Diagnostic value of ultrasound in the evaluation of Carotid artery stenosis

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1 LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

DEPARTMENT OF RADIOLOGY

Tural Abdullayev

Diagnostic value of ultrasound in the evaluation of

Carotid artery stenosis

Final Master’s Thesis Faculty of Medicine

Supervisor: MD, PhD Antanas Jankauskas Kaunas, 2019

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1. SUMMARY

Author: Tural Abdullayev. Supervisor: MD Ph.D. Antanas Jankauskas. Department of Radiology, LUHS Kaunas Clinics. Research title: Diagnostic value of ultrasound in the evaluation of carotid artery stenosis. Keywords: carotid artery stenosis, carotid artery disease, transient ischemic attack, vulnerable plaques, vasa vasorum, carotid duplex ultrasound, computed tomography angiography, contrast-enhanced ultrasound.

Aim: To evaluate the diagnostic value of ultrasound in the evaluation of carotid artery stenosis

Objectives: 1) to evaluate the morphology of plaque on ultrasound and computed tomography; 2) to evaluate the prognostic value of ultrasound determined plaque morphology; 3) to evaluate the degree of stenosis of the carotid artery on ultrasound and computed tomography

Methodology: A literature research was done for publications evaluating the diagnostic performance of DUS, CTA, or a combination of these two modalities in patients with carotid artery stenosis. To find the studies, PUBMED search was performed using the following keywords, and all related terms: carotid artery stenosis, duplex ultrasound, computed tomography angiography, carotid artery disease, transient ischemic attack. All reviewed studies were published in the English language. In addition, all the associated articles and reference lists of original publications on this topic was checked.

Results: In included 3 studies (387 patients, 774 arteries) the sensitivity of the US in the evaluation of the complicated plaques was significantly low comparing to that of MDCTA. However, DUS has satisfactory specificity and sensitivity in the detection of unstable plaques. Observed studies including 826 patients have suggested that CEUS may be an appropriate an initial non-invasive method for determination of a vulnerable plaque.

In 6 included studies (699 patients, 1263 arteries) DUS was less reliable for 50-69% stenoses and more suitable in diagnosing 70-99% stenoses. Nevertheless, the use of additional non-invasive imaging modality shows better results than a DUS alone.

Conclusions: Based on the analyzed data, DUS is inferior to MDCT in evaluation morphological characteristics of the plaque.

Many studies have confirmed CEUS as a reliable noninvasive method in the evaluation of carotid plaque vulnerability. Nevertheless, the diagnostic accuracy of contrast

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4 ultrasound in the determination of the histological degree of vasa vasorum remains controversial.

CDUS is demonstrating better performance in evaluating high degree stenosis and occluded arteries; however, it is less reliable in the detection of mild to moderately stenosed vessels. CTA is illustrating better results in the assessment of stenosis in carotid arteries, nevertheless, errors can be observed while evaluating mild to moderately stenosed vessels, and therefore a combination of these techniques can be more effective in the evaluation of stenosis in carotid arteries.

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2. SANTRAUKA

Darbo pavadinimas: ultragarsinės diagnostikos reikšmė vertinant miego arterijos stenozę

Darbo tikslas: įvertinti ultragarso diagnostinę vertę, įvertinant miego arterijos stenozę. Tikslai: 1) Įvertinti plokštelės morfologiją naudojant ultragarsą ir kompiuterinę tomografiją; 2) Įvertinti ultragarso nustatomos plokštelės morfologijos prognozuojamą vertę; 3) Įvertinti ultragarso ir kompiuterinės tomografijos miego arterijos stenozės laipsnį

Metodika: Buvo atlikta literatūrinių publikacijų paieška, įvertinančių dvipusio ultragarso, somatinio tomografijos angiografijos diagnostiką arba šių dviejų modifikacijų derinio poveikį pacientams, kurie serga miego arterijų stenoze. Ieškant tyrimų, buvo atlikta paieška naudojant PUBMED su šiais raktiniais žodžiais ir susijusiais terminais: miego arterijos stenozė, dvipusis ultragarsas, kompiuterinės tomografijos angiografija, miego arterijos liga, trumpalaikis išeminis priepuolis. Tyrimas buvo publikuotas anglų kalba. Be to, buvo tikrinami visi su šia tema susiję straipsniai ir nuorodų sąrašai.

Rezultatai: įvykdytuose 3 tyrimuose (387 pacientai, 774 arterijos) UG jautrumas vertinant sudėtingas plokšteles buvo žymiai mažesnis, palyginti su MDCTA. Tačiau DUS pasižymi pakankamu specifiškumu ir jautrumu nustatant nestabilias plokšteles.

Tyrimuose, kuriuose dalyvavo 826 pacientai, teigė, kad CEUS gali būti tinkamas kaip pradinis neinvazinis metodas pažeidžiamam apnašui nustatyti.

6 tyrimuose (699 pacientai, 1263 arterijos) DUS buvo mažiau patikimas 50-69% stenozių ir labiau tinka diagnozuoti 70-99% stenozių. Nepaisant to, papildomo neinvazinio vaizdavimo modalumo naudojimas rodo geresnius rezultatus nei vien tik DUS.

Išvados: CDUS rodo geresnius rezultatus vertinant aukšto laipsnio stenozę ir užsikimšusias arterijas; kita vertus, jis yra mažiau patikimas nustatant lengvas ar vidutiniškai stenozuotuslaivus. Nors CTA parodo geresnius rezultatus, vertindami miego arterijų stenozę, galima pastebėti klaidas vertinant lengvas ar vidutiniškai stenozuotas kraujagysles, todėl šių metodų rinkinys gali būti veiksmingesnis karotidinių arterijų vertinimui.

