Clinical meaning
The NP must understand the ischemic stroke cascade to appreciate the rationale for time-critical reperfusion therapy. When a cerebral artery is occluded (by cardioembolism from atrial fibrillation in approximately 20-30%, large vessel atherothrombosis in 15-25%, or small vessel lacunar disease in 20-25%), the downstream territory is divided into two zones based on the severity of blood flow reduction. The ISCHEMIC CORE receives less than 10-12 mL/100g/min blood flow (normal is 50-55 mL/100g/min) and undergoes rapid irreversible neuronal death within minutes through energy failure, loss of ion homeostasis, cytotoxic edema, and necrosis. The ISCHEMIC PENUMBRA surrounds the core and receives 12-22 mL/100g/min blood flow from collateral circulation -- this tissue is functionally impaired (contributing to the neurological deficit) but structurally viable and represents the target for salvage through reperfusion. The penumbra undergoes a time-dependent cascade of injury: ATP depletion leads to failure of Na+/K+-ATPase pumps, causing depolarization and release of excitatory glutamate; glutamate activates NMDA and AMPA receptors, triggering massive calcium influx (excitotoxicity); intracellular calcium overload activates proteases, lipases, and endonucleases while also generating reactive oxygen species through mitochondrial dysfunction and xanthine oxidase activation; free radicals damage cell membranes through lipid peroxidation, damage DNA, and activate inflammatory pathways including microglial activation, blood-brain barrier disruption, and leukocyte infiltration. Without reperfusion, the penumbra is progressively recruited into the infarct core at a rate of approximately 1.9 million neurons per minute (the basis for the 'time is brain' concept). Reperfusion therapy (IV alteplase within 4.5 hours or mechanical thrombectomy within 24 hours for large vessel occlusion with salvageable penumbra on perfusion imaging) aims to restore flow before irreversible injury occurs. However, reperfusion itself can paradoxically worsen injury through reperfusion injury: restored oxygen delivery to damaged mitochondria generates a burst of reactive oxygen species, and blood-brain barrier disruption allows hemorrhagic transformation, which is the primary risk of thrombolytic therapy.