Journal List > J Stroke > v.26(3) > 1516088611

Zangana, Valls, Munuera, Werner, Remollo, Dorado, Serena, Puig, Ossa, Gomis, Bustamante, Pina, Martinez, Castaño, Muñoz, Massuet, Coutinho, Millán, and Hernández-Pérez: Role of Venous Delay on Stroke Outcome: Prospective Evaluation Before and After Mechanical Thrombectomy
Dear Sir:
Endovascular treatment (EVT) has become a routine therapeutic approach for acute ischemic stroke (AIS) patients with large vessel occlusion, emphasizing the importance of successful arterial reperfusion as a predictor of positive clinical outcomes. However, a significant subset of patients experiences poor functional outcomes despite achieving complete angiographic reperfusion. Factors contributing to this disparity include age, brain atrophy, pre-EVT National Institutes of Health Stroke Scale (NIHSS), large infarct core at admission, poor arterial collaterals, and the number of passes during the EVT procedure [1].
While the majority of AIS studies focus on the arterial system, some recent studies have shown an association between cortical venous drainage and clinical outcomes in AIS patients [2-4]. These studies included patients who underwent different treatments and used diverse methodologies. However, it is still unclear the impact of venous drainage delay in patients who undergo EVT and whether this delay persists after the procedure. We aimed to evaluate the predictive value of cortical venous delay, measured through dynamic magnetic resonance angiography (dMRA)—a time-resolved sequence capturing arterial filling and venous emptying—before and after EVT, on infarct volume and functional outcomes in patients with large anterior artery occlusion undergoing EVT.
This project is a preplanned substudy of the FUtile Recanalization in Ischemic Acute Stroke (FURIAS) study. The study design and methodology have been published [5]. The magnetic resonance imaging (MRI) protocol has been described in Supplementary Table 1. Briefly, we prospectively enrolled patients with acute intracranial carotid artery or middle cerebral artery M1 or proximal M2 occlusion undergoing EVT that received serial brain MRI. The Research Ethics Committee of the Germans Trias Hospital approved this study (approval number PI-15-071). Written informed consent was obtained from all patients. The brain MRI scans were systematically analyzed at three distinct time points: at hospital admission (pre-EVT), within 2 hours after EVT (postEVT), and 5 days after EVT by a trained investigator. A previous paper showed that the delay in cortical veins seems to be a stronger predictor of outcome than the delay in the deep veins [3]. Therefore, we decided to restrict our study to the cortical veins. Cortical venous delay was quantified by identifying the time point in which venous filling was maximal in the main cortical veins for both hemispheres and calculating the percentage of delay for each vein for both pre-EVT and post-EVT MRIs (Supplementary Figure 1). We considered successful reperfusion as a final modified Thrombolysis in Cerebral Infarction (mTICI) grade ≥2B. Associations between venous delay and infarct volumes post-EVT and on day 5 were studied using multivariable linear regression. An ordinal logistic regression was performed to study the influence of venous delay on the modified Rankin Scale (mRS) at 3 months. We did these analyses for the whole cohort and for the group of patients that achieved successful reperfusion. The analyses were adjusted by relevant variables according to previous literature (Supplementary Table 2).
We enrolled 94 stroke patients (mean age: 69.9; median NIHSS: 17; final mTICI ≥2b: 86.2%) undergoing EVT (the selection flowchart and further comparison are published elsewhere). From those, we could evaluate 89 pre-EVT dMRAs and 88 post-EVT dMRAs (Supplementary Figure 2). Eighty-two of them had evaluable pre-EVT and post-EVT dMRA. An overview of the patient sample characteristics is shown in Table 1 and Supplementary Table 3. Pre-EVT and post-EVT mean venous delays were 31.9% and 13.5%, respectively. Successful reperfusion resulted in a 15.5% reduction in post-EVT venous delay with no significant change for non-reperfused patients (Supplementary Figure 3). Pre-EVT venous delay showed no significant correlation with infarct volume or clinical outcome, adjusting for reperfusion success (Table 2). However, for each 10% increment in post-EVT venous delay, there was an adjusted 0.12 mL increase (95% confidence interval [CI], 0.05–0.19) in infarct volume at 5 days and higher odds of an elevated mRS score at 3 months (adjusted crude odds ratio 1.14; 95% CI, 1.01–1.29) (Table 2).
Our key finding was that post-EVT cortical venous delay was linked to larger infarct volume at 5 days and worse functional outcomes at 3 months. However, the association between preEVT venous delay and clinical and radiological outcomes was not significant after adjustments by collateral grade and reperfusion status. Previous studies have yielded mixed results in this respect [2-4,6-8]. Of note, venous delay in AIS can be explained by arterial occlusion, poor collateral flow, breakdown of the blood-brain barrier causing edema and venous compression, and microthrombi formation [9].
It is unclear whether our lack of significance is due to our small sample size or if reperfusion status and collateral grade might act as confounding variables, influencing radiological and clinical outcomes more than pre-EVT venous delay itself.
Notably, the study identified a trend for improved venous outflow post-EVT in successfully reperfused patients. Nevertheless, this group of patients still had some grade of venous delay, possibly due to tissue edema or microthrombi. While venous delay post-EVT was linked to larger infarct volumes, the association with clinical outcomes in the reperfused group was not significant, potentially due to limited statistical power.
Strengths of the study included systematic evaluation of veins using consistent radiological methods, quantitative assessment of venous delay, and dMRA allowing precise identification of maximal contrast enhancement. However, limitations included a small sample size, incomplete brain coverage in the imaging protocol, and the simplification of venous delay measures.
This study emphasized the need for further research on venous patterns in AIS, advocating for larger patient populations and using dynamic imaging techniques to better understand cerebrovascular circulation complexity. Our findings suggest that venous circulation plays a role in post-stroke recovery, highlighting the importance of comprehending venous function in ischemic stroke for identifying potential neuroprotective targets and improving outcomes.

