53
Cerebral Edema
Robert J. Weil and Edward H. Oldfield
OVERVIEW AND HISTORICAL BACKGROUND
Cerebral edema represents the accumulation of excess fluid in the
intracellular or extracellular spaces of the brain. It can result from
a variety of physiologic and pathologic processes and is frequently
responsible for much of the morbidity and mortality associated
with brain tumors and a variety of other disorders, including
trauma, infarction, hemorrhage, and infection. A basic conception
of the barriers that exist between and among blood, cerebrospinal
fluid (CSF), and the brain is required to fully understand cerebral
edema. In this chapter we outline the physiology of the blood-
brain barrier (BBB) and describe and discuss the principal types
and causes of cerebral edema. Reviews that outline the history of
research and recent advances in this area and that provide detailed
summaries beyond the scope of this chapter are cited in the
references.
Paul Ehrlich was the first to identify a potential barrier
between the vasculature and the brain after he observed that
intravenous albumin-bound dyes stained all tissues except the
brain.1 Goldmann carried Ehrlich’s studies further to demon-
strate that dye injected into the CSF did not circulate in the
systemic circulation.2 These barriers (Table 53-1), which are rate-
limiting steps in the movement of water, ions, solutes, and mac-
romolecules between compartments, help the brain regulate its
own environment distinct from the rest of the body. The BBB is
an essential component of brain homeostasis.
THE BLOOD-BRAIN BARRIER
The principal component of the BBB is the endothelial cells that
line the cerebral microvasculature (Fig. 53-1).3-10 The tight junc-
tions between adjacent endothelial cells in the brain, which are
nonpermissive in comparison to those in the systemic circulation,
prevent the paracellular transport of most molecules. Although
small substances, such as oxygen and carbon dioxide, and small
lipophilic molecules, such as ethanol, may diffuse freely through
the lipid membranes that constitute the BBB, larger, bulkier,
more complex or hydrophilic molecules require active, transcel-
lular transport mechanisms, potentially on both the luminal
(endothelial) and abluminal (brain) membranes, to enter the
brain.11 The active transport mechanisms require energy in the
form of adenosine triphosphate (ATP).11
Several studies have identified a variety of molecular mecha-
nisms and metabolic barriers that indicate that the BBB is an
exceptionally active system.11-13 For example, endothelial cells
contain active peptides, peptidases that inactivate traversing pro-
teins, and numerous intracellular enzymes, such as cytochrome
P-450 (1A and 2B isoforms), that inactivate neuroactive and neu-
rotoxic substances.14,15 In general, to traverse the normal BBB,
large or hydrophilic molecules require an active transport
mechanism—either receptor-mediated or absorptive-mediated
transcytosis. In the cerebral endothelium, these mechanisms are
less efficient than in systemic (outside the central nervous system
[CNS]) endothelial cells, which enhances the potential BBB.
Thus the BBB contains active and passive features that regulate
the passage of substances from the systemic circulation into the
brain. Similar versions of these tight junctions and permeability
restrictions are found between CSF and the brain (except in the
circumventricular organs [area postrema, tuber cinereum, pineal
e424
