12
Neuropathology of Traumatic Brain Injury: Comparison of Penetrating, Nonpenetrating Direct Impact and Explosive Blast Etiologies Jung H. Kim, MD2
1 Department of Neurosurgery and Neurobiology, Yale School of
Medicine, New Haven, Connecticut 2 Department of Pathology, Yale School of Medicine, New Haven, Connecticut 3 Department of Neurology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland
Faris A. Bandak, PhD3 Address for correspondence Nihal C. de Lanerolle, D Phil, DSc, Department of Neurosurgery, Yale School of Medicine, FMB414, 333 Cedar Street, New Haven, CT 06520-8082 (e-mail: [email protected]).
Semin Neurol 2015;35:12–19.
Abstract Keywords
► ► ► ► ► ► ► ► ►
traumatic brain Injury neuropathology penetrating injury closed head injury explosive blast concussion microglia astrocytes diffuse axonal injury
The neuropathology of traumatic brain injury (TBI) from various causes in humans is not as yet fully understood. The authors review and compare the known neuropathology in humans with severe, moderate, and mild TBI (mTBI) from nonpenetrating closed head injury (CHI) from blunt impacts and explosive blasts, as well as penetrating head injury (PHI). Penetrating head injury and CHI that are moderate to severe are more likely than mTBI to cause gross disruption of the cerebral vasculature. Axonal injury is classically exhibited as diffuse axonal injury (DAI) in severe to moderate CHI. Diffuse axonal injury is also prevalent in PHI. It is less so in mTBI. There may be a unique pattern of periventricular axonal injury in explosive blast mTBI. Neuronal injury is more prevalent in PHI and moderate to severe CHI than mTBI. Astrocyte and microglial activation and proliferation are found in all forms of animal TBI models and in severe to moderate TBI in humans. Their activation in mTBI in the human brain has not yet been studied.
Traumatic brain injury (TBI) can be penetrating (PHI) or nonpenetrating/blunt in nature. A penetrating head injury (PHI) is when the skull and dura are breached by a foreign body. This can be from a slow moving object such as a knife or a fast moving one such as a bullet. A slow-moving sharp foreign body will pass through the skull and dura and cause damage along its line of travel. This will lead to slicing, shearing, and compression of brain along the track. A fastmoving foreign body, such as a bullet, will do the same, but also creates a shock wave causing high pressures to transmit through the brain before the penetrating phase ensues. During penetration, the bullet slices through the brain, creating a somewhat conical cavity rapidly pushing the brain parenchyma outwards away from the bullet path. Such cavities can be twice the diameter of the bullet to as much as 15 times for extremely high-velocity rifle bullets. Extremely
Issue Theme Traumatic Brain Injury; Guest Editor, Geoffrey Ling, MD, PhD, FAAN, FANA
high velocities are typically those exceeding the speed of sound. Therefore, the brain is not only damaged by the slicing effect, but also by the tissue deformation from the expansion and contraction of the cavity. This includes disruption of the parenchyma and vascular structures. For slow or unstable bullets, other types of brain damage occur, for instance, when a relatively low-velocity bullet does not have enough energy to exit the skull and bounces off the interior side of the skull back into the brain. Explosive blast devices can lead to PHI when fragments from the device’s casing and other ejecta (such as rocks) penetrate the cranium and brain parenchyma. Penetrating wounds from fragments from an explosive device produce damage from somewhat slower projectiles than those of bullet wounds. Differences are primarily due to the shape and velocity of the impacting projectile. This is because explosive fragments are not as aerodynamically efficient as
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1544240. ISSN 0271-8235.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Nihal C. de Lanerolle, D Phil, DSc1
Neuropathology of Traumatic Brain Injury
13
neuropathological examinations are conducted also may influence the observations.
Penetrating Brain Injury The most common form of penetrating brain injury is from projectiles. Typically, a low-velocity projectile passing through the brain creates a cavity along its path, in which brain tissue, including blood vessels, is destroyed. Histological investigation around the missile track shows many patterns. Oehmichen and coworkers12–14 have described in some detail the histopathological changes in the cavity zone. In the region immediately adjacent to the permanent track is a zone of bleeding where there is almost total destruction of neurons, axons, and astrocytes.14 In this necrotic zone are found polymorphonuclear leukocytes (PMNs), but no macrophages or β-APP positive axons during the first 24 hours postinjury. Surrounding this necrotic area is a zone scattered with axonal fragments as well as injured and deformed neurons showing hyperchromasia and vacuolation. Macrophages are also seen in this zone (outside the necrotic area) and are conspicuous only in edematous areas.13 With progressive distance from the cavity, neuronal cell bodies, axons, and astrocytes appear more normal. For instance, in a sample of 20 victims with gunshot injuries from low-velocity projectiles, Oehmichen and coworkers calculate that a zone of 3.6 cm around the permanent track corresponds to a “temporary cavity.”14 This temporary cavity is not associated with hypoxic or edematous changes.12 More widely distributed histopathological changes are reported in brains with penetrating trauma, in addition to those associated with the track of the projectile. β-APP positive axons are distributed widely within neural tissue and appear as parallel wave-like patterns and irregular aggregations of axons and axon fragments in areas with edematous changes.13 These changes are reported to be dependent on survival time. Injured axons appear predominantly as β-APP positive fibers and rarely as axon bulbs.13 Axonal injury is widespread throughout the hemispheres,15 and is detected as far as the brainstem (midbrain, pons, medulla, and cerebellum). Ischemic injury, detected as red neurons in H&E stains, is also observed.15 Leukocytes and macrophages are not found distant to the bullet track.13 Hemorrhages associated with cortical “contusions” in the cerebral hemispheres,14 in the brainstem, and subarachnoid and intraventricular spaces, are also reported.15 High-velocity bullets produce large and distant tissue damage. Such injury is more extensive than the track of the bullet.16 A fuller discussion of the extent of injury with highvelocity bullets can be found in Bakir et al.16
Closed Head Injury from Impact and Explosive Blast Axonal Injury Diffuse axonal injury is recognized as a TBI hallmark pathological lesion. It has been classically defined as “the occurrence of diffuse damage to axons in the cerebral hemispheres, Seminars in Neurology
Vol. 35
No. 1/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
bullets and tend to lose energy due to air friction. Consequently, they do less damage at comparable distances from the source than bullets. Nonpenetrating brain injury, generally referred to as a closed head injury (CHI), is defined as a brain injury without a dural breach.1 Closed head injury occurs when there is impact to the head following direct contact with a blunt object as opposed to a sharp object. Closed head injury can also be from explosive blast injury, where there is direct loading on the head through shock-wave pressures. Clinically, TBI is typically categorized according to the resulting loss of consciousness and based on the Glasgow Coma Scale (GCS). A GCS score of 13 to 15 is recognized as mild TBI (mTBI), 9 to 12 as moderate, and 8 as severe trauma.1 A study of over 1 million trauma patients in the United Kingdom found approximately 90% had mTBI, 5% moderate, and 5% severe.2 Several comprehensive reviews of TBI have been published.3,4 Here we briefly review the neuropathology of impact and explosive blast penetrating and nonpenetrating TBI, and devote some attention to the mild components of nonpenetrating TBI, which continues to be a focus of considerable emerging research. Neuropathological investigations of TBI have typically focused on changes in several histological components of the brain: neurons (cell bodies and axons), vasculature, and nonneural cellular components (microglia and astrocytes). Interpreting the reported literature requires a subtle combination of finesse and caution. Among others, axonal injury is a feature often reported. A variety of methods have been utilized in studies, including immunostaining methods employing antibodies to β-amyloid precursor protein (β-APP), neurofilament proteins (NF), tau protein, and silver impregnation staining methods. The range of axonal injury visible with immunostaining methods is different from that seen with silver impregnation methods, although there is some overlap.4,5 For instance, DAI is detected with silver impregnation in approximately 30% of fatal head injuries, but almost universally demonstrable by β-APP immunostaining,6,7 and as early as 35 minutes after severe head injury.8 Further, early silver impregnation techniques could not reliably identify axonal injury in patients with survival times < 18 hour. It is now clear that silver positive swellings and retraction bulbs identify only a subset of injured axons.4 Like traditional silver staining, β-APP immunostaining also has limitations in its ability to distinguish between axonal injury due to ischemia and axonal injury due to mechanical deformation. 4,5 This distinction is important, as ischemia is one of the secondary injuries associated with CHI and is reported in 88% of fatal head injuries.9 Caution is required in examining hematoxylin and eosin (H&E) stained sections for injured neurons, sometimes identified as “dark neurons.”10 Dark neurons are a common artifact of manipulation of the brain without proper fixation.11 Therefore, details of histological procedures need to be examined. Similarly, “red neurons” are often the result of anoxic/ischemic changes and may not be directly attributable to trauma. Posttrauma survival time at which
de Lanerolle et al.
