Neuropathology of tbi 2 [autosaved]

NEUROPATHOLOGY
OF TBI
BY OBOTH R, MMEN 2
Facilitator: Dr. Juliet N S
13th. Mar. 2021
By Dr. Oboth R, MMEN 2 Neurosurgery Resident, Makerere University - kampala

• Events that injure the nervous system share the common principle of
transfer of energy to the neural tissues,
• The severity of injury correlating with the quantity and rate of energy
delivered.
• The transfer of energy during the injury is the primary injury, but this sets
into motion a cascade of molecular, cellular, tissue level, and immune system
responses that contribute to secondary injury

• Secondary injury does not end, however, with hospital discharge; it can
continue to months, years, or perhaps decades as the secondary long-term
effects of TBI become manifest.
• The essential principle is recognition that TBI is a process, not an event.

ANATOMIC STRUCTURES INVOLVED IN
TBI
• The pathology can be grossly apparent or only be discernable
microscopically and biochemically.
• Traumatic brain injury, may occur in the following structures: the scalp, skull,
dura, brain, and blood vessels.
• Multiple types and anatomic locations of pathology usually coexist

The scalp
• Is well vascularized, and when lacerated, bleeds copiously and sufficiently to lead to
shock.
• Blows to the head lead to jagged stellate lacerations of the scalp, whereas bullet
wounds tend to be discrete rounded defects.
• The Scalp is highly resilient, and only the most severe avulsing injuries lead to
permanent damage.
• Avulsion injuries usually result from e.g.
• entanglement of hair in machinery or
• vehicular accidents in which the head is dragged on the pavement

The Skull
• Is the major protector of the brain
• Its function is to soften blows and to dissipate the energy of the impact.
• Fractures tend to radiate from the point of impact, can “Open or “Closed”;
can be Linear or Communited.
• Commonly fracture edges align at same level, but one can be deeper than
• Blood and CSF can seep through (Nose & ears, soft tissues of the head)

The Dura
• Lacerations of vessels of the dura lead to life-threatening accumulations of
blood within the cranial vault including epidural and subdural hematomas

Epidural Hematoma
• They usually occur in the context of a skull fracture involving the groove of
the middle meningeal artery in which that artery is lacerated by the jagged
edges of bone.
• This arterial bleeding can lead to rapid accumulation of blood in the epidural
space with concomitant increased intracranial pressure.
• Deceptive lucidity in the early phases of hematoma accumulation, but within
minutes to hours, progressive mental status deterioration occurs if the
hematoma is large, leading to mass effect and Uncal herniation

• Concurrent brain injuries (acute subdural hematoma, contusions, and lacerations) in
approximately 30% of cases of EDH, and these patients are usually unconscious
from the time of injury.
• Venous epidural hematomas are seen less commonly, have an indolent course
• A characteristic computed tomography (CT) scan appearance; they usually do not
cross suture lines of the skull.

• EDH is seen in 2% of all types of head injury; (up to 15% of lethal head injuries).
• EDHs usually occur in the temporoparietal regions (73%)
• EDHs can occur elsewhere, including the anterior cranial fossa (11% anterior
meningeal artery), the parasagittal regions (9% sagittal sinus), and the posterior fossa
(7% occipital meningeal artery and transverse and sigmoid sinuses)

• Disruption of venous dural sinuses, emissary veins, or venous lakes within the dura
mater may account for 10% to 40% of EDHs;
• These tend to occur in children and are not always associated with a skull fracture.
• Because of age-related differences in dural adherence to the overlying skull, EDHs
are uncommon before the age of 2 years.

Subdural Hematoma
• Blood accumulations classically regarded as occurring between the inner
aspect of the dura mater and the arachnoid. Tearing of bridging veins (old
concept)
• New concept (Haines): No potential space between Dura and arachnoid,
rather the “dural border cell layer” –sparser tight junctions in meningothelial
cells. Weak meningeal dura
• SDHs usually occur over the cerebral convexities, are bilateral in 15% of
cases, and, in contrast to the EDH, they do not respect suture lines.

Acute Subdural Hematoma
• ASDHs are similar to epidural hematomas in that they occur immediately in
the context of severe head injury usually with fractures of the skull, and
laceration of the underlying dura and brain.
• Can lead to rapid neurological deterioration because of the severity of the
initial injury,
• Alternatively it can pursue a more indolent course because of relatively slow
venous or capillary bleeding.

