Hypoperfusion index ratio and pretreatment with intravenous thrombolysis are independent predictors of good functional outcome in acute ischemic stroke patients with large vessel occlusion treated with acute reperfusion therapies.

INTRODUCTION: We aimed to investigate the performance of several neuroimaging markers provided by perfusion imaging of Acute Ischemic Stroke (AIS) patients with large vessel occlusion (LVO) in order to predict clinical outcomes following reperfusion treatments. METHODS: We prospectively evaluated consecutive AIS patients with LVO who were treated with reperfusion therapies, during a six-year period. In order to compare patients with good (mRS scores 0-2) and poor (mRS scores 3-6) functional outcomes, data regarding clinical characteristics, the Alberta Stroke Programme Early Computed Tomography Score (ASPECTS) based on unenhanced computed tomography (CT), CT angiography collateral status and perfusion parameters including ischemic core, hypoperfusion volume, mismatch volume between core and penumbra, Tmax > 10 s volume, CBV index and the Hypoperfusion Index Ratio (HIR) were assessed. RESULTS: A total of 84 acute stroke patients with LVO who met all the inclusion criteria were enrolled. In multivariable logistic regression models increasing age (odds ratio [OR]: 0.93; 95%CI: 0.88-0.96, p = 0.001), lower admission National Institute of Health Stroke Scale (NIHSS)-score (OR: 0.88; 95%CI: 0.80-0.95, p = 0.004), pretreatment with intravenous thrombolysis (OR: 3.83; 95%CI: 1.29-12.49, p = 0.019) and HIR (OR:0.36; 95%CI: 0.10-0.95, p = 0.042) were independent predictors of good functional outcome at 3 months. The initial univariable associations between HIR and higher likelihood for symptomatic intracranial hemorrhage (sICH) and parenchymal hematoma type 2 (PH2) were attenuated in multivariable analyses failing to reach statistical significance. DISCUSSION: Our pilot observational study of unselected AIS patients with LVO treated with reperfusion therapies demonstrated that pre-treatment low HIR in perfusion imaging and IVT were associated with better functional outcomes.

Overview of systematic reviews comparing endovascular to best medical treatment for large-vessel occlusion acute ischaemic stroke: an umbrella review.

Background: The literature on endovascular treatment (EVT) for large-vessel occlusion (LVO) acute ischaemic stroke (AIS) has been rapidly increasing after the publication of positive randomized-controlled clinical trials (RCTs) and a plethora of systematic reviews (SRs) showing benefit compared to best medical therapy (BMT) for LVO. Objectives: An overview of SRs (umbrella review) and meta-analysis of primary RCTs were performed to summarize the literature and present efficacy and safety of EVT. Design and methods: MEDLINE via Pubmed, Embase and Epistemonikos databases were searched from January 2015 until 15 October 2023. All SRs of RCTs comparing EVT to BMT were included. Quality was assessed using Risk of Bias in Systematic Reviews scores and the RoB 2 Cochrane Collaboration tool, as appropriate. GRADE approach was used to evaluate the strength of evidence. Data were presented according to the Preferred Reporting Items for Overviews of Reviews statement. The primary outcome was 3-month good functional outcome [modified Rankin scale (mRS) score 0-2]. Results: Three eligible SRs and 4 additional RCTs were included in the overview, comprising a total of 24 RCTs, corresponding to 5968 AIS patients with LVO (3044 randomized to EVT versus 2924 patients randomized to BMT). High-quality evidence shows that EVT is associated with an increased likelihood of good functional outcome [risk ratio (RR) 1.78 (95% confidence interval (CI): 1.54-2.06); 166 more per 1000 patients], independent ambulation [mRS-scores 0-3; RR 1.50 (95% CI: 1.37-1.64); 174 more per 1000 patients], excellent functional outcome [mRS-scores 0-1; RR 1.90 (95% CI: 1.62-2.22); 118 more per 1000 patients] at 3 months. EVT was associated with reduced 3-month mortality [RR 0.81 (95% CI: 0.74-0.88); 61 less per 1000 patients] despite an increase in symptomatic intracranial haemorrhage [sICH; RR 1.65 (95% CI: 1.23-2.21); 22 more per 1000 patients]. Conclusion: In patients with AIS due to LVO in the anterior or posterior circulation, within 24 h from symptom onset, EVT improves functional outcomes and increases the chance of survival despite increased sICH risk. Registration: PROSPERO Registration Number CRD42023461138.

