Closed Brain Injuries

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Closed Brain Injuries 9

9.1 Classification 177 9.2 Concussion Injury

and Cortical Hemorrhage 179 9.2.1 Biomechanical Aspects 179 9.2.1.1 Injury by Fall 183

9.2.1.2 Injury by Blow 184

9.2.2 Cellular and Molecular Mechanisms 185 9.2.2.1 Cytological Reaction 185

9.2.2.2 Necrosis 187 9.2.2.3 Apoptosis 188 9.2.2.4 ApoE-Genotype 189 9.2.3 Pathology 189 9.2.3.1 Concussion Injury 189 9.2.3.2 Contusion Injury 189

9.2.3.3 Posterior Fossa Hemorrhage 190 9.2.3.4 Scar Formation 190

9.2.4 Dating of Cortical Hemorrhages 190 9.3 Intracerebral Hemorrhages 194 9.3.1 Classification 194

9.3.2 Pathology and Differentiation 196 9.3.3 Brain Stem Hemorrhages 198 9.3.3.1 Primary Brain Stem Hemorrhage 199 9.3.3.2 Secondary Brain Stem Hemorrhage 200 9.3.4 Intraventricular Hemorrhage 201 9.4 Diffuse Brain Injuries 202 9.4.1 Edema 202

9.4.2 Ischemia 204 9.4.3 Axonal Injury 205 9.4.4 Vascular Lesion 207 9.4.5 Boxing Brain Injury

(Punch Drunk Syndrome) 207 9.5 CNS Involvement in Mechanical Injury

without Primary Brain Injury 208 9.5.1 Fat Embolism 208

9.5.2 Air Embolism 209 9.5.3 Vascular Injury 210 9.5.4 Coagulation Disorders 210 9.5.5 Ischemic Injury 210

Bibliography 210

References 210

9.1

Classification

This chapter discusses the differentiating aspects of closed brain injury in adults. Concussion injury (mild brain injury) is distinguished both clinically and morphologically from contusion injury (mod- erate to severe brain injury). Due to significant differences in their presentation and prognosis, closed brain injuries in infants and children are discussed elsewhere (Chap. 24, pp. 471 ff).

Cerebral concussion injury refers to a sudden brief impairment of consciousness, paralysis of reflex activity, and loss of memory but in the absence of focal neurological signs and morphological alterations (for review see Shaw 2002). Consciousness returns within 1 h. It typically occurs after blunt impact or deceleration of the frontal or occipital areas that creates tissue strains within the deep white matter of the brain associated with local brain displacements. The sequelae include seizures, transient headache, nausea, and vomiting (Stein 1995). Victims experience retrograde and posttraumatic amnesia. The duration of the retrograde amnesia is dependent on the severity of the injury. In some patients, memory disturbances, dizziness, nausea, anosmia, and depression are long-term. Because concussion leaves no visible morphologic changes, the entire syndrome appears to be functional in nature.

Cerebral contusion injury is clinically character- ized by long-term loss of consciousness (>1 h) and other neurological disturbances, the morphological correlates of which can be demonstrated by CT or MRT. The neurological deficits, e.g., paralyses, speech disturbances, seizures, etc., can be tempo- rary or of long duration. The temporal courses of the sequelae of brain injury as well as prognosis can be assessed by appraisal of the clinical symptoms ac- cording to the Glasgow Coma Scale (Jennett et al.

1980; Gennarelli et al. 1982 − see pp. 104 f) and/or the morphological findings according to the Glasgow Contusion Index (Adams et al. 1985):

▬ The clinical (Glasgow Coma Scale) score is arrived at by adding the results of three tests, including eye opening, best motor response and best

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verbal response (Table 6.2). The Glasgow Coma Scale score and duration of unconsciousness are then used to differentiate five degrees of severity (Table 6.3), ranging from temporary confusion without amnesia or loss of consciousness (category 1) to long-term loss of consciousness with complete amnesia and focal neurological deficits (categories 3−4) or respirator brain (brain death) syndrome (category 5).

▬ Morphological changes are quantified using the contusion index, which assesses both the depth and severity of cortical hemorrhages (Table 9.1), and the principle site(s) of injury, namely the frontal, temporal, parietal, and occipital lobes, or the Sylvian fissures and cerebellum. These two indices are multiplied to produce a “contusion index.”

Adams et al. (1980, 1985) applied these instruments to show that: (1) cortical hemorrhages are more severe in patients with skull fracture than in patients without fracture, but are (2) less severe in patients with diffuse axonal injury (DAI) than in patients without; (3) mechanically induced hemorrhages are most common and most massive in the frontal and temporal lobes; (4) brain damage is worst directly opposite the site of impact; but cortical hemorrhages are not more severe in the hemisphere contralateral to a fracture, or in the occipital lobes in patients with predominantly frontal fractures; (5) the duration of posttraumatic amnesia has a direct bearing on prognosis.

The prognosis of cortical hemorrhages does not depend on the effective forces or the type or extent of the injury of the brain alone, but is also a function of the severity and type(s) of simultaneous injuries of other organs. A contusio cordis or hemorrhagic shock resulting from multiple impact mechanisms with attendant respiratory and circulatory disturbances can aggravate the effect of brain injury-induced hypoxic injury via secondary disruption, for example, of the blood−brain barrier (brain edema).

Particularly in children, but also in adults, the subsequent course and sequelae of a traumatic event are greatly dependent upon whether an edema develops or not (Adams et al. 1980).

We have to differentiate between cortical hem- orrhages and intracerebral hemorrhages. There are principal differences in the biomechanical back- ground and the morphological alterations as well as the clinical sequelae. Closed brain injuries can be further classified according to whether the lesion is focal or diffuse (Graham et al. 1995; cf. Table 9.2) as determined by morphological criteria and biomechanical principles. Contact-induced closed head injury is distinguished from injury caused by acceleration forces (non-contact injury, Gennarelli and Thibault 1982; Gennarelli 1993). Contact injury is caused by an object striking the head or vice versa and is commonly associated with focal injury of the scalp, skull, and/or brain (dura hemorrhages, surface contusion injuries or lacerations). In contrast, acceleration injury results from shear/tensile and

Table 9.1. Contusion index grading the depth and the extension of hemorrhages in the human brain after loading.

