• Increases in intracranial volume that are not caused by the tumor itself or by hemorrhage, for example, are generally described as cerebral edema. However, the term is also used for increases in intravascular volume within the intracranial space which are more correctly described as brain swelling.
• Vasogenic edema occurs as a result of increased capillary permeability. Such changes in permeability can be caused by the breakdown of capillary endothelial cells, by relative opening of tight junctions, or because of failure of certain transport mechanisms within endothelial cells.
• Cytotoxic edema refers to an increase in the brain-water content because of major disturbance in ionic homeostasis within the brain. Cerebral ischemia and trauma are the major causal factors.
• Interstitial or hydrocephalic edema is less frequent. Under these circumstances edema is a result of the movement of water from the ventricles through the brain because of obstruction of the outflow of cerebrospinal fluid.
Increases in intracranial volume as a result of a variety of processes within the brain are among the most dreaded consequences of neurological disease. The lethality of many disorders of the central nervous system, such as infection, neoplasms, and traumatic injury, stem in large part from the secondary reaction of the brain to insults. Increases of volume within the intracranial space are dangerous because the brain resides within the skull, which is a closed box with no substantial possibility of venting. While the displacement of cerebral spinal fluid out of the intracranial space is a mechanism which gives the system some capacitance, this is a relatively limited defense mechanism for compensating for increases in intracranial volume.
Increases in intracranial volume that are not caused by the tumor itself or by hemorrhage, for example, are generally described as cerebral edema. However, the term is also used for increases in intravascular volume within the intracranial space which are more correctly described as brain swelling. Because these processes often occur concurrently, they are discussed under the general rubric of brain swelling, with brain edema referring specifically to an increase in the water content of the brain.
In a series of classic papers, Klatzo divided brain edema into two types ( Klatzo.1,967). The first of these is vasogenic edema which occurs as a result of increased capillary permeability. Such changes in permeability can be caused by the breakdown of capillary endothelial cells, by relative opening of tight junctions, or because of failure of certain transport mechanisms within endothelial cells. The blood-brain barrier is extremely efficient in keeping out even small ions. In general, water entering the brain under normal conditions does so without solute and only because of hydrostatic forces. Therefore the osmotic gradient is directed at returning the water to the plasma. The term 'blood-brain barrier breakdown' has also been used to describe vasogenic edema; however, the term is somewhat imprecise. Increases in brain water content with vasogenic edema are often quite dramatic because the fluid which results from increased capillary permeability is usually rich in proteins and is similar to plasma. A number of factors influence the rapidity and severity of vasogenic edema. The first, obviously, is the degree of impaired capillary permeability. The second is the systemic arterial pressure and its relationship to local tissue pressure. The third is the influence of edema which is already present on the brain microcirculation. The continued deterioration of patients under these circumstances is often a result of the spread of edema, resulting in brain ischemia. This can lead to the second type of edema, cytotoxic edema, and to the progressive breakdown of both astrocytes and neurons. This breakdown generates both a significant osmotic load and the release of substances such as excitatory amino acids, catecholamines, and other biological products which may influence both vasogenic and cytotoxic edema.
Cytotoxic edema refers to an increase in the brain-water content because of major disturbance in ionic homeostasis within the brain. Although there are a number of causes of cytotoxic brain edema, clearly cerebral ischemia and trauma are the major causal factors. When the brain is ischemic, energy metabolism falls rapidly and thus the ability of the brain to pump ions actively also begins to deteriorate. Transport systems which normally move charged substances, glucose, and amino acids fail relatively quickly. Sodium enters the cell at an excessively rapid rate, pulling water with it and causing a subsequent temporary decrease in the extracellular space. Because the relative concentration of sodium in the extracellular space drops as it enters the astrocytes and neurons, sodium enters the extracellular space from the blood in an attempt to maintain osmotic equilibrium. The failure of active transport mechanisms in the brain, when coupled with cellular injury, results in the release of a number of vasoactive compounds which may further affect the blood-brain barrier or, in the case of glutamate for example, may produce a neurotoxic effect on the cell resulting in edema. Kim.e.!berg i1995) has postulated that cytotoxic edema is frequently exacerbated by the release of excitatory amino acids from already swollen astrocytes which then produce neurotoxic injury. If this injury is of sufficient severity to cause damage to the cell, calcium influx and cell death will further perpetuate edema formation. Thus a vicious cycle may develop where initially cytotoxic edema is primary, but the release of these potent factors results in impaired capillary permeability with ensuing vasogenic edema ( Fig 1). This again results in ischemia because of impairment, from edema formation, of the microcirculation and a vicious cycle ensues which, if it is not adequately interrupted, can lead to coma and death.
