Ep. 213: Plaque / Atherosclerosis at risk

00:00:00: Welcome to EANcast, your weekly source for education, research, and updates from the European Academy of Neurology.

00:00:15: Hello and welcome to EANcast Weekly Neurology. My name is Jurgita Valaikienė. I'm an associate professor at Vilnius University Center of Neurology, Lithuania.

00:00:26: Today, we're going to be talking about the latest research on cerebrovascular risk factors and the multimodal assessment of carotid plaques at risk.

00:00:36: We will introduce a new stroke risk classification system known as Carotid Plaque-RADS, and how it can be applied using different imaging modalities, such as ultrasound, computed tomography, and magnetic resonance imaging, and how to identify high-risk patients in order to prevent ischemic stroke.

00:00:58: My guest today is Cristina Duque. She is a neurologist and neurosonologist at Hospital Pedro Hispano, Matosinhos Local Health Unit, Portugal.

00:01:08: Welcome, Cristina, and thank you for joining us today.

00:01:12: Thank you, Jurgita. It's a real pleasure to be here and to talk about this very relevant subject.

00:01:20: As we all know, cardiovascular diseases are a leading cause of death and disability, mainly due to heart attack and stroke.

00:01:25: According to the latest data, the incidence of atherosclerotic cardiovascular disease has increased and is recognized as a leading determinant of morbidity and mortality.

00:01:32: Let's begin our talk with the terminology and definitions. Which atherosclerotic plaques are considered plaques at risk? And what does it mean for the cardiovascular-risk patient?

00:01:40: To be more specific, what actually makes a plaque dangerous beyond how much it narrows the artery?

00:01:45: What structural features define vulnerability, and how do they link to the risk of stroke?

00:01:49: Yeah, that's a really great question. So, the essential idea is that most carotid strokes are not caused by the arteries simply being too narrow. They are caused by embolism.

00:02:02: A plaque becomes dangerous when its surface ruptures, a thrombus forms on it, and material embolizes to the brain or the eye.

00:02:12: So, that tendency to rupture has surprisingly little to do with the degree of stenosis. And, as you said, the structural features that define vulnerability are well described.

00:02:26: We know that they include a large lipid-rich necrotic core, a thin or ruptured fibrous cap, intraplaque hemorrhage, and also intraplaque neovascularization.

00:02:38: This means that there is ingrowth of fragile new vessels from the vasa vasorum that can leak and bleed.

00:02:46: We can also add outward, or positive, remodeling, where the plaque grows outward rather than into the lumen.

00:02:55: So it can stay angiographically almost hidden while becoming biologically dangerous.

00:03:01: From the data we know, and specifically from the statement on the transition from the vulnerable plaque to the vulnerable patient, this concept has shifted.

00:03:14: This shift has been from thinking about a percentage of narrowing to thinking about the biology of the plaque and, ultimately, also the risk profile of the whole patient.

00:03:27: So we would say that a plaque at risk would be an unstable, emboligenic, lipid-rich plaque.

00:03:34: And, of course, identifying it matters because that is the patient in whom we can intervene to prevent a first or recurrent stroke.

00:03:45: Thank you. Are the location, size, and number of carotid plaques also important in evaluating atherosclerosis at risk?

00:03:53: How does the location of atherosclerosis differ between Caucasian and other populations?

00:03:59: And how and when can we detect and accurately evaluate carotid plaques and monitor them, applying appropriate treatment for their stabilization?

00:04:10: Yes, of course, the burden matters, not just the single tightest lesion.

00:04:18: And this concept of a carotid plaque burden score, where we sum plaque across multiple segments and on both sides, will reflect this local atherosclerotic load.

00:04:38: And that total burden is itself predictive of vascular events, independent of any one stenosis.

00:04:50: So counting and measuring plaques and following them over time gives information that the single stenosis percentage does not.

00:05:06: As you said, the location differs significantly between populations, and this is very relevant for our clinical practice.

00:05:13: So, in Caucasian populations, atherosclerosis is predominantly extracranial, particularly at the carotid bifurcation and proximal internal carotid artery.

00:05:22: In East Asian populations, intracranial atherosclerotic disease is far more common. It can affect the distal internal carotid artery and the middle cerebral artery.