Investigating the Role of Brain Natriuretic Peptide (BNP) and N-Terminal-proBNP in Thrombosis and Acute Ischemic Stroke Etiology.

The need for biomarkers for acute ischemic stroke (AIS) to understand the mechanisms implicated in pathological clot formation is critical. The levels of the brain natriuretic peptides known as brain natriuretic peptide (BNP) and NT-proBNP have been shown to be increased in patients suffering from heart failure and other heart conditions. We measured their expression in AIS clots of cardioembolic (CE) and large artery atherosclerosis (LAA) etiology, evaluating their location inside the clots, aiming to uncover their possible role in thrombosis. We analyzed 80 thrombi from 80 AIS patients in the RESTORE registry of AIS clots, 40 of which were of CE and 40 of LAA etiology. The localization of BNP and NT-BNP, quantified using immunohistochemistry and immunofluorescence, in AIS-associated white blood cell subtypes was also investigated. We found a statistically significant positive correlation between BNP and NT-proBNP expression levels (Spearman's rho = 0.668 p < 0.0001 *). We did not observe any statistically significant difference between LAA and CE clots in BNP expression (0.66 [0.13-3.54]% vs. 0.53 [0.14-3.07]%, p = 0.923) or in NT-proBNP expression (0.29 [0.11-0.58]% vs. 0.18 [0.05-0.51]%, p = 0.119), although there was a trend of higher NT-proBNP expression in the LAA clots. It was noticeable that BNP was distributed throughout the thrombus and especially within platelet-rich regions. However, NT-proBNP colocalized with neutrophils, macrophages, and T-lymphocytes, suggesting its association with the thrombo-inflammatory process.

Update of Anticoagulation Use in Cardioembolic Stroke With a Special Reference to Endovascular Treatment.

Cardioembolic stroke is a major cause of morbidity, with a high risk of recurrence, and anticoagulation represents the mainstay of secondary stroke prevention in most patients. The implementation of endovascular treatment in routine clinical practice complicates the decision to initiate anticoagulation, especially in patients with early hemorrhagic transformation who are considered at higher risk of hematoma expansion. Late hemorrhagic transformation in the days and weeks following stroke remains a potentially serious complication for which we still do not have any established clinical or radiological prediction tools. The optimal time to initiate therapy is challenging to define since delaying effective secondary prevention treatment exposes patients to the risk of recurrent embolism. Consequently, there is clinical equipoise to define and individualize the optimal timepoint to initiate anticoagulation combining the lowest risk of hemorrhagic transformation and ischemic recurrence in cardioembolic stroke patients. In this narrative review, we will highlight and critically outline recent observational and randomized relevant evidence in different subtypes of cardioembolic stroke with a special focus on anticoagulation initiation following endovascular treatment. We will refer mainly to the commonest cause of cardioembolism, non-valvular atrial fibrillation, and examine the possible risk and benefit of anticoagulation before, during, and shortly after the acute phase of stroke. Other indications of anticoagulation after ischemic stroke will be briefly discussed. We provide a synthesis of available data to help clinicians individualize the timing of initiation of oral anticoagulation based on the presence and extent of hemorrhagic transformation as well as stroke severity.

White blood cell subtypes and neutrophil extracellular traps content as biomarkers for stroke etiology in acute ischemic stroke clots retrieved by mechanical thrombectomy.