Source: Adams et al. 1985

Depth of mechanically induced hemorrhages (D)

Not present 0

Partial thickness of the cortex 1

Full thickness of the cortex 2

Extending into digitate white matter 3

Extending into deep white matter 4

Extension of hemorrhages (E)

Not present 0

Localized (one gyrus or two adjacent gyri) 1

Moderately extensive (involvement of the greater part of the surface of one lobe) 2

Extensive (more than the surface of the lobe involved) 3

CI = D × E (for each anatomical locator).

TCI is the total contusion index for a given brain:

Addition of CI of all locators

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compressive strains or cavitation; the morphological picture is dominated by subdural hemorrhage (SDH) and DAI. In addition to these primary mechanically caused brain injuries, secondary diffuse injuries may also occur, including edema, ischemia, and vascular injuries (see below).

In the scientific literature the term “deceleration”

means negative “acceleration.” The biomechanical effect is the same except that the force is acting in the opposite direction. In the following text only one term will be used for both events, the term “acceleration.”

9.2

Concussion Injury and Cortical Hemorrhage

9.2.1

Biomechanical Aspects

The following common biomechanical finding has become the basis of many theoretical and experimental considerations: a blow (i.e., a moving object strikes the resting head) is likely to cause injuries (contusion injuries or cortical hemorrhages) (Fig. 9.1) of the brain directly beneath the impact site (homolateral = “coup” hemorrhages), whereas a fall (i.e., the moving head strikes a firm or unyielding surface or an object) tends to induce cortical hemorrhages at a location directly opposite the point of impact (contralateral = formerly known as “contrecoup” cortical hemorrhages) (Figs. 9.2, 9.3). Such lesions occur with greater frequency at the frontal and temporal poles and on the inferior surfaces of the frontal and

temporal lobes than they do elsewhere in the brain;

cortical hemorrhages are rare at the occipital poles.

Biomechanical considerations must be based on the following phenomena (Dawson et al. 1980; Leestma 1988; Gennarelli and Meaney 1996):

1. Biomechanically, it makes no difference whether the moving head strikes a big stationary object (deceleration) or a moving big and massy object strikes the stationary head (acceleration). Impact is the dynamic interaction of two bodies collid- ing.

2. As a deformable (non-rigid) object, the skull is capable of significant local and global deformation during impact.

3. The brain is a glycerin-like, non-homogeneous body that consists of different types of tissue; for example, the dura mater with its falx and tentorium, the connecting structures of the interhemi- spheric commissures, i.e., the corpus callosum, or the brain stem. The brain parenchyma is dif- ferentiated according to the white and gray matter and the course of the axons. By impact or impulsive loading to the head, the brain is set under local and global strains and displacements, and there may be considerable pressure swings (especially negative) acting on the tissue, leading to vascular, axonal, and brain tissue damage.

4. Blunt impact to the occiput is likely to induce cortical hemorrhage at sites opposite the application of force. In addition, contralateral hemorrhages tend to be fewer and less severe when the skull fractures than if it remains intact.

The published data on the biomechanics of impact to the head are based on head models in which the skull does not fracture on impact. This results in focal in-

Table 9.2. Classification and relative frequency of the different types of lesion associated with fatal non-missile head injury.

Source: Graham et al. 1995

Relative frequency (%) Focal lesions

Fracture of the skull 75

Cortical hemorrhage and laceration 95

Intracranial hemorrhage 60

Damage secondary to raised intracranial pressure 75

Diffuse lesions

Axonal injury (DAI) 90

Ischemic brain damage 55

Brain swelling 53

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juries at the contralateral site of impact. These are usually visible macroscopically due to cortical hem- orrhaging. The biomechanics of diffuse injuries are in part assessed using a brain deformation model in which the impact is delivered to the brain parenchyma and exposed dura in a form simulating impulsive loading (see Sect. 9.4).

The severity of focal injury depends on the mag- nitude of energy delivered, the skull‘s resistance to deformation, and the direction of deformation. At

the same time, acceleration and rotational forces may create shearing which results in tearing of ax- ons and myelin sheaths, sometimes also of vessels in the depths of the white matter with consequent immediate loss of consciousness (Voigt et al. 1977) and simultaneous diffuse axonal injury.

The forces transferred to the brain from the out- side, the period of impact, and the acceleration of the skull upon blunt impact depend upon the kinematics and size of the striking object, but also on properties

Fig. 9.1a−d. Ipsilateral hemorrhages caused by blow. a Contu- sion injury in the scalp; b hemorrhages in the temporal muscle

beneath the skin wound; c skull fracture beneath the skin wound;

d focal cortical and subarachnoid hemorrhages

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of the tissues of the face, the scalp, and the skull covering the brain and, to an extent, on the anatomical site of contact. The cushioning effect of the facial soft

tissues is greater than that of the back of the head; the skull‘s elasticity and resistance to fracture are different in the temporal region than in the parietal or

Fig. 9.2a−e. Contralateral wounding of the brain caused by fall (two cases). a Galeal hematoma in the right parietal region and b corresponding, i.e., contralateral subarachnoid hemorrhage on the left frontal pole. c Blunt impact on the right frontal bone by

fall associated with circular and radial fracture lines; d, e associ- ated with cortical hemorrhages at the gyral crests of the left occipital pole

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occipital regions. The mechanical load on the brain depends not only on the cushioning and elastic properties of the coverings, but also on the direct effects of the impact, e.g., whether the covering remains intact or is destroyed, whether the scalp is contused or lacerated, whether bending or compression fracturing of the skull occurs on the side of impact and/or secondary bursting fractures take place.