00:05:31: And this has direct consequences for us as neurosonologists. So, a cervical duplex study that is entirely normal will not exclude significant intracranial atherosclerosis.

00:05:41: In patients from populations at higher risk of intracranial disease, and when assessing cerebrovascular risk, we need a lower threshold for studying intracranial vessels with transcranial Doppler.

00:05:53: And this is also part of why conditions like Moyamoya disease, which, as we know, is an intracranial steno-occlusive disease, will enter the differential diagnosis more prominently in these populations.

00:06:05: And when we think about when or who should perform these examinations, this would ideally be done by a trained neurosonologist, ideally again with a high-resolution ultrasound system and in a laboratory with quality standards.

00:06:24: The reality is that duplex ultrasound is used widely. It's widely available.

00:06:30: With proper training, the detection of plaque and characterization of its features can be performed quite broadly.

00:06:40: And this is exactly where monitoring is where ultrasound excels, because it is repeatable and non-invasive.

00:06:49: So we can actually follow the plaque over time and escalate treatment if it progresses or if we find new high-risk features.

00:07:00: I totally agree with you. You mentioned age when talking about risk factors for atherosclerosis, young and old.

00:07:18: What can we find by performing cervical duplex ultrasound in younger patients?

00:07:31: Yes, age is very important. It changes what we call the pre-test probability enormously.

00:07:36: If we think about younger patients, if we find abnormalities on Doppler ultrasound, we have to investigate whether it's truly atherosclerosis, because we can see several non-atherosclerotic causes on ultrasound that are more common in young people and that have distinctive imaging features.

00:07:55: For example, carotid artery dissection will produce an intramural hematoma with a tapering lumen. Sometimes we can see an intimal flap.

00:08:03: If we see fibromuscular dysplasia, it can give a beaded appearance, mostly in the mid to distal internal carotid artery.

00:08:11: A carotid web, which is increasingly recognized and is considered by some to be an atypical manifestation of fibromuscular dysplasia, will appear as a thin shelf-like projection from the posterior wall of the carotid bulb.

00:08:25: And this can be a very important cause of cryptogenic stroke in young patients. Of course, if the disease is intracranial and progressive, we have to consider Moyamoya disease.

00:08:37: And so, in older patients, of course, the overwhelming likelihood would be atherosclerosis.

00:08:42: We know from ancillary studies, such as the Rotterdam Study and others, that age, hypertension, and smoking drive the prevalence and progression of carotid disease at the population level.

00:08:55: Thank you. You already mentioned that patients with vulnerable plaques were initially described in the context of coronary arteries.

00:09:04: It was pointed out that these plaques may contribute to the conversion of chronic coronary atherosclerosis to acute coronary artery disease.

00:09:14: And in recent years, the Coronary Artery Disease Reporting and Data System, CAD-RADS, was developed to standardize the reporting of coronary CT angiography.

00:09:26: What is the newly introduced Carotid Plaque-RADS? How are the categories structured? And what does it add?

00:09:33: Would it be applicable in everyday clinical practice in addition to stenosis grading by NASCET?

00:09:40: Is Plaque-RADS ready to guide intervention decisions, or perhaps is it still a research and stratification tool?

00:09:49: That's very important to discuss because this parallel with CAD-RADS is exactly the right way to look at it.

00:09:59: In cardiology, they recognized that writing reports freely in our own way would lead to inconsistency.

00:10:08: CAD-RADS standardized these findings into reproducible categories that, in the end, help guide management.

00:10:18: So we now have the Carotid Plaque-RADS, which applies the same philosophy to carotid plaques. The system ranges from Plaque-RADS 1 to Plaque-RADS 4.

00:10:32: Plaque-RADS 1 indicates the absence of atherosclerotic plaque. Plaque-RADS 2 indicates a plaque with low attributable risk.

00:10:44: Plaque-RADS 3 represents a plaque with moderate risk and includes subcategories 3a, 3b, and 3c, depending on features such as a lipid-rich necrotic core, fibrous-cap characteristics, or a healed ulcerated plaque.

00:11:04: And Plaque-RADS 4 represents a complicated plaque with high risk. It includes 4a, intraplaque hemorrhage; 4b, fibrous-cap rupture; and 4c, intraluminal thrombus.

