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2 BIOLOGY OF TRAUMATIC BRAIN INJURY This chapter presents a general overview of the pathobiology of traumatic brain injury (TBI) and describes two traditional classifications of TBI that are based on findings in animal models and in brain-injured patients. It also addresses the emerging field of blast-induced neurotrauma (BINT) with an emphasis on the biomechanics and physics of injury, pathobiology, and their implications in the context of medical treatment. PATHOBIOLOGY OF TRAUMATIC BRAIN INJURY Damage to the traumatized brain is a consequence of the initial mechanical insult and the subsequent activation of secondary pathogenic cascades that collectively influence the temporal progression of the primary insult (McIntosh, 1994; Werner and Engelhard, 2007). It is important to emphasize that human TBI is a heterogeneous disorder in which pathogenic factors may have variable magnitude and occur in various combinations (Graham et al., 2000; Faden, 2002). Single isolated lesions are relatively uncommon in human TBI (Graham et al., 2000). The more common presentation is one of multiple lesionsâan outcome that probably reflects injury severity (Graham et al., 2000). A more generalized picture has emerged from studies of the injured human brain and in animal models of TBI in which the pathobiology of TBI is considered in the context of four phases (described below) (Graham et al., 2002). That categorization has provided a context for better understanding the relationship between the primary insult and secondary pathogenic events. However, the temporal sequence of events may overlap substantially (Moppett, 2007). Phase 1 represents the initial mechanical damage that results in rupture of cellular and vascular membranes, release of intracellular contents, and cessation of blood flow (McIntosh, 1994; Werner and Engelhard, 2007). Impairment of cerebral blood flow and metabolism leads to anaerobic glycolysis and accumulation of lactic acid (Werner and Engelhard, 2007). Energy- dependent membrane ion pumps fail as adenosine triphosphate (ATP) stores become depleted (Werner and Engelhard, 2007). This phase is governed by the nature of the injury and the profile of the host (Graham et al., 2002). The location and magnitude of brain damage reflect the characteristics of the primary insult; for example, gunshot wounds and vehicular collisions produce different patterns of injury. Specifics of the hostâincluding age, health, sex, and geneticsâinfluence the outcome of the primary insult (Moppett, 2007). 19
20 GULF WAR AND HEALTH Phase 2 involves the progressive deterioration of the neural axis that arises from biochemical and molecular events that collectively promote necrotic and apoptotic cell death (Graham et al., 2002; Thompson et al., 2005). The events include release of the excitatory amino acid neurotransmitters, such as glutamate and aspartate; activation of glutamate receptors; influx of calcium into cells and release of calcium from intracellular stores; free-radical generation; and inflammation (Graham et al., 2002; Thompson et al., 2005; Werner and Engelhard, 2007). In both animal and human studies, TBI results in increased extracellular glutamate concentrations (Schouten, 2007). The increase has been attributed to disruption of the bloodâ brain barrier and exposure of the brain to humoral-derived glutamate, excessive synaptic release, and decreased glutamate transporter (Yi and Hazell, 2006). Glutamate is the most abundant excitatory neurotransmitter in the brain. In the setting of TBI, an increase in glutamate results in overstimulation of ion-channelâlinked and G-proteinâlinked glutamate receptors. Excessive activation of those ion channels results in prolonged depolarization and ionic imbalance, depletion of ATP stores, and increases in intracellular free calcium that potentially activate numerous pathogenic cascades (Yi and Hazell, 2006). Intracellular calcium increases rapidly after TBI. That is attributed to an increased influx of Ca2+ from the extracellular compartment and a release of Ca2+ from intracellular stores, including mitochondria. The increase in intracellular Ca2+ leads to activation of intracellular proteases, including calcium-activated neutral proteases (calpains), phospholipases, and endonucleases. Those downstream events mediate cytoskeletal damage, increase intracellular concentrations of free fatty acids, promote free-radical generation, and lead to cell injury and death (Marklund et al., 2006; Werner and Engelhard, 2007). An important component of the secondary injury cascade results from the generation of reactive oxygen species (ROSs) that include superoxides, hydrogen peroxide, hydroxyl radicals, nitric oxide, and peroxynitrite. Each ROS has an unpaired electron in its outer electron shell and thus is highly reactive and unstable (Calabrese et al., 2008). The excessive production of ROSs is due in part to excitotoxicity, free iron, and interactions between ROSs (Potts et al., 2006). Glutamate-mediated excitotoxicity leads to an increase in intracellular calcium and the subsequent induction of enzymes, such as nitric oxide synthase and xanthine oxidase, that produce free radicals. Mitochondria, when exposed to increased intracellular calcium, become sources of ROSs (Sullivan et al., 2005; Bayir and Kagan, 2008). Accumulation of free iron, resulting from the degradation of heme, catalyzes the formation of superoxide from free oxygen and of the hydroxyl radical from hydrogen peroxide. It is important to note that free radicals such as superoxide and nitric oxide interact with one another to produce other free radicals, including peroxynitrite. Under physiologic conditions, endogenous antioxidantsâincluding superoxide dismutase, glutathione peroxidase, and catalaseâprevent oxidative damage (Potts et al., 2006). Superoxide dismutase catalyzes the conversion of superoxide to hydrogen peroxide, which is further degraded by glutathione peroxidase and catalase to molecular oxygen and water. Low- molecular-weight antioxidantsâincluding glutathione, melatonin, and uric acidâand dietary sources of tocopherols, ascorbic acid and lipoic acid, are also available in the brain. A group of genes, referred to as vitagenes, function to preserve cellular homeostasis during stress. This family consists of the heat-shock proteins HO-1 and Hsp32. HO-1 confers protection by degrading the pro-oxidant heme and producing biliverdin, the precursor of the
BIOLOGY OF TRAUMATIC BRAIN INJURY 21 antioxidant bilirubin. Hsp70 inhibits NF- B signaling and intrinsic apoptotic pathways (Calabrese et al., 2008). In the setting of TBI, each of those neuroprotective systems in the brain becomes overwhelmed, and cell damage arises from free-radicalâmediated lipid peroxidation. protein and DNA oxidation, and inhibition of the mitochondrial electron-transport chain. In general, an inflammatory response in the brain differs from that in other organs. It is exemplified by a more modest and delayed recruitment of leukocytes into the brain than into peripheral organs (Lucas et al., 2006). Brain microglia, in contrast, are activated and release inflammatory mediators beginning within minutes to hours after TBI (Lucas et al., 2006). The mediators often express neurotoxic and neuroprotective properties (Morganti-Kossmann et al., 2007). For example, cytokines may either promote damage or support recovery processes; in some cases, cytokines, such as interleukin-6, may perform both functions (Morganti-Kossmann et al., 2007). Collectively, the pathogenic cascade of events described in the preceding paragraphs culminates in death of neurons and glia and white matter degeneration. Distinct anatomic patterns of cell death that accompany TBI are evident in neuronal and glial populations and reflect both apoptosis and necrosis (Raghupathi, 2004; Bramlett and Dietrich, 2007). Necrotic death and apoptotic cell death of neurons and glia have been identified in contused areas, the tissue bordering a contusion, and subcortical regions, including the hippocampus, cerebellum, and thalamus (Raghupathi et al., 2000; Raghupathi, 2004; Yakovlev and Faden, 2004). In the case of the contused cortex, gross loss of neurons culminates in a distinct lesion, enlarges with time postinjury, and coincides with progressive atrophy of gray and white matter (Bramlett and Dietrich, 2007). The vulnerability of astrocytes to TBI has also been recently reconsidered (Floyd and Lyeth, 2007). Historically, the dogma has been that astrocytes are more resistant to injury than neurons (Lukaszevicz et al., 2002). Beyond the characteristic swelling that is seen (Castejon, 1998), those cells show an early injury response that coincides with regional patterns of neuronal vulnerability. Kinetic studies suggest that loss of astrocytes precedes neuronal injury suggesting that early impairment of astrocytes contributes to neuronal death (Floyd and Lyeth, 2007). Astrocytes play time-dependent diverse roles in TBI (Chen and Swanson, 2003); here we consider their involvement in the acutely injured brain (modulation of extracellular glutamate and K+ concentrations, scavenging of ROSs, and inflammation) and during wound healing (glial scar formation, restoration of the bloodâbrain barrier, and growth factor production) (Chen and Swanson, 2003). Neurons depend on astrocytes for their survival in an acutely injured brain (Chen and Swanson, 2003). After brain injury, glutamate is cleared from the extracellular space by Na+- dependent glutamate transporters that are localized on astrocytes. Thus, astrocytes are thought to play a critical role in maintaining extracellular glutamate concentrations below toxic levels. Glutamate transport occurs across a steep concentration gradient with much higher concentrations (1â10 mM) in neurons and glia and lower concentrations (less than 10 mM) in the extracellular compartment. That gradient is overcome by the coupling of the intracellular influx of glutamate ions to the inward movement of 3 Na+ ions and 1 H+ ion and the outward movement of 1 K+, a process that shifts energy expenditure from neurons to astrocytes. Glutamate transporters can move substrate both inward and outward.