As mentioned above, closed brain injuries are characterized − depending on the intensity and type of inner loads generated − by bleeding in the area of impact and/or focal hemorrhages in the gyral crests of the contralateral cortex. Extensive, confluent or focal hemorrhaging can occur at the site of impact or may be totally absent. If the skull remains intact, bleeding often occurs only at a site opposite the site of impact; this agrees with clinical observations that cortical foci of bleeding are far more common at the contralateral pole. Hemorrhages can also occur in deep brain areas distant from the site of impact; this bleeding can be interpreted as being due to shearing or tensile forces or as a result of localized motions within the brain.

The dynamic load exerted on the brain by a hard blunt impact to the head is generated by positive and negative pressures and shearing forces. Numerous hypotheses exist as to which of these loads are responsible for which types and localizations of brain injury (for review see Leestma 1988). One hypothesis that has found general acceptance is the cavitation theory.

According to Sellier and Unterharnscheidt (1963; cf.

also Bandak 1997), the foci of cortical bleeding at the contralateral pole are not due to compression (contusion) as a result of an impact on the contralateral site (“contrecoup”), but to the cavitations created by negative pressure. According to these authors, the cortical hemorrhages result from an external hard blunt impact with short impact time and sufficient force accelerating the skull, creating transient positive pressure at the impact site and − depending on the degree of skull deformation − a temporary zone of lowered pressure at the contralateral pole. If the vapor pressure remains below normal levels (negative pressure), gases dissolved in fluids such as CSF and blood are released as bubbles (cavitations), with consequent rupture of small vessels as a result of the following collapse of these bubbles.

The cavitation hypothesis was first put forth by Goggio (1941 − cf. also Gross 1958), who experimentally demonstrated the formation of gas bubbles in fluids during brief periods of lowered pressure. The hypothesis has been subsequently confirmed by high-speed cinematographic documentation (Gurd- jian 1975) and by experimental studies on cadavers (Nahum et al. 1977; Table 9.3), on which the finite el- ement models of direct head impact created by Ruan et al. (1993) were based. According to the latter, hard blunt impact to the central occiput lasting several milliseconds generates sufficient force (a lower limit of 125 g head acceleration is given) only fractions of milliseconds later at the contralateral pole to create maximum temporary negative pressures of ca.

Fig. 9.3a, b. Cortical hemorrhages of the gyral crests of the ce- rebral surface − associated with subarachnoid hemorrhage (two cases). a Frontal hemorrhages caused by a fall associated with an occipital impact as seen on a horizontal section at autopsy;

b nearly the whole surface of the right hemisphere and the cortex

of the left temporal lobe are marked by stripe-like hemorrhages on a frontal section after formalin fixation. The arrowheads mark the secondary cortical hemorrhages while the thick arrow mark the areas of the impact and the primary contusion injuries

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100 kPa (approximately 1 atm), which is sufficient to induce cavitation.

Young and Morfey (1998) used simple finite el- ement modeling to study the formation of cavitation following blunt impacts lasting from 0.05 ms to 10 ms. For such brief impact times, the primary pressures were higher at the impact site, the negative pressures higher at the contralateral pole. Since the further temporal course was characterized by a reversal of the pressure distribution, negative pressures occurring at the impact pole, positive pressures at the contralateral pole, they concluded that formation of cavitation at the impact pole may also account for the foci of cortical bleeding observed there.

Lubock and Goldsmith (1980) were able to experimentally demonstrate that the collapse of gas bubbles at the end of the period of temporary negative pressure creates transient pressure spikes of at least 400−500 MPa, which they thought was sufficient to cause the observed vessel injury. The greatest structural injury therefore results from the collapse of the cavitation bubbles. Spikes created in this manner have been calculated to be capable of attaining up to 1−10 GPa.

Other forces, however, also have an (additional) effect (Gennarelli and Thibault 1982), particularly rotational shearing forces. Shear strains are especially common in the frontal/temporal regions, re- gardless of the impact site, and in locations where the surface of the overlying skull is relatively uneven.

Shear strains can cause tearing of cerebral blood vessels and thus induce cortical hemorrhages.

The term “contrecoup” is misleading for two rea- sons: first, contralateral cortical hemorrhage is not the result of an “inner impact” of the brain parenchyma against the inner table of the skull, but results from negative pressure. Second, cortical hemorrhages are caused by inertial forces and not by contact forces. Cortical hemorrhages in the sense of “contrecoup,” therefore, do not necessarily occur contralat-

eral to the site of impact, but rather at the opposite temporal and frontal poles (Ommaya 1995). If the mechanism of injury is a lateral impact to the head, ipsilateral (40%) or contralateral cortical hemorrhages (50%) are almost equally likely, the remain- ing 10% occurring bilaterally (Sano et al. 1967).

A fundamental question in forensic neuropathol- ogy is the differentiation of wounds (their topogra- phy and the associated injuries) caused by fall and by blow, as mentioned above (p. 114, see Fig. 7.3).

Further criteria in cases with closed brain injury are summed up below.

9.2.1.1 Injury by Fall

Falls on a level plane are often used in traumatology in establishing standardized control cases for estima- tion of the forces generated when the head strikes a hard, immovable object. Forensic medical experience shows, for example, that if an adult slips while walking and falls on his back without reacting to cushion the force of the fall and strikes the back of the head on a hard level surface, the force of the impact is just sufficient to cause a bursting skull fracture. The force of such a fall can be estimated as follows:

While walking, the average adult bears his head at a height (h) of about 1.6 m and thus at a potential energy level relative to the ground of Epot=m g h ≈70 J (with a head mass m=4.5 kg, and gravitational accel- eration g=10 m/s²). If there is a complete conversion of energy, this value corresponds to the experimentally measured threshold load for inducement of skull fractures.