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gland, the subcommissural organ (SCO), the posterior pituitary,
the pineal gland, the median eminence and the intermediate lobe
of the pituitary gland], where the endothelium is penetrated more
easily to permit secreted neuropeptides to act systemically; see
Table 53-1).11-16
The BBB has an extensive surface area—which some research-
ers have estimated to be approximately 20 m2/1.3 kg of brain.
Consequently, no neuron is more than 20 to 25 µm away from a
brain capillary, and thus the BBB plays several critical roles in
regulation of the brain’s microenvironment.17,18 It manages the
entry of nutrients and controls elimination of wastes. The BBB
also limits distribution and thus contains within the brain neuro-
regulators and neurotransmitters produced within the brain that
act centrally, while excluding or regulating entry into the brain
of similar molecules intended to act peripherally. This reduces
or prevents debilitating biochemical crosstalk within the CNS.
Finally, the BBB regulates movement of fluid and ions between
the circulation and the brain, which permits maintenance of
an ideal interstitial fluid that enhances neuronal function. The
brain’s interstitial fluid has some similarities with plasma but
has a lower protein content and lower concentration of calcium
(Ca2+) and potassium (K+) ions and a higher concentration of
magnesium (Mg2+), which generates a significant buffering capac-
ity. This limits the effect of fluxes of systemic metabolism, such
as occur with exercise, a meal, or starvation.5,11,19 Continuous
turnover of interstitial fluid and CSF, which is regulated by the
cerebral endothelium and its barriers (see Table 53-1), is critical
to homeostasis of the brain’s microenvironment.
MOLECULAR EVENTS IN CEREBRAL EDEMA
Cerebral edema is a common end result of a variety of neurologi-
cal and systemic disorders. Most classifications of cerebral edema
describe four categories (summarized in Table 53-2): cytotoxic,
or cellular swelling secondary to cell injury; vasogenic, which
results from vascular leakage through a disrupted BBB and con-
sequently increased fluid and altered concentrations of ions, pep-
tides, and macromolecules in the extracellular space; interstitial,
which occurs with transependymal flow of CSF in patients with
hydrocephalus; and osmotic, when the brain is hyperosmolar rela-
tive to plasma and thus induces water to flow passively across an
intact BBB along its concentration gradient. It may be difficult
to separate edema into these distinct classes in every patient
because more than one of these types exist simultaneously as a
result of the nature and timing of the underlying disorder (see
Table 53-2). Because interstitial edema and osmotic edema have
fewer causes or are uncommon in neurosurgical patients, our
principal focus in this chapter is on vasogenic and cytotoxic
edema.
Tissue swelling—edema—may be intracellular or extracellu-
lar. It has the potential to result in profound shifts in the relative
volumes occupied by the cellular and interstitial elements. Con-
tinued redistribution of water, ions, peptides, and other neuroac-
tive substances within and between the cells of the CNS (neurons,
glia, microglia, and endothelial cells) may exacerbate the severity
of the edema. These failures lead to a variety of molecular events
and cascades that potentiate cerebral and BBB dysfunction, some
of which are summarized later and are discussed in greater detail
in several recent, specialized monographs.4,5,20
 CHAPTER 53  Cerebral Edema e425