22 GULF WAR AND HEALTH Astrocytes can scavenge ROSs, limiting the rise in extracellular K+, and are active participants in the proinflammatory response (Chen and Swanson, 2003). Astrocytes express higher levels of the antioxidant glutathione than neurons and thus may support neuronal survival. As brain tissue becomes ischemic, extracellular K+ increases, and this leads to cell swelling and glutamate release. Astrocytes can also limit the increase in intracellular K+ both indirectly and directly. The former occurs by passive movement of K+ from the extracellular space into astrocytes that is facilitated by electric coupling between glia. With more K+, K+ is actively taken up by the action of astrocyte Na+/K+ ATPase. Finally, there are parallels between the astrocyte response to injury and the proinflammatory response seen in tissues outside the central nervous system. Astrocytes are sources of inducible nitric oxidase synthase and produce cytokines, interleukins, and interferons. The consequences of production of those factors are not completely understood, in part because of their cross-talk with one another and the context of their involvement, which is probably cell- specific. In the more chronically injured brain, astrocytes are integral to both adverse and beneficial wound-healing events (Chen and Swanson, 2003). They form a glial scar that represents both physical and chemical barriers to axonal regeneration. Counter to that adverse role, reactive astrocytes also participate in the re-establishment of the bloodâbrain barrier and release trophic factors that may foster plasticity. Damage to white matter fiber tracts is also a hallmark of TBI. White matter injury is evidenced in part by axonal degeneration, oligodendrocyte death, and demyelination. White matter damage in relative isolation (âpureâ diffuse axonal injury) is sufficient to result in severe and persistent morbidity. White matter damage is also often found in combination with other injuries, such as contusion (as produced in many experimental models). With the advent of imaging, including diffusion-tensor imaging (DTI), evolving white matter damage can be measured in detail and validated against more conventional anatomic outcomes. This approach is exemplified in a recent study that used DTI to assess axonal injury over time (MacDonald et al., 2007). Pericontusional white matter damage was evident in both the acute and subacute periods after experimental TBI. DTI revealed the stereotypic response of early axonal injury followed by demyelination and edema at later periods postinjury. Those findings provide a foundation for translation to the clinical setting where findings in the animal model can be tested for their predictability in human TBI. Diffuse axonal injury is triggered by accelerationâdeceleration forces (Buki and Povlishock, 2006). Although instantaneous direct damage to axons may result from shear and tensile forces, the more common presentation is one whereby axons undergo an evolving process (Maxwell et al., 1997) that begins with focal axolemmal permeability, which permits influx of calcium that is normally excluded by the axon (Buki and Povlishock, 2006) . In vitro studies of fine, unmyelinated fibers also suggest that deformation of axons induces sodium influx via Na+ channels, which triggers an increase in intra-axonal calcium via the opening of voltage-gated calcium channels and reversal of the Na+âCa2+ exchanger (Wolf et al., 2001). Calcium-induced proteolytic pathways are key components of evolving axonal pathogenesis (Buki and Povlishock, 2006). Calcium-induced activation of the cysteine protease calpain results in degradation of spectrin, a major constituent of the subaxonal cytoskeleton. Calcium-mediated spectrin proteolysis is evident on the surface of mitochondria, and it is
BIOLOGY OF TRAUMATIC BRAIN INJURY 23 possible this proteolysis mediates mitochondrial damage. Mitochondrial damage can lead to energy failure and thus disrupt ionic homeostasis, activation of the caspase death cascade, and ultimately structural proteolysis and axonal disconnection. Cell death is the downstream consequence of perturbations that begin within minutes after injury and extend over a period of days and in some cases months. The kinetics of cell death varies according to cell type, location, nature of the initial insult, and the collective profile of secondary pathogenic events. The mechanisms of cell death, necrosis and apoptosis, have been studied in detail. Necrotic cell death involves membrane failure, disruption of ion homeostasis, and rapid degradation of the cytoskeleton (Povlishock and Katz, 2005). In classical light microscopy, neurons initially appear swollen with pyknotic nuclei (Povlishock and Katz, 2005) and show an affinity for histochemical markers of cell injury, including acid fuchsin (Cortez et al., 1989) and fluorojade (Hallam et al., 2004). The nucleus and cytoplasmic organelles, including mitochondria, are swollen; there is cytoplasmic vacuolation; and the integrity of the plasma membrane is compromised (Dietrich et al., 1994; Raghupathi et al., 2000). The pathobiology of apoptotic cell death has yet to be clearly elucidated. In contrast with necrosis, apoptosis is not linked to disruption of the cell membrane. Rather, the classic picture of an apoptotic neuron includes an intact membrane with internucleosomal DNA strand breaks, nuclear shrinkage, chromatin compaction, and cytoplasmic condensation and disintegration. The end stage of apoptosis is characterized by blebbing of the cell membrane and the emergence of spherical bodies. In contrast with the rapid death seen in necrosis, apoptotic cell death occurs over a longer period. Data also show that apoptosis is associated with a shift in the balance between proapoptotic and antiapoptotic factors (Raghupathi, 2004). Apoptosis has been linked to the excitatory amino acid cascade, increased intracellular calcium, and free radicals (Raghupathi, 2004). Data also show that apoptosis is associated with a shift in the balance between proapoptotic and antiapoptotic factors (Raghupathi, 2004). Neuronal apoptosis occurs by two pathways: one involves the activation of caspases, and a second is caspase-independent and involves the release of apoptotic factors from mitochondria (Zhang et al., 2005a). Proteolytic cleavage of substrates by caspases, whether by an extrinsic or intrinsic pathway, produces the characteristic phenotype of apoptosis. Some mitochondrial proteins, such as apoptosis-inducing factor (AIF), can induce apoptosis in the absence of activation of caspases. AIF-mediated cell death has been demonstrated in an experimental model of TBI (Zhang et al., 2005a). The secondary mechanisms occurring during phase 2 are potential targets for therapeutic intervention because of their kinetic profiles (Marklund et al., 2006). They are typically delayed in onset and may extend for hours or months after TBI (Graham et al., 2002; Thompson et al., 2005; Marklund et al., 2006). A key challenge, however, is to translate findings from animal models of TBI to the head-injured patient. Animal models are designed to produce a relatively homogeneous type of injury whereas a key feature of human TBI is heterogeneity. That distinction may partially account for differences in the kinetics of secondary pathogenic events when one compares findings in the animal model with the human condition. For example, with few exceptions, increased extracellular glutamate returns to control values within the first several hours after experimental TBI (Marklund et al., 2006). In contrast, microdialysis data from human TBI have demonstrated an increase in glutamate that is sustained for up to 9 days after injury (Bullock et al., 1998; Vespa et al., 1998; Marklund et al., 2006). A recent review addressed the
24 GULF WAR AND HEALTH failure of large, multicenter phase II clinical trial to produce an improvement in outcome in TBI patients (Marklund et al., 2006) and raised concern about the ability to translate from bench to bedside. (For detailed discussion of why therapies shown to be efficacious in animals failed to translate to human TBI, see recent reviews: Statler et al., 2001; Cernak, 2005; Morales et al., 2005; Thompson et al., 2005; Marklund et al., 2006; Kokiko and Hamm, 2007.) In phase 3, secondary eventsâsuch as hypoxia, hypotension, ischemia, increased intracranial pressure (ICP) and brain swelling, and metabolic failureâperturb brain function further and augment cell injury (Statler et al., 2001; Graham et al., 2002; Marklund et al., 2006). As in phase 2, those secondary insults occur over an extended period of time postinjury and so are suitable targets for therapeutic intervention. In human TBI, hypoxia and hypotension occur in one-third of patients with TBI (Statler et al., 2001; Morganti-Kossmann et al., 2007). Hypotension is a principal predictor of poor outcome after TBI: a single episode of systolic blood pressure of less than 90 mm Hg is associated with a 150% increase in mortality (Statler et al., 2001). In a recent prospective multicenter study, about 40% of patients with TBI sustained a secondary insult before reaching the hospital (Chi et al., 2006). Of those patients, 65% had episodes of hypoxia, 11% were hypotensive, and 24% showed a combination of those two secondary insults. Episodes of hypoxia were particularly notable in that they were independently predictive of death. Moreover, the episodes occurred despite aggressive medical management, including endotracheal intubation. Posttraumatic ischemia has been demonstrated in both animal models and humans after TBI and is associated with poor neurologic outcome. The factors mediating posttraumatic ischemia include mechanical damage to blood vessels, hypotension in concert with autoregulatory failure, and lack of available endogenous vasomodulators, such as nitric oxide and prostaglandins (Werner and Engelhard, 2007). Injury severity is a determinant of the magnitude of increase in ICP (Thompson et al., 2005). Increased ICP is usually a consequence of brain swelling that occurs in response to disruption of the bloodâbrain barrier and the later evolution of cerebral edema (Pasternak and Lanier, 2007). Edema has a profound effect on the brain because of the restrictions imposed by the bony calvarium, which limit further expansion of the edematous brain and lead to an increase in ICP. Metabolic failure arises from mitochondrial dysfunction, reduced availability of the nicotinic coenzyme pool, and intramitochondrial overload (Werner and Engelhard, 2007). Outcome is worsened in accordance with the degree of metabolic failure (Werner and Engelhard, 2007). An alternative finding has been hypermetabolism of glucose, which reflects an uncoupling of cerebral blood flow and metabolism. It is a scenario whereby massive transmembrane ionic fluxes and neuroexcitation are not adequately met by increases in cerebral blood flow (Werner and Engelhard, 2007). Phase 4, representing recovery and functional outcome, is influenced by primary and secondary injury responses and by wound-healing events, including phagocytic removal of cellular debris, glial scar formation, and plastic changes in neural networks. Recovery of function after brain injury is described in three phases (Wieloch and Nikolich, 2006). Phase 1 involves reversal of inhibition of function and initiation of cell repair, phase 2 entails a change in the properties of existing pathways, and phase 3 involves the formation of new connections
BIOLOGY OF TRAUMATIC BRAIN INJURY 25 (Wieloch and Nikolich, 2006). Efforts have been made to reverse secondary pathogenesis with an emphasis on extending treatment beyond the acute injury into this recovery phase (Kokiko and Hamm, 2007). One result is the concept that enhancing neuronal activity may facilitate cognitive recovery (Kokiko and Hamm, 2007). Strategies to support recovery also include early activation of noradrenergic, dopaminergic, and cholinergic pathways to promote functional plasticity and growth factors to support plasticity; cortical stimulation and physical therapy can enhance recovery during the chronic phase (Wieloch and Nikolich, 2006). On the basis of the complex pathophysiology of TBI, there has been a concerted effort to develop biomarkers of injury that would serve as both diagnostic and prognostic measures of injury or recovery (Kochanek et al., 2008). The availability of cerebrospinal fluid, brain tissue, and interstitial fluid from both experimental models of TBI and brain-injured patients has made it possible to identify candidate biomarkers. Putative serum biomarkers of interest have included cyclic adenosine monophosphate, thought to be an indicator of depth of coma, and neuron- specific enolase, myelin basic protein, and S100B, markers of structural damage. In more recent years, proteomics and multibead technology, based on multiple enzyme immunosorbent assays, have been developed to assay multiple proteins from a relatively small sample. Those advanced technologies offer the opportunity to track the complex injury cascade that accompanies TBI and ultimately to generate a panel of biomarkers that can be applied to the brain-injured patient. TRADITIONAL CLASSIFICATIONS OF TRAUMATIC BRAIN INJURY TBI may be classified according to the extent of the pathology of the injury or according to the biomechanics of the injury. Both these classifications are discussed below. CLASSIFICATION ACCORDING TO EXTENT OF PATHOLOGY TBI has been described pathologically as focal and/or diffuse (Smith et al., 2003; Werner and Engelhard, 2007) (Figure 2.1). Focal damage is characterized by cerebral contusions resulting from forces related to impact (Povlishock and Katz, 2005). Contrecoup contusion may be apparent but is thought to be a consequence of acceleration and deceleration rather than impact (Graham et al., 2002). Diffuse injuries arise from rapid rotations of the head that result in tissue distortion or shear and typically occur in motor-vehicle collisions and less often in falls and assaults (Smith et al., 2003; Morales et al., 2005). It is important to emphasize that focal and diffuse injuries overlap (Povlishock and Katz, 2005). Human TBI, particularly severe TBI, is heterogeneous (Graham et al., 2000; Faden, 2002). It is unusual to find a single lesion and more common to find both focal and diffuse patterns of damage. Moreover, the number of lesions increases in proportion to the severity of the injury and correlates with morbidity (Graham et al., 2000). Pathologic Features of Focal Traumatic Brain Injury Focal injuries are evidenced by lacerations, contusions, and hematomas resulting from overt vascular damage (Morales et al., 2005). Localization of a hematoma depends in part on which elements of the vascular tree are injured. Rupture of meningeal vessels, bridging veins, and intrinsic vasculature leads to extradural, subdural, and intracerebral hematomas, respectively.
