Porth's Essentials of Pathophysiology, 4e

918

Nervous System

U N I T 1 0

(see Fig. 37-1). The gray matter of the cerebral cortex receives its major blood supply through short pene- trating arteries that emerge at right angles from larger vessels and then form a cascade as they repeatedly branch, forming a rich capillary network. An abrupt loss of arterial blood pressure markedly diminishes flow through these capillary channels. Global ischemia occurs when blood flow is inad- equate to meet the metabolic needs of the entire brain. 3 The result is a spectrum of neurologic disorders reflect- ing diffuse brain dysfunction. Unconsciousness occurs within seconds of severe global ischemia, such as that resulting from cardiac arrest. If the cerebral circula- tion is restored immediately, consciousness is regained quickly. The unique vulnerability of the brain is attrib- uted to its limited tolerance of ischemia and its response to reperfusion. The metabolic depletion of energy associated with ischemia can result in an inappropri- ate release of excitatory amino acid neurotransmitters, disrupted calcium homeostasis, free radical formation, mitochondrial injury, and activation of cell-death path- ways. 1,4 Although the threshold for ischemic neuro- nal injury is unknown, there is a period during which neurons can survive if blood flow is reestablished. Unfortunately, brain injury may be irreversible if the duration of ischemia is such that the threshold of injury has been reached. Excitatory Amino Acid Injury In many neurologic disorders, injury to neurons may be caused by inappropriate release of excitatory amino acid neurotransmitters such as glutamate. 1,3,5,6 The neurologic conditions involved in excitotoxic injury range from acute events such as stroke, hypoglycemic injury, and trauma to chronic degenerative disorders such as Huntington disease and possibly Alzheimer dementia. During prolonged ischemia, metabolic depletion of adenosine triphosphate (ATP) results in the inappropri- ate release of glutamate. This initiates cell damage by allowing excessive influx of calcium ions (Ca ++ ) through glutamate– N -methyl- d -aspartate (NMDA) glutamate channels. Excess intracellular Ca ++ leads to a series of calcium-mediated processes called the calcium cascade (Fig. 37-2), which results in the release of intracellular enzymes that cause protein breakdown, free radical formation, lipid peroxidation, deoxyribonucleic acid (DNA) fragmentation, mitochondrial injury, nuclear breakdown, and eventually cell death. The effects of acute glutamate toxicity may be reversible if the excess glutamate can be removed or if its effects can be blocked before the full cascade pro- gresses. Various strategies that would protect viable brain cells from irreversible damage in the setting of excitotoxicity are currently under investigation. Pharmacologic strategies being explored include those that inhibit the synthesis or release of excitatory trans- mitters; block the NMDA receptors; prevent initiation of the calcium cascade; or block release of intracellular enzymes.

Glutamate

Ca 2+

NMDA receptor

Increase in intracellular calcium

Calcium cascade

• Release of intracellular enzymes • Protein breakdown • Free radical formation • Lipid peroxidation • Fragmentation of DNA • Nuclear breakdown

Brain cell injury and death

FIGURE 37-2. The role of the glutamate–N-methyl- d -aspartate (NMDA) receptor in brain cell injury. DNA, deoxyribonucleic acid.

Cerebral Edema Cerebral edema, or brain swelling, is an increase in tis- sue volume secondary to abnormal fluid accumulation. There are two types of brain edema: vasogenic and cytotoxic. 1,7 Vasogenic edema occurs with conditions that impair the function of the blood–brain barrier and allow trans- fer of water and proteins from the vascular into the interstitial space. It occurs in conditions such as hemor- rhage, brain injury, and infectious processes (e.g., men- ingitis). Vasogenic edema occurs primarily in the white matter of the brain, possibly because the white matter is more compliant than the gray matter. Vasogenic edema can result in displacement of a cerebral hemisphere and various types of brain herniation. The functional mani- festations of vasogenic edema include focal neurologic deficits, disturbances in consciousness, and severe intra- cranial hypertension. Cytotoxic edema involves an increase in intracellular fluid. It can result from hypoosmotic states such as water intoxication or severe ischemia that impair the function of the sodium–potassium membrane pump. Ischemia also results in the inadequate removal of anaerobic meta- bolic end products such as lactic acid, producing extra- cellular acidosis. If blood flow is reduced to low levels for extended periods or to extremely low levels for a few minutes, cellular edema can cause the cell membrane to