Associations of internal carotid artery stenosis and collateral circulation with cerebral edema after ischemic stroke

Introduction

Stroke is a leading cause of death worldwide (1), with ischemic stroke accounting for approximately 70% of all strokes (2). Cerebral edema is a common cause of neurological deterioration and death during acute phase (3). Currently, there is limited treatment for cerebral edema (4). Case fatality of patients with malignant cerebral edema under conservative treatment could be as high as 80% (5). Although decompressive hemicraniectomy improves survival of patients with malignant cerebral edema, many survivors remain severe disability after surgery (6). Given the devastating consequences of cerebral edema after ischemic stroke, there is an urgent need to optimize early identification of individual patients who are at a high risk of cerebral edema.

The development of cerebral edema is associated with deficits in cerebral blood perfusion (7), which can be caused by insufficient arterial inflow by upstream stenosis of proximal arterials (8,9). Reperfusion treatment could restore blood supply to the brain and thus reduce the risk of cerebral edema (10). Nevertheless, even in patients who have achieved successful reperfusion, some would still suffer from cerebral edema (11). Cerebral edema after reperfusion therapies is partially attributed to the persistently reduced cerebral blood flow (12), which is associated with poor collateral circulation (13,14). Stenosis of the contralateral internal carotid artery (ICA) is associated with large infarct volume and poor outcome of stroke, possibly due to reduced collateral circulation (15-17). In addition, the circle of Willis connects the anterior and posterior circulation, and leptomeningeal collaterals connect distal arterial branches of bilateral hemispheres (18). In the condition of the occlusion of a major cerebral artery, these collaterals provide compensatory blood supply to the peri-infarct brain tissues (19,20).

Therefore, we hypothesized that, in patients with stroke in anterior circulation, the development of cerebral edema was influenced by the stenosis of ipsilateral ICA, as well as the stenosis of contralateral ICA and status of collateral circulation. Based on this hypothesis, the current study aimed to investigate the morphological features of bilateral ICAs, the circle of Willis, and leptomeningeal collaterals for their associations with cerebral edema after acute ischemic stroke. We present this article in accordance with the STROBE reporting checklist (21) (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-811/rc).

Methods

Study population

This study was part of a bidirectional cohort study (ChiCTR2400086038). We retrospectively screened consecutive patients with presumed stroke admitted to the Department of Neurology, West China Hospital, Sichuan University, between January 2020 and June 2021. The inclusion criteria were: (I) aged ≥18 years; (II) clinically diagnosed as stroke and confirmed by brain imaging for anterior circulation infarction; (III) admitted within 24 hours of stroke onset; (IV) received non-contrast brain computed tomography (CT) and head and neck CT angiography within 24 hours of onset; and (V) had at least one follow-up brain CT or magnetic resonance imaging (MRI) between 24 hours and 7 days after onset. We excluded patients who had poor image quality, severe dysfunction of vital organs, or subarachnoid hemorrhage or parenchymal hematoma on any brain imaging. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Biomedical Research Ethics Committee of West China Hospital, Sichuan University (No. 2024 [632]) and written informed consent was obtained from participants (or legal proxies or families).

Data collection

We collected demographics (age, sex), medical history (hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, myocardial infarction, atrial fibrillation, prior stroke, prior transient ischemic attack, and smoking), time from stroke onset to admission, and baseline level of random blood glucose. We recorded the use of acute reperfusion treatment, including intravenous thrombolysis and endovascular thrombectomy, and the time duration from stroke onset to the initiation of reperfusion treatment. We recorded stroke severity, which was assessed by responsible neurologists on admission by the National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS). We categorized stroke etiology according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification.

Neuroimaging assessment

We evaluated baseline brain CT for the extent of ischemic lesion by the Alberta Stroke Program Early CT Score (ASPECTS, higher ASPECTS scores represent smaller extent of ischemic lesion); conducted baseline head and neck CT angiography for occlusion site of the responsible artery [i.e., ICA or ICA tandem, the first (M1) and second (M2) segments of middle cerebral artery, and distal or no occlusion]; and performed digital subtraction angiography immediately after endovascular thrombectomy for reperfusion status [successful recanalization was defined as a score of 2b or 3 on the revised arterial occlusion scale (rAOL) (22) and successful reperfusion was defined as a score of 2b or 3 on the modified treatment in cerebral ischemia (mTICI) scale] (23).