BACKGROUND: Lymphocytes, macrophages, neutrophils, and neutrophil extracellular traps (NETs) associate with stroke risk factors and form a thrombus through different mechanisms. We investigated the total WBCs, WBC subtypes and NETs composition in acute ischemic stroke (AIS) clots to identify possible etiological differences that could help us further understand the process of thrombosis that leads to AIS. METHODS: AIS clots from 100 cases each of atherothrombotic (AT), cardioembolic (CE) and cryptogenic stroke etiology were collected per-pass as part of the CÚRAM RESTORE registry of AIS clots. Martius Scarlet Blue stain was used to identify the main histological components of the clots. Immunohistochemical staining was used to identify neutrophils, lymphocytes, macrophages, and NETs patterns. The cellular and histological components were quantified using Orbit Image Analysis software. RESULTS: AT clots were larger, with more red blood cells and fewer WBCs than CE clots. AT clots had more lymphocytes and cryptogenic clots had fewer macrophages than other etiologies. Most significantly, CE clots showed higher expression of neutrophils and extracellular web-like NETs compared to AT and cryptogenic clots. There was also a significantly higher distribution of web-like NETs around the periphery of the CE clots while a mixed distribution was observed in AT clots. CONCLUSION: The difference in neutrophil and NETs expression in clots from different etiologies may provide insight into the mechanism of clot formation.

Clinical Characteristics, Neuroimaging Markers, and Outcomes in Patients with Cerebral Amyloid Angiopathy: A Prospective Cohort Study.

Background and purpose: Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease, resulting from progressive amyloid-ß deposition in the media/adventitia of cortical and leptomeningeal arterioles. We sought to assess the prevalence of baseline characteristics, clinical and radiological findings, as well as outcomes among patients with CAA, in the largest study to date conducted in Greece. Methods: Sixty-eight patients fulfilling the Boston Criteria v1.5 for probable/possible CAA were enrolled and followed for at least twelve months. Magnetic Resonance Imaging was used to assess specific neuroimaging markers. Data regarding cerebrospinal fluid biomarker profile and Apolipoprotein-E genotype were collected. Multiple logistic regression analyses were performed to identify predictors of clinical phenotypes. Cox-proportional hazard regression models were used to calculate associations with the risk of recurrent intracerebral hemorrhage (ICH). Results: Focal neurological deficits (75%), cognitive decline (57%), and transient focal neurological episodes (TFNEs; 21%) were the most common clinical manifestations. Hemorrhagic lesions, including lobar cerebral microbleeds (CMBs; 93%), cortical superficial siderosis (cSS; 48%), and lobar ICH (43%) were the most prevalent neuroimaging findings. cSS was independently associated with the likelihood of TFNEs at presentation (OR: 4.504, 95%CI:1.258-19.088), while multiple (>10) lobar CMBs were independently associated with cognitive decline at presentation (OR:5.418, 95%CI:1.316-28.497). cSS emerged as the only risk factor of recurrent ICH (HR:4.238, 95%CI:1.509-11.900) during a median follow-up of 20 months. Conclusions: cSS was independently associated with TFNEs at presentation and ICH recurrence at follow-up, while a higher burden of lobar CMBs with cognitive decline at baseline. These findings highlight the prognostic value of neuroimaging markers, which may influence clinical decision-making.

Medical Management Versus Endovascular Treatment for Large-Vessel Occlusion Anterior Circulation Stroke With Low NIHSS.

BACKGROUND: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with National Institutes of Health Stroke Scale score of 0 to 5 is common in clinical practice but has not yet been proven safe and effective. Our objective is to assess whether EVT on top of best medical treatment (BMT) in AIS patients with large-vessel occlusion of the anterior circulation presenting with mild symptoms is beneficial compared with BMT. METHODS: We searched MEDLINE, SCOPUS, and reference lists of retrieved articles published until December 28, 2022. A systematic literature search was conducted to identify clinical trials or observational cohort studies evaluating patients with AIS due to anterior circulation large-vessel occlusion and admission National Institutes of Health Stroke Scale score ≤5 treated with EVT versus BMT alone. The primary outcome was excellent functional outcome (modified Rankin Scale score 0-1) at 3 months. The protocol had been registered before data collection (PROSPERO). RESULTS: Eleven observational eligible studies were included in the meta-analysis, comprising a total of 2019 AIS patients with National Institutes of Health Stroke Scale score ≤5 treated with EVT versus 3171 patients treated with BMT. EVT was not associated with excellent functional outcome (risk ratio, 1.10 [95% CI, 0.93-1.31]). When stratified for different study design (per-protocol versus intention-to-treat), there were no significant subgroup differences. EVT was not associated with good functional outcome (modified Rankin Scale score 0-2; risk ratio, 1.01 [95% CI, 0.89-1.16]) or reduced disability at 3 months (common odds ratio, 0.92 [95% CI, 0.60-1.41]). Symptomatic intracranial hemorrhage was more common in the patients receiving EVT (risk ratio, 3.53 [95% CI, 2.35-5.31]). No correlation was found between EVT and mortality at 3 months (risk ratio, 1.34 [95% CI, 0.83-2.18]). The same overall associations were confirmed in the sensitivity analysis of studies that performed propensity score matching. CONCLUSIONS: EVT appears equivalent to BMT for patients with anterior circulation large-vessel occlusion AIS with low baseline National Institutes of Health Stroke Scale, despite the increased risk for symptomatic intracranial hemorrhage. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42022334417.

