Salvageable Penumbra Research Articles

Multiparametric Model for Penumbral Flow Prediction in Acute Stroke.

Identification of salvageable penumbra tissue by dynamic susceptibility contrast magnetic resonance imaging is a valuable tool for acute stroke patient stratification for treatment. However, prior studies have not attempted to combine the different perfusion maps into a predictive model. In this study, we established a multiparametric perfusion imaging model and cross-validated it using positron emission tomography perfusion for detection of penumbral flow. In a retrospective analysis of 17 subacute stroke patients with consecutive magnetic resonance imaging and H2O15 positron emission tomography scans, perfusion maps of cerebral blood flow, cerebral blood volume, mean transit time, time-to-maximum, and time-to-peak were constructed and combined using a generalized linear model (GLM). Both the GLM maps and the single perfusion maps alone were cross-validated with positron emission tomography-cerebral blood flow scans to predict penumbral flow on a voxel-wise level. Performance was tested by receiver-operating characteristics curve analysis, that is, the area under the curve, and the models' fits were compared using the likelihood ratio test. The GLM demonstrated significantly improved model fit compared with each of the single perfusion maps (P<1×e-5) and demonstrated higher performance, with an area under the curve of 0.91. However, the absolute difference between the performance of GLM and the best-performing single perfusion parameter (time-to-maximum) was relatively low (area under the curve difference =0.04). Our results support a dynamic susceptibility contrast magnetic resonance imaging-based GLM as an improved model for penumbral flow prediction in stroke patients. With given perfusion maps, this model is a straightforward and observer-independent alternative for therapy stratification.

Optimal thresholds for ischemic penumbra predicted by computed tomography perfusion in patients with acute ischemic stroke treated with mechanical thrombectomy

Background and purposeOptimal thresholds for ischemic penumbra detected by CT perfusion (CTP) in patients with acute ischemic stroke (AIS) have not been elucidated. In this study we investigated optimal thresholds...

Penumbral salvage and thrombolysis outcome: a drop of brain, a week of life.

Penumbral salvage and thrombolysis outcome: a drop of brain, a week of life.

Abstract WP248: Pre-treatment Perfusion CT in Stroke Thrombolysis Can Predict Disability-free Life

Introduction: Stroke shortens an individual’s disability-free life. We aimed to assess the relative prognostic influence of pre- and post-treatment perfusion CT imaging variables (e.g. ischemic core and penumbral volumes) compared to standard clinical predictors (such as onset-to-treatment time) on long-term stroke disability in patients undergoing thrombolysis. Methods: We used data from a prospectively collected international, multicenter, observational registry of acute ischemic stroke patients who had perfusion CT and CT angiography before treatment with intravenous alteplase. Baseline perfusion CT and follow-up MRI were analysed to derive the baseline penumbra volume, baseline ischemic core volume, and penumbra salvaged from infarction. The primary outcome measure was the effect of imaging and clinical variables on disability-adjusted life years (DALY). Clinical variables were age, sex, NIHSS score, and onset-to-treatment time. Age, sex, country, and 3-month modified Rankin Scale were extracted from the registry to calculate DALY due to stroke, such that one year of DALY equates to 1 year of healthy life lost due to stroke. Results: Seven hundred seventy two patients were treated with alteplase therapy. 17.5 DALY-days were lost per 1 mL of baseline ischemic core volume (95%CI, 13.2 - 21.9 days, p &lt; 0.001). For every mL of penumbra salvaged, 7.2 days of DALY-days were saved (95%CI, 4.1 - 10.4 days, p &lt; 0.001). Each minute of earlier onset-to-treatment time resulted in a saving of 4.4 disability-free days after stroke (1.3 - 7.5 days, p = 0.006). However, after adjustment for imaging variables, onset-to-treatment time was not significantly associated with savings in DALY-days. Conclusions: Pre-treatment perfusion CT scan defined penumbra (independently of clinical variables) predict significant gains, or loss, of disability-free life in patients undergoing reperfusion therapy for stroke. The effect of earlier treatment on disability-free life appears explained by salvage of penumbra.

Perfusion computed tomography in patients with stroke thrombolysis.

