Use of ABC/2 method for rapidly estimating the target mismatch on computed tomography perfusion imaging in patients with acute ischemic stroke

Background Target mismatch (ischemic core, mismatch volume and mismatch ratio) in patients with acute ischemic stroke (AIS) highly relies on the automated perfusion analysis software. Purpose To evaluate the feasibility and accuracy of using the ABC/2 method to rapidly estimate the target mismatch on computed tomography perfusion (CTP) imaging in patients with AIS, using RAPID results as a reference. Material and Methods In total, 243 patients with anterior circulation AIS who underwent CTP imaging were retrospectively reviewed. Target mismatch associated perfusion parameters were derived from RAPID results and calculated using the ABC/2 method. Paired t-test was used to assess the difference of volumetric parameters between the two methods. The ability of using the ABC/2 method to predict the important cutoff volumetric metrics was also evaluated. Result There was no significant difference in the volumes of ischemic core ( P = 0.068), ischemic area ( P = 0.209), and mismatch volume ( P = 0.518) between ABC/2 and RAPID. Using RAPID results as reference, the ABC/2 method showed high accuracy for predicting perfusion parameters (70 mL and 90 mL: sensitivity=98.5% and 98.5%, specificity=100% and 100%, positive predictive value [PPV]=100% and 100%, negative predictive value [NPV]=93.8% and 92.9%; 10 mL and 15mL: sensitivity=99.6% and 99.5%, specificity=55.6% and 50.0%, PPV=96.6% and 94.8%, NPV=90.9% and 92.3%; 1.2 and 1.8: sensitivity=99.6% and 94.8%, specificity=75.0% and 96.9%, PPV=98.7% and 99.5%, NPV=90.0% and 73.8%). Conclusion The ABC/2 method may be a feasible alternative to RAPID for estimation of target mismatch parameters on CTP in patients with AIS.

Effect of early Sanguinate (PEGylated carboxyhemoglobin bovine) infusion on cerebral blood flow to the ischemic core in experimental middle cerebral artery occlusion

BackgroundSanguinate, a bovine PEGylated carboxyhemoglobin-based oxygen carrier with vasodilatory, oncotic and anti-inflammatory properties designed to release oxygen in hypoxic tissue, was tested to determine if it improves infarct volume, collateral recruitment and blood flow to the ischemic core in hyperacute middle cerebral artery occlusion (MCAO).MethodsUnder an IACUC approved protocol, 14 mongrel dogs underwent endovascular permanent MCAO. Seven received Sanguinate (8 mL/kg) intravenously over 10 min starting 30 min following MCAO and seven received a similar volume of normal saline. Relative cerebral blood flow (rCBF) was assessed using neutron-activated microspheres prior to MCAO, 30 min following MCAO and 30 min following intervention. Pial collateral recruitment was scored and measured by arterial arrival time (AAT) immediately prior to post-MCAO microsphere injection. Diffusion-weighted 3T MRI was used to assess infarct volume approximately 2 hours after MCAO.ResultsMean infarct volumes for control and Sanguinate-treated subjects were 4739 mm3 and 2585 mm3 (p=0.0443; r2=0.687), respectively. Following intervention, rCBF values were 0.340 for controls and 0.715 in the Sanguinate group (r2=0.536; p=0.0064). Pial collateral scores improved only in Sanguinate-treated subjects and AAT decreased by a mean of 0.314 s in treated subjects and increased by a mean of 0.438 s in controls (p<0.0276).ConclusionPreliminary results indicate that topload bolus administration of Sanguinate in hyperacute ischemic stroke significantly improves infarct volume, pial collateral recruitment and CBF in experimental MCAO immediately following its administration.

