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Anatomically and functionally, the brain is the most complex structure in the body. It controls our ability to think, our awareness of things around us, and our interactions with the outside world. Brain functions are diverse and highly localized within the brain. Therefore, unlike other organs that have a global function, the brain is much more vulnerable to focal lesions. For example, an isolated renal infarct would not be expected to have a significant effect on kidney function, whereas an infarct of comparable size in the brain could have serious impact on an isolated brain function, such as complete paralysis on one side of the body.
Mechanism and Manifestation of Brain Injury
The brain is protected from external forces by the rigid confines of the skull and the cushioning afforded by the cerebrospinal fluid (CSF). The metabolic stability required by its electrically active cells is maintained by a number of regulatory mechanisms, including the blood-brain barrier and autoregulatory mechanisms that ensure its blood supply. Nonetheless, the brain remains remarkably vulnerable to injury by ischemia, trauma, tumors, degenerative processes, and metabolic derangements. MECHANISM OF INJURY Injury to brain tissue can result from a number of conditions, including trauma, tumors, stroke, metabolic derangements, and degenerative disorders. Brain damage resulting from these disorders involves several common pathways, including the effects of ischemia, excitatory amino acid injury, cerebral edema, and injury due to increased intracranial pressure (ICP). In many cases, the mechanisms of injury are interrelated. Hypoxic and Ischemic Injury. The energy requirements of the brain are provided mainly by adenosine triphosphate (ATP), the ability of the cerebral circulation to deliver oxygen in sufficiently high concentrations to facilitate metabolism of glucose and generate ATP is essential to brain function. Although the brain makes up only 2% of the body weight, it receives one sixth of the resting cardiac output and accounts for 20% of the oxygen consumption. Thus, deprivation of oxygen or blood flow can have a deleterious effect on brain structures. By definition, hypoxia denotes a deprivation of oxygen with maintained blood flow, whereas ischemia is a situation of greatly reduced or interrupted blood flow. The brain tends to have a different sensitivities to the two conditions. Whereas
hypoxia interferes with the delivery of oxygen, ischemia, interferes with delivery of oxygen and glucose as well as the removal of metabolic wastes. Hypoxia usually is seen in conditions such as exposure to reduced atmospheric pressure, carbon monoxide poisoning, severe anemia, and failure to oxygenate the blood. Because hypoxia indicates decreased oxygen levels in all brain tissue, it produces a generalized depressant effect on the brain Contrary to popular belief, neurons are capable of substantial anaerobic metabolism and are fairly tolerant of pure hypoxia; it commonly produces euphoria, listlessness, drowsiness, and impaired problem solving. Unconsciousness and convulsions may occur when hypoxia is sudden and severe. However, the effects of severe hypoxia (I.e., anoxia) on brain seldom are seen because the condition rapidly leads to cardiac arrest and ischemia. Ischemia can be focal, as in stroke, or global, as in cardiac arrest. Persons with global ischemia have no collateral circulation during the ischemic event. In contrast, collateral circulation, provides blood flow to uninvolved brain areas during focal ischemia. The collateral perfusion may even provide sufficient substrates to the focal ischemic region to maintain a low level of metabolic activity, thereby preserving membrane integrity. At the same time, the delivery of glucose under these anaerobic conditions may result in additional lactic acid production and worsening of lactic acidosis. Global Ischemia. Global ischemia occurs when blood glow is inadequate to meet the metabolix needs of the entire brain, as in cardiac arrest or circulatory shock. The result is a spectrum of neurologic disorders reflecting global brain dysfunction. Unconsciousness occurs within seconds of severe global ischemia, such as that resulting from complete cessation of blood glow, as in serious cardiac dysrhythmias. If circulation is restored immediately, consciousness is regained quickly. However, if blood flow is not promptly restored, severe pathologic changes take place. Energy sources, glucose and glycogen, are exhausted in 2 to 4 minutes, and cellular ATP stores are depleted in 4 to 5 minutes. Approximately 50% to 75% of the total energy requirement of neuronal tissue is spent on mechanism for maintenance of ionic gradients across the cell membrane (e.g., sodium-potassium pump), resulting in fluxes of sodium, potassium, and calcium ions. (Table 1.1) Excessive influx of sodium results in neuronal and interstitial edema, the influx of calcium initiates a cascade of events, including release of intracellular and nuclear enzymes that cause cell destruction. When ischemia is sufficiently severe or prolonged, infarction or death of all the cellular elements of the brain occurs. Table 1.1 Consequences Depletion of oxygen Depletion of glucose Conversion to anaerobic metabolism Exhaustion of celluar ATP Consequences Efflux of Potassium Pathophysiologic Consequences of Impaired Cerebral Perfusion Timing 10 sec 2-4 min 2-4 min 4-5 min