See Saver (doi:10.1093/awx020) for a scientific commentary on this article.Stroke shortens an individual's disability-free life. We aimed to assess the relative prognostic influence of pre- and post-treatment perfusion computed tomography imaging variables (e.g. ischaemic core and penumbral volumes) compared to standard clinical predictors (such as onset-to-treatment time) on long-term stroke disability in patients undergoing thrombolysis. We used data from a prospectively collected international, multicentre, observational registry of acute ischaemic stroke patients who had perfusion computed tomography and computed tomography angiography before treatment with intravenous alteplase. Baseline perfusion computed tomography and follow-up magnetic resonance imaging were analysed to derive the baseline penumbra volume, baseline ischaemic core volume, and penumbra salvaged from infarction. The primary outcome measure was the effect of imaging and clinical variables on Disability-Adjusted Life Year. Clinical variables were age, sex, National Institutes of Health Stroke Scale score, and onset-to-treatment time. Age, sex, country, and 3-month modified Rankin Scale were extracted from the registry to calculate disability-adjusted life-year due to stroke, such that 1 year of disability-adjusted life-year equates to 1 year of healthy life lost due to stroke. There were 772 patients receiving alteplase therapy. The number of disability-adjusted life-year days lost per 1 ml of baseline ischaemic core volume was 17.5 (95% confidence interval, 13.2-21.9 days, P < 0.001). For every millilitre of penumbra salvaged, 7.2 days of disability-adjusted life-year days were saved (β = -7.2, 95% confidence interval, -10.4 to -4.1 days, P < 0.001). Each minute of earlier onset-to-treatment time resulted in a saving of 4.4 disability-free days after stroke (1.3-7.5 days, P = 0.006). However, after adjustment for imaging variables, onset-to-treatment time was not significantly associated with savings in disability-adjusted life-year days. Pretreatment perfusion computed tomography can (independently of clinical variables) predict significant gains, or loss, of disability-free life in patients undergoing reperfusion therapy for stroke. The effect of earlier treatment on disability-free life appears explained by salvage of penumbra, particularly when the ischaemic core is not too large.

Investigating potentially salvageable penumbra tissue in an in vivo model of transient ischemic stroke using sodium, diffusion, and perfusion magnetic resonance imaging.

Background Diffusion magnetic resonance imaging (MRI) is the current-state-of-the-art technique to clinically investigate acute (0–24 h) ischemic stroke tissue. However, reduced apparent diffusion coefficient (ADC)—considered a marker of tissue damage—was observed to reverse spontaneously during the subacute stroke phase (24–72 h) which means that low ADC cannot be used to reflect the damaged tissue after 24 h in experimental and clinical studies. One reason for the change in ADC is that ADC values drop with cytotoxic edema (acute phase) and rise when vasogenic edema begins (subacute phase). Recently, combined 1H- and 23Na-MRI was proposed as a more accurate approach to improve delineation between reversible (penumbra) and irreversible ischemic injury (core). The aim of this study was to investigate the effects of reperfusion on the ADC and the sodium MRI signal after experimental ischemic stroke in rats in well-defined areas of different viability levels of the cerebral lesion, i.e. core and penumbra as defined via perfusion and histology. Transient middle cerebral artery occlusion was induced in male rats by using the intraluminal filament technique. MRI sodium, perfusion and diffusion measurement was recorded before reperfusion, shortly after reperfusion and 24 h after reperfusion. The animals were reperfused after 90 min of ischemia.ResultsSodium signal in core did not change before reperfusion, increased after reperfusion while sodium signal in penumbra was significantly reduced before reperfusion, but showed no changes after reperfusion compared to control. The ADC was significantly decreased in core tissue at all three time points compared to contralateral side. This decrease recovered above commonly applied viability thresholds in the core after 24 h.ConclusionsReduced sodium-MRI signal in conjunction with reduced ADC can serve as a viability marker for penumbra detection and complement hydrogen diffusion- and perfusion-MRI in order to facilitate time-independent assessment of tissue fate and cellular bioenergetics failure in stroke patients.

Theophylline as an add-on to thrombolytic therapy in acute ischaemic stroke (TEA-Stroke): A randomized, double-blinded, placebo-controlled, two-centre phase II study.