Comparison of Two Automated Computed Tomography Perfusion Applications to Predict the Final Infarct Volume After Thrombolysis in Cerebral Infarction 3 Recanalization

Background and Purpose: Several automated computed tomography perfusion software applications have been developed to provide support in the definition of ischemic core and penumbra in acute ischemic stroke. However, the degree of interchangeability between software packages is not yet clear. Our study aimed to evaluate 2 commonly used automated perfusion software applications (Syngo.via and RAPID) for the indication of ischemic core with respect to the follow-up infarct volume (FIV) after successful recanalization and with consideration of the clinical impact. Methods: Retrospectively, 154 patients with large vessel occlusion of the middle cerebral artery or the internal carotid artery, who underwent endovascular therapy with a consequent Thrombolysis in Cerebral Infarction 3 result within 2 hours after computed tomography perfusion, were included. Computed tomography perfusion core volumes were assessed with both software applications with different thresholds for relative cerebral blood flow (rCBF). The results were compared with the FIV on computed tomography within 24 to 36 hours after recanalization. Bland-Altman was applied to display the levels of agreement and to evaluate systematic differences. Results: Highest correlation between ischemic core volume and FIV without significant differences was found at a threshold of rCBF<38% for the RAPID software ( r =0.89, P <0.001) and rCBF<25% for the Syngo software ( r =0.87, P <0.001). Bland-Altman analysis revealed best agreement in these settings. In the vendor default settings (rCBF<30% for RAPID and rCBF<20% for Syngo) correlation between ischemic core volume and FIV was also high (RAPID: r =0.88, Syngo: r =0.86, P <0.001), but mean differences were significant ( P <0.001). The risk of critical overestimation of the FIV was higher with rCBF<38% (RAPID) and rCBF<25% (Syngo) than in the default settings. Conclusions: By adjusting the rCBF thresholds, comparable results with reliable information on the FIV after complete recanalization can be obtained both with the RAPID and Syngo software. Keeping the software specific default settings means being more inclusive in patient selection, but forgo the highest possible accuracy in the estimation of the FIV.

Collateral Circulation Augmentation and Neuroprotection as Adjuvant to Mechanical Thrombectomy in Acute Ischemic Stroke

Purpose of the ReviewMechanical thrombectomy (MT)–mediated endovascular recanalization has dramatically transformed treatment and outcomes after acute ischemic stroke caused by a large vessel occlusion (LVO). Current guidelines recommend MT up to 24 hours from stroke onset in carefully selected patients based on favorable clinical and imaging parameters. Despite optimal patient selection and low complication rates with current recanalization technology, approximately 1 in 2 patients with LVO stroke do not achieve functional independence at 3 months. This ceiling effect of MT efficacy may be explained by ischemic core expansion into the ischemic penumbra before recanalization and neuronal loss occurring after recanalization. Factors affecting the efficacy of MT, or the degree of irreversible injury, include time from symptom onset to recanalization, collateral circulation status, and differences in neuronal vulnerability. The purpose of this brief review is to discuss potential targets for neuroprotection, present and future potential pharmacologic and nonpharmacologic agents, and the data available in the literature.Recent FindingsIn experimental ischemia models, several authors reported that pharmacologic and nonpharmacologic agents are able to slow the progression of ischemic core expansion. However, in the era of unsuccessful recanalization of the occluded artery, several neuroprotective agents that were promising in the preclinical stage failed phase II/III clinical trials.SummaryProviding neuroprotection before and after recanalization of an LVO may play an important role in improving outcomes in the era of MT. Neuroprotection is classically defined as a process that results in the salvage, recovery, or regeneration of neuronal (and other supporting CNS cell) structure or function. The advent of successful recanalization of acute LVO by MT in the majority of patients may spur the growth of effective neuroprotection.