TABLE 53-1  Principal Features of the Blood-Brain Neurovascular Unit

53
Location of the
Interface Blood-Brain Junction Functional Outcome
Blood-brain Capillary endothelial Active transport of most materials. The Na+,K+-ATPase pump on the apical surface of the capillary
cell (see Fig. 53-1) endothelium transports materials across high-resistance tight junctions. Tight junctions restrict
the entry of hydrophilic materials and high-molecular-weight molecules.
Blood-CSF Choroid plexus Ultrafiltration of plasma with active secretion of CSF; this high-energy process requires ATP.
Essential components are ATPase and carbonic anhydrase.
CSF–venous blood Arachnoid granulations Arachnoid granulations transmit CSF into the cerebral venous sinuses along a pressure gradient.
ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; CSF, cerebrospinal fluid.

Astrocyte Pericyte
Basement
membrane
Endothelial cell
Tight junction
A The edema associated with brain tumors results from this
1 3
2 1 2
B C
Figure 53-1. Microscopic representations of the blood-brain
barrier (BBB) and the two most common forms of cerebral
edema. A, The BBB is created by compact apposition of endothelial
cells to create a barrier between the vascular system and the brain
parenchyma. This is reinforced by numerous pericytes. A thin
basement membrane surrounds the endothelial cells and provides
both structural support and a dense physical barrier between the
circulation and the microenvironment of the brain. Astrocytes extend
cellular processes (astrocytic “foot processes”) that cover the
basement membrane, which enhances the BBB by limiting the ability
of macromolecules or circulating cells to gain access to the central
nervous system. B, In vasogenic edema, increased permeability of the
capillaries, through dehiscent or incompetent tight junctions, leads to
exudation of a plasma ultrafiltrate and water into the extracellular
space. Arrows demonstrate flow through the tight junctions and into
the extracellular space. C, In cytotoxic edema, depletion of energy
and metabolites leads to failure of the sodium-potassium adenosine
triphosphatase (Na+,K+-ATPase) pump and accumulation of sodium
within the cells (astrocytes and endothelial cells, as well as neurons);
water follows the concentration gradient into the cells, which swell in
response. Arrows demonstrate the path of water into cells from the
vascular space. 1, Astrocytes and astrocytic foot processes; 2,
endothelial cells; 3, neurons. (A, Reprinted with permission, Cleveland
Clinic Center for Medical Art & Photography © 2005-2010. All Rights
Reserved.)
Vasogenic Edema
Vasogenic edema shares some mechanisms with cytotoxic and
other forms of brain edema. However, the principal source of
edema formation is abnormal permeability of the BBB.21 The
most common source is a primary or secondary brain tumor, in
which case the nascent microvessels are deficient in tight junc-
tions. A recent study histologically examined the perivascular
architecture between the astrocyte and the endothelial cell in
gliomas and metastatic tumors and demonstrated breakdown of
the normal astrocyte−endothelial cell relationship in regions of
magnetic resonance imaging (MRI) enhancement.22 This “blood-
tumor barrier” is an incompetent obstacle that permits leakage
of plasma ultrafiltrate into the brain’s extracellular space.18,23,24
passive deficiency and from cellular invasion and migration.10,25,26
In addition, many tumors have active mechanisms to promote
vascular permeability and neovascularity. The most widely studied
permeability and angiogenic agent secreted by tumor cells is
vascular endothelial growth factor (VEGF), which induces capil-
lary permeability, endothelial proliferation, and migration and
organization of new capillaries that lack tight junctions.27 Addi-
tional chemokines, cytokines, growth factors, and inflammatory
mediators that play similar or complementary roles in blood-
tumor permeability and angiogenesis have been identified. For
example, angiopoietin-1, angiopoietin-2, fibroblast growth factor,
hepatocyte growth factor/scatter factor, platelet-derived growth
factor, interleukin-3 (IL-3), IL-4, IL-8, transforming growth
factor-α (TGF-α), TGF-β, a variety of adhesion molecules and
proteases such as urokinase plasminogen activator, multiple
matrix metalloproteinases, integrins αvβ3 and αvβ5, and even
oncogenes such as mutated Ras and tumor suppressor gene prod-
ucts such as Tp53 and vhl protein can affect BBB function. Many
of these are discussed elsewhere in this volume.
The most thoroughly studied mechanism that produces cere-
bral edema is the vasogenic edema mediated by tumor produc-
tion of a macromolecular protein initially identified as vascular
permeability factor (VPF) and later, after its angiogenic activity
had been identified, as VEGF. VPF/VEGF was initially identified
by Senger and Dvorak in 1983.28 Their landmark study demon-
strated that the ascites caused by the intraperitoneal injection of
hepatocarcinoma cells into guinea pigs was a product of excess
permeability of the small vessels that line the peritoneal cavity
and, furthermore, that a protein secreted by the tumor and acting
on the vessels was responsible for the enhanced vascular perme-
ability. Hepatocarcinoma lines that did not produce the protein
did not cause ascites. In addition, in an in vivo biologic assay of
vascular permeability by intradermal injection, the Miles assay,
the enhanced vascular permeability produced by the protein was
blocked by antibodies to the partially isolated protein. Secre-
tion of the same protein was subsequently shown to occur in
many systemic and CNS tumors.29-31 Bruce and colleagues30 and
Heiss and associates32 demonstrated that vascular permeability
is increased by conditioned media from cultures of high-grade
gliomas and meningiomas, the types of human brain tumors that

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e426 SECTION 2  Basic and Clinical Sciences

