Venous outflow profiles are associated with early edema progression in ischemic stroke

Background: In patients with acute ischemic stroke due to large vessel occlusion (AIS–LVO), development of extensive early ischemic brain edema is associated with poor functional outcomes, despite timely treatment. Robust cortical venous outflow (VO) profiles correlate with favorable tissue perfusion. We hypothesized that favorable VO profiles (VO+) correlate with a reduced early edema progression rate (EPR) and good functional outcomes. Methods: Multicenter, retrospective analysis to investigate AIS–LVO patients treated by mechanical thrombectomy between May 2013 and December 2020. Baseline computed tomography angiography (CTA) was used to determine VO using the cortical vein opacification score (COVES); VO+ was defined as COVES ⩾ 3 and unfavorable as COVES ⩽ 2. EPR was determined as the ratio of net water uptake (NWU) on baseline non-contrast CT and time from symptom onset to admission imaging. Multivariable regression analysis was performed to assess primary (EPR) and secondary outcome (good functional outcomes defined as 0–2 points on the modified Rankin scale). Results: A total of 728 patients were included. Primary outcome analysis showed VO+ (β: –0.03, SE: 0.009, p = 0.002), lower presentation National Institutes of Health Stroke Scale (NIHSS; β: 0.002, SE: 0.001, p = 0.002), and decreased time from onset to admission imaging (β: –0.00002, SE: 0.00004, p < 0.001) were independently associated with reduced EPR. VO+ also predicted good functional outcomes (odds ratio (OR): 5.07, 95% CI: 2.839–9.039, p < 0.001), while controlling for presentation NIHSS, time from onset to imaging, general vessel reperfusion, baseline Alberta Stroke Program Early CT Score, infarct core volume, EPR, and favorable arterial collaterals. Conclusions: Favorable VO profiles were associated with slower infarct edema progression and good long-term functional outcomes as well as better neurological status and ischemic brain alterations at admission.

Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?

Ischaemic stroke involves the rapid onset of focal neurological dysfunction, most commonly due to an arterial blockage in a specific region of the brain. Stroke is a leading cause of death and common cause of disability, with over 17 million people worldwide suffering from a stroke each year. It is now well-documented that neuroinflammation and immune mediators play a key role in acute and long-term neuronal tissue damage and healing, not only in the infarct core but also in distal regions. Importantly, in these distal regions, termed sites of secondary neurodegeneration (SND), spikes in neuroinflammation may be seen sometime after the initial stroke onset, but prior to the presence of the neuronal tissue damage within these regions. However, it is key to acknowledge that, despite the mounting information describing neuroinflammation following ischaemic stroke, the exact mechanisms whereby inflammatory cells and their mediators drive stroke-induced neuroinflammation are still not fully understood. As a result, current anti-inflammatory treatments have failed to show efficacy in clinical trials. In this review we discuss the complexities of post-stroke neuroinflammation, specifically how it affects neuronal tissue and post-stroke outcome acutely, chronically, and in sites of SND. We then discuss current and previously assessed anti-inflammatory therapies, with a particular focus on how failed anti-inflammatories may be repurposed to target SND-associated neuroinflammation.

Deep Learning Analyses to Delineate the Molecular Remodeling Process after Myocardial Infarction

Specific proteins and processes have been identified in post-myocardial infarction (MI) pathological remodeling, but a comprehensive understanding of the complete molecular evolution is lacking. We generated microarray data from swine heart biopsies at baseline and 6, 30, and 45 days after infarction to feed machine-learning algorithms. We cross-validated the results using available clinical and experimental information. MI progression was accompanied by the regulation of adipogenesis, fatty acid metabolism, and epithelial–mesenchymal transition. The infarct core region was enriched in processes related to muscle contraction and membrane depolarization. Angiogenesis was among the first morphogenic responses detected as being sustained over time, but other processes suggesting post-ischemic recapitulation of embryogenic processes were also observed. Finally, protein-triggering analysis established the key genes mediating each process at each time point, as well as the complete adverse remodeling response. We modeled the behaviors of these genes, generating a description of the integrative mechanism of action for MI progression. This mechanistic analysis overlapped at different time points; the common pathways between the source proteins and cardiac remodeling involved IGF1R, RAF1, KPCA, JUN, and PTN11 as modulators. Thus, our data delineate a structured and comprehensive picture of the molecular remodeling process, identify new potential biomarkers or therapeutic targets, and establish therapeutic windows during disease progression.