Neuropathology of Traumatic Brain Injury
de Lanerolle et al.
the corpus callosum, the brainstem and sometimes also in the cerebellum resulting from head injury.”6 Such injury can only be identified microscopically. Three grades of DAI have been recognized. Grade 1 is as defined above, with grade 2 having the additional feature of focal lesions in the corpus callosum, and grade 3 having focal lesions in the corpus callosum and in the brainstem.6 Much of the early work describing DAI is from patients with fatal head injury. In a study of 151 necropsies from patients with fatal nonmissile head injuries and survival times of 12 hours to 21 months,17 19 are reported to have diffuse damage to white matter. In those who survived many months after their injury, there is loss of white matter in the cerebral hemispheres and ventricular enlargement. In a comprehensive review of 434 fatal nonmissile head injury cases, Adams and coworkers6 point out some of the shortcomings in identifying DAI. The first is that sinusoidally enlarged axons, when present on their own, can be indistinguishable from postmortem artifact. Thus, DAI should not be assumed unless at least occasional axonal bulbs can be recognized. The second is that a lesion in the corpus callosum is not indicative of DAI because focal infarcts can be brought about by distortion and shifts of the brain caused by intracranial hematoma leading to compromised circulation. The third is that axonal bulbs are not restricted to head injury because they can occur in any situation in which axons are disrupted. There is little neuropathological information on mTBI in humans, as this condition is rarely fatal. There are, however, two studies of patients who suffered mTBI and died subsequently of other causes. In one study,18 the brains were examined of five patients aged 59 to 89 years, who sustained mTBI and died 2 to 99 days postinjury. They had concussive head injury of GCS 14 to15 with transient brief loss of consciousness. Axonal injury as seen by β-APP immunostaining was found in all five cases, located within the hippocampal fornices and corpus callosum. There was no evidence of hematoma, skull fracture, or prior cerebral infarctions. In a subsequent study,5 six cases with mTBI were compared with six cases with severe TBI (GCS 2–8). Both groups had axonal injury in the hippocampal fornices and corpus callosum, with additional axonal injury in the cerebellar peduncles in the severe trauma group alone. There was no β-APP stained axons in the controls. Only the mTBI group showed an absence of vascular damage. A whole-brain functional magnetic resonance imaging (fMRI) study of 30 patients with mTBI (GCS 13–15) compared their resting-state whole-brain functional connectivity (identified by independent component analysis [ICA] of fMRI data) with that of 30 controls.19 Abnormal functional connectivity in each of 12 separate networks was identified by ICA, and included visual processing, motor, limbic, and many circuits thought to be involved in executive cognition. Abnormalities not only included functional deficits, but also enhancements. Enhancements were found in a secondary visual processing network, the limbic circuit, and cingulo-opercular circuit, associated with mental set maintenance and cognitive control. There was no evidence of vascular-related damage to neurons associated with functional connectivity changes. Seminars in Neurology
Vol. 35
No. 1/2015
Such data suggest the possibility of changes in axonal pathways, but these remain to be confirmed histologically. The clinical features of explosive blast TBI are described by Ling and coworkers.20 Neuropathological findings from primary blast exposure in humans are limited because the condition is rarely fatal. The earliest studies on small cohorts21–24 report neuropathological features such as small hemorrhages in white matter, chromatologic changes indicative of neuronal injury, and subdural hemorrhage. Mott23 described an “extremely congested cortex,” enlargement of perivascular space, subpial hemorrhages, venous engorgement, and hemorrhage into myelin sheaths and perivascular spaces as microscopic features attributed to a blast.25 The degree of trauma in these patients is not clear. Evidence for axonal injury in patients with mTBI resulting from explosive blast (and blunt) trauma has relied on diffusion tensor imaging (DTI). Taber and Hurley26 and Hetherington et al27 provide good reviews of these studies. In general, the findings are diverse28–30 and are associated with many interpretative issues as discussed by others.26,27 Among the interpretative issues that have been identified are group-wise comparisons and varying regions of interest (ROI) examined in various studies rather than a focus on wholebrain studies in individual cases26 differences in metrics used to describe changes; lack of correlation of clinical symptoms with functions associated with specific tracts29 and the contribution of edema, hemorrhage, inflammation, and gliosis. Collectively, these studies have reported many regions of injury, including the middle cerebellar peduncles, cingular bundles, uncinate fasciculus, anterior limb of the internal capsule and orbitofrontal white matter, with lesser abnormalities in the corpus callosum and posterior limb of the internal capsule.29 Additional abnormalities are reported in the right corticospinal tract, bilateral inferior frontal occipital fasciculus, bilateral inferior longitudinal fasciculus, and left superior longitudinal fasciculus.28,30 A fluorodeoxyglucose positron emission tomography (FDG-PET) study also reports cerebellar white matter lesions.31 Allowing for the interpretative issues of DAI studies, what seems to emerge is that there may be abnormalities in several axonal tracts and thus the presence of diffuse axonal injury. To histopathologically assess axonal injury patterns in response to pure explosive blast shockwave pressure, studies were undertaken with large animal models (Yorkshire swine and Yucatan minipigs) exposed to blast pressure waves under controlled conditions in three operationally relevant scenarios—shock tube to simulate free field conditions, mock high mobility multipurpose wheeled vehicle (HUMVEE) to simulate a commonly used U.S. military vehicle, and a four-walled concrete structure to simulate a typical building.32 The animals were protected so that only the head was exposed directly to explosive blast and was constrained to minimize head accelerations. The distribution of injured axons was examined with β-APP immunohistochemistry on formaldehyde fixed paraffin embedded sections. The most prominent location of β-APP positive injured axons was around the lateral ventricles, extending out 200 µm from the ventricular border. This periventricular axonal injury was observed in
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
14
animals in all three scenarios. It was detected as early as 2 weeks and up to 8 months postblast, when the studies were terminated. Periventricular axonal injury was more prominent in the rostral half of the brain, and the density increased with a second and third exposure. Interestingly, no β-APP positive axons were observed in the major white matter tracts, which are commonly associated with DAI. A few β-APP positive axons were seen in the cerebellum of only 2 of 40 explosive blast animals examined. This pattern of immunostaining is a distinctive feature of explosive blast, compared with β-APP staining in direct head-impact trauma.