Early reperfusion of brain tissue at risk of injury (penumbra salvage) is crucial in treating acute ischaemic stroke. Neuroprotective agents may extend the time window for the reperfusion. The vasoactive agent theophylline redistributes the perfusion to ischaemic brain tissue and thus reduces brain damage, brain tissue oedema and mortality in animal stroke models. Furthermore, treatment with theophylline has been shown to result in considerable and rapid clinical improvement, albeit only temporary, in some stroke patients.We hypothesize that treatment with theophylline will improve the collateral supply in acute ischaemic brain tissue and thus facilitate reperfusion despite proximal vessel occlusion. The primary study objective is to evaluate whether theophylline is safe and efficient in acute ischaemic stroke patients as an add-on to thrombolytic therapy. The TEA-Stroke Trial is a two-centre, proof of concept phase II clinical study with a randomized, double-blinded, placebo-controlled design. One hundred and twenty patients with acute ischaemic stroke and significant perfusion-diffusion mismatch, as determined by magnetic resonance imaging, are randomized 1:1 to either theophylline or placebo as an add-on to standard thrombolytic therapy. The dual primary outcome measures include penumbra salvage (penumbral tissue not developing into infarcted tissue) and clinical improvement at the 24-h follow-up. Results from studies of theophylline in stroke animal models, clinical case series and randomized clinical trials are controversial. A Cochrane analysis from 2004 concluded that there was not enough evidence to assess whether theophylline is safe and improves outcomes in patients with acute ischaemic stroke. The TEA-Stroke Trial will clarify whether theophylline as an add-on to standard thrombolytic therapy improves penumbra salvage with a reduced risk of reperfusion damage, reduced final infarct size, and improved clinical outcome.

Baseline collateral status and infarct topography in post-ischaemic perilesional hyperperfusion: An arterial spin labelling study

Focal hyperperfusion after acute ischaemic stroke could be of prognostic value depending upon its spatial localisation and temporal dynamics. Factors associated with late stage (12–24 h) perilesional hyperperfusion, identified using arterial spin labelling, are poorly defined. A prospective cohort of acute ischaemic stroke patients presenting within 4.5 h of symptom onset were assessed with multi-modal computed tomography acutely and magnetic resonance imaging at 24 ± 8 h. Multivariate logistic regression analysis and receiver operating characteristics curves were used. One hundred and nineteen hemispheric acute ischaemic stroke patients (mean age = 71 ± 12 years) with 24 h arterial spin labelling imaging were included. Forty-two (35.3%) patients showed perilesional hyperperfusion on arterial spin labelling at 24 h. Several factors were independently associated with perilesional hyperperfusion: good collaterals (71% versus 29%, P < 0.0001; OR = 5, 95% CI = [1.6, 15.7], P = 0.005), major reperfusion (81% versus 48%, P = < 0.0001; OR = 7.5, 95% CI = [1.6, 35.1], P = 0.01), penumbral salvage (76.2% versus 47%, P = 0.002; OR = 6.6, 95% CI = [1.8, 24.5], P = 0.004), infarction in striatocapsular (OR = 9.5, 95% CI = [2.6, 34], P = 0.001) and in cortical superior division middle cerebral artery (OR = 4.7, 95% CI = [1.4, 15.7], P = 0.012) territory. The area under the receiver operating characteristic curve was 0.91. Our results demonstrate good arterial collaterals, major reperfusion, penumbral salvage, and infarct topographies involving cortical superior middle cerebral artery and striatocapsular are associated with perilesional hyperperfusion.

Abstract WP244: How Many Potential Mechanical Thrombectomy Patients Are Missed Because of Emergency Medical Systems Transport Windows of 4.5 Hours or Less Since Last Known Normal in the Field?

Intro: Many EMS transport protocols exclude patients last known normal (LKN) &gt;4.5 or &gt;6 hours from transport to Comprehensive Stroke Center (CSC) as acute stroke codes. Because recent Mechanical Thrombectomy (MET) studies enrolled few patients last known normal (LKN) &gt; 6 hours prior to imaging, the incidence of CTP or ASPECTS suggesting possible benefit from MET in this time window for Large Vessel Occlusion (LVO) ischemic stroke is unclear. Method: Through retrospective review of a prospective database, the percentage of LVO patients with ASPECTS or CTP suggesting possible benefit from MET, defined as ASPECTS score &gt;5 or salvageable penumbra and &lt;70ml ischemic core on CTP, was compared between a group of 42 patients imaged &gt; 6 hours since LKN and 106 patients imaged &lt;6 hours since LKN. Results: 33% (14 of 42) of LVO patients LKN &gt; 6 hours at time of CTP imaging (median 8 hours, range 6-20 hrs) received MET based on favorable CTP imaging and disabling clinical deficits. This was not statistically significantly different than the 40.5% (43 of 106) of LVO patients LKN &lt; 6 hours at time of CTP imaging (median 128 min) that received MET based on same criteria (OR 95% CI, 0.73 0.34 – 1.55; P=0.42). The LKN &gt; 6 hour MET patients (median NIHSS 18) had a trend towards less frequent favorable home or rehab discharge destination than the LKN &lt; 6 hour MET patients (median NIHSS 16) (29% vs 57%, OR 0.3040, 95 % CI: 0.08 to 1.12, P = 0.07). There were no significant differences between the &gt; 6 hour and &lt;6 hour groups in factors associated with poor outcome after intervention or poor collateral circulation: median ASPECTS score (9 for both), percentage of ASPECTS scores &gt;5 (80% vs 90%, p=0.31) median age (74 for both), ED glucose &gt;150 mg/dl (16.6% vs 23.5%, p= 0.51), Atrial fibrillation (38% vs 37%). With a 30 minute door-to-CTP time, a &lt; 4.5 hour LKN EMS transport policy would have excluded 24.5% of patients who received MET at our CSC. 6, 8, 10 and 13 hour LKN EMS transport windows would have excluded 11%, 9%, 2% and 0% MET intervention patients respectively. Conclusion: &lt; 4.5 hour LKN EMS transport protocols may exclude a significant number of LVO patients with CTP and ASPECTS results possibly suitable for MET. These data need to be confirmed with a prospective multicenter study.