TABLE 53-2  Characteristics of the Principal Types of Cerebral Edema

Feature Cytotoxic Edema Vasogenic Edema Interstitial Edema Osmotic Edema
Pathophysiology Osmotic gradient because of Increased vascular Transependymal flow of water The brain is hyperosmolar
metabolic failure of the permeability at the level and solutes into the with respect to plasma;
Na+,K+-ATPase pump, with of the blood-brain barrier periventricular extracellular water moves along the
cellular swelling of all (or blood-tumor barrier), space; caused by osmotic gradient
elements (neurons, glia, and with extracellular fluid hydrocephalus and
endothelial cells) accumulation of an impaired absorption of CSF
ultrafiltrate of plasma
Composition of Net intracellular accumulation of Ultrafiltrate of plasma CSF Extracellular greater than
edema fluid water and sodium intracellular
Location of edema Gray and white matter White matter principally Periventricular white matter White matter
Extracellular fluid Decreased Increased Increased Increased
volume
Typical etiology Anoxia, diabetic ketoacidosis, Brain tumors (primary and Hydrocephalus Hemodialysis, hypertensive
hepatic encephalopathy, metastatic), abscess and crisis, syndrome of
hypothermia, infarction or encephalitis, infarction in inappropriate antidiuretic
ischemia, infection, the late stages, lead hormone secretion,
meningitis, Reye’s syndrome, toxicity, trauma water intoxication
trauma, water intoxication
Response to Yes/no Yes Yes Yes/no
therapy
Corticosteroids Not effective Yes Not effective Not effective
Diuretics Transiently effective Minimally or not effective Transiently effective Not effective
Other Reversal of primary insult Reversal of primary insult Reversal of primary insult (e.g., Reversal of primary insult
(e.g., removal of tumor) ventriculoperitoneal shunt or
third ventriculostomy)
ATPase, adenosine triphosphatase; CSF, cerebrospinal fluid.

