Vet Res Commun (2014) 38:297305
DOI 10.1007/s11259-014-9616-z
REVIEW ARTICLE
Pathology of traumatic brain injury
John W. Finnie
Received: 10 July 2014 / Accepted: 22 August 2014 / Published online: 3 September 2014
# Springer Science+Business Media Dordrecht 2014
Abstract Although traumatic brain injury (TBI) is frequently
encountered in veterinary practice in companion animals,
livestock and horses, inflicted head injury is a common meth-
od of euthanasia in domestic livestock, and malicious head
trauma can lead to forensic investigation, the pathology of
TBI has generally received little attention in the veterinary
literature. This review highlights the pathology and pathogen-
esis of cerebral lesions produced by blunt, non-missile and
penetrating, missile head injuries as an aid to the more accu-
rate diagnosis of neurotrauma cases. If more cases of TBI in
animals that result in fatality or euthanasia are subjected to
rigorous neuropathological examination, this will lead to a
better understanding of the nature and development of brain
lesions in these species, rather than extrapolating data from
human studies.
Keywords Traumatic brain injury . Pathology . Pathogenesis
Introduction
Traumatic brain injury (TBI) can be broadly classified as
blunt, non-missile or penetrating missile injury (Blumbergs
2005; Blumbergs et al. 2008). Non-missile head injury is
commonly encountered in veterinary practice as a result of
animals being struck by motor vehicles or involved in falls,
assaults, predation or crushing injuries. Dogs are most
J. W. Finnie (*)
SA Pathology, Hanson Institute Centre for Neurological Diseases,
PO Box 14 Rundle Mall, Adelaide, SA 5005, Australia
e-mail: john.finnie@health.sa.gov.au
J. W. Finnie
School of Veterinary Science, University of Adelaide, Adelaide,
South Australia, Australia
frequently struck by automobiles, cats may sustain head inju-
ries after falling from buildings and being hit by motor vehi-
cles, and horses and ruminants can suffer cranial injuries
during periods of excitement, falling when rearing, and with
attempted restraint. Horses also incur brain injuries from being
kicked in the head (Summers et al. 1995). Penetrating missile
head injury is commonly used for the humane euthanasia of
livestock by firearms to produce immediate unconsciousness
and a rapid and relatively painless death either by gunshot
wound to the head or a penetrating captive bolt pistol (humane
stunner) (Finnie 1997). Cognizance of brain lesions produced
by intentional head injury can also be important to veterinary
pathologists involved in forensic investigations.
TBI has received little attention in the veterinary literature.
Although much of our understanding of TBI in animals is
derived from neuropathological studies of human neurotrauma
cases, animal models have been invaluable in elucidating the
pathology and pathogenesis of human head injury as many
replicate the important cerebral lesions produced by traumatic
brain injuries in man. Moreover, while human studies have
been valuable in informing our knowledge of TBI in animals,
veterinary care would benefit greatly from species-specific
TBI research (Finnie and Blumbergs 2002).
This review discusses the principal diagnostic brain lesions
constituting non-missile and missile head injury and their
pathogenesis.
Biomechanical factors determining traumatic cerebral lesions
The mechanisms of brain damage differ in many respects
between closed, non-missile and missile head injury. In the
former, acceleration/deceleration forces impart large momen-
tum, rotational and shear forces to the head and brain, but
relatively low kinetic energy. By contrast, penetrating head
wounds produced by firearms deliver high focal kinetic energy
and relatively low cranial momentum (Ommaya et al. 2002).
298 Vet Res Commun (2014) 38:297305

Most head injuries are produced by contact or acceleration/ Table 1 Pathological features of TBI
deceleration forces. Contact injuries such as scalp lacerations, Blunt, non-missile head injury
skull fractures (with or without an associated epidural Primary traumatic brain damage
haematoma), contusions and lacerations occur when the head Focal, multifocal or diffuse
strikes or is struck by an object. However, the absence of Axonal injury
evidence of a contact injury such as scalp bruising or skull Vascular injury
fracture does not necessarily imply that there was no head
Vascular injury resulting in
impact (Anderson and McLean 2005; Denny-Brown and
Subarachnoid haemorrhage
Russell 1941; Gennarelli and Thibault 1985; Ommaya and
Subdural haemorrhage
Gennarelli 1974; Shaw 2002).
Extradural (epidural) haemorrhage
Impact to a head that is free to move (and change in velocity)
Contusion
more often produces loss of consciousness than one
Laceration
constrained, the latter being more likely to cause localized
Secondary traumatic brain damage
defects of the skull and brain. When the head is freely mobile,
Focal, multifocal or diffuse
direct impact produces significant acceleration/deceleration
Ischemic-hypoxic damage
forces, with rotational movement in the coronal (transverse)
Brain swelling (congestion/oedema)
plane more productive of diffuse axonal injury and coma than
Raised intracranial pressure
translational (linear) movements. If the line of action of an
Neuroinflammation
impact force passes through the centre of gravity of the head,
Infection
it will be accelerated without rotation; if not, the head will
sustain both linear and angular acceleration (Anderson and Hydrocephalus
McLean 2005; Denny-Brown and Russell 1941; Gennarelli
Missile head injury
and Thibault 1985; Ommaya and Gennarelli 1974; Shaw 2002).