Oxygen or cooling, to make a decision after acute ischemia stroke.

The presence of a salvageable penumbra, a region of ischemic brain tissue with sufficient energy for short-term survival, has been widely agreed as the premise for thrombolytic therapy with tissue plasminogen activator (tPA), which remains the only United States Food and Drug Administration (FDA) approved treatment for acute ischemia stroke. However, the use of tPA has been profoundly constrained due to its narrow therapeutic time window and the increased risk of potentially deadly hemorrhagic transformation (HT). Blood brain barrier (BBB) damage within the thrombolytic time window is an indicator for tPA-induced HT and both normobaric hyperoxia (NBO) and hypothermia have been shown to protect the BBB from ischemia/reperfusion injury. Therefore, providing the O2 as soon as possible (NBO treatment), freezing the brain (hypothermia treatment) to slow down ischemia-induced BBB damage or their combined use may extend the time window for the treatment of tPA. In this review, we summarize the protective effects of NBO, hypothermia or their use combined with tPA on ischemia stroke, based on which, the combination of NBO and hypothermia may be an ideal early stroke treatment to preserve the ischemic penumbra. Given this, there is an urge for large randomized controlled trials to address the effect.

Very Early Carotid Endarterectomy After Intravenous Thrombolysis

The timing of carotid endarterectomy (CEA) after thrombolysis is still a matter of debate. The aim of this study was to analyse a cohort of patients undergoing urgent endarterectomy after intravenous thrombolysis for acute ischaemic stroke. This was an observational study. Prospective databases were reviewed and matched to identify patients who underwent CEA early after intravenous thrombolysis (2009-14). The focus was carotid surgery performed within 12 hours of stroke onset in patients with a high grade (≥70%) symptomatic carotid stenosis, associated with vulnerable plaques or stroke in evolution, and evidence of a significant salvageable ischaemic penumbra on perfusion computed tomography scan. Demographic and clinical information, as well as data on relevant outcomes were extracted. Thirty four consecutive stroke patients who underwent CEA within 2 weeks of thrombolysis for acute ischaemic stroke and ipsilateral high grade carotid stenosis were identified. In 11 patients the surgical procedure was performed within 12 hours of the onset of symptoms. All patients showed a clinical improvement after combined treatment. The 3 month outcome was favourable (modified Rankin Scale≤2) in 10 patients. No haemorrhagic complications were registered. There was neither peri-operative stroke nor stroke within 3 months of surgery. One patient died from acute myocardial infarction 3 days after intervention. This experience suggests that very early CEA after thrombolysis, aimed at removing the source of potential embolisation and restoring blood flow, may be safe and can lead to a favourable outcome.

