Neuropathology of Traumatic Brain Injury

Published on 14/03/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 3340 times

CHAPTER 325 Neuropathology of Traumatic Brain Injury

It is conceptually useful to divide traumatic brain injury (TBI) into primary and secondary types of damage provided that it is understood that the primary types of brain damage are not static but dynamic lesions that evolve over time and thus may be potentially amenable to treatment.¹^–³

Primary traumatic brain damage is the result of mechanical forces producing tissue deformation at the moment of injury. These deformations may directly damage the blood vessels, neurons and their processes, glia, and microglia in a focal, multifocal, or diffuse pattern and initiate dynamic and evolving processes that differ for each cellular component (Table 325-1). At the least severe end of the spectrum, the changes may be only molecular, and with increasing damage, microscopic and macroscopic lesions become increasingly apparent. This temporal evolution implies that at any given point in time, the pathologic picture is a summative complex of the evolving cascades of damage involving the blood vessels, neurons and their processes, glia, and microglia.⁴

TABLE 325-1 Features of Primary Traumatic Brain Injury

Note: Most fatal cases of traumatic brain injury are mixtures of focal, multifocal, and diffuse injuries.

Secondary traumatic brain damage (Table 325-2) occurs as a complication of the different types of primary brain damage and includes ischemic and hypoxic damage, expansion of hemorrhagic lesions, cerebral swelling, and consequences of raised intracranial pressure (ICP). Secondary insults such as hypotension, hypoxemia from respiratory complications, electrolyte abnormalities, and pyrexia may further add to the total injury burden.

TABLE 325-2 Features of Secondary Traumatic Brain Injury

1 Focal, multifocal, or diffuse brain swelling as a consequence of primary brain damage

2 Focal, multifocal, or diffuse ischemic injury from perfusion failure in microcirculation or macrocirculation

3 Increased ICP due to swelling and expanding hemorrhagic mass lesions

a Permanent global ischemia when ICP = CPP permanently

b Transient global ischemia when ICP = CPP transiently

c Spectrum of anterior cerebral artery and posterior cerebral artery infarcts and ischemia as a result of deformation of the anterior and posterior cerebral arteries and their branches by internal herniation.

CPP, cerebral perfusion pressure; ICP, intracranial pressure.

Biomarkers of this structural damage, such as S-100, tau, neuron-specific enolase (NSE), and myelin basic protein (MBP), may have potential utility as diagnostic, prognostic, and therapeutic adjuncts.⁵

The clinical assessment of the severity of head injury is usually based on the Glasgow Coma Scale (GCS), which is a measure of functional impairment of the neurological mechanisms subserving speech, motor function, and eye movement at a given point of time. The GCS is only an indirect measure of the conscious state, the loss or alteration of which is the cardinal feature of TBI.

Consciousness is mediated by parallel distributed neuronal networks involving thalamic (cholinergic) and extrathalamic (serotoninergic, noradrenergic, and histaminergic) ascending arousal systems, responsible for wakefulness, and ascending sensory cortical and thalamocorticothalamic loops responsible for awareness of self. These neuronal networks may all be damaged to varying degrees by direct mechanical injury or raised ICP, leading to the various grades of coma, or may be differentially damaged, as in the vegetative state in which the circuits subserving wakefulness are intact but the awareness circuits are not functioning.⁶

In any given patient, there may be a complex and dynamic interplay of the different primary and secondary types of brain damage and secondary insults to produce a constellation of lesions that is unique both in anatomical site and number. For example, the consequences of primary vascular damage may be bleeding into brain tissue to produce an intracerebral hematoma or interference in the perfusion of the brain tissue with resultant ischemic damage (secondary brain damage), or a combination of the two resulting in increased ICP leading to its sequelae. Thus, head injury is not a single entity but consists of many different types of lesion that may occur rarely in isolation, or more commonly, in varied combinations. This heterogeneity of lesions in TBI makes it unlikely that there is any single pharmacologic agent that will be effective in treating all these intersecting cascades of damage.^7,⁸

Age, genetic predisposition, preexisting disease, drugs, alcohol, and nutritional status are all factors that may influence traumatic injury. The delayed consequences of traumatic injury may continue to evolve for years after the event and include processes such as atrophy, gliosis, neural deafferentation and reinnervation, synaptic plasticity, trans-synaptic degeneration, immune reactions, wallerian degeneration, and neurogenesis.⁹

Traumatic Axonal Injury

The visualization of damaged axons by traditional silver stains has been greatly improved by a battery of immunocytochemical methods targeting molecules such as amyloid precursor protein-β (APP-β) carried by fast axoplasmic transport and cytoskeletal proteins such as the various neurofilament proteins (NFPs) and tubulins carried by slow axoplasmic transport. Impairment of fast and slow axoplasmic flow leads to progressive axonal swelling and eventual disconnection and formation of axonal retraction bulbs (ARBs) (Fig. 325-1), a process termed secondary axotomy. Current techniques are unable to distinguish traumatic axonal injury (TAI) due to mechanical deformation from axonal injury (AI) due to nontraumatic pathologic processes such as infarcts, hemorrhages, abscesses, neoplasms, and demyelination. The term AI is thus nonspecific and refers to axonal damage of any etiology. TAI may be focal, multifocal, or diffuse. There is increasing recognition of different types of TAI (Table 325-3) and that the anatomic distribution in a detailed neuropathologic work-up including large brain sections may give a clue to the putative mechanism of injury.¹⁰

FIGURE 325-1 Amyloid precursor protein (APP)-immunopositive axonal injury showing a spectrum of axonal abnormalities, including axonal swellings, axonal retraction bulbs, and immunoreactive lengths (APP immunostain, corpus callosum; ×200).

TABLE 325-3 Types of Traumatic Axonal Injury

Primary axotomy	Tissue tears or lacerations at the severe end of mechanical deformation
Secondary axotomy	Progressive impairment of axonal transport resulting in axonal swelling and eventual disconnection with the formation of axonal retraction bulbs
Neurofilament compaction	Neurofilament side-arm cleavage
Impaired axonal transport without swelling	Impaired axoplasmic transport

APP-immunopositive axonal damage is an almost universal finding in cases of fatal TBI,¹¹ whereas traditional silver stains only showed damage in about 30% of fatal head injuries.¹²

Axonal Amyloid Precursor Protein in Traumatic Axonal Injury

APP can be demonstrated immunohistochemically in damaged axons within 35 minutes of the insult.¹³ APP is normally anterogradely transported along the axon by fast axoplasmic transport as a membrane-bound vesicular protein that accumulates rapidly proximal to the site of injury.¹⁴ Reversible APP-β immunoreactive axonal changes have been shown in some experimental animal studies, but whether this also occurs in humans is unknown.