• In ASDH with coexisting contusions and lacerations, the subdural hematoma forms
adjacent to damaged brain and these patients are unconscious from the time of injury.
• In these cases, the ASDH may be continuous through contused, lacerated brain tissue with
intracerebral hemorrhage.
• The combination of ASDH, contusion or laceration, and adjacent intracerebral hemorrhage
is a burst lobe with the temporal or frontal lobes are most frequently involved

• Patients with burst lobes may have delayed neurological deterioration
between 24 and 72 hours after injury ( cerebral edema and contusion
enlargement)
• ASDH can sometimes result from rupture of bridging veins or superficial
cortical arteries.

• In these cases of ruptured bridging vein ASDH, there may be little or no
concomitant contusion or laceration.
• These patients may experience a lucid interval before undergoing
deterioration similar to that seen in EDH.
• Bridging veins appear to be susceptible to angular acceleration forces.

• 73% of traumatic ASDHs occur because of falls and assaults where short
duration angular acceleration forces dominate the injury biomechanics.
• In contrast, only 11% of ASDHs occurred in motor vehicle crashes, in
which linear acceleration–deceleration dominate and the angular acceleration
is less prominent.

• The mortality rate of traumatic ASDH varies from 30% to 90%,
• Lower mortality rates occurring in patients with early surgical intervention.
• Concomitant primary injuries such as contusions, lacerations, and
intracerebral hemorrhages are strong determinants of mortality

• Secondary injury mechanisms such as
1. cerebral edema,
2. increased intracranial pressure,
3. hypoperfusion,
4. hypoxia,
5. acidosis,
6. bioenergetics failure, and
7. excitotoxicity
• contribute to delayed deterioration.

Chronic Subdural Hematoma
• Are slowly progressive accumulations of blood that result from separation
of the inner dural border cell layer at points of contact with bridging veins that
normally connect venous sinuses and the cortical surface.
• These veins traverse a longer, more tightly tethered course as the brain
undergoes atrophy with aging or substance abuse; therefore, the high-risk
populations are composed of elderly or alcoholic persons

• A subdural hematoma is chronic when it is discovered 2 to 3 weeks or longer after the
initiating injury.
• The clinical course can be indolent, but chronic subdural hematomas can be deceptively
dangerous.
• The lesions are bilateral in 15% to 20% of cases.
• The inciting TBI is often mild and is not recalled in up to 50% of cases.

• The outer layer of dura thickens with granulation tissue and the inner surface
of the hematoma is covered by a thinner layer of fibroblasts and granulation
tissue.
• These inner and outer membranes encase a core of degenerating blood that
is gradually encroached upon by the expanding membranes.

• Because these membranes possess numerous delicate blood vessels, recurrent
hemorrhage occurs often leading to gradual expansion of the lesion.
• Surgical drainage of the hematoma and removal of the membranes is
necessary for definitive treatment.

• Organization and reabsorption of blood in the dural border cell layer takes place on
the outer aspect of the hematoma,
• The proliferating fibroblasts and capillaries form a robust outer membrane of
granulation tissue (parietal layer), which completely covers the hematoma by
approximately 1 week,
• The formation of the outer layer membranes proceeds at a predictable pace and is
useful for the forensic dating of the hematoma

• Later, between 2 and 3 weeks, a thin inner membrane (the visceral layer) forms
between the hematoma and the thin residual inner border cell, resulting in complete
encapsulation of the hematoma.
• By the time the inner membrane forms, the outer membrane is mature and is the
same thickness as overlying external layer of dura.
• The hematoma is invaded by granulation tissue and is, under the best of
circumstances, resorbed.

• The delicate vessels are subjected to shear forces associated with everyday
head movements, leading to microhemorrhages, leading to gradual
enlargement of the hematoma. (new concept)
• Osmotic forces drawing fluid into the degrading hematoma (old concept)

• CSDH is a dynamic living structure with vigorous granulation tissue
formation, vascular remodeling, inflammation, and even occasional foci of
extramedullary hematopoiesis.

Brain Parenchymal Injury
• Ranges in severity from transient physiologic disturbances to gross
disruption of parenchyma.

1. Concussion
• Is a transient alteration of consciousness following a non-penetrating blow
to the head.
• The structural and physiological basis of this phenomenon is unclear BUT
• Torsion with malfunction of the reticular activating system.

• The autopsy in the rare death: may disclose no structural abnormalities or
minimal swelling.
• Ordinary Imaging studies are normal; but
• Diffusion Tensor Imaging (DTI) hold substantial promise in demonstrating
abnormalities.

