Comparative Studies of Cerebral Reperfusion Injury in the Posterior and Anterior Circulations After Mechanical Thrombectomy

Cerebral reperfusion injury is the major complication of mechanical thrombectomy (MT) for acute ischemic stroke (AIS). Contrast extravasation (CE) and intracranial hemorrhage (ICH) are the key radiographical features of cerebral reperfusion injury. The aim of this study was to investigate CE and ICH after MT in the anterior and posterior circulation, and their effect on functional outcome. This is a retrospective study of all consecutive patients who were treated with MT for AIS at University of California Irvine Medical Center between January 1, 2014, and December 31, 2017. Patient characteristics, clinical features, procedural variables, contrast extravasation, ICH, and outcomes after MT were analyzed. A total of 131 patients with anterior circulation (AC) stroke and 25 patients with posterior circulation (PC) stroke underwent MT during the study period. There was no statistically significant difference in admission NIHSS score, blood pressure, rate of receiving intravenous tPA, procedural variables, contrast extravasation, and symptomatic ICH between the 2 groups. Patients with PC stroke had a similar rate of favorable outcome (mRS 0–2) but significantly higher mortality (40.0% vs. 10.7%, p < 0.01) than patients with AC stroke. Multivariate regression analysis identified initial NIHSS score (OR 1.1, CI 1.0–1.2, p = 0.01), number of passes with stent retriever (OR 2.1, CI 1.3–3.6, p < 0.01), and PC stroke (OR 9.3, CI 2.5–35.1, p < 0.01) as independent risk factors for death. There was no significant difference in functional outcomes between patients with and without evidence of cerebral reperfusion injury after MT. We demonstrated that AC and PC stroke had similar rates of cerebral reperfusion injury and favorable outcome after MT. Cerebral reperfusion injury is not a significant independent risk factor for poor functional outcome.

The Clinical Significance of the Hyperintense Acute Reperfusion Marker Sign in Subacute Infarction Patients

Purpose: The hyperintense acute reperfusion marker (HARM) is characterized by the delayed enhancement of the subarachnoid or subpial space observed on postcontrast fluid-attenuated inversion recovery (FLAIR) images, and is considered a cerebral reperfusion marker for various brain disorders, including infarction. In this study, we evaluated the cerebral distribution patterns of HARM for discriminating between an enhancing subacute infarction and an enhancing mass located in the cortex and subcortical white matter. Materials and methods: We analyzed consecutive patients who experienced a subacute ischemic stroke, were hospitalized, and underwent conventional brain magnetic resonance imaging including postcontrast FLAIR within 14 days from symptom onset, as well as those who had lesions corresponding to a clinical sign detected by diffusion-weighted imaging and postcontrast T1-weighted imaging between May 2019 and May 2021. A total of 199 patients were included in the study. Of them, 94 were finally included in the subacute infarction group. During the same period, 76 enhancing masses located in the cortex or subcortical white matter, which were subcategorized as metastasis, malignant glioma, and lymphoma, were analyzed. We analyzed the overall incidence of HARM in subacute ischemic stroke cases, and compared the enhancement patterns between cortical infarctions and cortical masses. Results: Among 94 patients with subacute stroke, 78 patients (83%) presented HARM, and among 76 patients with subcortical masses, 48 patients (63%) presented peripheral rim enhancement. Of 170 subcortical enhancing lesions, 88 (51.8%) showed HARM, and 78 (88.6%) were determined to be subacute infarction. Among 94 patients with subacute stroke, 48 patients (51%) had diffusion restrictions, and HARM was found in 39 patients (81.2%). Of the 46 patients (49%) without diffusion restriction, 39 patients (84.8%) showed HARM. Conclusions: The presence of HARM was significantly associated with subacute infarctions. For the masses, a peripheral rim enhancement pattern was observed around the mass rather than the cerebral sulci on postcontrast FLAIR.

Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke

Background Astrocytic glycogen works as an essential energy reserve for surrounding neurons and is reported to accumulate excessively during cerebral ischemia/reperfusion (I/R) injury. Our previous study found that accumulated glycogen mobilization exhibits a neuroprotective effect against I/R damage. In addition, ischemia could transform astrocytes into A1-like (toxic) and A2-like (protective) subtypes. However, the underlying mechanism behind accumulated glycogen mobilization-mediated neuroprotection in cerebral reperfusion injury and its relationship with the astrocytic A1/A2 paradigm is unknown. Methods Astrocytic glycogen phosphorylase, the rate-limiting enzyme in glycogen mobilization, was specifically overexpressed and knocked down in mice and in cultured astrocytes. The I/R injury was imitated using a middle cerebral artery occlusion/reperfusion model in mice and an oxygen–glucose deprivation/reoxygenation model in cultured cells. Alterations in A1-like and A2-like astrocytes and the expression of phosphorylated nuclear transcription factor-κB (NF-κB) and phosphorylated signal transducer and activator of transcription 3 (STAT3) were determined by RNA sequencing, immunofluorescence and immunoblotting. Metabolites, including glycogen, NADPH, glutathione and reactive oxygen species (ROS), were analyzed by biochemical analysis. Results Here, we observed that astrocytic glycogen mobilization inhibited A1-like astrocytes and enhanced A2-like astrocytes after reperfusion in an experimental ischemic stroke model in vivo and in vitro. In addition, glycogen mobilization could enhance the production of NADPH and glutathione by the pentose phosphate pathway (PPP) and reduce ROS levels during reperfusion. NF-κB inhibition and STAT3 activation caused by a decrease in ROS levels were responsible for glycogen mobilization-induced A1-like and A2-like astrocyte transformation after I/R. The astrocytic A1/A2 paradigm is closely correlated with glycogen mobilization-mediated neuroprotection in cerebral reperfusion injury. Conclusions Our data suggest that ROS-mediated NF-κB inhibition and STAT3 activation are the key pathways for glycogen mobilization-induced neuroprotection and provide a promising metabolic target for brain reperfusion injury in ischemic stroke.

The Impact of Age on Mortality and Disability in Patients With Ischemic Stroke Who Underwent Cerebral Reperfusion Therapy: A Brazilian Cohort Study

Introduction: The main driver for increased stroke prevalence is the aging of the population; however, the best evidenced-based strategies for stroke treatment and prevention are not always followed for older patients. Therefore, the aim was studying the association of age with clinical outcomes (mortality and functional disability) in stroke patients who underwent cerebral reperfusion therapy at hospital discharge and 90 days after ictus.Methods: This was a retrospective (stroke databank analysis) cohort study of participants who had been diagnosed with ischemic stroke and undergone intravenous cerebral reperfusion therapy or mechanical thrombectomy. The variable of interest was patient age, which was categorized into four groups: (1) up to 59 years; (2) 60 to 69 years; (3) 70 to 79 years old; and (4) above 79 years. The primary outcome was mortality at hospital discharge and 90 days after stroke, and the secondary outcome was functional capacity at hospital discharge and 90 days after stroke.Results: A total of 281 patients was included in the study (235 treated by thrombolysis alone, and 46 treated with mechanical thrombectomy). The mean age of the total sample was 67 ± 13.1 years. The oldest patients had the most unfavorable outcomes, except for mortality rate, at hospital discharge (mRS &gt; 2; OR: 1.028; 95% CI 1.005 to 1.051; p = 0.017; mRS &gt; 3; OR: 1.043, 95% CI 1.018 to 1.069; p = 0.001) and 90 days after stroke (mRS &gt; 2; OR: 1.028; 95% CI 1.005 to 1.051; p = 0.017; mRS &gt; 3; OR: 1.043, 95% CI 1.018 to 1.069; p = 0.001).Conclusion: Cerebral reperfusion was a viable treatment for ischemic stroke in both elderly and very elderly patients, as it did not increase mortality. However, it was observed that older individuals had worse functional outcomes at hospital discharge and 90 days after stroke.

Abstract P833: Standardized Protocols Reduce Response Times for LVO Strokes

Introduction: Acute ischemic stroke treatment is time sensitive especially for large vessel occlusion (LVO) strokes with the goal to achieve early cerebral reperfusion. Research suggests standardized protocols incorporate early notification to reduce time from arrival to mechanical thrombectomy (MT). The MT workflow at a certified stroke center required multiple phone calls to mobilize staff and resources resulting in treatment delays. The average time from neurosurgery notification (NN) to case start (CST) was 60.4 minutes (min) resulting in average door-to-puncture (DTP) time of 124.8 min further delaying early reperfusion. Purpose: Standardize MT workflows and incorporate a 1-step notification system to reduce average NN to CST by 20% to 45 min to achieve 90 min average DTP time by 90 days post implementation. Methods: Baseline data for MT cases admitted 1/1/18 - 9/2/19 arriving in the emergency room (ER) and occurring inpatient were abstracted from stroke alert logs and the electronic health record. MT transfers were excluded. A multidisciplinary group of key stakeholders completed both high level process and workflow analysis maps and mock simulations to identify gaps. Both an analysis of variance and Tukey-Kramer’s T Test were performed revealing NN to CST was most statistically significant (p<.0001) and largest root cause for overall increased DTP times. New service-specific workflows were developed including 1-step notification activated via an existing group paging system used for other purposes. Activation notified on call staff of the MT case and patient location. Data points collected were NN to CST (ED and inpatient) and DTP (ED only). Results: Average NN to CST time was 26.7 min (33.3 min decrease or 55.1%; p<.0001, n=12) resulting in DTP average of 83.4 min (41.4 min decrease or 35.3%, n=10) 90 days post-implementation. The paging system was cost-neutral due to existing licensing agreements. Conclusion: In conclusion, streamlined workflows incorporating 1-step notification reduced time from notification to staff response so MT procedures could start sooner. A multidisciplinary approach along with key stakeholder buy-in was instrumental in successful project implementation.

