Mechanisms of cerebral edema in traumatic brain injury:
therapeutic developments
James J. Donkina and Robert Vinkb
a
Department of Pathology and Laboratory Medicine,
University of British Columbia, Vancouver BC, Canada
and bThe Discipline of Anatomy and Pathology,
University of Adelaide, Adelaide SA, Australia
Correspondence to James Donkin, PhD, Department
of Pathology and Laboratory Medicine, University of
British Columbia, Child and Family Research Institute,
950 West 28th Avenue, Vancouver, BC V5Z4H4,
Canada
Tel: +1 604 875 2345x7146; fax: +1 604 875 3120;
e-mail: jdonkin@cmmt.ubc.ca
Current Opinion in Neurology 2010, 23:293–299
Introduction
The mechanisms associated with the development of
tissue damage following traumatic brain injury (TBI)
have been extensively studied over the past few decades
and it has become increasingly evident that the for-
mation of cerebral edema is one of the major factors
leading to the high mortality and morbidity in affected
individuals. Indeed, some studies have reported that
cerebral edema may account for up to half of the
mortality in all victims of TBI [1], and in younger victims
of TBI, up to half of all mortality and morbidity [2].
Edema is harmful because it causes cell swelling, swel-
ling that alters cellular metabolite concentration and
therefore cellular physiology, biochemistry and function.
When the swelling involves not only the cells themselves
but also the tissue parenchyma, there is a rapid increase
in intracranial pressure (ICP), which results in com-
pression of blood vessels, reduced tissue blood flow,
reduced oxygenation and eventually shifts tissue down
pressure gradients (herniations) that may crush vital
1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Purpose of review
Although a number of factors contribute to the high mortality and morbidity associated with
traumatic brain injury (TBI), the development of cerebral edema with brain swelling remains
the most significant predictor of outcome. The present review summarizes the most recent
advances in the understanding of mechanisms associated with development of
posttraumatic cerebral edema, and highlights areas of therapeutic promise.
Recent findings
Despite the predominance of cytotoxic (or cellular) edema in the first week after
traumatic brain injury, brain swelling can only occur with addition of water to the cranial
vault from the vasculature. As such, regulation of blood–brain barrier permeability has
become a focus of recent research seeking to manage brain edema. Aquaporins, matrix
metalloproteinases and vasoactive inflammatory agents have emerged as potential
mediators of cerebral edema following traumatic brain injury. In particular, kinins
(bradykinins) and tachykinins (substance P) seem to play an active physiological role in
modulating blood–brain barrier permeability after trauma. Substance P neurokinin-1
receptor antagonists show particular promise as novel therapeutic agents.
Summary
Attenuating blood–brain barrier permeability has become a promising approach to
managing brain edema and associated swelling given that increases in cranial water
content can only be derived from the vasculature. Inflammation, both classical and
neurogenic, offers a number of attractive targets.
Keywords
aquaporins, cytotoxic edema, neurogenic inflammation, neurotrauma, neurovascular
unit, trauma, vasogenic edema
Curr Opin Neurol 23:293–299
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1350-7540
brain centres such as those involved in respiration and
cardiac function.
Although interventions targeting brain edema and swel-
ling have existed for some time, therapies have not
changed in over 50 years, largely because the mechanisms
associated with edema development are incompletely
understood. Accordingly, treatments have focussed on
management of the symptoms rather than control of the
mechanisms. Recently, significant progress has been
made toward identifying factors that mechanistically
contribute to edema formation after TBI. The present
review will summarize current understanding of edema
formation following TBI before considering recently
identified factors that contribute to the process of
edema development.
Classification of edema
It has long been established that cerebral edema can be
classified into two main categories, namely cytotoxic (also
DOI:10.1097/WCO.0b013e328337f451
 294 Inflammatory diseases and infection

known as cellular) edema or vasogenic edema [3]. Cyto- Figure 1 Schematic demonstrating cytotoxic and vasogenic
toxic edema is characterized by an increase in water cerebral edema
content within the intracellular compartment in response
to an osmotic gradient. It is usually associated with a
failure of the ATP-dependent Naþ/Kþ-pumps under
conditions of energy failure typically observed in cerebral
ischemia, anoxic-ischemic encephalopathy and severe
TBI. This leads to an increase in cellular ionic content,
an overall increase in cell osmolality and the influx of
water into the cells. It is essentially a compartment shift
of water in the skull, with water shifting from the extra-
cellular to the intracellular compartment (Fig. 1). As such,
cytotoxic edema of itself does not result in an increase in
brain water content or brain swelling, and no rise in ICP.
It does however, adversely impact on cellular function by
altering intracellular metabolite concentration.

