Recanalization and Reperfusion Therapies of Acute Ischemic Stroke: What Have We Learned, Where Are We With Still Unanswered Questions, and Where Are We Headed?

Stroke remains a major cause of disability and mortality, while important questions on the extraordinary complexity of biochemical/pathophysiological events underlying etiopathogenetic mechanisms and remarkable therapeutic challenges are still unresolved. Undoubtedly, in the last decades, the introduction of thrombolysis has had the crucial role of catalyzing and driving all the advancements and changes occurred in the management of acute ischemic stroke (AIS). The rationale for the application of systemic or local thrombolytic agents or other endovascular techniques is the lysis/removal-disruption of thrombus/emboli occluding brain vessels that lead to a critical cerebral perfusion reduction and, eventually, to ischemic infarction with a central core of irreversible neuronal damage, where blood flow decreases below the threshold of energy failure, and a surrounding more or less large area of brain tissue, the so called ischemic penumbra, biochemically dynamic, with constrained perfusion but preserved energy state and still salvageable if blood flow is rapidly restored. Currently, IV thrombolysis with t-PA is the only specific pharmacological reperfusion therapy for AIS proven to be effective by large randomized clinical trials. The 3-hour therapeutic window has been recently extended in Europe to 4.5 hours after the ECASS III successful results. But, still a minority of patients remains eligible due to the strict therapeutic window and several contraindications. Moreover, there are patients that do not respond to systemic thrombolysis both in terms of efficacy, for the lack of recanalization/reperfusion, and safety, for the occurrence of symptomatic/fatal hemorrhagic transformation of the infarcted area. In the last years, a number of studies have been focused on these issues. Advanced neuroimaging has allowed us to understand that the rate and timing at which ischemic brain tissue dies vary considerably among different individuals, and imaging criteria could help in identifying appropriate candidates for which the treatment opportunity might be extended beyond the currently defined therapeutic window. Other studies have found that some of the established contraindications to thrombolysis are mostly arbitrary and do not affect the treatment efficacy/safety, suggesting that there is room for their revision. In the last years, the need of finding different approaches for IV t-PA non-responders, of achieving a higher rate of recanalization/reperfusion, and of increasing the number of eligible patients has directed the scientific interest to new fibrinolytic agents, sonothrombolysis, and endovascular treatments, intra-arterial alone or combined with mechanical techniques, bridging with systemic thrombolysis for non-responders, or as sole rescue approach in patients not candidate to IV therapy and selected with multimodal neuroimaging techniques. Unfortunately, so far, endovascular treatment has failed to be proven as a beneficial treatment. For this Research Topic we ask experts in the stroke-related research field to point out to the still multiple unanswered questions on recanalization/reperfusion therapies for AIS, focusing on the state of art of basic and clinical science regarding the rationale and application of these treatments, with an updated and critical literature review, but also discussing their research work, and giving their opinion on potential future perspectives in terms of methods for increasing the number of treated patients, including revision of treatment protocol for relative contraindications and telemedicine technologies; in terms of definition of clinical, imaging and molecular factors as biomarkers for improving brain tissue fate and clinical outcome prediction, also in awakening/unwitnessed stroke, selection of patients eligible for a successful systemic/endovascular thrombolytic treatment; and finally in terms of novel, more homogeneous methodologies in designing trials on endovascular therapy.