Penetrating or perforating
Primary axonal and vascular damage following a head
Resulting brain damage
impact are well correlated with the amount of brain deforma-
Permanent, haematoma-filled primary wound track
tion (strain) rather than stress (force applied per unit area)
Temporary cavity formation (widespread axonal/vascular injury)
caused by rotational acceleration/deceleration of the head,
Secondary bone/bullet fragment tracks
with the cerebral hemispheres seemingly more vulnerable
than the brainstem (Anderson and McLean 2005).
damage. Focal and diffuse brain damage also have individual
Blunt, non-missile head injury
pathophysiology and, while it is usually possible to ascertain
the nature of a focal lesion, this is often more difficult when
TBI of this type is comprised of many different neural lesions
diffuse brain damage is present, particularly in the absence of
that may occur singly or, more commonly, in various combi-
an intracranial mass lesion (Blumbergs 2005; Blumbergs et al.
nations, and each patient with TBI has a unique and complex
2008; Gennarelli et al. 1982a; Graham et al. 1989a, 2000;
pattern of cerebral damage. Brain damage after TBI is hetero-
Jennett and Bond 1975; Marshall et al. 1991; Mendelow and
geneous and the injury severity increases with the multiplicity
Crawford 2005; Reilly et al. 1975; Teasdale and Jennett 1974).
of lesions (Adams 1990; Adams 1992).
The pathological substrate for ongoing neurological defi-
Blunt, non-missile TBI may be categorized as primary or
cits is the sum of the different types of primary and secondary
secondary, with parenchymal damage occurring in a focal,
brain damage. This interplay between primary and secondary
multifocal or diffuse pattern (Table 1). From a clinical per-
injury explains why an animal presenting initially with a mild
spective, recognition of these types of brain damage is impor-
brain injury may subsequently develop severe brain damage
tant. Primary brain damage occurs at the time of head impact,
and, conversely, why one with a seemingly life-threatening
has an almost immediate clinical effect, and is refractory to
condition substantially recovers (Adams 1992; Blumbergs
most treatment. By contrast, secondary brain damage occurs
2005; Blumbergs et al. 2008).
in a dynamic and evolving manner at varying times post-
impact and may be amenable to treatment, although it can be
manifest very rapidly after a head impact. If a head-injured Primary brain damage
animal survives the initial traumatic insult, any increase in a
neurological deficit or deeper level of unconsciousness will be Primary injury (Table 1) is produced by mechanical forces
determined by the severity of secondary injury events. Ac- causing brain deformation at the moment of head impact, with
cordingly, an important part of the clinical management of neural elements (blood vessels, axons, neurons and glia) di-
TBI is the differentiation between primary and secondary rectly damaged in a focal, multifocal or diffuse pattern.
Vet Res Commun (2014) 38:297305
Moreover, injury thresholds for the various neural elements
also differ (Blumbergs 2005; Blumbergs et al. 2008).
Contusions are regular features of TBI and their presence
confirms that a head injury has occurred, but they may be
minimal or even absent with fatal, diffuse injuries. Contusions
(Figs. 1 and 2) are focal surface injuries generally resulting
from damage to small blood vessels and they often increase in
size over subsequent hours to days. They are most severe on
the crests of gyri, cause damage to outer cortical layers (often
with attendant subarachnoid haemorrhage), and may extend to
involve digitate white matter. By contrast, these cortical areas
are generally preserved with cerebral infarcts. Contusions
often occur beneath the impact site (coup contusions) and
are produced in the cortex by compressive forces operating
beneath an area of skull inbending or tensile forces generated
when a region of skull inbending suddenly returns to its
original position. Because contusions are mainly impact-
related phenomena, they are frequently associated with skull
fractures, and contrecoup contusions may also be found more
or less opposite the impact site (Adams et al. 1980b; Blumbergs
2005; Blumbergs et al. 2008; Lindenberg and Freytag 1960;
Loberg and Torvik 1989; Maxie and Youssef 2007).
Contusions may be subdivided into contusion
haemorrhages (Fig. 2) when vascular injury predominates or
contusion necrosis (with or without haemorrhage) when pa-
renchymal injury is the principal feature; however most con-
tusions express a combination of these two extremes of the
contusion spectrum. Neuronal red cell change (formerly in-
correctly termed ischemic neuronal necrosis as other aetiol-
ogies will also produce this morphological change) with
shrunken, hypereosinophilic cytoplasm and nuclear pyknosis
can be seen 12 h after an initial insult and the number of these
damaged neurons increases with time after a head impact.
Neurons in superficial cortical areas are also frequently mark-
edly elongated, appearing to have been stretched, termed
plastic creep (Fig. 3). In terms of contusion resolution, small
haemorrhages may be cleared in a few days, while larger
extravasations require weeks to months. Infiltration of neutro-
phils into damaged neural tissue commences within 24 h
Fig. 1 Right hemispheric impact contusion
299
Fig. 2 Left hemispheric impact contusion showing cortical haemorrhage
with distortion and midline shift of the brain
following an acute injury and invasion of macrophages, which
become foamy, lipid-laden gitter cells, increases after 2
5 days. The final outcome is a golden-brown, shrunken scar
at the gyral crest. Laceration results when there is physical
disruption of the neural parenchyma. Lacerations and contu-
sions form part of a continuous spectrum of damage at the
surface of the brain (Adams et al. 1980b; Blumbergs 2005;
Blumbergs et al. 2008; Lindenberg and Freytag 1960; Loberg
and Torvik 1989; Maxie and Youssef 2007).