Influx of sodium Influx of calcium The pattern of global ischemia reflects the anatomic arrangement of the cerebral vessels and the sensitivity of various brain tissues to oxygen deprivation. Selective neuronal sensitivity to a lack of oxygen is most apparent in the Purkinje cells of the cerebellum and neurons in Sommer’s sector of the hippocampus. The anatomic arrangement of the cerebral blood vessels predisposes to two types of injury: watershed infarcts and laminar necrosis. (Figure 1.1) Watershed infarcts are concentrated in anatomically vulnerable border zones between overlapping territories supplied by the major cerebral arteries, notably the middle, anterior, and posterior cerebral arteries. The overlapping m=territory at the distal ends of these vessels forms extremely vulnerable areas in terms of ischemia, called watershed zones. During events such as severe hypotension, these distal territories undergo a profound lowering of blood glow, predisposing to ischemia and infarction of brain tissues. As a consequence, areas of the cortex that are supplied by the major cerebral arteries usually regain function on recovery of adequate blood flow; however, infarction may occur in the watershed boundary strips, resulting in focal neurologic deficits. Laminar necrosis occurs in areas supplied by the penetrating arteries. The gray matter of the cerebral cortex receives its major blood supply through short penetrating arteries that emerge at right angles from larger vessels in pia mater 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. Because of the branching arrangement of these vessels, the necrosis that develops is laminar and is most severe in the deeper layers of the cortex. Although the threshold for ischemic neuronal injury is unknown, there is a period during which neurons can survive if blood flow is re-established. Unfortunately, brain injury may not be reversible if the duration of ischemia is such that the threshold of injury has been reached. Even after circulation has been reestablished, damage to blood vessels and changes in blood flow can prevent the return of adequate tissue perfusion. This period of postichemic hypoperfusion is
thought to be associated with mechanisms such as desaturation of venous blood, capillary, and venular clotting, or sludging of blood flow. Because of sludging, blood viscosity increases, and there is increased resistance to blood flow. There is also evidence of compromised flow to immediate vasomotor paralysis of the surface conducting blood vessels due to extracellular acidosis, followed by ischemic vasoconstriction. Hypermetabolism due to increased circulating catecholamines also has been implicated as a contributing factor in postischemic hypoperfusion. Catecholamine release results in an increased cerebral metabolic rate and increased need for all energy-producing substrates, which the damaged brain is unable to sustain. The neurologic deficits that result from global ischemic injury vary widely. If the period of nonflow or low flow is minimal, the neurologic damage usually is minimal to nonexistent. When the period is extensive or resuscitation is lengthy, the early neurologic clinical picture is that of fixed and dilated pupils, abnormal motor posturing, and coma. If the brain recovers, there is gradual improvement in neurologic status, although cognitive and focal deficits usually persist and can prevent a return to preischemic levels of functioning. An exception to this time frame is the circumstance of cold-water drowning in which the person, especially a child, is submerged in cold water for longer than 10 minutes. Hypothermia develops and reduces the cerebral metabolic requirements for oxygen; It subsequently serves as a protective mechanism for the neurons. In this case, recovery can be rapid and remarkable, and resuscitation efforts should not be discontinued precipitously. Treatment of global ischemia is aimed at providing oxygen to the troubled brain and decreasing the metabolic needs of brain tissue during the nonflow state. Methods that decrease brain temperature as a means of decreasing brain metabolism have shown promise. Normovolemic hemodilution may be used to overcome sludging of cerebral blood flow during reperfusion. Because both hypoglycaemia and hyperglycemia adversely affect the outcome in persons with global ischemia, control of blood glocuse within a range of 100 to 200 mg/dL has been advocated. Although several pharmacologic agents have been advocated as a means of preventing brain damage in global ischemia, none has proved highly effective. In the past, barbiturates were used as a means of decreasing brain metabolism. However, the beneficial effects of barbiturates are minimal unless they are administered before the anticipated ischemia (e.g., before neurosurgery). Recent interest has focused on inducing hypothermia and on pharmacologic agents that could minimize injury from free radicals and excitatory amino acids.
