Ischemic stroke occurs when a blood clot blocks a vessel supplying blood to the brain, causing brain tissue to die from lack of oxygen and nutrients (ischemia). This sudden loss of blood flow leads to rapid neurological deficits and requires immediate medical intervention to prevent permanent disability. Endovascular Therapy (EVT) is a powerful treatment used to physically remove the clot, particularly for blockages in large arteries, known as Large Vessel Occlusions (LVOs). The urgency of this condition makes the time window for intervention the single most important factor in determining a patient’s outcome.
Endovascular Therapy and the Definition of Last Known Normal
Endovascular Therapy (EVT), specifically mechanical thrombectomy, is a minimally invasive procedure. It is performed by guiding a catheter through an artery, usually starting in the groin, up to the blocked vessel in the brain to restore blood flow. Primary techniques involve using a specialized wire-mesh device called a stent retriever to capture the clot or using a catheter to directly aspirate the thrombus.
To determine eligibility for this time-sensitive procedure, clinicians rely on the “Last Known Normal” (LKN) metric. The LKN is defined as the most recent time the patient was observed to be at their neurological baseline, without any signs or symptoms of stroke. This metric is the absolute starting point for the treatment clock. For patients with a “wake-up stroke,” the LKN is set to the time they were last seen well before falling asleep.
The Standard Treatment Window: 0 to 6 Hours
The standard time frame for endovascular therapy is within six hours of the Last Known Normal time. This window was established by successful randomized controlled trials that demonstrated the benefit of mechanical thrombectomy over medical management alone for LVOs. Patients presenting within this six-hour window are considered for immediate treatment if a large vessel occlusion is confirmed through basic imaging, such as a CT angiogram.
Selection criteria within this standard window focus mainly on confirming the LVO and ruling out a large area of established, irreversible brain damage. Treatment is highly effective in this early phase. Historically, it was assumed that beyond six hours, too much brain tissue would have died, making reperfusion futile. The success within this initial window set the baseline for acute stroke care.
Advanced Imaging and Extending the Time Limit to 24 Hours
The maximum time window for endovascular therapy has been extended up to 24 hours from the Last Known Normal time, but this extension is strictly limited to highly selected patients. This breakthrough was driven by the landmark DAWN and DEFUSE 3 clinical trials, which proved that a subgroup of patients could benefit from clot removal long after the traditional six-hour limit. Patient selection in this extended window relies entirely on advanced brain imaging, shifting the treatment paradigm from a time-based approach to a tissue-based approach.
Clinicians use advanced imaging modalities, such as CT Perfusion (CTP) or MRI, to identify a mismatch between the size of the irreversibly damaged brain tissue and the overall threatened area. This mismatch suggests a significant amount of salvageable brain tissue, known as the penumbra, remains viable despite the prolonged occlusion. The DAWN trial selected patients based on a clinical-core mismatch, while the DEFUSE 3 trial focused on a perfusion mismatch identified by advanced imaging.
The 24-hour mark represents the current maximum time limit for EVT. This late-window intervention is reserved only for patients whose advanced imaging confirms the presence of a substantial amount of at-risk, salvageable tissue. The success of these trials emphasized that some patients progress more slowly toward irreversible brain damage due to better collateral blood flow.
The Biological Basis: Why Time Determines Brain Salvage
The urgency of stroke treatment is rooted in the biological process of ischemic brain injury, summarized by the concept “Time is Brain.” When a major vessel is blocked, the tissue immediately affected experiences a near-complete cessation of blood flow, leading to the rapid and irreversible death of neurons, forming the ischemic core.
Surrounding the core is the ischemic penumbra, a zone of tissue that is severely under-perfused but potentially salvageable. Neurons within the penumbra are stunned but survive on minimal blood flow, often supplied by collateral vessels from other arteries. The fate of the penumbra is directly proportional to the time until reperfusion, as this tissue will progressively convert into the irreversible ischemic core.
The goal of endovascular therapy is to save this penumbral tissue before its conversion to core is complete, minimizing permanent neurological deficit. A typical stroke causes the death of approximately 1.9 million neurons every minute, emphasizing the need for quick intervention. The extended 24-hour time window works only for select patients whose unique physiology, often due to robust collateral circulation, has slowed the rate of penumbral conversion.