Supplementary materials

Supplementary materials related to this article can be found online at https://doi.org/10.5853/jos.2024.00150.
Supplementary Table 1.
The MRI protocol used in the study
jos-2024-00150-Supplementary-Table-1.pdf
Supplementary Table 2.
Statistical analyses
jos-2024-00150-Supplementary-Table-2.pdf
Supplementary Table 3.
Characteristics of the stroke patients undergoing EVT
jos-2024-00150-Supplementary-Table-3.pdf
Supplementary Figure 1.
Cortical veins on maximum intensity projection in the three planes of space. SMCV, superficial middle cerebral vein; VOT, vein of Trolard; VOL, vein of Labbé.
jos-2024-00150-Supplementary-Fig-1.pdf
Supplementary Figure 2.
Flowchart of the dMRA selection. dMRA, dynamic magnetic resonance angiography; EVT, endovascular treatment.
jos-2024-00150-Supplementary-Fig-2.pdf
Supplementary Figure 3.
Box plot representing the change in maximum delay pre- and post-EVT in reperfused and non-reperfused patients. EVT, endovascular treatement.
jos-2024-00150-Supplementary-Fig-3.pdf

Notes

Funding statement

The project was supported by a grant from the Spanish Ministry of Health co-financed by Carlos III Health Institute, FIS PI 14/01955 and RICORS RD21/0006/0024. Lara Zangana was funded by the Erasmus+ program.

Conflicts of interest

The authors have no financial conflicts of interest.

Author contribution

Conceptualization: LZ, JM, MHP. Study design: JM, MHP. Methodology: AV, JM, MHP. Data collection: MW, SR, LD, JS, JP, NPO, MG, AB, BFP, MM (Marina Martinez), CC, LM, AM, MM (Monica Millan), LZ, JM, MHP. Statistical analysis: AV. Writing—original draft: LZ, MHP. Writing—reveiw & editing: all authors. Funding acquisition: NPO, MM (Monica Millan), MHP. Approval of final manuscript: all authors.