Axonal Amyloid Precursor Protein Patterns in Traumatic Axonal 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 (VAI) 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 ¹⁵ (Fig. 325-2).

FIGURE 325-2 Zigzag pattern of amyloid precursor protein (APP)-immunopositive axonal injury secondary to internal herniation dueto raised intracranial pressure (APP immunostain, corpus callosum; ×100).

Amyloid precursor protein immunoreactivity is not specific for trauma and is often present around focal lesions such as infarcts and hemorrhages. Axonal damage in most fatal cases comprises a variable mixture of AI due to mechanical deformation and secondary ischemia, and APP immunopositivity per se is unable to distinguish between axonal damage secondary to mechanical trauma or ischemia.

Recent studies in humans have confirmed that APP-immunopositive axons may persist for years after the injury and that this may be associated with the formation of intra-axonal amyloid-β but without evidence of extracellular amyloid-β plaque deposition.^16,¹⁷ This is in contrast to previous studies that have shown extracellular deposition of amyloid-βcontaining plaque-like structures close to damaged axons just hours after trauma^18,¹⁹ linking TBI to the development of Alzheimer’s disease.²⁰

Pathogenesis of Traumatic Axonal Injury

Detailed experimental investigation of the pathobiology of TAI has revealed a spectrum of axonal damage.²¹ Most traumatically injured axons are not mechanically severed at the time of impact as originally believed; instead, they progress gradually to axonal disconnection over several hours.²²^–²⁴

Axonal deformation at the moment of injury results in a focal impairment of axoplasmic transport and subsequent focal swelling of the axon due to abnormal accumulation of neurofilaments and membranous organelles, and over the next 6 to 12 hours, there is disconnection of the proximal axonal segment from the distal segment. The separated distal segment undergoes wallerian degeneration over time. The transient focal disruption of the axonal membrane allows an influx of Ca²⁺, which activates multiple Ca²⁺-dependent deleterious cascades that involve calpains, caspases, and calcineurin and cause disruption of the cytoskeleton. Calcium-linked dephosphorylation of neurofilament side arms results in focal neurofilament compaction (NFC) type of axonal injury.^25,²⁶

Diffuse Axonal Injury

Diffuse axonal injury (DAI) was first described as a clinicopathologic syndrome in patients unconscious from the time of trauma, with widespread traumatic axonal damage throughout the brain in the absence of intracranial mass lesions. Similar less severe axonal changes were also found in mild and moderate TBI resulting in the concept that these axonal changes were also the substrate for the transient disorders of consciousness associated with mild and moderate TBI.²⁷ Thus, it was conceptualized that there was a spectrum of DAI, with the severe end of the spectrum correlating with post-traumatic dementia and the mild end of the spectrum correlating with the concussive syndromes.²⁸

The application of more sensitive immunocytochemical techniques such as APP has expanded the spectrum of axonal damage demonstrable in mild, moderate, and severe TBI.²⁹

The severity of DAI has been graded on the basis of the combination of macroscopic and microscopic lesions using silver impregnation techniques to identify axonal swellings and bulbs.¹² In grade 1 DAI, widespread axonal damage is present in the corpus callosum, white matter of the cerebral hemispheres, brainstem, and cerebellum. In grade 2 DAI, there are additional focal abnormalities (usually small hemorrhages) in the corpus callosum (Fig. 325-3). In grade 3 DAI, there are, in addition to the findings of grade 2, small focal lesions in the rostral brainstem (Fig. 325-4). Focal lesions in the corpus callosum and dorsolateral rostral brainstem in grades 2 and 3 DAI may be visible on neuroimaging, but in grade 1 DAI without macroscopic focal marker lesions, conventional imaging techniques may not reveal any abnormalities. Neuroimaging of the small focal hemorrhagic lesions in the deep white matter, corpus callosum, and rostral brainstem have been used as surrogate markers of DAI.

FIGURE 325-3 Splenium showing scattered petechial hemorrhages in diffuse axonal injury type 2. Note crescent of subcortical petechial hemorrhages beneath congested cerebral cortex and hemorrhage in occipital horns.

FIGURE 325-4 Rostral pons showing dorsolateral hemorrhagic lesions in diffuse axonal injury type 3. Recent hemorrhage is seen in aqueduct.

The principal mechanical loading associated with the induction of DAI is rotational acceleration of the unrestricted head, resulting in shear, tensile, and compressive strains that produce dynamic deformation of brain tissue.³⁰ The large size of the human brain plays an important role in the generation of relatively high shear strains between different regions of tissue. The concentration of AI in midline structures may be due to dural barriers such as falx cerebri and tentorium cerebelli, which act as partial barriers to motion of the brain in a given direction.

Although DAI may occur in the absence of impact (contact) forces, most fatal human head injuries are the result of head impacts.³¹ The contact forces when the head is struck by or strikes a hard object characteristically produce focal lesions such as contusions, but they may also induce rapid acceleration-deceleration, potentially damaging axons. Nonimpact rotational acceleration of the head during car crashes may be followed by single or multiple head impacts against the interior of the motor car or road in the case of pedestrians, motor cyclists, and pedal cyclists.

Traumatic Vascular Injury

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 due to compression, tension, and shear can cause tearing of blood vessel walls and hemorrhage into the surrounding tissue provided there is sufficient moving blood in the circulatory system. In exsanguination from traumatic cardiac or aortic rupture, there may be insufficient blood in the cerebral circulation to bleed into the tissues. The amount of the hemorrhage into the neural tissue depends on a number of factors, including the nature of the blood vessels damaged (i.e., capillary, venule, vein, arteriole, small or large artery) and systemic factors such as body temperature (hyperthermia and hypothermia), shock associated with hypoxia, coagulation factor changes, blood pressure, age, acute alcohol intoxication, effects of medications or illegal drugs, effects of accompanying injuries (multiple trauma), and prior or associated diseases such as arteriosclerosis.