Remiantis analizuojamais duomenimis, DUS yra mažesnis nei MDCT, vertinant plokštelės morfologines charakteristikas. Daugelis tyrimų patvirtino, kad CEUS yra patikimas neinvazinis metodas, įvertinantis miego arterijos apnašų pažeidžiamumą. Nepaisant to,

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6 kontrastinio ultragarso diagnostinis tikslumas nustatant histologinį kraujagyslių kraujotakos laipsnį lieka neaiškus.

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3. ACKNOWLEDGMENTS

Author thanks MD Ph.D. Antanas Jankauskas from the Department of Radiology of LUHS Kaunas Clinics for his dedicated support throughout the research.

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4. CONFLICTS OF INTERESTS

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5. ABBREVIATIONS

CAS – Carotid artery stenting

CDUS – Carotid Doppler ultrasound CEA – Carotid endarterectomy CE-MRA – Contrast-enhanced MRA CEUS – Contrast enhance ultrasound CTA – Computed tomography angiography DSA – Digital subtraction angiography DUS – Duplex ultrasound

EDV – End-diastolic volume

ESCT – European Carotid Surgery Trial ICA – Internal carotid artery

IEL – Internal elastic lamina IMT – intima-media thickness IPH – Intraplaque hemorrhage ISR – In-stent restenosis

MDCT – Multidetector computed tomography MRA – Magnetic resonance angiography

NASCET – North American Symptomatic Trial Collaborators OD – Original diameter

PSV – Peak systolic volume RD – Residual diameter TCD – Transcranial Doppler TIA – Transient ischemic attack TOF-MRA – Time-of-flight MRA

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6. INTRODUCTION

In the Western world, ischemic stroke is considered the first cause of a long-term disability and the third cause of death. Atherosclerosis of large arteries, primarily internal carotid artery stenosis is responsible for approximately 20% of all ischemic strokes 1_.

Since the degree of ICA stenosis is an essential parameter in the assessment of the risk of stroke and decision making regarding the possible revascularization strategy, it is crucial to perform a neuroimaging in order to evaluate the extent of stenosis 2_.

Currently, several imaging techniques are utilized in the evaluation of internal carotid artery stenosis, including duplex ultrasound, computed tomography angiography, magnetic resonance angiography and digital subtraction angiography 2_.

Although, intra-arterial angiography is a gold standard in the evaluation of the degree of stenosis, minimal or non-invasive methods have been studied in detecting carotid artery stenosis. With the development of imaging techniques over the past decade diagnostic accuracy of non-invasive techniques has been considerably improved 2_.

Carotid ultrasound is a cheap and low-risk method used in the evaluation of stenosis, and there is a growing interest in performing a carotid endarterectomy or carotid artery stenting based on results of DUS alone 3_{. Notwithstanding the fact, that US is accurate in} detection of high-grade stenosis it is less reliable in the assessment of the mild-moderate degree of stenosis. Combination of DUS with other non-invasive methods such as MR angiography or CT angiography may increase the diagnostic sensitivity to up to 100% and could be recommended as a reliable alternative to invasive angiography 2, 3_.

On the other hand, identification of plaque characteristics by a noninvasive method such as CEUS may help in the prediction of further revascularization strategy. Determination of intraplaque neovascularization can aid in risk stratification of disease and could eliminate the need for CEA for patients with stable plaque 4_.

With the development of carotid artery stenting, there is an increased interest in the evaluation of the capability of US to distinguish plaque morphology. CAS is associated with risk of recurrent stenosis. Follow-up and surveillance with CDU are necessary for the prevention of late stroke prevention following CAS 3_.

This study is done to evaluate the effectiveness of US in the assessment of carotid artery disease.

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7. AIM AND OBJECTIVES

Aim: To evaluate the diagnostic value of US in the evaluation of carotid artery stenosis Objectives:

1. To evaluate the morphology of plaque on ultrasound and computed tomography 2. To evaluate the prognostic value of US determined plague morphology

3. To evaluate the degree of stenosis of the carotid artery on ultrasound and computed tomography in comparison to invasive angiography

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8. LITERATURE REVIEW

8.1 Pathophysiology of carotid stenosis

Turbulent blood flow, inflammation, activation of clotting factors and abnormal endothelium of a vessel results in plaque formation. Plaque formation more frequently appears within 2 cm of the common carotid bifurcation, mainly affecting internal carotid artery 5_.

In areas of non-luminal flow, such as carotid bifurcation, hypertension induces remodeling of angioarchitecture resulting in luminal narrowing, smooth muscle relaxation defects, and medial thickening. A persistent injury caused by factors such as hypertension, high lipid profile and smoking results formation of atherosclerotic plaque and intimal hyperplasia. Rupture of a plaque into the vessel lumen activates thrombosis which may result in local occlusion, distal embolism, or progressive luminal stenosis 6, 7_.

Factors such as degree, duration, and location of stenosis and associated symptoms help to predict the degree of ischemic event 5_{. Presence of cervical bruit may indicate the} existence of carotid stenosis of more than 70 %, and if left untreated it can progress to complete occlusion of a vessel. In order to decide about the further treatment plan, imaging studies should be done in patients with signs of transient ischemic attack (TIA) or ischemic strokes 5, 6_.

8.2 Plaque morphology and its types

Currently, the risk determination of carotid atherosclerosis is mainly assessed by measuring luminal stenosis. However, in acute coronary syndrome, plaque stability and vulnerability are more important than the degree of the stenosis to risk stratify asymptomatic patients. It can be explained by differences in hemodynamic status and the diameter of those vessels. In comparison to carotid arteries, coronary arteries have a smaller diameter, therefore plaque rupture results in luminal occlusion and associated symptoms 8_.

