Absent filling of ipsilateral superficial middle cerebral vein is associated with poor outcome after reperfusion therapy

Abstract

Background and purpose

Our aim was to study the effect of drainage of cortical veins, including the superficial middle cerebral vein (SMCV), vein of Trolard (VOT), and vein of Labbé (VOL) on neurological outcomes after reperfusion therapy.

Methods

Consecutive ischemic stroke patients who underwent pretreatment CT perfusion (CTP) and 24-hour CTP or MR perfusion after intravenous thrombolysis were included. We defined “absent filling of ipsilateral cortical vein” (e.g. SMCV-) as no contrast filling of the vein across the whole venous phase on four-dimensional CT angiography in the ischemic hemisphere.

Results

Of 228 patients, SMCV-, VOT- and VOL- were observed in 50 (21.9%), 27 (11.8%), and 32 (14.0%) patients, respectively. Only SMCV- independently predicted poor outcome (3-month modified Rankin Scale score>2) (OR=2.710, p=0.040). No difference was found in reperfusion rate after treatment between patients with and without SMCV- (p>0.05). In patients achieving major reperfusion (≥80%), there was no difference in 24-hour infarct volume, or rate of poor outcome between patients with and without SMCV- (p>0.05). However, in those without major reperfusion, patients with SMCV- had larger 24-hour infarct volume (p=0.011), higher rate of poor outcome (p=0.012), and death (p=0.032), compared to those with SMCV filling. SMCV- was significantly associated with brain edema at 24 hours (p=0.037) which, in turn, was associated with poor 3-month outcome (p=0.002).

Conclusions

Lack of SMCV filling contributed to poor outcome after thrombolysis, especially when reperfusion was not achieved. The main deleterious effect of poor venous filling appears related to the development of brain edema.

Introduction

Stroke pathophysiology is not only related to responses in neuronal tissue, but also to the vascular neural network, composed of upstream arteries, arterioles, capillaries and downstream venules and veins.¹ The venous compartment is responsible for 70% to 80% of the circulatory volume inside the cranial cavity. In the setting of acute ischemic stroke (AIS), animal studies have shown that microthrombi in venules are present within 30 minutes after acute reduction of cerebral blood flow (CBF).² Moreover, the absence of cerebral venous flow draining the ischemic region was associated with increased severity of hemiparesis and larger infarct volume.³ These findings support a view that the cerebral veins play a vital role in maintenance of CBF and brain function after ischemia. However, most current neuroradiological assessments primarily focus on cerebral arterial circulation/perfusion status, while prognostic information on cerebral venous outflow on AIS is rare.

Recently, the importance of the venous drainage pattern has been described in AIS. The Prognostic Evaluation on Cortical Vein Score Difference in Stroke (PRECISE) score, assessed on single-phase CT angiography (CTA), was shown to predict poor outcome in patients with a proximal arterial occlusion of the anterior circulation.⁴ With time-resolved dynamic CTA, a combined assessment of extent and velocity of cortical venous filling had additional prognostic value over established predictors of outcome.⁵ These studies highlighted that cerebral venous drainage provided additional prognostic information in AIS, but the mechanism of how poor venous outflow relates to worse outcome was not addressed. Furthermore, these prior methods could not objectively reflect the distribution of cortical venous filling, as they focused on the opacification of all vessels presented at venous phase, when cortical veins could be confused with late-filling retrograde-flow arterial collaterals.⁶

Thus, the aim of this study was to investigate the impact of cortical venous filling on neurological outcome during the process of ischemia-reperfusion, and the potential mechanisms behind poor venous and adverse stroke outcome. We hypothesized that lack of venous filling may have an effect on the subsequent development of brain edema, and we were also interested in exploring if quality of venous filling had an effect on subsequent reperfusion.

Subjects and Methods

Ethics statement

Written informed consent was obtained from each patient or an appropriate family member. The local human ethics committee approved the protocol of this study (#2011-018). All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.

Study Subjects

We reviewed our consecutively collected AIS patients who received intravenous thrombolysis (IVT) between June 2011 and November 2015. We then enrolled patients who: (i)received IVT within 6 hours after onset; (ii)underwent computed tomography perfusion (CTP) before IVT, and CTP or magnetic resonance perfusion (MRP) at 24 hours after IVT; (iii)had follow-up modified Rankin Scale (mRS) score at 3 months; (iv)had prestroke mRS ≤2. Intravenous recombinant tissue plasminogen activator (rt-PA) was administered according to the international guidelines.