26 GULF WAR AND HEALTH Intracerebral hematomas are commonly found in the gray matter or at boundaries between gray and white matter (Povlishock and Katz, 2005). Classification of TBI According to Pathology Pathologic features: Focal Contusions Epidural injury Hematomas Subdural Intracerebral Diffuse axonal injury Diffuse Hypoxic-ischemic brain damage injury Brain swelling Petechial white matter hemorrhage FIGURE 2.1 Pathologic classification of TBI. Disruption of the bloodâbrain barrier is a feature of TBI, including focal insults. Trauma produces physical damage to blood vessels, manifested in part by hemorrhage. Barrier disruption allows entry of toxic molecules while also providing an avenue for delivery of therapeutic agents into the damaged tissues (Saunders et al., 2008). It is the latter that has prompted investigators to define the window of barrier disruption better. There is evidence that the barrier to plasma- proteinâsize molecules is about 4 hours, whereas smaller molecules (smaller than 10 kDa) can access the brain for up to 4 days (Saunders et al., 2008). In the head-injured patient, disruption of the barrier is associated with life-threatening cerebral edema and is the basis of treatment with intravenous hyperosmolar solutions. However, the mechanism of action is not clearly understood, and there is no gold standard, on the basis of evidence from a clinical trial, of its effectiveness (Narayan et al., 2002). Neuronal injury is also a feature of focal TBI. However, the patterns of neuronal injury are not necessarily restricted to contusional and pericontusional cortical sites (Raghupathi, 2004). Neuronal loss has been reported in more remote regions, including the hippocampus (Cortez et al., 1989; Kotapka et al., 1992; Lowenstein et al., 1992; Hicks et al., 1996), thalamus (Hicks et al., 1996; Sato et al., 2001), and the cerebellum (Sato et al., 2001; Park et al., 2006; Ai et al., 2007; Igarashi et al., 2007) in experimental models of TBI. Similar findings are seen in human TBI (Adams et al., 1985; Kotapka et al., 1992; Raghupathi, 2004). At the contusional site, neuronal injury is apparent within hours after trauma. Neurons initially appear swollen and with time assume a shrunken phenotype bearing a pyknotic nucleus, swollen mitochondria, and vacuolated cytoplasm. The volume of the lesion expands coincidentally with a chronic pattern of neuronal degeneration (Colicos et al., 1996; Hicks et al., 1996; Bramlett et al., 1997; Conti et al., 1998; Raghupathi, 2004). Pathologic Features of Diffuse Traumatic Brain Injury Four pathologic conditions have been attributed to diffuse TBI: traumatic axonal injury, hypoxic brain damage, brain swelling, and vascular injury (Morales et al., 2005; Povlishock and Katz, 2005). The disabling symptoms seen in TBI can arise from widespread traumatic axonal damage (Hurley et al., 2004; Morales et al., 2005) that is evident in postmortem brains after mild, moderate, or severe injury (Morales et al., 2005).
BIOLOGY OF TRAUMATIC BRAIN INJURY 27 Diffuse axonal injury, an important predictor of outcome (Graham et al., 2002), evolves over hours to days and is characterized by axonal swellings and bulbs (Hurley et al., 2004). Primary axotomy, that is, the severing of an axon, is rare in human TBI and is associated with severe TBI. Diffuse axonal injury may culminate in axotomy, but this process is likely delayed in onset, beginning 12â24 hours after injury (Moppett, 2007). It was originally thought that mechanically induced damage to axons impaired axonal transport and that this impairment led to axonal swelling and ultimately axonal disconnection. Recent work, however, has shed light on the pathobiology of axonal injury (Povlishock and Katz, 2005). Although tearing of the axon may occur, it is usually limited to more severe injuries. Rather, axonal injury evolves as a consequence of focal changes in the plasmalemma, including altered permeability, which ultimately impede axonal transport. Data suggest that altered axolemmal permeability allows the influx in calcium and the subsequent activation of proteases that then disrupt the cytoskeleton. Under conditions of normal transport kinetics, focal swelling occurs as a consequence of the buildup of transported molecules and leads ultimately to disconnection of the axon. Traumatic axonal swellings are not the only indicator of axonal damage. In fact, cytoskeletal perturbations after TBI need not culminate in axonal swellings (Povlishock and Katz, 2005). Rather, there may be a switch from anterograde to retrograde transport, which prevents the buildup of transported molecules (Povlishock and Katz, 2005). The complexity of axonal injury is also evidenced by recent studies of unmyelinated fiber tracts that showed that ionic dysregulation contributes to impairment of anterograde transport (Iwata et al., 2004). There are also data that show that unmyelinated, small-caliber axons may be particularly vulnerable to TBI (Reeves et al., 2005) and may play an important role in morbidity. Hypoxia, brain swelling, and vascular injury are also seen in diffuse injuries (see above as a description of those events is provided in more detail). CLASSIFICATION ACCORDING TO BIOMECHANICS OF INJURY Human head injury is also categorized according to the type of primary injury, either closed (blunt and not caused by a missile) or penetrating injuries (Graham et al., 2002; Morales et al., 2005) (Figure 2.2). Closed Injury Closed injury includes static and dynamic loading. Static loading occurs when a gradual force is applied to the brain whereas dynamic loading is characterized by rapid acceleration and deceleration. Static loading is not common in human head injury. It may occur in victims of natural disasters, such as earthquakes and landslides, who become trapped under heavy debris. In such a scenario, the head is particularly vulnerable to injury imposed by a gradual force, greater than 200 ms (Graham et al., 2002). Dynamic loading is more common in human brain injury and is associated with rapid acceleration and deceleration of the brain (Graham et al., 2002). In contrast with static loading, the forces associated with dynamic loading occur in less than 200 ms. Outcome is governed by tissue strain, which is defined as the amount of deformation that occurs as a consequence of the force applied to the brain (Graham et al., 2002; Morales et al., 2005).