Quality metrics in the management of acute stroke in Greece during the first 5 years of Registry of Stroke Care Quality (RES-Q) implementation.

Introduction: Establishment of a prospective stroke registry may promote the documentation and improvement of acute stroke care. We present the status of stroke management in Greece using the Registry of Stroke Care Quality (RES-Q) dataset. Methods: Consecutive patients with acute stroke were prospectively registered in RES-Q registry by contributing sites in Greece during the years 2017-2021. Demographic and baseline characteristics, acute management, and clinical outcomes at discharge were recorded. Stroke quality metrics, with a specific interest in the association between acute reperfusion therapies and functional recovery in ischemic stroke patients are presented. Results: A total of 3590 acute stroke patients were treated in 20 Greek sites (61% men, median age 64 years; median baseline NIHSS 4; 74% ischemic stroke). Acute reperfusion therapies were administered in almost 20% of acute ischemic stroke patients, with a door to needle and door to groin puncture times of 40 and 64 min, respectively. After adjustment for contributing sites, the rates of acute reperfusion therapies were higher during the time epoch 2020-2021 compared to 2017-2019 (adjusted OR 1.31; 95% CI 1.04-1.64; p < 0.022; Cochran-Mantel-Haenszel test). After propensity-score-matching, acute reperfusion therapies administration was independently associated with higher odds of reduced disability (one point reduction across all mRS scores) at hospital discharge (common OR 1.93; 95% CI 1.45-2.58; p < 0.001). Conclusions: Implementation and maintenance of a nationwide stroke registry in Greece may guide the stroke management planning, so that prompt patient transportation, acute reperfusion therapies, and stroke unit hospitalization become more widely accessible, improving the functional outcomes of stroke patients.

Bilateral dural arteriovenous fistula diagnosed with neurovascular ultrasonography.

BACKGROUND: Intracranial dural arteriovenous fistulas (dAVFs) are pathological anastomoses between meningeal arteries and dural venous sinuses or cortical veins. Diagnosis of dAVFs can be challenging due to their broad range of clinical manifestations and the lack of specificity in their symptoms. We present a rare case of a patient with bilateral dAVFs, who was referred to our department for carotid doppler ultrasonography/transcranial color Doppler. CASE REPORT: A 67-year-old man was referred by his treating physician for neurovascular ultrasonography due to vision impairment associated with papilledema of both eyes. On ultrasound examination both external carotid arteries showed a "pseudo-internalization" pattern with high end-diastolic velocities and reduced resistance indices. Subsequent magnetic resonance and digital subtraction angiography revealed dAVF of both transverse sinuses, with occipital and medial meningeal arteries as feeders. CONCLUSIONS: Neurovascular sonography may serve as a screening and follow-up tool when a DAVF in the transverse sinus/sigmoid sinus is suspected.

Endovascular treatment for anterior circulation large-vessel occlusion ischemic stroke with low ASPECTS: a systematic review and meta-analysis.