The injuries caused by falls resulting in hard blunt impact of the head are classified as acceleration traumas. There is always a relevant accelerated mass (the head) and the sudden deceleration over a few milliseconds from speeds of 5−6 m/s in 1−2 cm generates head accelerations of more than 200 g (see

Table 9.3. Differences in brain pressures and shearing forces in the brain parenchyma induced by impact to the head at vari- ous anatomical sites, with consequent hemorrhages in the homolateral and/or contralateral cortex. Source: Nahum et al. 1977

Impact localization Head acceleration (g)

Force (kN)

Brain pressure Shear

force (kPa) Impact

point (kPa)

Contralateral site (kPa)

Frontal 233 8.1 275 −92 75

Occipital 199 6.9 252 −118 199

Temporal 220 7.6 270 −86 47

Parietal 174 6.4 205 −15 29

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also pp. 99 ff). This exceeds the critical threshold for the formation of cavitation at the contralateral pole.

Fall-induced cortical hemorrhages tend to occur at sites opposite the site of impact (Figs. 9.2, 9.3a, 9.4). Since, in falls, the most common impact site is the occipital area, cortical bleeding is encountered mainly in the frontobasal area. Forward falls on a level plane are frequently accompanied by reflexive actions to break the fall, whereas falls to the side are often cushioned by the intervening shoulder. Those arguments may explain why contralateral cortical hemorrhages in the occipital lobe are very rare (Fig. 9.2c−e).

Falls constitute the classic model of deceleration in which, in addition to cortical hemorrhages opposite the impact site, subdural hematomas (SDH) and DAI are observed. This means that falls generate not only pressure, but shearing forces as well (see Sect. 9.4, pp. 201 ff).

The presence of foci of cortical bleeding at a single site in the brain is sometimes useful in reconstruct- ing the impact site and direction of the blunt impact.

If there are cortical hemorrhages in the brain, the impact site will be located diametrically opposite to them (with one exception: frontal blunt impacts are rarely associated with contralateral, i.e., occipital cortical hemorrhages). The direction of impact generally runs from the pole of impact toward the focus of cortical bleeding (contralateral pole).

9.2.1.2 Injury by Blow

A blow inflicts brain injuries (Figs. 9.1, 9.5) mainly at the impact side (impact pole). If the skull remains intact, injury of the brain is due to local deformation (depression and recoil) of the bone. In very vio- lent blows, the energy is transformed and delivered by deformation and fracture along a relatively long pathway. Acceleration is lower at the contralateral pole and the resulting injuries − mainly caused by negative pressure − are minimal or absent altogeth- er. In contrast to falls, under these conditions, mas- sive hemorrhages develop at the impact site and are limited not merely to the gyral crests, but can extend deep into the white matter.

Manually induced forceful impact of blunt instruments with small surface areas, but relatively low accelerated masses, generally do not create the critical negative pressure at the contralateral pole.

Most of the energy is delivered locally to the impact site, where it causes contusion and/or laceration of the scalp and depressed fractures of the skull, sometimes even bursting fractures. At the impact pole, the injury is largely confined to a depressed skull fracture. The global effect on the skull, in the form of transient high acceleration, is too small to generate the necessary negative pressures at the contralateral pole to cause cavitation, even if the head is unsup- ported when it is struck.

The most common impact site is the parietal region. Most of the other sites of impact occur when the victim, who will be injured by a blow, is lying on the ground and his head is therefore supported. If the head is resting on a hard surface when struck, it cannot be accelerated, so contralateral cortical hemorrhages are uncommon under such circumstances.

Cortical hemorrhages located on the side of impact are a direct result of the forces delivered by the blow. Light force induces discrete cortical hemorrhages morphologically indistinguishable from con-

Fig. 9.4a−c. Contralateral cortical hemorrhages at the base of the frontal lobe, the most frequent phenomenon after occipital impact caused by fall (three cases). The different extensions of the hemorrhages are correlated with the increasing intensity of impact − see text. a Discrete stripe-like hemorrhages in the rectal and pararectal gyri; b more distinct hemorrhages combined with bleeding in the white matter; c extensive, space-occupying hem- orrhages of gray and white matter

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tralateral hemorrhages. The greater the force, the more extensive the focal brain injury, with slight or severe depression fracturing of the skull. The frac- tured bone causes lacerations of the dura or leptome- ninx as well as of the surface of the cortex. Depend- ing on the force of the impact, destruction of brain tissue occurs with massive, space-occupying hemorrhaging. The brain injury can involve an entire hemisphere and lead to breaching of the blood−brain barrier and bleeding into the ventricular system.

There have been repeated attempts to establish morphological criteria for the differentiation between brain injuries induced by falls and by blows.

Among the criteria discussed has been the formation of DAI (Adams et al. 1982; Geddes et al. 1997, 2000), which is more common after falls, i.e., after high acceleration loading (see also Oehmichen et al. 1997).

In any given case, however, this criterion alone is not sufficient for reliable discrimination.

9.2.2

Cellular and Molecular Mechanisms

9.2.2.1

Cytological Reaction

The wounding of the brain (ipsilateral or contralateral) is characterized by extravasal red blood cells (Fig. 9.6). The cellular response following non-missile closed brain injury includes emigration of leukocytes and macrophages and the aggregation of thrombocytes. The earliest reaction is emigration of polymorphonuclear leukocytes (Fig. 9.7), which are attracted by endothelial release of L-selectin. Leu- kocytes release interleukins (IL) IL-1, IL-2, and IL-6, and tumor necrosis factor (TNF) as well as several lipid mediators (Biagas et al. 1992). Platelets release P-selectin and lipid mediators, while macrophages and activated microglia release L-selectin, IL-1, IL-2, IL-6 and lipid mediators, which are upregulated at the endothelial surface.

