1. Introduction
Asymptomatic internal carotid artery (ICA) stenoses are clinically significant, with 2%-9% of the general population found to have asymptomatic stenoses ³50%[1]. It is discovered that, during a mean follow-up period of 3.6 years, the first vascular event occurred in 253 out of 2684 patients with asymptomatic ICA stenosis[2]. This article addresses the importance of artery-artery embolisation in determining whether a patient with asymptomatic internal carotid artery stenosis, should receive prophylactic treatment. Firstly, different treatment modalities are stated and explained. Secondly, artery-artery embolisation in the context of internal carotid artery stenosis is elucidated. This article highlights the particular importance of middle cerebral artery (MCA) occlusion, relative to other vessels in the anterior circulation. Thirdly, this article explains the three factors of the parent stenosis underlying the risk of artery-artery embolisation, namely (1) degree, (2) location, and (3) morphology. Fourthly, this article details the risks involved in treatment modalities. The conclusion is reached that although there are inherent peri- and post-operative risks associated with the treatment modalities, artery-artery embolisation is a formidable risk factor which could warrant intervention.
2. Treatment Modalities
Three treatment modalities are available for patients with asymptomatic ICA stenoses, namely (a) medical therapy, (b) stenting, and (c) endarterectomy.
(a) Medical Therapy
JA Beckman[3] states that medical therapy can reduce stroke risk for such patients to approximately 1% per year. Whether this includes the stroke risk incurred from artery-artery embolisation is unknown. Best medical treatment currently includes[4] lifestyle modification, anti-platelet (aspirin as suggested by American guidelines[5]), anti-lipid (statin) and blood pressure-monitoring therapy. Of which, a relevant trial[6] highlights the more paramount roles played by antiplatelet therapy and blood-pressure control. Much of the risk highlighted in aggressive medical therapy is presented in the anti-platelet component. Patrono et al finds that the risk of having major bleeds after aspirin treatment is 1-2 events / 1000 patients, which is double that of the placebo group.[7] Lifestyle modification is increasingly important as reflected by recent studies. A study utilising a Swedish cohort finds that healthy lifestyles reduced the risk of stroke in women by 60%, and the risk of myocardial infarction in men with hyperlipidaemia and hypertension (both being risk factors of myocardial infarction) by 80%.[8] Smoking cessation is described by JD Spence et al as the single most important measure for stroke prevention. This means smoking should not be treated as an afterthought in clinical intervention. Due to the high risk of relapse, clinicians are advised to provide adequate nicotine replacement therapy, such as nicotine patches and inhalers, for heavy smokers.[9] In terms of dietary changes, the Cretan Mediterranean diet is advocated for patients with asymptomatic internal carotid artery stenosis.[10] The diet is mainly vegetarian, which is high in olive oil, canola oil, fruits and so forth. As a modality for primary prevention, the risk of stroke is found to be reduced by nearly 50%.[11]
(b) Carotid Revascularisation: Stenting and Endarterectomy.
Current European and American guidelines[12][13]suggest that asymptomatic patients with 60% of ICA stenoses should receive carotid revascularisation, i.e. by either stenting or endarterectomy. There are various trials comparing relative risks and benefits between stenting and endarterectomy in patients with internal carotid artery stenosis. However, very little literature focuses on comparisons of stroke/death risk between medical treatment and either or both of endarterectomy and stenting[14]. The ACT Trial[15] states that, for asymptomatic patients with ICA stenoses bearing no high risk of surgical complications, there are no significant differences between endarterectomy and stenting, up to 5 years of follow-up, in procedure-unrelated stroke, all-stroke and death. In a similar trial, CREST[16], investigators have reported that endarterectomy and stenting present with non-significant differences in the risks of 4-year stroke or death. However, a systematic review reported that there was moderate-quality evidence that carotid endarterectomy presented with better outcomes than stenting. Stroke or death rate at 30 days is significantly higher in the stenting group, as compared to the endarterectomy group (64/2176 [2.94%] vs 27/1431 [1.89%]; OR, 1.57; 95% CI, 1.01-2.44; P = .044). In terms of the long-term outcome of stroke or death rate at 30 days, plus ipsilateral stroke during the follow-up period, again, it is significantly higher in the stenting group as compared to the endarterectomy group (79/2173 [3.64%] vs 35/1430 [2.45%]; OR, 1.51; 95% CI, 1.02-2.24; P = .04). A possible limitation is the inclusion of only nine randomised controlled trials. Another limitation is the exclusion of contralateral stroke, of any time limit, as an investigated outcome. Only ipsilateral stroke at one year and stroke or death rate at thirty days are included as primary outcomes. This renders the study incapable of comprehensively assessing the efficacy of carotid revascularisation in reducing the incidence of artery-artery embolisation, since emboli can travel to the contralateral side through the Circle of Willis. Last but not least, the threshold degree of stenosis and the modality of detection for therapeutic intervention vary among the nine trials significantly, from ³ 50% detected on angiography to ³ 80% on ultrasound. Such discrepancies may hinder the systematic review from drawing conclusive opinions.[17]