Traumatic brain haemorrhage generally results from tear-
ing of blood vessels at the moment of head impact, but
gradually expanding, delayed post-traumatic haematomas
may not be clinically manifest until hours or days after the
initial injury. Small haematomas may completely organize
with time, but large haematomas may only partially organize,
persisting with a cystic, fluid-filled centre. During the first
48 h after a head injury, the haematoma is composed of clot,
which gradually liquefies over the ensuing 2 weeks. Bleeding
into the subarachnoid space (subarachnoid haemorrhage)
(Fig. 4) is the most common form of traumatic vascular injury
and, while generally minor, may evolve into a significant
space-occupying lesion. Subdural haemorrhage is usually
Fig. 3 Many red neurons in a contusion are markedly elongated
(plastic creep) (arrows). Bar=15 m
300
Fig. 4 Marked subarachnoid haemorrhage around the midbrain
produced by rupture of bridging veins from rapid angular
acceleration forces, and haemorrhage may extend over an
entire hemisphere; it can also form adjacent to contusions.
Epidural (extradural) haemorrhages cause progressive separa-
tion of the dura from the skull after tearing of meningeal blood
vessels. Intraventricular haemorrhage is a frequent complica-
tion of a head impact and haematomas may also arise in the
brain substance (intracerebral haematomas), the latter
surrounded by a region of ischemia. If a head injury victim
dies within minutes of a severe head impact, there may be
numerous petechial haemorrhages scattered throughout the
brain (diffuse vascular injury) (Blumbergs et al. 2008;
Gennarelli et al. 1982a; Jones et al. 1986; Gennarelli and
Thibault 1982).
While complete mechanical transaction of axons (primary
axotomy) can occur after severe head injury, axonal injury
(AI) more commonly evolves over time (secondary axotomy),
leading to eventual disconnection. However, not all damaged
axons are irreversibly injured and some may recover, thus
providing a potential window for therapeutic intervention.
Calcium influx is important in the pathogenesis of traumatic
AI, the increased intraaxonal calcium activating calpain pro-
teolytic activity, leading to microtubular disorganization and
loss, with impaired axonal transport. Since there is a constant
antero- and retrograde movement of various cargoes in axons,
they react to any transport disruption by swelling and forming
spheroids. The term axonal spheroid is now widely accept-
ed to describe the ovoid enlargements found in injured axons,
but they have been termed axonal retraction balls, retraction
bulbs, dystrophic axons, axonal torpedoes (if located in
Purkinje cells), axonal balloons, axonal swellings and axonal
varicosities. The number and size of these axonal spheroids
then increases over the ensuing 24 h. Accumulation of pro-
teins transported by fast axoplasmic transport, including am-
yloid precursor protein (APP), neurofilament proteins,
synaptophysin and ubiquitin, can be used as sensitive, early
immunohistochemical markers of AI. APP is normally
transported in undetectable quantities, but accumulates rapidly
Vet Res Commun (2014) 38:297305
in damaged fibres proximal to the site of injury (Fig. 5), being
visible by light microscopy as early as 1.753 h post-injury;
only injured axons are labelled by APP (Fig. 5). By contrast,
silver impregnation techniques are unable to identify AI reli-
ably with survival times<18 h (Adams 1990; Blumbergs et al.
1989; Blumbergs et al. 1994; Blumbergs et al. 1995;
Gennarelli et al. 1982b; Gennarelli 1996; Maxwell et al.
1997; Povlishock 1992; Povlishock and Christman 1995).
AI may be focal or diffuse and the total burden of AI in a
given brain may be a combination of mechanical deformation
and ischemic-hypoxic injury, the latter due to a failure of
cerebral perfusion and constituting one of the major secondary
insults after a head injury. However, while current histological
techniques are unable to distinguish between these two types
of AI, AI due to ischemia probably comprises a large propor-
tion of the total AI in fatal human TBI cases. When AI in
head-injured humans is widely distributed in the brain (diffuse
AI or DAI), it may induce days to weeks of unconsciousness,
months to years of residual neurological dysfunction, and
even coma and death. If DAI is mild, there may be a brief
period of unconsciousness or confusion or a residual neuro-
logical deficit that persists for days to months. DAI impedes
consciousness by damaging white matter tracts connecting the
cerebral hemispheres to the brainstem activating centres and,
in more severe neurotrauma, may additionally injure these
neuroanatomical sites (Adams 1990; Blumbergs et al. 1989;
Blumbergs et al. 1994; Blumbergs et al. 1995; Gennarelli et al.
1982b; Gennarelli 1996; Maxwell et al. 1997; Povlishock
1992; Povlishock and Christman 1995).
Diffuse brain injuries which disrupt the awake state by
injuring pathways from the brainstem reticular activating sys-
tem to the cerebral cortex may result in concussion, defined as
a clinical state characterized by immediate impairment of
neural functions such as changes in consciousness and distur-
bance of vision, motion and sensation due to mechanical
forces. Classically, concussion was conceived as a reversible
Fig. 5 Injured APP-immunopositive axons, with most running longitu-
dinally in the same direction; uninjured axons are not labelled. Bar=
15 m
Vet Res Commun (2014) 38:297305
syndrome without detectable pathology, but this has evolved
into a concept of graded concussion. There is temporary
confusion, with retention of consciousness, at the mildest
end of the concussion spectrum, to more severe concussion
with loss of consciousness and post-traumatic amnesia. Some
grades of concussion are also attended by a degree of perma-
nent axonal damage and, with repeated head injuries, the
functional impairment may be more severe and prolonged
(cumulative concussion) (Blumbergs et al. 2008; Shaw 2002).