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with Alberta Stroke Program Early CT Score (ASPECTS) 0-5 has not yet proven safe and effective by clinical trials. Objectives: The aim of the study was to assess whether EVT in AIS patients presenting with low ASPECTS is beneficial. Design: Systematic review and meta-analysis of available studies in accordance with the PRISMA statement. Data sources and Methods: We have searched MEDLINE, the Cochrane Central Register of Controlled Trials, and reference lists of articles published until 28 May 2022 with the aim to calculate (1) modified Rankin scale (mRS) score 0-3 at 3 months, (2) mRS score 0-2 at 3 months, (3) symptomatic intracranial hemorrhage (sICH), and (3) mortality at 3 months. Results: Overall, 24 eligible studies were included in the meta-analysis, comprising a total of 2539 AIS patients with ASPECTS 0-5 treated with EVT. The pooled proportion of EVT-treated patients achieving mRS 0-3 at 3 months was calculated at 38.4%. The pooled proportion of EVT-treated patients achieving mRS 0-2 at 3 months was 25.7%. Regarding safety outcomes, sICH occurred in 12.8% of patients. The 3-month pooled mortality was 30%. In pairwise meta-analysis, patients treated with EVT had a higher likelihood of achieving mRS 0-3 at 3 months compared with patients treated with best medical therapy (BMT, OR: 2.41). sICH occurred more frequently in EVT-treated patients compared with the BMT-treated patients (OR: 2.30). Mortality at 3 months was not different between the two treatment groups (OR: 0.71). Conclusion: EVT may be beneficial for AIS patients with low baseline ASPECTS despite an increased risk for sICH. Further data from randomized-controlled clinical trials are needed to elucidate the role of EVT in this subgroup of AIS patients. Registration: The protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO; Registration Number: CRD42022334417.

Cerebral Amyloid Angiopathy-Related Inflammation: A Single-Center Experience and a Literature Review.

Background: Limited data exist regarding the prevalence of clinical, neuroimaging, and genetic markers among patients diagnosed with Cerebral Amyloid Angiopathy−related inflammation (CAA-ri). We sought to determine these characteristics in patients diagnosed in our center and to summarize available literature published either as single-case reports or small case series (<5 patients). Methods: We reported our single-center experience of patients diagnosed with CAA-ri according to international criteria during a seven-year period (2015−2022), and we abstracted data from 90 previously published cases. Results: Seven patients (43% women, mean age 70 ± 13 years) were diagnosed with CAA-ri in our center. The most common symptom at presentation was focal neurological dysfunction (71%), and the most prevalent radiological finding was the presence of T2/FLAIR white matter hyperintensities (100%). All patients were treated with corticosteroids and had a favorable functional outcome. Among 90 previously published CAA-ri cases (51% women, mean age 70 ± 9 years), focal neurological dysfunction was the most common symptom (76%), followed by a cognitive decline (46%) and headache (34%). The most prevalent neuroimaging findings were cerebral microbleeds (85%), asymmetric T2/FLAIR white matter hyperintensities (81%), and gadolinium-enhancing T1-lesions (37%). Genetic testing for the Apolipoprotein-E gene was available in 27 cases; 59% carried the APOE ε4/ε4 genotype. The majority of the published CAA-ri cases (78%) received corticosteroid monotherapy, while 17 patients (19%) were treated with additional immunosuppressive treatment. Favorable functional outcome following treatment was documented in 70% of patients. Conclusion: Improving the vigilance of clinicians regarding the early recognition and accurate diagnosis of CAA-ri is crucial for swift therapy initiation, which may result in improved functional outcomes.

Diagnosis and treatment of acute isolated proximal internal carotid artery occlusions: a narrative review.

The clinical manifestations of proximal (extracranial) internal carotid artery occlusions (pICAOs) may range from asymptomatic to acute, large, and devastating ischemic strokes. The etiology and pathophysiology of the occlusion, intracranial collateral status and patient's premorbid status are among the factors determining the clinical presentation and outcome of pICAOs. Rapid and accurate diagnosis is crucial and may be assisted by the combination of carotid and transcranial duplex sonography, or a computed tomography/magnetic resonance angiography (CTA/MRA). It should be noted that with either imaging modalities, the discrimination of a pseudo-occlusion of the extracranial internal carotid artery (ICA) from a true pICAO may not be straightforward. In the absence of randomized data, the management of acute, symptomatic pICAOs remains individualized and relies largely on expert opinion. Administration of intravenous thrombolysis is reasonable and probably beneficial in the settings of acute ischemic stroke with early presentation. Unfortunately, rates of recanalization are rather low and acute interventional reperfusion therapies emerge as a potentially powerful therapeutic option for patients with persistent and severe symptoms. However, none of the pivotal clinical trials on mechanical thrombectomy for acute ischemic stroke randomized patients with isolated extracranial large vessel occlusions. On the contrary, several lines of evidence from non-randomized studies have shown that acute carotid endarterectomy, or endovascular thrombectomy/stenting of the ICA are feasible and safe, and pοtentially beneficial. The heterogeneity in the pathophysiology and clinical presentation of acute pICAOs renders patient selection for an acute interventional treatment a complicated decision-making process. The present narrative review will outline the pathophysiology, clinical presentation, diagnostic challenges, and possible treatment options for pICAOs.