We retrieved demographic, clinical, laboratory, and radiological data including age, sex; comorbid conditions such as history of hypertension, diabetes mellitus, and atrial fibrillation; time from onset to imaging; National Institutes of Health stroke scale (NIHSS) score; and mRS score after 3 months. Patients were dichotomized into good (mRS≤2) versus poor outcome (mRS>2) at 90 days.

Imaging protocols

All patients underwent baseline CTP, including non-contrast CT (NCCT) and volume perfusion CT (VPCT), and 24 hours CTP or MRP in accordance with our routine stroke imaging protocol.⁷ The effective dose (calculated by multiplying dose-length products with published conversion factors) amounted to 3.68 mSV for VPCT and 2.19 mSV for NCCT acquisition. All images were reconstructed using commercial software (MIStar; Apollo Medical Imaging Technology, Melbourne, Australia). VPCT images were reconstructed to obtain Tmax map and four-dimensional (4D) CTA images, presented in axial, coronal and sagittal planes with 20-mm-thick maximum intensity projection.

Image analysis

The Alberta Stroke Program Early CT Score (ASPECTS) was assessed by a neuroradiologist (X.D.) to detect early ischemic changes on pretreatment NCCT.⁸ A threshold of Tmax >6 seconds was used for volumetric measurement of pretreatment and 24-hours hypoperfusion areas.⁹ Pretreatment relative cerebral blood flow (rCBF) < 30% was used for calculating ischemic core volume,¹⁰ and 24-hours DWI or NCCT for final infarct volume.¹¹ Hemorrhagic transformation (HT) was classified as hemorrhagic infarction (HI) and parenchymal hemorrhage (PH), according to the ECASS definition. Symptomatic intracranial hemorrhage (sICH) was defined as any intracranial hemorrhage associated with an increase of ≥4 points on NIHSS, or leading to death.¹²

Definition of absent filling of ipsilateral cortical veins

Arterial input function (AIF) and venous output function (VOF) were automatically selected by the software MIStar from middle cerebral artery/ anterior cerebral artery and superior sagittal sinus of non-ischemic hemisphere, respectively. According to the VOF curve, the venous peak phase was identified and selected to reconstruct the single-phase three dimensional CT venography (3D CTV) by the software NeuroDSA (Siemens, Germany).

Based on this 3D CTV (Supplemental video I, please see http://stroke.ahajournals.org), three veins including the superficial middle cerebral vein (SMCV), vein of Trolard (VOT), and vein of Labbé (VOL), in each hemisphere were separately assessed. The principles for identifying these three cortical veins including 1) SMCV, VOT and VOL are the largest cortical veins; 2) As SMCV, VOT and VOL join the sphenoparietal sinus, superior sagittal sinus (SSS) and transverse sinus, respectively, these three cortical veins on sagittal view are visualized as claws stretching out from the left, top and right side of brain surface. When the three veins meet, they form a “Y” structure (see figure 1A); 3) Due to the difficult differentiation of VOT from other ascending anastomosis, we set three steps to better identify the presence of VOT if it was not obvious: ➀find the corresponding vein within the ipsilateral hemisphere with reference to the contralateral VOT; ➁find the vein which has similar luminal diameter to SMCV or VOL¹³; ➂check the level of post central vein on the SSS where the dominant VOT is presented in most cases¹⁴.

Figure 1.

Identification of cortical veins. SMCV, superficial middle cerebral vein; VOT, vein of Trolard; VOL, vein of Labbé. A: According to locations of the 3 cortical veins (“Y” structure) shown on the venous peak-phase 3D CTV, the appearance of contrast flow in the targeted cortical vein was defined as the presence of the targeted cortical vein (marked as SMCV+/VOT+/VOL+). B: Visual assessment for cortical veins, eg. ipsilateral superficial middle cerebral vein (SMCV) on 4D CTA. The presence (red arrow) and the absence (red broken circle) of cortical veins were displayed. Based on venous output function (VOF) curve, the contrast in the SMCV of non-ischemic hemisphere appeared in the early venous phase, enhanced at the maximum of the peak venous phase, and disappeared at the late venous phase (yellow arrow). In comparison, no contrast in the ischemic hemispheric SMCV was shown in any of these three time points. C: Example of the presence of SMCV, VOT and VOL in axial, coronal, and sagittal planes of both hemispheres across the whole venous phase (SMCV+/VOT+/VOL+). D: Example of absent filling of SMCV, VOT and VOL in the ischemic hemisphere across the whole venous phase (SMCV-/VOT-/VOL-), in axial, coronal, and sagittal planes.