Fig. 1 Cytotoxic edema may release vasoactive compounds which increase capillary permeability and lead to vasogenic edema: ECS, extracellular space. (Reproduced with permission from Kime!berg..(1995).■)
Interstitial or hydrocephalic edema is less frequent. Under these circumstances edema is a result of the movement of water from the ventricles through the brain because of obstruction of the outflow of cerebrospinal fluid. Brain imaging will reveal a zone of edema directly adjacent to the ventricles, almost always bilaterally.
While the classification of various types of edema is useful in attempting to define specific treatment for certain disorders, it should also be recognized as somewhat arbitrary as cytotoxic and vasogenic edema frequently occur concurrently, although in varying proportions. In fact, each of these processes may cause the other
Recent studies of closed head injury in laboratory models have demonstrated, using diffusion-weighted imaging, that the acute phase of brain injury is characterized primarily by cytotoxic edema (Ito...etai 1996). This contrasts with the previous view that vasogenic edema is a primary factor early in acute head injury.
Further evidence to support the fact that cytotoxic edema occurs early in head injury and that vasogenic edema is primarily a late phenomenon is provided by the data of Bullock..etaL (1990), who used single-photon emission CT (SPECT) mapping of blood-brain barrier defects in humans, and by a study using gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) enhanced magnetic imaging in human head injury ( LangeLal 1990). The latter study failed to show evidence of altered blood-brain barrier permeability to gadolinium within the first 4 days following head injury. Thus it can be concluded that therapeutic strategies in head injury need to take account of this new information regarding the time course of various types of edema.
Another example of a mixed cytotoxic edema is that associated with the treatment of hyperglycemia. If blood glucose is reduced too rapidly, a dramatic influx of water into the cerebral tissue can occur in an attempt to regain osmotic equilibrium and this will result in significant cytotoxic edema. This will lead to generalized cerebral ischemia, resulting in further cytotoxic edema because of ischemia.
The process of cytotoxic edema is quite complex because it has not yet been possible to identify all the osmols resulting from cellular injury which can draw water from the intravascular space, and because these osmols and other substances may differ quite substantially depending on the intracranial process responsible for their generation.
Brain edema in particular and increases in intracranial volume in general are particularly dangerous because of the limited capacitance of the brain to tolerate increases in volume. This relationship is described in the Monroe-Kelley doctrine, which states that the relationship between volume and pressure within the intracranial space is not linear and that increases in volume initially result in no increase in pressure, but as one moves to the right on the curve, small additional increments in intracranial volume result in dramatic rises in intracranial pressure. This relationship is made more complex by the fact that the intracranial space, which for many years was believed to be a single compartment, is made up of many compartments which eventually result in generalized increments in pressure but can act as semi-independent compartments producing focal compression. The most dramatic examples of this are separation of the supratentorial from the infratentorial compartment because of obstruction at the tentorium and the substantial pressure differential resulting from a balloon of equal size when inflated in the temporal versus the high parietal region. In the former, pressures within the brainstem are significantly higher than when the lesion is in the parietal lobe. This appears to be because there is a substantial dampening effect of the falx which reduces the transmission of pressure downward; however, when a lesion is located in the temporal lobe, the vector force is directed at the brainstem resulting in higher pressures and much more risk to the patient. This explains why, in the pre-CT era, patients with temporal lobe gliomas were often discovered only after acute deterioration which occasionally was fatal.
The influence of focal versus generalized edema is also quite important. As indicated earlier, the transmission of forces from lesions within the temporal lobe appears to be substantially greater than for disorders of the parietal region and for more generalized processes, where much larger increments in volume and much higher pressures are necessary to produce coma and/or death than when a focal lesion either compresses the brainstem directly or where there are significant amounts of midline shift (of the order of millimeters) resulting in distortion or kinking of the brain stem. Neurosurgeons generally use the degree of midline shift associated with focal lesions to determine whether or not emergency surgical intervention is required, particularly in patients with traumatic injuries, because shifts in excess of 5 mm usually result in compression of the brainstem.
Aggressive surgical treatment of focal lesions of the brain, particularly traumatic contusions and hematomas, and also tumors which result in edema formation and focal inflammatory processes such as brain abscesses, has developed because of a number of laboratory investigations which have clearly shown that these lesions are edematogenic, i.e. they serve to generate edema themselves and their removal will result in the cessation of that process. Some of the clearly demonstrated improvement in the outcome of acute severe head injury is due to early aggressive removal of intraparenchymal hemorrhages and brain contusion before brain edema becomes fully developed.
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