Histopathological studies of a plaque can be informative in the prediction of stroke. According to the American Heart Association, there are 6 morphological types of plaques provided in Table 1. An ulcerated plaque surface is associated with a high risk of recurrent stroke, whereas plaques with a smooth surface are having a relatively lower risk of recurrence 8, 9, 10_.

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13 The initial process of a plaque formation involves deposition of macrophages and foam cells, followed by intracellular accumulation of lipid, and deposition of extracellular lipids within the plaque. Type I-III plaques are not vulnerable, and they are clinically silent. As the lipid core forms within the intima, the atheroma (type IV lesion) forms. At this point, luminal surface lacks fibrous covering, as a result, proteoglycans and foam cells are left on the luminal surface. Presence of a great number of macrophages on the intimal surface makes plaque susceptible to fissuring. Type V plaques are characterized by the presence of increased vascular supply and fibrous cap over the lipid core. At this stage arterial lumen starts to narrow 8_.

Type IV and V plaques are more prone to fissuring and consequent progression to type VI plaque, which is clinically significant. Type VI lesions are characterized by the presence of ulceration of plaques, intraplaque hemorrhage, and thrombotic deposits. This type of lesion may result in distal thromboembolic events 8_.

Plaque-type

Characterization Status

Type I Deposition of macrophages and formation of foam cells Asymptomatic Type II Fatty streak lesion with intracellular lipid accumulation Asymptomatic Type III Deposition of intracellular lipids within the plaque Asymptomatic Type IV Formation of lipid core. Infiltration by inflammatory cells. Possibly

symptomatic Type V Formation of the fibrous cap. Artery wall is prone to

hematoma, thrombus formation and fissuring.

Possibly symptomatic Type VI Fissuring & ulceration of plaque. Lipid core is necrotic.

Intraplaque hemorrhage & thrombus. Inflammation w/in the plaque.

Possibly symptomatic

Table 1. Features of different types of plaques and their association with the status of a patient.

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14 8.3 Imaging of the carotid arteries

8.3.1 Conventional cerebral angiography

Digital subtraction angiography (DSA) is an invasive test that involves the introduction of contrast material into the carotid arteries and remains as a gold standard for evaluation of the degree of stenosis in cerebral circulation. Despite its invasiveness, it is the only tool against which all noninvasive methods are compared 11_.

As DSA is an invasive test, it carries the risk of stroke, which might be a consequence of plaque dislodgement from the wall of the carotid artery. Angiography should be performed in selected patients, since some patients may be allergic to contrast material or may have a pre-existing renal disease which may result in acute kidney disease 12_.

8.3.2 Non- invasive imaging techniques 8.3.2.1 Duplex ultrasound

Carotid duplex ultrasound (DUS) is the most widely used modality in the screening of patients with TIA and asymptomatic patients with carotid bruits, and it's becoming the single examination method before the surgical intervention. As there is a high risk of stroke following TIA, patients with previous TIA attacks should be evaluated 13_.

DUS is combining pulse-wave Doppler ultrasound and brightness - modulation (B-mode) sonography. B-mode is aiding in the evaluation of morphological properties of a vessel, whilst Doppler ultrasound assessing the luminal stenosis based on fluctuations of velocity across the stenosed area 11_.

B-mode is very useful in the evaluation of luminal stenosis, the establishment of ulcerations and intraplaque hemorrhages, and to outline apparent wall characteristics of carotid arteries. Regardless of its accuracy in the differentiation of normal arteries from significantly stenosed arteries or those with minor plaques, if performed alone it has few limitations. This includes an inadequate display of vessels which is associated with the large size of the probe and significant angulations of arteries, calcifications and clots are not visible 14_.

Doppler sonography is assessing the blood flow velocity in the selected area. The severity of stenosis is measured based on the alterations in peak systolic frequency, the presence, and the degree of post-stenotic turbulence, and an increase of diastolic blood-flow velocity 14_.

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15 Combination of data obtained from B-mode and Doppler ultrasound helps to evaluate changes in blood flow and locations of the velocity changes14_.

Doppler measurements that are frequently used to assess the severity of stenosis include peak systolic velocity (PSV) and end diastolic velocity (EDV) of the internal carotid artery (ICA), and carotid index (ratio of ICA PSV and PSV of the common carotid artery) 11_.

Based on the ECST method, internal carotid artery stenosis ≥ 50% can be determined if PSV of ≥ 155 cm/s, ICA/CCA ratio of ≥ 2. PSV of ≥370, ICA/CCA ratio of ≥6 and EDV of ≥140 indicative of stenosis ≥80% 15_.

On the other hand, the determination of plaque morphology plays a crucial role in the evaluation of the risk of subsequent events. Turbulent blood flow present in the area of ulcerated plaque can promote thrombus formation and result in distal emboli resulting in a stroke. DUS can be used in the determination of distal flow alterations caused by ulcerated plaque by measuring turbulence intensity (TI) 16_.

Based on the images obtained by B-mode US lesions are classifies as uniformly echolucent (class I), predominantly echolucent (class II), predominantly echogenic (class III), or uniformly echogenic or extensively calcified (class IV) 17_.

DUS has the advantage to be noninvasive, relatively cheap, safe and a useful bedside method. Disadvantages include its dependence on operator's experience and an inability of precise visualization at the area of calcified vessels and high bifurcations15_.

8.3.2.2 Transcranial Ultrasound

Transcranial Doppler (TCD) is used to evaluate hemodynamic changes in major intracerebral arteries through the orbit and base of the skull. It can be used in conjunction with carotid Doppler ultrasound (CDUS) to improve the accuracy of velocity evaluation. TCD can be used for identification of cranial lumen stenosis and formation of collateral circulation and determination of brain death. TCD is evaluating the mean velocity of blood flow at the selected carotid vessel and comparing it to of contralateral artery at same area 18_.