There is a large potential spectrum of traumatic vascular injuries that may occur in isolation or in different combinations (Table 325-4). Injury to the intraparenchymal blood vessels may be (1) focal vascular injury, such as contusion, intracerebral hemorrhage, or subarachnoid hemorrhage; (2) multifocal vascular injury, which includes a combination of those injuries; or (3) diffuse vascular injury, such as petechial hemorrhage or microhemorrhage. Injury to the extraparenchymal blood vessels may include (1) injury that bridges veins and arteries, such as acute subdural hematoma (ASDH) or chronic subdural hematoma (CSDH); (2) injury to meningeal arteries and veins, such as extradural (epidural) hematoma (EDH); (3) injury to the venous sinuses, such as EDH; (4) injury to the large arteries in neck; (5) injury to the internal carotid and vertebral arteries, including thrombosis, dissection, subintimal hemorrhage, laceration, and arteriovenous fistula; (6) injury to the blood vessels of the circle of Willis; and (7) injury to the middle, anterior, and posterior cerebral arteries, basilar artery, intracranial internal carotid artery, and vertebral artery, including thrombosis, dissection, subintimal hemorrhage, laceration, and arteriovenous fistula.

TABLE 325-4 Traumatic Vascular Injury

Intraparenchymal Blood Vessels
Focal vascular injury	Contusions or intracerebral hemorrhage
Multifocal vascular injury	Contusions and intracerebral hemorrhage
Diffuse vascular injury	Numerous petechial hemorrhages and microhemorrhages
Extraparenchymal Blood Vessels
Bridging veins and arteries	Acute subdural hematoma, chronic subdural hematoma, subarachnoid hemorrhage
Meningeal arteries and veins	Extradural (epidural) hematoma, subarachnoid hemorrhage
Venous sinuses	Extradural (epidural) hematoma, subarachnoid hemorrhage
Large Arteries in the Neck
Internal carotid and vertebral arteries	Thrombosis, dissection, subintimal hemorrhage, laceration, A-V fistula
Blood Vessels of the Circle of Willis
Middle, anterior, and posterior cerebral arteries; basilar artery; intracranial, internal carotid, and vertebral arteries	Thrombosis, dissection, subintimal hemorrhage, laceration, A-V fistula, subarachnoid hemorrhage

A-V, arteriovenous.

Cerebral Contusions

Cerebral contusions (bruises) are focal injuries that result when mechanical forces damage the small blood vessels (capillaries, veins, or arteries) and other tissue components (nerve and glial cells and their processes) of the neural parenchyma. The bleeding from damaged blood vessels is usually the most obvious feature on macroscopic and microscopic examination, the manifestations ranging from microhemorrhages to confluent hemorrhage disrupting the tissue (Fig. 325-5). Contusions are typically surface lesions of the brain, but some also include similar hemorrhagic lesions in the deeper structures of the brain.

FIGURE 325-5 Multiple recent contusions of varying size and depth involving inferior frontal lobes. Intermediate contusions of central white matter and small gliding contusions are seen in left parasagittal subcortical white matter.

In a simple contusion, the overlying pial-glial membrane is intact. Disruption of this membrane with tearing of the underlying tissue constitutes a laceration. Contusions and lacerations form a continuum of tissue injury. Surface contusions of the brain show a wide spectrum of morphologic appearances, varying from microhemorrhages visible only under the microscope to confluent hemorrhagic necrotic lesions extending through the cortex into the subcortical white matter. Surface contusions typically affect the crests of gyri and involve the outer layers of the cortex, usually in association with subarachnoid hemorrhage.

Contusions are dynamic lesions that evolve with time. The progressive expansion or “blossoming” of contusions is demonstrated well by computed tomography (CT) and magnetic resonance (MRI) imaging.³² The damage to the blood vessels sets in train an intertwined cascade of events leading to hemorrhage, breakdown of the blood-brain barrier, and infarction secondary to compromise of the microcirculation (including compromise resulting from thrombotic occlusion of blood vessels).³³ This produces a spectrum of macroscopic changes varying from focally dilated blood vessels to burst brain lobes.

Acute surface contusions are characterized by focal vascular damage leading to punctate hemorrhages or small linear hemorrhages aligned at right angles to the cortical surface due to extension of hemorrhage along the perivascular plane. Occasionally, local subarachnoid hemorrhage adjacent to a contusion accumulates within the sulcus to form a sulcal hematoma. This may lead to an erroneous diagnosis of intracerebral hemorrhage on head CT scan. The radiating streak-like cortical hemorrhages on microscopy consist of perivascular accumulations of red cells, and serial sectioning may show evidence of focal traumatic rupture or tearing of the affected blood vessel with bleeding into the perivascular space or neural parenchyma. Damaged blood vessels may thrombose, leading to additional ischemic complications. Contusions often increase in size over hours to days owing to the evolving events related to the interplay of hemorrhage, vasogenic edema, and ischemic necrosis. In the first 24 hours after trauma, contused brain tissue biopsies show an inflammatory response, which is predominantly intravascular and consists of vascular margination of polymorphonuclear leukocytes. Extravascular polymorphonuclear leukocytes can be demonstrated in injured brain tissue only a few minutes after TBI. Three to 5 days later, the inflammation is predominantly parenchymal and consists of monocyte-macrophages, reactive microglia, polymorphonuclear cells, and CD4 and CD8 T-lymphocytes, correlating with delayed postcontusional brain swelling. Inflammatory cells produce free radicals and cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α, which mediate blood-brain barrier injury that leads to brain swelling and induce DNA fragmentation in neurons and oligodendrocytes.³⁴

Surgical and autopsy studies have also provided evidence that apoptosis (an active process requiring energy and protein synthesis) also occurs in human cerebral contusions in addition to necrosis.³⁵ Although necrosis and apoptosis have been considered as distinct separate mechanisms, it is possible that in TBI they represent poles in a continuum of cell injury.³⁶ TUNEL-positive neurons and oligodendrocytes have been identified in human contusions.³⁷ Increased expression of the antiapoptotic protein Bcl-2 has been observed in surviving neurons after human TBI.³⁸ Bcl-2 proteins may participate in the control of cell death and survival by regulating the release of mitochondrial cytochrome c, which is involved in the activation of caspases, especially caspase-3, which cleaves substrates associated with DNA damage and repair, including DNA-fragmentation factor (DFF45/40), poly (ADP-ribose) polymerase (PARP), and the cytoskeletal proteins actin and laminin. Caspase-3 is activated in the injured cerebral cortex of human TBI.³⁸

The next phase is that of resorption of damaged tissue and progressive reactive gliosis. Very small hemorrhages may be completely resorbed within 2 to 3 weeks, whereas larger hemorrhages may take many weeks or months to resorb. The extravasated red blood cells are sequentially broken down to various blood pigments, including hemosiderin. Necrotic brain tissue is phagocytosed by macrophages derived from monocytes at sites where there has been disruption of the blood-brain barrier and lipid macrophages appear 2 to 5 days after the insult. The end result of these processes of resorption is a shrunken brown cystic lesion involving the crests of gyri (plaque jaunt), often with fibrous scarring of adjacent meninges with the formation of a meningocerebral cicatrix (Fig. 325-6).

