Revisiting Incomplete Tissue-Level Reperfusion Following Successful Thrombectomy for Acute Ischemic Stroke

Among patients with acute ischemic stroke achieving successful large vessel recanalization (defined as expanded Thrombolysis in Cerebral Infarction [eTICI ≥2b]), incomplete tissue-level reperfusion, distinct from visually identifiable distal occlusion on digital-subtraction angiography, remains a significant challenge. Persistent tissue-level hypoperfusion, identified on post-thrombectomy perfusion imaging, involves complex pathophysiology comprising 2 primary mechanisms: territorial hypoperfusion, stemming from distal emboli that often manifest after eTICI 2b to 2c or a posteriori with eTICI 3 recanalization, obstructing small distal arterial branches and forming wedge-shaped patterns; and hypoperfusion within the ischemic core, potentially representing capillary no-reflow, a phenomenon of microvascular perfusion failure despite successful macrovascular recanalization well described in the preclinical literature. Such pathophysiological differences have driven inconsistent designations, causing reported incomplete tissue-level reperfusion rate to vary widely (0-42.5%) even in angiographically complete (eTICI 3) recanalization. Further clouding the scene, territorial hypoperfusion may spontaneously reverse within 24 hours (termed "delayed reperfusion"), yet a distinct delayed hypoperfusion can affect necrotic tissue regardless of no-reflow. Whereas persistent hypoperfusion is significantly associated with functional outcomes, the functional impact of true no-reflow remains unclear. Recent positive randomized controlled trials (RCTs) of intra-arterial thrombolysis after successful recanalization offer a promising therapeutic strategy. However, these trials lacked perfusion imaging, whereas the larger functional benefit in patients achieving eTICI 2b suggests intra-arterial thrombolysis likely acted on distal emboli rather than true microvascular dysfunction. Regarding microvascular dysfunction, preclinical findings highlight potential therapeutic strategies such as targeting pericyte constriction or inflammatory responses, that warrant clinical translation. This review synthesizes current evidence on the mechanisms, assessment methods, and therapeutic strategies for addressing incomplete tissue-level reperfusion following thrombectomy. Further research is warranted to establish standardized definitions, develop targeted therapies for both territorial hypoperfusion and true no-reflow, and translate promising preclinical findings into effective clinical interventions. ANN NEUROL 2026;99:668-683.