Carotid atherosclerosis—a buildup of plaque in the neck arteries—is a leading cause of stroke, and this review explains how modern ultrasound technology has moved far beyond simply measuring how narrow the artery has become. Researchers now recognize that the characteristics of the plaque itself—whether it is soft and fatty, whether it has a thin or ruptured cap, whether it contains new blood vessels or microcalcifications—are critical predictors of stroke risk. This article translates the latest advances in noninvasive carotid wall imaging, including plaque echogenicity grading, Gray-Scale Median (GSM) analysis, contrast-enhanced ultrasound (CEUS), and elastography, into clear, actionable information for patients and their families.
Your carotid arteries are the two large blood vessels on either side of your neck that carry oxygen-rich blood from your heart to your brain. When these arteries become narrowed or blocked by a buildup of fatty deposits, cholesterol, and other substances—a condition called carotid atherosclerosis—the consequences can be devastating.
Carotid atherosclerosis is a major cause of transient ischemic attacks (TIAs, often called "mini-strokes") and full-blown strokes, which are associated with significant illness and death in Western societies. According to this review, ultrasound remains the first-line imaging modality for screening, diagnosing, grading, and following up on carotid atherosclerotic disease. The technique's value lies not only in its cost-effectiveness, widespread availability, excellent safety profile, and reproducibility, but also in its evolving multiparametric nature.
Multiparametric ultrasound combines anatomic information from B-mode imaging (which creates a two-dimensional grayscale picture of the artery) with flow-visualization techniques and physiologic information acquired through pulsed-wave Doppler techniques (which measure the speed and direction of blood flow). Two newer additions—contrast-enhanced ultrasound (CEUS) and elastography—have expanded the diagnostic information available for evaluating carotid atherosclerosis.
For decades, doctors relied almost exclusively on one measurement to predict stroke risk: the percentage of luminal stenosis, or how much the plaque was blocking the artery. However, this traditional approach has been increasingly criticized. Both studies and clinical observations have shown that certain plaques producing milder degrees of stenosis may still lead to acute cerebral infarction (stroke).
The concept of the "vulnerable plaque" has emerged as a paradigm shift in how we think about stroke risk. A vulnerable plaque is one that is prone to rupture, leading to blood clot formation, acute occlusion of the artery, and embolic events (where a clot breaks off and travels to the brain). The main vulnerability features of carotid plaques include:
This shift in thinking is particularly important for a condition called embolic stroke of undetermined source (ESUS). The concept that ESUS is primarily of cardiogenic origin (originating from the heart) and potentially merits anticoagulation has not been confirmed by randomized clinical trials. Instead, nonstenosing thrombogenic atheromas (plaques that don't significantly narrow the artery but are prone to clot formation) may be the underlying pathology in a significant proportion of the etiologically heterogeneous ESUS population.
The numbers are striking: large non-stenosing internal carotid artery plaques on the same side as the cerebral ischemia (ipsilateral) have been identified in 35% of ESUS patients using CT angiography and in 25% using color Doppler imaging. Furthermore, intraplaque hemorrhage was identified using MRI in ipsilateral carotid atheromas in one out of five patients with ESUS.
This means that a considerable percentage of stroke survivors with symptomatic carotid plaques have less than 70% stenosis—a level that would traditionally have been considered relatively low risk. The traditional parameters used for describing carotid atheromas (degree of stenosis and systolic peak velocity) now appear to be insufficient predictors of the risk of embolization.
Plaque formation is the result of a chronic, progressive inflammatory process leading to deposits inside the sub-endothelial layer of the carotid wall. These deposits consist of lipids (fats), connective tissue extracellular matrix (collagen, proteoglycans, fibronectin, and elastic fibers), and cells such as macrophages, T-lymphocytes, and smooth muscle cells. Plaque echogenicity—how bright or dark a plaque appears on ultrasound—is the imaging visualization of this process.
In a historical study from the late 1980s, Gray-Weale and colleagues studied the importance of carotid plaque echogenicity, showing a correlation between the preoperative ultrasound appearance of atherosclerotic carotid plaques and the histological characteristics of carotid endarterectomy specimens (tissue removed during surgery). They demonstrated that plaques of lower echogenicity (darker appearance) were associated with an increased frequency of hemorrhage and lipid burden.
Based on B-mode ultrasound, Gray-Weale and Nicolaides proposed a grading system based on echogenicity that classifies atherosclerotic plaques into five types:
Hypoechoic plaques (types 1 and 2) are associated with intraplaque hemorrhage and lipid accumulation, whereas hyperechoic homogeneous plaques (types 3 and 4) are predominantly fibrous or calcified in nature. As a result, the first two categories appear to be associated with a higher risk for surface disruption or rupture and yield a subsequent significantly higher risk of ipsilateral stroke when compared with non-echolucent plaques.