Another reaction to closed head trauma at the cellular level is the reactivity of mononuclear phago- cytes, the so-called microglial reaction, which can be diffuse (Meyermann et al. 1997) or localized near to

Fig. 9.5a, b. Ipsilateral hemorrhages caused by blow. a, b Lateral-parietal blow and corresponding focal cortical and intracerebral hemorrhage

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the hemorrhage (Graeber et al. 1997) (Fig. 9.8). This reaction has been shown to follow a relatively con- sistent temporal course (Oehmichen and Raff 1980;

Oehmichen et al. 1981, 1986; Lassmann 1997), but is unrelated to the site of axonal injury (Oehmichen et al. 1999a, b). An activation of resident microglia by upregulation of major histocompatibility complex (MHC) class II expression (Beyer et al. 2000), CD14 expression (Beschorner et al. 2002), as well as of the inducible nitric oxide synthase isoform (iNOS) have recently been shown, which results in an enhance- ment of their production of nitric oxide (Possel et al.

2000; Orihara et al. 2001).

The next phase is characterized by an activation and proliferation of astrocytes (Fig. 9.9). They pro- vide structural, trophic, and metabolic support of neurons and modulate synaptic activity. According- ly, the impairment of these astrocytic functions during the mechanical insult may critically influence the survival of neurons. The functions of astrocytes influence the glutamate uptake, glutamate release, free radical scavenging, water transport, and the production of cytokines and nitric oxide. Astrocytes may affect the ultimate clinical outcome by means of neurogenesis and synaptic reorganization.

Fig. 9.6a−c. Cortical hemorrhages and their histological distri- bution at the crests of the gyri (a Gomori stain, b van Gieson stain, c H&E; magnification a ×100, b ×200, c ×1,000)

Fig. 9.7a−c. Leukocytic response. a Marginal leukocytes adher- ing at the inner vessel‘s wall; b emigrating leukocytes; c several leukocytes within the necrotic brain parenchyma (N-AS-DClAE, magnification ×1,000)

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Reactive alterations of astrocytes are characterized by the following criteria. At first, GFAP expression is upregulated only at the wound site, but later becomes widespread among astrocytes in the sur- rounding neuropil (Maxwell et al. 1990a, b) (Fig. 9.9a, b). The astrocyte activation proceeds very rapidly (Mandell et al. 2001) via the extracellular signal-reg- ulated kinase (ERK) [mitogen-activated protein kinase (MAPK)] pathway. An in vitro model has demonstrated ERK/MARK activation within 2−10 min in cells near the wound edge. Injury-induced signaling to ERK/MAPK requires Ras, as demonstrated by specific blockade. Later the astrocytes are characterized

mainly by a proliferation of fibers, exhibiting the features of so-called fibrous astrocytes.

Recently the regenerative activity of neuronal el- ements has also been discussed. Recent studies indi- cate the existence of progenitor cells and their potential neurogenesis in the subventricular zone and the hippocampus of the normal adult mammalian brain.

Using markers for immature and mature astrocytes, activated microglia, neural precursors, and mature neurons, the proliferating cells did not express any of the cellular markers used, indicating that they have not yet begun to differentiate (Chirumamilla et al. 2002).

9.2.2.2 Necrosis

The pathogenesis and morphology of necrosis have been described above, as have the associated cytokine cascade and cell reactions (Chap. 4, pp. 56 ff).

Here our remarks will be confined to the following issues.

Mechanical force with associated massive diffuse hemorrhage leads to a space-occupying situation in the cramped cranial vault. The resulting inadequate blood supply combines these factors to cause isch- emic cell necrosis, including primary neuronal death (Kermer et al. 1999). This is accompanied by a breakdown of the transmembrane K⁺/Na⁺ ion pump due to a lack of ATP.

Expression of the immediate early genes (IEG) and release of cell adhesion molecules − heat shock proteins and cytokines − begin 30 min after wounding and can last for 6−12 h (Raghupathi et al. 1997).

In the experimentally contused spinal cord, cytokine expression [tumor necrosis factor α (TNF-α), IL-1β]

was found to peak after 5−6 h (Semple-Rowland et al. 1997). When glial cells are exposed to injured or dead hippocampal neurons they release TNF-α (Viv- iani et al. 2000). This glial response may be induced by a primary neurodegenerative event involving the release of a neurospecific protein factor via activation of caspase.

The metabolic changes in the vicinity of brain contusion injuries were evaluated by means of pro- ton magnetic resonance spectroscopy in comparison with histological alterations (Schuhmann et al. 2003).

Creatine and phosphocreatine (−35%), N-acetylas- partate (−60%) and glutamate (−37%) immediately decreased after the incidence of MBI in the pericon- tusional zone and recovered at 7 days.

Another recent study (Stahel et al. 2000) found TNF-α and IL-6 to exert an additional protective ef- fect. The MBI-induced mortality of mice deficient in genes for these pro-inflammatory cytokines was significantly higher than that of wild-type animals.

Since no differences were found in blood−brain barrier dysfunction, neutrophilic granulocyte infiltra-

Fig. 9.8a−c. Macrophage response (immunoreactivity to CD68).

a Early macrophage reaction at the site of the hemorrhage;

b increase of number and immunoreactivity of macrophages;

c massive invasion of macrophages replacing decomposed tissue (magnification a ×1,000; b ×500; c ×100)

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tion and/or neuronal cell death, the pathophysiologi- cal sequelae of the cytokines following MBI remain unexplained.

The cell reaction is indispensable for discrimi- nating between necrosis and apoptosis: necrosis does not strike individual cells but entire areas sup- plied by the affected arterial vessels, i.e., cell groups and/or tissue areas. Necrosis is characterized by a primary immigration of neutrophils, followed by a secondary immigration of monocytes/macrophages and activation of resident microglia which scavenge the cell debris and myelin fragments in the necrotic area (cf. above − Chap. 3, pp. 28 f).

9.2.2.3 Apoptosis

MBI is regularly accompanied by apoptosis of neurons and glia (see also pp. 60 ff) together with the degeneration of cells demonstrating classic necrotic morphology (Clarke 1998; Raghupathi et al. 2000).