Abstract P217: Direct Myosin-2 Inhibition Restores Cerebral Perfusion in Cortical and Subcortical Regions Resulting in Functional Improvement After Ischemic Stroke

Inefficient cerebral reperfusion is a major unresolved problem in ischemic stroke treatment because hypoxia-induced constriction of capillaries remains persistent even after recanalization by thrombolysis or thrombectomy. Capillary constriction is mediated by actomyosin contraction in precapillary smooth muscle cells (SMCs). We have developed and tested a formulation and administration technique to target the ischemic brain region and developed a promising small-molecule myosin-2 inhibitor (para-aminoblebbistatin (AmBleb) that mainly exerts its effect through direct inhibition of smooth muscle myosin-2 (SMM) in SMCs. The efficacy of SMM inhibition was tested in a rodent transient Middle Cerebral Artery Occlusion (tMCAO) stroke model. SMM was targeted by the direct administration of AmBleb into the ischemic region. AmBleb significantly accelerated the improvement of neurological deficits. Regional cerebral blood flow (rCBF) in the most important cortical and subcortical regions (e.g. motor- and somatosensory cortices, optic pathways, striatum, corpus callosum) showed drastic improvement in the AmBleb treated animals in line with the significant reduction of neurological deficits. We further optimized AmBleb and developed our lead compound MPH-222, which possesses significantly improved pharmacological properties than those of AmBleb. As observed with AmBleb, MPH-222 also fully relaxed isolated human and rat cerebral arterioles, and improved neurological functions of tMCAO operated rats characterized by significantly improved neurological deficits as well as enhanced locomotor symmetry. Moreover, as opposed to AmBleb, markedly lower MPH-222 dose was enough to achieve efficient concentrations in the ischemic region when catheter-based direct intra-arterial administration was applied. This result suggests that direct myosin inhibitor administration may be an optimal add-on therapy to thrombectomy. Funded by the Hungarian National Research, Development and Innovation Office (NVKP 16-1-2016-0051 and PIACI-KFI-2019-00488).

Improved Outcomes after Reperfusion Therapies for Ischemic Stroke: A “Real-world” Study in a Developing Country

Background: It is unknown if improvements in ischemic stroke (IS) outcomes reported after cerebral reperfusion therapies (CRT) in developed countries are also applicable to the “real world” scenario of low and middle-income countries. We aimed to measure the long-term outcomes of severe IS treated or not with CRT in Brazil. Methods: Patients from a stroke center of a state-run hospital were included. We compared the survival probability and functional status at 3 and 12 months in patients with severe IS treated or not with CRT. From 2010 to 2011, we performed intravenous reperfusion when patients arrived within 4.5 h time-window (IVT group) and after 2011, mechanical thrombectomy (MT) combined or not with intravenous alteplase (IAT group). Those who arrived >4.5 h in 2010-2011 and >6 h in 2012-2017 did not undergo CRT (NCRT group). Results: From 2010 to 2017, we registered 917 patients: 74% (677/917) in the NCRT group, 19% (178/917) in the IVT group and 7% (62/917) in the IAT group. Compared to the NCRT group, IVT patients had a 28% higher (HR: 0.72; 95% CI 0.53-0.96) 3-month adjusted probability of survival and risk of functional dependence was 19% lower (adjusted RR: 0.81; 95% CI 0.73-0.91). For those who underwent MT, the adjusted probability of survival was 59 % higher (HR: 0.41; 95% CI 0.21-0.77) and the risk of functional dependence was 21% lower (adjusted RR: 0.79; 95% CI 0.66-094). These outcomes remained significantly better throughout the first year. Conclusion: CRT led to better outcomes in patients with severe IS in Brazil.