On the contrary, types 4 and 5 plaques are mainly encountered in patients with asymptomatic carotid disease (those who have not yet experienced symptoms). Calcifications have been found to play an important role in plaque stabilization, and lipid-rich plaques appear to be more often actively inflamed than either calcified or collagen-rich (hyperechoic) plaques. Thus, heavily calcified carotid plaques could represent a chronic, less actively inflamed form of atherosclerosis.
However, there is an important caveat: calcified intraluminal plaques may occasionally cause ischemia when the calcified material embolizes into the brain. The review illustrates a clinical case of a free-floating calcified plaque causing embolic stroke, where multiple calcific emboli were visible on brain CT scans.
The clinical significance of echolucent plaques extends beyond stroke risk. Patients with asymptomatic carotid plaques of low echogenicity have more frequently MRI (T2/FLAIR) T2 hyperintensities in the periventricular and subcortical white matter, silent lacunar lesions, or cerebral microbleeds—all of which convey an increased risk of cognitive decline and vascular dementia. Moreover, echolucent plaques are associated with an increased risk of stroke in patients undergoing carotid stenting and are associated with new cerebral ischemic lesions following endarterectomy (surgical removal of the plaque).
A study performed on 1,061 patients undergoing carotid endarterectomy associated plaque hypoechogenicity and ulcerations with the occurrence of new ischemic lesions on diffusion-weighted imaging 30 days post-surgery.
A meta-analysis involving 7,557 asymptomatic patients followed for more than 3 years demonstrated that plaques described as echolucent, showing intraplaque neovascularization and ulceration, were associated with twice the risk of ischemic symptoms compared to stable echogenic plaques.
While the Gray-Weale classification is useful, it is somewhat subjective. To address this, another parameter—the Gray-Scale Median (GSM)—was introduced to quantify plaque echogenicity in a more objective and reproducible manner.
Quantitative assessment of the plaque is performed by a computer system that assigns certain gray-scale values to blood and adventitia (the outer layer of the artery wall). GSM values from known tissue components are used, and the measurement of the region of interest is expressed in a 256 gray-tone range where 0 is black and 255 is white. The GSM value of an entire plaque is obtained from a histogram calculated by software analysis.
Plaques containing more calcium and fibrous tissue have higher GSM values, whereas plaques with richer lipid cores and hemorrhagic components have lower GSM values. Atherosclerotic lesions with lower GSM are more prone to rupture, and a lower GSM value may be considered an independent risk factor for stroke.
Carotid bifurcation plaques in patients with silent non-lacunar infarcts (small areas of brain damage that occur without noticeable symptoms) are usually hypoechoic and of low GSM, even in the absence of critical luminal stenosis. This reinforces the message that plaque composition matters independently of the degree of narrowing.
During the last decade, the term "juxtaluminal black area" (JBA) has been introduced in the study of plaque echogenicity. JBA is defined as an area with a GSM value of less than 25 adjacent to the lumen (the open channel through which blood flows) without a visible fibrous cap. This area has been linked linearly to elevated stroke risk.
Histologic studies performed on endarterectomy specimens have shown that JBA in ultrasound images is associated with lipid core proximity to the vascular lumen. The lipid-rich necrotic core is closer to the lumen in symptomatic plaques causing thromboembolic phenomena in comparison to more stable asymptomatic plaques.
A study showed that the size of the JBA in asymptomatic carotid atheromas is linked to the possibility of a future ischemic event and can be used in stroke risk stratification models. The risk numbers are specific and important:
A JBA greater than 4 mm is considered a considerable carotid disease indicator. These numbers give doctors and patients a more precise way to estimate individual risk and make treatment decisions.
The fibrous cap is a layer of fibrous connective tissue containing macrophages and smooth-muscle cells within a collagen-proteoglycan matrix associated with T-lymphocytes. It covers the necrotic lipid core and constitutes a barrier separating the vascular lumen from the thrombogenic (clot-promoting) atheromatous contents of the plaque.
Think of the fibrous cap as a safety shield: as long as it remains intact, the dangerous contents of the plaque are kept away from the bloodstream. Different caps vary in thickness, composition, and collagen content, and thus in stability. The rupture usually occurs in areas where the cap is the thinnest and often most heavily infiltrated by macrophage foam cells.
Fibrous cap thickness measurement of carotid atheromas with ultrasound is feasible, albeit technically demanding. Furthermore, discrimination of symptomatic from asymptomatic plaques based on ultrasound-measured mean cap thickness values is good and merits further development.