Sharp et al. (1990) have shown that brain injury stimulates the fos-antigens and the fos-dependent antigens. The stimulation is mediated by NMDA re- ceptors: brain trauma triggers the release of excitato- ry amino acids, which exert a depressive effect on the NMDA receptors (Smith and McIntosh 1995). The

consequent depolarization stimulates the release of fos in the cortical neurons, enabling the neurons to adapt biochemically to the trauma. The primary trauma also activates specific genes belonging to the bcl-2 gene family (which includes, e.g., Bax, bcl-x), which explains the phenomenon of apoptosis near the foci of hemorrhage (Yakovlev and Faden 1997).

Apoptosis begins 4 h after wounding and can be demonstrated for about 3 days thereafter (Yakovlev and Faden 1997). TNF-α and IL1-mRNA increase rapidly (20-fold) within 1 h after wounding. TNF- α levels begin to decrease again after 6 h, but IL6- mRNA levels continue to rise and do not normalize until after 3 days. A recent study found apoptosis occurring in white matter for as long as 1 year after setting head injury (Williams et al. 2001).

As described above, a cellular reaction after apoptosis is a rare occurrence. Neighboring cells phago- cytose the cell debris. If there is extensive necrosis with a cellular reaction or a different type of inflammatory process, apoptotic leukocytes are phagocy- tosed by specific phagocytes, a phenomenon that has been termed “safe phagocytic clearance of dying, yet intact leukocytes undergoing apoptosis” (Platt et al.

1998). Rapid recognition, uptake, and degradation of the apoptotic leukocytes has been described.

Fig. 9.9a−d. Astrocytic response. a, b Early response at the site of the hemorrhage demonstrating activated astrocytes (GFAP;

magnification a ×100, b ×500); c demonstration of reactive astro-

cytes by H&E stain (magnification ×1,000); d the last stage of as- trocytic reaction is characterized by increasing fiber production (GFAP; magnification ×500)

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9.2.2.4 ApoE-Genotype

It has been repeatedly (see pp. 105 f) shown that in- dividuals differ in their reaction to (and prognosis following) closed brain trauma depending on their apolipoprotein E (apoE) genotype (Nicoll and Gra- ham 1997). ApoE is thought to be responsible for the transportation of lipids within the brain maintain- ing structural integrity of the microtubule within the neurons and assisting with neural transmission.

Possession of the apoE epsilon4 allele has been shown to influence neuropathological findings in patients who die from MBI, including the accumulation of amyloid β protein (Nathoo et al. 2003).

The number of apoE immunoreactive plaques has recently been shown to correlate with levels of β-amyloid 42(43) (Horsburgh et al. 2000). Ad- ditional evidence linking a history of brain injury and Alzheimer's disease comes from studies of re- tired boxers with dementia pugilistica subsequent to repeated brain injury (Roberts et al. 1990a, b).

The apoE4 allele is the most important genetic de- terminant of susceptibility to Alzheimer's disease and acts synergistically with brain injury (Nicoll and Graham 1997). The suspected direct relation- ship between MBI and Alzheimer's disease (Gentle- man and Graham 1997; Jordan et al. 1997; Teasdale et al. 1997) could not be confirmed in the recent large (6645 patients) prospective Rotterdam Study (Mehta et al. 1999). Moreover, the epsilon4 allele may either function as a risk factor for cognitive impairment in normal aging across a broad spectrum of domains or exert detectable effects early in a long prodromal Alzheimer disease trajectory (Bretzky et al. 2003).

Moreover, from experimental and clinical brain injury studies it is evident that apoE plays an important role in the response of the brain to mechanical injury (Nathoo et al. 2003).

9.2.3 Pathology

The extent and type of clinical and morphological changes depend on the severity of injury.

9.2.3.1

Concussion Injury

The lowest grade of brain injury means “concussion”

or “commotio cerebri,” which produces a temporary loss of consciousness but no long-lasting neuronal deficits. The above mentioned definition (p. 177) of concussion is based largely on clinical findings (Congress of Neurological Surgeons 1966), its patho- physiological basis being yet poorly understood (Mc- Crory and Berkovic 2001). The morphological ap-

pearance is characterized at most by signs pointing to a slight increase in intracranial pressure. Animal experiments have shown a temporary disturbance of the blood−brain barrier without attendant nerve cell loss (Povlishock et al. 1979). Marked or repeated mechanical injury of the brain produces submicro- scopic mitochondrial swelling in the nerve cells and a major breakdown in the blood−brain barrier; these are sometimes the cumulative effect of repeated sub- threshold blunt impacts (Bakay et al. 1977; Liu et al.

1979). Other experimental results suggest that shear strains within the brain caused by rotational accelerations can place physical stress on individual neurons (Holbourn 1945). Discussing all available theo- ries, Shaw (2002) concluded in an excellent review that only the convulsive theory is readily compatible with all neurophysiological data and can provide a totally viable explanation for concussion injury. The chief tenet of the convulsive theory is that since the symptoms of concussion bear strong resemblance to those of a generalized epileptic seizure, then it is a reasonable assumption that similar pathological processes underlie them both.

It has recently been hypothesized that the functional failure associated with MBI is due in part to mechanoporation, the impact-induced deformation of the cell membrane‘s lipid bilayer resulting in ionic influx (Gennarelli and Graham 1998). The role of ion channel dysfunction is underscored by the finding that calcium channel subunit gene CACNA1A mu- tations are associated with fatal coma after minor brain wounding (Kors et al. 2001).

In this context, a further phenomenon is of in- terest: repetitive minor mechanical loadings to the brain have been shown to have a cumulative effect, especially in athletes engaged in contact sports such as American football and boxing (Cantu 1998) or in victims of repeated domestic violence (Roberts et al.

1990b), and child abuse (Duhaime et al. 1998; Lan- con et al. 1998). Recently this phenomenon has been demonstrated in a new experimental model (Laurer et al. 2001). The risk of neurodegenerative disease in later life is elevated even if the initial injury did not produce long-lasting disability or impairment (Gen- tleman et al. 1993a, b; Jordan et al. 1997).