Ghost infarct core following endovascular reperfusion: A risk for computed tomography perfusion misguided selection in stroke

Background Computed tomography perfusion (CTP) has been increasingly used for patient selection in mechanical thrombectomy for stroke. However, previous studies suggested that CTP might overestimate the infarct size. The term ghost infarct core (GIC) has been used to describe an overestimation of the final infarct volumes by pre-treatment CTP of >10 ml. Aim We sought to study the frequency and predictors of GIC. Methods A prospectively collected mechanical thrombectomy database at a comprehensive stroke center between September 2010 and August 2020 was reviewed. Patients were included if they had a successful reperfusion (mTICI2b-3), a pre-procedure CTP, and final infarct volume measured on follow-up magnetic resonance imaging. Uni- and multivariable analyses were performed to identify predictors of GIC. Results Among 923 eligible patients (median [IQR] age, 64 [55–75] years; NIHSS, 16 [11–21]; onset to reperfusion time, 436.5 [286–744.5] min), GIC was identified in 77 (8.3%) of the overall patients and in 14% (47/335) of those reperfused within 6 h of symptom onset. The median overestimation volume was 23.2 [16.4–38.3] mL. GIC was associated with higher NIHSS score, larger areas of infarct core and tissue at risk on CTP, unfavorable collateral scores, and shorter times from onset to image acquisition and to reperfusion as compared to non-GIC. Patients with GIC had smaller median final infarct volumes (10.7 vs. 27.1 ml, p < 0.001), higher chances of functional independence (76.2% vs. 55.5%, adjusted odds ratio (aOR) 3.829, 95% CI [1.505–9.737], p = 0.005), lower disability (one-point-mRS improvement, aOR 1.761, 95% CI [1.044–2.981], p = 0.03), and lower mortality (6.3% vs. 15%, aOR 0.119, 95% CI [0.014–0.984], p = 0.048) at 90 days. On multivariable analysis, time from onset to reperfusion ≤6 h (OR 3.184, 95% CI [1.743–5.815], p < 0.001), poor collaterals (OR 2.688, 95% CI [1.466–4.931], p = 0.001), and higher NIHSS score (OR 1.060, 95% CI [1.010–1.113], p = 0.018) were independent predictors of GIC. Conclusion GIC is a relatively common entity, particularly in patients with poor collateral status, higher baseline NIHSS score, and early presentation, and is associated with more favorable outcomes. Patients should not be excluded from reperfusion therapies on the sole basis of CTP findings, especially in the early window.

Endovascular treatment beyond 24 hours from the onset of acute ischemic stroke: the Italian Registry of Endovascular Thrombectomy in Acute Stroke (IRETAS)

BackgroundClinical trials and observational studies have demonstrated the benefit of thrombectomy up to 16 or 24 hours after the patient was last known to be well. This study aimed to evaluate the outcome of stroke patients treated beyond 24 hours from onset.MethodsWe analyzed the outcome of 34 stroke patients (mean age 70.7±12.3 years; median National Institutes of Health Stroke Scale (NIHSS) score 13) treated with endovascular thrombectomy beyond 24 hours from onset who were recruited in the Italian Registry of Endovascular Thrombectomy in Acute Stroke. Selection criteria for patients were: pre-stroke modified Rankin scale (mRS) score of ≤2, non-contrast CT Alberta Stroke Program Early CT score of ≥6, good collaterals on single phase CT angiography (CTA) or multiphase CTA, and CT perfusion mismatch with an infarct core size ≤50% of the total hypoperfusion extent or involving less than one-third of the extent of the middle cerebral artery territory evaluated by visual inspection. The primary outcome measure was functional independence assessed by the mRS at 90 days after onset. Safety outcomes were 90 day mortality and the occurrence of symptomatic intracranial hemorrhage (sICH).ResultsSuccessful recanalization (Thrombolysis in Cerebral Infarction score of 2b or 3) was present in 76.5% of patients. Three month functional independence (mRS score 0–2) was observed in 41.1% of patients. The case fatality rate was 26.5%. and the incidence of sICH was 8.8%.ConclusionsThese findings suggest that, in a real world setting, very late endovascular therapy is feasible in appropriately selected patients.