However, there are limitations. Some fibrous caps may be so thin that they are usually not visible on classical ultrasound, while in heavily calcified plaques, cap visualization may be impossible. Newer high-resolution ultrasound devices with shear-wave elastography are able to visualize thick fibrous caps, especially in hypoechoic plaques.
A recently introduced imaging technology called MicroPure™ (Toshiba Medical Systems Corp., Tokyo, Japan) may improve visualization of microcalcifications on ultrasound. These are tiny calcium deposits that are too small to be seen with conventional imaging but may be important markers of plaque vulnerability.
This imaging technology allows the identification of the "Firefly sign": microcalcifications are displayed as white dots on a blue background, similar to fireflies flickering in the dark. These signs are located in the fibrous caps of carotid atheromas and may be associated with plaque vulnerability.
A 4-point Firefly score system has been developed, and recent studies indicate that Firefly-positive atherosclerotic lesions are at an increased risk for rupture and embolic cerebral infarcts (strokes caused by clots traveling to the brain).
Contrast-enhanced ultrasound (CEUS) represents one of the most significant recent advances in carotid wall imaging. This technique involves the injection of microbubbles (tiny gas-filled microspheres) into the bloodstream, which then circulate through the blood vessels and can be visualized on ultrasound.
CEUS is particularly valuable for assessing intraplaque neovascularization—the growth of new, fragile blood vessels into the plaque itself. These new vessels are typically immature and leaky, allowing inflammatory cells and red blood cells to enter the plaque, which can contribute to plaque growth and instability. The presence and extent of intraplaque neovascularization as seen on CEUS has been correlated with:
The review emphasizes that CEUS can detect and grade the degree of intraplaque neovascularization, providing a functional assessment that complements the anatomic information from B-mode imaging. This is particularly valuable because intraplaque neovascularization is one of the key features of vulnerable plaques and cannot be reliably assessed with conventional ultrasound alone.
Elastography is another recent addition to the ultrasound toolkit that measures the mechanical properties of tissue—specifically, its stiffness or elasticity. The principle is simple: different tissues have different stiffness, and this can be measured by how they respond to mechanical stress.
In carotid plaque assessment, shear-wave elastography (SWE) is the most commonly used technique. It works by using an acoustic radiation force impulse to generate shear waves in the tissue, and then measuring the speed of these waves. Faster shear-wave velocities indicate stiffer tissue.
The clinical value of elastography lies in its ability to differentiate between different plaque components:
This information is complementary to echogenicity. A plaque that appears hypoechoic (dark) on B-mode could be either a soft lipid-rich plaque (high risk) or a relatively benign fibrous plaque. Elastography helps distinguish between these possibilities by measuring the actual mechanical properties of the tissue.
The review illustrates a clinical case where shear-wave elastography showed low shear-wave velocity values and thus lower stiffness in the plaque's core (appearing dark blue on the elastogram) but a slightly higher value and stiffness for the fibrous cap. This combination of findings—a soft core with a relatively stiffer cap—is characteristic of a vulnerable plaque.
The advances described in this review have several important implications for patients at risk of stroke:
First, the degree of stenosis is no longer the sole determinant of risk. Patients with non-significant narrowing of their carotid arteries may still be at substantial risk if their plaques have vulnerable features. This is particularly relevant for the large population of patients with ESUS, where nonstenosing atheromas may be the underlying cause in a significant proportion of cases.
Second, modern ultrasound can provide a comprehensive "plaque vulnerability profile." A state-of-the-art carotid ultrasound scan should now evaluate and report not just the degree of stenosis, but also plaque echogenicity (using both the Gray-Weale classification and GSM), surface morphology (looking for ulcerations), the presence of intraplaque neovascularization (using CEUS), plaque stiffness (using elastography), and the presence of microcalcifications (using MicroPure™ technology).
Third, treatment decisions can be better informed. The identification of vulnerable plaque features may influence decisions about:
Fourth, monitoring treatment response is possible. A plaque that appears to become progressively more echogenic over time is possibly an indicator that its histological composition is changing and its stability is increasing. Early and aggressive treatment with statins at high doses seems to increase the echogenicity of carotid plaques, making them less prone to rupture. This means that ultrasound can be used not just for diagnosis but also for monitoring the effectiveness of medical therapy.
Fifth, the field is moving toward artificial intelligence. There has been a lot of research during the last years toward the use of radiomics and machine learning. Carotid ultrasound, being operator-dependent, is expected to benefit from the use of artificial intelligence. Ultrasound-based radiomics models can be constructed by extracting features from grayscale images and may identify and quantify target features such as total plaque volume and composition (calcium, intraplaque hemorrhage, lipids), thereby predicting cerebrovascular ischemia risk. Latest studies show that radiomics can reveal information invisible on advanced ultrasound imaging.
