Lesion patterns and mechanism analysis of acute contralateral ischemic stroke accompanying stenosis of unilateral extracranial internal carotid artery

Abstract Background Previous studies on unilateral internal carotid artery occlusive disease have focused on the mechanisms of ipsilateral hemispheric stroke, and contralateral stroke is considered to be an accidental phenomenon. Little is known about the relationship between severe stenosis (including occlusion) of the unilateral extracranial segment of the internal carotid artery and contralateral cerebral stroke, and the infarct patterns and pathogenesis require further study. The purpose of this study was to investigate the clinical characteristics and pathogenesis of contralateral acute stroke with unilateral extracranial internal carotid artery stenosis (including occlusion). Methods Thirty‐four patients were enrolled in this study, and all patients underwent routine clinical evaluation, including medical history, physical examination, laboratory tests, and various imaging evaluations. The morphological characteristics of diffusion‐weighted magnetic resonance imaging were applied to determine infarct patterns. The etiological classification was confirmed according to the TOAST classification. Results There were six distinctive lesion patterns: small subcortical infarcts (six patients), large subcortical infarcts (one patient), diffuse infarcts (eight patients), multiple anterior circulation infarcts (eight patients), multiple posterior circulation infarcts (two patients), and multiple anterior and posterior circulation infarcts (nine patients). Conclusion Diffuse and multiple infarcts were the most common topographic patterns in ischemic stroke contralateral to internal carotid artery stenosis or occlusion. Hemodynamic impairment of the contralateral hemisphere due to hypoperfusion and blood theft is regarded as the basis of stroke occurrence. Low ischemic tolerance and embolism are the main causes of acute ischemic stroke.


INTRODUCTION
Atherosclerotic disease of the internal carotid artery (ICA) is one of the major risk factors for cerebral ischemic events, and approximately 75% of ischemic strokes occur in the area supplied by the ICA (Alagoz et al., 2016). The causes of ischemic strokes in Western countries have mostly been identified as extracranial carotid artery lesions; in China, they are mostly identified as intracranial vascular lesions, with carotid supply areas accounting for 80% of cases. However, with changes in dietary habits and lifestyle, the rate of extracranial vascular stenosis has gradually increased in China (Wityk et al., 1996). The prognosis of acute ischemic stroke (AIS) due to severe stenosis (including occlusion) of the ICA shows high disability and mortality rates. Intravenous or intraarterial thrombolysis with recombinant tissue plasminogen activator (rt-PA) therapy as well as endovascular interventions still face challenges and individualized limitations in efficacy. In addition to being related to collateral circulation and treatment time, the etiology and pathogenesis of ICA should not be ignored (Li et al., 2016). In many studies (Chen et al., 2011), magnetic resonance imaging (MRI), and especially diffusion-weighted imaging (DWI) sequences, have been used to investigate lesion patterns in ipsilateral stroke caused by extracranial ICA stenosis, but most of these studies have been performed in specific stroke subtypes. Embolism and hypoperfusion due to inadequate collateral circulation are considered the two basic mechanisms of ipsilateral stroke caused by severe stenosis or occlusion of the extracranial segment of the ICA. In contrast, very little attention has been paid to strokes in the hemisphere opposite to the lesioned vessel. Even when such patients are identified in studies, it is usually considered a coincidence due to microembolic transbulbar channels or small vessel occlusion, leading to the neglect of such disease (Georgiadis et al., 1993). This may be due to heterogeneity in etiology, with no significant correlation between the two. A lack of information on focal patterns and pathogenesis of ICA is common in the literature. Lee et al. (2008) summarized and analyzed eight patients and did not exclude strokes in the presence of responsible vascular lesions; they also did not provide an explanation for posterior circulation infarction.
This study summarized and analyzed the lesion patterns and mechanisms of acute contralateral ischemic stroke accompanying stenosis of the unilateral extracranial ICA.  (Bouthillier et al., 1996), the whole process of the ICA was marked with C1-C7 along the direction of blood flow.

Research methods
Detailed demographic characteristics of all patients were recorded. MRA was performed with the same system using a neurovascular coil.
As the stenosis rate of ICA is often high on carotid ultrasound, widely available methods (brain CTA or DSA) were used to clarify the steno-

Determination of stroke lesion patterns
The anatomic patterns of the ischemic lesions were determined based on the distribution of the intracranial arterial blood supply, as pre- The lesion patterns were divided into single and multiple lesions according to the cerebral arterial blood supply combined with the location, size, and number of lesions shown on DWI (Tatu et al., 2012;Wang et al., 2017;Yoon et al., 2013). Single lesions included cortical infarcts, cortical-subcortical infarcts, small subcortical infarcts with a diameter <15 mm, large subcortical infarcts with a diameter >15 mm, and bilateral isolated brainstem infarcts extending to the ventral side.
Multiple lesions included diffuse infarcts and multiple infarcts. Diffuse infarcts were defined as areas dominated by a single vessel, including diffuse lesions <15 mm or confluent lesions ≥15 mm with additional lesions. Multiple infarcts occurred in territories supplied by two or more vessels, including multiple infarcts in the anterior, posterior, and anterior-posterior circulation.

RESULTS
Of the patients included in the study, there were 22 men and 12 cases of multiple infarcts in the posterior circulation (Group 5. NO. 8, 25), and 9 cases of multiple infarcts in the anterior and posterior circulation (Group 6. NO. 9,11,17,20,21,28,29,31,32). And all lesions of each patient are plotted in Figure 1 to illustrate the staging.
Regarding clinical manifestations, symptoms differed depending on the site of involvement. In Group 6, the clinical manifestations involved aphasia, dysarthria, hemiparesis, hemianopia, blurred vision, and even Patients presenting with exacerbations or poor prognosis were considered to be associated with a higher number of involved vessels and critical infarct sites and more severe brain injury.

