There are numerous hospital based studies of stroke inIndia only a few population?based surveys have been done to determine theprevalence of stroke disorders.

During the last four decades community?basedstudies in different regions of the country showed crude prevalence rates ofcompleted strokes varying from 52–472 per 100000 persons(6). TheNorthern Manhattan Stroke Study (NOMASS) noted that 7 % of all first strokeswere associated with a >60 % carotid stenosis(7). A Texas population studyof 612 patients with TIA noted 10 % had evidence of >70 % stenosis in atleast one carotid artery(8).

In accordance, allpatients who present with the symptomatic disease should be evaluated with non-invasive imaging and risk of strokeshould be assessed. Carotid artery stenosis is classified clinically into 2types:•    Asymptomatic CA stenosis •    Symptomatic CA stenosisThe symptomatic carotid disease isdefined as focal neurologic symptoms that are sudden in onset and referable tothe appropriate carotid artery distribution (ipsilateral to significant carotidatherosclerotic pathology), including one or more transient ischemic attackscharacterized by focal neurologic dysfunction and/or one or more minor (nondisabling) ischemic strokes. The definition is contingent on the occurrence of carotidsymptoms within the previous six months.17 Although thereis no precise time limitation, remote carotid symptoms will not be consideredas indicative of symptomatic carotid disease. Symptoms may include contralateralweakness or numbness of the face or alimb, dysarthria, aphasia, or visual field deficits including amaurosis fugax. Patients without symptoms and those withsubjective complaints of dizziness, generalized weakness, pre-syncope, syncope,or confusion will be considered asymptomatic regardless of the degree ofcarotid stenosis.

PathophysiologyThe development of atherosclerosis is a slow process overseveral decades and the steps of the process, in particular the early steps,are difficult to study in humans. In the response-to-retention hypothesis(9), the atherosclerotic process starts with retention andaccumulation of small lipoprotein inside the intima. These small lipoproteins,like low density lipoprotein (LDL), can cross an intact endothelium and the majorityof LDL diffuses through the arterial wall, only a minority is trapped, orretained.

The retention mainly occurs because lipoproteins are bound toproteoglycans in the extra cellular matrix(9).Oxidation of the retained lipids induces local cytokinerelease and the cytokines attract monocytes to enter the intima, differentiateinto macrophages and start taking up the oxidated lipids. After doing this, themacrophages are called foam cells(2). Foam cells also work as inflammatory activators througha number of different pathways.

T-cells are recruited and can promote apoptosisof smooth muscle cells, endothelial cells and macrophages. If theatherosclerotic process continues, a lipid-rich necrotic core (LRNC) developsin the intima. The LRNC is an accumulation of acellular material containinglipid rich material and cholesterol crystals. This material is derived fromfoam cells and smooth muscle cells. Apoptosis of foam cells and smooth musclecells can be seen in the margins of the LRNC. Since the remnants are notremoved by phagocytes, the lipid rich cargo deposited in the tissues increasethe size of the LRNC(10). Smooth muscle cells are rarely found in the normalintima but as the lesion grows, their number increases.

Smooth muscle cellsmigrate from the media layer into the intima where they divide and expand theextracellular matrix of collagen and proteoglycan. The connective tissuegradually changes from normal, loose tissue into a collagen-rich fibroustissue(9). With increasing age, parts of the plaque can be calcified. Theprocess can begin with microscopic calcium granule that form and graduallyexpand into larger lumps and plates, more often seen at the base of the LRNCclose to the media. The mechanisms behind calcification is poorly understoodand the predictive value of calcification is debated(11).

As the plaque grows, diffusion distances for oxygen andnutrients increase and the plaque develops its own microcirculation, theneovascularization of the plaque. The neovessels may allow further growth ofthe plaque but they also may be fragile and prone to rupture(12). A rupture would lead to bleeding inside the plaquecalled intra plaque hemorrhage (IPH) ultimately making plaque vulnerable torupture.Contrast-enhancedultrasound: Current status”CEUS is an enhanced form of ultrasound scan usingintravenous administration of a microbubble contrast agent. Ultrasound scancontrast agents were introduced in clinical practice in the early 1990s. Thecurrently approved and used agents include SonoVue (Bracco SpA, Milan, Italy),Optison (GE Healthcare, Princeton, NJ), Definity (Lantheus Medical Imaging, N.Billerica, Mass), and Levovist (Schering AG, Berlin, Germany).