Intravenous Thrombolysis with Tenecteplase for the Treatment of Acute Ischemic Stroke.

OBJECTIVE: Intravenous thrombolysis (IVT) with tenecteplase has been associated with better clinical outcomes in acute ischemic stroke (AIS) patients with confirmed large vessel occlusions compared to IVT with alteplase. However, the utility of tenecteplase for the treatment of all AIS patients eligible for IVT has not been established. METHODS: We compared the safety and efficacy of tenecteplase versus alteplase in AIS patients by analyzing propensity score matched data from 20 centers participating in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register. Patients receiving IVT with tenecteplase were matched with up to 3 patients receiving alteplase from the same center. The primary outcome of interest was the distribution of 3-month functional outcomes. Secondary outcomes included the rates of patients with symptomatic intracranial hemorrhage (SICH) in the first 24 hours, excellent (modified Rankin Scale [mRS] score = 0-1) or good (mRS score = 0-2) functional outcome, and all-cause mortality at 3 months. RESULTS: A total of 331 tenecteplase-treated AIS patients were matched to 797 patients treated with alteplase (median age = 70 years, 43.9% women, median National Institutes of Health Stroke Scale score = 11, interquartile range = 6-17). Patients treated with tenecteplase had better 3-month functional outcomes (common odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.18-2.00) with higher odds of good functional outcome (OR = 2.00, 95% CI = 1.45-2.77) and a lower likelihood of all-cause mortality (OR = 0.43, 95% CI = 0.27-0.67) at 3 months, compared to alteplase-treated patients. No difference was found in the likelihood of the 3-month excellent functional outcomes (OR = 1.31, 95% CI = 0.96-1.78) and 24-hour SICH (1.0% vs 1.3%, OR = 0.72, 95% CI = 0.20-2.64). INTERPRETATION: IVT with tenecteplase was associated with better 3-month clinical outcomes compared to IVT with alteplase in AIS patients, with no increased risk of symptomatic intracranial bleeding. ANN NEUROL 2022;92:349-357.

Potential Biomarkers of Acute Ischemic Stroke Etiology Revealed by Mass Spectrometry-Based Proteomic Characterization of Formalin-Fixed Paraffin-Embedded Blood Clots.

Background and Aims: Besides the crucial role in the treatment of acute ischemic stroke (AIS), mechanical thrombectomy represents a unique opportunity for researchers to study the retrieved clots, with the possibility of unveiling biological patterns linked to stroke pathophysiology and etiology. We aimed to develop a shotgun proteomic approach to study and compare the proteome of formalin-fixed paraffin-embedded (FFPE) cardioembolic and large artery atherosclerotic (LAA) clots. Methods: We used 16 cardioembolic and 15 LAA FFPE thrombi from 31 AIS patients. The thrombus proteome was analyzed by label-free quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS). MaxQuant v1.5.2.8 and Perseus v.1.6.15.0 were used for bioinformatics analysis. Protein classes were identified using the PANTHER database and the STRING database was used to predict protein interactions. Results: We identified 1,581 protein groups as part of the AIS thrombus proteome. Fourteen significantly differentially abundant proteins across the two etiologies were identified. Four proteins involved in the ubiquitin-proteasome pathway, blood coagulation or plasminogen activating cascade were identified as significantly abundant in LAA clots. Ten proteins involved in the ubiquitin proteasome-pathway, cytoskeletal remodeling of platelets, platelet adhesion or blood coagulation were identified as significantly abundant in cardioembolic clots. Conclusion: Our results outlined a set of 14 proteins for a proof-of-principle characterization of cardioembolic and LAA FFPE clots, advancing the proteome profile of AIS human thrombi and understanding the pathophysiology of ischemic stroke.