Assessment of collateral circulation

We assessed ICA stenosis on both ipsilateral and contralateral sides of brain infarction on baseline CT angiography, for the site, degree and length of stenosis. Site of stenosis or occlusion was categorized as at the bulb of cervical segment of ICA, distal to the bulb of cervical segment of ICA, intracranial segment of ICA, and tandem stenosis of cervical and intracranial segments of ICA. Degree of stenosis was assessed based on the North American Symptomatic Carotid Endarterectomy Trial criteria (24), which was categorized as none stenosis, minor stenosis (>0 and <30% stenosis), mild stenosis (≥30% and <50% stenosis), moderate stenosis (≥50% and <70% stenosis), severe stenosis (≥70% and <100%) to occlusion. Length of stenosis was measured as the distance between the proximal and distal points of the stenotic segment (25).

The constituent vessels of the circle of Willis were assessed on baseline CT angiography, including bilateral ICAs, bilateral anterior cerebral arteries, the anterior communicating artery, bilateral posterior communicating arteries and bilateral posterior cerebral arteries. The anterior part of the circle of Willis was defined as incomplete if the anterior communicating artery or one/both precommunicating (A1) segment of anterior cerebral artery was less than 0.8 mm or undetectable in diameter, and the posterior part of the circle of Willis was defined as incomplete if one/both posterior communicating arteries or precommunicating (P1) segment of posterior cerebral artery was less than 0.8 mm or undetectable in diameter (26). We assessed the completeness of the circle of Willis by hemispheric side, where the circle of Willis was defined as incomplete if A1 segment or posterior communicating arteries or P1 segment on the ipsilateral and/or contralateral side of infarction was less than 0.8 mm or undetectable in diameter. The complete fetal-variant posterior communicating arteries were defined if the posterior communicating arteries were visible but did not have ipsilateral P1 segment (27). The grade of leptomeningeal collaterals in the ischemic hemisphere was assessed on baseline CT angiography, defined as grade 0 (absent collaterals), grade 1 (collateral filling ≤50%, but >0), grade 2 (collateral filling >50%, but <100%) or grade 3 (100% collateral filling) compared with the corresponding arterial territory on the contralateral side (28), with grade 0 or 1 defined as poor collaterals (29).

Outcomes

The primary outcome was cerebral edema, which was defined as the presence of midline shift (MLS) assessed within 24 hours and between 24 hours and 7 days after stroke onset, respectively. The midline was established at the level of the septum pellucidum by drawing a line between the anterior and posterior attachment of the falx cerebri, and the distance of MLS was quantified as the length of a straight line perpendicular to the midline (11). We recorded the maximal distance (in millimeter) of brain structure shifted from the midline within 24 hours (24h-MLS) and within 7 days (7d-MLS). We recorded the time from stroke onset to 7d-MLS. Trained researchers blinded to clinical information performed structured interviews by telephone to assess functional outcome at 3 months after stroke onset, where an unfavorable functional outcome was defined as a score of 3 or more on the modified Rankin scale (mRS).

Statistical analysis

We examined the normality of continuous variables by Shapiro-Wilk test. Non-normally distributed continuous variables were reported as median [interquartile range (IQR)] and analyzed using Mann-Whitney U test. Categorical variables were expressed as count (percentage) and were analyzed by Chi-squared test or Fisher’s exact test, as appropriate. We conducted multivariable binary logistic regression analysis to assess the associations of ipsilateral and contralateral cervical ICA stenosis and collateral circulation with MLS, with the adjustment for the effect of age, admission NIHSS, stroke subtypes, baseline ASPECTS, occlusion site of responsible artery, and the degree of cervical ICA stenosis. Odds ratio (OR) and 95% confidence interval (CI) were calculated for the strength of association. Kruskal-Wallis H test with Dunn’s non-parametric test was used to evaluate the association between degree of stenosis and distance of MLS. All data were analyzed with IBM SPSS Statistics, version 26 software, and a two-tailed P<0.05 was considered statistically significant.