FIGURE 325-6 Old hemosiderin-stained areas of gliotic and meningeal fibrotic scarring representing “healed” contusions of inferior frontal and temporal lobes. Note loss of olfactory bulbs and tracts. This type of meningocerebral cicatricial scarring may be epileptogenic.

Contusions most frequently involve the inferior frontal lobes and the inferolateral temporal lobes and poles where brain tissue comes in contact with the irregular bony surfaces of the anterior and middle cranial fossae due to the relative motion of the brain and skull at these sites.³⁹ The occipital lobes and cerebellum are rarely contused in the absence of skull fractures.

Types of Contusion

Coup contusions are contusions that occur beneath the site of impact. Coup contusions are a type of contact injury and are produced by compressive forces operating beneath an area of skull in-bending or tensile forces generated by the negative pressure produced beneath an area of skull in-bending suddenly snapping back into place. Contrecoup contusions occur opposite the impact site. Intermediate coup contusions are intracerebral lesions that occur deeply within the neural parenchyma between the impact site and the opposite side of the brain. Fracture contusions occur beneath the site of a fracture. Gliding contusions occur in the parasagittal regions and are believed to be due to the rostrocaudal movement of the brain resulting from impact or impulsive loading forces. The hemorrhages involve the deeper layers of the cortex and the convolutional white matter and spare the surface of the gyrus. Gliding contusions are often associated with DAI.⁴⁰ 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.

Contusion Patterns and Head Impacts

Previous studies have suggested that the contusion pattern depends on the direction and magnitude of the impacting force and whether the head is accelerated by the impact (e.g., blow to the movable head), is not accelerated by the impact (e.g., blow to the supported head), or is in a state of acceleration at the moment of impact (e.g., fall on head). Thus, a lateral impact in the frontotemporal area may produce a surface contusion of the contralateral temporal lobe and contusions of both uncinate gyri; a lateral temporoparietal impact may result in a contrecoup contusion of the temporal lobe; a midline occipital impact may produce bilateral frontal and temporal lobe contusions; an occipital impact lateral to the midline may cause contrecoup contusions of the frontal and temporal lobes; frontal impacts may result in bilateral or unilateral contusions of the frontal and temporal lobes; and vertex impacts may produce contusions of the brainstem and tears of the corpus callosum and pituitary stalk.⁴¹ 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 to impart movement of the brain over the irregular bony surfaces of the anterior and middle cranial fossae. Both frontal and occipital impacts result in contusions that are most severe in the frontal lobes, and it therefore cannot be extrapolated that the site of head impact necessarily is diametrically opposite the area of most severe contusion.⁴⁰

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 (Fig. 325-7). Contusions are also one of the causes of neurological deterioration after a lucid interval (“talk-and-die” patients), mimicking extracerebral hematomas.⁴² However, contusions may be totally absent in patients who have sustained severe or lethal head injury.

FIGURE 325-7 “Burst” frontal lobe (continuum of acute subdural hematoma, contusion, and intracerebral hemorrhage with surrounding vasogenic edema and ischemia). Note recent focal cortical infarction in anterior cerebral artery vascular territory.

Some patients with large contusions on head CT scan may not show any alteration in conscious state and remain in a stable clinical condition. Surface contusions are more severe in patients with skull fracture.

Traumatic Subarachnoid Hemorrhage

Bleeding into the subarachnoid space is the most common abnormality seen in fatal head injury, although in most cases it is minor and of little clinical significance. However, significant traumatic subarachnoid hemorrhage (SAH) is usually associated with cortical contusions and lacerations or traumatic rupture of intracranial arteries and bridging veins, the rupture being complete or incomplete and involving single or multiple vessels (veins more than arteries). The accumulation of blood may become so massive that it acts as a local space-occupying lesion.

Traumatic SAH may be a marker of adverse outcome owing to its association with other important cerebral lesions (subdural hematomas [SDHs] and contusions), which directly influence outcome, or to vasospasm and ischemia produced by mechanisms similar to those of aneurysmal SAH.⁴³

Fatal, massive, nonaneurysmal basal subarachnoid hemorrhage may follow assaults in the context of minor neck trauma and alcoholic intoxication.⁴⁴ The victims die rapidly, although a few cases have been described in which the patient has remained conscious for a few hours. Rupture of the vertebral artery is the most common cause of this type of injury, and the ruptures may be extracranial (28.8%), intracranial (50%), or within the junction zone (21.2%).⁴⁵

Sequelae of traumatic SAH include the following:

• Acute hydrocephalus from obstruction of cerebrospinal fluid (CSF) pathways, depending on the degree of bleeding and involvement of the basal arteries

• Increased frequency of cerebral vasospasm and increased secondary ischemic damage as demonstrated by angiographic and transcranial Doppler ultrasound studies

• Fibrous scarring (adhesive arachnoiditis) of the subarachnoid space, leading to a delayed progressive communicating hydrocephalus (uncommon)

Traumatic Intracerebral Hemorrhage

Traumatic intracerebral hemorrhages are defined as hematomas 2 cm or larger not in contact with the surface of the brain and are present in 15% of autopsy cases of severe head injury.⁴⁶ Lobar intracerebral hemorrhages are those that involve a lobe of the brain and occur usually in the temporal (Fig. 325-8) or frontal lobes. The pathogenesis of intracranial hemorrhage (ICH) 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 may result in the coalescence of many smaller hemorrhages. Traumatic ICHs are often multiple (Fig. 325-9), and 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.⁴⁷ One third to one half of patients with ICH are unconscious on admission, and up to 20% demonstrate a classic lucid interval before the onset of coma.⁴⁷ Patients who are deeply comatose with large hematomas have a high mortality rate. Large hematomas act as space-occupying lesions and result in intracranial hypertension and then transtentorial herniation. Animal studies have shown marked hypoperfusion around hematomas as well as ipsilateral hemisphere ischemia.

FIGURE 325-8 Recent lobar hemorrhage, left temporal lobe.

FIGURE 325-9 Multiple recent intracerebral hemorrhages of varying size. Left subfalcine herniation and hemorrhagic necrosis of corpus callosum are seen. Recent small intraventricular hemorrhage and multiple cerebral contusions are also apparent.

Traumatic intracerebral hemorrhages may evolve with time, and 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.