3. Artery-Artery Embolisation
The article then proceeds to the issue of artery-artery embolisation. Artery-Artery embolisation might result in more devastating consequences than the parent thrombotic lesion. For instance, it can induce ‘shower embolism’, where the parent lesion becomes a nidus for embolisation, as attested by several case reports[18][19]. The internal carotid artery directly gives the MCA. MCA Syndrome, prompted by the occlusion of the artery, can thus arise from the detachment of a thrombotic lesion situated at the ICA. The mortality rate can reach 28%.[20] However, Hacke W et al reported a mortality rate of 78%, with transtentorial herniation being the end-point for 78% of patients.[21] There is also a possibility of embolisation to the anterior cerebral artery (ACA), despite the fact that atherosclerosis is a more common aetiology there.[22]
(a) Consequences
Artery-artery embolisation entails serious consequences. According to the Asymptomatic Carotid Emboli Study[23], embolic signals were present in 77 / 467 (16.5%) patients at baseline. The hazard ratio for the risk of ipsilateral stroke and transient ischaemic attack from baseline to 2 years in patients with embolic signals compared with those without was 2·54 (95% CI 1·20–5·36; p=0·015). No specific literature is found that illustrates the direct relationship between MCA syndrome (and/or ACA syndrome) and ICA stenoses, let alone the prevalence of such phenomenon. However, artery-artery embolisation cannot be neglected due to its consequences. The severe consequences of MCA occlusion are very well-documented[24][25], including reduced experience of positive emotions, hemiparesis, sensory loss and ataxia. Sung HJ et al[26] states that after complete middle cerebral artery infarction, 70% of patients were able to walk independently but no patient achieved functional hand recovery. Aphasia usually accompanies left hemispheric lesions (presence of Wernicke’s and Broca’s Areas), whereas anosognosia and sensory neglect occur on the right hemisphere[27]. For anterior cerebral artery occlusion, Motor dysfunction (n=91) was recorded as the commonest symptom as stated by a Korean study.[28] Other possible symptoms reported by the study include hypobulia/apathy (n=43), urinary incontinence (n=30) and grasp reflex (n=25). Therefore, the risk and severe consequences of arterial occlusion following artery-artery embolisation should be factored into consideration when deciding if the patient should receive treatment.
(b) MCA and Artery-Artery Embolisation
The case is even stronger if we take into account the MCA, in consideration of its territorial coverage and the prevalence of occlusive events there. Some might wonder why the MCA is highlighted in such an occasion, since shower embolism can also affect, per logic, the ACA, as affirmed by research[29]. Anatomically speaking[30], the MCA supplies the majority of the lateral hemispheres, apart from the medial portions of the frontal and parietal lobes, as well as the inferior part of the temporal lobe. Lateral lenticulostriate branches from segment M1 also supply the majority of the basal ganglia. This, as contrasted to the smaller vascular territory of ACA, which includes part of the basal ganglia and the frontal lobes, has highlighted its significance when occluded. It is easier for the MCA to be affected first during shower embolisation from ICA stenoses due to its direct trajectorial inheritance. ACA territory infarcts are reported to only account for 3.0% of all cerebral infarctions as shown on CT material, as compared to 67.0% in the MCA.[31] The pattern is also supported by a Spanish study.[32] The ACAs are also less vulnerable to infarction due to collateral supply through the anterior communicating artery, which is only absent in 5% of patients as identified by surgery[33]. It is shown that there is higher in-hospital mortality rate in MCA stroke than its ACA counterpart (MCA stroke = 17.3%, ACA Stroke = 7.8%)33. The risk of MCA occlusion should thus be taken seriously when evaluating the impact of artery-artery embolisation. This being said, however, does not, by any means, denounce the importance of occlusive events in other arteries. It only buttresses the argument that artery-artery embolisation is, collectively speaking, a serious issue.
