The management of brain edema in brain tumors Evert C.A. Kaal and Charles J. Vecht This review focuses on pathophysiology, clinical signs, and Introduction imaging of brain edema associated with intracranial tumors Brain edema is a prominent feature of brain cancer and and its treatment. Brain edema in brain tumors is the result of often contributes to neurologic dysfunction and impaired leakage of plasma into the parenchyma through dysfunctional quality of life. This review focuses on treatment of brain cerebral capillaries. The latter type of edema (ie, vasogenic edema in brain tumors. Clinical features of patients with edema) and the role of other types in brain tumors is brain tumors are discussed, followed by pathologic and discussed. Vascular endothelial growth factor-induced pathophysiologic aspects of brain edema, and methods dysfunction of tight junction proteins probably plays an for diagnosing its presence. The practice of corticoste- important role in the formation of edema. Corticosteroids are roid administration, corticosteroid dependency, and the mainstay of treatment of brain edema. When possible, withdrawal effects are discussed, together with a number corticosteroids should be used in a low dose (eg, 4mg of new agents that can influence the development of dexamethasone daily) to avoid serious side effects such as brain edema. myopathy or diabetes. Higher doses of dexamethasone (16 mg/day or more), sometimes together with osmotherapy Clinical presentation (mannitol, glycerol) or surgery, may be used in emergency Papilledema, occipital headache worsening in the morn- situations. On tapering, one should be aware of the possible ing, nausea and vomiting, abnormal eye movements, and development of corticosteroid dependency or withdrawal impaired consciousness are the classic signs of raised in- effects. tracranial pressure. Headache can be a prominent feature Novel therapies include vascular endothelial growth factor of patients with brain edema and is probably caused by receptor inhibitors and corticotropin releasing factor, which traction or pressure on pain-sensitive structures such as should undergo further clinical testing before they can be dural coverings and blood vessels. In one large series, recommended in practice. 60% of patients with brain tumors reported headache. The pain seems dependent on size and location of the Keywords tumor (infra- vs supratentorial), presence of midline shift, brain tumor, edema, corticosteroids, toxicity, blood–brain a prior history of headaches, and the amount of edema barrier, imaging surrounding the tumor [1,2]. Headache in patients with cancer is an ominous sign: Intracranial metastases were Curr Opin Oncol 16:593–600. © 2004 Lippincott Williams & Wilkins. found in more than 30% of cancer patients with head- ache as the presenting symptom. Headache duration of 10 weeks or less, emesis, and pain not of a tension type are significant clinical predictors for the presence of brain metastases in cancer patients [3]. Department of Neurology, Medical Centre Haaglanden, The Hague, Netherlands Correspondence to Charles J. Vecht, MD, PhD, Department of Neurology, Medical Centre Haaglanden, PO Box 432, 2501 CK The Hague, The Netherlands An important, although less frequently found, feature is Tel: 31 70 330 2067; fax: 31 70 330 3113; e-mail: [email protected] papilledema. However, its absence would not exclude a Current Opinion in Oncology 2004, 16:593–600 brain tumor: Papilledema was absent in more than two Abbreviations thirds of patients with cerebellar metastases and head- CRF corticotropin-releasing factor ache. In older patients with atrophic brains, the occur- VEGF vascular endothelial growth factor rence of brain edema would often not result in increased VEGFR vascular endothelial growth factor receptor intracranial pressure, probably because of a surplus of © 2004 Lippincott Williams & Wilkins intracranial space, and this may explain the more con- 1040-8746 spicuous absence of papilledema in the elderly. Vomit- ing is more common in children than in adults, and is more often associated with infratentorial lesions. Hemiparesis, dysphasia, cognitive decline, and other fo- cal neurologic signs may either be the result of brain edema or of tumor growth. Thirty to 40% of patients with 593 594 Brain and nervous system brain tumors present with focal neurologic deficits, and a the ventricles and the brain parenchyma. Brain similar percentage develops epilepsy [4,5]. capillaries are not affected, and restitution of the normal cerebrospinal fluid flow will therefore lead Infratentorial lesions need special attention given the to clearance of hydrocephalic edema. vulnerability of the brainstem. Under these conditions, a Osmotic edema is the result of an altered