The author: Professor Yasser Metwally
http://yassermetwally.com
INTRODUCTION
November 9, 2009 — Vasogenic edema is characterized by increased permeability of brain capillary endothelial cells (as consequence of vascular injury with disruption of the BBB, or due to defective endothelial lining of the newly formed blood vessels in brain neoplasms) to macromolecules, such as the plasma proteins and various other molecules, whose entry is limited by the capillary endothelial cells (blood brain barrier). Grossly, the gyri are flattened and the sulci narrowed; the white matter is moist and swollen. Microscopically, there is micro-vacuolization of the white matter, poor staining, and "halo’s" around nuclei.
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Causes of vasogenic edema include trauma, tumor, abscess, hemorrhage, infarction, acute MS plaques, and cerebral contusion. It also occurs with lead encephalopathy or purulent meningitis and sinus thrombosis
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Vasogenic edema is the most common type of edema associated with brain tumors, venous congestion and other causes and results from local disruption of the blood brain barrier. This leads to extravasation of protein-rich filtrate of plasma into the interstitial space, with subsequent accumulation of vascular fluid. This disruption results from loosening of the tight junctions between endothelial cells, and the neoformation of pinocytic vesicles. Once the barrier is breached, hydrostatic and osmotic forces work together to extravasate intravascular fluid. Once extravasated, fluid is retained outside the vasculature, mostly in the white matter of the brain, and within the bundles of myelinated axons of long tracts and commissural fibers. This is because axons run in parallel bundles of fibers with loose extracellular space (that offer low resistance and facilitates the extension of vasogenic edema along myelinated axons which are spreaded apart by the edema) as opposed to gray matter, which has high cell density and is enmeshed in an interwoven network of connecting fibers that offer high resistance to the formation and spread of edema. By definition, this type of edema is confined to the extracellular space. (70)
Cerebral edema may be defined broadly as a pathologic increase in the amount of total brain water content leading to an increase in brain volume 39. It occurs when plasma-like fluid enters the brain extracellular space through impaired capillary endothelial tight junctions in tumors (vasogenic edema) 40 and is a significant cause of morbidity and mortality. The molecular constituents of brain endothelial tight junctions consist of transmembrane proteins occludin, claudin 1 and 5, and junctional adhesion molecules that bind their counterparts on neighboring cells, “gluing” the cells together and creating the blood-brain barrier (BBB) 40. Intracellularly, the occludins and claudins bind to zonula occluden (ZO) 1, ZO2, and ZO3, which in turn are attached to the actin cytoskeleton 40. Normal astrocytes help to maintain a normal BBB 41, which is illustrated in Plate. 1. In high-grade tumors, the deficiency of normal astrocytes leads to defective endothelial tight junctions, resulting in BBB disruption, allowing passage of fluid into the extracellular space 40. In addition, tumor cells produce factors, such as vascular endothelial growth factor (VEGF) 42,43 and scatter factor/hepatocyte growth factor 44,45, which increase the permeability of tumor vessels by downregulation of occludin and ZO1 40,44,46,47. In addition, the membrane water channel protein, aquaporin-4 (AQP4), is upregulated around malignant brain tumors 40. AQP4-mediated transcellular water movement is important for fluid clearance in vasogenic brain edema, suggesting AQP4 activation or upregulation as a novel therapeutic target in vasogenic brain edema 40,48. High VEGF expression is reported in human anaplastic astrocytoma and glioblastoma (GBM) 49,50 meningiomas 44, and brain metastases 51. VEGF is important especially when tumors outgrow their blood supply. Hypoxia is the driving force for VEGF production in glioblastomas and the most important trigger for angiogenesis and cerebral edema formation in glioblastoma 52.
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Plate 1. The BBB. Normal BBB demonstrating tight junctions between endothelial cells forming a barrier between the circulation and the brain parenchyma. Peritumoral edema formation occurs through defective endothelial junctions of an abnormal BBB. (Click to enlarge figure)
Increased capillary permeability to large molecules is the corner stone in the aetiopathogenesis of vasogenic edema. The increase in permeability is visualized when contrast enhancement is observed with CT or MRI.
The increase in permeability is visualized when contrast enhancement is observed with CT or MRI. Increased CSF protein levels are also indicative of increased endothelial permeability. MRI is more sensitive than CT in demonstrating the increased brain water and increased extracellular volume that characterize vasogenic edema. Vasogenic edema is characteristic of clinical disorders in which there is frequently a positive contrast-enhanced CT or increased signal intensity with MRI, including brain tumor, abscess, hemorrhage, infarction, and contusion. It also occurs with lead encephalopathy or purulent meningitis.