8.3.2.4 Contrast-enhanced ultrasound

Contrast-enhanced US (CEUS) is utilized to identify the plaque morphology by injection of microbubble-based contrast agents to enhance the ultrasound images, and are composed of 1–10 μm diameter albumin or lipid shells filled with air or high molecular weight

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16 gas. Compression and expansion of these microbubbles by the influence of ultrasound waves may add additional clues on plaque morphology 19_{. Contrast agents serve as blood} pool agents and can be applied to enhance the luminal surface of internal, common carotid arteries and carotid bifurcation 20_.

Injection of contrast material enhances the visualization of plaque morphology and it's mainly based on the presence of microbubble activity within the vasa vasorum of the plaque 17_{. Data regarding the plaque neovascularization obtained by CEUS can be} categorized based on the modified grading scale as provided in Table 2 21_.

Contrast agent enhancement

Characterization

Grade 0 Absent neovascularization within the lesion Grade 1 Minimal neovascularization within the plaque Grade 2 Intermediate neovascularization within the plaque Grade 3 Microbubbles moving into the newly arisen arteries

within the plaque

Table 2. Grading of plaque activity based on the flow of contrast agent within the vasa vasorum.

CEUS is capable to identify ulcerations, real-time visualization of newly formed vessels within the plaque, and may aid to assess the thickness of carotid IMT 22_{. Since} plaque tissue appears dark, identification of contrast-enhanced microbubbles within plaque tissue is made visible by carefully adjusting the imaging settings and contrast-specific modality. 23_.

As mentioned previously, newly formed vessels within the lesions play a crucial role in the destabilization of a plaque and are associated with intraplaque hemorrhage which later takes a role in the build-up of a thrombus 24_.

A result of the recently published study suggests that the rate of neovessels were higher in echolucent plaques and in highly stenosed vessels. Therefore, it can be suggested that CEUS may aid in the identification of ulcerated plaques and risk stratification 17_.

Carotid plaque contrast-agent enhancement with sonographic agents is a promising tool to study plaque vasa vasorum in the clinical setting. CEUS is able to differentiate between hypoechoic and highly vascular lesions. Although results obtained in

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17 ultrasonography was able to show highly vascularized areas it doesn't correlate with the histological density of vasa vasorum 23_.

8.3.2.5 Carotid CT Angiography

Carotid Computed Tomography Angiography (CTA) can estimate the risk of thromboembolic events by evaluation of plaque composition which is a necessary indicator of plaque stability 25_.

The procedure requires injection of an iodinated contrast material which helps in the determination of areas of the brain with diminished perfusion 26_.

CTA is helpful in the determination of ulcerations, intraplaque hemorrhage, calcifications, and a fibrous cap. Leakage of contrast media through the lumen into the surrounding tissues indicates the presence of ulceration, whereas IPH is detected by the presence of low HU waves. High-density structures seen inside the plaques are suggestive of the presence of calcifications 27_.

8.3.2.6 Magnetic Resonance Angiography

MR angiography (MRA) is one of the most widely used techniques in the estimation of extracranial carotid arteries. MRA techniques utilize time-of-flight (TOF) MRA and contrast-enhanced (CE) MRA (also known as gadolinium-contrast-enhanced MRA) 28_.

Sensitivity and specificity of MRA in the detection of stenosis between 70% - 99% is 95% and 90% respectively. For all stenoses, MRA has sensitivity 98% and specificity 86% 29_.

8.4 NASCET and ECST Methods

Nowadays, 2 main criteria used for quantification of ICA stenosis, NASCET (North American Symptomatic Trial Collaborators) and ESCT (European Carotid Surgery Trial) are mainly based on angiography. Results of both methods are expressed in percentages and decision regarding the further management plan can be made in accordance with the severity of stenosis 30_.

In spite of the fact that both methods are used to evaluate the degree of stenosis different methods are used for calculation. ECST method is comparing the residual lumen in

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18 the area of stenosis with the original lumen, whereas NASCET method is comparing the stenosed area with the diameter of the normal ICA lumen distal to the bulb (Figure 1) 31_.

Figure 1. Diagram of determination of NASCET and ECST method.

ECST: The degree of stenosis (A) is determined based on the original lumen of the ICA (C).

C-A/C x 100%

NASCET: The degree of stenosis (A) is determined based on the distal lumen of the ICA (B).

B-A/B x 100%

It is possible to convert NASCET value to ECST (ECST% = 40 + 0.6 × NASCET %) or vice versa (NASCET% = (ECST – 40) % / 0.6). Accordingly, we can compare degrees of stenosis evaluated by ECST to the ones of the same stenoses measured by the NASCET method (Table 3) 31, 32_: ECST NASCET 50 - 60% 30% 70% 50% 75% 60% 80% 70% 90% 80%

Table 3. Comparison of the degree of stenosis between NASCET and ECST methods.

The only hemodynamic parameter used in NASCET is PSV which is used as a threshold to identify stenosis of ≥70 31_.

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19 8.5 Evaluation of plaque morphology on US and CT

Currently, DSA and other non-invasive imaging techniques are mainly focused on the determination of the degree of stenosis; however, it may give incomplete information about the plaque vulnerability 33_.

According to vascular remodeling phenomenon introduced by Glagov et al, at the beginning atheroma forms eccentrically and no luminal stenosis can be observed due to compensatory dilation of the lumen. As atheroma grows and covers about 40% of the area delineated by the internal elastic lamina (IEL), luminal invasion begins 33_.

As mentioned in previous sections, DSA is considered as a gold standard in diagnosing the degree of stenosis, but it is incapable to display the plaque morphology which is crucial in the prediction of plaque vulnerability 33_.