(c) Factors for evaluating risk of artery-artery embolisation
With the dangers of artery-artery embolisation stemming from ICA lesions established, what factors can be employed to evaluate the risk of artery-artery embolisation? This article argues that three are the most crucial: (1) degree of stenosis, (2) location of stenosis, and (3) morphology of atheromatous plaque. They are elaborated in the following.
In terms of the degree of stenosis, logic dictates that the chance of stroke increases regardless of territory, with the increase in reduction of lumen diameter. The larger size of the thrombotic lesion, subjected to haemodynamic forces, more easily detaches from the vascular wall and travels forwards, hence affecting vessels of smaller calibre in the cerebrovascular system. However, controversial data are presented in the literature. Den Hartog AG et al[34] divides patients with asymptomatic ICA stenosis according to the degree of stenosis (50%-99% and 70%-99%). No significant increase in ischaemic stroke risk (hazard ratio, 1.5; 95% confidence interval, 0.7–3.5) is found. In the NASCET trial[35], it is discovered that there is a positive correlation between stroke risk and degree of asymptomatic ICA stenosis (annualised risk of stroke at 1.9 percent), but the risk decreases for the stenotic range 95% to 99% (near-occlusion). Cardioembolism is suggested in the study as a possible, confounding mechanism. It does not necessarily follow that this impacts detrimentally on clinical decision-making, when a holistic approach is expected in such contexts. For instance, for patients with atrial fibrillation, the CHA2DS2-VASc score of the patient can be interpreted in line with the risk of artery-artery embolisation[36]. These factors are cumulative in deciding on an appropriate treatment plan.
The location of the carotid stenosis also determines relative risk. The variations of stroke risk with a shift in location of the stenotic event throughout the ICA in literature is very scarce. The ICA is divided into 7 segments under the Bouthillier Classification.[37] Due to differences in trajectory and anatomical distance, C7 stenoses might bear greater risk of ICA-MCA embolism with respect to C1 or C2. The closer the portion affected is to the Circle of Willis, the higher the probability of which neighbouring vessels are affected. For purposes of convenience in the clinical setting, the extracranial-intracranial dichotomy can be utilised instead, where the extracranial ICA covers segments C1 and C2. The remainder is categorised as the intracranial ICA.[38] This can hopefully aid clinicians to decide, upon diagnosis of where the stenotic event(s) is/are throughout the ICA, whether treatment is required with additional concern over altered risk of artery-artery embolisation.
The morphology of the atheromatous plaque can influence the risk of ulceration and most importantly, artery-artery embolism. Ultrasound is the primary diagnostic modality for determining atheromatous plaque morphology[39]. A study has stated the limitations of assessing lesion vulnerability of high-risk patients using carotid MRI.[40] Such morphology can be categorised in various ways, one being either homogenous or heterogenous. Homogeneity is defined as where the plaque shows regularity and smoothness whereas heterogeneity, identification of areas of different echogenicity[41]. Alternatively, Gupta A et al[42] states that there is a significant, positive relationship between predominantly echolucent plaques and the risk of future ipsilateral stroke (for all stenotic severities: relative risk [RR], 2.31, 95% CI, 1.58-3.39, P<.001). Peak cap stress and thickness of fibrous cap are also deemed as categories of differentiation[43]. Such classification can further stratify asymptomatic patients according to the instability of their atheromatous lesions over the ICA. Treatment can be subsequently given to asymptomatic patients with plaques anchoring high risk of embolisation. A possible argument against the use of ultrasound is its steep learning curve. MR modalities such as susceptibility-weighted imaging (SWI), can be employed concurrently. It is discovered that SWI is comparable to angiography and MR angiography in the detection of thrombotic location and length.[44] Thrombotic length, as a parameter of morphology, indicates the extent of thrombotic extension which can affect plaque stability and the risk of embolisation.
(d) Metabolic Factors – a new research direction?
In addition to the aforementioned factors, risk prediction can also include the metabolic composition of a particular thrombotic lesion. Composition might influence the likelihood of embolisation. There are two main factors for consideration: (i) substance, and (ii) arrangement. Research can be done in evaluation of the types of substances present in the thrombus, as well as the percentages of such types. The patterns of arrangement of various substances can also influence the stability of the clot. This differs from plaque morphology since it focuses on the microscopic aspect of affairs, while morphology is inclined to be macroscopic.