Figure 1. A, Loss of the gray-white interface with obscuration of the lentiform nucleus, loss of the insular ribbon, sulcal effacement and mass effect are seen in the left hemisphere due to vasogenic edema, B, Grossly , the gyri are flattened and the sulci narrowed; the white matter is moist and swollen. Notice uncal herniation (arrow). (Click to enlarge figure)
The functional manifestations of vasogenic edema include focal neurologic deficits, focal EEG slowing, disturbances of consciousness, and severe intracranial hypertension. In patients with brain tumor, whether primary or metastatic, the clinical signs are often caused more by the surrounding edema than by the tumor mass itself. Ultimately, these changes can lead to herniation.
Figure 2. Occipital glioblastoma surrounded by vasogenic edema involving only the white matter. (Click to enlarge figure)
Highly aggressive tumors (glioblastomas, metastatic tumours, etc.) occur at all ages; however, there is a strong trend toward increasing malignancy with age. Highly malignant tumours and rapidly growing tumours are more commonly surrounded by vasogenic tumours than more benign tumours and tumours with a lower grade of malignancy. Highly aggressive tumors are diffusely invasive tumors that typically have a destructive cellular core. Radiological signs characteristic of vasogenic brain edema is described in the following table.
Table 1. Radiological signs characteristic of vasogenic brain edema
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RADIOLOGICAL SIGN
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COMMENT
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Contrast enhancement.
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Contrast enhancement is due to break down of blood brain barrier which is the corner stone in the aetiopathogenesis of vasogenic edema. The microscopic correlate of enhancement is hypercellularity, mitotic activity, neovascularity (in brain tumours) and breakdown of blood brain barrier resulting in increased permeability of brain capillary endothelial cells to macromolecules, such as the plasma proteins and various other molecules, whose entry is limited by the capillary endothelial cells (blood brain barrier)
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Diffuse low density on CT scan, diffuse MRI T1 hypointensity and diffuse MRI T2 hyperintensity with loss of the gray-white interface, obscuration of the lentiform nucleus, loss of the insular ribbon.
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Obscuration of the lentiform nucleus, loss of the insular ribbon is simply due to loss of the gray-white interface.
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Sulcal effacement.
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Grossly , the gyri are flattened and the sulci narrowed; the white matter is moist and swollen. Microscopically, there is micro-vacuolization of the white matter, poor staining, and "halo’s" around nuclei.
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Mass effect, with ventricular effacement.
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Is a common cause of brain herniation.
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The relationship between neuroimaging actual tumor extent is critical to the use of these studies in diagnosis and treatment design. In general three zones are identified in malignant brain tumours (1) A central zone (hypointense on the MRI T1 images, hyperintense on the MRI T2 images and hypodense on CT scan) (2) A peripheral enhanced rim with multiple enhanced mural nodules and (3) An ill-defined diffuse large zone surrounding the first two zones. (hypointense on the T1 images, hyperintense on the T2 images and hypodense on CT scan). The first zone corresponds to the necrotic tumour tissues, the microscopic correlate of enhancement is hypercellularity, mitotic activity, and neovascularity with breakdown of blood brain barrier resulting in increased permeability of brain capillary endothelial cells to macromolecules, such as the plasma proteins and various other molecules, whose entry is limited by the capillary endothelial cells (blood brain barrier), while the third zone corresponds to edema, malignant glial cell infiltrations and reactive gliosis. The surrounding zone of edema demonstrates a decreasing gradient of infiltrating tumor cells. The infiltrating tumor cells primarily follow white matter tracts, accompanied by vasogenic edema that may facilitate migration. 1,2,3,4,5 Although tumor cells may spread a great distance, typically, most are within 2 cm of the enhancing margin.6
Table 2. In general three zones are identified in malignant brain tumours
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ZONE
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DESCRIPTION
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Central zone
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Formed of necrotic tumour tissue
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Intermediate contrast enhancing rim
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Formed of viable tumour tissue
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Peripheral diffuse zone
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Formed of edema, reactive gliosis and malignant cell infiltrations
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Glioblastomas characteristically send malignant cells streaming into the surrounding brain. This mode of spread is apparently facilitated by the widened extracellular spaces created through vasogenic edema.
