Poor Internal Jugular Venous Outflow Is Associated with Poor Cortical Venous Outflow and Outcomes after Successful Endovascular Reperfusion Therapy

Many patients show poor outcomes following endovascular reperfusion therapy (ERT), and poor cortical venous outflow is a risk factor for these poor outcomes. We investigated the association between the outflow of the internal jugular vein (IJV) and baseline cortical venous outflow and the outcomes after ERT. We retrospectively enrolled 78 patients diagnosed with an acute anterior circulation stroke and successful ERT. Poor IJV outflow on the affected side was defined as stenosis ≥50% or occlusion of ipsilateral IJV, and poor outflow of bilateral IJVs was defined as stenosis ≥50% or occlusion of both IJVs. Poor cortical venous outflow was defined as a cortical vein opacification score (COVES) of 0 on admission. Multivariate analysis showed that poor outflow of IJV on the affected side was an independent predictor for hemorrhagic transformation. The poor outflow of bilateral IJVs was an independent risk factor for poor clinical outcomes. These patients also had numerical trends of a higher incidence of symptomatic intracranial hemorrhage, midline shift >10 mm, and in-hospital mortality; however, statistical significance was not observed. Additionally, poor IJV outflow was an independent determinant of poor cortical venous outflow. For acute large vessel occlusion patients, poor IJV outflow is associated with poor baseline cortical venous outflow and outcomes after successful ERT.

In most clinical studies, arterial collaterals are considered a key factor in determining treatment strategy and prognosis [5,6]. However, in clinical practice, it is not uncommon for ERT patients with good arterial collaterals to have serious complications and poor outcomes. Increasingly, evidence shows that collateral circulation is an overall process from arteries to veins, and the increased arterial blood flow requires sufficient downstream venous collaterals [7][8][9][10]. Even a single cortical vein occlusion can cause a decrease in regional cerebral perfusion and brain edema [11]. Recently, a number of clinical studies We retrospectively reviewed the data of consecutive patients diagnosed with an acute ischemic stroke treated with ERT in our institution from November 2017 to March 2022. The institutional ethics committee approved the study, and all clinical investigations were conducted according to the Declaration of Helsinki or comparable ethical standards.
Patients were included if they (1) had an acute or near occlusion of an internal carotid artery (ICA) or MCA; (2) underwent ERT within 24 h from symptom onset with successful recanalization defined as modified thrombolysis in cerebral ischemia ≥ 2b; (3) had a prestroke modified Rankin Scale (mRS) score of ≤2; and (4) had complete clinical and imaging data during hospitalization. Patients with a pre-stroke mRS score of ≥3 and incomplete clinical and imaging data were excluded.