Neuron Cell Body Injury Whereas considerable attention is paid to CHI axonal injury, evidence for changes in the number and size of neurons is lacking. Maxwell and colleagues address this deficiency via a stereological study of the cerebral cortex after TBI.33 Using an archival source of TBI brains that had been carefully handled and preserved to minimize artifacts such as dark neurons, they compared brains from patients labeled as “Moderately Disabled,” “Severely Disabled,” and “Vegetative State” on the basis of the Glasgow Outcome Scale (GOS) and DAI presence. All of these cases would be equivalent to moderate and severe TBI. The patients were mostly men, with no significant difference in age between groups. The neuronal distribution in the ventromedial and dorsolateral prefrontal cortex, anterior cingulate, and motor cortices across the groups was compared. There is a significant thinning of gray matter in all four cortical areas compared with controls, with greater thinning in some areas in patients with DAI compared with those without. Comparing the thickness of individual cortical layers, thinning of different layers in the four cortical areas was found, with greater thinning seen with DAI in some cortical areas. In this regard, there is variability between cortical areas and subject groups.33 Additionally, there is a greater loss of large pyramidal and nonpyramidal neurons with a more severe score on the GOS from all four cortical regions, with the greatest loss of neurons in the prefrontal cortex of patients with DAI. Further, there is a reduced density of neurons across all subject groups. This analysis suggests a loss of neuron cell bodies in cortical areas of the moderate to severely traumatized brains. No neuronal number assessments were made in deeper brain structures such as the hippocampus, or in brains with mTBI. For explosive blast TBI, to evaluate the presence of neuronal injury, magnetic resonance spectroscopic imaging (MRSI) studies have proven useful: MRSI studies focus on the measurement of millimolar concentrations of low-molecularweight molecules. These molecules include N-acetyl-acetate (NAA) a compound found only in neurons,34 choline, a trimethylamine that is associated with membrane damage and repair35 and creatine, both phosphorylated and unphosphorylated forms of phosphocreatine, the primary buffer for ATPrequiring processes.27 Reductions in NAA are typically interpreted as reflecting neuronal loss or injury. In contrast, choline increases are seen in diseases that result in axonal damage.27 Recently, MRSI studies done in veterans exposed to an explosive blast and with a history of self-reported memory impairment found significant reductions in the ratio of NAA
de Lanerolle et al.
to choline (Ch) and NAA/Cr in the anterior hippocampus. Metabolite ratio reductions in the right hippocampus were more extensive than in the left. Hippocampal volume measurements revealed that the right hippocampus was 20% smaller than the left. These findings suggest neuronal injury in the hippocampus. These changes were independent of comorbidities such as posttraumatic stress disorder (PTSD) and depression.27,36,37 These hippocampal changes in mTBI were associated with reductions in visual memory.36 As a means of confirming that such reductions in metabolite ratios were indeed associated with neuronal injury, swine exposed to pure blast pressure waves were studied with MRSI at 2 weeks, 1 month, and 8 months postblast. At the 8-month time point, statistically significant decreases in the NAA/Ch ratio were observed in the hippocampus, but not in the thalamus, basal ganglia, or cortex. Neuropathological studies performed at 8 months postblast and neuron density estimates revealed a significant decrease in neurons in hippocampus area CA1 compared with controls (15%), with an almost significant decrease in area CA4 (32 and unpublished data). Thus, even mTBI is associated with neuronal injury in functionally critical areas, but the injury to the brain may not be as extensive as in moderate to severe trauma.
Microglial Activation There have been few pathological studies that have examined the activation of microglia in human TBI brains. Studies of diffuse axonal injury in moderate to severe impact CHI TBI have reported the presence of small clusters of microglia in the white matter.6 Smith and colleagues38 have reported on the expression of activated astrocytes in 99 TBI patients, 57 of whom survived for < 12 months, and 42 for longer terms. Of this population, 37 had severe TBI (GCS 8), 3 with moderate TBI (GCS 9–12) and 3 with mTBI (GCS 13–15). In 11 of these cases, TBI appears to be moderate or severe, but there is no clear indication to confirm this. Patients were compared with age-matched controls without TBI or other neurologic disease. The study seemed to focus on the severe to mTBI groups as a whole, with little indication of differences in the mild group. Immunohistochemistry for activated microglia was performed with two antibodies: anti-CD68, which recognizes microglia with phagocytic function; and anti-CR3/43, which recognizes microglia with class II MHC. The expression of microglia in the hippocampus, inferior temporal gyrus, corpus callosum, and cingulate gyrus was studied.38 They found that the postmortem interval and period of formalin fixation had no influence on immunostaining for these markers. CR3/ 34 immunostaining revealed that survivors > 1 year had lower expression levels than < 1-year survivors and controls, whereas CD68 immunostains failed to show any statistical differences between > 1-year survivors, < 1-year survivors and controls. In general, microglial activation is thought to decrease from control levels in the first 24 hours, then increase to a maximum around 3 hours and then decrease again, with greater activation seen in those with DAI compared with those without. The expression of activated microglia or a surrogate maker for them has not been studied in humans who have suffered Seminars in Neurology
Vol. 35
No. 1/2015
15
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Neuropathology of Traumatic Brain Injury
Neuropathology of Traumatic Brain Injury
de Lanerolle et al.
mTBI. Though ligands exist (e.g., translocator protein) for PET imaging of microglial and astrocyte activation associated with inflammation, such studies are unavailable for TBI cases. Microglial activation was examined in a swine model of explosive blast mTBI.32 Immunostaining for microglia performed with two markers, CD68 and ionized calcium-binding adaptor molecule 1 (Iba-1), showed the same pattern of staining. Morphologically recognizable activated microglia (more numerous, enlarged nuclei and somata, increased processes and some with rod-like shape) are seen in the central white matter and corpus callosum of explosive blast exposed animals, even though injured axons were not seen in these areas. The hippocampus and superior frontal cortex did not show activated microglia. There was no morphologic evidence of activated phagocytic microglia (cells with shortened processes that are rounded or ameboid) even in white matter areas in which other signs of microglial activation were noted. This is consistent with the absence of axonal injury in these areas.32 In general, activated microglia are interpreted as evidence of an inflammatory response, releasing several factors including pro- and anti-inflammatory cytokines, chemokines, and other molecules, modulating secondary injury and recovery after injury.2,39 However, recent research shows that microglia participate in a wide variety of functions, some in conjunction with innate immune mechanisms leading to neural network reorganization.40 The role activated microglia play in traumatic brain injury remains an important area of research.