Therefore, the presence of the targeted cortical vein (marked as SMCV+/VOT+/VOL+) was firstly confirmed on 3D CTV, which was defined as the appearance of contrast flow in the targeted cortical vein. We then reassessed the cortical veins on 4D CTA reconstructed from CTP, if there was absent or obscure contrast filling in the targeted cortical vein. As Figure 1 shows, on 4D CTA, the presence of contrast filling of the targeted cortical vein at any time point of venous phase were still defined as SMCV+/VOT+/VOL+, while the absence of ipsilateral cortical veins (marked as SMCV-/VOT-/VOL-) was defined as no contrast filling of the targeted cortical vein across the whole venous phase in the ischemic hemisphere. The absence of the targeted cortical vein in non-stroke patients and the comparison between venous anatomy in stroke and non-stroke patients are described in the online-only Data Supplement (Supplemental study I, please see http://stroke.ahajournals.org).

The two raters (S.Z. and Y.L.) who jointly evaluated the images of veins were blinded to the patients’ other imaging and clinical data. A single trained observer (S.Z.) measured the veins of all patients twice, at an interval of 3 months apart. Another observer (Y.L.) independently made the same evaluation.

During the tracking process for each vein on 4D CTA, the software allowed raters to simultaneously identify if hypoperfusion (Tmax >6 seconds) was distributed within the drainage area of the targeted vein (Figure 2), based on previous literature.¹³ Accordingly, patients were dichotomized into 2 groups: hypoperfusion within or outside the drainage territories of the targeted vein. Patients with hypoperfusion area within the drainage territory of the targeted vein were classified as the matched group, while the others with hypoperfusion area outside the drainage territory of the targeted vein as the unmatched group.

Figure 2.

Matching hypoperfusion area on Tmax map with the drainage territory of the selected cortical vein on 4D CTA. A: The representative drainage territories of superficial middle cerebral vein (SMCV, green), vein of Labbé (VOL, red), and superior sagittal sinus (blue) which receives the drainage of vein of Trolard (VOT) and was then used for matching with VOT, due to the location variation of VOT. B, C and D show the ipsilateral hypoperfusion (colored voxels) on Tmax map located within the drainage territories of SMCV (B), VOT (C) and VOL (D), respectively. The suspected location of the ipsilateral targeted cortical vein (yellow box) can be simultaneously viewed on Tmax map.

Reperfusion and brain edema

Reperfusion rate (RR) = (baseline hypoperfusion volume - 24h hypoperfusion volume) /baseline hypoperfusion volume. Based on RR, we defined 2 patient groups: major reperfusion (≥80%) and no major reperfusion (<80%).¹⁵ In the major reperfusion group, we defined ratio of penumbra tissue salvage as: (baseline hypoperfusion volume - final infarct volume)/(baseline hypoperfusion volume - baseline ischemic core volume).¹⁶ In the no major reperfusion group, penumbra tissue loss ratio was defined as: (final infarct volume - baseline ischemic core volume)/(baseline hypoperfusion volume - baseline ischemic core volume).¹⁷

Brain edema was assessed by a stroke neurologist (Y.L.) and a neuroradiologist (XF.D) independently by grading hemispheric swelling on a 7-point scale at baseline NCCT and 24 hours NCCT or DWI.^{18, 19} Brain edema expansion was defined as an increase in grade from baseline to 24 hours after IVT.

Statistical analysis

Metric and normally distributed variables were reported as mean ± standard deviation; non-normally distributed variables as median (25th-75th percentile). Categorical variables were presented as frequency (percentage). Kappa statistics were used to test inter- and intra-rater reliability for detecting the presence of each cortical vein and the degree of baseline and 24-hours brain edema. Comparison between groups were assessed with student t test for parametric data, Mann-Whitney U test for nonparametric data, and Pearson Chi-Square test for categorical data. Spearman correlation coefficient was used to analyze the associations among radiological and clinical variables. Independent factors for the absent filling of each cortical vein, poor outcome and reperfusion were evaluated using binary logistic regression analysis, respectively. A p value of < 0.05 was considered to be statistically significant. Statistical analyses were conducted using SPSS, Version 19.0 (IBM, Armonk, New York).

