Ischemic Penumbra: A Personal View

The concept of the ischemic penumbra was defined over 40 years ago by Lindsay Symon and his group and is now an established principle of all acute ischemic stroke therapies. These reperfusion treatments rescue threatened, critically hypoperfused brain tissue and have been proven to improve clinical outcomes. We have been fortunate to have observed and played a small part in the penumbral story from its beginnings in the 1970s to its pivotal position today. Over this period, we have witnessed penumbral imaging evolve from positron emission tomography through to magnetic resonance imaging and now predominantly computed tomography perfusion, with the advent of automated imaging facilitating case selection for reperfusion therapies. We and others have conducted clinical trials using penumbral imaging to extend the time window for intravenous thrombolysis and select patients for thrombectomy. Together with the concept of fast- and slow-growing ischemic infarct patterns, this embeds the penumbral principle in everyday clinical management. The opportunity now exists to make penumbral imaging even more portable, affordable, and more widely available using mobile platforms, novel imaging techniques, digital linkage, and artificial intelligence.

Abstract TP62: Frequency, Characteristics, and Outcomes of Acute Ischemic Stroke Patients With “Total Mismatch” on Penumbral Imaging Before Reperfusion Therapy

Background: When penumbral imaging shows “total mismatch” (large perfusion lesion and no irreversibly infarcted core), the entirety of jeopardized brain is still salvageable and the benefits of reperfusion therapy may be enhanced. The frequency, characteristics, and reperfusion therapy outcomes of total mismatch patients has not been well-characterized. Methods: Analysis of consecutive acute cerebral ischemia patients in anterior circulation undergoing CT or MR penumbral imaging prior to intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT). Patients were classified in four groups: 1) total mismatch (core 0% of perfusion lesion), 2) non-total but substantial mismatch (core 1-20% of perfusion lesion), 3) moderate or no mismatch (core 20-100% of perfusion lesion), and 4) small perfusion lesion (perfusion lesion volume <10 ml). Results: Among 180 patients, pretreatment imaging patterns were: total mismatch 28.9%, substantial mismatch 22.8%, moderate or no mismatch 22.8%, and small perfusion lesion 25.6%. Among total mismatch patients, the Tmax>6 sec perfusion lesion volume was 56.5 ml (IQR 28.3-85.6) and time from last known well to imaging was 89 mins (IQR 65-296). Compared to moderate patients, clinical features of total mismatch patients were: older (76.0 vs 65.9, p=0.006), lower NIHSS (median 12 vs 18, p=0.019), and more cardioembolism (76.9% vs 48.8%, p=0.005). Total mismatch patients more often had CT than MR (65.4% vs 14.6%, p=0.000), less ICA occlusion (15.4% vs 34.1%, p=0.035), and smaller perfusion lesions (median 56.5 vs 82.1 ml, p=0.007). Total mismatch patients were treated with combined IVT+EVT in 32.7%, IVT alone in 26.9%, and EVT alone in 40.4%. Freedom from disability (mRS 0-1) at discharge was more frequent, 35.6% vs 16.2%, p=0.049 and disability levels at day 90 were lower in total mismatch patients, mean mRS 2.7 vs 3.9, p=0.029. Conclusion: Total mismatch is present in one-quarter of patients undergoing reperfusion therapy, more often in older patients with cardioembolism as etiology of stroke. Total mismatch patients have better disability outcomes from reperfusion therapy, but more than half show disability indicating need for more complete reperfusion.

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 >15 ml and penumbra volume >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.