Results

Baseline characteristics

Of 914 patients with presumed stroke admitted within 24 hours during recruitment period, 605 patients (66.2%) had ischemic stroke in the anterior circulation. We excluded 197 patients for the lack of imaging or poor image quality of head and neck CT angiography (n=100), absence of follow-up imaging (n=24), brain metastases (n=3), severe dysfunction of vital organs (n=8), secondary subarachnoid hemorrhage (n=1), and parenchymal hematoma (n=61; Figure 1). Of 408 patients finally included for analysis [median age 71 years (IQR, 61–79 years); 60.7% male; median baseline NIHSS score 8 (IQR, 3–13); median baseline ASPECTS score 9 (IQR, 7–10)], 206 patients (50.5%) had stenosis or occlusion in ICA on the ipsilateral side of brain infarction, including 41 patients (19.9%) in cervical segments only, 104 patients (50.5%) in intracranial segments only, and 61 patients (29.6%) with tandem stenosis of cervical and intracranial segments. One hundred and twenty-six patients (30.9%) had stenosis or occlusion in ICA on the contralateral side of infarction, including 57 patients (45.3%) in cervical segments only, 41 patients (32.5%) in intracranial segments only, and 28 patients (22.2%) with tandem stenosis of cervical and intracranial segments. Two hundred and sixty-two patients (64.2%) had incomplete circle of Willis, including 42 had incomplete anterior part of the circle of Willis, 123 had incomplete posterior part of the circle of Willis, and 97 had both incomplete anterior and posterior parts of the circle of Willis. Two hundred and forty patients had incomplete circle of Willis by side, including 54 had ipsilateral incomplete circle, 71 had contralateral incomplete circle, and 115 had incomplete circle at both sides. Fifty patients had unilateral complete fetal-variant posterior communicating arteries, and 9 patients had bilateral complete fetal-variant posterior communicating arteries. One hundred and forty-seven patients (36.0%) had poor leptomeningeal collaterals.

Figure 1 Flowchart of patient recruitment, selection and follow-up. CT, computed tomography; MLS, midline shift; mRS, modified Rankin scale.

Eighty patients (19.6%) developed MLS within 24 hours and 142 patients (34.8%) developed MLS within 7 days (including 62 patients (15.2%) who developed MLS between 24 hours and 7 days) after stroke onset. The median time from stroke onset to 7d-MLS was 3 days (IQR, 2–5 days). Of 397 patients who completed 3-month follow-up interviews, 23 patients (5.8%) died and 145 patients (36.5%) had an unfavorable functional outcome. Compared to patients without MLS, patients with 24h-MLS or 7d-MLS had higher proportions of atrial fibrillation, cardioembolism and proximal artery occlusion, higher admission NIHSS score, lower GCS and ASPECTS scores, and worse functional outcome. In addition, patients with 7d-MLS had lower proportions of male and hyperlipidemia, less thrombolysis, more endovascular thrombectomy, more combined therapy of thrombolysis and thrombectomy, and a lower proportion of successful reperfusion (Table 1).

Association between collateral circulation and MLS

The site of stenosis in either ipsilateral or contralateral ICA had no significant association with the presence of 24h-MLS or 7d-MLS (Table 1). For ipsilateral cervical ICA, compared with patients with none or minor stenosis, those with severe stenosis to occlusion had higher degree of 24h-MLS [none or minor stenosis: median distance of MLS = 0 (IQR, 0-0) mm vs. severe stenosis to occlusion: median = 0 (IQR, 0-2.2) mm, P<0.001; Figure 2A]. For contralateral cervical ICA, compared with patients with none or minor stenosis [median distance of MLS = 0 (IQR, 0-1.8) mm], those with moderate stenosis [median 1.9 (IQR, 0-5.6) mm, P=0.039] and severe stenosis to occlusion [median 2.1 (IQR, 0-3.2) mm, P=0.014] had higher degree of 7d-MLS (Figure 2B). The increased length of stenosis in contralateral cervical ICA was associated with the presence of 24h-MLS (n=80, P=0.029), but the association was not significant after adjusting for the effect of age, NIHSS, stroke subtypes, ASPECTS, and occlusion site of responsible artery. In multivariable logistic regression (Table 2, Figures 3,4), severe stenosis to occlusion in ipsilateral cervical ICA (n=50) was associated with an increased risk of 24h-MLS (adjusted OR 2.922, 95% CI: 1.126–7.583, P=0.028) and severe stenosis to occlusion in contralateral cervical ICA (n=17) was associated with an increased risk of 7d-MLS (adjusted OR 5.896, 95% CI: 1.723–20.173, P=0.005). Neither the incompleteness of circle of Willis nor the presence of complete fetal-variant posterior communicating arteries was associated with an increased risk of the presence of MLS (Table 1). Poor leptomeningeal collaterals were associated with an increased risk of the presence of both 24h-MLS (P<0.001) and 7d-MLS (P<0.001) (Table 1, Figures 3,4), but the associations were not significant in multivariable regression (adjusted OR 0.906, 95% CI: 0.437–1.877, P=0.790 for 24h-MLS; adjusted OR 1.185, 95% CI: 0.611–2.300, P=0.616 for 7d-MLS).