While the advances described in this review are significant, it is important to acknowledge the limitations of current ultrasound techniques:
Based on the findings of this review, here are actionable recommendations for patients:
In summary, the field of carotid wall imaging has evolved dramatically. The traditional focus on the degree of stenosis has been replaced by a more nuanced understanding of plaque vulnerability. Modern ultrasound, with its multiparametric capabilities, is well-suited to provide accurate evaluation of the vulnerability of carotid plaques. For patients, this means more precise risk stratification, better-informed treatment decisions, and the potential for earlier intervention to prevent devastating strokes.
Carotid atherosclerosis is a buildup of fatty deposits, cholesterol, and other substances in the carotid arteries, the large blood vessels on each side of your neck that supply blood to your brain. This buildup can narrow or block the arteries, and it is a major cause of transient ischemic attacks (TIAs or mini-strokes) and full-blown strokes.
Traditional risk assessment focused only on how much the plaque blocks the artery. However, research shows that some plaques causing milder narrowing can still lead to stroke. The concept of the 'vulnerable plaque' emphasizes that plaque characteristics—such as a soft, fatty core, a thin or ruptured cap, or new blood vessels—are critical predictors of stroke risk, even when stenosis is less than 70%.
Plaque echogenicity refers to how bright or dark a plaque appears on ultrasound. Darker (hypoechoic) plaques are associated with hemorrhage and lipid accumulation, making them more prone to rupture and causing a higher risk of stroke. Brighter (hyperechoic) plaques are more fibrous or calcified and are generally more stable. This is graded using the Gray-Weale classification.
Gray-Scale Median (GSM) is a computer-based method that assigns a numerical value (0 to 255) to the overall brightness of a plaque on ultrasound. Lower GSM values indicate softer, lipid-rich plaques that are more prone to rupture, while higher values indicate more calcified or fibrous plaques. A lower GSM is considered an independent risk factor for stroke.
Juxtaluminal Black Area (JBA) is a dark area (GSM less than 25) adjacent to the artery lumen, indicating a lipid core close to the surface. The size of JBA is linked to stroke risk: 4-8 mm gives an annual stroke risk of 1.4%, 8-10 mm gives 3.2%, and greater than 10 mm gives 5%. A JBA greater than 4 mm is considered significant.
Contrast-enhanced ultrasound (CEUS) involves injecting tiny microbubbles into the bloodstream to visualize blood flow. It is particularly valuable for detecting intraplaque neovascularization—new, fragile blood vessels that grow into the plaque. These vessels are leaky and can contribute to plaque instability. CEUS can grade the degree of neovascularization, which is a key feature of vulnerable plaques.
Elastography measures the stiffness of tissue using shear-wave ultrasound. In carotid plaques, it can differentiate between soft lipid-rich cores (low stiffness) and harder fibrous or calcified tissue (high stiffness). This complements echogenicity, helping to identify vulnerable plaques that have a soft core and a stiffer cap, which are more prone to rupture.
Original Article Title: Greece Noninvasive Carotid Wall Imaging with Ultrasound- A Narrative Review
Authors: Maria Alexandratou, Angeliki Papachristodoulou, Xin Li, Sasan Partovi, Andjoli Davidhi, Vasileios Rafailidis, Panos Prassopoulos, Vasileios Kamperidis, Ioanna Koutroulou, Georgios Tsivgoulis, Nikolaos Grigoriadis, Christos Krogias, and Theodore Karapanayiotides
Journal: Journal of Clinical Medicine, 2022, Volume 11, Issue 20, Article 6196
Publication Date: October 20, 2022
Affiliations: Department of Clinical Radiology, AHEPA University Hospital of Thessaloniki, Aristotle University of Thessaloniki, Greece; Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Section of Interventional Radiology, Imaging Institute, Cleveland Clinic Main Campus, Cleveland, OH, USA; 1st Cardiology Department, School of Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece; 2nd Department of Neurology, School of Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece; Second Department of Neurology, School of Medicine, 'Attikon' University Hospital, National and Kapodistrian University of Athens, Greece; Department of Neurology, St. Josef-Hospital Bochum, Ruhr University Bochum, Germany.
This patient-friendly article is based on peer-reviewed research published in an open-access journal under the Creative Commons Attribution (CC BY) license. It has been written to make the findings accessible to a general audience while preserving all key data, statistics, and conclusions from the original scientific publication.
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