most commonly produce clinically significant cerebral edema.
In addition, they demonstrated that antibodies to VPF/VEGF
block the permeability-enhancing effects of conditioned media
from tumor types that produce cerebral edema and showed that
glucocorticoids block the permeability-enhancing effects of VPF/
VEGF on the vessel wall and inhibit tumor cell production of
VPF/VEGF.30,32 CNS tumors that are frequently associated with
marked edema, such as glioblastomas, meningiomas, and metas-
tases, contain high levels of VPF/VEGF gene expression, whereas
the types of CNS tumors that are not commonly associated
with significant cerebral edema do not produce levels of VPF/
VEGF messenger RNA higher than found in normal brain.31
The clinical relevance of VPF/VEGF as a principal mediator
of peritumoral edema is confirmed by the reduction in con-
trast enhancement (vascular permeability) and surrounding
cerebral edema on clinical imaging studies after treatment of
glioblastoma patients with bevacizumab, an anti-VEGF antibody
(Fig. 53-2).33-35
Cytotoxic Edema
Cytotoxic edema occurs after cerebral infarction or ischemia,
meningitis, Reye’s syndrome, trauma, seizures, and water intoxi-
cation. Several overlapping mechanisms underlie cytotoxic cere-
bral edema. One common mechanism of cytotoxic edema
associated with cerebral ischemia implicates a direct role for
excess glutamate.36-38 After hypoxia, neuronal swelling results
from sodium influx through α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptors and kainite receptor
activity and from influx of chloride ion and water, which enter
passively.36-38 The glial swelling associated with glutamate toxicity
is due to enhanced sodium entry into astrocytes by glutamate
transporter hyperactivity.11,12,17,39 Additional and complementary
mechanisms, including dysfunction of the sodium-potassium
adenosine triphosphatase (Na+,K+-ATPase) pump, which permits
sodium influx, and activation of the Na+/H+ and Cl–/HCO3–
exchangers and the Na+/K+/2Cl– cotransporter contribute to
combined neuronal and astrocytic swelling.11,12,17,39 The altered
extracellular potassium ion concentration that occurs, for example,
with primary epilepsy or with seizures after ischemia causes swell-
ing through the Na+/K+/2Cl– cotransporter.40-42 The same trans-
mitter, because it passively allows passage of ammonium ions, has
been implicated in cerebral edema associated with hepatic
encephalopathy. Aquaporin-4, a member of the family of aqua-
porin water channels, is enriched in astroglial end-feet and plays
a central role in the entry of water into astrocytes.43-45 Further-
more, the Kir4.1 potassium channel that colocalizes with
aquaporin-4 regulates extracellular potassium concentration.
Elevated levels of potassium ions passing through Kir4.1 chan-
nels depolarize astrocytes (as they do neurons), which enhances
astroglial uptake of sodium and bicarbonate through the Na+/
HCO3– cotransporter.19 This increases intracellular osmolarity
and allows water to move passively into the cell through
aquaporin-4 channels. Aquaporin-1 and aquaporin-4, which are
overexpressed in primary and secondary brain tumors, also can
enhance water uptake.43-45
Other mechanisms that lead to or enhance cytotoxic edema
occur after hypoxic, ischemic, or traumatic brain injury. Loss of
intracellular ATP and glutamate release enhance the influx of
calcium ions. Efflux of one calcium ion is associated with the
uptake of three sodium ions, which potentiates the osmotic gradi-
ent and draws more water into the cell. Excess intracellular
calcium ions can initiate apoptosis, activate inflammatory cas-
cades through activation of immediate early genes such as c-fos
and c-jun, and generate the release of a variety of cytokines,
free radicals, and proteases that act on surrounding neuronal and
glial cells, the extracellular matrix, and the cerebral endothe-
lium.17,38,39,46-48 Furthermore, nitric oxide (NO), which serves as a
vasodilator but may also exert toxic effects through interactions
with superoxide anions to generate peroxynitrite anions (ONOO–),
may exacerbate cerebral edema in certain circumstances.49 NO is
synthesized by nitric oxide synthase (NOS), which has three
distinct forms. Neuronal NOS produces toxic free radicals early
after cytotoxic injury; endothelial NOS produces NO that
enhances blood flow through vasodilation; and inducible NOS,
produced by macrophages and microglia, can exacerbate injury

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 CHAPTER 53  Cerebral Edema e427

through generation of NO—and free radicals—24 to 48 hours

after the initiating insult has passed.3,49 53
Inflammation may also figure prominently in disruption of
the BBB. For example, inflammatory cascades enhance the
expression of bradykinin, substance P, leukotrienes, serotonin,
and histamine, all of which nonselectively open the BBB to
varying degrees.3,5,50 Lipopolysaccharides, released during infec-
tion, induce the production of tumor necrosis factor and reactive
oxygen species from microglia with potent effects on BBB perme-
ability and can worsen cytotoxic injury.3,5,11 Finally, Simard and
coworkers recently identified a nonselective cation channel
(NCCA) or NCCa-ATP channel, that when opened by depletion
of ATP, causes cytotoxic edema associated with ischemia. This
channel is regulated by sulfonylurea receptor 1, which can be
blocked by low doses of glibenclamide and thus provides a poten-
tial new approach to treat cerebral edema associated with cerebral
infarction and brain trauma.51-53 Preliminary results from a pro-
spective phase IIa trial have been encouraging.54