Astrocyte Activation Astrocytes are an important cellular component of the brain and play an important role in normal neural function as well as influencing brain injury and recovery. Experimental animal studies have found that astrocyte activation is a prominent feature of CHI TBI. Controlled cortical impact-induced brain injury in mice produced not only neuronal damage, but also astrogliosis.41,42 In a study of swine exposed to explosive blast pressure waves, glial fibrillary acidic protein (GFAP) immunostaining revealed a significant increase in activated astrocytes in the hippocampus and cortical gray and white matter in the parasagittal cortices, including the cingulate gyri, superior, middle and inferior frontal gyri, and corpus callosum. The density of activated astrocytes in the hippocampus of blastexposed animals was higher than in controls, and in animals with repeat blast exposure higher than with a single exposure. The activated astrocytes are found in areas they are not normally found or at best weakly expressed, such as in gray matter. The new astrocytes have a distinctive stellate appearance, with the processes of adjacent astrocytes not overlapping and maintaining a tiled appearance,32 in contrast to astrocytes that are seen in areas of dense neuronal injury where their processes interdigitate. Such a pattern of astrogliosis has not been reported in human patients with mTBI, although increased GFAP is reported in athletes with chronic traumatic encephalopathy (CTE) consequent to multiple traumatic experiences. Seminars in Neurology
Vol. 35
No. 1/2015
Cerebrovascular Injury following PHI and CHI Cerebrovascular injury and hemorrhage commonly accompany PHI and severe head trauma resulting from head impact or an explosive blast. Armonda and coworkers43,44 report that a significant number of patients with severe TBI resulting from a blast or high-velocity gunshot wounds to the head develop some form of vascular injury—pseudoaneurysms, subarachnoid hemorrhage, and other hemorrhages (epidural, subdural, intraventricular hemorrhages), with a significantly large number showing traumatic cerebral vasospasm (TCV). Traumatic cerebral vasospasm is the reduction in the normal caliber of a blood vessel by smooth muscle contraction, resulting in increased blood flow velocity.43 Traumatic cerebral vasospasm is associated with both blunt and penetrating brain injury in 30 to 40% of cases (studies summarized in43). A low GCS score and the presence of subarachnoid hemorrhage are strongly predictive of TCV. Ischemic damage is also significantly high ( 90%) in a group of 635 patients with fatal, nonmissile head injury, and survival times of 1 hour to 14 years.45 At the cellular level, an ischemic cascade results in free radical release, which results in the breakdown of neuronal membranes that trigger an inflammatory response, the release of excitotoxic amino acids (glutamate), an increase in intracellular calcium, and eventually neuronal death.46 Ischemic brain damage is believed to be an important cause of mortality.45 Cerebrovascular injury is less common in mTBI. Head computed tomography examinations of patients with mild or minor complicated TBI were typically negative on the first day after the event.47 In approximately 20% of cases that were subsequently positive, the abnormalities were subtle, seen as petechial hemorrhages, mild edema, and/or small contusions.48,49 In another study of mTBI patients, although DAI was found in 29%, none had evidence of hemosiderin, suggesting that they were all nonhemorrhagic lesions. In a subgroup of 32%, dilated perivascular (Virchow-Robin) spaces were detected, and were commonly located in the parietal subcortical white matter.50 In an experimental model of mild TBI produced in swine exposed to pure blast pressure waves in three operationally relevant scenarios, no evidence of hemorrhage was observed, even 8 months postblast (32 and unpublished findings). However, in an experimental study of nonhuman primates to lateral head acceleration, subtle cellular evidence of vascular changes were reported.51 Three types of changes in cellular morphology were observed: (1) ultrastructural evidence of lucency and enlargement of perivascular astrocyte foot processes; (2) development of microvilli on the luminal endothelial surface; and (3) numerical changes in the number of pinocytotic vesicles, a component of transendothelial transport. Some of these changes resolved over time.
Tau Expression and Chronic Traumatic Encephalopathy A meta-analysis of 15 case-controlled studies of patients with TBI estimated that 50% of those who suffered loss of consciousness were at increased risk of Alzheimer-type dementia.52 Additionally, the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology) study found that the
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
16
Neuropathology of Traumatic Brain Injury
17
blast pressure. Thus, the evidence that explosive blast results in CTE is weak. Studies of a large animal model (swine) exposed to pure blast pressure did not show any hyperphosphorylated tau or β-amyloid, even as late as 8 months postblast.
Comparisons Despite the many studies being done on the neuropathology of TBI in animal models, the neuropathology of human TBI remains incompletely understood. However, even with the limited data available, it can be discerned that there are similarities and differences between the neuropathology resulting from the differing TBI etiologies. Penetrating head injury and moderate to severe CHI are more likely than mTBI to cause disruption in the cerebral vasculature. Bissett46 identified some points for comparison. Penetrating injuries from missiles may cause petechial and linear hemorrhages. With the destruction of the vasculature, contusions and hemorrhages form rapidly, and edema may begin as early as 30 minutes after injury.46,62 Stab wound injuries lead to hemorrhage and related mass effect, whereas gunshot wounds result in cerebral edema.46,62 At the cellular level, an ischemic cascade similar to that with nonpenetrating closed head trauma can occur.45 Unlike CHI, PHI can cause bleeding that results in hypovolemic hypotension, hemorrhagic shock, and cardiopulmonary arrest.46,62 In contrast to PHI and moderate or severe CHI, mTBI is associated with little or no vascular injury, and rarely even petechial hemorrhages are observed. Axonal injury occurs in PHI and is similar to classical DAI6 described in moderate to severe CHI. It is unclear from the literature if such a pattern is also present in impact mTBI. On the contrary, the distributional pattern of injured axons in explosive blast mTBI is likely (on the basis of animal experiments) to be quite different, and is found at the interface of brain parenchyma and cerebrospinal fluid periventricularly. Studies are unavailable to confirm this pattern in human mTBI. Glial fibrillary acidic protein-positive astrocyte activation and proliferation is increased in models of mTBI, where the astrocytes retain a more normal tiled appearance rather than the morphology associated within regions of neuronal injury, where they have long intertwining processes that form a glial scar. Such scars are more common in moderate and severe TBI. Reactive astrocytes in mTBI may play a role in inflammatory processes by releasing a variety of inflammatory molecules.63 Microglial activation appears to be limited in mTBI compared with severe and moderate TBI in animal models. However, the expressions of activated astrocytes and microglia have not been investigated in mTBI in humans. In summary, the review of studies on the neuropathology of TBI suggests that the pathological profiles of severe and moderate CHI may differ from mTBI, as the former shows extensive neuronal injury while mTBI may have limited neuronal injury but increased glial activation. Furthermore, the neuropathology of mTBI resulting from explosive blast may have a distinctive neuropathological profile. Seminars in Neurology