9.2.3.2

Contusion Injury

Contact-induced loading to the brain leading to tissue damage that induces cortical hemorrhages at the gyral crests is termed contusional injury. The term

“contusion” is applied if the pia is not breached, the term “laceration” if it is torn. Contusional injuries and lacerations are both the result of the local brain tissue movements within the cranium (Graham et al. 1995). Mechanical loading to the head gives rise to neurological deficits and visible morphological

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changes. The main injury is a hemorrhage, mainly of the gyral crests of the cerebral surface (Figs. 9.1−9.3, 9.6), especially of the gyri of the frontal basis, partly spreading to adjoining white matter. Macroscopical- ly the hemorrhages appear streaked or pooled and are often confluent. The microscopic changes depend on survival time and the presence or absence of ad- ditional factors such as acidosis, hypoxia, hypoten- sion, electrolyte disturbances, etc. The time-depen- dent morphological changes are useful in estimating the age of the hemorrhages, a common requirement in forensic pathology (see pp. 190 ff).

Homolateral cortical (focal) hemorrhages: ce- rebral contusional injuries are characterized by a combination of tissue and vascular disruption that is most severe at the crests of the gyri and extends into the white matter (Teasdale and Mathew 1996).

Specific mechanisms of injury are associated with certain locations and patterns of contusional injury (see Sect. 9.2.1). Deformations of the skull creating a direct compressive strain exceeding the tolerance of the pial vessels and brain tissue will give rise to a contusional injury at the impact site (Fig. 9.1). Corti- cal hemorrhages opposite the impact site, formerly called “contrecoup contusions”, bear a morphologi- cal resemblance to their counterparts near the site of impact (Figs. 9.2−9.4).

The injury of the brain accompanying transla- tional acceleration is primarily due to the differences in mass density of the skull and dura relative to the brain as described above, and not to strain deep within the brain as produced by angular accelera- tion. This explains why focal injuries such as cortical hemorrhages, intracerebral hematomas, and subdural hemorrhages do not always induce immediate loss of consciousness. The brain must be subjected to angular acceleration for diffuse axonal injury (DAI) and immediate loss of consciousness to occur (see Sect. 9.4).

9.2.3.3

Posterior Fossa Hemorrhage

Cerebellar cortical hemorrhages: cerebellar contu- sional injuries and hematomas result from substan- tial local pressure to the occipital area. The muscula- ture of the neck, the massive occipital skull bone with its smooth and regular internal contours, the elastic tentorium of the cerebellum in combination with the

“fluid cushions” of the subarachnoid cisterns and fourth ventricle constitute a “buffer” that greatly re- duces the energy acting upon the cerebellum. Dorsal cerebral and cerebellar contusional injuries and hematomas are therefore much less frequent than cortical hemorrhages in other regions of the brain. But every infratentorial hemorrhage is capable of caus- ing an obstructive hydrocephalus and herniation of cerebellar tissue into the foramen magnum and in-

cisura tentorii. Therefore, the sequelae of posterior fossa hemorrhages may be fatal.

Cerebellar cortical hemorrhages were found in about 12% of 152 autopsies of victims of MBI (Gurd- jian 1972). They occur in the gyral crests of the cerebellar surface, usually at the occipital poles. Clinical symptoms associated with cortical hemorrhages of the cerebellum include: ataxia, cerebellar flaccidity, dysarthria, dysmetria, resting and motor imbalance, elevated intracranial pressure, headache, stiffness of the neck, vomiting, and nystagmus. Primary intra- cerebellar hematomas are extremely rare. The pau- city of symptoms renders clinical diagnosis difficult.

Roentgenography often frequently reveals fracture of the occipital bone.

Posterior fossa epidural hemorrhage (EDH) com- prise only 1.2−1.7% of all MBI cases in hospitals.

The bone deformation caused by local impact to the occipital region can lead to a separation of the dura mater, with detachment of the sinus and superficial venous vessels. A posterolateral impact can produce a diastasis of the lambdoid or occipito-mastoid su- tures or a fracture running between the midline and medial segment of the transverse sinus. Fractures of the posterior fossa are observed in 64% of posterior fossa EDHs (Glowacki 1991).

Cerebellar subdural hemorrhage (SDH) in the posterior fossa, a consequence of acceleration mechanisms, is associated with tearing of veins along the cerebellar surface. These tears are caused by the same biomechanical effects underlying SDH of the cerebrum and have a high mortality rate, especially in the acute stage.

9.2.3.4 Scar Formation

Degradation and scavenger mechanisms of the injured tissue and extravascular blood create a cystic cavity in the form of a glial-mesenchymal scar (Figs. 9.9−9.13) as well as a broad mantle of marked demyelination. On the margins, thin remnants of the molecular layer often extend beyond the shrunk- en schizogyric alteration on the cerebral surface (Fig. 9.12a, b). These marginal zones of the cortex often possess mineralized (ferruginated) neurons and astrocytes (Fig. 9.13). Gentleman et al. (1992) described diffuse β-amyloid-precursor-protein-positive plaques in some cases of extremely severe MBI after survival times of only 3 days.

9.2.4

Dating of Cortical Hemorrhages

Forensic practice often requires dating of contusional (and intracerebral) hemorrhages (cf. Müller 1930; Lindenberg and Freytag 1957; Krauland 1973;

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Oehmichen and Raff 1980; Oehmichen et al. 1981;

Oehmichen 1990; Hausmann 2002). A temporal classification is possible within certain limits based on neuronal degeneration and the leukocyte, glial cell, and mesenchymal reactions.

Analysis of more than 300 cases of mechanically induced cortical hemorrhage produced detailed sta- tistical data regarding the individual phenomena, which will only be dealt with briefly here (cf. Oehmi- chen et al. 2003). The results may be transferred to timing problems in instances of intracerebral hemorrhages − within certain limitations. The temporal course is given in Table 9.4 and the following observations were made.