Results

Overall Characteristics

There were 247 patients who met the inclusion criteria, with 228 patients included in the final analysis after 4 patients with incomplete imaging data and 15 patients with inadequate quality of post-processed images for assessment of venous drainage were excluded. The median age was 69 years (IQR 59-78 years), with 85 (37.3%) being women. The median baseline NIHSS was 10 (IQR 5-15), and median onset to needle time (ONT) was 198 min (IQR 133-270 min). 23 (10.1%) patients received mechanical thrombectomy. Poor outcome occurred in 107 (46.9%) patients, 21 (9.2%) patients died, 52 (22.8%) patients had HT, and 11 (4.8%) had sICH.

Excellent inter- and intra-observer reliability was seen in distinguishing the presence of SMCV- (κ=0.856 and 0.973), VOT- (κ=0.795 and 0.903), and VOL- (κ=0.727 and 0.935). The occurrence of SMCV-, VOT- and VOL- were found in 50 (21.9%), 27 (11.8%), and 32 (14.0%) patients in ischemic hemisphere, respectively, while they were found in 9 (3.9%), 3 (1.3%) and 6 (2.6%) patients in the non-ischemic hemisphere, respectively.

The relationship between venous filling and neurological outcome

In the unmatched group of SMCV, no significant difference of rate of poor outcome was observed between ipsilateral SMCV+ and SMCV- (Supplemental table I, please see http://stroke.ahajournals.org). As Table 1 shows, in the matched group of SMCV, the rate of poor outcome was higher in patients with ipsilateral SMCV- than those with SMCV+ (72.1% vs 46.6%, OR=2.710, 95%CI=1.049-7.005, p=0.040). Neither the presence of ipsilateral VOT- (76.0% vs 50.0%, OR=1.699, 95%CI=0.455-6.348, p=0.431) nor the presence of ipsilateral VOL- (66.7% vs 58.3%, OR=0.501, 95%CI =0.116-2.163, p=0.354) was independently associated with poor outcome, even when hypoperfusion was within the drainage territory of respective vein.

Table 1.

Binary logistic regression analysis for poor outcome

Parameters	OR	95%CI	p value
Ipsilateral SMCV-	2.710	1.049-7.005	0.040
Baseline NIHSS	1.190	1.091-1.298	<0.001
Baseline CT-ASPECTS	0.785	0.621-0.994	0.044
Baseline hypoperfusion volume, mL	1.006	0.999-1.013	0.078
Onset to needle time, min	1.002	1.089-1.296	0.324
Large artery occlusion	0.987	0.386-2.524	0.978

SMCV-: absence of ipsilateral superficial middle cerebral vein; CT-ASPECTS: The Alberta Stroke Program Early CT Score on non-contrast CT; NIHSS: National Institutes of Health Stroke Scale.

Of interest, the rate of poor outcome was elevated with increasing number of venous drainage areas affected by hypoperfusion (ρ=0.279, p<0.001). Patients with hypoperfusion in ≥1 venous drainage areas had higher rate of poor outcome than those with none or only one venous drainage area involved (59.8% vs 29.2%, χ²=21.007, p<0.001).

The relationship between perfusion, venous drainage and reperfusion

Baseline hypoperfusion volume (OR=1.014, 95%CI=1.008-1.020, p<0.001) and serum glucose (OR=1.192, 95%CI=1.009-1.409, p=0.039) were independently associated with the presence of ipsilateral SMCV-.

Among patients with hypoperfusion located within the drainage territory of SMCV, reperfusion could be evaluated in 122 patients. Major reperfusion was found in 55 (45.1%) patients at 24 hours. No difference was found in either reperfusion rate (0.49±0.83 vs 0.52±0.44, t=-0.143, p=0.886) or occurrence of major reperfusion (42.9% vs 46.0%, χ²=0.098, p=0.754) between patients with SMCV- and SMCV+.