DUS is non-invasive and relatively cheap imaging modality that can be utilized in the assessment of luminal stenosis, however additional imaging is mandatory to confirm the degree of stenosis prior to carotid endarterectomy (CEA). Apart from the assessment of the degree of stenosis, DUS can be used to determine the plaque morphology based on the echogenicity, and patients with echolucent plaques are at increased risk compared to those with echo-rich plaques 33_.

Figure 2. Assessment of plaque echogenicity on brightness mode ultrasonography

CEUS can be more useful in the detection of plaques and evaluate their neovascularization, by illustrating the plaque instability, and according to Coli et al., plaques with low echogenicity have a higher degree of contrast enhancement (Fig.2) 33_.

In the study done by Lunakova et al, 100 patients were admitted for CEA for high-grade carotid stenosis. In total 116 atherosclerotic plaques were examined. Of these, 75

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20 were men and 25 women with a median age of 66. 32 of them were symptomatic and 68 were asymptomatic. CEA found 31 soft plaques and 26 solid fiber calcifications. US found 29 of 31 unstable and 28 stable plaques. Duplex US were able to detect 9 plaques with a ruptured fibrous cap, and histological examination suggested ulcerated 7 plaques 34_.

In the case of a multidetector computed tomography (MDCT), the results were different if compared to those found on US. MDCT was able to identify an identical amount of plaques as in a histological examination, 18 unstable and 11 stable plaques. This outcome was associated with the presence of an equal amount of false-negative and false-positive results. MDCT recognized 3 unstable plaques as stable and 3 stable plaques as unstable 34_.

As a result, the sensitivity of ultrasound and multidetector computed tomography is 94%, 83%, and the specificity is 93%, 73% for the detection of unstable carotid plaque 34_.

In the study done by M.Ajduk et.al, carotid plaques from 50 patients undergoing the CEA were evaluated. Results of MDCT and US performed in approximately one week before the surgery were compared with histological findings of plaque areas. Sensitivity and specificity of MDCT in the detection of plaques complicated with intraplaque hemorrhage were 100% and 70.4% respectively. DUS was able to detect plaques complicated with hemorrhage at a sensitivity of 21.7% and specificity of 89.6% 35_.

A study conducted in Italy by Saba L. has involved 237 patients with an average age of 64 years. 163 of these patients were men and 74 were women, a total of 474 arteries were examined with CTA. Doppler US examinations were performed by 1 vascular surgeon and 4 residents. Parameters such as plaque echogenicity, plaque surface, and plaque texture were used in the evaluation of plaques characteristics by Doppler US. As a result, Doppler US detected 12 of 32 ulcerations confirmed at surgery and 6 ulcerations were not confirmed at surgery. Based on these findings, sensitivity and specificity of Doppler US in the identification of ulcerated plaques were 37.5% and 91.5 % respectively 36_.

On the other hand, MDCT demonstrated better result compared to those found on US. MDCT identified 31 of 32 histological specimens with ulcerations; 30 of these plaques were corresponding to the ones identified on surgical specimens, and 1 was not confirmed at surgery. Based on these finding sensitivity and specificity of MDCT in the detection of ulcerated plaques were 93.75% and 98.59% 36_.

8.6 Prognostic value of US determined plaque morphology

Presence and degree of intraplaque neovascularization are well associated with the plaque rupture. Therefore, the main interest is directed towards the assessment of the ability

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21 of noninvasive imaging methods to detect and quantify the degree of neovasculature within the plaque. Although MRI with gadolinium infusion has a good correlation with histological findings in the identification of vasa vasorum, contrast-enhanced ultrasound is able to demonstrate accurate architecture of a vascular lumen as well 4, 23_.

As B-mode and Doppler US is widely available imaging modality in most healthcare centers, many studies have been directed to evaluate its diagnostic value in determination and quantification of a plaque 37_.

Kagawa et al. demonstrated that B-mode is capable to detect border irregularities with sensitivity and specificity of 97% and 81% respectively. Border irregularity may assist to predict the presence of intraplaque hemorrhage with sensitivity and specificity of 81% and 85% respectively. Several studies have introduced the B-mode US to evaluate the plaque ulceration in addition to border irregularities, the specificity and sensitivity were unsatisfactory, and the addition of Doppler US to B-mode have shown a slight improvement in sensitivity and specificity 37_.

Recent studies are mainly focused on the evaluation of the capability of contrast ultrasound in the enhancement of carotid lumen and morphology of a plaque, improved resolution of carotid intima-media of a proximal and distal wall, and identification of neovascular alterations within the adventitial vasa vasorum and plaques 22_.

Considering the association of plaque vulnerability and clinical manifestations with the intraplaque neovascularization, early identification of vascularization within the intima-media and plaque could be more practical than identification of the plaque itself. Furthermore, these microvessels are fragile and prone to rupture and hemorrhage, which consequently leads to gradual detachment of a plaque from the lumen. Consequent processes including accumulation of cholesterol, macrophage results in increased size of thrombus causing distant thromboembolism 23_.

Coli et al. reported that there is a good correlation between vasa vasorum density at histology and the degree of contrast agent enhancement by US imaging. Considering, that contrast agent microbubbles can only reach plaque tissue by vascular channels, contrast agent enhancement can be considered as a reliable sign indicating the presence of high-risk lesions 23_.

Similarly, during his study M.F.Giannoni et al. have observed the distribution of contrast agent in the smaller diameter microvessels at the base of plaques in patients with symptomatic disease. Histological specimens of identical areas have shown the presence of microvessels with high density which confirms the presence of neovascularization within the

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22 plaque. In comparison to patients with symptomatic disease, microvessels in asymptomatic patients had a larger diameter and diffusely distributed 38_.