28 GULF WAR AND HEALTH Tolerance of deformation varies with the type of tissue: bone is the strongest, and neural and vascular elements are the most vulnerable (Graham et al., 2002). Tensile strain and shear strain are the two types that most commonly cause damage to the vasculature and brain (Graham et al., 2002). Dynamic loading is categorized as either impulsive or impact loading. Impulsive loading occurs when the head is stopped or set into motion by an indirect impact, such as a blow to the thorax. Head injury results from the inertia produced by the movement of the head. Impact loading, the more common form of dynamic loading, results when a blunt object strikes the head. Inertia and contact occur in combination. An example would be deceleration of the head when a moving automobile strikes a tree and then the driverâs head strikes the steering wheel. Classification of TBI Based on Primary Insult Initiating Events Closed injury Missile injury Penetrating/ Perforating injuries Static Dynamic Depressed Penetrating Perforating Impulsive Impact FIGURE 2.2 Classification of TBI based on primary insult. Penetrating and Perforating Injuries Missile injuries, such as gunshot wounds, are a common cause of TBI. These injuries are classified as either penetrating or perforating depending on how the missile traverses the head (Graham et al., 2002). In penetrating injuries, the object enters and lodges within the cranial cavity. Perforating injuries occur when the object traverses the cranial cavity and leaves through an exit wound. The extent of damage is governed by features of the missile (shape and mass) and by its direction and velocity (Morales et al., 2005). Damage is also related to the amount of energy that is released in passage through the brain (Graham et al., 2002). Although brain damage is often severe, there are instances when the bullet bypasses critical centers and the person maintains consciousness (Graham et al., 2002). THERAPEUTICS AND TRAUMATIC BRAIN INJURY A number of recent reviews have addressed pharmacologic strategies of treatment for TBI (Faden, 2002; Morales et al., 2005; Thompson et al., 2005; Marklund et al., 2006; Schouten, 2007). The strategies have targeted secondary injury cascades, including those related to excitotoxicity, calcium channels, oxidative stress, inflammation, cell-death pathways, calpains, endocrine-related abnormalities, altered neurotransmission, and growth factors (Marklund et al., 2006). Pharmacologic blockade targeting those pathways has improved the outcome in animal
BIOLOGY OF TRAUMATIC BRAIN INJURY 29 models of TBI, but clinical trials have failed to reproduce the benefit seen in those studies (Faden, 2002; Marklund et al., 2006). The failure to translate to success in human TBI may reflect both limitations of the experimental model and differences in the design of the animal studies (Faden, 2002; Faden and Stoica, 2007) and has led to consideration of developing a model that would be more relevant to human TBI (Morales et al., 2005). It has been suggested that no single animal model can accurately reproduce the complex, heterogeneous human TBI (Morales et al., 2005). It is also possible that the current models should be refined to involve a more comprehensive experimental design that includes doseâresponse studies in concert with measures of both behavior and pathology; incorporates secondary insults, such as hypotension, hypovolemia, and hypoxia, that are seen in human TBI; addresses the consequences of repeated brain injuries; considers age and sex as variables in the experimental design; and provides monitoring of measures (cerebral perfusion pressure, ICP, blood pressure, and blood gases) that would parallel those used in the management of human TBI (Statler et al., 2001; Faden, 2002; Morales et al., 2005; Thompson et al., 2005). Finally, with the recommendation to develop a classification for human TBI based on pathoanatomic measures (Saatman et al., 2008), future efforts to develop and/or refine animal models will need to consider the findings that emerge from this clinical effort. SUMMARY OF PATHOBIOLOGY OF TRAUMATIC BRAIN INJURY The pathobiology of TBI can be summarized as follows: The traditional classifications of TBI have been based on the type of injury (focal vs. diffuse) and on the biomechanics of the primary injury (closed and missile injuries). The primary insults damage both gray and white matter and initiate secondary pathogenic events at the cellular, biochemical, and molecular levels that collectively mediate widespread damage. The final common pathways for TBI are similar despite differences in the initiating event. For example, calcium-mediated activation of neurotoxic factors, production of free radicals, and mitochondrial dysfunction are general features of TBI. However, regional patterns of vulnerability and the magnitude and kinetics of those downstream events are governed by the initiating event. Unlike animal models that are designed to reproduce a particular characteristic of TBI, human TBI is characteristically heterogeneous, particularly after a severe injury, with features of both focal and diffuse brain damage. The diversity of clinical outcomes reflects that heterogeneity at least in part. Although this chapter is focusing on TBIs that are typically seen in civilians, an emerging field of research addresses brain injuries related to the military. This research includes missile- related and blast-induced brain injuries. What is clear from the effort to date is that the pathobiology of military TBIs, particularly blast injuries, has characteristics not seen in other types of brain injury, despite similar secondary injury cascades.
30 GULF WAR AND HEALTH TRAUMATIC BRAIN INJURIES RELEVANT TO THE MILITARY Throughout Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), explosive devices have become more powerful, their detonation systems more creative, and their additives more devastating. According to the Department of Defense (DoD) Personnel and Procurement Statistics, 75% of all US military casualties in OEF and OIF are caused by explosive weaponry (DMDC, 2008). As of January 2008, DoD reported that over 5,500 soldiers had suffered TBIs (CRS, 2008). As a continuing threat to troops, blast injury, especially BINT, has been called the signature wound of the war in Iraq. Explosive devices are also used against civilians. Indeed, the use of explosive weaponry is the most common cause of casualties in terrorist incidents. Terrorists increasingly use suicidal-homicidal bombers that deliberately accompany the explosive device, often wearing it, to ensure the maximal harm. The bombers walk or drive into buses, subways, residential areas, shopping malls, and government buildings. BLAST WAVE DEATH Injuries with immediate manifestation Hidden injuries with long-term consequences FIGURE 2.3 Potential consequences of blast exposure. In both civilian and military environments, exposure to a blast (see Figure 2.3) might cause instant death, injuries with immediate manifestation of symptoms, or injuries with delayed manifestation. Protection from blast injuries presents several challenges. Body armor protects from shrapnel and projectiles, but it also constitutes an improved contact surface for shock-frontâbody interaction and energy transfer and may also serve as a reflecting surface that can concentrate the power of an explosion as the blast wave is reflected by the armor front and back (Phillips et al., 1988). The improved interceptive properties of body armor have increased the survival rate of soldiers by protecting them from penetrating injuries. In parallel with the increased survival rate, however, the rate of severe debilitating long-term consequences has also increased (Warden, 2006). Moreover, besides being acutely injured, soldiers serving in theater and some military professionals during their daily activity or training are also subjected to repeated low-level blast
BIOLOGY OF TRAUMATIC BRAIN INJURY 31 exposure. The cumulative effects of the exposures might lead to serious short-term and long-term health impairments (Richmond et al., 1981). For those without body armor, the effects of blast are more deadly, and the whole spectrum of blast injuries can be seen (Table 2.3). Apart from the injuries caused by blast overpressure (primary blast effects), they have an increased potential for penetrating injuries from shrapnel and other debris (secondary blast effects) and for acceleration and deceleration of the body and head (tertiary blast effects) (Figure 2.6). Moreover, although barriers and check points may be used to prevent vehicles and personnel carrying explosives from entering a facility, in urban areas it may not be possible to achieve the recommended standoff distances shown in Table 2.1, and even those distances may not be adequate to prevent BINT injuries. BASIC MECHANISMS OF EXPLOSIVE INJURIES Physics A blast wave generated by an explosion starts with a single pulse of increased air pressure that lasts a few milliseconds. The negative pressure or suction of the blast wave follows the positive wave immediately (Owen-Smith, 1981). The duration of the blast waveâthat is, the time that an object in the path of the shock wave is subjected to the pressure effectsâdepends on the type of explosive and the distance from the point of detonation (Clemedson, 1956). Table 2.1 summarizes the safety zonesâthat is, the standoff distancesâfor various types of bomb explosions. TABLE 2.1 Safety Recommendations for Standoff Distances from Different Types of Exploding Bombs Maximum Maximum Container or Vehicle Explosives Lethal Air-Blast Evacuation Falling-Glass Description Capacity Range Distance Hazard Pipe 2 Ã 12 in 5â6 lb 850 ft (259 m) Pipe 4 Ã 12 in 20 lb Pipe 8 Ã 24 in 120 lb Bottle 2 L 10 lb Bottle 2 gal 30 lb Bottle 5 gal 70 lb Boxes or shoebox 30 lb Briefcase or satchel 50 lb 1,850 ft 1,250 ft bomb (564 m) (381 m) 1-ft3 box 100 lb Suitcase 225 lb 1,850 ft 1,250 ft (564 m) (381 m) Compact sedan 500 lb in trunk 100 ft 1,500 ft 1,250 ft (30 m) (457 m) (381 m) Full-size sedan 1,000 lb in trunk 125 ft 1,750 ft 1,750 ft (38 m) (534 m) (534 m) Passenger van or cargo 4,000 lb 200 ft 2,750 ft 2,750 ft van (61 m) (838 m) (838 m) Small box van 10,000 lb 300 ft 3,750 ft 3,750 ft (91 m) (1,143 m) (1,143 m) Box van or water or fuel 30,000 lb 450 ft 6,500 ft 6,500 ft truck (137 m) (1,982 m) (1,982 m) Semitrailer 60,000 lb 600 ft 7,000 ft 7,000 ft (183 m) (2,134 m) (2,134 m)
32 GULF WAR AND HEALTH NOTE: Table compiled from several publications of the Advanced Technical Group for Blast Mitigation and Technical Support Working Group. SOURCE: Reprinted with permission from Stewart, 2006. The blast wave progresses from the source of the explosion as a sphere of compressed and rapidly expanding gases, which displaces an equal volume of air at a high velocity (Rossle, 1950). The velocity of the blast wave in air may be extremely high, depending on the type and amount of the explosive used. The blast wave is the main determinant of the primary blast injury and consists of the front of high pressure that compresses the surrounding air and falls rapidly to negative pressure. It travels faster than sound and in a few milliseconds damages the surrounding structures. The blast wind following the wave is generated by the mass displacement of air by expanding gases; it may accelerate to hurricane proportions and is responsible for disintegration, evisceration, and traumatic amputation of body parts. Thus, a person exposed to an explosion will be subjected not only to a blast wave but to the high-velocity wind traveling directly behind the shock front of the blast wave (Rossle, 1950). A hurricane-force wind traveling about 200 km/h exerts overpressure of only 1.72 kPa (0.25 psi), but a blast-induced overpressure of 690 kPa (100 psi) that causes substantial lung damage and might be lethal travels at about 2,414 km/h (Owen-Smith, 1981). The magnitude of damage due to the blast wave depends on the peak of the initial positive-pressure wave (an overpressure of 414â552 kPa or 60â80 psi is considered potentially lethal), the duration of the overpressure, the medium of the explosion, the distance from the incident blast wave, and the degree of focusing due to a confined area or walls. For example, explosions near or within hard solid surfaces become amplified two to nine times because of shock-wave reflection (Rice and Heck, 2000). Moreover, victims positioned between the blast and a building often suffers 2â3 times the degree of injury of a person in an open space. Indeed, people exposed to explosion rarely experience the idealized pressure-wave form, known as the FriedlÃ¤nder wave. Even in open-field conditions, the blast wave reflects from the ground, generating reflective waves that interact with the primary wave and thus changing its characteristics. In a closed environment (such as a building, an urban setting, or a vehicle), the blast wave interacts with surrounding structures and creates multiple wave reflections, which, interacting with the primary wave and between each other, generate a complex wave (Mainiero and Sapko, 1996; Ben-Dor et al., 2001) (Figure 2.4). Table 2.2 summarizes the effects of different levels of overpressure on material surrounding the explosion and unprotected persons exposed to blast. Complex wave Simple free-field wave FriedlÃ¤nder wave FIGURE 2.4 Explosion-induced shock waves: (a) idealized representation of pressure-time history of an explosion in air; (b) shock wave in open air; (c) complex shock-wave features in closed or urban environment. SOURCE: Mayorga, 1997. Reprinted with permission from Elsevier Science, Ltd. 2008.