Since AI is a critical component of TBI and a major
determinant of clinical outcome, it is pertinent to briefly
examine the mechanism and consequences of disrupted axo-
nal transport. Axonal transport is comprised of 3 basic com-
ponents: the cargo (including organelles, mitochondria, cyto-
solic and cytoskeletal proteins), the motor proteins (kinesin
and dynein) that move the cargo, and the tracks (mainly
microtubules) upon which the cargo travels. Traumatic dam-
age to any of these elements, as well as impairment of energy
supply to motors from mitochondrial injury, can potentially
lead to neurological disturbance. However, while disruption
of axonal transport may contribute to the development and
progression of neurological signs after TBI, the precise causal
relationship remains unclear. Some cargoes that are normally
transported along axons can accumulate, but whether these
aggregates are the cause or a consequence of axonal transport
disruption is debated (Goldstein et al. 2008; Verhey et al.
2011; Beirowski et al. 2010).
The axon, being largely devoid of any biosynthetic capa-
bility, is dependent upon the transport of essential nutrients
produced by the neuronal cell body and the long length of
many axons renders them vulnerable to transport deficits. The
motor proteins, kinesin and dynein, move cargoes in an
antero- and retrograde direction, respectively, the former con-
veying myriad proteins, lipids and polysaccharides bound to
organelles and vesicles towards the synapse. Retrograde trans-
port facilitates the removal of misfolded and recycled proteins,
and effete organelles, to prevent a build-up of toxic aggregates
and enables signalling from the periphery of the axon to
permit neurons to respond to trophic influences and stressful
stimuli (Goldstein et al. 2008; Verhey et al. 2011).
After attachment of kinesin motors to a cargo, kinesin
converts the chemical energy derived from adenosine triphos-
phate (ATP) hydrolysis into mechanical work, allowing it to
walk along microtubules, taking consecutive steps along
these tracks without dissociating (termed processivity). Dy-
nein also walks in a similar manner, but its stepping is
more irregular. Axonal transport has conventionally been
classified as either fast or slow but, in fact, all motor
proteins are fast and the overall velocity of a particular cargo
is determined by the length of pauses between movements
when it is dissociated from its motor protein. Regulation, and
cooperation, between motor proteins bound to a cargo is
required to increase the force and distance travelled along
301
the axon (same motor type) or produce bidirectionality of
movement (different motor types). Two mechanisms have
been proposed to explain directional transport and intermittent
pausing during transit and both are probably operative. Firstly,
there may be regulated switching of motor activity such that
only one type of motor is active at a given time and, secondly,
there may be a tug-of-war between opposing motors, the
final direction of movement being determined by the domi-
nant motor (Bryantseva and Zhapparova 2012; Gennerich and
Vale 2009; Hirokawa et al. 2010).
When axonal swellings or spheroids form after traumatic
disruption to axonal transport, most are long-lasting and re-
main stable in size and location, but some become larger by
fusing with their neighbours, suggesting retention of some
axoplasmic flow. Moreover, spheroid formation may be re-
versible under some circumstances, leading to functional ax-
onal recovery (Bryantseva and Zhapparova 2012; Gennerich
and Vale 2009; Hirokawa et al. 2010).
In addition to AI, dendritic injury in the form of loss of
microtubule-associated protein (MAP-2) has also been dem-
onstrated following TBI. MAP-2 is an immunohistochemical
marker of dendritic damage as it is principally expressed in
these processes (Manavis et al. 1999). A diffuse microglial
reaction may be demonstrated after TBI using ionized calcium
binding adaptor molecule 1 (Iba 1) as an immunocytochemi-
cal marker of these glia and there is almost invariably
astrogliosis, reactive astrocytes showing increased glial fibril-
lary acidic protein (GFAP) immunopositivity and an often
expanded, eosinophilic cytoplasm due to uptake of extrava-
sated plasma protein (Blumbergs et al. 2008; Clark and
Kochanek 2001).
Secondary brain damage
Secondary or delayed TBI occurs as a complication of the
different types of primary brain damage. It develops over
hours, days or weeks after the initial insult and exacerbates
the already altered homeostasis of the injured brain. There is
evidence of secondary brain injury at autopsy in 7090 % of
all fatally head-injured human patients (Blumbergs et al. 1995;
Blumbergs et al. 2008; Chesnut et al. 1993).
Trauma-induced neurochemical changes alter regional ce-
rebral blood flow, bloodbrain barrier (BBB) permeability,
cerebral metabolism, and ion homeostasis. There are also
direct neurotoxic effects on regional populations of neurons
and glia. Oxidative stress, excitotoxic damage, inflammation,
and mitochondrial dysfunction ensue. This complex interplay
of vascular, cellular and biochemical cascades leads to
ischemic-hypoxic damage, cerebral swelling, the results of
elevated intracranial pressure (ICP) such as distortion, shift
(Fig. 2) and herniation of the brain, hydrocephalus and infec-
tion. Post-traumatic events may involve both neuroprotective
302
and autodestructive or neurotoxic cascades (Blumbergs et al.
1995; Blumbergs et al. 2008; Chesnut et al. 1993).
While primary brain damage is produced by mechanical
forces operating at the moment of head impact, most brain
injury evolves as a progressive cascade of delayed, secondary
events that are complications of the initial injury (Blumbergs
2005; Blumbergs et al. 2008).