Off-Label Use of Tenecteplase for the Treatment of Acute Ischemic Stroke: A Systematic Review and Meta-analysis.

Importance: Tenecteplase is being evaluated as an alternative thrombolytic agent for the treatment of acute ischemic stroke (AIS) within ongoing randomized clinical trials (RCTs). In addition, nonrandomized clinical experiences with off-label use of tenecteplase vs alteplase for AIS treatment are being published. Objective: To evaluate the available evidence on the safety and efficacy of intravenous tenecteplase compared with intravenous alteplase provided by nonrandomized studies. Data Sources: Eligible studies were identified by searching MEDLINE and Scopus databases. No language or other restrictions were imposed. The literature search was conducted on October 12, 2021. This meta-analysis used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) proposal. Study Selection: Nonrandomized studies (prospective or retrospective) comparing intravenous tenecteplase (at any dose) with intravenous alteplase in patients with AIS were included in the analysis. Data Extraction and Synthesis: The crude odds ratios (ORs) and 95% CIs were calculated for the association of tenecteplase vs alteplase with the outcomes of interest and adjusted ORs were extracted if provided. Estimates using random-effects models were pooled. Main Outcomes and Measures: The primary outcome was the probability of good functional outcome (modified Rankin scale [mRS] score, 0-2) at 90 days. Results: Six studies were identified including a total of 1820 patients (618 [34%] treated with tenecteplase). Patients receiving tenecteplase had higher odds of 3-month good functional outcome (crude odds ratio [OR], 1.22; 95% CI, 0.90-1.66; adjusted OR, 1.60, 95% CI, 1.08-2.37), successful recanalization (crude OR, 2.82; 95% CI, 1.12-7.10; adjusted OR, 2.38; 95% CI, 1.18-4.81), and early neurological improvement (crude OR, 4.88; 95% CI, 2.03-11.71; adjusted OR, 7.60; 95% CI, 1.97-29.41). No significant differences were detected in 3-month excellent functional outcome proportions (mRS score 0-1; crude OR, 1.53; 95% CI, 0.81-2.91; adjusted OR, 2.51; 95% CI, 0.66- 9.49), symptomatic intracranial hemorrhage (crude OR, 0.97; 95% CI, 0.44-2.16; adjusted OR, 1.16; 95% CI, 0.13-10.50), or parenchymal hematoma (crude OR, 1.20; 95% CI, 0.24-5.95). Conclusions and Relevance: Evidence from nonrandomized studies suggests tenecteplase is as safe as alteplase and potentially associated with improved functional outcomes compared with alteplase. Based on these findings, enrollment in the ongoing RCTs appears to be appropriate.

Does prior administration of rtPA influence acute ischemic stroke clot composition? Findings from the analysis of clots retrieved with mechanical thrombectomy from the RESTORE registry.

BACKGROUND AND PURPOSE: There is still much debate whether bridging-therapy [intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT)] might be beneficial compared to MT alone. We investigated the effect of IVT on size and histological composition of the clots retrieved from patients undergoing bridging-therapy or MT alone. METHODS: We collected mechanically extracted thrombi from 1000 acute ischemic stroke (AIS) patients included in RESTORE registry. Patients were grouped according to the administration (or not) of IVT before thrombectomy. Gross photos of each clot were taken and Extracted Clot Area (ECA) was measured using ImageJ software. Martius Scarlett Blue stain was used to characterize the main histological clot components [red blood cells (RBCs), fibrin (FIB), platelets/other (PTL)] and Orbit Image Analysis was used for quantification. Additionally, we calculated the area of each main component by multiplying the component percent by ECA. Chi-squared and Kruskal-Wallis tests were used for statistical analysis. RESULTS: 451 patients (45%) were treated with bridging-therapy while 549 (55%) underwent MT alone. When considering only percent histological composition, we did not find any difference in RBC% (P = 0.895), FIB% (P = 0.458) and PTL% (P = 0.905). However, bridging-therapy clots were significantly smaller than MT-alone clots [32.7 (14.8-64.9) versus 36.8 (20.1-79.8) mm2, N = 1000, H1 = 7.679, P = 0.006*]. A further analysis expressing components per clot area showed that clots retrieved from bridging-therapy cases contained less RBCs [13.25 (4.29-32.06) versus 14.97 (4.93-39.80) mm2, H1 = 3.637, P = 0.056] and significantly less fibrin [9.10 (4.62-17.98) versus 10.54 (5.57-22.48) mm2, H1 = 7.920, P = 0.005*] and platelets/other [5.04 (2.26-11.32) versus 6.54 (2.94-13.79) mm2, H1 = 9.380, P = 0.002*] than MT-alone clots. CONCLUSIONS: Our results suggest that previous IVT administration significantly reduces thrombus size, proportionally releasing all the main histological components.