BIOLOGY OF TRAUMATIC BRAIN INJURY 33 Previous attempts to define the mechanisms of blast injury suggested the involvement of spalling, implosion, and inertial effects as major physical components of the blastâbody interaction and later tissue damage (Benzinger, 1950). Spallation is the disruption that occurs at the boundary between two media of different densities; it occurs when a compression wave in the denser medium is reflected at the interface. Implosion occurs when the shock wave compresses a gas bubble in a liquid medium, raising the pressure in the bubble much higher than the shock pressure; as the pressure wave passes, the bubbles can re-expand explosively and damage surrounding tissue (Benzinger, 1950; Chiffelle, 1966; Phillips, 1986). Inertial effects occur at the interface of the different densities: the lighter object will be accelerated more than the heavier one, so there will be a large stress at the boundary. Recent results suggest that there is a frequency dependence of the blast effects: high-frequency (0.5â1.5 kHz) low-amplitude stress waves target mostly organs that contain abrupt density changes from one medium to another (for example, the airâblood interface in the lungs or the bloodâparenchyma interface in the brain), and low-frequency (<0.5 kHz) high-amplitude shear waves disrupt tissue by generating local motions that overcome natural tissue elasticity (for example, at the contact of gray and white brain matter). Explosions may cause four major patterns of injury: primary blast injury caused by the blast wave itself, secondary injury caused by the fragments of debris propelled by the explosion, tertiary injury due to the acceleration of the body or part of the body by the blast wind, and flash burns due to the transient but intense heat of the explosion (Mellor, 1988). TABLE 2.2 Overpressure Effects on Surrounding Materials and Unprotected Persons Pressure, kPa Effects on Unprotected (psi) Effects on Material Pressure, kPa (psi) Person 0.69â34.47 (0.1â Shatter single-strength glass 34.47 (5) Slight chance of eardrum 5) rupture 6.89â13.79 (1â2) Crack plaster walls, shatter 103.42 (15) 50% chance of eardrum asbestos sheet, buckle steel rupture sheet, failure of wood wall 13.79â20.68 (2â Crack cinder-block wall, crack 206.84â275.79 (30â Slight chance of lung damage 3) concrete block wall 40) 13.79â55.16 (2â Crack brick wall 551.58 (80) 50% chance of severe lung 8) damage 34.47â68.95 (5â Shatter car safety glass 689.48 (100) Slight chance of death 10) 896.32â1,241.06 50% chance of death (130â180) 1,378.95â1,723.69 Death usual (200â250) SOURCE: Owen-Smith, 1981. General Medical Effects In general, primary blast injuries are characterized by the absence of external injuries and by potential parenchymal damage, mostly of the lungs (Rossle, 1950; Chiffelle, 1966); thus, internal injuries are often unrecognized, and their severity underestimated (Dedushkin et al., 1992). Table 2.3 summarizes some of the injuries induced by concomitant primary, secondary, tertiary, and quaternary blast effects as defined by the Centers for Disease Control and Prevention (CDC, 2003).
34 GULF WAR AND HEALTH According to the latest experimental results, the extent and types of primary blast- induced injuries depend not only on the peak of the overpressure but on other characteristics, such as the number of overpressure peaks, the lag between overpressure peaks, the shear fronts between overpressure peaks, frequency resonance, and electromagnetic pulse. Previously, exposure to blast overpressure was considered to damage primarily gas- containing organs or those containing structures of different specific weights (such as ears, lungs, and the gastrointestinal tract) (Benzinger, 1950; Clemedson, 1956; Phillips and Zajtchuk, 1989). Therefore, most research focused on the mechanisms of blast injuries within gas-containing organs or organ systems, primary BINT was underestimated, and safety recommendations (Table 2.1) focused on the injurious effects of blast on extracerebral body parts and organs and not on hidden brain damage and potential neurologic consequences. TABLE 2.3 Summary of Most Important Body-System Injuries Induced by Concomitant Primary, Secondary, Tertiary, and Quaternary Effects of Blast System Injury or Pathologic Condition Auditory system Eardrum rupture Disruption of ossicles Cochlear damage Respiratory system Blast lunga Hemothorax Pneumothorax Pulmonary contusion Pulmonary hemorrhage Airway epithelial damage Aspiration pneumonitis Sepsis Arteriovenous fistula (air embolism) Gastrointestinal Bowel perforation system Hemorrhage, fracture, rupture of liver or spleen Mesenteric ischemia caused by air embolism Sepsis Nervous systemb Concussion Closed (blunt) brain injury Open (penetrating) brain injury Stroke from air embolism Spinal-cord injury Cardiovascular Myocardial contusion system Myocardial infarction from air embolism Cardiogenic shock Peripheral vascular injury Peripheral ischemia from air embolism Shock Genitourinary system Renal contusion Renal laceration Acute renal failure due to shock or rhabdomyolysis Testicular rupture Visual systemc Perforated eye globe Foreign bodies in eye
BIOLOGY OF TRAUMATIC BRAIN INJURY 35 System Injury or Pathologic Condition Air embolism Orbital fractures Extremities Fractures Amputations Crush injuries Compartment syndrome Burns Cuts Lacerations Acute occlusion of artery Air-embolismâinduced injury a Blast lung is a direct and best known consequence of a high-energy overpressure wave; it is the most common fatal primary blast injury in initial survivors of an explosion. b Primary blast effects can induce blast-induced neurotrauma without a direct blow to the head. c Up to 10% of unprotected blast survivors have substantial eye injuries. NOTE: Information added to the original table as compiled by Centers for Disease Control and Prevention. SOURCE: CDC, 2003. Complex morphologic and functional impairments caused by blast injuries are often underestimated. Survivors of blast injury commonly experience apathy, lethargy, and psychomotor dystonia and rarely convulsion and paralysis (Ascroft and Lond, 1940; Stewart and Russel, 1941; Garai, 1944; Huller and Bazini, 1970; Harmon and Haluszka, 1983). Deafness, tinnitus (Phillips and Zajtchuk, 1989; Khilâko et al., 1997; Cripps et al., 1999), thoracic pain, and vertigo are the most common subjective sensations in people who were near an explosion (Cernak et al., 1999b). The specific clinical signs that might be seen in a physical examination on admission are scanty and irregular: cyanosis; blood oozing from the nose, mouth, and ears; tympanic membrane hyperemia, hemorrhage, or rupture (Phillips and Zajtchuk, 1989); tachypnea preceded by a short period of apnea, dyspnea, hemoptysis, or moist crepitations in both lung fields (Damon et al., 1968; Mellor, 1988; Hirshberg et al., 1999; Lavery and Lowry, 2004); tachycardia; and decrease in mean arterial pressure (Guy et al., 1998; Weiss et al., 1999). Chest radiography may reveal pneumothorax, bilateral intrapulmonary hemorrhage, and edema with a characteristic pattern called snowstorm (Caseby and Porter, 1976). Electrocardiographic examination rarely shows specific signs; it might occasionally show alterations similar to those of myocardial ischemia or infarction (Cooper et al., 1983). Measurement of some readily available biochemical characteristics in the blood (serum enzymes, blood-urea nitrogen, leukocyte count, and hemoglobin concentration) fails to aid in the diagnosis of blast injury (Harmon et al., 1988). Some clinical (Cernak et al., 1999a) and experimental studies (Cernak et al., 1996a; Huang et al., 1996) have shown that measurement of sulfidopeptide leukotrienes (sLTs: LTC4, D4, and E4) and of 6-keto-PGF1 alpha and TxB2, the stable products of prostacyclin (PGI2) and thromboxane A2 (TxA2), respectively, and identification of those compounds in the plasma would be a useful tool for diagnosing blast injuries in the early stage. Indeed, it has been reported that patients with blast injury had significantly higher mean circulating TxB2 and sLT concentrations and significantly lower plasma 6-keto-PGF1 alpha:TxB2 ratio during the 5 days after injury than patients with the most severe injuries but without blast injury (Cernak et al., 1999a). Because of the complexity of blast injury, its diagnosis should be based on a history of blast exposure, the presence of subjective symptoms characteristic of blast injuries, pathognomonic findings in a physical examination, and suggestive results of clinical tests (Cernak et al., 1999a, 1999b) (Figure 2.5).