Abstract 1122‐000167: Hyperintense Acute Reperfusion Marker and Hemorrhagic Conversion in Stroke Patients Undergoing Mechanical Reperfusion

Introduction : Endovascular thrombectomy (EVT) is a highly effective treatment to improve clinical outcome in patients with acute ischemic stroke due to large vessel occlusion (AIS‐LVO). However, blood‐brain barrier (BBB) disruption causing hemorrhagic transformation and reperfusion injury can potentially negate the beneficial effect of reperfusion. Studying determinants, frequency, and outcomes of the hyperintense acute reperfusion marker (HARM) sign, a biomarker of BBB disruption, would help to identify individual patients at increased risk, as well as developing therapies to prevent BBB breakdown. Methods : In consecutive AIS‐LVO patients with AIS‐LVO who underwent EVT followed by MRI within the next 24 hours, we evaluated frequency, determinants, and outcomes of HARM sign. Results : Among 81 patients meeting study criteria, age was 71.0 (SD 19.7), 58% female, mean NIHSS was 14.5 (SD 6.8), and time from last known well to treatment was 355 min (IQR 206.5 ‐ 664). HARM sign was observed in 64% (52/81) of patients. On multivariate logistic analysis, presence of HARM sign was independently associated with greater periventricular white matter hyperintensity, higher pre‐EVT ischemic core volume, more proximal target vessel occlusion, and achievement of successful reperfusion or better. Hemorrhagic conversion was seen in 31.8% of patients with HARM sign and 26.7% of patients without HARM sign. Multivariate analysis identified higher blood glucose, lower ASPECT, score and greater post‐EVT ischemic core volume as independent predictors of hemorrhagic conversion. HARM sign was identified to correlate with poor clinical outcome in bivariate analysis, but multivariate analysis only identified less neurological deficits, lower baseline systolic BP, lower degree of periventricular white matter hyperintensities, shorter time to device deployment and reduced post EVT ischemic core volume as independent predictors of good clinical outcome (mRS 0–2) upon discharge. Conclusions : The HARM sign indicating disruption of the blood‐brain barrier following EVT is common, present in about 6 of every 10 treated patients. Independent risk factors for HARM sign are chronic ischemic microangiopathy, greater acute ischemic core, and successful reperfusion. HARM sign presence is associated with worse functional outcome.

Low Baseline Ischemic Water Uptake is Directly Related to Overestimation of CT Perfusion-Derived Ischemic Core Volume

Background Computed-tomography perfusion (CTP) is frequently used to screen acute ischemic stroke (AIS) patients for endovascular treatment (EVT), despite known problems with ischemic “core” overestimation. This potentially leads to the unfair exclusion of patients from EVT. We propose that net water uptake (NWU) can be used in addition to CTP to more accurately assess the extent and/or stage of tissue infarction. Methods Patients treated for AIS between 06/2015-07/2020 were retrospectively analyzed. Baseline CTP-derived core volume (pCore) and NWU were determined. Logistic regression tested the relationship between baseline clinical and imaging variables and core-overestimation (primary outcome). The secondary outcomes comprised 90-day functional independence (modified Rankin score) and lesion growth. Results 284 patients were included. Median NWU was 7.2% (IQR:2.6–12.8). ASPECTS (RR:1.28,95%CI:1.09-1.51), NWU (RR:0.94,95%CI:0.89-0.98), onset to recanalization (RR:1.00,95%CI:0.99-1.00) and imaging (RR:1.00,95%CI1.00-1.00) times, and pCore (RR:1.02,95%CI:1.01-1.02) were significantly associated with core overestimation. Core-overestimation was more likely to occur in patients with large pCores and low NWU at baseline. NWU was significantly correlated with lesion growth. Conclusion NWU can be used as a supplemental tool to CTP during admission imaging to more accurately assess the extent of ischemia, particularly relevant for patients with large CTP-defined cores who would otherwise be excluded from treatment.