• Metabolic positron emission tomography (PET) studies: have demonstrated
significant global reduction in cerebral glucose metabolism.
• There is substantial concern that repetitive minor head trauma may initiate a
chronic neurodegenerative process called chronic traumatic encephalopathy
(CTE)

2. Contusion
• A contusion consists of an area of hemorrhagic necrosis usually occurring on the
crests of gyri in contrast to watershed infarcts that occur in the depths of sulci.
• The irregular boney contours of the floor of the anterior and middle cranial fossae
are particularly prone to inflict injury.
• Hence, contusions are frequently seen on the subfrontal and anterior temporal
cortical surfaces

• The severity and distribution of cerebral contusions is determined in part by the
mobility of the head at impact.
• If the head is struck while immobilized, the focus of the injury will be at the impact
site—a so-called coup injury.
• If the head is not immobilized when struck, the majority of the injury may be to the
brain on the opposite side of the head from impact—a contra-coup injury

• Contra-coup injuries are thought to result from acceleration or deceleration (in the
case of falls) imparted to the brain by the impact.
• Histologically, acute contusions consist of hemorrhagic necrosis; later, the dead
tissue is removed by macrophages leaving an irregular tan defect with a glial floor
on the cortical surface.
• The yellow-tan color of remote contusions lead to the designation plaques jaunes.

• Coup contusions occur immediately beneath the site of impact.
• Contra-coup contusions occur 180 degrees away from the impact site on the
opposite side of the brain.
• Intermediate contusions, also known as gliding contusions, are intracerebral contusions
that occur deep within the neuroglial parenchyma between the impact site and the
opposite side of the brain

• The hemorrhages involve the deeper layers of the cortex and the
convolutional white matter, and they spare the surface of the gyrus.
• Intermediate contusions are often associated with diffuse axonal injury,
reflecting the shared underlying biomechanics.

• Herniation contusions involve the medial temporal lobes and the cerebellar
tonsils and are produced by movement of the brain impacting on the rigid
tentorium cerebelli or the bony margins of the foramen magnum.
• The surface contusions will be most severe in the frontal and temporal lobes
irrespective of the cranial impact site, provided the forces acting on the head
are sufficient.

• Both frontal and occipital impacts result in contusions that are most severe
in the frontal lobes.
• Patients with contusions may show progressive or sudden deterioration.
• Sudden deterioration is a feature especially of patients with severe bifrontal
contusions, temporal pole pulping, and “burst” lobes.

• Contusions are also one of the causes of neurological deterioration after a
lucid interval, mimicking extracerebral hematomas.
• Some patients with large contusions on head CT scan might not show any
alteration in a conscious state and remain in a stable clinical condition.

• Cerebral contusions are focal injuries that result when mechanical forces
damage the small blood vessels and neuroglial tissue.
• Bleeding from damaged blood vessels is the most conspicuous feature on
macroscopic and microscopic examination with the lesions ranging from
microhemorrhages to confluent hemorrhage disrupting the tissue.

• In a simple contusion, the overlying pial membrane remains intact, whereas
disruption of the pial membrane with tearing of the underlying tissue
constitutes a laceration.
• Surface contusions of the brain show a range of morphologic appearances
from microhemorrhages visible only with the microscope to confluent
hemorrhagic necrotic lesions extending through the cortex into the
subcortical white matter.

• Omalu et al., proposed a two-tier system quantifies contusions of the brain by the
gyral spread of contusions and by the parenchymal depth of penetration of
contusions with a redefinition of the lobar distinctions and classifications of the
brain.
• Gyral spread is assigned a grading scheme of 0 to 3,
• Parenchymal depth of contusions is assigned a grading scheme of 0 to 4

• A lobar contusion score is derived by multiplying the two assigned grades.
• A total brain contusion index is derived by summating all the lobar contusion
scores
• These contusion index systems have been used in experimental contusion
research and forensic neuropathology.

• Contusions are complex dynamic lesions that evolve with time and
progressive expansion or “blossoming” of contusions is frequently seen.
• Damage to parenchymal blood vessels sets into motion a cascade of events
leading to hemorrhage, breakdown of the blood-brain barrier, and infarction
secondary to compromise of the microcirculation

• This focal vascular damage results in punctate hemorrhages or small linear
hemorrhages aligned at right angles to the cortical surface because of
extension of hemorrhage along the perivascular plane.
• Subarachnoid blood from a contusion can fill an adjacent sulcus, forming a
sulcal hematoma that can lead to an erroneous diagnosis of intracerebral
hemorrhage on imaging.