Collateral Circulation Predicts the Size of the Infarct Core and the Proportion of Salvageable Penumbra in Hyperacute Ischemic Stroke Patients Treated with Intravenous Thrombolysis

Background: We studied the impact of collateral circulation on CT perfusion (CTP) parametric maps and the amount of salvaged brain tissue, the imaging and clinical outcome at 24 h and at 3 months in a retrospective acute (<3 h) stroke cohort (105 patients) with anterior circulation thrombus treated with intravenous thrombolysis. Methods: Baseline clinical and imaging information were collected and groups with different collateral scores (CS) were compared. Binary logistic regression analyses using good CS (CS ≥2) as the dependent variable were calculated. Results: CTP Alberta Stroke Program Early CT Score (ASPECTS) was successfully assessed in 58 cases. Thirty patients displayed good CS. Poor CS were associated with more severe strokes according to National Institutes of Health Stroke Scale (NIHSS) at arrival (15 vs. 7, p = 0.005) and at 24 h (10 vs. 3, p = 0.003) after intravenous thrombolysis. Good CS were associated with a longer mean onset-to-treatment time (141 vs. 121 min, p = 0.009) and time to CTP (102 vs. 87 min, p = 0.047), better cerebral blood volume (CBV) ASPECTS (9 vs. 6, p < 0.001), better mean transit time (MTT) ASPECTS (6 vs. 3, p < 0.001), better noncontrast CT (NCCT) ASPECTS (10 vs. 8, p < 0.001) at arrival and with favorable clinical outcome at 3 months (modified Rankin Scale ≤2, p = 0.002). The fraction of penumbra that was salvageable at arrival and salvaged at 24 h was higher with better CS (p < 0.001 and p = 0.035, respectively). In multivariate analysis, time from the onset of symptoms to imaging (p = 0.037, OR 1.04 per minute, 95% CI 1.00-1.08) and CBV ASPECTS (p = 0.001, OR 2.11 per ASPECTS point, 95% CI 1.33-3.34) predicted good CS. In similar multivariable models, MTT ASPECTS (p = 0.04, OR 1.46 per ASPECTS point, 95% CI 1.02-2.10) and NCCT ASPECTS predicted good CS (p = 0.003, OR 4.38 per CT ASPECTS point, 95% CI 1.66-11.55) along with longer time from the onset of symptoms to imaging (p = 0.045, OR 1.03 per minute, 95% CI 1.00-1.06 and p = 0.02, OR 1.05 per minute, 95% CI 1.00-1.09, respectively). CBV ASPECTS had a larger area under the receiver operating characteristic curve for good CS (0.837) than NCCT ASPECTS (0.802) or MTT ASPECTS (0.752) at arrival. Conclusions: Favorable CBV ASPECTS, NCCT ASPECTS and MTT ASPECTS are associated with good CS along with more salvageable tissue and longer time from the onset of symptoms to imaging in ischemic stroke patients treated with intravenous thrombolysis.

Abstract W MP31: Penumbral Imaging-Based Thrombolysis with Tenecteplase is Feasible Up to 24 Hours After Symptom Onset

Introduction: Penumbral imaging-based selection of patients for thrombolysis with tenecteplase (TNK) has been shown to be feasible up to 6 h after onset. We aimed to demonstrate the feasibility and safety of thrombolysis in ischemic stroke patients with penumbral patterns presenting 4.5-24 h after symptom onset. Methods: We conducted an open label single arm trial. Acute ischemic stroke patients presenting between 4.5-24 h after symptom onset were assessed with perfusion imaging. Patients with pretreatment perfusion CT/MRI that demonstrated a perfusion deficit volume &gt;15 ml and penumbra volume &gt;20% of the infarct core were eligible for TNK treatment. They received 0.25 mg/kg IV TNK. The primary outcome was symptomatic hemorrhagic transformation. Patients screened with perfusion CT/MRI who met trial criteria, but were not enrolled in the study, formed a parallel cohort. Results: A total of 26 patients were screened with perfusion CT/MRI. Thirteen patients received TNK (mean±SD age = 62±12 y). The 13 parallel cohort patients were of similar age (55±18 y, p=0.257). Median (IQR) baseline NIHSS in TNK treated patients (13(9)) was similar to that in the parallel cohort (14(10), p=1.00). Median time to TNK treatment was 8.7 h(range: 5.1-23.3). Reperfusion and recanalization occurred in 54.5% and 50% of TNK treated patients at 24 h, respectively. Infarct growth at 24 h was attenuated in TNK treated patients (8.7 (31.3) ml) relative to the parallel cohort (53.0 (91.5) ml, p=0.017). Penumbral salvage volume was greater in TNK treated patients (51.7 (58.2) ml) than parallel cohort patients (-16.7 (112.2) ml, p=0.001). There was one symptomatic hemorrhage in the TNK group (ECASS grade PH1). Two other TNK treated patients developed asymptomatic hemorrhages (ECASS grade PH1). The rate of good functional outcome (modified Rankin Score ≤2) at day 90 was greater in TNK patients (8/12, 66.7%) than in the parallel cohort (2/13, 15.3%, p=0.015). Conclusion: Thrombolysis with TNK treatment in appropriately selected patients is feasible even up to 24 hours after onset. Randomized studies of penumbral imaging-based selection of TNK candidates in an extended therapeutic time window are warranted.