00:11:19: Another very important aspect is that this categorization is designed to work across different imaging modalities: ultrasound, CT, and MRI.

00:11:32: The same language can therefore be used to describe plaque, regardless of where or how it is imaged.

00:11:42: What it adds over NASCET, which we use more for quantification, is a sort of second axis of information. NASCET, as we know, tells you how tight the stenosis is.

00:12:00: Plaque-RADS actually tells you more about how high-risk the plaque morphology is.

00:12:09: And used together, they should be far more informative than either alone, especially in the gray area of moderate stenosis.

00:12:22: I think that currently it is not yet a decision-maker for surgery or stenting.

00:12:31: We really do lack prospective trials that will show that the Plaque-RADS category alone should determine whether to intervene.

00:12:45: So it is a powerful stratification and research tool, and it's a structured way to incorporate the vulnerable-plaque concept into clinical decision-making, of course alongside symptoms and stenosis.

00:13:08: That's interesting. Are you already using Carotid Plaque-RADS in your hospital, I would like to ask?

00:13:16: And could a lack of time, lack of experienced sonographers, or lack of high-resolution ultrasound systems negatively influence the implementation of Carotid Plaque-RADS into clinical practice?

00:13:32: What do you think?

00:13:34: We are beginning to apply these principles, doing this systematic characterization and trying to provide a structured description.

00:13:42: I think that, for most centers, including ours, it is still being integrated rather than already fully embedded. I think the barriers you name are exactly the important ones.

00:13:54: Time—proper plaque characterization will take, of course, longer than simply reporting a velocity and a percentage.

00:14:02: So we all know we work in busy laboratories where time pressure is really significant. So this would be one limitation.

00:14:10: The other one, which is transversal to the whole field of neurosonology, is that expertise is very important.

00:14:18: Reproducible classification will require trained, experienced sonographers.

00:14:23: This variability between observers is a genuine limitation without adequate training, and even sometimes among highly trained specialists.

00:14:33: We need good equipment. We need a machine that can assess surface features and this fine morphology, which requires high-resolution systems.

00:14:46: And, which is very important, also contrast capability—the possibility of performing contrast-enhanced ultrasound (CEUS) to assess neovascularization.

00:15:00: Not every center will have this ability.

00:15:04: I think none of these limitations is impossible to overcome, but they mean that adoption will probably be gradual and will depend on training programs and, of course, on the results of studies that prove that this effort really changes outcomes.

00:15:28: Thank you. Would you like to point out how CT angiography, MRI, and digital subtraction angiography compare for vulnerable-plaque imaging?

00:15:48: How would you compare these imaging modalities?

00:15:55: When we use B-mode ultrasound, we know that it has really high temporal resolution. It's in real time.

00:16:00: It's widely available, it doesn't involve radiation, and it is really good at assessing echogenicity, so distinguishing an echolucent, lipid-rich, potentially more dangerous plaque from an echogenic or calcified plaque.

00:16:13: For surface details and ulceration, it can be harder to assess.

00:16:16: And, of course, we know that if there is calcification, we can have acoustic shadowing that will make our assessment more difficult.

00:16:23: When we use contrast-enhanced ultrasound, we add something that B-mode cannot provide.

00:16:28: We use microbubble contrast agents that can demonstrate plaque neovascularization, and this has been associated with intraplaque hemorrhage and a large lipid-rich core.

00:16:38: It is not commonly used because of the time required and the need for a trained operator.

00:16:43: It is also not yet embedded in guidelines, so it is a selective tool rather than a routine one. Maybe we hope that with time this changes.

00:16:51: If we think about other modalities that we use to study atherosclerosis and unstable plaque, we know that CT angiography is fast and excellent for assessing calcification and grading stenosis—a sort of anatomical roadmap.

00:17:08: The trade-offs would be radiation, contrast administration, and sometimes calcium blooming, which can obscure the lumen.

00:17:17: When we think and know more and more about vessel-wall MRI, this is particularly strong for plaque composition.

00:17:26: It allows us to study the fibrous-cap integrity and to detail plaque characteristics. Not all centers will have this available, and it is also slower and sensitive to motion.