• Damaged blood vessels can thrombose or vasoconstrict, leading to
secondary ischemic damage.
• Contusions increase in size over hours to days because of recurrent
hemorrhage, vasogenic edema, inflammation, and ischemic necrosis.

• In the first 24 hours after injury, tissue from evacuated contusions shows a vigorous
acute inflammatory response with vascular margination of polymorphonuclear
leukocytes with subsequent rapid parenchymal infiltration.
• After 3 to 5 days, the inflammation is predominantly parenchymal and consists of
monocyte–macrophages, activated microglia, polymorphonuclear cells, and
lymphocytes, correlating temporally with delayed postcontusional brain swelling.

• The contusional core has hemorrhages, inflammation, and astrogliosis,
• whereas the surrounding pericontusion displays edema, vacuolation, microglial
activation, axonal loss, and dystrophy.
• Proteomic analysis demonstrated altered immune response, synaptic and
mitochondrial dysfunction in the contusional core, and altered regulation of
neurogenesis and cytoskeletal architecture in the pericontusion region.

• The core has more oxidative damage, mitochondrial, and synaptic dysfunction than
the pericontusional tissue.
• If the patient survives the injury, there is gradual resorption of damaged tissue and
progressive reactive gliosis.
• Small contusions may be completely resorbed within 2 to 3 weeks, whereas larger
lesions can take weeks to months to resorb.

• The extravasated red blood cells are degraded with release of hemosiderin.
• Necrotic neuroglial tissue is phagocytosed by macrophages that appear 2 to 5 days
after the insult.
• The end result of this resorptive processes is a shrunken brown cystic space
involving the crests of gyri (plaques jaunes), often with fibrous thickening of adjacent
meninges forming a meningocerebral cicatrix.

3. Penetrating Brain Injury
• Brain lacerations are tears in the brain parenchyma with necrosis and
hemorrhage.
• These lacerations result from penetration by a foreign body or skull
fragments, or they can occur in extremely high-energy vehicular accidents.

• Like the contusion, the laceration resolves via macrophage infiltration and
gliosis,
• But instead of being confined to the cortical surface, a laceration can extend
deep into the brain or be a perforating (ie, through and through) injury.

• Lacerations often result from bullets, shrapnel, or other missiles passing
through the brain.
• The extent of injury by a bullet is related to the amount of kinetic energy
possessed by the bullet, which is transferred to the tissue during transit.
• Kinetic energy = 1/2 MV2

• Rifles Vs. Handgun manufacturing
• Missile passage through the soft compliant brain is associated with cavitation,
lasting several milliseconds with subsequent collapse of the cavity to form
the bullet track within the tissue.

• The histopathology of the penetrating injury caused by a gunshot shows a
concentrically arranged pattern of damage centered on the trajectory of the
bullet.
• Centrally, there is a cavity with no tissue but only blood and coagulum.
• The diameter of this cavity depends on the size and kinetic energy of the
bullet.

• Next, there is a thin rim of necrotic tissue devoid of glial fibrillary acidic
protein immunoreactivity, indicating that the astrocytes in this zone are no
longer viable.
• Extending for approximately 20 to 25 mm is a zone of reactive gliosis and
axonal damage associated with neuronal damage and loss.

• The neuroglial tissue changes are accompanied within 2 hours by infiltration
by polymorphonuclear cells in the rim of tissue surrounding the central
cavity.
• If the patient survives the initial injury, the necrotic tissue is resorbed by
macrophages, and the distal portions of axons transected by the injury will
undergo Wallerian degeneration.

• Reactive astrogliosis will persist indefinitely, as will macrophage neuroinflammatory
reaction.
• Intraparenchymal microhemorrhages can occur within the brain in both closed and
penetrating head injury.
• They tend to occur in the corpus callosum, quadrigeminal plate, and diencephalon.
• Some can result from impact against relatively unyielding falcine or tentorial dura

Traumatic Axonal Injury
• Some patients who sustain TBI are severely impaired in the absence of gross
lacerations or hematomas.
• They have sustained widespread microscopic axonal injury evidenced by the
presence of ruptured axons that retract to form spheroids.
• Believed to result from shearing forces that damage axons during acceleration or
deceleration.

• It is conceptualized that there is a spectrum of TAI, with the severe end of
the spectrum correlating with posttraumatic persistent vegetative state and
the mild end of the spectrum correlating with the concussive syndromes.