Vol. 35
No. 1/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
odds ratio for dementia after head trauma with loss of consciousness was double that for TBI without loss of consciousness.53 Moderate and severe head injury, but not mTBI, were associated with an increased risk of Alzheimer disease (AD).54 Multiple mTBIs, such as in professional athletes, are associated with a clinical entity described as chronic traumatic encephalopathy (CTE), formerly called “punch drunk” or dementia pugilistica. Chronic traumatic encephalopathy was recently suggested to also be present in veterans exposed to explosive blast.55 The pathological signs of CTE are thought to resemble those in AD.56 McKee et al57 reviewed 48 published cases of neuropathologically verified CTE as well as three of their own cases, and classified CTE as a distinct disease state. Histopathologically, they identify neuronal loss and gliosis in the hippocampus, substantia nigra, and cerebral cortex, with mammillary bodies, medial thalamus, locus ceruleus, and nucleus accumbens also susceptible to neuronal loss. Chronic traumatic encephalopathy is classified as a neurodegenerative tauopathy. Tauopathy is a condition associated with hyperphosphorylated tau proteins that aggregate to form neurofibrillary tangles (NFTs). Tau immunohistochemical localization studies show that the protein tangles in CTE are similar to those in AD.58 However, the distribution of tau protein is different in CTE compared with AD. In CTE the tau protein is distributed in multiple foci, often dense in superficial layers (layers II and III) of the cortex and usually around blood vessels. This is in contrast to AD, where tau protein is less dense and preferentially located in deeper layers V and VI.59 β-amyloid is not commonly seen in CTE. Goldstein et al60 reported on postmortem examination of four men (22–45 years of age) with a history of exposure to explosive blast. Two were comorbid with PTSD and had a prior history of mTBI at an early age, whereas the other two had no PTSD and only one with a previous history of concussion. Their brains were compared with brains of subjects without a history of explosive blast exposure and athletes with history of head impact. The scope of the study was narrow, with the focus mostly on the expression of phosphorylated and nonphosphorylated tau proteins. In the subjects with explosive blast exposure and/or impact, perivascular foci of tau-immunoreactive neurofibrillary tangles (NFTs) and glial tangles in the inferior frontal, dorsolateral frontal, parietal and temporal cortices, particularly near sulcal depth, were reported. Phosphorylated tau immunoreactive dystrophic axons and NFTs were also found in the superficial layers of the frontal and parietal cortices and the hippocampus. Tau immunoreactive degenerating axons, axon retraction bulbs, and axon dystrophy were observed in subcortical white matter adjacent to cortical tau pathology and perivascular areas. Immunoreactive activated clusters of microglia were also reported in subcortical white matter underlying focal tau pathology, but not in unaffected brain regions. Commenting on the Goldstein study,60 Tsao61 points out some limitations. Three of the four patients studied had a previous medical history of concussion, and the fourth had injuries severe enough to cause concussion. Therefore, it is possible that the phosphorylated tau deposition seen in these patients was due to secondary head impact and not explosive
de Lanerolle et al.
Neuropathology of Traumatic Brain Injury
de Lanerolle et al.
References
23 Mott FW. The microscopic examination of the brains of two men
1 Teasdale G, Jennett B. Assessment of coma and impaired con2
3 4
5
6
7
8
9
10 11
12
13
14
15
16
17
18
19
20
21
22
sciousness. A practical scale. Lancet 1974;2(7872):81–84 Smith C. Review: the long-term consequences of microglial activation following acute traumatic brain injury. Neuropathol Appl Neurobiol 2013;39(1):35–44 Blennow K, Hardy J, Zetterberg H. The neuropathology and neurobiology of traumatic brain injury. Neuron 2012;76(5):886–899 Blumbergs PC, Reilly P, Vink R. Trauma. In: Love S, Jouis DN, Ellison DW, eds. Greenfields Neuropathology. London, UK: Edward Arnold; 2008:733–832 Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ. Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury. J Neurotrauma 1995;12(4):565–572 Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI, McLellan DR. Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology 1989;15(1):49–59 Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, Roberts GW. Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett 1993;160(2):139–144 Hortobágyi T, Wise S, Hunt N, et al. Traumatic axonal damage in the brain can be detected using beta-APP immunohistochemistry within 35. min after head injury to human adults. Neuropathol Appl Neurobiol 2007;33(2):226–237 Geddes JF, Whitwell HL, Graham DI. Traumatic axonal injury: practical issues for diagnosis in medicolegal cases. Neuropathol Appl Neurobiol 2000;26(2):105–116 Cammermeyer J. The importance of avoiding “dark” neurons in experimental neuropathology. Acta Neuropathol 1961;1:245–270 Jortner BS. The return of the dark neuron. A histological artifact complicating contemporary neurotoxicologic evaluation. Neurotoxicology 2006;27(4):628–634 Oehmichen M, Meissner C, König HG. Brain injury after gunshot wounding: morphometric analysis of cell destruction caused by temporary cavitation. J Neurotrauma 2000;17(2):155–162 Oehmichen M, Meissner C, König HG. Brain injury after survived gunshot to the head: reactive alterations at sites remote from the missile track. Forensic Sci Int 2001;115(3):189–197 Oehmichen M, Meissner C, König HG, Gehl H-B. Gunshot injuries to the head and brain caused by low-velocity handguns and rifles. A review. Forensic Sci Int 2004;146(2-3):111–120 Koszyca B, Blumbergs PC, Manavis J, et al. Widespread axonal injury in gunshot wounds to the head using amyloid precursor protein as a marker. J Neurotrauma 1998;15(9):675–683 Bakir A, Temiz C, Umur S, Aydin V, Torun F. High-velocity gunshot wounds to the head: analysis of 135 patients. Neurol Med Chir (Tokyo) 2005;45(6):281–287, discussion 287 Adams JH, Graham DI, Scott G, Parker LS, Doyle D. Brain damage in fatal non-missile head injury. J Clin Pathol 1980;33(12): 1132–1145 Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ. Staining of amyloid precursor protein to study axonal damage in mild head injury. Lancet 1994;344(8929):1055–1056 Stevens MC, Lovejoy D, Kim J, Oakes H, Kureshi I, Witt ST. Multiple resting state network functional connectivity abnormalities in mild traumatic brain injury. Brain Imaging Behav 2012;6(2):293–318 Ling G, Eklund J, Bandak FA. Blast brain injury from explosive blast: description and clinical management. In: Grafman J, Salazar AM, eds. Handbook of Clinical Neurology. Amsterdam: Elsevier; 2015 Cramer F, Paster S, Stephenson C. Cerebral injuries due to explosion waves, cerebral blast concussion; a pathologic, clinical, and electroencephalographic study. Archives Neurol Psychiatr 1949; 61:1–20 Hirsch AE, Ommaya AK. Head injury caused by underwater explosion of a firecracker. Case report. J Neurosurg 1972;37(1): 95–99