In a study comparing the composition of arterial, venous and pulmonary thrombi[45], it was found that arterial thrombi were composed mainly of fibrin (amounting to 43% of total thrombus volume) and platelets (31%). Heterogeneity was exemplified by the presence of fibrin bundles (amounting to 55% of fibrin types), as well as ‘fibrin sponge’, defined as a highly branched network of thin fibres. Evidence of clot contraction is also seen. Clot contraction is described as platelets pulling on fibrin fibres and compressing against erythrocytes. This leads to a transformation in erythrocytic morphology from biconcave to polyhedral and various indeterminate forms. The vast majority of erythrocytes found in arterial thrombi (88.2%; where 17% are erythrocytes in total thrombus volume) are polyhedral or of other compressed forms. It has also been found that fibrin increases the strength of the clot by 12-28 folds, as compared to thrombi formed from thrombin only.[46] Therefore, if patients are found to harbour thrombotic lesions with lower fibrin content, or aberrant fibrin networks, the stability of the lesion can be substantially reduced. Clot contraction is postulated to be a significant factor influencing embolisation. In patients with MYH9-related defects, due to the impaired release of a cytoskeletal contractile protein by platelets, clot contraction is impaired. These patients present with higher risk of bleeding and lowered stability of the thrombus.[47]
Basic scientific concepts, notwithstanding attractiveness in their theories, contribute little unless they are crystallised into clinical practice, which emphasises on convenience and low cost. Patients can be actively screened for genetic mutations which can lead to weakened clot contraction (such as MYH9) and fibrin production. Moreover, studies can be performed to assess the differences in radiological findings in thrombotic lesions of higher fibrin content, more regular fibrin arrangement and more rigid clot structure, which is evidence to more superior clot contraction. These findings are expected to contribute substantially to our understanding towards thromboembolisation in general and aid better risk stratification.
4. Striking a balance
One should, however, not be blind-sighted by artery-artery embolisation. On the other side of the scale, such treatment modalities also carry different types of peri- and post-operative risks that ought to be taken into account.
Noiphithak R et al[48] states that certain factors are to be heeded: patient status (especially those with severe cardiovascular disease); vascular anatomy for endarterectomy; plaque morphology and vessel anatomy for stenting, due to elevated risk of distal embolisation during manipulation. Such risks are rather arbitrary since they depend on the expertise of surgeons and individual anthropometric factors, influencing the overall benefit of the modality. According to Brajesh K Lal et al[49], during a 2-year follow-up period, restenosis and occlusion were infrequent and the rates were similar after carotid stenting and carotid endarterectomy despite there being no differentiation between asymptomatic patients and those who had history of transient ischaemic attack(s) in the cohort. Some risk-calculation scores are established for aiding the clinician to determine if the asymptomatic patient bears high risk of peri-procedural death or stroke, like CEA-8.[50] This can be, as part of a holistic exercise, used to assess whether asymptomatic patients should receive treatment.
5. Conclusion
All in all, artery-artery embolisation should be taken into account when deciding whether a patient with asymptomatic ICA lesion(s) should receive treatment. Artery-artery embolisation is a lethal consequence and its risk can be determined by the degree, location and morphology of the parent stenosis. Metabolic composition of the thrombus is a possible research direction which enhances our understanding towards arterial thromboembolism and aids risk stratification. It should be noted that due to interactions between the degree of stenosis and the risk of artery-artery embolisation, the threshold of ICA stenosis for endarterectomy can be downward-adjusted. At the same time, no one should be blind-sighted. Peri- and post-operative risks of treatment modalities do exist and should be considered as part of a holistic exercise in clinical decision-making. It is recommended that future research focuses on the construction of scoring models in assessment of the likelihood of artery-artery embolisation according to aforementioned variables, as well as anthropometric factors like prior immunodeficiency, coagulopathy or diabetes mellitus which can influence the risk of post-operative risks. Such scoring models can hence be utilised in deciding on the appropriate treatment modality.
*The cover image is extracted from: https://www.verywellhealth.com/thmb/Ch4pLRyZiplZ5iEdpkglLKYS1nc=/3543x2662/filters:fill(87E3EF,1)/artwork-of-cerebral-embolism--cause-of-stroke-680794163-a6be11a1027a45c0be18aeca44381bea.jpg.
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