Ischemic-hypoxic injury is usually related to cerebral per-
fusion failure. It can be focal or global. Focal (regional)
ischemia occurs when impaired cerebral blood flow leads to
reduced perfusion within the area of supply of the affected
vessel and the collateral circulation is inadequate. It impedes
the delivery of substrates, especially oxygen and glucose, and
the final expression is reduced availability of ATP. This leads
to membrane pump failure, activation of calcium channels (for
example N-methyl-D-aspartate or NMDA) with an influx of
calcium ions (which are neurotoxic), cellular swelling and
death by necrosis or apoptosis, the latter occurring particularly
when ischemia is brief. Calcium ions are an essential messen-
ger in many cellular processes, but are also often the final
common pathway to cell death. Excessive increases in calci-
um levels severely impede virtually all anabolic and metabolic
cell functions in the brain (Young 1992). Further ischemia
may result in free radical release, damaging phospholipid cell
membranes and resulting in an additional influx of calcium
and water. Calcium influx is also abetted by the release of
excitatory amino acids such as glutamate and aspartate. Glob-
al cerebral ischemia, for example following cardiac arrest, is
induced when cerebral perfusion pressure (mean arterial blood
pressure minus ICP) falls below a certain threshold, because
of either increased ICP or reduced arterial blood pressure.
Global ischemia will eventually compromise vital brainstem
centres, leading to cardiorespiratory arrest. In such a non-
perfused brain, there is selective neuronal necrosis in vulner-
able regions, including laminar cerebrocortical necrosis (es-
pecially in the depths of the sulci), hippocampus, central gray
matter (particularly thalamus), and cerebellar Purkinje cells
(Blumbergs 2005; Blumbergs et al. 2008; Graham et al.
1989b).
Elevated ICP is the most important secondary complication
of TBI and is the commonest cause of death after such an
injury. It results from space-occupying contusions,
haematomas, and the spreading oedema (largely vasogenic)
surrounding them. Raised ICP is usually an indicator of the
severity of the underlying brain injury and represents exhaus-
tion of compensatory mechanisms. Initially, displacement of
an equal volume of cerebrospinal fluid and venous blood
limits the rise in ICP (Monro-Kellie doctrine) but, when no
further compensation is possible, ICP can rise rapidly with a
concomitant fall in cerebral perfusion and ischemic-hypoxic
damage as ICP approaches blood pressure. Although elevated
ICP is found in most severe head injuries, marked distortion
and herniation of the brain can result from slowly expanding,
Vet Res Commun (2014) 38:297305
space-occupying lesions, without significantly increasing ICP.
By contrast, very rapid elevations of ICP may cause minimal
distortion and herniation. Moreover, when distortion and her-
niation of the brain are found at necropsy, it does not neces-
sarily indicate the existence of elevated ICP ante-mortem as
these change might have occurred as part of the compensatory
mechanism before there was a significant change in ICP
(Graham et al. 1987; Miller and Adams 1972).
Brain swelling after TBI may be due to vascular engorge-
ment (congestion) from arterial dilatation and/or venous ob-
struction, which can occur rapidly or be delayed by several
days, or to increased brain water content (oedema). Apart
from haematomas, it is the major cause of raised ICP. Head
injury results in two main types of cerebral oedema, both of
which are usually present in varying combinations and can
alter over time, but may occur sequentially. Vasogenic (open
barrier) oedema occurs after bloodbrain barrier (BBB) break-
down, resulting in extravasation of a protein-rich fluid; it can
be demonstrated using albumin immunohistochemistry as a
surrogate marker of increased BBB permeability. Vasogenic
oedema can occur within a few minutes of injury or develop
after several days around contusions and intraparenchymal
haemorrhage. Cytotoxic (closed barrier) oedema occurs with
ischemia-hypoxia from loss of high-energy phosphates and
derangement of the sodium/potassium pumps. Water then
enters cells, especially astrocytes, calcium channels open
and there is an influx of these ions (Miller 1993; Nag et al.
2009).
When the brain is subjected to a traumatic insult,
inflammation is one of the major delayed, evolving responses,
with recruitment of inflammatory cells during secondary dam-
age cascades. Neuroparenchymal damage elicits a non-specif-
ic, but complex and programmed cellular and molecular pro-
cesses constituting inflammation, which may have substantial
pathologic consequences and can be an important determinant
of the eventual neurological outcome. The initiation and or-
chestration of inflammation following TBI is multifactorial,
encompassing pro- and anti- inflammatory cytokines,
chemokines, adhesion molecules, complement factors, and
reactive oxygen and nitrogen species. Neuroinflammatory
events are a double-edged sword, having dual and opposing
roles after TBI. While inflammation is responsible for some of
the secondary brain damage and adverse clinical outcomes, it
may also be neuroprotective and promote neuroreparative
mechanisms. These beneficial and deleterious effects also
often differ between the acute and more delayed phases after
a head injury (Finnie 2013; Morganti-Kossmann et al. 2002).
Infection of the brain is an ever-present threat when the
integrity of the protective skull is traumatically breached.
Meningitis is a well recognized complication after a head
injury and subdural or intracerebral abscesses may form,
being more common after penetrating than non-penetrating
head injuries. Another complication of non-missile head
Vet Res Commun (2014) 38:297305
injury is post-traumatic hydrocephalus, which is usually due
to impairment of cerebrospinal fluid absorption via the arach-
noid granulations due to the presence of subarachnoid haem-
orrhage or fibrosis and haemosiderosis of the meninges. How-
ever, ventricular dilatation can also be secondary to loss of
brain tissue after a severe injury (ex vacuo ventriculomegaly)
(Blumbergs 2005; Blumbergs et al. 2008).