Figure 2 The distance of (A) 24h-MLS and (B) 7d-MLS as continuous variable based on the degree of cervical ICA stenosis on the ipsilateral and contralateral sides of brain infarction, respectively. The black dotted line shows the median and the purple dotted line showed the interquartile range. *, P<0.05 vs. none or minor stenosis; ***, P<0.001 vs. none or minor stenosis, ns representing no statistical difference vs. none or minor stenosis. ICA, internal carotid artery; MLS, midline shift.

Figure 3 Illustrative example of the associations between ipsilateral cervical ICA occlusion and leptomeningeal collaterals with 24h-MLS after ischemic stroke. (A) Complete occlusion of cervical ICA (red arrow) on the ipsilateral side of brain infarction, (B) a poor collateral flow to left hemisphere on baseline CT angiography, (C) 5.4 mm distance of MLS (short red line) in left hemisphere on brain CT at 8 hours after stroke onset. CT, computed tomography; ICA, internal carotid artery; MLS, midline shift.

Figure 4 Illustrative example of the associations between contralateral cervical ICA occlusion and leptomeningeal collaterals with 7d-MLS after ischemic stroke. (A) Complete occlusion of cervical ICA (red arrow) on the contralateral side of brain infarction in patient with ischemic stroke due to occlusion of left middle cerebral artery, (B) a poor collateral flow to left hemisphere on baseline CT angiography, (C) 7.6 mm distance of MLS (short red line) in left hemisphere on brain CT at 3 days after stroke onset. CT, computed tomography; ICA, internal carotid artery; MLS, midline shift.

Subgroup analysis

Of 86 patients who had achieved successful reperfusion after endovascular thrombectomy, 13 patients had stenosis and 7 patients had occlusion in ipsilateral cervical ICA, and 16 patients had stenosis in contralateral cervical ICA. The presence of 24h-MLS was not associated with the degree of ipsilateral cervical ICA stenosis (P=0.856), the completeness of circle of Willis by the anterior and posterior parts (P=0.956), the completeness of circle of Willis by hemispheric side (P=0.331), or status of leptomeningeal collaterals (P=0.712). The presence of 7d-MLS was not associated with the degree of contralateral cervical ICA stenosis (P=0.133), the completeness of circle of Willis by the anterior and posterior parts (P=1.000), the completeness of circle of Willis by hemispheric side (P=0.412), or status of leptomeningeal collaterals (P=0.633).

In 176 patients with proximal occlusion in ipsilateral responsible artery, we stratified patients by the occlusion site of the responsible artery to investigate its effect on the association between the degree of contralateral artery stenosis and the presence of 7d-MLS. In patients with distal or no occlusion of responsible artery (n=232), the higher degree of stenosis in contralateral cervical ICA was associated with an increased risk of the presence of 7d-MLS (P=0.027), but there was no significant association in patients with occlusion in ICA/tandem segment (n=52), M1 segment (n=81) or M2 segment (n=43) (Table 3).

Discussion

In this cohort of patients with acute ischemic stroke in anterior circulation, we explored the association of cerebral edema with ICA stenosis on the ipsilateral and contralateral sides of cerebral infarction, the completeness of the circle of Willis, and the status of leptomeningeal collaterals. Severe stenosis to occlusion of ipsilateral cervical ICA was associated with an increased risk of the presence of 24h-MLS, and severe stenosis to occlusion of contralateral cervical ICA was associated with an increased risk of the presence of 7d-MLS. Our findings provide a new imaging biomarker for early identification of patients at risk of MLS during acute phase of stroke.