Image Analysis
All patients underwent head and neck CT angiography (CTA) on admission and a follow-up non-contrast head CT (NCCT) within 24-48 h of ERT. The number of reexaminations was determined according to the patients' clinical symptoms. A 320-detector row 640-slice cone-beam multidetector CT scanner (Aquilion One, Toshiba Medical Systems, Otawara, Tochigi, Japan) was used for imaging. A non-contrast scan of the cervical vessels covering the aortic arch to the middle cranial fossa was performed first, followed by a whole-brain NCCT in wide-volume mode (five rotations with a 4 cm width per detector). After NCCT, 40 mL of contrast agent (Ultravist 370; Bayer HealthCare, Berlin, Germany) was administrated (5 mL/s) chased by 40 mL of saline (acquisition parameters: 120 kV, 112 mAs, total collimation width: 16 cm); 19 pulse rotation scanning points were collected within 55 s. Next, scans of the carotid artery and delayed phases were acquired by administrating 40 mL of contrast agent (5 mL/s) followed by 40 mL of saline (acquisition parameters: 120 kV, 112 mAs, total collimation width: 16 cm, slice thickness = 0.5 mm).
Two authors, both with over three years of experience in neuroimaging, assessed the imaging data independently, blinded to the clinical data. TS hypoplasia was defined as a degree of stenosis at least 50% greater than that on the contralateral side [26]. We evaluated the outflow of IJV (including the brachiocephalic vein) based on the standards of Zaharchuk et al. [27]: (1) favorable outflow = normal or mild flattening of IJV, stenosis < 50%; (2) poor outflow = moderate-severe flattening or no visualization of IJV, stenosis ≥ 50%, or occlusion. The outflow of bilateral IJVs was further classified into three grades: (1) favorable outflow = normal or stenosis < 50% of bilateral IJVs; (2) intermediate outflow: normal or stenosis < 50% of one IJV, and stenosis ≥ 50% or occlusion of the other IJV; (3) poor outflow = stenosis ≥ 50% or occlusion of bilateral IJVs. Cortical venous outflow was evaluated by cortical vein opacification score (COVES) on the original head CTA images on admission [13]. COVES assigned 0-2 points to each of the three cortical veins according to the degree of opacification of the superficial middle cerebral vein, sphenoparietal sinus, and vein of Labbe (0: invisible, 1: moderate, 2: complete). The total score of COVES is 6, and poor cortical venous outflow was defined as COVES = 0 [13]. We classified the arterial collaterals on admission into two grades (good-intermediate and poor) according to the criteria of Menon et al. [28].

Neurological Outcomes
Following the European Cooperative Acute Stroke Study criteria, we classified HT into hemorrhagic infarction (HI) 1, HI2, parenchymal hemorrhage (PH) 1, or PH2. In the follow-up NCCT, any HT related to an increase of ≥4 points on NIHSS was considered symptomatic intracranial hemorrhage (sICH) [29]. We measured the farthest point on the septum, perpendicular to the ideal midline, which joined the most anterior and posterior visible points on the falx. According to the distance of the septum perpendicularly shifted to the healthy side, midline shift was classified into four grades: 0-2 mm, 2-5 mm, 5-10 mm, and >10 mm [30]. An mRS score of ≥3 at discharge was classified as a poor clinical outcome.

Statistical Analyses
We used the κ coefficient to assess interobserver agreement for TS hypoplasia, IJV stenosis, arterial collaterals, HT, and midline shift. Normally distributed continuous variables are shown as means ± standard deviations (SDs), and non-normally distributed continuous variables are presented as medians and interquartile ranges (IQRs). Frequencies (percentages) are used to describe categorical variables. According to the normality of the distribution, Student's t-test or the Mann-Whitney U test was used to compare the differences between groups of continuous variables. We used the χ2 test and Fisher's exact test to compare dichotomous variables between groups, and we used the Kruskal-Wallis H test for ordered categorical variables. Independent outcome predictors were identified by multiple binary logistic regression analyses. In the univariate analysis, any covariates with a p-value of ≤0.1 were entered into the logistic regression model. The favorable outflow of the affected IJV and bilateral IJVs were entered into the model, respectively. Results are presented as odds ratios (ORs) and 95% confidence intervals (CIs). Results were considered statistically significant when the two-tailed p-value was <0.05 (SPSS for Windows, Version 22.0; IBM, Armonk, NY, USA).

Patient Characteristics
We identified 119 patients with acute large artery occlusion or near occlusion who underwent ERT within 24 h and excluded 41 patients ( Figure 1). Finally, we examined 78 patients (near occlusion: n = 5).
The interobserver agreements (κ) for TS hypoplasia, IJV stenosis, COVES, arterial collaterals, HT, and midline shift were 0.91, 0.90, 0.71, 0.87, 0.92, and 0.83, respectively. Table 1 presents the clinical and radiological characteristics of all patients at baseline. Among these patients, the mean age was 68 years, and twenty-seven patients (34.6%) were female. Twenty-eight patients (35.9%) had a favorable outflow of IJV on the affected side. Women were more likely to have a favorable outflow of IJV, and there was no significant difference in other characteristics among groups. The interobserver agreements (κ) for TS hypoplasia, IJV stenosis, COVES, ar collaterals, HT, and midline shift were 0.91, 0.90, 0.71, 0.87, 0.92, and 0.83, respect Table 1 presents the clinical and radiological characteristics of all patients at bas Among these patients, the mean age was 68 years, and twenty-seven patients (34.6%) female. Twenty-eight patients (35.9%) had a favorable outflow of IJV on the affected Women were more likely to have a favorable outflow of IJV, and there was no signi difference in other characteristics among groups.