NEUROIMAGING STUDIES AND CLASSIFICATION

Figure 53-2. Effects of treatment with an antibody to vascular
endothelial growth factor on the contrast enhancement of a
glioblastoma and the surrounding cerebral edema. Magnetic
resonance imaging (MRI) in the upper set of images was performed
before treatment, and MRI in the lower set of images was performed
4 weeks after beginning therapy. T1-weighted MRI with contrast
enhancement is shown on the left and T2-weighted MRI on the right.
(Courtesy of Dr. David Schiff, Department of Neurology, University of
Virginia School of Medicine.)
OF CEREBRAL EDEMA
The principal types of cerebral edema—cytotoxic, interstitial, and
vasogenic—can be characterized in patients, at least to some
degree, through neuroimaging studies, especially MRI (Figs. 53-3
to 53-5; see Fig. 53-2).55-57
In vasogenic edema (see Figs. 53-2 and 53-3), the edematous
tissue is hypodense with respect to normal brain on both
non–contrast-enhanced computed tomography and T1-weighted
MRI. This feature is highlighted after the administration of con-
trast material.56 On MRI, the edema primarily affects the white
matter and tends to spare the gray matter, unlike cytotoxic edema.
T2-weighted and fluid-attenuated inversion recovery (FLAIR)
sequences accentuate the appearance of vasogenic edema and can,
in FLAIR sequences, distinguish edema from normal brain water
content, such as CSF. FLAIR images, in particular, are also useful
to demonstrate the extent of tumor cell migration beyond the
enhancing bulk of tumor because these MRI sequences are espe-
cially sensitive to the changes in brain water content induced by
migrating or invading cells. Because vasogenic edema is primarily
extracellular, the interstitial spaces also appear enlarged, a feature

A B C
Figure 53-3. Imaging of vasogenic edema. A, Axial T1-weighted, gadolinium-enhanced magnetic
resonance imaging (MRI) showing an enhancing 1-cm diameter metastatic tumor (lung cancer primary) with
surrounding vasogenic edema seen on T2-weighted (B) and fluid-attenuated inversion recovery (C) MRI.

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e428 SECTION 2  Basic and Clinical Sciences

A B C D
Figure 53-4. Imaging of cytotoxic edema. A 55-year-old man suffered an embolic stroke that affected the
left cerebral hemisphere. Axial fluid-attenuated inversion recovery (FLAIR) (A) and T2-weighted magnetic
resonance imaging (MRI) (B) demonstrate a small acute cortical infarct in the left superior frontal gyrus that is
hyperintense on FLAIR and T2-weighted MRI. C, On the diffusion-weighted image, this same tissue is also
hyperintense. D, The corresponding apparent diffusion coefficient (ADC) map demonstrates that the affected
parenchyma has a low ADC, thus indicating that the infarct is acute. The shift of extracellular water to the
intracellular space with cytotoxic edema restricts the random diffusion of water molecules into the tissue,
hence a low ADC.

A B C
Figure 53-5. Imaging of interstitial edema in an adult with hydrocephalus. A, Axial, non–contrast-
enhanced computed tomography (CT) shows hypodense areas of edematous brain (arrows) produced by
cerebrospinal fluid (CSF) passing into the periventricular white matter. B, This is prominently also seen with
fluid-attenuated inversion recovery magnetic resonance imaging, where the CSF within the ventricular system
is dark and the interstitial brain edema surrounding the ependyma is bright. C, Postoperative CT performed
the day after placement of a ventriculoperitoneal shunt demonstrates a reduction in the hypodense,
periventricular interstitial edema.

that increases the apparent diffusion coefficient (ADC) on diffu-
sion studies.55,56 MRI perfusion sequences can also demonstrate
the enhanced vascularity and permeability associated with tumor
angiogenesis, alone or with provocative testing, such as with the
administration of dexamethasone.24 Finally, dynamic, contrast-
enhanced MRI can be used to quantify the permeability of the
BBB and assess the effects of treatments that target the BBB.56,57
Cytotoxic edema, found in patients with ischemic (see Fig.
53-4) or hemorrhagic stroke and traumatic brain injury,58,59
induces a rapid intracellular influx of water because of energy
failure that evolves clinically and neuroradiographically.55 Within
12 hours, there is loss of the visible gray-white junction and gyral
edema, and at 12 to 24 hours, T2-weighted images show hyper-
intensity. The changes in diffusion-weighted MRI signal intensity
may occur rapidly (within minutes after the insult); acute infarcts
have a lower ADC than normal brain does, and these ADC maps
sensitively indicate early cytotoxic edema.44
TREATMENT OF CEREBRAL EDEMA
Most current treatments of cerebral edema are indirect and
focused on amelioration of the effects of edema, whereas more
specific treatments are directed at the causative disease or condi-
tion (see Table 53-2).21 For cytotoxic, osmotic, and interstitial

