Cellular Injury During Ischemia

Edema Formation Ischemic brain edema is a combination of two major types of edema: cytotoxic (cellular) and vasogenic [Fishman RA. Cerebrospinal Fluid in Diseases in the Nervous System. 2nd Ed. Philadelphia, PA: W.B. Saunders Co; 1992:103-155]. Cytotoxic edema evolves over minutes to hours and may be reversible, while the vasogenic phase occurs over hours to days, and is considered an irreversibly damaging process. Cytotoxic edema is characterized by swelling of all the cellular elements of the brain (shown). In the presence of acute cerebral ischemia, neurons, glia (indicated by astrocytes), and endothelial cells swell within minutes of hypoxia due to failure of ATP-dependent ion (sodium and calcium) transport. With the rapid accumulation of sodium within cells, water follows to maintain osmotic equilibrium. Increased intracellular calcium activates phospholipases and the release of arachidonic acid, leading to the release of oxygen-derived free radicals and infarction. Vasogenic edema (not shown) is characterized by an increase in extracellular fluid volume due to increased permeability of brain capillary endothelial cells to macromolecular serum proteins (e.g., albumin). Normally, the entry of plasma protein-containing fluid into the extracellular space is limited by tight endothelial cell junctions, but in the presence of massive injury there is increased permeability of brain capillary endothelial cells to large molecules. Vasogenic edema can displace the brain hemisphere and, when severe, lead to cerebral herniation. Acute hypoxia initially causes cytotoxic edema, followed within the next hours to days by the development of vasogenic edema as infarction develops (Fishman, 1992). The delayed onset of vasogenic edema suggests that time is needed for the defects in endothelial cell function and permeability to develop.

Cellular Injury During Ischemia

Deterioration of Ion Gradients Inadequate energy supply leads to deterioration of ion gradients. Anoxic depolarization (equilibration of intracellular and extracellular ions) causes potassium to leave the cell and sodium, chloride, and calcium ions to enter. It also stimulates the massive release of the amino acids glutamate and aspartate, excitatory neurotransmitters in the brain. Glutamate further activates sodium and calcium ion channels in the neuron membrane. As sodium and calcium ions rapidly accumulate within the cells, accompanied by an inflow of water, cytotoxic edema causes rapid swelling of neurons and glia.

Activation of calcium channels results in further influx of calcium into the cell. One of the most intensely studied calcium channels is the N-methyl-D aspartate (NMDA) channel.

Consequences of Calcium Overload Entry of calcium through the NMDA (and similar channels) can be devastating. First, attempts to get rid of the excess calcium use up already scarce supplies of ATP. Second, excessive calcium influx causes the disordered activation of a wide range of enzyme systems (proteases, lipases, and nucleases). These enzymes and their metabolic products, such as oxygen free radicals, damage cell membranes, genetic material, and structural proteins in the neurons, ultimately leading to cell death. This sequence of events has been termed excitotoxicity because of the pivotal role of excitatory amino acids such as glutamate. Several agents are under investigation to block these steps.

The Ischemic Penumbra Within the ischemic cerebrovascular bed, there are two major zones of injury: the core ischemic zone and the "ischemic penumbra" (the term generally used to define ischemic but still viable cerebral tissue). In the core zone, which is an area of severe ischemia (blood flow below 10% to 25%), the loss of inadequate supply of oxygen and glucose results in rapid depletion of energy stores. Severe ischemia can result in necrosis of neurons and also of supporting cellular elements (glial cells) within the severely ischemic area.

Brain cells within the penumbra, a rim of mild to moderately ischemic tissue lying between tissue that is normally perfused and the area in which infarction is evolving, may remain viable for several hours. That is because the penumbral zone is supplied with blood by collateral arteries anastomosing with branches of the occluded vascular tree (see inset). However, even cells in this region will die if reperfusion is not established during the early hours since collateral circulation is inadequate to maintain the neuronal demand for oxygen and glucose indefinitely. In this example, the ischemic penumbra is shown as a rim of tissue surrounding the severely ischemic core lying within the vascular territory of the pre-Rolandic branch of the left middle cerebral artery. The Rolandic artery is occluded by a thromboembolus. The extent of the penumbra varies directly with the number and patency of collateral arteries. The penumbra is where pharmacologic interventions are most likely to be effective. However, it may also be possible to salvage cells within the severely ischemic core zone. Although severe ischemia kills selectively vulnerable neurons, glial cells may be spared if blood flow is restored early. Therefore, timely recanalization of the occluded vessel should theoretically restore perfusion in both the penumbra and in the severely ischemic core. Partial recanalization should markedly reduce the size of the penumbra as well.

Cerebral Infarction / Effects of Edema Shown is a brain slice viewed from the back following a stroke. Blood flow to the region on the left was interrupted due to a thrombus or embolus. The lack of blood flow resulted in severe damage (infarct) to some of the brain tissue. The infarcted tissue caused fluids to accumulate (edema) and result in swelling. The center of the brain is shifted to the right due to swelling from the left. The rigid container of the cranium allows limited room for expansion, and any condition that causes an increase in volume of one or more structures within this vault will cause an increase in intracranial pressure (ICP) or will shift one compartment of the brain, thereby compressing others. As the pressure increases, the brain shifts or is distorted, compressing neurons, nerve tracts, and cerebral arteries. A sustained increase in pressure causes persistent ischemia, irreversible damage to brain cells, and potentially death.