Injury From Excitatory Amino Acids. In many neurologic disorders, injury to neurons may be caused by overstimulation of receptors for specific amino acids such as glutamate and aspartate that act as excitatory neurotransmitters. These neurologic conditions range from acute insults such as stroke, hypoglycemic injury, and trauma to chronic degenerative disorders such as Huntington’s disease and possibly Alzheimer’s dementia. The term excitotoxicity has been coined for the final common pathway for neuronal cell injury and death associated with excessive activity of the excitatory neurotransmitters and their receptor-mediated functions. Glutamate is the principal excitatory neurotransmitter in the brain, and its interaction with specific receptors is responsible for many higher-order functions, including memory, cognition, movement, and sensation. Many of the actions of glutamate are coupled with receptor-operated channels. One subtype in particular, called the glutamate N-methyl-D-Aspartate (NMDA) receptor, has been implicated causing central nervous system injury. This subtype of glutamate receptor opens a large-diameter calcium channel that permits calcium and sodium ions to enter the cell and allows potassium to exit, resulting in prolonged (seconds) action potentials. The uncontrolled opening of NMDA receptor-operated channels produces an increase in intracellular calcium and leads to a series of calcium-mediated processes called the calcium cascade (Figure 2.2). Activation of the calcium cascade leads to the release of intracellular enzymes that cause protein breakdown, free radical formation, lipid peroxidation, fragmentation of DNA, and nuclear breakdown. The intracellular concentration of glutamate is approximately 16 times that of the extracellular concentration. Normally, extracellular concentrations of glutamate are tightly regulated, with excess amounts removed and actively transported into astrocytes and neurons. During prolonged ischemia, these transport mechanisms become immobilized, causing extracellular glutamate to accumulate. In the case of cell injury and death, intracellular glutamate is released from the damaged cells, causing injury to surrounding cells. The uncontrolled opening of NMDA receptor-operated channels by glutamate produces an increase in intracellular calcium and leads to the calcium cascade. Activation of the calcium cascade eventually causes cell death within several hours after exposure to glutamate. The effects of acute glutamate toxicity do not necessarily lead to cell death; they are reversible if excess glutamate can be removed or if its effects can be blocked. Drugs called neuroprotectants are being developed to interfere with the
glutamate-NMDA pathway and thus reduce brain cell injury. These pharmacologic strategies may protect viable brain cells from irreversible damage in the setting of excitotoxicity. Pharmacologic strategies that are being explored include those that inhibit the synthesis or release of excitatory amino acid transmittersl; block the NMDA receptors; stabilize the membrane potential to prevent initiation of the calcium cascade using lidocaine and certain barbiturates; and specifically block certain intracellular proteases, endonucleases, and lipases that are known to be cytotoxic. The drug riluzole, which acts presynaptically to inhibit glutamate release, currently is being used in the treatment of amyotrophic lateral sclerosis. Nimodipine, a calcium channel blocker that acts at the level of the NMDA receptoroperated channels, is being investigated for use of subarachnoid haemorrhage and acquired immunodeficiency syndrome dementia. In the setting of ischemic stroke, multiple mechanisms of pharmacologic action, including NMDA receptor blockade, nitric oxide potentiation, and potassium channel opening, are being studied. Central nervous system neurons can be divided into two major categories: macroneurons and microneurons. Macroneurons are large cells with long axons that leave the local network of intercommunicating neurons to send action potentials to other regions of the nervous system at distances of centimeters to meters (e.g., upper motoneurons that communicate with lower motoneurons that control leg movement). Microneurons are very small cells that are intimately involved in local circuitry. Their axons transmit action potentials to other members of the same local network. In contrast to macroneurons, which number in the thousands, microneurons account for most of the many billions of CNS neurons. Many macroneurons use glutamate as a neurotransmitter in their excitatory communication with microneurons.It is the microneuron network that provides the analytic, integrative, and learning circuitry that is the basis for the higher-order function of the CNS. The microneurons of the cerebral cortex and hippocampus are particularly vulnerable to excessive stimulation of the glutamate NMDA receptors and the neurotoxic effects of increased intracellular calcium levels. Because of their increased vulnerability, many of the small interneurons that make up essential parts of the complex control and memory functions of the brain are selectively damaged, even if the remainder of the brain survives the insult. This pattern may account for the long-term effects of brain insult, which frequently include subtle and noticeable reductions in cognitive and memory functions. Brain Injury: A Special Report from www.medicalvillage.blogspot.com to be continued. . . . .