Abstract W P40: Predicting Tissue at Risk for Infarction Within an Optimal Arterial Spin Labeling Cerebral Blood Flow Threshold in Patients with Acute Stroke

Background: and Purpose: The aim of this study was to investigate whether pseudo-continuous arterial spin-labeling (ASL) in combination with an appropriate cerebral blood flow (CBF) threshold can reliably detect tissue at-risk for infarction. Methods: The retrospective study included 50 patients with acute stroke in the middle cerebral artery (MCA) territory who underwent perfusion-weighted magnetic resonance imaging (PW-MRI) within 24 hr of symptom onset and again in the subacute phase. After image co-registration the core and mismatch were segmented on ASL maps. Receiver operating characteristic (ROC) curve analysis was performed to calculate the optimal ASL-CBF threshold. Volumes on PW-MRI were recorded based on their ASL-CBF threshold (≧19-, 20-, 21-, 22-, 23-, 24- and 25 sec). Then the correlation between the penumbral salvage area and infarct growth, defined as the size difference between the lesion on baseline PWI- and the baseline diffusion-weighted images, and the final infarct volume were determined. Results: ROC analysis showed that the optimal threshold was 21.2 mL/100 g/min (area under the curve 0.88). The correlation between infarct growth and the penumbra salvage volume was significantly better for PWI lesions defined by ASL≦21 mL/100 g/min (r=-0.66; p&lt;0.001). In 9 patients without recanalization on MRI obtained in the subacute phase, the ASL≦21 mL/100 g/min threshold more closely predicted the final infarct volume (r=0.82; p=0.006). Conclusion: PWI (ASL≧21 ml/100 g/min) volumes may provide an approximation of the volume of tissue at-risk for infarction in patients with acute stroke in the MCA territory.

A cost-effective rabbit embolic stroke bioassay: insight into the development of acute ischemic stroke therapy.

Preface: 30 Years a ModelThis article was written to acknowledge the scientificachievement of Dr. Justin A. Zivin, the originator ofthe rabbit embolic stroke model and investigator respon-sible for the “translational stroke research” that led tothe NINDS rt-PA trial and eventual approval of tissueplasminogen activator (tPA) for the treatment of acuteischemic stroke 20 years ago. In 1984–1985, the term“translational stroke research” did not exist, nor did thisjournal bearing the name Translational Stroke Research.Nevertheless, over the years, the rabbit embolic strokemodel has been integral in the development and testingof novel therapies, and the model remains important fortranslational stroke therapy development. TranslationalStroke Research has become an important means of dis-seminating advances in basic and translational strokeresearch and will be integral in future stroke therapydiscovery.tPA, a Cost-Effective TreatmenttPA has been described as a cost-effective treatment forstroke [1]whenadministered3to4.5hafterastroke.The specific conclusion is derived using a disease-baseddecision analytic model, which included probabilisticsensitivity analyses, indicating that “improvement inlong-term patient outcomes in most patient subgroups(except for diabetes and atrial fibrillation) and is a goodeconomic value versus no treatment” [1]. This has beenconfirmed in two recent reports using extensive patientdatabases [2, 3].In 1996, the Food and Drug Administration (FDA)approved the thrombolytic tPA for the treatment ofacute ischemic stroke resulting from blockage of a ves-sel due to an embolus or blood clot. tPA, a thrombolyticthat promotes clot lysis, is also known as a clot busterthat increases blood flow to the formerly clot-affectedcore and possibly salvageable penumbra [4–13]; thisresults in clinical and/or behavioral improvement onthe National Institutes of Health Stroke Scale (NIHSS)andmodifiedRankinScale(mRS).Almost20yearshave passed without the approval of another stroketreatment despite the tremendous financial investmentsand achievements of many investigators worldwide!A Rigorous Model and Bioassay for Therapy Testingand DevelopmentThe approval of tPA was based upon a randomized andblinded clinical trial comparing tPA to tPA-placebo; thetrial was initiated based upon preclinical data by Zivinandcolleagues,whichwaspublished30yearsagoinalandmark science paper [14] and eventually detailed in avolume dedicated to the history of tPA [15]aswellasother comprehensive books on thrombolytics and trans-lational stroke research [16–19]. In retrospect, the au-thors simply showed that tPA could effectively improvebehavioral function when tested in a noninvasive rabbitembolic stroke model, now known as the rabbit small

The growth rate of early DWI lesions is highly variable and associated with penumbral salvage and clinical outcomes following endovascular reperfusion.