Primary mechanically induced hemorrhage is followed by three phenomena that occur simultane- ously: (1) red blood cell flooding, (2) degeneration of neurons, axons, and white matter, and (3) emigration of leukocytes.

Red blood cells (Fig. 9.6) are the hallmarks of a vessel tear caused by mechanical injury. The degradation of the erythrocytes takes time and depends on the extent of the bleeding. Because of spontane- ous rebleeding, which cannot be definitively ruled out, intact red blood cells are present for nearly 5 months after the initial blunt impact, but only in very rare cases.

The changes in the degenerating neurons (Fig. 9.14) consist of a cloudy swelling and/or a shrinkage and nuclear pyknosis. They become visible within the first few minutes after external violence to the brain. Ischemic nerve cell injury is uncommon. Over the ensuing hours and days, the neurons disappear, in part without a reaction, in part in the form of a satellitosis (after 4 h and 45 min at the earliest). Sometimes, however, they remain in loco and are mineralized in situ (ferruginated) for 6 days to several years.

Between 10 and 70 min after wounding, extravasal polymorphonuclear leukocytes (neutrophils) (Fig. 9.7) may appear within and around the hemorrhage. This phenomenon is especially conspicuous if perivascu- lar bleeding is accompanied by neuropil destruction, i.e., if the hemorrhages are associated with destruction of brain tissue at the site of impact. The earliest neutrophilic emigration is seen as a reactive process in contusion injuries associated with subarachnoid hemorrhage. The number of neutrophils decreases during the first 3 days after wounding.

Macrophages and/or activated microglia (Fig. 9.8) are seen within 11−12 h (Oehmichen 1978). Their number increases during the ensuing 7−14 days, then their numbers decline again. In many instances, macrophages can still be demonstrated in the vicinity of the scar tissue years later.

Fig. 9.10a−d. Scar formation process. The end phase of reactiv- ity is characterized by a cystic scar produced by glial and collag-

enous fibers (a, b van Gieson, c H&E, d Prussian blue reaction;

magnification a−d ×10)

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The behavior of lipid-containing macrophages over time is a function of the type of fat they con- tain (Oehmichen et al. 1986). The lipid within the macrophages is the result of myelin degradation. Us- ing a myelin stain such as Luxol fast blue (Fig. 9.15) myelin-containing macrophages (Fig. 9.15b) are demonstrated. Intracellular neutral fat first appears 17 h post impact (Fig. 9.16a). Immunohistochemical demonstration of myelin debris (Lassmann 1997) can provide further information regarding the temporal course of the phagocytic process in brain macrophages.

1. In the acute phase of myelin breakdown, as a result of the traumatic event, the presence of immunoreactivity for both myelin oligodendrocyte

glycoprotein (MOG) and myelin-associated glycoprotein (MAG) within macrophages is a reliable marker.

2. During the further digestion of myelin within macrophages the minor myelin proteins, such as MOG and MAG, are lost. The macrophages contain degradation products reactive for myelin ba- sic protein (MBP) and proteolipid protein.

3. After 1−2 weeks, all myelin proteins have been degraded and macrophages contain only neutral lipids (Oil Red O). This stage may last up to 6 months. Other markers of early macrophage activation are the antigens 27E10 and MRP14 (Brück et al. 1995).

Fig. 9.11a−f. Scar formation process. a, b Endothelial prolifera- tion associated with macrophages; c−f different stages of an in-

crease of glial and collagenous fibers (a, d, e, f van Gieson stain;

b, c Gomori stain; magnification a, b, d ×500, c, e, f ×100)

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Hemosiderin-containing macrophages (Fig. 9.17) are easy to date since they almost always appear after 4−5 days, in rare cases after 3 days (Oehmichen 1976). Hematoidin as well as hematoidin-containing macrophages (Fig. 9.18) also follow a regular tem- poral course, becoming evident in frozen sections within 3−4 days, in paraffin sections after 12 days (Laiho 1995).

Some of the first signs of vital phenomena are al- terations caused by axonal injury (Fig. 9.19), which can be demonstrated in single cases as early as 105 min after impact (Blumbergs et al. 1995) by expression of β-amyloid precursor protein (β-APP) by injured axons, and regularly after 3 h (in our own material after 2.75 h). The reperfusion during resuscitation may succeed in extraordinary cases to make axonal flow possible: in one case, a 20-min survival time was followed by a 90-min resuscitation attempt, which led to the incipient expression of β-APP in axons (personal observations; see also Gorrie et al.

2002).

As described by Zhao et al. (2003) astrocytes are marked by a loss of GFAP immunohistochemistry

in rat ipsilateral hippocampal CA3 neurons within 30 min to 4 h after a traumatic event. Reactive astrocytes (Fig. 9.9) express GFAP and sometimes vimen- tin after only a 7-h survival time (Chen and Swanson 2003). Hypertrophic astrocytes can be demonstrated in the early days after wounding of the brain, in H&E- stained slides after several days. Primarily activated GFAP-expressing astrocytes evolve into fibrocytic astrocytes beginning on the sixth day post-impact, and by the conclusion of the degradation process they have formed a glial-mesenchymal scar.

Endothelial proliferation (Fig. 9.11) first becomes evident through the expression of proliferation markers on the third day after wounding. Collag- enous fibers and fibrosis (Fig. 9.10) appear during the first 5 days and increase over the ensuing weeks.

They constitute the end product of the healing process, namely a cystic scar.

Fig. 9.12a−d. Macroscopic aspect of the final stages of cortical hemorrhages. a Cystic alteration of the left frontal pole with rust- colored mesenchymal tissue; b schizogyric alteration of the later- al parts of the right occipital, parietal, and temporal lobe; c cystic

defect of the crest of the inferior temporal gyrus; d discrete color alteration at the crests of both the rectal and pararectal gyri as an indication of an old mechanically caused cortical hemorrhage