The inability of cytotoxic edema to cause brain swelling

is not always readily apparent and is perhaps best illus-
trated using an example as originally described by Simard
et al. [4]. If a piece of tissue is excised from a live brain, it
will show all the typical signs of cytotoxic edema such as
shifts in ionic and water content between the extracellu-
lar and intracellular compartments. However, over time,
that excised piece of tissue will not gain ionic content,
will not gain water content and will not swell. There
simply is no source for the ions and water; these can only
come from the vasculature. Swelling, and any associated
increase in ICP, therefore requires a vascular contribution
and active blood flow.

A vascular contribution is the hallmark of vasogenic

edema. By definition, vasogenic edema is the result of
the movement of water from the vasculature to the
extracellular space in response to an osmotic gradient
generated by the leakage of vascular components into
the brain parenchyma (Fig. 1). It is characterized by an
open blood–brain barrier (BBB) typically observed in
conditions such as TBI, brain tumours, infection, intra-
cerebral hemorrhage and inflammation. Given that
vasogenic edema results in an increase in brain water Cytotoxic edema is essentially a water compartment shift with no change
content, tissue swelling and an increase in ICP will in tissue water content or volume. In contrast, vasogenic edema
be observed. increases tissue water content, leading to swelling. Tissue swelling thus
requires a vascular contribution if it is to occur.

Variants of these two major forms of edema have also

been described for specific situations. For example,
transependymal edema describes an increase in periven-
tricular interstitial fluid due to a failure of the ependymal
lining of the ventricular wall, common in obstructive or
communicating hydrocephalus. Hydrostatic edema is a
variant of vasogenic edema that occurs when cerebral
perfusion pressure increases to a level at which autore-
gulatory mechanisms break down. This type of edema is
observed in hypertensive encephalopathies. Finally,
osmotic (or ionic) edema occurs when plasma osmolality
falls below brain osmolality and there is a net movement
of water from the vasculature to the brain interstitial fluid
in the absence of gross disruption of the BBB. Despite
these distinct classifications of cerebral edema, in most
clinical situations there is a combination of different
types of edema depending on the disorder and time
course of the disease [5].
Edema in traumatic brain injury
Debate over which type of edema predominates in TBI
has persisted for a number of decades. Early studies