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edema, the main therapeutic intervention is to reverse the cause.
In interstitial edema, resolution of transependymal CSF flow
requires temporary or permanent diversion of spinal fluid (see
Fig. 53-5). In vasogenic edema, the volume of extracellular fluid
is a function of the relative rates of production and resorption of
extracellular fluid. Higher pressure within the tumor and perme-
able tumor vessels initiates hydrostatic flow away from the tumor
margin and into the extracellular space surrounding it until it
reaches (convects to) the ventricles and subarachnoid spaces.
There are dynamic limits to resorption: local capillaries absorb
extracellular fluid slowly (estimated at 0.0086 mL/hr/cm3), and
normal astrocytic cells have a defined capacity to absorb extrava-
sated protein, ions, and water.5,19,21,60-62 These resorptive mecha-
nisms may often be overwhelmed when the BBB is defective and
are not generally capable, without adjunctive methods, of han-
dling the amount of extracellular fluid commonly produced with
many tumor types.61-64
Several agents, including glucocorticoids, diuretics, and man-
nitol and other osmotic agents (reviewed in detail elsewhere21),
have a moderate effect when used to control peritumoral edema.
Although ineffective for cytotoxic edema and only modestly but
transiently efficacious in the short-term treatment of interstitial
edema, glucocorticoids often improve the neurological symptoms
and signs caused by vasogenic edema, especially in patients with
brain tumors, in whom clinical features often result from the mass
effect contributed by the peritumoral edema. Experimental evi-
dence indicates that the effects of glucocorticoids occur primarily
by reducing vascular permeability of vessels rather than reduced
VEGF production.27,32,65,66 This inhibition of the effects of VPF/
VEGF on the vasculature is by interference with VEGF action
on vessels and requires the glucocorticoid receptor.27,32 Thus the
effect of steroids on tumor-induced vasogenic edema is to restrict
permeability of the BBB to macromolecules. By contrast, steroids
are not effective when the BBB is not functional.3,27,32,61
Diuretics, such as the loop diuretic furosemide, act by induc-
ing systemic dehydration, which may reverse osmotic flow. This
therapeutic effect is limited in time and efficacy.21 The carbonic
anhydrase inhibitor acetazolamide decreases CSF production by
reducing hydrogen and bicarbonate production. Like diuretics,
acetazolamide’s efficacy is modest and short in duration, and
systemic metabolic derangements may occur with prolonged
use.21 Osmotic agents such as glycerol, mannitol, hypertonic
saline, and urea create an osmotic gradient between the brain and
blood, down which extracellular water flows.21 Because this activ-
ity is limited temporally, osmotherapy is generally reserved for
settings of acute edema with mass effect and is used to provide
time for the initiation of definitive treatment to eliminate the
cause of the edema. Furthermore, prolonged use of osmotic
agents can lead to the accumulation of solute (mannitol, glycerol)
within the tissues, which can then serve as a “reverse sink” and
produce a circumstance in which the edema is refractory to
further osmotic therapy. Agents such as mannitol or hypertonic
saline may also have other actions, such as vasoconstriction,
enhanced cerebral blood flow, and altered rheology, among
others, that can alter the content or effect of edema. Many free
radical scavengers and neuroprotective agents that have shown
promise in the laboratory or in animal models have generally
failed in human trials. Whether new agents that modulate the
activity of aquaporins, sulfonylurea receptor 1, or other pathways
will prove effective awaits new human trials.54,67-69 New agents
that can mitigate the secondary neural damage caused by cerebral
edema and can do so without the side effects of the current
therapies are clearly needed.
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Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.