Neuroimaging has shown that many traumatic hematomas develop hours to days after the injury and may not be visible on scanning soon after the traumatic event. Delayed traumatic intracerebral hematoma (DTICH) is a common cause of secondary neurological deterioration after head injury, and progressive increase in size of the ICH has been reported in up 51% of patients on repeated CT scans in the first 24 hours.⁴⁸

DTICH can occur in severely brain-injured patients as well as patients sustaining relatively mild injuries. Hematomas may be discovered within hours or days to weeks after the injury.

Traumatic Intraventricular Hemorrhage

A small amount of intraventricular hemorrhage (IVH) is frequently found in head-injured patients who do not survive long enough to reach the hospital, but bleeding may be significant (at the severe end of the spectrum) (Fig. 325-10). It is often impossible to determine the source of hemorrhage, but 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 has been suggested that the sudden dilation of the ventricular system at the time of impact leads to deformation and rupture of subependymal veins.

FIGURE 325-10 Traumatic intraventricular hemorrhage involving frontal horns and third ventricle with disruption of fornices and septum pellucidum. Recent hemorrhage in the left thalamus and petechial hemorrhages in the hypothalamus are seen. Patchy recent subarachnoid hemorrhage is apparent.

Delayed Deterioration after Traumatic Brain Injury

Patients who “talk and die” after TBI constitute an important group that would be expected to survive because the brain has not sustained a diffuse injury sufficient to produce an initial coma. In 75% of cases, the deterioration is due to an expanding intracranial hematoma.⁴² Between 12% and 32% of patients speak at some time between trauma and subsequent deterioration (“talk and deteriorate”), and 30% to 40% of these die or are left with severe disability.⁴⁹

Extradural (Epidural) Hematoma

EDH is defined by blood in the epidural space. When the hemorrhage is more than 1 cm deep or more than 25 mL in volume, the epidural hematoma is usually clinically significant; in fatal cases, the hemorrhage volume is at least 100 mL.

EDH occurs in about 2% of all types of head injury and in up to 15% of fatal head injuries.⁵⁰ The clots are most frequently found in the temporoparietal regions (73%), where the middle meningeal arteries and veins have been damaged usually by a fracture involving the squamous temporal bone. Eleven percent of clots occur in the anterior cranial fossa (anterior meningeal artery), 9% in the parasagittal regions (sagittal sinus), and 7% in the posterior fossa (occipital meningeal artery and transverse and sigmoid sinuses).⁵¹ Bruising of the overlying scalp is usually a reliable guide to the site of the hematoma.

About 10% to 40% of EDHs are of venous origin as the result of tearing of venous dural sinuses, emissary veins, or venous lakes within the dura mater.⁵² Most traumatic venous EDHs occur in children, and most are not associated with a skull fracture.⁵²

The ultimate size of the hematoma depends on the size and nature of the vessels lacerated and how tightly the dura is adherent to the inner table of the skull. The dura mater of infants is firmly adherent to the developing skull, and the meningeal vessels are not embedded in the skull as is often the case in later life, so that hematomas are uncommon before the age of 2 years. Deformation of the more elastic skulls of adolescents and young adults may strip the dura mater from the bone, without fracturing the bone, and produce a hematoma. With increasing age, the meningeal vessels may become embedded in bone and are at a greater risk for being damaged with bone trauma.

Often, the initial injury may be apparently trivial, and the patient may experience a lucid interval (only present in about 20% of EDHs). In about one third of cases, there are also other significant brain injuries such as ASDHs, contusions, and lacerations, and then the patient may experience no lucid interval and be unconscious from the time of injury.⁵¹ The systematic use of CT has resulted in the increased recognition of EDH from about 4% before to 9% after the introduction of head CT scanning.⁵³

Subdural (Intradural) Hematoma

The SDH is a collection of blood in the potential space between the arachnoid and the dura and is formed when venous, or rarely arterial, blood dissects between the dura and the arachnoid.

Organization and reabsorption of blood in the subdural space takes place on the outer or dural aspect, where proliferating fibroblasts and capillaries form an outer membrane of granulation tissue (parietal layer), which covers the hematoma in about 1 week. The development of this layer proceeds at a relatively predictable rate, thus being useful for the dating of the hematoma. Between 2 and 3 weeks, an inner membrane (visceral layer) forms between the hematoma and the arachnoid surface of the brain, with complete encapsulation of the hematoma. At this time, the outer membrane is well formed and of about equivalent thickness to the overlying dura.

A striking feature in the outer layer is the presence of giant capillaries (sinusoids), which on electron microscopy show large endothelial fenestrations and gap junctions and lack basement membranes and pericytes. There may be repeated bleeding within this neomembrane, and depending on the size, this may result in enlargement of the SDH.

The outer membrane constitutes a source of inflammatory, angiogenic, fibrinolytic, and coagulation factors and is infiltrated by variable proportions of acute and chronic inflammatory cells associated with increased concentrations of the inflammatory cytokines IL-6 and IL-8.⁵⁴ Striking eosinophilic infiltration of the neomembranes may occur and lead to a futile search for an associated infectious, inflammatory, or neoplastic condition.

Studies of the composition of the hematoma fluid have found marked imbalance of factors involved in regulation of coagulation and fibrinolysis, the effect of which is to prevent clotting of the hematoma fluid, and it has been suggested that the chronic SDH is a type of local coagulopathy.⁵⁵

The contents gradually liquefy during this period, changing from solid clotted blood to an orange-colored protein-rich fluid. The histologic aging of SDH is based on estimation of the thickness of the outer and inner fibroblastic neomembranes, the degree of lysis of erythrocytes, the presence of siderophages, and the sequence of changes in the vasculature, from the early appearance of giant capillaries to the formation and subsequent hyalinization of the vascular sinusoids. The accuracy of this process depends on having adequate material for examination. Small biopsies of the hematoma membrane often provide limited information.

SDHs are unusual in that the normal “walling-off” reaction of the body to hemorrhage paradoxically results in an evolving expanding lesion. Some hematomas resolve completely, whereas others undergo extensive calcification or ossification with extramedullary hematopoiesis.

Acute Subdural Hematoma

There are two main types of traumatic ASDH. In traumatic ASDH related to contusions and lacerations, the subdural hematoma forms adjacent to damaged brain, often in association with severe diffuse primary brain damage, and these patients are unconscious from the time of injury. Often, the ASDH is continuous through contused, lacerated brain tissue with an intracerebral hemorrhage. This complex of SDH, cerebral contusion or laceration, and adjacent intracerebral hematoma is termed a burst lobe (the temporal or frontal lobes are most frequently involved) (see Fig. 325-7). Patients with burst lobes often show delayed neurological deterioration at about the third or fourth day after injury due to swelling of the damaged brain.