Seminars in Neurology
Vol. 35
No. 1/2015
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39 40 41
42
43
44
dead of commotio cerebri (shell shock) without visible external injury. J R Army Med Corps 1917;29:662–677 Murthy JM, Chopra JS, Gulati DR. Subdural hematoma in an adult following a blast injury. Case report. J Neurosurg 1979;50(2): 260–261 Taber KH, Warden DL, Hurley RA. Blast-related traumatic brain injury: what is known? J Neuropsychiatry Clin Neurosci 2006; 18(2):141–145 Taber KH, Hurley RA. Update on mild traumatic brain injury: neuropathology and structural imaging. J Neuropsychiatry Clin Neurosci 2013;25(1):1–5 Hetherington HP, Bandak A, Ling G, Bandak F. Advances in imaging explosive blast mild traumatic brain injury. In: Grafman J, Salazar AM, eds. Handbook of Clinical Neurology. Netherlands: Elsevier; 2015: In press Davenport ND, Lim KO, Armstrong MT, Sponheim SR. Diffuse and spatially variable white matter disruptions are associated with blast-related mild traumatic brain injury. Neuroimage 2012;59(3): 2017–2024 Mac Donald CL, Johnson AM, Cooper D, et al. Detection of blastrelated traumatic brain injury in U.S. military personnel. N Engl J Med 2011;364(22):2091–2100 Morey RA, Haswell CC, Selgrade ES, et al. Effects of chronic mild traumatic brain injury on white matter integrity in Iraq and Afghanistan war veterans. Hum Brain Mapp 2013;34(11): 2986–2999 Peskind ER, Petrie EC, Cross DJ, et al. Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war Veterans with persistent post-concussive symptoms. Neuroimage 2011;54(Suppl 1):S76–S82 de Lanerolle NC, Bandak F, Kang D, et al. Characteristics of an explosive blast-induced brain injury in an experimental model. J Neuropathol Exp Neurol 2011;70(11):1046–1057 Maxwell WL, MacKinnon M-A, Stewart JE, Graham DI. Stereology of cerebral cortex after traumatic brain injury matched to the Glasgow outcome score. Brain 2010;133(Pt 1):139–160 Urenjak J, Williams SR, Gadian DG, Noble M. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993;13(3):981–989 Brooks WM, Friedman SD, Gasparovic C. Magnetic resonance spectroscopy in traumatic brain injury. J Head Trauma Rehabil 2001;16(2):149–164 de Lanerolle NC, Hamid H, Kulas J, et al. Concussive brain injury from explosive blast. Ann Clin Transl Neurol 2014;1(9): 692–702 Hetherington HP, Hamid H, Kulas J, et al. MRSI of the medial temporal lobe at 7T in explosive blast mild traumatic brain injury. Magn Reson Med 2014;71:1358–136710.1002/mrm.24814 Smith C, Gentleman SM, Leclercq PD, et al. The neuroinflammatory response in humans after traumatic brain injury. Neuropathol Appl Neurobiol 2013;39(6):654–666 Loane DJ, Byrnes KR. Role of microglia in neurotrauma. Neurotherapeutics 2010;7(4):366–377 Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science 2013;339(6116):156–161 Garman RH, Jenkins LW, Switzer RCI III, et al. Blast exposure in rats with body shielding is characterized primarily by diffuse axonal injury. J Neurotrauma 2011;28(6):947–959 Kernie SG, Erwin TM, Parada LF. Brain remodeling due to neuronal and astrocytic proliferation after controlled cortical injury in mice. J Neurosci Res 2001;66(3):317–326 Armonda RA, Bell RS, Vo AH, et al. Wartime traumatic cerebral vasospasm: recent review of combat casualties. Neurosurgery 2006;59(6):1215–1225, discussion 1225 Ling G, Bandak F, Armonda R, Grant G, Ecklund J. Explosive blast neurotrauma. J Neurotrauma 2009;26(6):815–825
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
18
Neuropathology of Traumatic Brain Injury
46 47
48
49
50
51
52
53 54
common in fatal non-missile head injury. J Neurol Neurosurg Psychiatry 1989;52(3):346–350 Blissitt PA. Care of the critically ill patient with penetrating head injury. Crit Care Nurs Clin North Am 2006;18(3):321–332 Bigler ED, Maxwell WL. Neuropathology of mild traumatic brain injury: relationship to neuroimaging findings. Brain Imaging Behav 2012;6(2):108–136 Iverson GL, Lovell MR, Smith S, Franzen MD. Prevalence of abnormal CT-scans following mild head injury. Brain Inj 2000;14(12): 1057–1061 Smits M, Hunink MG, van Rijssel DA, et al. Outcome after complicated minor head injury. AJNR Am J Neuroradiol 2008;29(3): 506–513 Orrison WW, Hanson EH, Alamo T, et al. Traumatic brain injury: a review and high-field MRI findings in 100 unarmed combatants using a literature-based checklist approach. J Neurotrauma 2009; 26(5):689–701 Maxwell WL, Whitfield PC, Suzen B, et al. The cerebrovascular response to experimental lateral head acceleration. Acta Neuropathol 1992;84(3):289–296 Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry 2003; 74(7):857–862 Guo Z, Cupples LA, Kurz A, et al. Head injury and the risk of AD in the MIRAGE study. Neurology 2000;54(6):1316–1323 Plassman BL, Havlik RJ, Steffens DC, et al. Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 2000;55(8):1158–1166
19
55 Miller G. Neuropathology. Blast injuries linked to neurodegenera-
tion in veterans. Science 2012;336(6083):790–791 56 Lakis N, Corona RJ, Toshkezi G, Chin LS. Chronic traumatic enceph-
57
58
59
60
61
62
63
alopathy - neuropathology in athletes and war veterans. Neurol Res 2013;35(3):290–299 McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 2009;68(7):709–735 Schmidt ML, Zhukareva V, Newell KL, Lee VM, Trojanowski JQ. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer’s disease. Acta Neuropathol 2001;101(5): 518–524 Hof PR, Delacourte A, Bouras C. Distribution of cortical neurofibrillary tangles in progressive supranuclear palsy: a quantitative analysis of six cases. Acta Neuropathol 1992;84(1):45–51 Goldstein LE, Fisher AM, Tagge CA, et al. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 2012;4(134): 134ra60 Tsao JW. Comment on “chronic traumatic encephalopathy in blastexposed military veterans and a blast neurotrauma mouse model”. Sci Transl Med 2012;4(157):157le7, author reply 157lr5 Campbell GA. The pathology of penetrating wounds of the brain and its enclosures. In: Aarabi B, Kaufman HH, eds. Missile wounds of the head and neck. Park Ridge, IL: American Association of Neurological Surgeons; 1999:73–89 Ahmed F, Gyorgy A, Kamnaksh A, et al. Time-dependent changes of protein biomarker levels in the cerebrospinal fluid after blast traumatic brain injury. Electrophoresis 2012;33(24): 3705–3711
Seminars in Neurology
Vol. 35
No. 1/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
45 Graham DI, Ford I, Adams JH, et al. Ischaemic brain damage is still
de Lanerolle et al.
Copyright of Seminars in Neurology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Neuropathology of Traumatic Brain Injury: Comparison of Penetrating, Nonpenetrating Direct Impact and Explosive Blast Etiologies Jung H. Kim, MD2
1 Department of Neurosurgery and Neurobiology, Yale School of
Medicine, New Haven, Connecticut 2 Department of Pathology, Yale School of Medicine, New Haven, Connecticut 3 Department of Neurology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland
Faris A. Bandak, PhD3 Address for correspondence Nihal C. de Lanerolle, D Phil, DSc, Department of Neurosurgery, Yale School of Medicine, FMB414, 333 Cedar Street, New Haven, CT 06520-8082 (e-mail: [email protected]).
Semin Neurol 2015;35:12–19.