TAI Grading
• In grade 1 TAI, widespread axonal damage is present in the corpus callosum, white
matter of the cerebral hemispheres, brainstem, and cerebellum.
• In grade 2 TAI, there are additional focal abnormalities (usually small hemorrhages)
in the corpus callosum.
• In grade 3 TAI, there are, in addition to the findings of grade 2, small focal lesions
in the rostral brainstem

• Focal lesions in the corpus callosum and dorsolateral rostral brainstem in
grades 2 and 3 TAI may be visible on neuroimaging
• Neuroimaging of the small focal hemorrhagic lesions in the deep white
matter, corpus callosum, and rostral brainstem have been used as surrogate
markers of TAI.

• The propensity of TAI to occur in midline structures suggests that the falx
cerebri and tentorium cerebelli may impede motion of the brain in these
areas and increase loading of axons.
• There is compelling evidence that axonal alterations mature over a period of
hours to days and may therefore be potentially amenable to therapeutic
intervention

• Initially, the axons appear normal, but soon there is focal accumulation of
axoplasmic cytoskeletal components and organelles indicating disruption of
axonal transport.
• After several hours of increasing focal swelling, the axon splits and the
severed ends retract.

• Injury-induced impairment of axoplasmic transport results in progressive
axonal swelling and eventual disconnection with formation of axonal
retraction bulbs over a period of hours to days after injury.
• It is essential to recognize that axonal retraction bulbs and axonal swelling
are nonspecific axonal reactions to injury that may be seen adjacent to
hematomas, abscesses, neoplasms, and demyelinating processes in addition to
trauma

• When the axonal injury occurs in the context of trauma, the process is
designated as TAI rather than diffuse axonal injury (DAI), because the
process may be focal, multifocal, or diffuse.
• APP-immunopositive axonal damage is an almost universal finding in cases
of fatal TBI

• APP can be demonstrated immunohistochemically in damaged axons within
5 minutes of the insult
• APP is normally transported anterogradely along the axon by fast axoplasmic
transport as a membrane-bound vesicular protein that accumulates rapidly
proximal to the site of injury

Multifocal (diffuse) traumatic axonal injury
• Is defined as axonal swellings and bulbs scattered throughout the white
matter of cerebral hemispheres, brainstem, and cerebellum as individually
affected axons.
• A spectrum of change is seen that is usually multifocal rather than truly
diffuse.

Vascular axonal injury
• Is defined as axonal swellings and bulbs that cluster around infarct or in
ischemic brain in a distribution of vascular compromise associated with
raised ICP.
• The affected axons are often arranged in clusters that have a zigzag, irregular,
or geographic pattern.

• Studies in brain-injured humans have confirmed that APP-immunopositive
axons can persist for years after the injury and that this may be associated
with the formation of intra-axonal amyloid β
• Extracellular deposition of amyloid β–containing diffuse plaques have been
described close to damaged axons just hours after trauma;

• These plaques rarely become the distinctive mature neuritic plaques seen in
Alzheimer’s disease.
• Axonal deformation at the moment of injury results in a focal impairment
of axoplasmic transport and subsequent focal swelling of the axon because
of abnormal accumulation of neurofilaments and membranous organelles

• The transient focal disruption of the axonal membrane allows an influx of
Ca2+,
• This activates multiple deleterious Ca2+-dependent cascades that involve
quenching of mitochondria, leading to bioenergetic depletion and activation
of apoptosis, as well as activation of proteases including cause disruption of
the cytoskeleton.
• Released protein fragments have potential use as biomarkers of axonal injury

Cerebrovascular Damage
• As the cerebral vessels penetrate the brain parenchyma, they branch
repeatedly, reducing in size until they end in capillaries, which vary in density
throughout the brain, being richer in areas with high metabolic rates, such as
gray matter.

• Mechanical deformation owing to compression, tension, and shear can cause
tearing of blood vessel walls and hemorrhage into the surrounding tissue.
• Injury to the intraparenchymal blood vessels may be
• 1) Focal vascular injury, such as contusion, ICH, or SAH;
• 2) Multifocal vascular injury, which includes a combination of those injuries;
• (3) Diffuse vascular injury, such as petechial hemorrhage or microhemorrhage.