Change in venous filling after treatment could be evaluated in 55 patients with 24-hour CTP. We found that baseline ipsilateral SMCV- was more likely to be reversed to SMCV+ at 24 hours in patients with reperfusion, compared with those without reperfusion (87.5% vs 33.3%, χ²=4.381, p=0.036). In contrast, no patient with baseline SMCV+ deteriorated to SMCV- at 24 hours, even in the absence of major reperfusion. However, SMCV- patients that reversed to SMCV+ at 24 hours showed no lower rate of poor outcome in comparison of those with persistent SMCV- at 24 hours (60.0% vs 66.7%, χ²=0.062, p=0.622).

The different impact of venous filling on outcome based on reperfusion status

We did subgroup analysis based on reperfusion status. In patients with no reperfusion, ipsilateral SMCV- patients had higher rates of poor outcome (OR=11.302, 95%CI=1.153-110.819, p=0.037), and larger 24-hour infarct volume (p=0.011) and death (p=0.032), compared to SMCV+ patients (Table 2). However, in patients with reperfusion, no significant difference was found in outcome between ipsilateral SMCV+ and SMCV- patients (p=0.247).

Table 2.

Univariate analysis according to reperfusion and SMCV status

	No reperfusion (n=67)				Reperfusion (n=55)
Parameters	SMCV+(n=47)	SMCV(n=20)	test value	p value	SMCV+(n=40)	SMCV-(n=15)	test value	p value
Age, y	69.8±11.6	71.9±12.1	t=-0.654	0.515	69.7±12.6	68.8±14.4	t=0.227	0.821
Baseline NIHSS, (IQR)	13 (8-16)	13.5 (10.3-17)	t=-1.081	0.284	10(6-16)	11 (7-15)	t=0.620	0.538
24-hours CT scan, n(%)	24 (51.1)	9 (45.0)	χ2=0.206	0.650	19 (47.5)	9 (60.0)	χ2=0.682	0.409
Baseline CT-ASPECTS, (IQR)	8 (7-9)	7(6-9)	t=1.206	0.232	9(8-10)	9(8-10)	t=0.190	0.850
24hour infarct volume, mL,	49.0±58.6	118.0±112.7	Z=-2.558	0.011	18.3±33.3	11.4±12.6	t=0.703	0.485
Penumbral loss ratio, %	0.2 ± 1.3	0.5 ± 1.4	t=-1.252	0.215	-	-	-	-
Penumbral salvage ratio, %	-	-	-	-	1.4±1.1	1.5±0.5	t=-0.109	0.913
Baseline brain edema, (IQR)	0 (0-0)	0 (0-1)	Z=-0.266	0.790	0 (0-0)	0 (0-1)	Z=-0.990	0.322
24hour brain edema, (IQR)	1 (1-2)	2 (1-4.3)	Z=1.772	0.076	1 (0-2)	1 (0-2)	Z=-0.060	0.953
Brain edema expansion within 24hour, (IQR)	1 (1-2)	2 (1-3.3)	Z=-2.076	0.038	1 (0-2)	1 (0-1)	Z=-0.383	0.702
Poor outcome, n(%)	31 (66.0)	19 (95.0)	χ2=6.250	0.012	12(30.0)	7 (46.7)	χ2=1.340	0.247
Death, n(%)	3 (6.4)	5 (25.0)	χ2=4.625	0.032	0 (0)	2 (13.3)	χ2=5.535	0.071
Hemorrhagic infarction, n(%)	7 (14.9)	4 (20.0)	χ2=0.267	0.606	7 (17.5)	2 (13.3)	χ2=0.138	0.710
Parenchymal hematoma, n(%)	5 (10.6)	1 (5.0)	χ2=0.547	0.460	4 (10.0)	3 (20.0)	χ2=0.982	0.322
Symptomatic intracerebral hemorrhage, n(%)	3 (6.4)	0 (0)	χ2=1.336	0.549	1 (2.5)	1(6.7)	χ2=0.540	0.475

SMCV-: absence of ipsilateral superficial middle cerebral vein; SMCV+: presence of ipsilateral superficial middle cerebral vein; NIHSS: National Institutes of Health Stroke Scale; IQR: interquartile range; CT-ASPECTS: The Alberta Stroke Program Early CT Score on non-contrast CT.

The impact of venous filling on penumbral evolution

We found similar penumbral salvage ratio (p=0.913) in the reperfusion group and penumbral loss ratio (p=0.215) in the no reperfusion group between patients with ipsilateral SMCV+ and SMCV- (Table 2). Venous filling did not seem to have an influence on penumbral evolution.