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Two types of cysts—peritumoral and intratumoral— are associated with CNS tumors. Peritumoral cysts develop within the brain or spinal cord and form at the margin of the tumor. Alternatively, intratumoral cysts develop within the tumor itself and are usually the result of intratumoral necrosis. Overall, cysts are associated with approximately 10% of benign, malignant, and metastatic tumors of the CNS. They are most frequently associated with hemangioblastomas (83%), cerebellar astrocytomas (77%), and cerebral astrocytomas (29%). The presence of peritumoral cysts can lead to significant neurological impairment due to mass effect and increased intracranial pressure. Based on advances in imaging, histological, and molecular techniques, insight into the mechanism behind peritumoral cyst formation has been provided, and evidence indicates that peritumoral edema precedes and underlies the propagation of these cysts.
Peritumoral cysts (those arising immediately adjacent to the tumor mass) are frequently associated with benign and malignant tumors of the brain and spinal cord (syringomyelia). The cystic component of central nervous system (CNS) tumors and associated peritumoral cysts are often the cause of clinical symptoms. Because of the common occurrence of peritumoral cysts with CNS neoplasms and the morbidity associated with them, advanced imaging, histological, and molecular techniques have been used to determine the mechanism underlying cyst formation and propagation. Based on evidence from such studies, edema appears to be a common precursor to peritumoral cyst formation in the CNS. Mediators of vascular permeability acting locally in the tumor and/or hydrodynamic forces within abnormal tumor vasculature appear to drive fluid extravasation. When these forces overcome the ability of surrounding tissue to resorb fluid, edema and subsequent cyst formation occur. These findings support the concept that the tumor itself is the source of the edema that precedes cyst formation and that resection of tumors or medical therapies directed at decreasing their vascular permeability will result in the resolution of edema and cysts.
Cerebral edema tends to extend along white matter tracts. CT and MRI are helpful in the diagnosis of edema. Therapy includes tumor-directed measures, such as debulking surgery, radiotherapy (RT), chemotherapy, and the use of corticosteroids. Ingraham and coworkers pioneered the use of cortisone to treat postoperative cerebral edema in neurosurgical patients in 1952. He first used steroids in an attempt to ameliorate postoperative adrenal insufficiency in patients undergoing craniotomy for craniopharyngioma resection and noted the favorable effect on postoperative cerebral edema 53. Galicich and colleagues 54 and French and Galicich 55 introduced dexamethasone therapy as the standard treatment for tumor-associated edema. Despite their well-known side effects, better alternatives do not exist and corticosteroids have remained the mainstay of treatment ever since.
The mechanism of action of corticosteroids is not well understood. It has been argued that their antiedema effect is the result of reduction of the permeability of tumor capillaries by causing dephosphorylation of the tight junction component proteins occludin and ZO1 40. Corticosteroids usually are indicated in any patients who have brain tumor who have symptomatic peritumoral edema. Dexamethasone is used most commonly as it has little mineralocorticoid activity and, possibly, a lower risk for infection and cognitive impairment compared with other corticosteroids 57. The choice of starting dose of a corticosteroid largely is arbitrary and depends on the clinical context. The usual starting dose is a 10-mg load, followed by 16 mg per day in patients who have significant symptomatic edema. Lower doses may be as effective, especially for less severe edema 58. The dose may be increased up to 100 mg per day if necessary 59. Dexamethasone can be given twice daily, although many clinicians prescribe it 4 times daily. As a general rule, patients should be treated with the smallest effective dose for the shortest time possible to avoid the harmful effects of steroids. For asymptomatic patients who have peritumoral edema on imaging studies, corticosteroids are unnecessary. Dexamethasone usually produces symptomatic improvement within 24 to 72 hours. Generalized symptoms, such as headache and lethargy, tend to respond better than focal ones. Improvement on CT and MRI studies often lags behind clinical improvement. Contrast enhancement of tumors typically decreases, suggesting partial restoration of the BBB 60, whereas tumor perfusion can increase because of reduced peritumoral water content and local tissue pressure 61. Using diffusion tensor MRI, administration of corticosteroids decreases peritumoral extracellular water content in edematous brain without affecting the water content of contralateral normal brain. 62
Occasionally, when there is significant mass effect and impending herniation, other measures may be required until corticosteroids have had a chance to take effect or until patients undergo debulking surgery. These include elevation of the head of the bed, fluid restriction, mannitol, hypertonic saline, diuretics, and hyperventilation 63,64.
After more surgical debulking, steroids should be tapered. The taper can start within a week after surgery but should be delayed in symptomatic patients undergoing RT. In general, patients who have brain tumors exerting significant mass effect should receive steroids for 24 hours before starting RT to reduce intracranial pressure and minimize neurologic symptoms.
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