Intravenous thrombolysis for acute ischemic stroke: why not?

PURPOSE OF REVIEW: The aim of this study was to summarize available evidence regarding the safety and efficacy of intravenous thrombolysis (IVT) using recombinant tissue-plasminogen activator (rt-PA) in acute ischemic stroke (AIS) patients with specific comorbidities and potential contraindications to systemic reperfusion therapy. Recent advances in IVT implementation in wake-up stroke and in extended time window using advanced neuroimaging will also be highlighted. RECENT FINDINGS: Despite theoretical concerns of a higher bleeding risk with IVT, there are no data showing increased risk of symptomatic intracerebral haemorrhage (sICH) in patients with stroke mimics, including seizures, increasing age and dual antiplatelet pretreatment. In addition, recent randomized evidence allows us to expand the time window of IVT for AIS using advanced neuroimaging both in wake-up stroke patients and in patients presenting within 4.5-9 h from symptom onset fulfilling certain neuroimaging criteria (based on DWI/FLAIR mismatch or perfusion mismatch). SUMMARY: IVT is a highly effective systemic reperfusion therapy that counts 25 years of everyday clinical experience but still presents several challenges in its application. Appropriate patient selection and adherence to rt-PA protocol is paramount in terms of safety. The effort to simplify the indications, expand the therapeutic time window and eliminate specific initial contraindications is continuously evolving.

S100b in acute ischemic stroke clots is a biomarker for post-thrombectomy intracranial hemorrhages.

Background and purpose: Post-thrombectomy intracranial hemorrhages (PTIH) are dangerous complications of acute ischemic stroke (AIS) following mechanical thrombectomy. We aimed to investigate if S100b levels in AIS clots removed by mechanical thrombectomy correlated to increased risk of PTIH. Methods: We analyzed 122 thrombi from 80 AIS patients in the RESTORE Registry of AIS clots, selecting an equal number of patients having been pre-treated or not with rtPA (40 each group). Within each subgroup, 20 patients had developed PTIH and 20 patients showed no signs of hemorrhage. Gross photos of each clot were taken and extracted clot area (ECA) was measured using ImageJ. Immunohistochemistry for S100b was performed and Orbit Image Analysis was used for quantification. Immunofluorescence was performed to investigate co-localization between S100b and T-lymphocytes, neutrophils and macrophages. Chi-square or Kruskal-Wallis test were used for statistical analysis. Results: PTIH was associated with higher S100b levels in clots (0.33 [0.08-0.85] vs. 0.07 [0.02-0.27] mm2, H1 = 6.021, P = 0.014*), but S100b levels were not significantly affected by acute thrombolytic treatment (P = 0.386). PTIH was also associated with patients having higher NIHSS at admission (20.0 [17.0-23.0] vs. 14.0 [10.5-19.0], H1 = 8.006, P = 0.005) and higher number of passes during thrombectomy (2 [1-4] vs. 1 [1-2.5], H1 = 5.995, P = 0.014*). S100b co-localized with neutrophils, macrophages and with T-lymphocytes in the clots. Conclusions: Higher S100b expression in AIS clots, higher NIHSS at admission and higher number of passes during thrombectomy are all associated with PTIH. Further investigation of S100b expression in AIS clots by neutrophils, macrophages and T-lymphocytes could provide insight into the role of S100b in thromboinflammation.