References

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3. Parthasarathy R, Kate M, Rempel JL, Liebeskind DS, Jeerakathil T, Butcher KS, et al. Prognostic evaluation based on cortical vein score difference in stroke. Stroke. 2013; 44:2748–2754.
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4. Singh N, Bala F, Kim BJ, Najm M, Ahn SH, Fainardi E, et al. Time-resolved assessment of cortical venous drainage on multiphase CT angiography in patients with acute ischemic stroke. Neuroradiology. 2022; 64:897–903.
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5. Hernández-Pérez M, Werner M, Remollo S, Martín C, Cortés J, Valls A, et al. Early and delayed infarct growth in patients undergoing mechanical thrombectomy: a prospective, serial MRI study. Stroke. 2023; 54:217–225.
6. van den Wijngaard IR, Wermer MJ, Boiten J, Algra A, Holswilder G, Meijer FJ, et al. Cortical venous filling on dynamic computed tomographic angiography: a novel predictor of clinical outcome in patients with acute middle cerebral artery stroke. Stroke. 2016; 47:762–767.
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7. Bala F, Singh N, Menon BK, Demchuk AM, Poppe AY, McTaggart RA, et al. Poor cortical venous opacification on baseline computed tomography angiography predicts parenchymal hemorrhage after thrombectomy. Stroke Vasc Interv Neurol. 2022; 2:e000299.
8. Bhaskar S, Bivard A, Stanwell P, Attia JR, Parsons M, Nilsson M, et al. Association of cortical vein filling with clot location and clinical outcomes in acute ischaemic stroke patients. Sci Rep. 2016; 6:38525.
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9. Munuera J, Blasco G, Hernández-Pérez M, Daunis-I-Estadella P, Dávalos A, Liebeskind DS, et al. Venous imaging-based biomarkers in acute ischaemic stroke. J Neurol Neurosurg Psychiatry. 2017; 88:62–69.
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Table 1.
Comparison between patients with assessable dMRA pre-EVT and patients with assessable dMRA post-EVT
Characteristic Assessable dMRA pre-EVT (n=89) Assessable dMRA post-EVT (n=88) P (overall)
Age (yr) 69.9±13.5 70.0±13.2 0.964
Sex 0.761
 Male 51 (57.3) 48 (54.5)
 Female 38 (42.7) 40 (45.5)
Hypertension 62 (69.6) 61 (69.3) >0.999
Diabetes 14 (15.7) 15 (17.0) >0.999
Dislipidemia 38 (42.6) 37 (42.0) >0.999
Atrium fibrillation 27 (30.7) 30 (34.1) 0.747
Clinical category 0.814
 Cardioembolism 32 (35.9) 36 (40.9)
 Large-artery atherosclerosis 30 (33.7) 27 (30.7)
 Stroke of undetermined etiology 27 (30.3) 25 (28.4)
NIHSS baseline 17.0 [12.0–20.0] 17.5 [12.0–21.0] 0.598
Occluded artery 0.996
 M1 MCA 46 (51.6) 46 (52.3)
 M2 MCA 10 (11.2) 12 (13.6)
 Tandem (ICA+MCA) 22 (24.7) 21 (23.9)
 TICA (ICA terminal) 11 (12.4) 9 (10.2)
Glycemia (mg/dL) 116 [101–140] 121 [101–144] 0.661
Wake up 21 (23.5) 22 (25.0) >0.999
rTPA 38 (42.7) 36 (40.9) 0.878
Onset-puncture (min) 314 [236–528] 322 [238–546] 0.758
Sedoanalgesia 84 (95.5) 84 (95.5) >0.999
Final mTICI 0.999
 mTICI 0 5 (5.61) 6 (6.82)
 mTICI 2a 7 (7.86) 7 (7.95)
 mTICI 2b 19 (21.3) 19 (21.6)
 mTICI 2c 24 (26.9) 24 (27.3)
 mTICI 3 34 (38.2) 32 (36.4)
Ischemia duration (min) 366 [266–598] 376 [269–608] 0.771
First MRI to recanalization (min) 103 [77–142] 102 [78–144] 0.930
DWI volume pre-EVT (mL) 12.0 [5.5–20.0] 12.0 [6.0–21.8] 0.752
DWI volume post-EVT (mL) 17.7 [7.2–38.4] 21.3 [7.5–40.4] 0.707

Values are presented as mean±standard deviation, n (%), or median [interquartile range].

dMRA, dynamic magnetic resonance angiography; EVT, endovascular treatment (pre-EVT, at hospital admission; post-EVT, <2 hours after EVT); NIHSS, National Institutes of Health Stroke Scale; MCA, middle cerebral artery; M1, M1 segment of the MCA; M2, M2 segment of the MCA; ICA, internal cerebral artery; TICA, terminal internal cerebral artery; rtPA, recombinant tissue plasminogen activators; mTICI, modified Thrombolysis in Cerebral Infarction; MRI, magnetic resonance imaging; DWI, diffusion-weighted imaging.

Table 2.
Associations of venous delay pre-EVT and venous delay post-EVT with outcomes on multivariable analysis
Outcome Multivariable model Adjustment covariates Venous time point evaluation Cohort Effect size§ [95% confidence interval] P
Infarct volume post-EVT (mL) Linear regression Number of passes, site of occlusion, time from onset to MRI, successful reperfusion, volume of infarct pre-EVT Venous delay pre-EVT* Complete cohort 0.01 [-0.04–0.05] 0.672
Reperfused patients 0.00 [-0.05–0.05] 0.991
Infarct volume at 5 days (mL) Linear regression Number of passes, site of occlusion, time from onset to MRI, successful reperfusion, volume of infarct pre-EVT Venous delay pre-EVT* Complete cohort 0.01 [-0.04–0.06] 0.631
Reperfused patients 0.00 [-0.05–0.05] 0.997
Venous delay post-EVT Complete cohort 0.12 [0.05–0.19] 0.007
Reperfused patients 0.12 [0.04–0.20] 0.003
mRS 3 months Ordinal regression Age, sex, NIHSS at hospital arrival, site of occlusion, HIR, successful reperfusion, ischemia duration Venous delay pre-EVT* Complete cohort 1.04 [0.96–1.12] 0.291
Reperfused patients 1.06 [1.00–1.01] 0.193
Venous delay post-EVT Complete cohort 1.14 [1.01–1.29] 0.035
Reperfused patients 1.11 [0.96–1.28] 0.138

* Venous delay pre-EVT was measured in the assessable pre-EVT dMRA group and included 89 patients;

Venous delay post-EVT was measured in the assessable post-EVT dMRA group and included 88 patients;

In the subset of reperfused patients, no adjustment by final mTICI grade was done;

§ The effect size is calculated per each increase of a 10% venous delay. All results of the ordinal regression are expressed as crude odds ratio [95% confidence interval].

EVT, endovascular treatment (pre-EVT, at hospital admission; post-EVT, <2 hours after EVT); MRI, magnetic resonance imaging; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; HIR, hypoperfusion intensity ratio.

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