Abstract Keywords
► ► ► ► ► ► ► ► ►
traumatic brain Injury neuropathology penetrating injury closed head injury explosive blast concussion microglia astrocytes diffuse axonal injury
The neuropathology of traumatic brain injury (TBI) from various causes in humans is not as yet fully understood. The authors review and compare the known neuropathology in humans with severe, moderate, and mild TBI (mTBI) from nonpenetrating closed head injury (CHI) from blunt impacts and explosive blasts, as well as penetrating head injury (PHI). Penetrating head injury and CHI that are moderate to severe are more likely than mTBI to cause gross disruption of the cerebral vasculature. Axonal injury is classically exhibited as diffuse axonal injury (DAI) in severe to moderate CHI. Diffuse axonal injury is also prevalent in PHI. It is less so in mTBI. There may be a unique pattern of periventricular axonal injury in explosive blast mTBI. Neuronal injury is more prevalent in PHI and moderate to severe CHI than mTBI. Astrocyte and microglial activation and proliferation are found in all forms of animal TBI models and in severe to moderate TBI in humans. Their activation in mTBI in the human brain has not yet been studied.
Traumatic brain injury (TBI) can be penetrating (PHI) or nonpenetrating/blunt in nature. A penetrating head injury (PHI) is when the skull and dura are breached by a foreign body. This can be from a slow moving object such as a knife or a fast moving one such as a bullet. A slow-moving sharp foreign body will pass through the skull and dura and cause damage along its line of travel. This will lead to slicing, shearing, and compression of brain along the track. A fastmoving foreign body, such as a bullet, will do the same, but also creates a shock wave causing high pressures to transmit through the brain before the penetrating phase ensues. During penetration, the bullet slices through the brain, creating a somewhat conical cavity rapidly pushing the brain parenchyma outwards away from the bullet path. Such cavities can be twice the diameter of the bullet to as much as 15 times for extremely high-velocity rifle bullets. Extremely
Issue Theme Traumatic Brain Injury; Guest Editor, Geoffrey Ling, MD, PhD, FAAN, FANA
high velocities are typically those exceeding the speed of sound. Therefore, the brain is not only damaged by the slicing effect, but also by the tissue deformation from the expansion and contraction of the cavity. This includes disruption of the parenchyma and vascular structures. For slow or unstable bullets, other types of brain damage occur, for instance, when a relatively low-velocity bullet does not have enough energy to exit the skull and bounces off the interior side of the skull back into the brain. Explosive blast devices can lead to PHI when fragments from the device’s casing and other ejecta (such as rocks) penetrate the cranium and brain parenchyma. Penetrating wounds from fragments from an explosive device produce damage from somewhat slower projectiles than those of bullet wounds. Differences are primarily due to the shape and velocity of the impacting projectile. This is because explosive fragments are not as aerodynamically efficient as
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1544240. ISSN 0271-8235.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Nihal C. de Lanerolle, D Phil, DSc1
Neuropathology of Traumatic Brain Injury
13
neuropathological examinations are conducted also may influence the observations.
Penetrating Brain Injury The most common form of penetrating brain injury is from projectiles. Typically, a low-velocity projectile passing through the brain creates a cavity along its path, in which brain tissue, including blood vessels, is destroyed. Histological investigation around the missile track shows many patterns. Oehmichen and coworkers12–14 have described in some detail the histopathological changes in the cavity zone. In the region immediately adjacent to the permanent track is a zone of bleeding where there is almost total destruction of neurons, axons, and astrocytes.14 In this necrotic zone are found polymorphonuclear leukocytes (PMNs), but no macrophages or β-APP positive axons during the first 24 hours postinjury. Surrounding this necrotic area is a zone scattered with axonal fragments as well as injured and deformed neurons showing hyperchromasia and vacuolation. Macrophages are also seen in this zone (outside the necrotic area) and are conspicuous only in edematous areas.13 With progressive distance from the cavity, neuronal cell bodies, axons, and astrocytes appear more normal. For instance, in a sample of 20 victims with gunshot injuries from low-velocity projectiles, Oehmichen and coworkers calculate that a zone of 3.6 cm around the permanent track corresponds to a “temporary cavity.”14 This temporary cavity is not associated with hypoxic or edematous changes.12 More widely distributed histopathological changes are reported in brains with penetrating trauma, in addition to those associated with the track of the projectile. β-APP positive axons are distributed widely within neural tissue and appear as parallel wave-like patterns and irregular aggregations of axons and axon fragments in areas with edematous changes.13 These changes are reported to be dependent on survival time. Injured axons appear predominantly as β-APP positive fibers and rarely as axon bulbs.13 Axonal injury is widespread throughout the hemispheres,15 and is detected as far as the brainstem (midbrain, pons, medulla, and cerebellum). Ischemic injury, detected as red neurons in H&E stains, is also observed.15 Leukocytes and macrophages are not found distant to the bullet track.13 Hemorrhages associated with cortical “contusions” in the cerebral hemispheres,14 in the brainstem, and subarachnoid and intraventricular spaces, are also reported.15 High-velocity bullets produce large and distant tissue damage. Such injury is more extensive than the track of the bullet.16 A fuller discussion of the extent of injury with highvelocity bullets can be found in Bakir et al.16
Closed Head Injury from Impact and Explosive Blast Axonal Injury Diffuse axonal injury is recognized as a TBI hallmark pathological lesion. It has been classically defined as “the occurrence of diffuse damage to axons in the cerebral hemispheres, Seminars in Neurology
Vol. 35
No. 1/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
bullets and tend to lose energy due to air friction. Consequently, they do less damage at comparable distances from the source than bullets. Nonpenetrating brain injury, generally referred to as a closed head injury (CHI), is defined as a brain injury without a dural breach.1 Closed head injury occurs when there is impact to the head following direct contact with a blunt object as opposed to a sharp object. Closed head injury can also be from explosive blast injury, where there is direct loading on the head through shock-wave pressures. Clinically, TBI is typically categorized according to the resulting loss of consciousness and based on the Glasgow Coma Scale (GCS). A GCS score of 13 to 15 is recognized as mild TBI (mTBI), 9 to 12 as moderate, and 8 as severe trauma.1 A study of over 1 million trauma patients in the United Kingdom found approximately 90% had mTBI, 5% moderate, and 5% severe.2 Several comprehensive reviews of TBI have been published.3,4 Here we briefly review the neuropathology of impact and explosive blast penetrating and nonpenetrating TBI, and devote some attention to the mild components of nonpenetrating TBI, which continues to be a focus of considerable emerging research. Neuropathological investigations of TBI have typically focused on changes in several histological components of the brain: neurons (cell bodies and axons), vasculature, and nonneural cellular components (microglia and astrocytes). Interpreting the reported literature requires a subtle combination of finesse and caution. Among others, axonal injury is a feature often reported. A variety of methods have been utilized in studies, including immunostaining methods employing antibodies to β-amyloid precursor protein (β-APP), neurofilament proteins (NF), tau protein, and silver impregnation staining methods. The range of axonal injury visible with immunostaining methods is different from that seen with silver impregnation methods, although there is some overlap.4,5 For instance, DAI is detected with silver impregnation in approximately 30% of fatal head injuries, but almost universally demonstrable by β-APP immunostaining,6,7 and as early as 35 minutes after severe head injury.8 Further, early silver impregnation techniques could not reliably identify axonal injury in patients with survival times < 18 hour. It is now clear that silver positive swellings and retraction bulbs identify only a subset of injured axons.4 Like traditional silver staining, β-APP immunostaining also has limitations in its ability to distinguish between axonal injury due to ischemia and axonal injury due to mechanical deformation. 4,5 This distinction is important, as ischemia is one of the secondary injuries associated with CHI and is reported in 88% of fatal head injuries.9 Caution is required in examining hematoxylin and eosin (H&E) stained sections for injured neurons, sometimes identified as “dark neurons.”10 Dark neurons are a common artifact of manipulation of the brain without proper fixation.11 Therefore, details of histological procedures need to be examined. Similarly, “red neurons” are often the result of anoxic/ischemic changes and may not be directly attributable to trauma. Posttrauma survival time at which
de Lanerolle et al.