The contrastagents consist of microbubbles, generally filled with a perfluorinated gas thathas a low solubility, and stabilized with a phospholipid or protein shell toimprove circulation time. Microbubble contrast agents are intravascular tracersthat, because of their size, cannot leave the intravascular compartment. Themicrobubble shell is eliminated from the body through the reticuloendothelialsystem when the gas is exhaled. Contraindications for microbubble contrastagents are unstable angina, acute cardiac failure, acute endocarditis, knownright-to-left shunts, and known allergy for microbubble contrast agents. Micro-bubble contrast agents have been administrated in millions of patients and aresafe; side effects are extremely rare.”                      Figure: Mechanism of atherosclerosis and vulnerable plaque formation.”CEUS is an enhanced form of ultrasound scan usingintravenous administration of a microbubble contrast agent. Ultrasound scancontrast agents were introduced in clinical practice in the early 1990s.

Thecurrently approved and used agents include SonoVue (Bracco SpA, Milan, Italy),Optison (GE Healthcare, Princeton, NJ), Definity (Lantheus Medical Imaging, N.Billerica, Mass), and Levovist (Schering AG, Berlin, Germany). The contrastagents consist of microbubbles, generally filled with a perfluorinated gas thathas a low solubility, and stabilized with a phospholipid or protein shell toimprove circulation time. Microbubble contrast agents are intravascular tracersthat, because of their size, cannot leave the intravascular compartment.

Themicrobubble shell is eliminated from the body through the reticuloendothelialsystem when the gas is exhaled. Contraindications for microbubble contrastagents are unstable angina, acute cardiac failure, acute endocarditis, knownright-to-left shunts, and known allergy for microbubble contrast agents. Micro-bubble contrast agents have been administrated in millions of patients and aresafe; side effects are extremely rare”.”Many studies have been done on CEUS.

On literaturesearch 15 studies were found, most of them were observational. These 15 studiesincluded a total of 802 patients (69% men, mean age 66 years). The majority ofthe patients were asymptomatic for transient ischemic attack (TIA) or stroke(88%)”.”Feinstein etal was the first to report on the role ofCEUS of the carotid arteries in humans to identify the vasa vasorum in vivo. Inhis 2006 review on carotid ultrasound, a case report was presenteddemonstrating the identification of the vasa vasorum by CEUS and regression ofthe vasa vasorum 8 months after initiation of statin therapy. Six studies,including a total of 95 patients, provided histologic validation of the CEUSimages by carotid endarterectomy.

It was shown that plaque with a higher amountof contrast enhancement had a significantly increased density of small diameter(20-30 µm) microvessels in the corresponding region on histology.  No association has been found between plaqueecholucency and vessel density. Histologic staining for specific vascular(CD31, CD34, hemosiderin, and von Willebrand factor) and angiogenic markers(vascular endothelial growth factor) showed a correlation between intraplaquecontrast enhancement and the amount of staining.

Thus, contrast enhancement wasshown to correlate with the presence and degree of intraplaque neovascularization.Vicenziniet al identified plaque with an ulceration in the luminal border, and observedthat every ulceration had an intraplaque vessel present underneath theulceration. The clinical relevance of this observation deserves furtherinvestigation. Four studies evaluated the difference in contrast enhancementbetween patients symptomatic and asymptomatic for cardiovascular diseases.Patients with cerebrovascular symptoms (TIA or stroke) were shown to havesignificantly higher contrast enhancement compared to asymptomatic patientswith a similar plaque thickness (13.9 ± 6.4 dB vs 8.

8 ±  5.2 dB; P < .001). Staub et alinvestigated the association between CEUS findings and cardiovascular disease(peripheral artery disease, coronary artery disease, myocardial infarction, orcerebrovascular disease, including TIA and stroke) and events (myocardialinfarction, TIA, or stroke).

Carotid intima-media thickness (IMT) is a surrogate marker ofatherosclerosis and imparts prognostic information independent of traditionalcardiovascular risk factors.Itwas shown that the presence of an intraluminal plaque was significantlyassociated with cardiovascular disease (odds ratio, 4.7; 95% confidenceinterval, 1.6-13.

8), whereas intraplaque neovascularization was associated witha history of cardiovascular events (odds ratio, 4.0; 95% confidence interval,1.3-12.6).