Penetrating missile head injury
The degree of brain damage (Table 1) inflicted by gunshot
wounds is largely dependent upon the velocity of the wounding
missile, the magnitude of the wound being predominantly
determined by the amount of kinetic energy (KE) deposited in
the brain by a slowing projectile. The KE transferred to the
brain by any missile equals 0.5 missile mass x (missile
velocity)2 (Adams et al. 1980b). If the missile is retained within
the brain, then all the missile energy will be deposited in neural
tissue. Other retardant factors such as tissue specific gravity and
aerodynamic factors, principally yaw, also foster brain injury.
Yaw is deviation of the long axis of the projectile from its line
of flight, the energy imparted to the parenchyma being greatest
when the yaw angle is maximal (Carey 1989; Carey 1996;
Finnie 1993a; Finnie 1993b; Hollerman et al. 1990).
With head injuries produced by rifles, high velocity bullets
usually produce a perforating head injury, with both entry and
exit wounds. By contrast, lower velocity bullets produce a
penetrating injury, the projectile being retained within the
skull or soft tissues on the contralateral side of the head. Exit
wounds are considerably larger than entrance wounds. At
necropsy, fracture lines extend from the bullet holes into more
remote regions of the skull in most cases, sometimes radiating
from, and less commonly unrelated to, the entrance hole
(Hollerman et al. 1990; Carey 1989; Carey 1996). For effec-
tive of euthanasia of livestock, there are considerable advan-
tages in missile fragmentation and dissipation of KE of the
projectile within the cranial cavity, without penetration of the
contralateral skull bones, to enhance the severity of the
resulting brain damage (Finnie 1993a; Finnie 1993b).
When a missile enters the brain, it causes two main types of
injury: (1) a permanent, localized, primary wound track and
(2) a large temporary cavity created by high radial forces
imparted to the neural parenchyma (Carey 1989; Carey 1996;
Fackler et al. 1988).
The principal histopathological feature in the brain after a
traumatic insult from penetration of a rifle projectile is the
formation of a permanent hemorrhagic wound track due to
laceration and crushing of neural tissue. This injury is com-
plicated by the intrusion of bone fragments and portions of
lacerated scalp and subjacent soft tissues and penetrating head
injuries engender a high risk of infection. Secondary tracks
delineating the path of bone fragments are often found and
bullet fragments are frequently entangled with damaged hair
303
follicles acquired during skin penetration. Shotgun injuries
produce multiple tracks in the brain and a pellet can be found
at the terminus of each track, which vary in length according
to the KE deposited. A bullet imparts momentum to all parti-
cles which are struck and hard particles such as bone from the
perforated skull, especially the inner table, are driven in vary-
ing directions from the main wound path. In permanent
wound tracks of the cerebrocortical gray matter, neurons are
usually totally destroyed, while those in adjacent tissue are
markedly elongated and hyperchromatic (stretched or plas-
tic creep). In the penumbra of this primary track, many axons
are severely damaged but, at a distance from the permanent
wound track, there are also many injured axons and
perivascular ring haemorrhages due to temporary cavitation.
Copious intraventricular haemorrhage, with frequent detach-
ment of the choroid plexus, and midline shift and distortion/
displacement of the brain are also commonly found (Carey
1996; Adams et al. 1980a).
When a missile passes through the brain, KE is transferred
to the contiguous tissue, which is propelled radially from the
missile track, forming a large temporary cavity in the wake of
the projectile. This temporary cavity is mainly responsible for
a fatal outcome after missile injury to the brain, especially
with a high velocity projectile, unless vital structures are
damaged by tissue destruction in the immediate vicinity of
the wound track. The temporary cavity, which exists for only
microseconds, is much larger (up to 30 times) than the more
fusiform and permanent, haematoma-filled primary wound
track. The brain is very sensitive to the stretching effects of
cavitation (and the large internal pressures generated in its
expanding walls) as it is relatively inelastic. When the limit of
neural tissue elasticity is attained, the tissue collapses to the
point from which it was originally displaced. This cycle may
be repeated several times before the disrupted tissue settles
around the permanent wound track, enhancing tissue damage.
The oscillating movements of the cavity propagate pressure
waves widely throughout the brain, resulting in distortion and
damage to blood vessels and nerve fibres remote from the
primary missile track (Finnie 1993a; Finnie 1993b; Oemichen
et al. 2000; Oemichen et al. 2001).
Captive bolt stunning of domestic livestock is the most
frequently used method of euthanasia in abattoirs and for
humane killing of moribund animals. Both penetrating and
non-penetrating, mushroom-head captive bolt pistols (humane
stunners) are used (Finnie 1993b; Finnie 1997).
With a penetrating captive bolt projectile, the inner and
outer tables of the skull are fractured, with a subjacent impact
contusion. By contrast, non-penetrating, mushroom-head
stunners sometimes only fracture the outer table of the skull,
although impact contusions are frequently present. Focal vas-
cular and axonal injury is more severe with the penetrating
weapon, while such neural damage is more widely distributed
after a non-penetrating head impact. The latter causes rapid,
304
angular (rotational) acceleration of the head after impact of the
large, mushroom-shaped stunner head with the skull, while
the area of the head impacted by the cylindrical bolt of the
penetrating stunner is smaller and movement of the head
correspondingly reduced (Finnie 1993b; Finnie et al. 2000).
In the only study to compare brain damage in livestock (in this
case sheep) resulting from penetrating and non-penetrating
captive bolt stunning (Finnie et al. 2000), the severity and
mix of focal and diffuse injury suggested that both weapons
were an acceptable form of euthanasia. However, in sheep,
brain damage is substantially influenced by the region of the
head subjected to impact from a non-penetrating, mushroom-
head stunner, being greatest with a frontal impact, followed by
occipital, then a temporal approach (Finnie et al. 2001).
