Patient Selection Based on Penumbra-core Mismatch Using MR With Non-Perfusion Imaging for Endovascular Treatment Within 6 to 24 Hours: Rationale and Trial Design

The theory of mismatch between ischemic core and penumbra has long been regarded as the triage criterion for stroke patients undergoing urgent endovascular treatment (EVT). In 1977, Astrup and colleagues first proposed the concept of ischemic penumbra through animal experiments. In 1981, Astrup defined ischemic penumbra as brain tissue surrounding the infarct core, with blood flow levels lower than those required to maintain normal brain function but higher than those causing structural changes in brain morphology . During cerebral ischemia, brain tissue exhibits a concentric distribution of varying degrees of ischemia. Tissue in the ischemic core has blood flow below 10 ml/100 g per minute and is considered irreversibly damaged. In contrast, tissue in the penumbra has blood flow between 10 and 17 ml/100 g per minute, indicating a risk of progressing to the infarct core . Patients with a high volume of penumbral tissue and a small infarct core, termed "mismatch," are deemed to derive the greatest benefit from EVT and are least likely to incur reperfusion injury risk. This principle has been consistently applied in clinical practice for stroke reperfusion, particularly in patients with late time windows, where reperfusion therapy is traditionally associated with potentially higher risks . Based on this principle, researchers utilize complex quantitative perfusion or infarct core calculation programs, often supported by artificial intelligence technology, to obtain high-quality clinical evidence. This strategy has proven successful. The efficacy and safety of EVT in patients with acute ischemic stroke (AIS) due to anterior circulation LVO is well established in multiple RCTs in the late treatment time windows (6 to 24 hours). EVT has significantly improved the prognosis of patients with LVO stroke compared to medical therapy .

DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) and DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) enrolled patients showing evidence of salvageable brain tissue, determined by the presence of significant mismatch. This mismatch describes a state where the volume of viable brain tissue at risk of infarction due to ongoing vessel occlusion greatly exceeds the volume of already infarcted tissue. Mismatch evaluation used computer-generated volumetric imaging criteria, either independently (DEFUSE 3) or with clinical-core infarction criteria (DAWN) . The AURORA trial conducted a meta-analysis of data from six late-onset trials, including DAWN, DEFUSE 3, ESCAPE, REVASCAT, POSITIVE, and RESILIENT, assessing common odds ratios, favorable prognosis rates, mortality rates, and other indicators. These findings strengthen the evidence supporting the benefits of EVT for patients showing evidence of reversible cerebral ischemia within the 6-24 hour time window and are relevant to clinical practice . Detection of core infarction and penumbral mismatch is considered an effective patient screening method, capable of identifying those most likely to benefit and excluding those most likely to suffer from reperfusion injury. However, the use of urgent CTP or PWI in the emergency department is often limited in many centers worldwide . The reasons include insufficient access to appropriate technological resources, manpower requirements, and software for analyzing perfusion imaging may not be readily available. Additionally, the strict inclusion criteria based on perfusion parameters in clinical trials hinder patient selection for real-world clinical practice, leading to some patients missing the opportunity for EVT. Therefore, additional clinical and imaging criteria facilitating the identification of eligible patients would be beneficial .

In a prospective study, the presence of FVH (defined as focal, tubular, or serpentine hyperintensity in the lateral fissure, sulcus, or near the surface of the brain on the 2D FLAIR sequence) was associated with acute stroke . The exact pathophysiological mechanism of FVH remains unclear; however, its emergence suggests slow blood flow, impaired antegrade blood flow, and retrograde blood flow near the ischemic lesion . Recent research suggests that the FVH sign could serve as a significant and convenient imaging marker indicative of inadequate perfusion in patients with cerebral infarction associated with LVO. Additionally, FVH has been suggested to indirectly indicate the presence of LVO or vascular stenosis, with insufficient collateral circulation and a perfusion abnormality. The discrepancy between DWI volume and the FVH sign (FVH-DWI mismatch) in acute stroke patients could serve as a valuable penumbra-core based triage tool without the need for perfusion imaging to predict functional outcomes after stroke.

In this study, we used a randomized controlled approach to assess the risk and prognosis of EVT by identifying the presence of an ischemic penumbra using the FVH-DWI mismatch. Our aim was to establish a simple evaluation method based on the indirect assessment of penumbra-core triage without perfusion imaging on MRI to screen patients who underwent thrombolysis within 6 to 24 hours from symptom onset. We hypothesized that triage using MRI with non-perfusion imaging would be non-inferior to using perfusion imaging in demonstrating 90-day functional independence.