The impact of venous filling on brain edema

Excellent inter- and intra-observer reliability was seen in assessing the degree of baseline (κ=0.868, κ=0.827) and 24-hour brain edema (κ=0.859, κ=0.846).

As Figure 3 shows, in patients without major reperfusion, brain edema expansion within 24 hours was significantly higher in ipsilateral SMCV- patients (median (IQR): 1 (0-2) vs 2 (1-2.8), Z=-2.076, p=0.038). SMCV- was significantly associated with brain edema expansion at 24 hours (ρ=0.256, p=0.037) which in turn was associated with poor outcome (ρ=0.379, p=0.002).

Figure 3.

The difference in brain edema expansion within 24 hours between patients with SMCV- and SMCV+ among those without major reperfusion. A: Brain edema expansion was significantly higher in SMCV-, in comparison of SMCV+. B: A 48-year-old female with baseline CT-ASPECT of 7 (NIHSS:7) and acute left proximal middle cerebral artery occlusion (MCAO), presented with SMCV+. Even without recanalization after IVT, brain edema was mildly enlarged (score from 1 to 2). She achieved good outcome (3-month mRS:1). C: A 49-year-old male with baseline CT-ASPECT of 6 (NIHSS:9) and acute right MCAO, presented with ipsilateral SMCV-. Without recanalization, he had enlargement of brain edema (score from 1 to 5). He died within one week after stroke onset.

Discussion

The primary finding of this study is that the absent filling of the SMCV in the ischemic hemisphere independently predicted poor outcome after reperfusion therapy `in AIS patients, and, its mechanism appeared due to the development of brain edema at 24 hours, particularly in the absence of major reperfusion.

Our result supports the independent impact of SMCV drainage pattern on outcome, which is consistent with a previous finding that the occlusion of SMCV was the most important factor contributing to morbidity in patients undergoing pterional approach for aneurysm surgery.²⁰ However, it differs from previous finding which demonstrated that lack of all three SMCV, VOT and VOL filling was related to poor outcome.⁴ This variance may be attributed to the assessment of dynamic CTA in the current study, which clearly improves the sensitivity for delayed contrast arrival in vessels, compared with conventional single-phase CTA.²¹ Thus, late-filling cortical veins overlooked by conventional CTA could be detected by dynamic CTA. This is supported by the finding that rates of absent filling of cortical veins (SMCV, 22.4%; VOT, 11.8% and VOL, 14.0%) were much lower than those detected by conventional CTA (SMCV, 59%; VOT, 38.5% and VOL, 46.2%). Moreover, the anatomic features of veins may further explain the impact variance of three cortical veins on functional outcome. Compared with SMCV, less motor functional regions are involved in the drainage area of VOL. Moreover, previous studies also proved that the resection or thrombosis of VOL in epilepsy surgery might not be related to subsequent infarction or poor outcome.^{22, 23} Meanwhile, the drainage of VOT can be compensated by abundant superior anastomotic veins, which initiate the recruitment of venous collateral pathways.

Brain edema expansion was the key mechanism that linked SMCV- with poor outcome. The underlying pathophysiologic mechanism of the development of brain edema is probably due to elevated venous pressure (Figure 4). Due to micro-thrombotic occlusion in venules, the subsequent resistance to cerebrospinal fluid absorption will result in the elevation of venous pressure, which may increase fluid leakage into the perivascular space, resulting in brain edema.²⁴ Furthermore, the exacerbation of cytotoxic edema that occurs early after acute cerebral venous thrombosis may also be a factor in our study, and could potentially explain the large 24-hour edema volume in patients with SMCV-.²⁵ Additionally, injury of the insula, which is drained by SMCV, may also contribute to the expansion of brain edema in patients with SMCV-, as the insula plays a crucial role in the regulation of autonomic function.²⁶ Previous studies have shown that insular ischemia was associated with impaired baroreflex sensitivity and was found to be involved in the formation of fatal brain edema.²⁷ This anatomic feature of SMCV may also partially explain the impact variance between SMCV and the other two cortical veins on functional outcome.

Figure 4.