00:17:40: And, of course, digital subtraction angiography remains a reference technique for assessing the lumen and hemodynamics.

00:17:49: It is invasive and has a small procedural risk, so, of course, we use it mainly in inconclusive cases or when we are planning an intervention.

00:18:00: So I would summarize this as: ultrasound and contrast-enhanced ultrasound for plaque assessment and monitoring, MRI for composition, CT for anatomical mapping, and angiography for problem-solving and intervention planning.

00:18:18: Thank you very much for such a detailed explanation. I would like to return to ICA stenosis grading according to NASCET criteria.

00:18:37: Do we need to add ECST criteria very shortly, or not?

00:18:45: I think the important thing is that we have to report which method we are using and be consistent because they are not interchangeable.

00:18:54: We know that NASCET compares the residual lumen at the site of stenosis with the normal distal internal carotid artery.

00:19:03: ECST compares it with the estimated original diameter at the level of the stenosis. So this means that ECST will generally give a higher percentage for the same lesion.

00:19:14: The trials that established the thresholds for intervention used the NASCET methodology. So we have to know this.

00:19:22: That would be the standard reporting, and I would not add ECST for its own sake because it can create confusion and sometimes lead to overtreatment if the numbers are mixed.

00:19:35: I think that we have to be able to convert between the methods, know how to interpret them, and be consistent.

00:19:43: You are right. In your opinion, what is the difference between a standard carotid ultrasound and point-of-care ultrasound, or POCUS?

00:19:53: And what questions could POCUS answer in symptomatic patients in the emergency department, ICU, or ambulatory setting?

00:20:02: Could it change the management of stroke patients when we're talking about carotid artery stenosis and plaques?

00:20:11: Yes, POCUS is very important to discuss and reflect on because the difference is really one of scope and clinical question.

00:20:27: When we do a standardized carotid ultrasound, it would be comprehensive, bilateral, and systematic, ideally including assessment of the intracranial vessels in acute stroke patients as well.

00:20:52: We are doing full stenosis quantification. POCUS is focused, so we are asking a specific, time-critical question at the bedside.

00:21:10: For example, in a symptomatic patient in the emergency department or ICU, the question is: Is there a culprit lesion ipsilateral to the symptoms that changes what I will do in the next hour?

00:21:25: A significant ipsilateral plaque, near-occlusion, occlusion, or dissection—these findings will generally change management.

00:21:35: They will influence the urgency of definitive imaging, treatment options, and whether the patient needs urgent vascular assessment.

00:21:46: And, of course, after amaurosis fugax or TIA in an outpatient setting, a focused look at the ipsilateral carotid can rapidly confirm our suspicion of a significant symptomatic stenosis.

00:22:01: That, in the end, will set the pace of the work-up.

00:22:06: I think what a non-specialist can reliably do in a few minutes is assess the presence and side of a significant plaque, a gross morphological category, a peak-velocity estimate that can flag significant stenosis, and the color flow that can identify an obvious occlusion.

00:22:30: What they cannot do reliably is grade stenosis comprehensively or characterize the surface for ulceration, detailed plaque morphology, or exclude dissection.

00:22:44: This will require a more specialized examination. POCUS is therefore more about triage. It guides urgency; it does not replace a formal study.

00:22:57: And I think knowing that boundary is what makes it safe and very useful.

00:23:04: Yes, that's very important, thank you. Sometimes when performing POCUS, we can detect microembolic signals. Have you done that already or not?

00:23:20: Several microembolic signals may signal a source of embolism in stroke. What do you think about that?

00:23:32: Yeah, it's another high-risk feature associated with an unstable plaque.

00:23:35: And we know from previous studies that it can even help us to guide our decisions regarding the antiplatelet regimen.

00:23:41: So, of course, if we are able to perform a study of microembolic signals, whether spontaneously in an acute setting or during stroke-unit admission, it can be very important in guiding our decisions and characterizing the embolic risk of that patient.

00:23:53: Of course, microembolic signals do not necessarily originate from carotid plaques. They can also come from the heart or the aorta.

00:23:59: So it can help us and guide this initial evaluation.

00:24:02: Yes, yes, exactly.