Imaging markers are important predictors for cerebral edema after ischemic stroke, which help to understand its pathophysiological mechanisms (30). Findings from cohort study indicated that cerebral edema mainly developed in the first few days after stroke onset (3), thus the current study focused on the prediction of MLS within 7 days after onset of stroke. We found that the severity of cervical ICA stenosis on the ipsilateral and contralateral sides of infarction and poor leptomeningeal collaterals were associated with the increased risk of the presence of MLS. Severe stenosis to occlusion of ipsilateral cervical ICA results in decreased cerebral blood flow to the infarct brain tissue (31). High-grade stenosis of proximal arteries on the contralateral side may cause persistent reduction in cerebral blood flow, which compromises the protective effect of leptomeningeal collaterals (15). In addition, pre-existing stenosis of contralateral ICA has already motivated the potential of leptomeningeal collaterals to provide compensatory blood flow. Thus, when an ischemic stroke occurs, no further compensatory blood supply can be provided by contralateral ICA (15).

In patients with successful reperfusion after endovascular thrombectomy, there was no association of the presence of MLS with either the degree of cervical ICA stenosis or the status of leptomeningeal collaterals. This benefit of reperfusion therapies is consistent with previous studies where successful reperfusion reduced MLS and that MLS mediated the effect of reperfusion therapy on functional outcomes (11). In patients with occlusion in arteries distal to M2 or anterior cerebral artery or no occlusion on the infarction side, the higher degree of contralateral cervical ICA stenosis was associated with the increased risk of the presence of 7d-MLS. However, this association was not evident in patients with occlusion in more proximal arteries such as ICA, M1 or M2 segments on the ipsilateral side of the infarction. This implies that the effect of contralateral cervical ICA stenosis on MLS is diminished by the dominant effect of proximal artery occlusion on the infarction side. In our study, the incompleteness of the circle of Willis segments was not associated with MLS. The effect of circle of Willis configuration on outcomes of ischemic stroke may be modified by the location of arterial occlusion (32). However, the majority of our participants did not have major arterial occlusion, thus the benefit of the completeness of circle of Willis might have been underestimated. Further studies are needed to determine the association between circle of Willis configuration and MLS in stroke patients with large vessel occlusion.

The relationship among infarct size, collateral status, and cerebral edema is complex. Patients with larger infarct have a higher risk of cerebral edema (7), which is associated with the disruption of blood-brain barrier (33). Poor collaterals are often associated with larger infarcts (34) and greater infarct growth (35). Furthermore, poor collaterals increase the risk of cerebral edema by reducing blood flow supply to ischemic area (30). Vice versa, cerebral edema leads to elevated interstitial pressure, which increases the resistance of collateral arterioles and may therefore cause early collateral failure (36). In addition, successful revascularization could reduce the risk of cerebral edema (7). However, poor collateral circulation may increase the risk of in-stent restenosis after carotid artery stenting (37). The complex interplay among infarct size, collaterals, and cerebral edema requires further exploration of underlying pathophysiological mechanisms.

There are some limitations in this study. First, due to the tortuous route of intracranial segments of ICA, we did not analyze morphological features of intracranial arteries but mainly focused on cervical segments of ICA. We found no interaction of different sites of cervical or intracranial artery with the association between the presence of artery stenosis and the risk of MLS. Second, in this observational study, we were only able to analyze available imaging features such as angiography markers. More dynamic imaging markers and their underlying mechanism for the association with MLS need further investigation in longitudinal studies.

Conclusions

In patients with acute ischemic stroke in anterior circulation, severe stenosis to occlusion of ipsilateral cervical ICA was associated with the presence of MLS within 24 hours of stroke onset, and severe stenosis to occlusion of contralateral cervical ICA was associated with the presence of MLS within 7 days.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-811/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-811/dss

Funding: This work was supported by the National Natural Science Foundation of China (No. 82171285); the Science and Technology Department of Sichuan Province (No. 2024YFHZ0330); the Chengdu Science and Technology Bureau (No. 2024-YF05-00525-SN); the 1·3·5 project for disciplines of excellence-Clinical Research Fund, West China Hospital, Sichuan University (No. 2024HXFH022); and the Postdoctor Research Fund of West China Hospital, Sichuan University (No. 2024HXBH139).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-811/coif). The authors have no other conflicts of interest to declare, apart from the funding stated.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Biomedical Research Ethics Committee of West China Hospital, Sichuan University (No. 2024 [632]) and written informed consent was obtained from participants (or legal proxies or families).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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