DISCUSSION
Unilateral ICA occlusive disease has been reported in previous studies; however, most neuroimaging studies have focused on ischemic stroke ipsilateral to the occluded vessel. There are few reports on the lesion patterns and pathogenesis of unilateral atherosclerotic stenosis (or occlusion) of the ICA in extracranial segments with contralateral acute stroke. As it is often difficult to prove, AIS has only rarely been recognized as the result of contralateral ICA stenosis or occlusion.
Furthermore, incidental occlusion of small vessels is considered to be the major etiological mechanism. Therefore, it is urgently necessary to deepen the knowledge of the etiology, topographic patterns, and pathogenesis of this specific type of ICA.
Diffuse and multiple infarcts in this study was predominantly the lesion patterns, with eight cases of diffuse infarcts, eight cases of multiple infarcts in the anterior circulation, 2 cases in the posterior circulation, and nine cases in the anterior and posterior circulation.
Currently, the pathogenesis of AIS contralateral to the severe stenosis (or occlusion) of unilateral extracranial ICA is still unclear. Lee et al. (2008) hypothesized that synergistic effects of emboli and a hypoperfused state were assumed to be the main pathogenic mechanism.
The present study showed that the pathogenesis of such ischemic  (e.g., patient 15). The usual territory involved, supplied by small terminal arteries and the lowest perfusion pressure, is higher in the circulation and farther from the heart. It is more sensitive to hypoxia and is highly susceptible to hypotension or the effective circulating blood volume, especially in the centrum semiovale (Mangla et al., 2011). The patients here had a mismatch between the infarct site and the stenotic or occluded vessel, presumably with the possibility of intracranial blood theft.
In addition, arterial-arterial microembolus shedding is important in this type of infarct. Previous studies have shown that the rate of microembolus positivity increases with the degree of intracranial and extracranial arterial stenosis, which is significantly associated with accelerated blood flow velocity and vortex generation (Caplan & Hennerici, 1998). It is generally accepted that stenotic blood vessels are often prone to plaque formation and weaker than the normal arterial intima. The plaques are destroyed by high velocity blood flow, while the changes in hemodynamics accelerate the shedding of necrotic material within the plaque to form microemboli (Wong et al., 2002). With the exception of arterial plaque sources, emboli are also composed of diverse materials that originate in the heart. However, the accuracy of cardiac ultrasonography has led to a low detection rate in patients with a cardiac stroke origin, which is ultimately classified as a subtype of unknown source. In the present study, only two cases had a definite cardiac embolic origin. Emboli entering the cerebral circulation may convey an increased risk of blocking the blood vessels and the occurrence of ischemic events. Clinically, hypoperfusion and microembolic emboli coexist, and the interaction of their pathological features explains the infarction patterns of multiple lesions (Caplan & Hennerici, 1998). Hemodynamic damage of the contralateral brain secondary to atherosclerotic occlusion of a unilateral ICA may lead to slowed blood flow and increase the incidence of arterial-arterial emboli. The distal cortical areas, which are cross-fed by multiple vessels, are the most common locations for microemboli and lack collateral circulation, tending to infarction. Some studies have provided evidence that depletion of the CBF reserve impaired clearance of emboli. Similarly, the hemorheology in the above mechanisms is equally important. The presence of atheromatous plaques alters the flow pattern of blood through the area, which increases the viscosity of the blood and hemodynamic resistance, causing the blood flow rate to decrease or even causing the blood to stagnate (Caplan & Hennerici, 1998;Chung et al., 2016;Förster et al., 2008).
Also of note in the present study, cerebral ischemic tolerance has a profound effect on AIS. Repeated, transient ischemic burden induced greater ischemic tolerance than a single ischemic burden, as shown by Kitagawa et al. (1990) in a model of cerebral ischemia, who showed significant interhemispheric differences in ischemic tolerance in ipsilateral versus contralateral cerebral tissue. With stenosis or even occlusion of extracranial segments of the ICA, the ipsilateral hemisphere is in a prolonged low-flow state, and the tolerance of corresponding brain tissue increases. When there is a sharp drop in blood pressure or another hemodynamic injury event, cerebral infarction has already occurred in the healthy cerebral hemisphere due to poor tolerance to ischemia.
The main limitation of this study is the inclusion of a relatively small number of patients, although we retrospectively analyzed patients with AIS admitted to two affiliated hospitals over 6 years. Inevitably, there was bias because of the small sample size and retrospective assessment. Although the inclusion and exclusion criteria have been strictly limited to ensure the completeness and accuracy of the data.
Therefore, large-scale and multicenter participation is needed in the future to enhance the reliability of the results. In this study, CTA and DSA were performed to evaluate the degree of vascular stenosis. It is known that DSA is the gold standard for vascular evaluation, but there were nine patients who performed CTA because they refused atherosclerosis, whereas, in the present study, the location of lesions was mostly subcortical, in cases of both single and multiple infarcts. In addition, infarction involving the watershed area in this study was not explained by nonstenotic atherosclerosis, and hypoperfusion was still considered the main mechanism. Therefore, we do not think that the presence of atherosclerosis can be excluded, but the mechanism of its occurrence needs further confirmation.

CONCLUSION
In conclusion, the results of the present study showed that the patterns of AIS contralateral to severe stenosis (including occlusion) of a unilateral extracranial ICA is more common in diffuse infarctions and multiple cerebral infarctions. The etiology of this disease may be hemodynamic disturbance caused by hypoperfusion and blood theft in the contralateral hemisphere, followed by embolism, or it may be associated with poor ischemic tolerance. This study contributed reliable evidence to support these potential mechanisms, and further studies with more patients are required to confirm these findings.