Mechanical thrombectomy through a ‘carotid–carotid bypass’

An elderly patient presented with acute-onset right-sided weakness and aphasia. A large penumbra was noted in the left middle cerebral artery (MCA) territory without any infarct core. The patient was noted to have a carotid–carotid bypass. This posed certain technical challenge in accessing the intracranial circulation across the carotid bypass; however, the guiding catheter with soft distal segment was successfully navigated coaxially over the aspiration catheter across the bypass and intracranial circulation was accessed for mechanical thrombectomy. Complete recanalisation and reperfusion were achieved with significant neurological recovery of the patient post-thrombectomy. The aim of this report is to emphasise on this rarely encountered situation in thrombectomy and its successful management. The procedure should not be delayed or deferred due to lack of operator experience.

Abstract 1122‐000012: Study Design and Selection Criteria of a Large Core Thrombectomy Trial —— ANGEL‐ASPECT

Introduction : The ANGEL‐ASPECT trial (NCT 04551664) is an ongoing, multicenter, randomized controlled trial (RCT) currently being conducted in China. The goal of ANGEL‐ASPECT’s is to include the maximum patients with a true large core for whom EVT is not recommended under current guidelines with level 1 evidence. By enrolling patients with ASPECTS <6, expanding the window to 24h from stroke onset (beyond the windows in DAWN and DEFUSE3), and defining large core volume as >70 cc, ANGEL‐ASPECT maximizes the inclusion of patients with true large cores. What’s more, intracranial atherosclerotic disease (ICAD) is common in the Asian population while most of the previous trials have been performed in the Western world where ICAD is less prevalent. Methods : We reviewed the merits of ANGEL‐ASPECT’s design and suggest that it be included in the discussion of patient selection criteria in large core trials. Results : The primary goal of our trial is to determine whether EVT will benefit or harm AIS patients with LVO and a “large core” infarct. The inclusion criteria for ANGEL‐ASPECT are: 1. If ASPECTS is 3–5 and presentation is within 24 hours of onset, patients are enrolled without obtaining CTP. 2. If ASPECTS is >5 and presentation is beyond 6 hours of onset, only patients with relative cerebral blood flow (rCBF) of < 30% by CTP or apparent diffusion coefficient (ADC) of < 620 on MRI and estimated core volume of 70–100 cc are enrolled. 3. If ASPECTS is <3, only patients with rCBF < 30% or ADC on MRI < 620 and estimated core volume of 70–100 cc are enrolled. Patients are enrolled under a pre‐specified protocol. Each randomized patient is qualified by two core lab members who are available at all hours to calculate ASPECTS and infarct core volume using specialized, RAPID software. Conclusions : We believe that defining core volume using CTP can compensate for the inconsistencies of ASPECTS if we exclude patients with onset within six hours and core volume of 50–70 cc since these patients have already been shown to benefit from EVT in multiple RCTs. We believe that this decision captures more patients with true large core volumes for the trial. The ANGEL‐ASPECT inclusion criteria also eliminate the second group of “good ASPECTS + unfavorable CTP” . The sample size of our trial is calculated based on studies excluding these populations. The power of the trial was maintained for the relatively consistent large core volume patient population.