• Injury to the extraparenchymal blood vessels may include
1. Injury to the dura leading to ASDH or CSDH;
2. Injury to meningeal arteries, veins or sinuses leading to EDH; or
3. Injury to the carotid and vertebral arteries or their intracranial branches resulting in
thrombosis, dissection, sub-intimal hemorrhage, laceration, and arteriovenous fistula

Traumatic Intracerebral Hemorrhage
• Defined as hematomas 2 cm or larger that are not in contact with the surface
of the brain and
• Are present in 15% of autopsy cases of severe head injury.
• Lobar intracerebral hemorrhages are those that involve a lobe of the brain
and occur usually in the temporal or frontal lobes.

• A hemorrhagic mass should be considered an ICH when there is a
homogeneous collection of blood with relatively well-defined margins.
• By definition, an ICH is a parenchymal lesion composed of at least two thirds blood

• The pathogenesis of intracranial hemorrhage is likely due to deformation
and rupture of the intrinsic blood vessels (single or multiple) at the time of
injury.
• Damage to multiple small blood vessels can result in the coalescence of
many smaller hemorrhages

• Traumatic Intracranial hemorrhages are often multiple,
• 28% are associated with subdural and
• 10% with epidural hematoma, and they can arise in areas that appear normal on CT
scans obtained soon after injury

• One third to ½ of individuals with traumatic ICH are unconscious on
admission,
• Up to 20% demonstrate a classic lucid interval before the onset of coma
• Large hematomas act as space-occupying lesions and result in intracranial
hypertension and then transtentorial herniation.

• Traumatic intracerebral hemorrhages can evolve with time;
• The rate and extent of increase in volume are related to factors such as the
type and size of injured vessel, blood pressure, and any underlying bleeding
tendency.

• Individuals receiving antiplatelet or anticoagulant therapy, such as warfarin or
direct thrombin inhibitors, are at increased risk for intracerebral hemorrhagic
complications in TBI.
• Delayed traumatic intracerebral hematoma (DTICH) is a common cause of
secondary neurological deterioration after head injury,

• Progressive increase in size of the ICH has been reported in up 51% of
patients on repeated CT scans in the first 24 hours.

Traumatic Subarachnoid Hemorrhage and
Posttraumatic Vasospasm
• Traumatic SAH is relatively common after severe TBI, occurring in approximately
33% to 60% of all cases and strongly correlates with worse neurological outcome.
• The centripetal theory of Ommaya and Gennarelli suggests that lesion depth is
dependent on the force of injury
• High angular acceleration of long duration is necessary to produce a strain that
causes rupture of the superficial vessels in subarachnoid cisterns

• Posttraumatic vasospasm (PTV) is a significant secondary insult to the
injured brain that is an independent predictor of permanent neurological
deficit and poor outcome.
• The incidence of PTV varies by frequency of screening and diagnostic
modality, but is estimated to be
❑18.6% to 50% in the anterior circulation and
❑19% to 37% in the posterior circulation

• It typically develops between 12 hours and 5 days after injury and lasts
anywhere between 12 hours and 30 days

• Martin and colleagues used CBF and transcranial Doppler measurements to
identify three different circulatory stages after severe head injury ;
• Phase I (hypoperfusion),
• Phase II (hyperemia), and
• Phase III (vasospasm)

• Phase I:
• Occurs on the day of injury (day 0) and is defined by
❖ Low CBF,
❖ Normal middle cerebral artery (MCA) velocity,
❖ Normal hemispheric index (ratio of MCA velocity to internal carotid artery velocity), and
❖ Normal arteriovenous difference of oxygen (AVDO2).
• The cerebral metabolic rate of oxygen (CMRO2) is approximately 50% of normal
during this phase

• In phase II (relative hyperemia phase, days 1-3):
❖CBF increases,
❖AVDO2 falls,
❖MCA velocity rises, and
❖hemispheric index remains less than 3.

• In phase III (vasospasm phase, days 4 to 15) ;
❖ There is a fall in CBF,
❖A further increase in MCA velocity, and
❖A pronounced rise in the hemispheric index.