Association between the Outflow of TS and IJV on the Affected Side and Outcomes
There was no significant difference between ipsilateral TS outflow and imaging and clinical outcomes (Table S1). Patients with a poor outflow of IJV on the affected side had a higher incidence of HT (32.1% vs. 52.0%, p = 0.091). After adjusting to the admission NIHSS and arterial collaterals, the poor outflow of IJV on the affected side was an independent predictor of HT (odds ratio [OR], 3.708; p = 0.024). Moreover, patients with a poor outflow of IJV on the affected side had numerical trends of higher sICH rates (3.6% vs. 18.0%, p = 0.140), poor clinical outcomes (51.7% vs. 72.0%, p = 0.182), and in-hospital mortality (0.0% vs. 10.0%, p = 0.154); however, statistical differences were not observed. Tables 2  and 3 present detailed information about these associations.

Association between the Outflow of Bilateral IJVs and Outcomes
As shown in Table S2 and  Table 4). A representative case is shown in Figure 3.     . Three-dimensional reconstructed computed tomography (CT) venography shows that the right transverse sinus is larger than the left (C), and bilateral internal jugular veins are severely narrowed on the axial CT angiography (D,E, black arrows). On the non-contrast CT scan within 24 h after thrombectomy, a parenchymal hematoma, midline shift, and subfalcine hernia are present (F). Sixteen days after thrombectomy (15 days after decompressive craniectomy), there is an apparent cerebral edema (G). The patient's modified Rankin Scale score at discharge is 5.

Association between the Outflow of IJV and Cortical Venous Outflow
Three patients with unclear original images of head CTA were deleted. Patients with poor IJV outflow had a higher incidence of COVES = 0 (IJV on the affected side: 17.9 vs. 53.2%, p = 0.003; bilateral IJVs: 11.1 vs. 21.4 vs. 60.5%, p = 0.001). After adjusting for sex, poor IJV outflow was still an independent risk factor for COVES = 0 (IJV on the affected side: OR, 3.721; p = 0.021; bilateral IJVs: OR, 5.622; p = 0.002) ( Table 5). In this cohort, although the patients with poor cortical venous outflow had a numerical trend of a higher incidence of HT and poor clinical outcomes, there was no observed statistical difference (HT, 53.3 vs. 40%, p = 0.256; mRS score ≥3, 73.3 vs. 60%, p = 0.235).  shows that the right transverse sinus is larger than the left (C), and bilateral internal jugular veins are severely narrowed on the axial CT angiography (D,E, black arrows). On the non-contrast CT scan within 24 h after thrombectomy, a parenchymal hematoma, midline shift, and subfalcine hernia are present (F). Sixteen days after thrombectomy (15 days after decompressive craniectomy), there is an apparent cerebral edema (G). The patient's modified Rankin Scale score at discharge is 5.

Association between the Outflow of IJV and Cortical Venous Outflow
Three patients with unclear original images of head CTA were deleted. Patients with poor IJV outflow had a higher incidence of COVES = 0 (IJV on the affected side: 17.9 vs. 53.2%, p = 0.003; bilateral IJVs: 11.1 vs. 21.4 vs. 60.5%, p = 0.001). After adjusting for sex, poor IJV outflow was still an independent risk factor for COVES = 0 (IJV on the affected side: OR, 3.721; p = 0.021; bilateral IJVs: OR, 5.622; p = 0.002) ( Table 5). In this cohort, although the patients with poor cortical venous outflow had a numerical trend of a higher incidence of HT and poor clinical outcomes, there was no observed statistical difference (HT, 53.3 vs. 40%, p = 0.256; mRS score ≥ 3, 73.3 vs. 60%, p = 0.235).