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

proposed that vasogenic edema from BBB opening was
the main contributor following injury [6,7], although this
conclusion was largely based on a simplistic, cryogenic
model of traumatic injury that is limited in terms of
replicating many of the features associated with clinical
TBI. It is now recognized that TBI is a complex and
heterogenous injury and more recent experimental
models attempt to reproduce as many of the features
of clinical TBI as possible, including associated second-
ary conditions such as arterial hypotension, hypoxia or
ischemia. Using these more recent experimental models,
a biphasic profile encompassing both vasogenic and cyto-
toxic components has emerged. With the aid of novel
MRI techniques, vasogenic edema, as indicated by an
increased water diffusion distance, was demonstrated to
occur in the first few hours after TBI [8,9], followed by
cytotoxic edema that developed more slowly over the
next few days and persisted for up to 2 weeks [8]. These
observations, based on water diffusion distance, were
confirmed by BBB permeability measurements demon-
strating that the barrier was open to large plasma proteins
for only a few hours after TBI [10,11]. However, the BBB
does not simply close after this initial opening, with
recent evidence suggesting that the BBB closes gradu-
ally, with the smaller vascular components being per-
meable for up to 7 days after TBI [12]. What accounts for
this persistent permeability is unclear, although posttrau-
matic alterations to the endothelial cytoskeleton promot-
ing endothelial barrier opening have been implicated
[13
]. Thus, the BBB is maximally permeable at 4–6 h
after TBI, before commencing to close and becoming
differentially permeable to smaller molecules over a 7-
day period.
Given the critical role that the vascular contribution plays
in brain water content and ICP changes, it is clear that an
understanding of BBB changes following TBI, and their
contribution to edema, is essential to develop potential
interventions. Considerable evidence now exists support-
ing that brain water content after TBI is maximal at 2–3
days after trauma [1], which is also the point at which ICP
usually peaks. For brain water content and swelling to be
maximal at this time point, there must still be an active
vascular contribution despite the BBB being closed to
large plasma molecules after 6 h. Although a second
opening of the BBB has been mooted [14], such an event
is not essential given the gradual closing of the barrier to
smaller vascular molecules over time. We therefore pro-
pose that the initial transient opening of the BBB is
associated with a brief period of ‘pure’ vasogenic edema,
the presence of which would be permissive for the
development of any subsequent cytotoxic edema [15].
Cytotoxic edema would indeed develop with the gradual
development of cellular injury over time, and would
become more prominent as more cells were affected.
The intracellular shift of ions and water from the extra-
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Mechanisms of cerebral edema in TBI Donkin and Vink 295
cellular compartment would then indirectly drive the
entry of more ions and water from the vasculature, with
this entry being facilitated by the BBB being permeable
to ions and small molecules, albeit not to the larger
plasma proteins commonly used to measure BBB per-
meability. Thus, the ‘pure’ vasogenic phase would be
replaced by a mixed cytotoxic/vasogenic phase that
would be dominated by the cytotoxic, or cellular, com-
ponent as more cells become dysfunctional and die.
Nonetheless, the driving force for the increased brain
water content, brain swelling and increased ICP, would
be the vascular contribution. Thus, interventions that
target the vascular contribution to edema, even if the
dominant edema is cellular, may be particularly effective
in the management of brain swelling.
Mediators of brain edema
A number of mediators have been identified that play a
role in edema formation after TBI. Arguably, the most
exciting recent developments include the identification
of aquaporin water channels as critical participants in the
development of edema, and the focus on agents that
affect the BBB, and therefore the vascular contribution to
brain swelling. These aspects are summarized below.
Aquaporins
The identification of the water-channel proteins, aqua-
porins (AQPs), as a key player in the development and
resolution of cerebral edema has highlighted their poten-
tial as a therapeutic target to prevent brain swelling [16–
18]. AQPs are integral membrane proteins belonging to a
family that form pores in the membranes of mammalian
cells [19
]. Of the 13 AQPs known to exist in mammals,
AQP1, AQP4 and AQP9 are highly expressed in brain
[20]. AQP4 is predominately expressed in the astrocytic
end foot processes in close proximity to intracerebral
vessels and at the ventricular interface. AQP9 is co-
expressed with AQP4 in astrocytic foot processes,
whereas AQP1 is expressed in the choroid plexus epi-
thelium and in ganglionar sensory neurons. Other AQPs
have also been identified in brain, but these are expressed
at much lower concentrations [20].
A number of studies have now shown that AQP4 expres-
sion is markedly altered in both experimental and clinical
brain injury [5,17,21,22], and that genetic variation of the
channels may influence degree of edema [23]. Similar
increases in AQP1 and AQP9 after experimental TBI
have been reported [24,25]. Initial studies suggested that
upregulation of AQPs after brain injury promoted edema
formation [16] and it was accordingly postulated that
therapeutic inhibition of AQP4 would be beneficial in
edema control [18]. However, it subsequently became
evident that the alterations in AQP4 expression are
regionally distinct and dependent on the type of edema
 296 Inflammatory diseases and infection
[26–28]. For example, in a model of rat cerebral ischemia,
inhibition of AQP4 expression was associated with
reduction in edema, infarct area and an improvement
in functional outcome [29,30]. Rat cerebral ischemia
typically results in cytotoxic edema. In contrast, vaso-
genic edema induced by cold lesion injury was exacer-
bated in AQP4 knockout animals, suggesting that AQP4
is essential for clearance of vasogenic edema [27].
In experimental TBI, an increase in AQP4 expression in
the glia limitans was observed but a downregulation of
perivascular AQP4 was noted during the early period
when vasogenic edema would be present [26]. Notably,
pharmacological reduction of edema formation and
improved functional outcome was associated with restor-
ation of the AQP4 channels to their normal state. The
speed at which the reappearance of AQP4 channels on
the perivascular glial endfeet occurred after treatment
suggests that there was a posttranslational modification,
perhaps involving subunit aggregation, rather than
enhanced protein synthesis. Similarly, in a rat cortical
contusion model, exacerbation of injury by a secondary
insult involving hypoxia and hypotension led to a wor-
sening of brain edema, which was associated with a
reduction in the APQ4 expression [31
]. The increased
brain water content can only be attributed to a vascular
component as a cytotoxic compartment shift would not
increase brain water content. Thus, AQP4 upregulation is
associated with the development of cytotoxic edema
whereas perivascular downregulation occurs in regions
experiencing vasogenic edema. Generalized inhibition of
AQP4 channels may therefore not be beneficial in those
conditions in which vasogenic edema plays a critical role.
Indeed, AQP4 activators have the potential to facilitate
the clearance of the vasogenic component of edema,
whereas AQP4 inhibitors have the potential to protect
the brain in cytotoxic edema.
Matrix metalloproteinases
The ability of matrix metalloproteinases (MMPs) to
degrade many types of extracellular matrix proteins,
including the neurovascular basal lamina and tight junc-
tion proteins of the BBB, has been the subject of a
number of recent TBI investigations [32–34]. MMPs
are zinc-dependent endopeptidases involved in the pro-
cess of tissue remodeling following various pathologic
conditions. The regulation of MMP expression and acti-
vation is complex and tightly controlled, and loss of this
control has been identified as potentially playing a critical
role in the pathophysiology of synaptic loss and BBB
breakdown in TBI, stroke and neurodegeneration
[35