00:24:03: Neurologists with knowledge of cerebral vascular anatomy have the advantage of knowing where to look when using targeted ultrasound according to the neurological symptoms and signs, as you mentioned.

00:24:24: Would we teach non-neurologists how to do that? What do you think?

00:24:31: I think we can. I think we must. Of course, there are many, at least in my context, internal medicine doctors who act as the first line of care for stroke patients.

00:24:43: The neurologist's advantage is exactly what you describe. It's symptom-driven. We form a hypothesis and perform targeted scanning.

00:24:53: We localize based on the clinical picture, so we know which vessel and which vascular territory to study. And that clinical reasoning is teachable.

00:25:04: I think that with a structured curriculum, we can define competencies and have a clear understanding of focused ultrasound protocols and cerebrovascular anatomy.

00:25:17: So I think general POCUS training will teach people to operate the machine.

00:25:22: And I think that dedicated neuro-oriented POCUS, with proper anatomical orientation, will be very helpful.

00:25:31: That's so important. And how do you see the future of ultrasound diagnostics and stroke management?

00:25:44: What will most change how we stratify carotid stroke risk in the next few years, and what about using AI?

00:25:58: I think, on the one hand, we should really converge on standardized reporting. And I think that AI will have a role in this, of course.

00:26:28: Because, as we said before, the main limitation of plaque characterization is inter-observer variability.

00:26:37: Even two skilled readers can classify the same plaque differently, and that can undermine any risk system.

00:26:47: So maybe AI analysis, trained on histologically validated data, can make that assessment more reproducible and quantitative, in real time, directly from B-mode imaging.

00:27:02: If we combine this with enhancement using contrast for neovascularization and also with this standardized reporting framework, we will move from a largely qualitative exercise towards something that is reproducible—a risk score that is repeatable and that allows us to set up other large longitudinal studies.

00:27:30: And in the end, this will lead us to identify the truly vulnerable patient, and not just the vulnerable plaque.

00:27:40: So again, through large, multicenter, multimodal research, with comparison with other MRI vessel-wall imaging techniques and also PET scans, we can prove the value and cost-effectiveness before this will eventually reach routine guidelines.

00:28:02: Thank you, Cristina, for your interesting talk. Now it's time to summarize our talk.

00:28:05: Carotid plaques at risk are unstable, emboligenic, lipid-rich atherosclerotic plaques characterized by features such as a thin or ruptured fibrous cap, intraplaque hemorrhage, intraplaque neovascularization, and outward remodeling.

00:28:15: They may remain angiographically inconspicuous while becoming biologically dangerous, with the potential to cause embolic events in the brain or eye, including TIA and acute ischemic stroke.

00:28:24: The Carotid Plaque-RADS system provides a standardized evaluation of carotid plaque morphology using a multimodal approach.

00:28:29: Carotid Plaque-RADS may help to identify patients at increased risk of cerebrovascular events and improve communication and risk stratification.

00:28:35: As Cristina told us, it is recommended to grade stenosis according to NASCET criteria and, in addition, to apply standardized plaque characterization to improve risk stratification and optimize medical treatment.

00:28:45: Whether an intervention is indicated should continue to be based on the established clinical criteria, including symptoms and degree of stenosis, until prospective evidence demonstrates that Plaque-RADS categories themselves should guide intervention.

00:28:56: And non-invasive cervical color-coded duplex ultrasonography, with or without contrast agents, can be used for the detection, assessment, and monitoring of carotid plaques at risk.

00:29:11: Furthermore, as Cristina told us, large multicenter research on vulnerable carotid plaques, including ultrasound and AI-assisted plaque analysis, is needed to demonstrate the importance of POCUS and standardized neurological examination and to support their integration into cerebrovascular disease prevention and stroke guidelines.

00:29:39: Cristina, would you like to add something to this summary?

00:29:44: I think you summarized it pretty well.

00:29:49: And I think it's important that we use Doppler not only in the laboratory for our patients, not only in the stroke unit, but also in the emergency room and outpatient clinics.

00:30:14: So I think it really is a tool that has to be present at all times in the care of our stroke patients.

00:30:28: And it can allow us to really individualize treatment and follow-up and prevent new strokes.

00:30:42: Thank you for your wonderful and informative talk.

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