Relevance of Brain Regions’ Eloquence Assessment in Patients With a Large Ischemic Core Treated With Mechanical Thrombectomy

ObjectiveIndividualized patient selection for mechanical thrombectomy (MT) in patients with acute ischemic stroke (AIS) and large ischemic core (LIC) at baseline is an unmet need.We tested the hypothesis, that assessing the functional relevance of both the infarcted and hypo-perfused brain tissue, would improve the selection framework of patients with LIC for MT.MethodsMulticenter, retrospective, study of adult with LIC (ischemic core volume > 70ml on MR-DWI), with MRI perfusion, treated with MT or best medical management (BMM).Primary outcome was 3-month modified-Rankin-Scale (mRS), favourable if 0-3. Global and regional-eloquence-based core-perfusion mismatch ratios were derived. The predictive accuracy for clinical outcome of eloquent regions involvement was compared in multivariable and bootstrap-random-forest models.ResultsA total of 138 patients with baseline LIC were included (MT n=96 or BMM n=42; mean age±SD, 72.4±14.4years; 34.1% females; mRS=0-3: 45.1%). Mean core and critically-hypo-perfused volume were 100.4ml±36.3ml and 157.6±56.2ml respectively and did not differ between groups. Models considering the functional relevance of the infarct location showed a better accuracy for the prediction of mRS=0-3 with a c-Statistic of 0.76 and 0.83 for logistic regression model and bootstrap-random-forest testing sets respectively. In these models, the interaction between treatment effect of MT and the mismatch was significant (p=0.04). In comparison in the logistic regression model disregarding functional eloquence the c-Statistic was 0.67 and the interaction between MT and the mismatch was insignificant.ConclusionConsidering functional eloquence of hypo-perfused tissue in patients with a large infarct core at baseline allows for a more precise estimation of treatment expected benefit.

Mechanical Thrombectomy in Patients with a Large Ischemic Volume at Presentation: Systematic Review and Meta-Analysis

The benefits of mechanical thrombectomy (MT) for patients with acute ischemic stroke (AIS) and a large ischemic core (LIC) at presentation are uncertain. We aimed to obtain up-to-date aggregate estimates of the outcomes following MT in patients with volumetrically assessed LIC. We conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-conformed, PROSPERO-registered, systematic review and meta-analysis of studies that included patients with AIS and a baseline LIC treated with MT, reported ischemic core volume quantitatively, and included patients with a LIC defined as a core volume ≥50 mL. The search was restricted to studies published between January 2015 and June 2020. Random-effects-meta-analysis was used to assess the effect of MT on 90-day unfavorable outcome (i.e., modified Rankin Scale [mRS] 3–6), mortality, and symptomatic intracranial hemorrhage (sICH) occurrence. Sensitivity analyses were performed for imaging-modality (computed tomography-perfusion or magnetic resonance-diffusion weighted imaging) and LIC-definition (≥50 or ≥70 mL). We analyzed 10 studies (954 patients), including six (682 patients) with a control group, allowing to compare 332 patients with MT to 350 who received best-medical-management alone. Overall, after MT the rate of patients with mRS 3–6 at 90 days was 74% (99% confidence interval [CI], 67 to 84; Z-value=7.04; I2=92.3%) and the rate of 90-day mortality was 36% (99% CI, 33 to 40; Z-value=–7.07; I2=74.5). Receiving MT was associated with a significant decrease in mRS 3–6 odds ratio (OR) 0.19 (99% CI, 0.11 to 0.33; P<0.01; Z-value=–5.92; I2=62.56) and in mortality OR 0.60 (99% CI, 0.34 to 1.06; P=0.02; Z-value=–2.30; I2=58.72). Treatment group did not influence the proportion of patients experiencing sICH, OR 0.96 (99% CI, 0.2 to 1.49; P=0.54; Z-value=–0.63; I2=64.74). Neither imaging modality for core assessment, nor LIC definition influenced the aggregated outcomes. Using aggregate estimates, MT appeared to decrease the risk of unfavorable functional outcome in patients with a LIC assessed volumetrically at baseline.