In a study including 50 patients, CEUS with perflubutane was used prior to CEA. Plaque of high intensity observed in symptomatic patients or in vessels with ruptured plaque39_.

Another study conducted by Casadei et al., CEUS of coronary artery was performed in 747 patients and 518 patients found to have some degree of ICA stenosis. A total of 201 carotid arteries presented stenosis of 1%-69% and type 1 or type 2 plaques. These plaques, described as echolucent plaques are unstable and can become symptomatic in patients with asymptomatic carotid artery disease. Casadei et al. report that the application of CEUS in patients with potentially vulnerable plaques can be beneficial in terms of sonographic diagnosis and treatment 40_.

CEUS examinations may aid in identification and quantification of existence and extent of neovascularization of the vasa vasorum and atherosclerotic plaque, permitting a more reliable assessment of cardiovascular risk 22_.

8.7 Evaluation of the degree of carotid artery stenosis on US and CT

DUS has become the first-choice screening method in evaluation of ICA stenosis in asymptomatic patients 41_{. Although it is an inexpensive and non-invasive procedure, it is} highly dependent on the experience of the operator 41, 42_.

Main criteria that can be accepted in both US and angiography is the disperse of peak systolic velocity at the narrowed lumen. Morphological measurements gathered from Duplex ultrasound are the major criteria in the determination of low and moderate degrees of stenosis. Stenosis is identified by an increase of velocity at the narrowed area. High degree stenosis (>70%) is established by the presence of collateral blood flow and diminished post-stenotic flow velocity 43_.

The main predictor in the estimation of the relationship between the area and diameter reduction is the type of stenosis, i.e., whether it is concentric or eccentric. In the case of eccentric stenosis, diameter and area reduction are similar; however, in concentric narrowing, the degree of stenosis measured in percentage area reduction is higher than the measured diameter reduction. Despite the fact that both NASCET and ECST methods are based on the results of angiogram these methods are suitable with the B-mode US to visualize the residual lumen of the stenosis and the lumen of the post-stenotic segment 43_.

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23 In the case of moderate stenosis (50-60%) local increase of velocity, color flow, and B-mode imaging can be combined for grading.PSV is usually 220 cm/s and collateral flow is absent 43_.

High-degree (>70%) stenosis is considered as a hemodynamically significant and hemodynamic criterion, such as increased PSV or end-diastolic velocity or the carotid ratio are used to approve this condition. Doppler ophthalmic test is used to assess collateral flow by examining the ophthalmic artery branches. Reduction in post-stenotic velocity which is the result of decreased blood flow volume is another criteria and it's important in the assessment of the degree of stenosis. The degree of reduction of post-stenotic flow velocity helps to differentiate between 70% (severe) and >70% (very severe) stenosis, and this differentiation is not possible based only on PSV values. Comparison of a stenosed artery with the contralateral internal carotid artery is crucial to recognize post-stenotic flow reduction 43_.

In the study done in Samsung Medical Center in Seoul, Korea, the database of carotid ultrasonography and arteriogram in 101 patients were reviewed. Out of 101 patients, 133 carotid arteries (37 bilateral, 59 unilateral) in 96 patients were included 44_.

The most stenotic area of ICA was captured using 9-3 MHz linear transducer on a longitudinal image by B-mode US or color Doppler in order to measure the degree of stenosis. After evaluation of most stenotic segment of ICA on a B-mode US or color Doppler, the original diameter (OD) which represents the diameter from the outer media to the outer media of the affected artery on the same plane and at the same direction with the residual diameter (RD) which is the shortest diameter of the residual lumen at the most narrowed area of ICA and residual diameter, were measured using electronic calipers (Fig. 3). The degree of carotid artery stenosis on the B-mode US was calculated using the following equation: CS% = (1 - [RD/OD]) × 100% 44_.

Figure 3. Determination of degree of carotid artery stenosis on a transverse scan color flow

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24 DSA was used in order to evaluate the sensitivity and specificity of the B-mode US in determination of stenosis of different severities. When the accuracy of black-scale US was evaluated according to ECST method the sensitivities were 95.6%, 92.6%, 89.6% in a subgroup with degree of stenosis on B-mode >50%, >60%, and >65%, respectively, whilst specificities were 79%,76.9%, 69.6% respectively, and accuracy of >50%, >60%, and >65% respectively. On the other hand, according to NASCET sensitivities were 95.4%, 85.7%, 77.4% in a subgroup with CS% on B-mode >60%, >70%, and >75%, respectively, whilst the specificities were 70.2%, 79.4% and 85 % respectively, and accuracy of >60%, >70%, and >75%, respectively 44_.

AbuRahma et al. used the criteria introduced by the consensus panel to figure out the correlation between CDUS and angiography in 376 internal carotid arteries at their institution. As a result, in carotid stenosis between 50-69%, the sensitivity was 93%, specificity was 68%, and overall accuracy was 85%. Using a cutoff PSV of ≥230 cm/s for ≥70% stenosis, they illustrated a sensitivity of 99%, specificity of 86%, and overall accuracy of 95% 3_.

As stated before, the specificity of the CDUS in the detection of 50-69% stenosis is low, therefore the use of additional imaging modality such as CE-MRA should be considered before performing CEA or carotid artery stenting (CAS). In case there is a considerable difference between results of these imaging techniques, then CTA would be an appropriate method 3_.

Due to the risk of hemodynamically significant (≥80%), in-stent restenosis (ISR) accurate follow-up and surveillance with CDU are necessary. As the blood flow and vessel compliance are altered in stented arteries, previously published velocity criteria for CDU cannot be used since it was based on native arteries and it can over. Blood flow and vessel compliance are altered in stented arteries, and the use of existing criteria may augment the degree of restenosis 3_.