36 GULF WAR AND HEALTH ADMISSION HISTORY / URGENT RESUSCITATION PHYSICAL QUESTIONNAIRE INJURY SCORING EXAMINATION EMERGENCY SURGERY (if needed) Blood secretion in the Deafness, tinnitus, earache CLINICAL EXAMINATION external ear/nose Audiogram: somatosensory or Cyanosis Chest pain, reflex/dry cough, sensory hearing loss hemoptysis, tachypnea Eardrum X-ray - chest: hyperemia/rupture pneumomediastinum Nausea, vertigo, pneumothorax, hemothorax, Chest auscultation: retrograde amnesia, lung parenchyma infiltration, few localized to widespread confusion, indecisiveness pulmonary interstitial emphysema rales and rhonchi Hypopharyngeal petechiae/ ecchymoses Subcutaneous emphysema Fundoscopy: retinal air emboli Abdomen: rigid with direct and rebound tenderness X-ray - abdomen: gastric dilation, dilated loops of bowel Laboratory tests: impaired blood gases FIGURE 2.5 Examination and diagnosis algorithm for blast injuries. SOURCE: Cernak et al., 1999a. Reprinted with permission from Lippincott Williams and Wilkins, 2008. Blast-Induced Neurotrauma There is an outdated dogma that neurologic impairments caused by primary blasts are rare because the skull provides excellent protection for the brain; that is, brain injury is solely a consequence of air emboli in cerebral blood vessels (Clemedson, 1956; Owen-Smith, 1981). Despite recent clinical findings (Cernak et al., 1999a, 1999b, 1999c, 2000), experimental findings (Saljo et al., 2000; Cernak et al., 2001a, 2001b), and experience in contemporary military operations that suggests substantial short-term and long-term neurologic deficits caused by blast exposure without a direct blow to the head, old belief prevails in the professional literature and in clinical practice. Indeed, information on blast injuries (Table 2.3) lists mainly the consequences of secondary and tertiary blast mechanisms. Although BINT is one cause of in- theater injuries, it is often underdiagnosed. Its complex clinical syndrome is caused by the combination of all blast effects (Figure 2.6). It is noteworthy that blast injuries are usually manifested in a form of polytrauma, that is, injury involving multiple organs or organ systems. Primary blast injury of the chest produces bradycardia, hypotension, and apnea via vagal reflexes, which may induce cerebral hypoxia and ischemia (Cernak et al., 1996a, 1997; Ohnishi et al., 2001). Bleeding from injured organs, such as the lungs and intestine, causes a lack of oxygen in all vital organs, including the brain. Damage of the lungs reduces the surface for oxygen uptake from the air and reduces the amount of the oxygen delivered to the brain (Cernak et al., 1997). Tissue destruction initiates the synthesis and release of hormones and mediators into the blood that, when delivered to the brain, change the brainâs function (Cernak et al., 1996b). Irritation of the nerve endings in injured peripheral tissue and organs also contributes to BINT (Irwin et al., 1999).
BIOLOGY OF TRAUMATIC BRAIN INJURY 37 Secondary blast-induced neurotrauma Primary blast-induced neurotrauma (penetrating head injury) (without a direct blow to the head) kinetic energy transfer to the CNS, lung injury-induced hypoxia/ischemia hemorrhage-induced hypoxia/ischemia hormones released from injured tissue Tertiary blast mechanisms (i.e. effects of the impacts with other objects Tertiary blast-induced neurotrauma (coup-countrecoup) Primary blast mechanisms (i.e. effects of the blast wave itself Secondary blast mechanisms (i.e. effects of the missiles being propelled by blast force) FIGURE 2.6 Complex mechanisms of blast-induced neurotrauma. SOURCE: Reprinted with permission from Stewart, 2006. Primary Blast-Induced Neurotrauma There are theories of the vital mechanisms of blast-waveâbrain interaction underlying primary BINT. There are numerous assumptions that explain BINT as a type of postconcussion syndrome, that emphasize the psychologic dimension of blast experience (Jones et al., 2007), or, on the basis of clinical and experimental data, that posit that BINT can develop without a direct blow to the head and results from the kinetic-energy transfer of the blast wave through large blood vessels in the abdomen and chest to the central nervous system (Cernak et al., 1999a, 2001b; Bhattacharjee, 2008). As the front of the blast overpressure interacts with the body surface and compresses the abdomen and chest, it transfers its kinetic energy to the bodyâs fluid phase. The resulting hydraulic interaction initiates oscillating waves that traverse the body at about the speed of sound in water and deliver the kinetic energy of the blast wave to the brain. Once delivered, that kinetic energy causes both morphologic and functional damage in distinct brain structures. Although the damage might resemble the injury patterns that develop after mechanical TBI caused by direct interaction of a mechanical force and the skull, the injury manifestation, timeline, and complexity of pathologic changes make BINT a distinct health problem. Furthermore, frequency resonance between blast wave and electromagnetic pulse might also contribute to primary blast-induced neurologic disturbances (G. Ling, personal communication). Experimental Studies. Experimental studies on primary blast-induced biologic effects routinely use shock tubes or blast tubes, cylindrical metal tubes usually closed at one end. The blast overpressure and underpressure waves are generated either by compressed air (shock tubes) or by detonation of an explosive (blast tubes) in the closed end of the tube (Nishida, 2001; Robey, 2001). Anesthetized animals are fixed individually in special holders designed to prevent
38 GULF WAR AND HEALTH any movement of their bodies in response to blast and thus to prevent tertiary effects of the shock or blast wave (Wang et al., 1998; Cernak, 2005). Most shock and blast tubes used in current experimental models replicate the ideal blast wave from an open-air explosion without a capability to generate a nonideal blast wave with multiple shock and expansion fronts as seen in real-life conditions, and this limits the extent of comparability of experimental and clinical findings. A small number of studies use open-field exposure of animals to a blast wave generated by detonation of an explosive (Richmond, 1991; Cernak et al., 1996b, 1997; Axelsson et al., 2000; Saljo and Hamberger, 2004). Although such an experimental setting is more comparable with in-theater conditions, the physical characteristics (such as homogeneity of the blast wave) are less controllable, so a broader range of biologic response should be expected. A wide range of blast overpressure sustained for various durations has been used in single-exposure experimental studies. In most studies, the animals were subjected to a shock or blast wave with a mean peak overpressure of 52â340 kPa (7.54â49.31 psi) on the nearest surface of an animalâs body (Clemedson et al., 1969; Saljo et al., 2000; Cernak et al., 2001b; Chavko et al., 2007). Most experiments used rodents (mice and rats), but some have subjected nonhuman primates or other larger mammals to blast (Richmond et al., 1967, 1968; Bowen et al., 1968; Damon et al., 1968; Bogo et al., 1971). Considerable reductions in food intake and exercise performance have been found in rats exposed to low-intensity shock waves (83 kPa or 129 kPa) (Bauman et al., 1997). Similar findings have been reported in sheep (Mundie et al., 2000). Exposure to blast has been described as inducing hyperactivation of the autonomous nervous system and, via activation of such vagovagal reflexes as the BezoldâJarisch reflex, causing bradycardia (Cernak et al., 1996b). Indeed, bilateral vagotomy before blast exposure prevented depression of cardiovascular functions and prevented pulmonary edema in rabbits subjected to a shock wave of about 300 kPa (43 psi). Rhesus monkeys exposed to about 207 kPa (30 psi), about 276 kPa (40 psi), or about 345 kPa (50 psi) had significant albeit transient memory and performance deficits (Bogo et al., 1971). Considerable and persistent memory deficits have been shown in rats subjected to blast waves generated in an air-driven shock tube (Cernak et al., 2001a). Rats exposed to different charges of a plastic explosive (pentaerythritol tetranitrate), intended to generate a blast wave of 220 or 350 kPa in a blast tube, demonstrated significant decreases in amplitude and frequency of the brainâs electric activity measured with electroencephalography (EEG) continuously during 30 minutes after the blast (Risling et al., 2002). Those changes were more profound in rats exposed to 350 kPa or in those exposed repeatedly to 220 kPa. Similarly, transient flattening of the EEG was seen in pigs immediately after the blast, in contrast with the unchanged baseline EEG in control animals. That momentary depression of cortical activity was accompanied by brief apnea indicates a blast-waveâinduced effect on the brainstem or higher controlling center (Axelsson et al., 2000). Blast exposure has been reported to cause brain edema and considerable metabolic disturbances in the brain: significantly decreased glucose, magnesium, and ATP concentrations; increased lactate concentration and lactate:pyruvate ratio (Cernak et al., 1996b); and impaired function of the sodiumâpotassium ATPase pump (Cernak et al., 1997). Those changes clearly suggest energy failure or imbalance between energy demand and available energy, shift of glucose metabolism from the aerobic toward the anaerobic pathway, and impairment in neuronal cell membrane permeability (Cernak et al., 1997). Swelling of neurons, an astroglial response, and myelin debris in the hippocampus have been found after moderate blast injury in animals (Cernak et al., 2001b). Immunohistochemical analyses have shown significant damage to the