osmotic small amount of edema may result in severe symptoms of gradient between the plasma and the interstitial increased intracranial pressure such as impaired con- fluid. Severe osmotic edema can be seen after wa- sciousness, and emergency treatment is often necessary. ter intoxication, acute hyponatremia, or too rapid reduction of hyperosmolarity [7]. Pathology and pathophysiology Stasis, induced by tumor in venous drainage areas (eg, During the last decade, pathophysiologic mechanisms of compression of an adjacent cortical vein by the tu- brain edema have been extensively studied. Brain mor), with stasis at the site of the compression, edema can be defined as an expansion of brain volume results in peritumoral edema [8]. resulting from an increase in water and sodium content. An excretory–secretory mechanism in meningiomas in Two major types of edema can be characterized: intra- which tumor-produced substances appear in the and extracellular edema. peritumoral tissue was postulated in the 1980s. Based on electron microscopic studies, a close cor- Intracellular edema relation was found between secretory activity and Increased intracellular water content results in cellular production of edema [9]. swelling. This type of edema is often the result of cyto- Hydrodynamic processes, in which fluids originate toxic injury such as cerebral ischemia or trauma and is from the tumor itself, may contribute to the forma- therefore called “cytotoxic edema.” In this type of tion of edema. It was recently shown that contrast edema, the primary targets are the ATP-dependent so- agent effusion from the extracellular space of me- dium pumps: Energy depletion-induced dysfunction of ningiomas into the interstitium of the peritumoral these pumps results in increased intracellular sodium tissue was detectable 3 to 6hours after contrast levels and, as a consequence, results in the accumulation administration [10•]. of intracellular water. Cytotoxic edema is probably not an important component of brain tumor edema, although it Morphologic and molecular alterations in may play a role in situations when (micro)circulation is the blood–brain barrier impeded (eg, after brain herniation). The blood–brain barrier is a highly selective interface Extracellular edema separating the brain from the blood. Its most important In the extracellular compartment, water can either be component is the capillary endothelial cell. In contrast to part of the cerebrospinal fluid or of the interstitial fluid. extracerebral capillaries, cerebral endothelial cells are The production of interstitial fluid is probably driven by nonfenestrated, lack intracellular clefts, contain low a pressure and osmotic gradient, is often called “bulk numbers of pinocytotic vesicles, have a high mitochon- flow,” and it may have a role in transporting nutrients drial content, and are enclosed by astrocytic foot pro- and metabolites. An increase in extracellular water leads cesses. These endothelial cells are connected by tight to brain edema. This type of edema is mostly located in junctions, which have both a high electric impedance the white matter. Its properties, consisting of axons run- and a low permeability to polar solutes, and they con- ning parallel to one other and surrounded by an extra- tribute to the selective barrier in this way. Opening of cellular space with a low cell density, would contribute to tight junctions probably plays a key role in the formation a concentration of the edema within the white matter of vasogenic brain edema. and may also serve as a conduit for transporting fluid [6••]. Edema accumulates around brain tumors at a rate of 14 to 78 mL/day [11]. Absorptive mechanisms help to main- The various types of extracellular edema are as follows. tain equilibrium between edema formation and edema absorption. Edema is absorbed by transependymal flow Vasogenic edema is the most common type in brain into the ventricles and by absorption into microvessels. tumors. As a result of increased brain capillary per- The resulting excess of extracellular protein is removed meability and a pressure gradient from vascular to by phagocytosis by astrocytes and microglia. extracellular compartments, plasma leaks into the brain parenchyma and follows the pathways of bulk The proteins occludin, claudins, and the junctional ad- flow. This type of edema is described in more de- hesion molecule are all part of the molecular composition tail in the next section. of tight junctions in the normal brain [12–15,16•,17•]. Hydrocephalic edema is the result of the obstruction These transmembrane proteins bind intracellular pro- of cerebrospinal fluid flow. Edema is formed be- teins such as ZO-1 and ZO-2, and this binding results in cause of a hydrostatic pressure gradient between