The degree of variability in the rate of early diffusion-weighted imaging expansion in acute stroke has not been well characterized. We hypothesized that patients with slowly expanding diffusion-weighted imaging lesions would have more penumbral salvage and better clinical outcomes following endovascular reperfusion than patients with rapidly expanding diffusion-weighted imaging lesions. In the first part of this substudy of DEFUSE 2, growth curves were constructed for patients with >90% reperfusion and <10% reperfusion. Next, the initial growth rate was determined in all patients with a clearly established time of symptom onset, assuming a lesion volume of 0 ml just prior to symptom onset. Patients who achieved reperfusion (>50% reduction in perfusion-weighted imaging after endovascular therapy) were categorized into tertiles according to their initial diffusion-weighted imaging growth rates. For each tertile, penumbral salvage [comparison of final volume to the volume of perfusion-weighted imaging (Tmax > 6 s)/diffusion-weighted imaging mismatch prior to endovascular therapy], favorable clinical response (National Institutes of Health Stroke Scale improvement of ≥8 points or 0-1 at 30 days), and good functional outcome (90-day modified Rankin score of ≤2) were calculated. A multivariate model assessed whether infarct growth rates were an independent predictor of clinical outcomes. Sixty-five patients were eligible for this study; the median initial growth rate was 3·1 ml/h (interquartile range 0·7-10·7). Target mismatch patients (n = 42) had initial growth rates that were significantly slower than the growth rates in malignant profile (n = 9 patients, P < 0·001). In patients who achieved reperfusion (n = 38), slower early diffusion-weighted imaging growth rates were associated with better clinical outcomes (P < 0·05) and a trend toward more penumbral salvage (n = 31, P = 0·103). A multivariate model demonstrated that initial diffusion-weighted imaging growth rate was an independent predictor of achieving a 90-day modified Rankin score of ≤2. The growth rate of early diffusion-weighted imaging lesions in acute stroke patients is highly variable; malignant profile patients have higher growth rates than patients with target mismatch. A slower rate of early diffusion-weighted imaging growth is associated with a greater degree of penumbral salvage and improved clinical outcomes following endovascular reperfusion.

Vessel occlusion, penumbra, and reperfusion - translating theory to practice.

The management of ischemic stroke is at a critical juncture. Administration of intravenous tPA is currently restricted to within 4.5 h from stroke onset with several trials in longer time windows proving neutral (1, 2). Revascularization success with tPA in major vessel occlusion is widely recognized as suboptimal (3). Alternative thrombolytic agents with theoretical efficacy advantages such as tenecteplase and desmoteplase are yet to show benefit in phase 3 trials. The promise of endovascular therapy has also yet to translate into positive randomized trials (4–6), although a new generation of devices is currently being studied. While it is possible that these therapeutic approaches are simply ineffective, the heterogeneity of stroke pathophysiology is likely to be contributing to the neutral results we often observe. Imaging selection has been proposed as a means of reducing heterogeneity by identifying patients with the potential to benefit from revascularization and therefore enhancing the probability of success in trials of new therapies. However, whether it is sufficient to demonstrate an occluded artery as the target or to also require evidence of salvageable downstream tissue has been debated. The recent announcement of neutral results in DIAS 3 (7), a trial that compared desmoteplase versus placebo 3–9 h after stroke onset in patients with vessel occlusion, without reference to downstream tissue status other than what was visible on non-contrast CT, will no doubt further stimulate this discussion. It is, therefore, salient to consider the current methods to identify salvageable ischemic penumbra and the potential value of commonly used surrogates for clinical outcome, chiefly reperfusion, recanalization, and infarct growth.