BIOLOGY OF TRAUMATIC BRAIN INJURY 39 neuronal cytoskeleton in layers IIâIV of the temporal cortex, in the cingulated gyrus and the pirifom cortex, in the dentate gyrus, and in the CA1 region of the hippocampus over 7 days after blast exposure (Saljo et al., 2000). Oxidative stress, changes in antioxidantâenzyme defense systems (Cernak et al., 2001a, 2001b), increase in nitric oxide metabolism, and later cognitive deficits (Cernak et al., 2001a) have also been seen. Studies on the effects of repeated low-level (29â62 kPa) blast exposures demonstrated accumulating pathologic alterations involving multiple organs or organ systems (Yang et al., 1996; Elsayed and Gorbunov, 2007), with activation of the hypothalamicâpituitaryâadrenal axis and significant biochemical and hormonal changes in the brain (Mazurkiewicz-Kwilecki, 1980). Moreover, repeated exposures to low-intensity (20 kPa) blast caused significant motor deficits in rats (Moochhala et al., 2004). Clinical Studies. Experimental data and clinical observations suggest the involvement of multiple mechanisms in the development of brain damage and associated functional impairments and disabilities in those exposed to blasts. People exposed to blast frequently manifest loss-of- memory of events before and after the explosion, confusion, headache, impaired sense of reality, and reduction in decision-making ability (Cernak et al., 1999a, 1999b; Taber et al., 2006; Warden, 2006). Patients with brain injuries acquired in explosions often develop sudden, unexpected brain edema and cerebral vasospasm despite continuous monitoring (Armonda et al., 2006). Significant changes in blood chemistry suggest development of oxidative stress, electrolyte imbalance, and neuroendocrine alterations in blast casualties during the acute posttraumatic phase (Cernak et al., 1999a, 1999b, 1999c, 2000). The onset of mild BINT symptoms might be latent, occurring months or even years after the event. The symptoms include weight loss, hormonal imbalance, chronic fatigue and headache, and problems in memory, speech, and balance (Taber et al., 2006; Scherer, 2007). A study of patients subjected to explosion but with no visible injuries or only lower-extremity wounds has demonstrated that 51% had neurologic symptoms (such as headache, insomnia, psychomotor agitation, and vertigo); of those 36% had EEG alterations during the acute stage, such as hypersynchronous, discontinuous, or irregular brain activity. Both neurologic and EEG alterations progressed to the chronic stage in 30% of that group (Cernak et al., 1999a; Taber et al., 2006). Trudeau et al. reported that even veterans with a remote history of blast injury display permanent EEG changes similar to those often found after TBI, as well as persistent cognitive problems (Trudeau et al., 1998). In the study of male combat veterans, Yehuda (1999) suggested linking the memory dysfunction and the neuroendocrine alterations of posttraumatic stress with the neuroanatomic findings of reduced hippocampal volume. That opinion is consistent with the previously mentioned results published by Trudeau et al. (1998). Moreover, clinical studies involving blast- injured patients from the Afghanistan war reported biochemical alterations in the cerebrospinal fluid (CSF) suggestive of increased activity of cytoplasmic mitochondrial proteolytic enzymes; those changes have been shown to be directly related to the severity of brain trauma (Khil'ko et al., 1995a). Moreover, primary BINT has been shown to induce specific immune responses with increased concentrations of immunoglobulin G and immunoglobulin A in the CSF and increased circulation of immune complexes and altered function of the immune system that sometimes led to permanent immune deficiency (Khilâko et al., 1995b). Although studies confirm the biologic plausibility of BINT, rigorous human studies examining the consequences of these injuries, their recovery trajectory, and factors that determine their outcome are needed. Because of lack of information, adverse neurologic and
40 GULF WAR AND HEALTH behavioral changes in blast victims might be underestimated, and valuable time for preventive therapy or timely rehabilitation might be lost (Warden, 2006; Martin et al., 2008). Penetrating Traumatic Brain Injury Penetrating TBI is generally inflicted by munitions fragments, high-energy bullets, or other fragments generated by an explosion. In the recent warfare, penetrating TBI caused by secondary blast effects is only one of the elements of BINT. Penetration by a fragment or object depends on the energy of the projectile and the retardation caused by the fragmentâtissue interaction. The retardationâwhich is a function of the shape of the object (the presented area), the angle of approach, and the properties of the tissueâdetermines the amount of energy transferred into the tissue, whereas the extent of damage depends on delivered energy (Sapsford, 2003). Projectiles with high available energy, such as fragments generated by an improvised explosive device, usually transfer large quantities of energy and cause strong stress waves and large temporary cavities (Yoganandan et al., 1997). The temporary cavities, lasting only a few milliseconds, expand fast, decreasing pressure to below atmospheric and sucking debris into the wound (Sapsford, 2003; Zhang et al., 2005b). A cavityâs collapse is preceded by several smaller expansions and contractions of decreasing amplitude. The extent of damage to tissue in a nonelastic environment like the brain is estimated to be 10â20 times the size of the projectile. Experimental Studies. Experimental studies on wound ballistics demonstrate pathophysiologic wounding properties of a penetrating brain injury distinct from those of the other types of head injury (Carey et al., 1990b; Soblosky et al., 1992; Torbati et al., 1992; Carey, 1995; Williams et al., 2006a, 2006b). If a missile penetrates a cerebral hemisphere without severe disruption of vital brain structures, the indirect effect of ordinary pressure waves, set up by the interaction of missile and tissue, may damage the brain stem respiratory nuclei and cause death (Carey, 1995). Thus, the possibility of fatal apnea is directly related to the missile energy of deposit in the brain. Moreover, it has been shown that although transmitted ordinary pressure waves might interfere with the reticular activating system in the brainstem and induce persistent coma, specific long-lasting neurologic defects from a missile wound generally result from direct missile damage to the cerebral cortex or cortical projections (Carey, 1995). The pathobiology of penetrating TBI also includes vasogenic edema around the missile wound track in the injured hemisphere (Carey et al., 1990a, 1990b); increase in ICP; decrease in cerebral perfusion pressure (Carey et al., 1989; Carey, 1995); widespread stretch injuries of blood vessels, nerve fibers, and neurons; and distortion and displacement of the brain (Finnie, 1993). Recent experimental studies (Williams et al., 2006a, 2006b, 2007) used a unilateral right frontal trajectory to induce survivable penetrating TBI of the frontal cortex and striatum and identified three distinct phases of injury progression. Phase I (0â6 hours), the primary injury, began with immediate (<5 minutes) intracerebral hemorrhage; maximal volumetric size developed at 6 hours after the trauma. In phase II (6â72 hours), the secondary injury, cells undergoing necrotic cell death and infiltrated neutrophils (24 hours) and macrophages (72 hours) formed a core lesion of degenerate neurons surrounding the injury track. The core lesion expanded into perilesional areas and reached maximal volume at 24 hours after the trauma. Phase III, delayed degeneration, developed 3â7 days after the trauma and involved neurogenic inflammation and degeneration of neurons and fiber tracts in structures remote from the core lesion, such as the thalamus, the internal capsule, the external capsule, and the cerebral peduncle (Williams et al., 2006a, 2007).
BIOLOGY OF TRAUMATIC BRAIN INJURY 41 Clinical Studies. Despite continuing efforts of the International Brain Injury Association, the Brain Injury Association of America, and other international and national surgical and neurosurgical associations, there is no consensus about the management of patients who have suffered brain injury caused by missiles and other penetrating objects. The lack of consensus could underlie apparent discrepancies in clinical studies concerning diagnosis, therapy, and rehabilitation of patients with penetrating TBI (Blissitt, 2006; No Author, 2001a, 2001b; Pabuscu et al., 2003). For example, there are differing opinions about the usefulness of decompressive craniotomy, a method to convert the confined-space skull into an open one by removing part of the skull (Sahuquillo and Arikan, 2006); use of hypertonic saline solution vs mannitol in posttraumatic brain-edema treatment; aggressive vs less aggressive debridement of the wound (Taha et al., 1991; Levy, 2000; Tong et al., 2004); and treatments of CSF leaks, a frequent consequence of penetrating head wounds (Brandvold et al., 1990; Aarabi et al., 1998). Guidelines that have a sound scientific basis are necessary to achieve a consistent approach to the management of penetrating TBI patients. Diffuse Brain Injury As described above, movement of the brain caused by sudden acceleration followed by deceleration, in which the inertial effect depends on the brain mass and determines the extent of tissue deformation, has been identified as one of the most important mechanisms of diffuse brain injury (Ommaya and Gennarelli, 1974; Adams et al., 1989). In military settings, diffuse brain injury is often caused by tertiary blast effects (for example, a body flying through the air and hitting other objects), which then contribute to the complexity of BINT. Diffuse axonal injury, characterized by morphologic changes in axons throughout the brain and brainstem, has contributions from both primary and secondary injury mechanisms, and is recognized as one of the main consequences of nonmissile TBI leading to the diffuse degeneration of cerebral white matter (Adams et al., 1989). It is noteworthy that the distribution of the types of diffuse axonal injuries seen in BINT are substantially different from that of TBI of nonblast origin (Cernak et al., 2001b). The most common locations involve the brainstem, the cerebellum, gray matterâ white matter junctions, and the internal capsule. SEVERITY SCORING OF BLAST INJURIES AND TRAUMATIC BRAIN INJURY Severity Scoring of Blast Injuries The severity of injuries inflicted by explosive weaponry is usually scored by using the Abbreviated Injury Scale (AIS) or the Injury Severity Score (ISS). The AIS was first reported in 1971 for classification of anatomic injury from motor-vehicle collisions (Committee on Medical Aspects of Automotive Safety, 1971); it was not designed primarily to measure penetrating injury and high-velocity ballistic injuries. In an attempt to develop an improved injury-scoring system, the ISS was derived from the AIS and the Comprehensive Injury Scale, both of which were established to measure anatomic injury (Baker et al., 1974). The ISS correlated well with survival of the multiply injured blunt-trauma patient (Bull, 1978), but a similar relation for penetrating and war or gunshot injuries was not seen (Beverland and Rutherford, 1983) until the 1985 version of the AIS (American Association of Automotive Medicine, 1985). That was important not only for the improvement of injury scaling of blunt trauma but as an extension that made it possible to include penetrating injuries. The last revision of the AIS (AIS, 2005) contains
