Ischemic Stroke: Pathogenesis Small artery occlusion
Acute injury (<20mm diameter) of basal or brainstem penetrating arteries Large artery atherosclerosis Cholesterol plaque ↓ diameter of intra- or extracranial vessel Cardiac embolism Blood clot in heart breaks free, travels to brain Other E.g. volume loss, severe infection Unknown E.g. 2 or more mechanisms Modest ↓ in O2 at penumbra (see figure) Authors: Mizuki Lopez Andrea Kuczynski Illustrator: Mizuki Lopez Reviewers: Sina Marzoughi Usama Malik Hannah Mathew Ran (Marissa) Zhang Andrew M Demchuk* Gary M. Klein* * MD at time of publication Significant ↓ in O2 at ischemic core (see figure) ↑ Anaerobic metabolism ↓ ATP Production Dysfunction of Na+/K+ ATPase pump (for 1 ATP molecule, 3 Na+ moved out of cell, 2 K+ moved into cell) H2O influx following Na+ Cerebral edema Compression of vessels and surrounding tissue damages blood-brain barrier ↑ Permeability of damaged blood-brain barrier Infiltration by peripheral immune cells Immune cells release inflammatory cytokines ↓ Cerebral Blood Flow Penumbra Ischemic core Metabolic demands are greater than supply of ATP Cell death Microglia (resident neural immune cells) activate to clean dead cell debris Microglia release inflammatory cytokines (TNFα, IFγ, IL-1β) Cytokines lead to astrocyte activation (support cells for neurons) Astrocytes release more inflammatory cytokines Inflammation of brain tissue ↑ Na+, Ca2+ influx, K+ outflux ↓ Glutamate (excitatory neurotransmitter) reuptake by astrocytes (support cells for neurons) ↑ Glutamate in extracellular fluid Spreading depolarization from core (unclear mechanism) Activate biochemical pathways including glutamate receptor activation ↑ Glutamate activity Activate glutamate receptors that conduct Ca2+ ↑ Ca2+ influx into neuron Activation of catabolic proteases, lipases, nucleases in neuron Dysfunction of neuronal protein synthesis and activity Neuronal cell death ↑ Volume of dead (infarcted) brain tissue Neurons depolarize and release glutamate Reversal of Na+ Dependent Glutamate Reuptake Transporters on astrocytes (normally 3 Na++ 1 H+ + 1 glutamate into cell, for 2 K+ out) ↑ Glutamate in extracellular fluid Stroke symptoms (e.g. weakness, slurred speech, visual field losses, autonomic dysfunction) (see Ischemic Stroke: Impairment by Localization stroke slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 14, 2017; updated November 6, 2022 on www.thecalgaryguide.com