Modified velocity criteria thresholds proposed by Lal et al. and AbuRahma et al. can be applied in significant ISR following CAS and should be used for CDU surveillance in these patients 45, 46_.

Screening for carotid artery stenosis may be considered in patients with a diagnosis of coronary artery disease or peripheral artery disease, or with 2 or more risk factors for atherosclerosis 3_.

Cheng et al. used CDUS to examine a group of patients with a mean age of 70.6 years and known peripheral artery disease for asymptomatic carotid stenosis. The

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25 prevalence of severe (≥70%) internal carotid artery stenosis in this group was 24.7%. The degree of carotid stenosis also associated with age and the amount and duration of cigarette smoking 3_.

In a study where 194 carotids were included, both CDUS and MDCTA were utilized to evaluate the degree of stenosis. There was a minimal agreement between US and CTA in 36 vessels with <50% stenosis with correlation coefficient r of 0.9681 (95% CI 0.9379– 0.9838; p<0.0001). Remaining 158 carotids with stenosis >50% provided an excellent

agreement with correlation coefficient r of 0.9882 47_.

Another study included 187 scans in the comparison. The overall concordance between both CDUS and CTA was 79.1% (148/187) (95% CI 0.72–0.83). CDUS under-estimated and over-under-estimated the degree of stenosis in 26/187 (14%, 95% CI 0.09–0.19) and 13/187 (7%, 95% CI 0.04–0.12), respectively. When CTA was considered in conjunction with CDUS, the decision regarding operative treatment was changed in 29/187 cases (16%) (95% CI 0.11–0.21) 48_.

In a different study, 32 patients referred for CTA with 41 ICA-stenoses were included in this prospective study. MD-CTA was performed using a 64-row scanner with a CTDIvol of 13.1 mGy/cm. In CTA, CCDS, PD, and B-flow, the degree of stenosis was evaluated by the minimal intrastenotic diameter in comparison to the post-stenotic diameter. Two radiologists performed a quantitative evaluation of the stenoses in consensus blinded to the results of the ultrasound. These were correlated to CTA, CCDS, PD and B-flow, intraoperative findings and clinical follow-up. Grading of the stenoses in B-flow ultrasound outperformed the other techniques in terms of accuracy with a correlation coefficient to CTA of 0.88, while PD and CCDS measurements yield coefficients of 0.74 and 0.70. Bland-Altman analysis additionally shows a very little bias of the three US methods between 0.5 and 3.2 %. There is an excellent correlation (coefficient 0.88, CI 0.77–0.93) with 64-MD-CTA and B-flow ultrasound in terms of accuracy for intrastenotic and post-stenotic diameter. Duplex sonography is useful for screening purposes 49_.

On the other hand, one of the researches determined the degree of stenosis was using CDS velocities according to 5 published sets of criteria. The best overall agreement was achieved by applying the criteria sets of Hwang (k50.70) and AbuRahma (k50.68). All 5 occlusions were correctly identified with both modalities. CTA detected 73 ICA stenoses .70%; the best correlation was with the application of Hwang criteria, which correctly identified 69 (94.5%). 70% stenoses. In order of increasing tendency to underscore the grade of stenosis, the corresponding results for the other criteria sets were 62 (84.9%) for Mittl, 59

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26 (80.8%) for AbuRahma, 55 (75.3%) each for Nicolaides and Filis, and 50 (68.5%) for Nederkoorn. CTA detected 85 stenoses .50%; the sensitivity of all applied CDS criteria sets exceeded 90% 50_.

A study examined 303 acute cerebral ischemia patients with a mean age of 72 ± 12 years; provided 593 DUS and CTA vessel pairs for comparison. There was a positive correlation between DUS and CTA (rs = 0.783, p < 0.001) with a mean difference in the degree of stenosis measurement of 3.57 %. The Bland-Altman analysis further revealed widely varying differences (95%limits of agreement−29.26 to 22.84) between the two modalities 51_.

Another study compared duplex CCI and three CTA modalities exhibited only a moderate agreement in terms of regression analysis (R2 [0.41-0.54) and Bland-Altman analysis (the standard deviation of the stenosis differences was >20%). In terms of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy, DEGUM stenosis graduation was best balanced by duplex CCI (50% stenosis: 100%, 93%, 85%, 100%, 95%; 70% stenosis: 71%,100%, 100%, 97%, 98%) followed by CTAarea (50% stenosis: 80%, 73%, 54%, 90%, 75%; 70% stenosis: 66%, 94%, 55%, 96%, 96%). University of Washington stenosis was best balanced by duplex CCI followed by CTAarea 52_.

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27

9. DISCUSSION

The aim of this study was to find out the diagnostic value of ultrasonography in the evaluation of coronary artery stenosis. In reviewed studies, we have found a good correlation between the vasa vasorum detected by CEUS with results of histological analysis of specimens obtained by CEA. In comparison to CEUS, CDUS is capable to demonstrate delineation of the vessel wall only if it does not have any clinical significance and does not affect the decision making regarding the following revascularization strategy. On the other hand, based on the analyzed studies, it can be suggested that CDUS is showing better performance in the determination of highly stenosed vessels, but may under or overestimate the stenoses of mild or moderate degree. Adoption of a superior noninvasive technique, such as CTA or MRA, seems to be beneficial in decision making regarding surgical therapy.

Clinically apparent cardiovascular disease frequently arises as a late manifestation of widespread atherosclerosis. Although DSA is the gold standard method in imaging for suspected carotid artery stenosis, it carries a risk of thrombosis following the procedure. Due to its safety and low-cost, DUS is the initial imaging modality used for detection of the stenosed area, plaque morphology, and composition. The main disadvantage that could be noticed in the use of US is its operator dependence and difficulties in detection calcified vessel and highly bifurcated vessels 1, 32_.