Discussion
This study found that poor outflow of IJV on the affected side is an independent predictor for HT, and poor outflow of bilateral IJVs is an independent risk factor for poor Brain Sci. 2023, 13, 32 8 of 12 clinical outcomes. Patients with a poor outflow of bilateral IJVs also had the numerical trends of a higher incidence of symptomatic intracranial hemorrhage, midline shift > 10 mm, and in-hospital mortality, but statistical significance was not observed. We also found that poor IJV outflow was independently associated with poor cortical venous outflow, which has proved to be an independent risk factor for poor prognosis after ERT [13][14][15]. These results are independent of the arterial collaterals, indicating that the increased cerebral blood flow that enters the brain tissue from the successfully reopened artery and passes smoothly through the venous end to ensure the balance between arterial and venous systems may be very important for a good prognosis in patients who underwent ERT.
Our study shows that patients with poor IJV outflow have a higher incidence of HT. In patients with a favorable outflow of bilateral IJVs, not only the incidence of HI was lower, but also no one developed PH. These are consistent with the results of the study by Winkelmeier et al. [14] in which they reported that unfavorable cortical venous outflow increased the risk of HT. The pathology of HT is likely multifactorial and thus undefined [31]. Injured cerebral autoregulation due to large artery occlusion would cause more blood than usual to enter the brain after successful recanalization and increased blood-brain barrier permeability [32,33]. On the one hand, poor venous outflow might aggravate the cerebral autoregulation impairment, and on the other hand, it might limit the drainage of increased arterial blood and raise venous pressure, which would all further aggravate blood-brain barrier injury and cause HT [7][8][9]20,34].
Our study's results are not statistically significant despite a numerical trend of the proportion of higher sICH in patients with poor IJV outflow. Hence, this could be attributed to the small number of patients recruited in this study. This is also similar to the results of the study by Winkelmeier et al. [14] in which multivariate analysis of sICH was not performed because of the small number of sICH patients. However, their study found that even non-sICH HT can have a negative effect on long-term prognosis. This is consistent with the results of some other studies that found that the occurrence of HI after ERT was also related to poor clinical outcomes [35][36][37]. These findings suggest that although some previous studies [38] have found that mild reperfusion bleeding indicates successful reperfusion and favorable functional outcomes, the potential effects of mild reperfusion bleeding after ERT on functional outcomes still need to be further studied. Additionally, in clinical practice, mild reperfusion bleeding would also affect clinicians' judgment on the use of antithrombotic drugs.
Our study also shows that patients with a poor outflow of bilateral IJVs had a significantly worse functional prognosis than those with a favorable outflow of bilateral IJVs. This is similar to the results of Jansen et al. [13] and Faizy et al. [15] whom both reported the association between absent opacification of superficial cerebral veins and no benefit from intra-arterial therapy for patients receiving ERT. However, in the studies of stroke patients without ERT, the relationship between TS-IJV and stroke outcomes is contradictory. Yu et al. [19] and Volny et al. [24] showed that dysplasia or occlusion of the ipsilateral TS-IJV was associated with severe cerebral edema. Conversely, Puetz et al. [39] reported that abnormal TS-IJV outflow was not associated with poor functional outcomes. In addition to the differences in the study population, the lack of bilateral IJV analysis may be one of the reasons. When one side of the TS-IJV is narrow, the contralateral side can be partially compensated [40]. Therefore, bilateral IJV can reflect the overall venous outflow more sensitively than unilateral IJV. In our study, both outflows of ipsilateral IJV and bilateral IJVs were associated with HT, but only bilateral IJV outflow was related to functional prognosis.