Abstract 1122‐000202: Two World Wars, Two Pandemics and Then Stroke:Thrombectomy, Angioplasty and Stenting in a 110‐Year‐Old Patient

Introduction : Endovascular thrombectomy (EVT) is the standard of care in patients with acute stroke due to large vessel occlusion. In an aging population it is important to know EVT outcomes in old age, despite patients over 80 years are mostly excluded from major trial. While the oldest reported patients undergoing EVT was 102 years old, we report a 110 years old patient as the oldest patient undergoing EVT for stroke reported in the literature, and discuss the technical details and outcome. Methods : n/a Results : A 110‐ year‐old patient presented with right side weakness and slurred speech and found to have left middle cerebral artery occlusion. She received tenecteplase and transferred to angio‐suite 1 hour and 35 minutes after onset of symptoms. Left middle cerebral artery underwent two passes with stentriever, balloon angioplasty and stent deployment resulting in thrombolysis in cerebral infarction (TICI) 3 reperfusion. Brain MRI showed infarction in the left basal ganglia and left temporal cortex. After thrombectomy she was able to hold right arm and leg against gravity and follow commands. However, patient developed aspiration pneumonia and passed away after family chose to focus care on her comfort and refused tracheostomy and gastric tube. Conclusions : Despite poor clinical outcome, this case presents technical success in good recanalization, resulting in small infarct core and immediate neurological improvement in the oldest reported acute stroke patient undergoing thrombectomy.

Association of CT-Based Hypoperfusion Index With Ischemic Core Enlargement in Patients With Medium and Large Vessel Stroke

Objective:The rate of infarct core progression in patients with acute ischemic stroke is variable and affects outcome of reperfusion therapy. We evaluated hypoperfusion index (HI) to estimate the initial rate of core progression in patients with medium-vessel-occlusion (MeVO) compared to large-vessel-occlusion (LVO) stroke and within a larger time frame since stroke onset.Methods:Core progression was assessed in 106 patients with acute stroke and CT perfusion. Using reperfusion trial core-time criteria, fast progressors had core>70-mL within 6-hours of stroke onset and slow progressors had core ≤70mL, mismatch ≥15mL and mismatch-to-core-ratio ≥1.8 within 6-24-hours. The relationship between HI and infarct core progression (core/time) was examined using receiver-operating-characteristics to determine optimal HI cut-off. The HI cut-off was then tested in overall cohort, compared between MeVO and LVO, and evaluated in patients up to 24-hours from stroke onset to differentiate fast from slow rate of core progression. HI threshold was assessed in a second independent cohort of 110 acute ischemic stroke patients.Results:In 106 patients with acute stroke, 6.6% were fast progressors, 27.4% were slow progressors, and 66% were not classified as fast or slow progressor by reperfusion trial core-time criteria. HI>0.5 was associated with fast progression and able to distinguish fast from slow progressors (AUC=0.94;95%CI=0.80-0.99). In MeVO patients (n=26) HI>0.5 had a core progression of 0.30-mL/min compared to 0.03-mL/min with HI≤0.5 (p<0.001). In LVO patients (n=80), HI>0.5 had a core progression of 0.26-mL/min compared to 0.02-mL/min with HI≤0.5 (p<0.001). In patients not classified as fast or slow progressor by reperfusion trial criteria, those with HI>0.5 had progression rate of 0.21-mL/min compared to 0.03-mL/min with HI≤0.5 (p<0.001). Validation in a second cohort of patients with acute ischemic stroke (n=110; MeVO n=42, LVO n=68) yielded similar results for HI>0.5 to distinguish fast and slow core progression with an AUC of 0.84(95%CI=0.72-0.97).Conclusions:HI can differentiate fast from slow core progression in MeVO and LVO patients within the first 24-hours of acute ischemic stroke. Consideration of core progression rate at time of stroke evaluation may have implications in the selection of MeVO and LVO stroke patients for reperfusion therapy that warrant further study.