The second type of ASDH is related to rupture of bridging veins (those segments of the superficial cerebral veins that cross the subdural space to reach the venous sinuses) or occasionally to rupture of superficial cortical arteries or vessels within vascular stalks bridging the subdural space. Cortical bridging veins within the subarachnoid space are of uniform thickness, whereas in the potential subdural space, they are of irregular thickness, with the wall in some areas consisting only of endothelium, basement membrane, sparse collagen fibers, and a single layer of dural border cells.⁵⁶ This predisposes to rupture into the potential subdural space rather than the subarachnoid space. In some cases of ruptured bridging vein ASDH, there is little or no associated brain damage, and these patients may experience a brief lucid interval before undergoing rapid neurological deterioration similar to that seen in typical cases of EDH. Unfortunately, the neurological deterioration is often so rapid that these patients fare no better than those in whom the hematoma is merely an extension of severe primary brain damage. Bridging vein ASDHs are found in about 13% of fatal TBI cases in the Glasgow series. It has been shown that bridging veins are most susceptible to angular acceleration forces and that 73% of traumatic ASDHs occur as the result of falls and assaults when short-duration, high-strain rate loading typically occurs.⁵⁷ Only 11% of ASDHs occurred in the occupants of vehicle crashes, in which the angular acceleration is often of longer duration and less likely to rupture the bridging vessels.⁵⁷

The reported mortality rate of traumatic ASDH varies from 30% to 90%, with the lower mortality rates occurring in patients who are operated on within 4 hours of injury.⁵⁸ The severity of the underlying brain injury determines the outcome, even when the surgery has been prompt. This poor outcome has been correlated with neuropathologic studies showing ischemic brain damage in the hemisphere underlying the hematoma.⁵⁹ An important factor leading to this ischemic damage is raised ICP producing impaired cerebral perfusion. Removal of the ASDH may result in the immediate reversal of global ischemia. However, mass effect and hemisphere compression are not the only factors of importance; hemisphere swelling beneath an ASDH often occurs even when the hematoma is thin. Excessive activation of excitatory neurotransmitter receptors, particularly the glutamatergic N-methyl-D-aspartate (NMDA) receptor, can cause neuronal damage indistinguishable from ischemic necrosis.

Chronic Subdural Hematoma

A subdural hematoma is chronic when it is discovered 2 to 3 weeks or longer after the initiating injury. Most patients are elderly people or chronic alcoholics, and cerebral atrophy appears to be an important predisposition.^60,⁶¹ The lesions are bilateral in about 15% to 20% of cases. The head injury is often mild and, in up to half of cases, is denied altogether.^60,⁶¹ The exact cause of the hemorrhage into the subdural space is usually unknown, although often attributed to rupture of a bridging vein. An atrophic brain permits the development of a subdural hematoma without the development of intracranial hypertension, although paradoxically, brain distortion is often so severe that even when the hematoma is evacuated, the brain remains depressed beneath the dura. Neuroimaging has shown that most smaller ASDHs normally resolve spontaneously and do not progress to a chronic SDH.

Brain Swelling

Massive swelling of all or part of the brain may be due to increased tissue water content of the brain (cerebral edema), increased intravascular blood volume (congestive brain swelling), or a combination of the two. Cerebral edema may be divided into cytotoxic, vasogenic, osmotic, hydrocephalic-interstitial, and hydrostatic subtypes.⁶²

Cytotoxic and Vasogenic Edema

Cytotoxic (intracellular) edema is the result of an influx of ion particles (Na⁺) due to failure of energy-dependent ion pumps, leading to a shift of water from the extracellular to the intracellular space. Energy failure may be due to mitochondrial dysfunction as the result of ischemia or direct mechanical injury of the mitochondria. Cytotoxic edema affects all cell types, but astrocytic swelling is especially prominent because of localization of aquaporin-4 (AQP-4), a bidirectional transmembrane water channel, to the perivascular foot processes at the blood-brain barrier (BBB).⁶³ AQP-4 plays an essential role in the formation and resorption of edema fluid from the brain parenchyma. AQP-4 deletion in models of cytotoxic edema reduces edema. Because the BBB remains intact, there is no enhancement on CT or MRI scans after intravenous contrast enhancement.

Impairment of the BBB leads to vasogenic edema due to a shift of water from the intravascular to the extravascular compartments and is characterized by protein-rich fluid in the extracellular space (hypodense white matter on CT). AQP-4 deletion in vasogenic edema results in decreased edema reabsorption.⁶³

Diffusion-weighted imaging (DWI) and the calculated apparent diffusion coefficient (ADC) are able to differentiate vasogenic and cytotoxic edema.⁶⁴ Cytotoxic and vasogenic edema often occur together or sequentially.

The sudden increase of intravascular or transmural pressure in an intact vascular bed results in the extracellular accumulation of protein-poor fluid. Hydrostatic edema may follow the sudden decompression of a mass lesion or when autoregulation is defective after head injury.

Ischemic Brain Edema (Biphasic Cytotoxic and Vasogenic Edema)

Ischemic brain edema is initially cytotoxic owing to failure of the ion exchange pumps when cerebral blood flow decreases below a threshold of about 10 mL/100 g per minute and later vasogenic when BBB breakdown occurs with extravasation of serum proteins into the extracellular space.

Congestive Brain Swelling

Congestive brain swelling occurs when the cerebral blood volume is increased owing to arterial dilation or venous obstruction. This may occur very rapidly in children and in patients with acute subdural hematomas.

Brain Swelling in Head Injury

Some degree of brain swelling is present in most TBIs and may be an important contributor the raised ICP. Three main patterns of brain swelling follow head injury.

Swelling around Cerebral Contusions and Intracerebral Hemorrhages

The swelling surrounding these areas may be due to a variable combination of vascular damage leading to BBB disruption and vasogenic edema and ischemic damage resulting in cytotoxic (intracellular) swelling. Osmotic edema may also contribute because of the high osmolality of the central necrotic areas of contusions.

Diffuse Swelling of One Cerebral Hemisphere

Diffuse swelling of one cerebral hemisphere unrelated to contusion, intracerebral hemorrhage, or infarction may be associated with an ipsilateral ASDH (Fig. 325-11) but may also occur with larger epidural hematomas or as an isolated event.