The hypothesized pathogenesis of venous outflow dysfunction. Due to large arterial occlusion seen on 4D CTA (a) and hypoperfusion seen on Tmax map (b), venous flow is subsequently reduced, leading to microthrombi formation and occlusion in venules, which is visualized as the absent filling of draining cortical vein (c). Due to occlusion in venules, the subsequent resist of cerebrospinal fluid absorption will result in the elevation of venous pressure, which might increase fluid leakage from the disrupted tight junctions of endothelial cells (EC) into the perivascular space, leading to the development of brain edema, as shown on non-contrast CT (d).

Interestingly, our finding relating brain edema due to the absent filling of ipsilateral SMCV is different from previous studies where cortical venous injury generally resulted in hemorrhage.¹³ This discrepancy may reflect that the vein-mediated pathophysiology in AIS is likely to be caused by an imbalance between arterial inflow and venous outflow. Constant arterial inflow with damaged venous outflow may lead to neurovasular injury with subsequent hemorrhage, while reduced arterial inflow with venous outflow dysfunction would tend to develop brain edema.

In the current study, absent filling of ipsilateral SMCV was associated with the volume of baseline hypoperfusion. We further found that timely reperfusion lowered the rate of poor outcome (and of brain edema) and was able to restore venous filling. These findings strongly suggest that venous outflow is influenced by the severity of reduction in arterial flow, and refutes the view that lack of venous filling purely relates to the compression of venules by brain edema after cerebral ischemia.²⁸ Experimental studies in vein occlusion models demonstrated that the growth of the venous thrombi coincided with decrease in regional CBF.²⁹ After arterial reperfusion, the obstructed lumina of venules might re-open, with venous microemboli being cleared from the microcirculation within 2 hours after reperfusion.³⁰ It is thus reasonable to infer that the change of venous flow represents a combined dynamic result of the extent of both initial ischemia and arterial reperfusion.

Conversely, absent filling of SMCV did not affect the rate of reperfusion or the effect of successful reperfusion on penumbra salvage. This is consistent with the concept that the venule is a crucial contributor to cerebrovascular resistance, but its role in regulation of flow is minimal under physiologic conditions.³¹ Improvement in antegrade CBF and/or arterial collateral flow appear to be the main mechanisms leading to early reperfusion.

In this study, we did not validate the absent filling of cortical veins on CTP by DSA for patients who received endovascular therapy as a superselective catheterization of the target occluded artery was used during surgery for saving the onset-reperfusion time. However, we found that the inter-rater agreement for the identification of the absent filling of three cortical veins were excellent, indicating that it was feasible to assess cortical veins on CTP in acute ischemic stroke patients. A recent study also published that the inter-rater agreement was high in assessing the velocity and extent of cortical venous filling using CTP-derived 4D CTA⁵, supporting that CTP is reliable to depict venous outflow and may be a better way to assess the drainage status of cortical veins.

Other limitations in this study include a retrospective design and a potential risk of selection bias. However, the use of consecutive AIS patients in our prospective registry with highly homogenous and standardized treatment regimen might have minimized this problem. Secondly, the use of both CT and MRI as follow-up imaging might result in heterogeneity of volume measurement, but it may not affect our results since the distribution of follow-up CT or MRI were almost identical between SMCV- and SMCV+ patients. Thirdly, there is a certain proportion of congenital absence of cortical veins in healthy population, our study did not evaluate whether this has any impact on neurological outcome. We specifically focused on hypoperfusion within the drainage territories of the targeted veins and its relationship with absent venous filling. Finally, the sample size was modest and was performed retrospectively. The benefit for SMCV- patients that reversed to SMCV+ at 24 hours from aggressive reperfusion therapy should be confirmed and extended in larger sample-size, randomized prospective clinical trials in future.

In conclusion, this is the first study to systematically examine the relationship between venous filling of major cortical veins and arterial perfusion after AIS. The absent filling of ipsilateral SMCV was strongly related to severe hypoperfusion, and reperfusion was able to refill the absent SMCV, while the status of venous filling itself had no influence on the occurrence of reperfusion. Through expansion of brain edema, the absent filling of ipsilateral SMCV was associated with poor outcome after IVT, especially when reperfusion was not achieved. Therefore, successful revascularization still should be the primary goal for AIS, and patients with absent filling of ipsilateral SMCV would appear to benefit most from reperfusion therapy. The clinical implications of these results are that SMCV- patients should undergo more aggressive reperfusion strategies (e.g. thrombectomy) as their outcomes in the absence of reperfusion are poor.