,36–38]. MMPs, and in particular MMP-2, MMP-
3 and MMP-9, are upregulated following TBI [33,39,40]
in which they cause acute disruption of the BBB, leading
to vasogenic edema and subsequent cell death. Indeed,
the upregulation of MMP-9 in particular has been
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
temporally and spatially associated with BBB disruption
and edema formation [41,42]. Consistent with this, mice
lacking the MMP-9 gene have been shown to be pro-
tected in both focal and global ischemia as well as TBI
[41,43,44], with gene knockout mice having reduced
BBB disruption and edema, a reduced inflammatory
response, improved integrity of white matter components
plus improved functional outcome.
MMP inhibitors, such as minocycline or TIMP-1, have
also been shown to block BBB injury, cerebral edema and
cell death in a number of experimental animal models
[35

,45–47]. However, recent data suggest a more bipha-
sic role for MMPs in TBI [48], with MMPs reported to
play an important role in neurogenesis, neurovascular
remodeling and matrix-trophic signaling in the later
stages of recovery from TBI and stroke [39,48]. Inhibition
at these delayed time points may in fact worsen recovery.
As such, the most challenging aspect with respect to
MMP inhibitors is the timing of administration in an
effort to coordinate their beneficial and detrimental
effects following TBI. This balance between positive
and detrimental effects has been recognized for some
time in inflammation [49].
Vasoactive agents
It is well established that inflammatory, vasoactive agents
can increase BBB permeability and lead to cerebral
edema [50]. Recent studies in TBI have focused not
only on mediators related to classical inflammation, but
also those derived from neurogenic inflammation. In
terms of classical inflammation, the bradykinin family
of kinins has been strongly implicated in the develop-
ment of edema following acute brain injury [51]. The
bradykinins are formed from the cleavage of kininogen by
kallikreins, with the active peptides (bradykinins and
kallidin) producing their effects through two subtypes
of bradykinin receptors known as B1 and B2 receptors.
Following TBI in mice [52
], bradykinin itself was maxi-
mally increased at 2 h after trauma whereas both the B1
and B2 receptors were significantly upregulated in the
first 24 h. Despite the increase in both receptors after
trauma, only B2 receptor knockout mice had significantly
less edema and better functional outcomes after TBI
[52
], implying that B2 receptor binding may play an
integral role in edema formation after trauma. Adminis-
tration of a B2 receptor antagonist was subsequently
shown to reduce ICP and contusion volume in a rodent
focal contusion model [53], which confirmed earlier find-
ings in other models of acute brain injury [51,54,55].
Despite these positive findings, no positive effects of
the B2 antagonists have been noted in subsequent
clinical trials of the compounds [56,57