Another important finding of our study was that poor outflow of IJV is significantly associated with the poor cortical venous outflow. COVES is the main imaging scoring method for evaluating cortical venous outflow. A number of recent large clinical studies using COVES have shown that poor cortical venous outflow was associated with poor baseline arterial collaterals, complications, and poor functional prognosis after ERT [13][14][15]. However, the mechanism of poor cortical venous outflow is not clear. One possible cause is Brain Sci. 2023, 13, 32 9 of 12 thrombosis in arterioles and venules after arterial occlusion because patients who received intravenous thrombolysis before examination have a lower proportion of poor cortical venous outflow [15]. As mentioned above, the vast majority of cortical veins are drained to IJV through the venous sinus. Poor IJV outflow can lead to increased venous pressure downstream of cortical veins, which hinders the clearance of emboli in arterioles and venules [5]. Our results supported the possibility that poor outflow of IJV could be a promising therapeutic target after ERT, as clinical practices have shown that relieving large venous outflow tract obstruction can significantly reduce cerebral venous pressure and intracranial pressure and relieve severe brain edema [20,22,23].
Additionally, there was an interesting difference between puncture onset and poor IJV outflow. However, as we mentioned above, most of the causes of IJV poor outflow are because of the muscles and bones whose anatomical positions appear difficult to change in a short time [9,[19][20][21]. In contrast, the outflow of cortical veins is more likely to change over time. Therefore, a more extensive study with a broader time from onset to CTA is needed to assess whether the outflow profiles of cortical veins and IJV, their effects on prognosis change over time, and the factors that affect the outflow changes.
There are several limitations to our study. First, this was a retrospective single-center study with a relatively small sample size, causing inevitable selection bias and a relatively low lower confidence limit for bilateral IJVs in multivariate analysis. Nonetheless, the strict inclusion and exclusion criteria make the interpretation of the results more targeted. Second, we included five cases of ICA or MCA near occlusion because the hemodynamic changes before and after the lesions detected by ultrasound were almost the same in patients with ICA occlusion and near occlusion [41]. However, if the sample size is large enough, they should be analyzed separately to generate a more targeted interpretation of the results. Third, some patients may have been identified as HT from contrast staining rather than an actual hemorrhage, explaining the higher proportion of patients with HT in this cohort. However, Renu et al. [42] found that both contrast staining and hemorrhage (both blood-brain barrier disruptions) were associated with poor outcomes for stroke patients who received endovascular treatment. In addition, isolated contrast staining was related to delayed HT. Fourth, the clinical outcome was observed over a short period of time. However, given that the neurological function of patients with acute large artery occlusion may rapidly aggravate after ERT, hospitalization is a key period that requires close attention [12]. In the future, prospective studies with larger sample sizes and longer follow-up times are needed to confirm our results.

Conclusions
Patients with acute ICA or MCA stroke who experience successful recanalization following endovascular treatment have a higher risk of poor outcomes if the outflow of IJV is poor, especially on both sides. What's more, a poor outflow of IJV is an independent determinant of poor cortical venous outflow. A larger prospective study with an extended observation period is necessary to confirm these results.

Supplementary Materials:
The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/brainsci13010032/s1, Table S1: Clinical and imaging characteristics at baseline and post-reperfusion of the study cohort classified by the outflow of transverse sinus. Table S2: Clinical and imaging characteristics at baseline and post-reperfusion of the study cohort classified by the outflow of bilateral internal jugular veins.

Informed Consent Statement:
The need for informed consent was waived by the institutional review board in view of the retrospective nature of the study, and all the procedures performed in this study were part of the routine care. Patient information was anonymized, and the paper does not include images that may reveal the identity of patients.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author. The data are not publicly available because it contains information that could identify the patients.

Conflicts of Interest:
The authors declare no conflict of interest.