In conclusion, while most domestic animal species have a
relatively large, gyrencephalic brain resembling that of
humans and the general pattern of reaction of their brains to
a traumatic insult appears to be similar, there are, nevertheless,
significant craniocerebral anatomical differences and the ori-
entation of the neuraxis is very different. In human medicine,
advanced neuroimaging combined with detailed neuropatho-
logical examinations has greatly improved our understanding
of TBI. It is hoped that similar studies in traumatically head-
injured animals will lead to a better appreciation of the pa-
thology and pathogenesis of TBI in different animal species.
These studies should be conducted on non-fatally head injured
animals, permitting time for the development of secondary,
evolving lesions of the type likely to be encountered in clinical
practice and warranting, and being potentially amenable, to
therapeutic intervention.
Acknowledgments I thank Professor Peter Blumbergs, Senior Consul-
tant Neuropathologist, SA Pathology, Adelaide, for helpful discussion in
preparation of this manuscript.
Disclosure statement The author declares that he has no conflict of
interest.
References
Adams JH (1990) Brain damage in fatal non-missile head injury in man.
In: Braakman R (ed) Handbook of clinical neurology. Elsevier,
Amsterdam, pp 4363
Adams JH (1992) Head injury. In: Adams JH, Duchen LM (eds)
Greenfields neuropathology. Edward Arnold, London, pp 106152
Adams JH, Graham DL, Scott G et al (1980a) Brain damage in fatal non-
missile head injury. J Clin Pathol 33:11321145
Adams JH, Scott G, Parker LS et al (1980b) The contusion index: a
quantitative approach to cerebral contusions in head injury.
Neuropathol Appl Neurobiol 6:319324
Anderson R, McLean J (2005) Biomechanics of closed head injury. In:
Reilly PL, Bullock R (eds) Head injury. Pathophysiology and man-
agement. Hodder Arnold, London, pp 2640
Vet Res Commun (2014) 38:297305
Beirowski B, Nogradi A, Babetto E et al (2010) Mechanisms of axonal
spheroid formation in central nervous system Wallerian degenera-
tion. J Neuropathol Exp Neurol 69:455472
Blumbergs PC (2005) Pathology. In: Reilly PL, Bullock R (eds) Head
injury. Pathophysiology and management. Hodder Arnold, London,
pp 4172
Blumbergs PC, Jones NR, North JB (1989) Diffuse axonal injury in head
trauma. J Neurol Neurosurg Psychiatry 52:838841
Blumbergs PC, Scott G, Manavis J et al (1994) Staining of amyloid
precursor protein to study axonal damage in mild head injury.
Lancet 344:10551056
Blumbergs PC, Scott G, Manavis J et al (1995) Topography of axonal
injury as defined by amyloid precursor protein and the sector scoring
method in mild and severe closed head injury. J Neurotrauma 12:
565572
Blumbergs PC, Reilly PL, Vink R (2008) Trauma. In: Louis DN, Love S,
Ellison DW (eds) Greenfields neuropathology, 8th edn. Arnold,
London, pp 733832, Vol 1
Bryantseva SA, Zhapparova ON (2012) Bidirectional transport of organ-
elles: unity and struggle of opposing motors. Cell Biol Int 36:16
Carey ME (1989) Experimental missile wounding to the brain. J
Neurosurg 71:754764
Carey ME (1996) Experimental missile wounding of the brain. In:
Narayan RK, Wilberger JE, Povlishock J (eds) Neurotrauma.
McGraw-Hill, New York, pp 13471356
Chesnut RM, Marshall LF, Klauber MR et al (1993) The role of second-
ary brain injury in determining outcome from severe head injury. J
Trauma 34:216222
Clark RSB, Kochanek P (2001) Brain injury. Kluwer, Boston
Denny-Brown D, Russell WR (1941) Experimental cerebral concussion.
Brain 64:93164
Fackler MI, Bellamy RF, Malinowski JA (1988) The wound profile:
illustration of the missile-tissue interaction. J Trauma 28:S2129
Finnie JW (1993a) Pathology of experimental traumatic craniocerebral
missile injury. J Comp Pathol 108:93101
Finnie JW (1993b) Brain damage caused by a captive bolt pistol. J Comp
Pathol 109:253258
Finnie JW (1997) Traumatic head injury in ruminant livestock. Aust Vet J
75:204208
Finnie JW (2013) Neuroinflammation: beneficial and detrimental effects
after traumatic brain injury. Inflammopharmacol 21:309320
Finnie JW, Blumbergs PC (2002) Animal models. Traumatic brain injury.
Vet Pathol 39:679689
Finnie JW, Blumbergs PC, Manavis J et al (2000) Evaluation of brain
damage resulting from penetrating and non-penetrating captive bolt
stunning using lambs. Aust Vet J 78:775778
Finnie JW, Van den Heuvel C, Gebski V et al (2001) Effect of impact on
different regions of the head of lambs. J Comp Pathol 124:159164
Gennarelli T (1996) The spectrum of traumatic axonal injury.