• PTV results in decreased CBF with decreased transcranial Doppler velocity
• Development of PTV is not always associated with significant SAH and has been reported
in patients with extra-axial hematomas
• In a recent study, fever on admission and the presence of intracerebral contusions were
identified as independent risk factors for the development of PTV,
• Suggesting both inflammatory and mechanical mechanisms

• PTV also differs in its time course, occurring earlier and resolving more quickly on
serial CT in traumatic than aneurysmal SAH.
• Vasospasm of the large intracranial arteries is accompanied by an increase in CBV,
owing to compensatory dilatation of the vessels in the microcirculation.
• Reduced CBF in the presence of increased CBV thus supports the diagnosis of
large artery spasm

Traumatic Intraventricular Hemorrhage
• Bleeding may be due to small tears in the veins of the ventricle walls; tears in the
corpus callosum, septum pellucidum, and fornices; or tears in the choroid plexus
• It is often impossible to determine the source of hemorrhage
• Intraventricular hemorrhage is frequently found in head-injured patients who do not
survive long enough to reach the hospital,

• There may be a correlation between intraventricular hemorrhage and traumatic
axonal injury
• Patients with IVH are also more likely to demonstrate intraparenchymal and basal
ganglia hemorrhages.
• Although traumatic IVH has the potential of obstructing CSF flow, acute
hydrocephalus is an uncommon manifestation.

INCREASED INTRACRANIAL PRESSURE
AND HERNIATION
• Any pathologic process that occupies space does so at the expense of the
brain, CSF, or blood.

• The normal mean ICP is less than 200 mm H2O or 15 mm Hg for a patient
in the lateral decubitus position
• The first line of physiologic compensation is reduction in CSF volume;
hence, the ventricles and sulci are effaced

• If the volume of the lesion exceeds compensatory CSF volume reduction,
then blood volume reduction occurs.
• This reduction in cerebral blood flow can have immediate adverse
consequences, because the brain is critically dependent on an uninterrupted
supply of oxygen and nutrients.

Brain Herniation Syndromes

Brain Herniation
• The intracranial compartment is subdivided by dural boundaries; the tentorium
cerebelli divides the vault into the supra and infratentorial compartments, and
• The falx divides the supratentorial compartment into two equal right and left
compartments.
• Depending on the location of the space-occupying lesion, the brain may be forced
out of one compartment into another.
• Such shifts are brain herniations

Cingulate Herniation
• If one hemisphere is forced under the falx, the cingulate lobe is the first
portion of that hemisphere to be displaced.
• Such herniations are called subfalcine or cingulate herniations
• The anterior cerebral artery is also displaced beneath the falx, and infarction
within this vessel’s territory may occur,

• leading to contralateral lower extremity weakness and urinary incontinence.

Uncal Herniation
• If one hemisphere is forced from the supratentorial compartment toward the
infratentorial compartment, the medial portion of temporal lobe, the uncus,
is the first portion of the hemisphere displaced;
• This is an uncal or transtentorial herniation

• The ipsilateral oculomotor nerve (cranial nerve III) is crushed by the
displaced temporal lobe, leading to ipsilateral pupillary dilatation and paresis
of all the extraocular muscles except the lateral rectus (cranial nerve VI) and
the superior oblique (cranial nerve IV).
• The unopposed action of the lateral rectus results in the eye deviating
laterally.

• As medial displacement continues, the midbrain is shifted away from the
descending hemisphere with the contralateral cerebral peduncle being driven
into the unyielding tentorium.
• This crushing injury of the cerebral peduncle is known as Kernohan’s notch,
and it results in hemiparesis on the same side of the body as the offending
mass.

• Because a hemispheric mass will normally produce hemiparesis on the
opposite side of the body, this paradoxic finding of ipsilateral hemiparesis
can be clinically confusing and is called a false-localizing sign
• compression of one or both posterior cerebral arteries as they ascend from
the infratentorial compartment into the now crowded supratentorial
compartment.

• This occipital lobe infarction and its attendant signs is also “false-localizing.”

Central Herniation
• If both hemispheres herniate transtentorially, the central herniation
syndrome is said to be present.
• Both pupils dilate; flaccidity and coma ensues.

Cerebellar Tonsillar Herniation
• the brainstem and cerebellum can herniate through the foramen magnum.
• The cerebellar tonsils and medulla are forced together at this opening with
lethal compression of vital medullary centers.
• Mild tonsillar grooving is frequently seen at brain cutting, and it does not
reflect significant antemortem increased intracranial pressure

• Many neuropathologists require that the cerebellar tonsils be touching and
preferably necrotic and hemorrhagic before rendering a definitive diagnosis
of tonsillar herniation.
• Immediately before and after tonsillar herniation, the downward
displacement of the brainstem can dislodge vessels from their parenchymal
beds within the midbrain and pons,

• Leads to multiple linear hemorrhages called Duret hemorrhages or secondary
hemorrhages of herniation
• These hemorrhages can coalesce, becoming difficult to distinguish from
hypertensive pontine hemorrhage

Fungus Cerebri
• A traumatic or surgical defect is present in the skull, brain under increased
pressure can extrude from the opening.