FIGURE 325-11 Massive swelling of left cerebral hemisphere with necrosis of anterior medial temporal lobe, including uncus, preoptic area, medial portion globus pallidus and periventricular gray matter. Note midline shift to the right and dilation of right temporal horn.

Diffuse Cerebral Swelling of the Entire Brain

The reported incidence of diffuse brain swelling following head trauma on head CT scanning varies from 5% to 40%.^65,⁶⁶ Diffuse cerebral swelling occurs more frequently in children than in adults and may occur rapidly.⁶⁷ A particularly severe catastrophic fatal form without obvious evidence of contusions or hemorrhages on neuroimaging occurs in young children. The pathogenesis of this progressive diffuse swelling unresponsive to treatment is poorly understood.⁶⁸

Brain Damage Secondary to Raised Intracranial Pressure

The most important secondary complication of head injury is raised ICP, usually due to brain swelling or the added volume of contusions and intracranial hematomas. During the initial stages of expansion of an intracranial mass, the rise in ICP is minimal because the volume of CSF and venous blood displaced from the cranium almost equals that of the expanding mass (stage of spatial compensation). When this compensating capacity is exhausted, a sharp rise in ICP occurs, with progressive decrease in cerebral perfusion, abnormal pressure waves on ICP monitoring, and finally vasomotor paralysis where the ICP equals the blood pressure and there is no cerebral perfusion. This results in global ischemia, which may be complete and permanent (if the ICP is not lowered) and transient or episodic, depending on ICP control.

Patterns of Raised Intracranial Pressure

Transtentorial Hernia from a Unilateral Supratentorial Mass Lesion

In raised ICP from supratentorial space-occupying lesions (e.g., intracerebral hematoma), the medial part of the temporal lobe on the side of the lesion is squashed against the midbrain (Fig.325-12) and squeezed through the tentorial hiatus (incisura), resulting in a swollen necrotic uncal hernia. Anteriorly placed mass lesions may produce uncal and anterior parahippocampal herniation, whereas more posteriorly placed mass lesions produce deep grooving and herniation of the posterior part of the parahippocampal gyrus.

FIGURE 325-12 Right transtentorial herniation with deep grooving of the lateral parahippocampal gyrus (indentation from tentorium cerebelli) and compression of adjacent midbrain and oculomotor nerve.

The oculomotor nerve may be compressed against the free edge of the tentorium by the herniating uncus. The peripherally located pupillary constrictor fibers in the oculomotor nerve are the fibers first injured by uncal herniation, resulting in initial impairment of the pupillary light reflex and finally a fixed and dilated pupil on the side of herniation when there is no longer conduction by the compressed preganglionic parasympathetic fibers. Bilateral oculomotor compression may also occur.

The uncal groove may extend along the entire length of the medial temporal lobe in massive herniation due to temporal lobe mass lesions. In massive herniation, the cerebral peduncle on the opposite side to the hernia may be indented by the tentorium, producing a Kernohan’s notch and a false localizing and paradoxical ipsilateral hemiparesis.

The medial temporal hernia may also compress one or more branches of the posterior cerebral artery that supplies the inferior temporal and occipital lobes. If the hernia is of sufficient size and the vascular obstruction is intermittent, then variable hemorrhagic infarction in the posterior cerebral artery territories may occur, usually involving the posterior inferior temporal lobe and the medial occipital lobe (Fig. 325-13), including the calcarine cortex. Cortical blindness (Anton’s syndrome) results if the patient survives, and there may also be impairment of the ability to form new memories because of bilateral hippocampal involvement.

FIGURE 325-13 Recent hemorrhagic infarction of the medial left occipital lobe, including the calcarine cortex, in part of the vascular territory of supply of the posterior cerebral artery due to compression of left posterior cerebral artery from left transtentorial hernia.

In transtentorial herniation, the parahippocampal gyri show medial wedge-shaped areas of hemorrhagic necrosis visible with the naked eye (Fig. 325-14) or nonhemorrhagic necrosis visible only on microscopy. These changes are invariably present when the ICP is greater than 5.3 kilopascal (kPa) (40 mm Hg) during life, in most patients with ICP between 2.7 and 5.3 kPa (22 and 40 mm Hg), and in no patients with ICP less than 2.7 kPa (20 mm Hg).⁶⁹

FIGURE 325-14 Bilateral (asymmetric) wedges of hemorrhagic necrosis of the parahippocampal gyri secondary to bilateral (central) transtentorial herniation.

Bilateral (central) transtentorial herniation occurs when there is diffuse swelling of both cerebral hemispheres (Fig. 325-15).

FIGURE 325-15 Bilateral (central) transtentorial herniation with multiple, midline, secondary (Duret’s) hemorrhages disrupting the midbrain.

Brainstem Hemorrhages and Raised Intracranial Pressure

Transtentorial herniation results in secondary hemorrhages of the midbrain and pons. The hemorrhages are most common in the midline of the pons and midbrain and usually do not extend to involve the medulla. The perforating branches supplying the brainstem arise from the firmly anchored circle of Willis, and these are progressively stretched and torn when their tensile limits are exceeded as the brainstem is pushed caudally.

Tonsillar Herniation (Medullary Coning)

The downward descent of the cerebellar tonsils progressively obstructs the foramen magnum and compresses the tonsils against the bony margins, resulting in a spectrum of tonsillar grooving with necrosis of the tonsils at the most severe end of the process. If the obstruction is intermittent, hemorrhagic necrosis may ensue. Necrotic cerebellar tonsillar tissue (especially in association with the “respirator brain”) may shed into the spinal subarachnoid space. The tonsillar herniation may be asymmetric, with the more prominent tonsil correlating with the unilateral transtentorial herniation above the tent. The combination of direct pressure and ischemia of the medulla leads to progressive loss of consciousness and respiratory and vasomotor failure.

Medullary coning with rapid death can occur after lumbar puncture in a patient with raised ICP.

Transfalcine (Subfalcine) Herniation

Subfalcine herniation of the cingulate gyrus occurs when a mass lesion in a cerebral hemisphere enlarges sufficiently to squeeze the ipsilateral gyrus beneath the free margin of the falx cerebri (see Fig. 325-11). This may lead to compression of the pericallosal branches of the anterior cerebral artery, with a spectrum of ischemic and hemorrhagic infarction in the corpus callosum in the anterior cerebral artery territories of supply of the superior aspect of the cerebellar hemispheres. There may be compromise of branches of the superior cerebellar arteries, producing hemorrhagic and ischemic necrosis in the superior cerebellar artery vascular territories.