42 GULF WAR AND HEALTH more than 2,000 injury descriptors, each of which can be localized to a small section of the body, if desired, by using precise methods incorporated into the scale (Gennarelli and Wodzin, 2006). Moreover, AIS 2005 includes new sections that cover blast and other nonmechanical injuries (Gennarelli and Wodzin, 2006). The Red Cross Wound Classification (RCWC) was developed as a grading system for use under adverse conditions on the battlefield, scoring such wound features as degree of tissue damage, presence or absence of metallic fragments, and presence or absence of a cavity. Once scored, the wound can be further graded according to severity and typed according to structures injured; thus, wounds can be identified by their clinical significance (Coupland, 1992). However, there has been some discrepancy between the RCWC, routinely performed on the battlefield during combat operations in the former Yugoslavia, and clinical signs and outcomes of patients with blast injuries (Savic et al., 1993, 1995). With regard to blast injuries, there is not an easily applicable and reliable scoring system. Experimental studies have often used the Walter Reed Army Institute of Research Blast Injury Subjective Score, which establishes blast-injury severity on the basis of the extent of lung damage (Jaffin et al., 1987; Mayorga, 1997) but does not take into account injuries in other organs or organ systems due to blast exposure. A pathology scoring system (PSS) for blast injuries (Yelverton, 1996) uses an alphanumeric measure of the severity of various lesions caused in animals by a blast wave, including those induced by secondary or tertiary effects, to arrive at a severity-of-injury index (SII) for each subject. That complex system correlates external lesion, injury grade, severity type, and severity depth or disruption of the injury with the presence or absence of some complications (such as pneumothorax, hemothorax, hemoperitoneum, coronary air, and cerebral air) and with the trauma outcome (nonfatal or fatal). A modified Yelverton scoring system has been helpful in some clinical studies (Cernak et al., 1999b). Severity Scoring of TBI Assessment of injury severity is of fundamental importance in the clinical management of patients with TBI and for developing novel diagnostic and therapeutic approaches. The Glasgow Coma Scale (GCS) has been the gold standard of neurologic assessment of trauma patients since its development by Teasdale and Jennett in 1974 (Teasdale and Jennett, 1974). Other TBI severity-classification systems grade single indicators, such as loss of consciousness (LOC) and duration of posttraumatic amnesia (PTA). The predictive value of those measures has been demonstrated (Dikmen et al., 1990; Levin, 1990, 1995; Levin et al., 1990; Sherer et al., 2008), but each may be influenced by factors unrelated or indirectly related to the severity of TBI, such as intoxication, sedation, and other treatments. Glasgow Coma Scale The GCS is used to determine the depth and duration of impaired consciousness and for continued assessment. It includes three independently measured components of behavior: eye opening, motor responsiveness, and verbal performance (Teasdale and Jennett, 1974). Eye Opening. Spontaneous eye opening is most highly scored (4) and indicates active arousal mechanisms in the brainstem. Eye opening in response to speech, which is scored a 3, is a response to any verbal approach and indicates functional cerebral cortex in
BIOLOGY OF TRAUMATIC BRAIN INJURY 43 processing information. Eye opening in response to pain is scored a 2, suggesting functioning of lower levels of the brain. The lowest score, a 1, is assigned to patients when there is no eye opening in response to speech or pain. Motor Response. The highest score, 6, is assigned when the patient can process instructions and respond by obeying a command (Fischer and Mathieson, 2001). In the absence of response to a command, a painful stimulus is applied. When the patient makes an attempt to remove the source of the painful stimulusâthat is, the arm crosses the midline in such an attemptâa score of 5 is assigned. If the patient withdraws from the painful stimulus, a score 4 is assigned. Abnormal responses to painful stimulus, such as flexion or extension of the upper extremities, indicate more severe brain dysfunction. Decortication is manifested by adduction of the upper extremities with flexion of the arms, wrists, and fingers, whereas the lower extremities will extend and rotate internally with plantar flexion of the feet (a score of 3). That response suggests lesions in the cerebral hemispheres or internal capsule. Decerebration is manifested with adduction and hyperpronation of the upper extremities, whereas the legs are extended with plantar flexion of the feet. Opisthotonus, a backward extension of the head and arching of the back, is also a manifestation of decerebration, damage extending from the midbrain to the upper pontine (a score of 2). A score of 1 is assigned when the patient fails to respond to a painful stimulus. Verbal Response. Orientationâthe patientâs ability to know his or her identity (person), where he or she is (place), and the current year, season, and month (time)âis the first component tested. When the patient is oriented, the maximum score of 5 is assigned. In the case of confused conversation, a score 4 is given, and inappropriate speech is scored a 3. Incomprehensible speech that refers to moaning and groaning but without any recognizable words is scored a 2, and a score of 1 is assigned to patients without verbal response. Overall Score. The final GCS is derived as the sum of all scores. On that basis, TBI can be classified as mild (GCS 13), moderate (GCS 9â12), or severe (GCS 8). To improve the sensitivity of the GCS and its prognostic value, Stein and Spettel (1995) developed a head-injury severity scale for closed TBI, defining five GCS intervals: minimal head injury (GCS = 15, no LOC or amnesia), mild head injury (GCS = 14, or 15 plus amnesia, or <5 minutes LOC, or impaired alertness or memory), moderate head injury (GCS = 9â13, or LOC 5 minutes, or focal neurologic deficit), severe head injury (GCS = 5â8), and critical head injury (GCS = 3â4). The Mayo Classification System Taking into account the unreliability of some TBI indicators and the incidence of missing or incomplete documentation in the medical records, the Mayo Classification Systemâs aim was to take advantage of positive evidence regularly available in the medical records for each case (Malec et al., 2007). The system was proposed for use in retrospective studies and for estimating TBI severity in cases presenting postacutely for medical care or rehabilitation. The Mayo Classification System classifies TBI in three major categories: moderate-severe (definite), mild (probable), and symptomatic (possible). Moderate-severe (definite) TBI includes patients manifesting one or more of the following criteria: death due to the TBI, LOC of 30 minutes or more, posttraumatic anterograde amnesia of 24 hours or more, a worst GCS full score in the first 24 hours of less than 13 (unless
44 GULF WAR AND HEALTH invalidated on review, for example, attributable to intoxication, sedation, or systemic shock), and the presence of one or more of intracerebral hematoma, subdural hematoma, epidural hematoma, cerebral contusion, hemorrhagic contusion, penetrating TBI (dura penetrated), subarachnoid hemorrhage, and brainstem injury. Mild (probable) TBI includes patients without any criteria of moderate-severe (definite) TBI and with one or more of LOC momentary to less than 30 minutes, posttraumatic anterograde amnesia of momentary to less than 24 hours, and depressed, basilar, or linear skull fracture (dura intact). Symptomatic (possible) TBI includes patients without any criteria of moderate-severe (definite) and mild (probable) TBI and with one or more of blurred vision, confusion (mental- state changes), daze, dizziness, focal neurologic symptoms, headache, and nausea. Comparisons with traditional single-measure systems (such as LOC or PTA) and approximate calculations of sensitivity and specificity have indicated that the Mayo system classifies TBI severity with reasonable accuracy (Malec et al., 2007). The Brief Traumatic Brain Injury Screen The Brief Traumatic Brain Injury Screen (BTBIS) is a one-page paper-and-pencil questionnaire designed by the Defense and Veterans Brain Injury Center (DVBIC) to screen for TBI in soldiers (DVBIC, 2007; Schwab et al., 2007) (Figure 2.7). It begins with a few questions about basic demographics and deployment history over the preceding 2 years, which are followed by three questions designed to identify possible TBI. The first of those, question S3, inquires about any injuries received during deployment with checkboxes indicating blast, vehicular, bullet, falls, and âotherâ as categories of injuries. Question S4 asks about neurologic features of TBI, including alterations in consciousness and LOC that resulted from injuries identified by the previous question. Question S4 also includes the categories âhaving symptoms of concussion afterwardâ and âhead injury,â which are not part of the definition of TBI; those were included to provide further description of the injury for clinicians. Finally, question S5 aims at identifying specific symptoms and problems that are thought to be possibly associated with a head injury or concussion. Generally, it takes about 3â4 minutes to complete the BTBIS.
BIOLOGY OF TRAUMATIC BRAIN INJURY 45 FIGURE 2.7 Brief Traumatic Brain Injury Screen. SOURCE: DVBIC, 2007. Reprinted with permission from Lippincott Williams and Wilkins, 2008. The Military Acute Concussion Evaluation The Military Acute Concussion Evaluation (MACE) has been developed by the DVBIC as a tool for determining cognitive deficits due to mild TBI (DVBIC, 2006a, 2006b). The major goals of the MACE are to confirm the diagnosis of mild TBI, and to provide further assessment data by using the Standardized Assessment of Concussion (McCrea et al., 1997), to record neurocognitive deficits. The MACE can be easily used by medics and corpsmen and can be administered within 5 minutes. The four cognitive domains tested are orientation, immediate memory, concentration, and delayed recall. The MACE is recommended for use in military theater at levels I, II, and III. It is recommended that beyond the use of the MACE other neurocognitive measures be implemented at level III to evaluate the cognitive state of an injured service member comprehensively. Severity Scoring of BINT Because moderate, moderate-to-severe, and severe BINTs are often part of complex polytrauma, proper diagnosis of BINT should include both classification of blast injuries and severity scoring of the head injury. The most recent version of the AIS (AIS, 2005) (Gennarelli and Wodzin, 2006) incorporates blast injuries and is regularly used by the US Army; the global scoring of all injuries can be accomplished with that scoring system. In hospitals calculation of the modified PSS SII (Yelverton, 1996; Cernak et al., 1999b) can give additional information that might be valuable for treatment strategies and outcome prediction. A combination of head AIS, as an anatomic measure, and the GCS, as a physiologic measure of brain-injury severity, is useful for initial estimation of brain damage.
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