Temporal and Spatial Expression Characteristics of MiR-155 and Rheb/mTOR Signaling Pathway in Ischemia–Reperfusion Injury of Rats

Backgrouds: Stroke is the second most prevalent cause of death and the first cause of longterm disability worldwide. Inhibition of miR-155 was found playing a protective role in ischemic stroke, one possible mechanism was regulating Ras-homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) pathway. For possible specific intervention strategy, further exploring the expression characteristics of miR-155 and mRNAs of the Rheb/mTOR pathway in ischemic stroke is neccesary. Results: Our results demonstrated that the infarction volume decreased with the prolongation of the reperfusion in the MCAO/R model rats (P < 0.05). Meanwhile, the miR155 expression obviously increased in both the ischemic core and the ischemic penumbra (IP) area of the model rats, but this trend weakened as the reperfusion time increased. Besides, the expression of mRNAs of Rheb, mTOR, S6kb1, and 4Ebp1 seemed to increase in both the ischemic core and the IP area of the model rats.Interestingly, the mRNA level of S6kb1 obviously increased of all model groups in both the ischemic core and the IP area (P < 0.05),while the mRNA levels of Rheb, mTOR, and 4Ebp1 increased in the first 24 h and rapidly decreased after 48 h and as a result, a statistically significant difference was found only in the 48-h group (P < 0.05). Conclusion: Along with the shrinked infarct volume, the levels of miR-155 decreased and the S6kb1 mRNA level increased as the leghtening of re-perfusion, as to the mRNA levels of Rheb, mTOR, and 4Ebp1,statistical significance was found only in the 48-h group. Unexpectedly, there was no difference between the ischemic core and the IP area for all the above molecules.Indicating that intervention measures targeting to miR155 should be taken systemicly as early as possible after stroke onset,especially within the early 48 hours.

Automated Perfusion-Diffusion Magnetic Resonance Imaging in Childhood Arterial Ischemic Stroke

Background and Purpose: Recent studies using automated perfusion imaging software have identified adults most likely to benefit from reperfusion therapies in extended time windows. The time course of penumbral tissue is poorly characterized in childhood arterial ischemic stroke (AIS). We explore the feasibility of using automated perfusion-diffusion imaging software to characterize penumbra in childhood AIS. Methods: An observational cohort study of children with acute unilateral AIS presenting to our institution. Diffusion-weighted imaging and dynamic susceptibility contrast perfusion magnetic resonance imaging performed within 72 hours of symptom onset were necessary for inclusion. Perfusion-diffusion mismatch was estimated using RAPID software. Ischemic core was defined as apparent diffusion coefficient <620×10 −6 mm 2 /s and hypoperfusion as Tmax >6 seconds. Favorable mismatch profile was defined as core volume <70 mL, mismatch volume ≥15 mL, and a mismatch ratio ≥1.8. Results: Twenty-nine children (median 8 years old, interquartile range, 4.4–14.6) were included (26 unilateral middle cerebral artery and 3 unilateral cerebellar infarcts). Median Pediatric National Institutes of Health Stroke Scale was 4 (interquartile range, 3–11). Most cases had cryptogenic (n=11) or focal cerebral arteriopathy (n=9) causes. Median time-to-imaging =13.7 hours (interquartile range, 7.5–25.3). RAPID detected an ischemic core in 19 (66%) patients. In the remaining cases, the mean apparent diffusion coefficient values were mostly higher than the threshold as the majority of these presentations were delayed (median >21 hours) and infarct volumes were small (<3.5 mL). Overall, 3 children, imaged at 3.75, 11, and 23.5 hours had favorable mismatch profiles. Conclusions: This study demonstrates it is feasible to rapidly assess perfusion-diffusion mismatch in childhood AIS using automated software. Favorable mismatch profiles, using adult-based parameters, persisted beyond the standard 4.5 hours window for thrombolysis, suggesting potential therapeutic benefit of RAPID use. Further work is required to determine the utility of perfusion-based imaging to guide clinical decision making, whether adult thresholds require modification in childhood AIS, and to investigate the effect of time-delay and cause on mismatch characteristics.