These findings support the concept that intraplaqueneovascularization is a sign of plaque vulnerability. Prospective follow-upstudies have been initiated to further elucidate this issue. Owen et alinvestigated the in vivo value of late phase-contrast enhancement (6 minutesafter contrast injection) as a marker for damaged endothelium and plaqueinflammation. In vitro studies have demonstrated that untargeted microbubblesare both phagocytosed by mono monocytes and directly adhere to damagedendothelium. The retention of microbubbles in a plaque might thus indicate thepresence of inflammatory cells adhering to the vessel wall and endothelialdamage. Owen et al reported a significant increase in contrast enhancement 6minutes after contrast injection in symptomatic patients, comparedto asymptomatic patients. Hence, late phase-contrastenhancement might have the potential to identify plaque inflammation and endothelialdamage in vivo.

In a second study, it was shown that late phase enhancementcorrelates with biological features of inflammation and angiogenesis onhistology(12).There are very few studies determining associationbetween contrast ultrasound and microemboli detection by transcranial doppler.Ritter MA et al in 2012 found an association between the occurrence ofmicroemboli signal and the presence of neo-vascularization in patients withsymptomatic atherosclerotic carotid plaque and concluded that  plaque neo-vascularization might also be asurrogate marker of future stroke risk”.  Transcranial doppler and vasomotor reactivity: “Vasomotorreactivity (VMR) represents the response of cerebral circulation to variousvasomotor stimuli for maintaining a near-constant blood flow. Vasomotor changesin response to various stimuli can be studied in real-time by TCD. Carbondioxide (CO2) is the strongest vasodilatory stimulus to cerebralcirculation.

Increased levels of CO2 cause vasodilatation and the responseis reflected by increased flow velocities on TCD. BHI of <0.69 is consideredto represent an impaired cerebral vasodilatory reserve (CVR) regulated by theparasympathetic nervous system.

A decreased BHI represents failure of thecollateral flow to maintain adequate cerebral perfusion in response to thehypercapnic challenge. It is always advisable to monitor both MCAssimultaneously. A normal flow acceleration in the contralateral (normal) MCAestablishes the adequacy of hypercapnic challenge and the expected response inthe ipsilateral MCA.

BHI can be used to identify patients at a higher risk of stroke among the cohort ofasymptomatic carotid stenosis or previously symptomatic carotid occlusion”. Intracranial collateral assessment using CTAngiography: For assessmentof intracranial collaterals in individuals with ischemic stroke various methodshave been described using Ct angiography, however, it is not known which is thebest method to evaluate and grade collaterals. Current methods of assessment ofcollaterals are without any clear indication of the superiority of one methodover another.”Miteff System. The system of Miteff et al is a 3-pointscore that grades middle cerebral artery collateral branches with respect to theSylvain fissure and can be performed rapidly. The grades as- signed are the following:3 (if the vessels are reconstituted distal to the occlusion), 2 (vessels can beseen at the Sylvian fissure), or 1(when the contrast opacification is merelyseen in the distal superficial branches.  Maas System.

The system of Mass et al is a 5-point scorethatcompares collaterals on the affected hemisphere against those ontheunaffected side. It uses the Sylvian fissure vessels or leptomeningealcollaterals as internal controls. The score ranges are 5 (exuberant), 4 (morethan thoseonthe contralateral side), 3 (equal tothose on the contralateralside), 2 (less than those on the contralateral side), and 1 (no vesselopacification)  Modified Tan Scale. The modified scale of Tan et al isthe simplest system that classifies the collaterals as “good” if seen in morethan 50% of the MCA territory and “poor” when they are seen in less than 50% ofthe territory. This system allows a rapid assessment andis less prone todifferences in opinion. We used modified tan scale as it is less prone todifferences in opinion”(13).

  “Mechanism of intracranial collaterals : Although thespecific pathophysiological factors leading to the development of collateralsare uncertain, diminished blood pressure in downstream vessels is considered acritical variable. The opening of collaterals likely depends on severalcompensatory hemodynamic, metabolic, and neural mechanisms Angiogenesis may stimulatecollateral growth at the periphery of an ischemic region. Focal cerebralischemia may lead to the secretion of angiogenic peptides with some potentialfor collateral formation. Chronic hypoperfusion due to arterial flowrestrictions such as extracranial carotid stenosis or intracranial stenoticdisease promotes collateral development, although the relationship of thesecollaterals with cerebral blood flow and clinical symptomatology remainsunclear(14). Secondary collateral pathways that require time todevelop are presumed to be recruited once primary collaterals at the circle ofWillis have failed.

Increasing severity of carotid stenosis has been correlatedwith a greater extent of collateralization”(15).  

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