].
The other distinct family of kinins is the tachykinins, a
group of peptide mediators that have been implicated in

neurogenic inflammation. Neurogenic inflammation is a
process that encompasses vasodilation, plasma extravasa-
tion and neuronal hypersensitivity caused by the release
of neuropeptides from sensory neurons [58]. Although
several neuropeptides have been implicated in neuro-
genic inflammation, calcitonin gene-related peptide
(CGRP) has been identified as being associated with
the vasodilation whereas substance P is thought to
enhance plasma protein extravasation.
Although few studies have suggested a role for neuro-
genic inflammation in edema formation following TBI
[59,60], Donkin et al. [61

] recently demonstrated that
injury results in an elevated perivascular substance P
immunoreactivity that is associated with enhanced vas-
cular permeability and edema formation in a rodent
model of moderate diffuse TBI. A similar increase in
substance P immunoreactivity was also reported follow-
ing mild concussive head injury [62] and reperfusion
injury [63]. Subsequent studies in human TBI by the
same group also reported elevated substance P immu-
noreactivity in human TBI [64]. Specifically, patients
who had sustained traumatic head injuries, who had died
within 1 week and who had undergone postmortem and
detailed neuropathological examination, demonstrated
an elevation in substance P immunoreactivity in cortical
microvasculature. Moreover, the localization to perivas-
cular neurons suggested that injury to the neuron may
result in a localized perivascular release of neuropeptides,
with a resultant increase in BBB permeability and edema
formation. Notably, substance P is stored and co-released
with CGRP, a potent endogenous vasodilator that
potentiates edema formation in the presence of mediators
of increased vascular permeability, such as substance P
[65]. Thus, their combined release during neurogenic
inflammation would theoretically facilitate a profound
edema response.
Given the increased perivascular substance P after acute
injury to the brain, Donkin et al. [61

] subsequently
administered the substance P neurokinin-1 receptor
antagonist N-acetyl-tryptophan after TBI and noted a
marked attenuation of BBB permeability and subsequent
edema formation. Similar findings were noted in a reper-
fusion model of transient ischemia [66], with highly
significant reductions in edema formation as measured
at 24 h after the induction of stroke. Although the results
using neurokinin-1 antagonists were useful in establish-
ing a role for substance P in brain injury, an alternative
approach to establishing a more general role for neuro-
genic inflammation in TBI is by inhibition of central
neurogenic inflammation by neuropeptide depletion.
Neuropeptide depletion can be accomplished by chronic
preinjury administration of the vanilloid receptor agonist
capsaicin, which stimulates the release of neuropeptides
from the presynaptic sensory nerve terminals to the point
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mechanisms of cerebral edema in TBI Donkin and Vink 297
of depletion. Nimmo et al. [59] used this approach to
demonstrate that neuropeptide depletion results in a
marked attenuation of early posttraumatic BBB per-
meability and any subsequent edema formation. Remark-
ing that their study validated the assumption that vaso-
genic edema is permissive for cytotoxic edema formation
[15], they concluded that early inhibition of neurogenic
inflammation may present a novel approach to the treat-
ment of posttraumatic edema formation.
Conclusion
Although a number of factors contribute to the high
mortality and morbidity associated with TBI, the devel-
opment of cerebral edema with brain swelling remains the
most significant predictor of outcome. Brain swelling can
only occur with addition of water from the vasculature
(vasogenic edema), as cytotoxic edema is essentially a
compartment shift of water from the extracellular to intra-
cellular compartment. As such, attenuating BBB per-
meability has increasingly become a promising approach
to managing brain edema and associated swelling. AQPs,
MMPs and vasoactive inflammatory agents have emerged
as potential mediators of cerebral edema following TBI.
Inflammation, both classical and neurogenic, offers a num-
ber of attractive targets, with the tachykinins (substance P)
in particular seeming to play an active physiological role in
modulating BBB permeability after trauma.
Acknowledgement
R.V. is supported by the Neurosurgical Research Foundation, Australia.
J.J.D is supported by the Alzheimer’s Society of Canada Postdoctoral
Fellowship. We thank Tavik Morgenstern for the medical illustration.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest


of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 337–338).
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