External (“Fungus”) Herniation

Craniectomy may result in herniation of swollen brain tissue through the surgical defect in the skull vault.

Upward Transtentorial Herniation

Mass lesions in the posterior fossa may result in upward herniation of the superior cerebellum through the tentorial hiatus, resulting in deep grooving in the medial part of the superior aspect of the cerebellar hemispheres. There may be compromise of branches of the superior cerebellar arteries, producing hemorrhagic and ischemic necrosis in the superior cerebellar artery vascular territories.

Ischemic Brain Damage in Traumatic Brain Injury

Neuropathologic evidence of ischemic brain damage is found in about 90% of patients who survive for several hours after injury and is significantly associated with a known episode of hypoxia, such as cardiac arrest, status epilepticus, or raised ICP.⁷⁰

Ischemic changes in fatal head injury have been classified as boundary zone (watershed), arterial territory, multiple focal, diffuse, and mixed. Most ischemic damage can be identified only in the properly fixed and dissected brain, and even then it may be impossible to recognize with the naked eye severe and extensive neural necrosis, even of several days duration.

When the cerebral perfusion pressure ([CPP] = mean arterial blood pressure [MAP] − ICP) drops below 6 kPa (45 mm Hg) and is not corrected, global ischemia or nonperfused brain (respirator brain) results. Global ischemia may be transient, intermittent-recurrent, or permanent.

Some patients with raised ICP and marginal CPP (about 30 to 40 mm Hg) producing global oligemia may survive hours to days. This situation causes diffuse neuronal necrosis in the regions of selective vulnerability as well as the spectrum of “watershed” infarction. In the neocortex, there is laminar necrosis, more severe in the depths of sulci than crests, diffuse neuronal necrosis in the hippocampi, amygdaloid and central gray matter nuclei, particularly the thalamic nuclei, and necrosis of Purkinje’s cells of the cerebellum. A similar pattern of damage may occur in transient global ischemia due to total circulatory failure for a short period of time.

In experimental models, global ischemia and mechanical injury appear synergistic, producing more severe changes together than individually. When combined, mild global ischemic and fluid percussion mechanical insults that are insufficient to cause neuronal death by themselves cause massive hippocampal neuronal necrosis, even when the trauma and ischemia are separated by 24 hours.⁷¹

Permanent cardiac arrest results in global ischemia or nonperfused brain (respirator brain). Perfusion failure due to systemic arterial hypotension produces watershed infarcts that may be visible only on microscopic examination. Ischemic damage is confined to the arterial boundary zones in the cerebral and cerebellar hemispheres. The affected zones tend to be wedge shaped, with their base at the surface of the brain and the apex pointing into the brain.

Microvascular Damageand Traumatic Brain Injury

Studies have revealed profound regional reductions in flow (18 mL/100 g per minute) around contusions and intracerebral hematomas, consistent with a “traumatic penumbra.” The tissue in the traumatic penumbra,⁷² similar to the ischemic penumbra, is at most risk for undergoing irreversible damage. This cerebral ischemia is most likely the result of microvascular compromise. In a study, intravascular microthrombosis correlated with selective neuronal necrosis.⁷³

Focal Ischemia in Traumatic Brain Injury

The traumatic vascular damage may involve intimal damage, dissection, subintimal hemorrhage, or laceration, all of which may be complicated by thrombosis or embolism. The large arteries in the neck (internal carotid and vertebral arteries), blood vessels of the circle of Willis, and intraparenchymal blood vessels may be affected singly or in varying combinations.

These types of traumatic vascular damage may lead to altered cerebral blood flow and reduced or absent perfusion of brain tissue in the vascular territory of supply of the affected blood vessels and consequent ischemia if the collateral circulation is inadequate. This type of ischemia in the territory of supply of a blood vessel is termed focal or regional ischemia.

This may result in a spectrum of tissue damage, varying from selective neuronal necrosis to pan-necrosis involving neurons as well as other cellular components of neural tissue termed infarction. Neuronal “red cell change” (neuronal acidophilia) or acute ischemic cell change is the neuronal morphologic correlate of this ischemic process and is a dynamic evolving change that progresses over days after the insult.

Early brain tissue hypoxia as measured by intraparenchymal microelectrodes was frequently observed in severe head injury (GCS ≤ 8) despite aggressive treatment for ICP and CPP.

A brain PO₂ of 22 mm Hg corresponds to the ischemic threshold cerebral blood flow of 18 mL/100 g per minute.

Brainstem Lesions

CT and MRI have shown that the brainstem is frequently damaged in TBI.⁷⁴ Brainstem lesions were found on MRI in 64% of patients with severe TBI.⁷⁵ Before the advent of modern neuroimaging, primary focal brainstem lesions were considered to occur rarely in isolation from damage in the cerebral hemispheres.

Brainstem lesions may be primary, due to mechanical forces damaging the individual cellular components of the brainstem at the moment of injury and initiating a dynamic series of changes, which evolve with time, or secondary, due to brain displacements produced by raised ICP. Primary brainstem lesions usually occur in an undistorted brainstem and may be focal or diffuse. Focal primary brainstem lesions include hemorrhages, contusions, lacerations, and disruptions at the pontomedullary, mesencephalic-pontine, and medullocervical junctions.

Hemorrhage is one of the earliest recognizable signs of injury, and its presence in the brainstem (macroscopic or microscopic) may be the only evidence of a fatal injury. Numerous small hemorrhages in the brainstem, usually in association with similar lesions scattered throughout the cerebral hemispheres, are often seen in patients who die within minutes of a closed head injury. These are believed to be vascular markers of a type of diffuse brain damage incompatible with life.⁷⁶ The bleeding may be periarterial, perivenous, pericapillary, or within the neuropil; microscopy reveals many more hemorrhages than can be seen with the naked eye.

Contusions and lacerations of the brainstem are often associated with ring fractures of the base of the skull, which may be produced by a number of different mechanisms, including extreme hyperextension or anteroflexion, shearing, torsion, and impression of the vertebral column into the base of the skull.

Pontomedullary Disruption

Traumatic damage of the pontomedullary junction is a well-recognized forensic entity. Tears at the pontomedullary junction may be complete or partial (Fig. 325-16), and differentiation from artifactual disruption may be aided by the presence of microscopic hemorrhages in the marginal surrounding tissue, subarachnoid or intraventricular hemorrhage, and adjacent axonal accumulation of APP. Complete disruptions are immediately fatal, but partial tears are compatible with several weeks’ survival.⁷⁷