Acute extracranial occlusion of the internal carotid artery: emergent surgery remains a viable option

Acute symptomatic occlusion of extracranial internal carotid artery (eICA) can lead to a critical and potentially devastating stroke associated with high morbidity and mortality. Optimal treatment remains unclear. We analyzed our institutional experience with emergent surgical recanalization of acutely occluded eICA. Retrospective analysis of hospital records, surgical reports, imaging studies and outpatient records. Final outcome was assessed according to modified Rankin Scale (mRS). Between January 2010 and September 2013, 22 patients underwent emergent surgical recanalization. There were 17 men and five women, mean age 65.4years (range 37-85). Mean admission National Institute of Health Stroke Scale (NIHSS) was 12 (range 6-21). All patients had evidence of salvageable penumbra on perfusion computed tomography. Tandem intracranial lesion was present in nine patients. Surgical recanalization was successful in 16 patients (72.7%). Twenty-four hours after surgery, 17 patients (77.2%) improved by a minimum of 1 point on NIHSS, 14 patients (63.6%) improved by three and more points; two patients deteriorated by two and five points, the latter treated initially with systemic thrombolysis due to intracranial hemorrhage. No other intracranial hematoma was observed. During 30days following surgery, two patients died (9% mortality rate) due to severity of initial stroke. On discharge, four patients were classified as mRS 0, five patients as mRS 1, five patients as mRS 2 and six patients as mRS 4. Favorable recovery (mRS 0-2) was achieved in 14 patients (63.6%). No change in mRS was observed at threemonths. Our results suggest that emergent surgical desobliteration of occluded eICA can lead to favorable recovery in a majority of patients. Patient selection based on penumbra imaging is crucial. Given the popularity and simplicity of carotid endarterectomy, the procedure should by no means be abandoned in the treatment of acute eICA occlusion.

Abstract T P27: Arterial Spin-Labeled Perfusion Imaging to Predict Mismatch in Acute Ischemic Stroke

Background and Purpose: We assigned a threshold to arterial spin-labeling (ASL) perfusion-weighted images (PWI) from patients with acute ischemic stroke (AIS) and compared them with dynamic susceptibility contrast (DSC) perfusion images to examine whether mismatch can be determined. Methods: Pseudo-continuous ASL was combined with DSC-PWI in 23 AIS patients. Scans were obtained within 24 hours of symptom onset. PWI volumes were defined by ASL cerebral blood flow- (&lt;15, &lt;20, and &lt;25 mL/100 g/min) and DSC-mean transit time (MTT) thresholds (&gt;10 seconds) that show a strong association with CBF &lt;20 mL/100 g/min in Xenon CT studies. Agreement between the ASL-DWI and MTT-DWI mismatch and the correlation between penumbra salvage and infarct growth, defined as the difference between the baseline PWI- and the baseline DWI lesion, respectively, and the final infarct volume were assessed. Results: The lesion volumes defined by MTT &gt;10 seconds and ASL &lt;20 mL/100 g/min showed an excellent correlation. There were 100% agreement on the mismatch status between MTT &gt;10 seconds and ASL &lt;20 mL/100 g/min. The correlation between infarct growth and penumbra salvage volume was significantly better for PWI lesions defined by ASL &lt;20 mL/100 g/min and MTT &gt;10 seconds. Conclusion: In AIS, PWI lesions based on ASL threshold of &lt;20 mL/100 g/min can provide a reliable estimate of mismatch in correspondence at MTT threshold of &gt;10 seconds.

Defining acute ischemic stroke tissue pathophysiology with whole brain CT perfusion

This study aimed to identify and validate whole brain perfusion computed tomography (CTP) thresholds for ischemic core and salvageable penumbra in acute stroke patients and develop a probability based model to increase the accuracy of tissue pathophysiology measurements. One hundred and eighty-three patients underwent multimodal stroke CT using a 320-slice scanner within 6hours of acute stroke onset, followed by 24hour MRI that included diffusion weighted imaging (DWI) and dynamic susceptibility weighted perfusion imaging (PWI). Coregistered acute CTP and 24hour DWI was used to identify the optimum single perfusion parameter thresholds to define penumbra (in patients without reperfusion), and ischemic core (in patients with reperfusion), using a pixel based receiver operator curve analysis. Then, these results were used to develop a sigma curve fitted probability based model incorporating multiple perfusion parameter thresholds. For single perfusion thresholds, a time to peak (TTP) of +5seconds best defined the penumbra (area under the curve, AUC 0.79 CI 0.74-0.83) while a cerebral blood flow (CBF) of <50% best defined the acute ischemic core (AUC 0.73, CI 0.69-0.77). The probability model was more accurate at detecting the ischemic core (AUC 0.80 SD 0.75-0.83) and penumbra (0.85 SD 0.83-0.87) and was significantly closer in volume to the corresponding reference DWI (P=0.031). Whole brain CTP can accurately identify penumbra and ischemic core using similar thresholds to previously validated 16 or 64slice CTP. Additionally, a novel probability based model was closer to defining the ischemic core and penumbra than single thresholds.