you, Mira.

00:29:09: Diana, your thoughts on that?

00:29:13: Yes, I agree.

00:29:14: I think in the future, we will go more and more to this carefully phenotyped high-risk subgroups.

00:29:21: So for example, intraplac bleeding is becoming more and more a feature that we know it's high risk.

00:29:29: So I agree, we do need to understand better these groups and then to do new trials to assess whether interventions such as in the track to mistanding maybe medical treatment, should be tailored for the specific groups of patients and probably the same.

00:29:46: within atrial cardiomyopathy and the other group also cancer related coagulopathy and all the other groups.

00:29:54: we will more and more have data on the pathophysiology on the risk of these subgroups and then we will have to move to highly selected trials with patient selection that is really according to these high-risk features and then we test the interventions that can improve outcomes in these groups of patients.

00:30:17: I think that's the next step in this field.

00:30:21: Thank you very much, both of you.

00:30:23: I will ask one more question and then we will close the session.

00:30:27: Looking ahead, what future research directions or ongoing trials might change how we diagnose?

00:30:33: And basically treat what Mira said from the beginning, we need to treat and prevent the next stroke in this field.

00:30:43: Diana, we'll start with you.

00:30:46: Yes, we do have these trials, navigators, respectees, articles, Arcadia as well.

00:30:52: And we now have to wait for the new studies that will have this subgroup analysis.

00:30:59: and also that will guide the future trials.

00:31:02: And I do think Miura probably wants to speak about the Moses trial and there are other trials also already ongoing trying to look into these specific subgroups.

00:31:12: So I really think, as I said, that we will shift away from treating Jesus and has an entity and we'll really go towards this mechanism-based strategy is very specific for each subgroup.

00:31:28: Carefully phenotype these subgroups.

00:31:30: And rather than simply labeling people as easels or cryptogenic stroke, we will more and more do more exams and use more patient features to develop new studies.

00:31:45: But I guess Mira wants to talk also about some of the ongoing trials.

00:31:52: Yes, please Mira enlighten us.

00:31:55: Yes, I don't know if I can enlighten you, but I can share some insights and some thoughts.

00:32:02: I think Diana also already put it very well, so I think the future moves maybe really away from just... using ISIS as a guiding label.

00:32:13: So I think it's really the new approach is more mechanism based and risk adapted.

00:32:18: So there are two factors, I think, which are important.

00:32:21: One thing is, what are the underlying mechanisms of the potentially future stroke?

00:32:29: And how is that risk?

00:32:31: So you could also have a mechanism potentially there, but very low risk.

00:32:38: And if you have a very low risk, there is also the question if you should treat them or not.

00:32:43: That's, for example, the issue with atrial fibrillation, which is very, very short.

00:32:49: You have a potential mechanism and you know how potentially if that mechanism has a high burden, high risk, how to treat it.

00:32:59: We don't really know what happens if we identify that mechanism and the burden is very low.

00:33:05: So I think these two things are important.

00:33:08: It's a shift towards mechanism-based and risk-adapted or risk-adjusted.

00:33:14: So what would really help is to have features, including blood biomarkers, but also other imaging biomarkers and so on, to really identify those patients with a specific underlying mechanism, such as, for example, cardiombolic mechanism, but also those who have the highest risk to have a re-event and then intervene there with the right drug and the right dose.

00:33:41: So that's kind of where I envision the future.

00:33:45: So, you know, tailoring the therapy to the most likely cause which will be relevant for the next stroke to happen.

00:33:53: And it's quite complex if you think about it because that changes over time as well.

00:33:58: So it might be that, you know, for a certain time point, you will benefit most from oral anticoagulation because you're underlying.

00:34:06: mechanisms of cardiomboleism.

00:34:09: risk is highest in that time period, which made shift over time as well.

00:34:14: So to have like sensors and monitor over time underlying mechanisms and then treat them accordingly, that would be maybe sounds a bit sense, sense, sense fiction right now.

00:34:26: But I think that's what we're trying to get at and and treat this multiple causes which have you know different attributable risks over time.

00:34:38: And I think that's actually its future.

00:34:40: So the future will be more precision prevention and maybe not just lying back to strict classifications one time point.

00:34:50: I think that's could be the future.

00:34:54: Thank you.

00:34:54: Thank you very much, both of you.

00:34:56: It was a very, very interesting discussion and a very interesting podcast.

00:35:01: I would like to thank all the listeners and hope to see you in another podcast of the EANcast.

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