Neuropathol Appl Neurobiol 22:509513
Gennarelli TA, Thibault LE (1982) The biomechanics of acute subdural
hemorrhage. J Trauma 22:680686
Gennarelli TA, Thibault LE (1985) Biomechanics of head injury. In:
Wilkins RH, Rengachary S (eds) Neurosurgery. McGraw-Hill,
New York, pp 15311535, Vol 2
Gennarelli TA, Spelman GW, Langfitt TW et al (1982a) Influence of the
type of intracranial lesion on outcome from severe head injury. J
Neurosurg 56:2632
Gennarelli TA, Thibault LE, Adams JH et al (1982b) Diffuse axonal
injury and traumatic coma in the primate. Ann Neurol 12:564
574
Gennerich A, Vale RD (2009) Walking the walk: how kinesin and dynein
coordinate their steps. Curr Opin Cell Biol 21:5967
Goldstein AY, Wang X, Schwarz TL (2008) Axonal transport and the
delivery of pre-synaptic components. Curr Opin Neurobiol 18:495
503
Vet Res Commun (2014) 38:297305
Graham DL, Lawrence AE, Adams JH et al (1987) Brain damage in non-
missile head injury secondary to high intracranial pressure.
Neuropathol Appl Neurobiol 13:209217
Graham DL, Ford L, Adams JH et al (1989a) Fatal head injury in
children. J Clin Pathol 42:1822
Graham DL, Ford L, Adams JH et al (1989b) Ischemic brain damage is
still common in fatal non-missile head injury. J Neurol Neurosurg
Psychiatry 52:346350
Graham DI, McIntosh TK, Maxwell WL et al (2000) Recent advances in
neurotrauma. J Neuropathol Exp Neurol 59:641651
Hirokawa N, Niwa S, Tanaka Y (2010) Molecular motors in neurons:
transport mechanisms and roles in brain function, development, and
disease. Neuron 68:610638
Hollerman JJ, Fackler MI, Coldwell DM et al (1990) Gunshot wounds: 1.
Bullets, ballistics, and mechanisms of injury. Am J Roentgenol 155:
685690
Jennett B, Bond M (1975) Assessment of outcome after severe brain
damage. Lancet 1:480484
Jones NR, Blumbergs PC, North JB (1986) Acute subdural hematomas:
etiology, pathology and outcome. Aust N Z J Surg 56:907913
Lindenberg R, Freytag E (1960) The mechanism of cerebral contusions.
Arch Pathol 69:440469
Loberg EM, Torvik A (1989) Brain contusions: the time sequence of the
histological changes. Med Sci Law 29:109115
Manavis J, Lee P-L, Blumbergs PC et al (1999) Widespread early
dendritic injury associated with loss of cortical MAP-2 immuno-
staining in a focal ovine head impact model. J Clin Neurosci 6:500
505
Marshall LE, Gautille T, Klauber MR (1991) The outcome of severe
closed head injury. J Neurosurg 75:528536
Maxie MG, Youssef S (2007) Nervous system. In: Maxie MG (ed) Jubb,
Kennedy and Palmers Pathology of domestic animals, 5th edn.
Elsevier, Philadelphia, pp 343344, Vol. 1
Maxwell WL, Povlishock JT, Graham DI (1997) The mechanistic anal-
ysis of non-disruptive axonal injury: a review. J Neurotrauma 14:
419440
Mendelow AD, Crawford PJ (2005) Primary and secondary brain injury.
In: Reilly PL, Bullock R (eds) Head injury. Pathophysiology and
management. Hodder Arnold, London, pp 7392
305
Miller JD (1993) Traumatic brain swelling and edema. In: Cooper PR (ed)
Head injury. Williams and Wilkins, Baltimore, pp 351354
Miller JD, Adams JH (1972) Physiopathology and management of in-
creased intracranial pressure. In: Critchley M, OLeary J, Jennett B
(eds) Scientific foundations of neurology. Heinemann Medical,
London, pp 308324
Morganti-Kossmann MC, Rancan M, Stahel PF et al (2002)
Inflammatory response in acute traumatic brain injury: a double-
edged sword. Curr Opin Crit Care 8:101105
Nag S, Manias JL, Stewart DJ (2009) Pathology and new players in the
pathogenesis of brain edema. Acta Neuropathol 118:197217
Oemichen M, Meissner C, Konig HG (2000) Brain injury after gunshot
wounding: morphometric analysis of cell destruction caused by
temporary cavitation. J Neurotrauma 17:155162
Oemichen M, Meissner C, Konig HG (2001) Brain injury after survived
gunshot to the head: reactive alteration at sites remote from the
missile track. Forensic Sci Int 115:189197
Ommaya AK, Gennarelli TA (1974) Cerebral concussion and traumatic
unconsciousness: correlation of experimental and clinical observa-
tions on blunt head injuries. Brain 97:633654
Ommaya AK, Goldsmith W, Thibault L (2002) Biomechanics and neuropa-
thology of adult and pediatric head injury. Br J Neurosurg 19:843853
Povlishock JT (1992) Traumatically induced axonal injury: pathogenesis
and pathobiological implications. Brain Pathol 2:112
Povlishock JT, Christman CW (1995) The pathobiology of traumatically
induced injury in animals and humans: a review of current thoughts.
J Neurotrauma 12:555564
Reilly PL, Adams JH, Graham DI et al (1975) Patients with head injury
who talk and die. Lancet 2:375377
Shaw NA (2002) The neurophysiology of concussion. Prog Neurobiol
67:281344
Summers BA, Cummings JF, de Lahunta A (1995) Veterinary neuropa-
thology. Mosby, St Louis, MO, pp 189192
Teasdale G, Jennett B (1974) Assessment of coma and impaired con-
sciousness. A practical scale. Lancet 2:8184
Verhey KJ, Kaul N, Soppina V (2011) Kinesin assembly and movement
in cells. Annu Rev Plant Physiol Plant Mol Biol 40:267288
Young W (1992) Role of calcium in central nervous system injuries. J
Neurotrauma 9(l):925