Nowadays, many studies aim to assess the capability of noninvasive techniques to identify stability and vulnerability of a plaque. Notwithstanding, that most studies have been directed to evaluate the significance of US in the detection of the degree of stenosis, detection of plaque stability is of higher importance, since it carries a high risk of embolization 8_{. Patients with low-grade stenosis are at high risk of experiencing clinical scenarios of a} stroke in the presence of an unstable plaque. Therefore, evaluation of a risk of stroke based only on the degree of stenosis may be not sufficient and additional parameters must be evaluated for prevention of consequent events56_{. Similar findings have been observed in a} study Mauriello et al., where 250 plaques were evaluated and 30% of thrombolytic plaques were observed in a segment of carotid artery with ≤50% stenosis. On the other hand, prevalence of healed lesions was higher in a segment of carotid artery with 70% stenosis57_.

Several studies have observed the diagnostic value of MDCTA and US in the evaluation of plaque morphology. Saba et al. have detected that MDCTA has a high sensitivity and specificity in detecting plaque ulcerations which correlates with results obtained by Wintermark et al. Sensitivity of DUS in detection of an ulcer was 37, 5%, which is higher than result obtained in a study done by M.Ajduk et al. where the sensitivity was 21.7%.

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28 In contrast to these results, Lunakova et al. have demonstrated that CDUS have significantly higher sensitivity in detection of ulcerations (77.8%) 34, 35, 37, 55_.

Numerous works of literature and in many studies results obtained by US were compared or confirmed by CTA which is considered as a superior imaging technique comparing to ultrasonography. An increase in internal media thickness is considered a predictor of atherosclerosis which can be observed using CD-US. As MD-CTA is not able to distinguish internal media from the other 2 layers, the complete carotid artery wall thickness is measured. L. Saba and his colleagues have observed an agreement between MD-CTA and CD-US. Despite the fact, that correlation coefficient was 0.9855, there was a minimal agreement in case of low-grade stenosis comparing to those with high-grade stenosis 47_.

As discussed in previous sections there is a strong association between the morphological features of a plaque and associated symptoms, thereby it is of a clinical importance to determine the morphology of a plaque. In addition to assessment of the degree of stenosis, US is able to evaluate the composition of a plaque and presence of plaque based on velocity change over the occluded area of a vessel and movement of microbubbles 2, 16, 24_. According to a study done in the vascular department of Burley General Hospital, calculated concordance between CD-US and CTA was 79.1%, and this result went down to 45.5% while evaluating stenoses of moderated degree 48_{. Such result is confirming the idea of the use of 2} noninvasive imaging methods such as CTA or MRA in addition to US or DSA in case of moderate stenosis.

A study done in Germany by 2 radiologists had similar results to that we have discussed in a previous section. The concordance rate between US and CTA in case of normal to mild, severe and moderate stenosis was 89.4%, 84.1%, and 45.5% respectively. Concordance rate in case of complete occlusion was 84% 49_.

Another study done in Departments of Angiography and Interventional Radiology and Angiology of Medical University in Vienna, has used 5 criteria to quantify the degree of stenosis. US was able to identify occluded arteries in most cases. Only 1 criterion set had a diagnostic accuracy of >90% 50_{. In other 4 criteria there were over or underestimations of} stenosis in both US and CTA.

Based on the results obtained by another study, DUS tend to underscore the stenosis of a mild degree and over scored in moderate to high degree of stenosis. Use of additional neuroimaging may be beneficial in the identification of patients amenable to revascularization therapy 51_.

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29 Recent meta-analyses pointed out that sensitivities and specificities of non-invasive imaging modalities for diagnosing 50-69 % stenosis are less accurate, however in 70–99 % carotid stenosis obtained results were satisfactory 53,54_.

Notwithstanding that DSA is the gold standard in the estimation of the degree of stenosis it has a limitation in the evaluation of vessel wall and plaque composition. DUS grading of carotid artery stenosis can provide highly consistent results. Use of a single noninvasive modality in severe cases of stenosis or combination of DUS and CTA in complicated cases can be sufficient in the decision making of CEA. When using CTA and DUS for clinical purposes, especially in cases of mild to moderate degree of stenosis radiologist should take into consideration the differences between the degree of stenosis 51_.

Majority of studies were mainly concentrated in co-operation of CTA and DUS rather than estimation of the practicality of a single noninvasive method. On the basis of reviewed articles, we can conclude, that concordance rate between US and CTA seems to be sufficient and can help in decision making prior to CEA.

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30

10. CONCLUSION

Based on the analyzed data, DUS is inferior MDCT in evaluation morphological characteristics of the plaque.

Many studies have confirmed the CEUS as a reliable noninvasive method in the evaluation of carotid plaque vulnerability. Nevertheless, the diagnostic accuracy of contrast ultrasound in the determination of the histological degree of vasa vasorum remains controversial.

CDUS is demonstrating better performance in evaluating high degree stenosis and occluded arteries; however, it is less reliable in the detection of mild to moderately stenosed vessels. CTA is illustrating better results in the assessment of stenosis in carotid arteries, nevertheless, errors can be observed while evaluating mild to moderately stenosed vessels, and therefore a combination of these techniques can be more effective in the evaluation of stenosis in carotid arteries.

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31

11. PRACTICAL RECOMMENDATIONS

According to the results of this literature review, it is recommended to combine results of US and CT studies by evaluating atherosclerotic changes in neck arteries.

By defining plaque morphology, clinical decision should be mainly based on CT study results, which show better performance an accuracy.

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