Cerebral Edema
• Is an absolute increase in brain water content.
• Cerebral edema can complicate any process that gives rise to increased
pressure, creating a self-perpetuating cycle in which increasing edema begets
increasing pressure which in turn begets more edema.

• The amount of water in brain tissue is tightly controlled by
1. the rate of production of CSF,
2. the rate of egress of CSF from the cranial vault, and
3. the flux of water across the blood-brain barrier.

• The structural basis of the blood-brain barrier is the endothelial cell with its
tight junctions lining the cerebral vessels.
• Water can enter the brain uncontrollably if the barrier is disrupted or if
osmotic forces across the barrier are sufficient to drive water into the
cerebral tissues.

Three major forms of cerebral edema
• Cytotoxic edema
• Water is driven across an intact blood-brain barrier by osmotic forces arising either
• because of failure of cells within the brain to maintain osmotic homeostasis or
• because of systemic water overload.
• In either case, water is driven down its concentration gradient into the cerebral tissues
until equilibrium occurs

Vasogenic edema
• The blood-brain barrier malfunctions permitting uncontrolled entry of water into
the tissues
• This is the most common cause of edema, and is seen with neoplasms, abscesses,
meningitis, hemorrhage, contusions, and heavy metal poisoning.
• A combination of cytotoxic and vasogenic edema is common in infarcts and TBI

• The above processes may disrupt the barrier properties of the endothelium,
or the vessels formed in neoplasms may be defective from their inception
• Vasogenic edema often responds dramatically to the administration of
corticosteroids that restore barrier integrity particularly in tumors,
• but corticosteroids are not helpful in the management of TBI related
cerebral edema.

Interstitial edema
• Involves overproduction or failure of egress of CSF so that the fluid seeps
across the ependymal lining of the ventricles to accumulate within the white
matter.

LONG-TERM EFFECTS OF TRAUMATIC
BRAIN INJURY
• Patients may remain comatose, reside in a persistent vegetative state, or show
varying degrees of motor, cognitive, affective, and coordination impairment.

Adams et al., studied the brains of 85 TBI patients who
had lived at least 1month after injury
• At the time of death,
• 35 were vegetative, 30 were severely disabled, and 20 were moderately disabled
• Neuropathologic assessment showed that ;
• 84% of patients had cerebral contusions, 58% of patients had diffuse axonal injury, and
67% of patients had ischemic brain damage
• Brainstem damage was seen in only 11 patients (13%).

• They concluded that diffuse or multifocal neuropathologic patterns of TBI
from primary axonal injury or secondary ischemic damage are associated
with the most severely impaired patients following TBI

Jellinger studied the brains of 100 patients with
unresponsive wakefulness syndrome, (vegetative state or
apallic syndrome)
• Found that patients in this state had a much higher incidence of brainstem damage
than did TBI patients who were not persistently vegetative.
• Clinical prognosis was related to the location and extent of brainstem damage
• Damage in central parts of the rostral brainstem, frequently associated with
extensive TAI, allowed no recovery from coma or vegetative state.

• In addition, only those few with small peripheral lesions in pontine
tegmentum had improvement in level of consciousness

• Epidemiologic studies have shown that TBI is a significant risk factor for
neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease,
and amyotrophic lateral sclerosis.
• Chronic traumatic encephalopathy is a neuropathologically unique condition
that has received increased study.

CHRONIC TRAUMATIC
ENCEPHALOPATHY
• Military service members returning from Iraq and Afghanistan
• Sportsmen like American football, boxers (dementia-“punch drunk”) or
dementia pugilistica”
• Corsellis and colleagues, in 1973 - chronic traumatic encephalopathy (CTE),
• Younger people (20-40 years old) tend to have a rapidly progressive course
primarily involving behavioral and mood changes

• Older people (50-70 years old) had slower disease progression involving primarily
cognitive difficulties.
• The most distinctive finding being the deposition of tau in neurons at the depths of sulci and
around blood vessels
• CTE can be established only by pathologic examination of brains from individuals
who have died
• PET imaging holds some promise for antemortem diagnosis

PROTEIN BIOMARKERS OF TRAUMATIC
BRAIN INJURY
• The ischemic, inflammatory, and neurocytotoxic cascades that follow TBI
result into:
1. Neuronal, axonal, and astroglial damage
2. Astrogliosis and neuroinflammation; and
3. Disruption of the blood-brain barrier
• Protein by-products have been evaluated as potential biomarkers

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