Neuropathology of Traumatic Brain Injury
de Lanerolle et al.
the corpus callosum, the brainstem and sometimes also in the cerebellum resulting from head injury.”6 Such injury can only be identified microscopically. Three grades of DAI have been recognized. Grade 1 is as defined above, with grade 2 having the additional feature of focal lesions in the corpus callosum, and grade 3 having focal lesions in the corpus callosum and in the brainstem.6 Much of the early work describing DAI is from patients with fatal head injury. In a study of 151 necropsies from patients with fatal nonmissile head injuries and survival times of 12 hours to 21 months,17 19 are reported to have diffuse damage to white matter. In those who survived many months after their injury, there is loss of white matter in the cerebral hemispheres and ventricular enlargement. In a comprehensive review of 434 fatal nonmissile head injury cases, Adams and coworkers6 point out some of the shortcomings in identifying DAI. The first is that sinusoidally enlarged axons, when present on their own, can be indistinguishable from postmortem artifact. Thus, DAI should not be assumed unless at least occasional axonal bulbs can be recognized. The second is that a lesion in the corpus callosum is not indicative of DAI because focal infarcts can be brought about by distortion and shifts of the brain caused by intracranial hematoma leading to compromised circulation. The third is that axonal bulbs are not restricted to head injury because they can occur in any situation in which axons are disrupted. There is little neuropathological information on mTBI in humans, as this condition is rarely fatal. There are, however, two studies of patients who suffered mTBI and died subsequently of other causes. In one study,18 the brains were examined of five patients aged 59 to 89 years, who sustained mTBI and died 2 to 99 days postinjury. They had concussive head injury of GCS 14 to15 with transient brief loss of consciousness. Axonal injury as seen by β-APP immunostaining was found in all five cases, located within the hippocampal fornices and corpus callosum. There was no evidence of hematoma, skull fracture, or prior cerebral infarctions. In a subsequent study,5 six cases with mTBI were compared with six cases with severe TBI (GCS 2–8). Both groups had axonal injury in the hippocampal fornices and corpus callosum, with additional axonal injury in the cerebellar peduncles in the severe trauma group alone. There was no β-APP stained axons in the controls. Only the mTBI group showed an absence of vascular damage. A whole-brain functional magnetic resonance imaging (fMRI) study of 30 patients with mTBI (GCS 13–15) compared their resting-state whole-brain functional connectivity (identified by independent component analysis [ICA] of fMRI data) with that of 30 controls.19 Abnormal functional connectivity in each of 12 separate networks was identified by ICA, and included visual processing, motor, limbic, and many circuits thought to be involved in executive cognition. Abnormalities not only included functional deficits, but also enhancements. Enhancements were found in a secondary visual processing network, the limbic circuit, and cingulo-opercular circuit, associated with mental set maintenance and cognitive control. There was no evidence of vascular-related damage to neurons associated with functional connectivity changes. Seminars in Neurology
Vol. 35
No. 1/2015
Such data suggest the possibility of changes in axonal pathways, but these remain to be confirmed histologically. The clinical features of explosive blast TBI are described by Ling and coworkers.20 Neuropathological findings from primary blast exposure in humans are limited because the condition is rarely fatal. The earliest studies on small cohorts21–24 report neuropathological features such as small hemorrhages in white matter, chromatologic changes indicative of neuronal injury, and subdural hemorrhage. Mott23 described an “extremely congested cortex,” enlargement of perivascular space, subpial hemorrhages, venous engorgement, and hemorrhage into myelin sheaths and perivascular spaces as microscopic features attributed to a blast.25 The degree of trauma in these patients is not clear. Evidence for axonal injury in patients with mTBI resulting from explosive blast (and blunt) trauma has relied on diffusion tensor imaging (DTI). Taber and Hurley26 and Hetherington et al27 provide good reviews of these studies. In general, the findings are diverse28–30 and are associated with many interpretative issues as discussed by others.26,27 Among the interpretative issues that have been identified are group-wise comparisons and varying regions of interest (ROI) examined in various studies rather than a focus on wholebrain studies in individual cases26 differences in metrics used to describe changes; lack of correlation of clinical symptoms with functions associated with specific tracts29 and the contribution of edema, hemorrhage, inflammation, and gliosis. Collectively, these studies have reported many regions of injury, including the middle cerebellar peduncles, cingular bundles, uncinate fasciculus, anterior limb of the internal capsule and orbitofrontal white matter, with lesser abnormalities in the corpus callosum and posterior limb of the internal capsule.29 Additional abnormalities are reported in the right corticospinal tract, bilateral inferior frontal occipital fasciculus, bilateral inferior longitudinal fasciculus, and left superior longitudinal fasciculus.28,30 A fluorodeoxyglucose positron emission tomography (FDG-PET) study also reports cerebellar white matter lesions.31 Allowing for the interpretative issues of DAI studies, what seems to emerge is that there may be abnormalities in several axonal tracts and thus the presence of diffuse axonal injury. To histopathologically assess axonal injury patterns in response to pure explosive blast shockwave pressure, studies were undertaken with large animal models (Yorkshire swine and Yucatan minipigs) exposed to blast pressure waves under controlled conditions in three operationally relevant scenarios—shock tube to simulate free field conditions, mock high mobility multipurpose wheeled vehicle (HUMVEE) to simulate a commonly used U.S. military vehicle, and a four-walled concrete structure to simulate a typical building.32 The animals were protected so that only the head was exposed directly to explosive blast and was constrained to minimize head accelerations. The distribution of injured axons was examined with β-APP immunohistochemistry on formaldehyde fixed paraffin embedded sections. The most prominent location of β-APP positive injured axons was around the lateral ventricles, extending out 200 µm from the ventricular border. This periventricular axonal injury was observed in
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
14
animals in all three scenarios. It was detected as early as 2 weeks and up to 8 months postblast, when the studies were terminated. Periventricular axonal injury was more prominent in the rostral half of the brain, and the density increased with a second and third exposure. Interestingly, no β-APP positive axons were observed in the major white matter tracts, which are commonly associated with DAI. A few β-APP positive axons were seen in the cerebellum of only 2 of 40 explosive blast animals examined. This pattern of immunostaining is a distinctive feature of explosive blast, compared with β-APP staining in direct head-impact trauma.
Neuron Cell Body Injury Whereas considerable attention is paid to CHI axonal injury, evidence for changes in the number and size of neurons is lacking. Maxwell and colleagues address this deficiency via a stereological study of the cerebral cortex after TBI.33 Using an archival source of TBI brains that had been carefully handled and preserved to minimize artifacts such as dark neurons, they compared brains from patients labeled as “Moderately Disabled,” “Severely Disabled,” and “Vegetative State” on the basis of the Glasgow Outcome Scale (GOS) and DAI presence. All of these cases would be equivalent to moderate and severe TBI. The patients were mostly men, with no significant difference in age between groups. The neuronal distribution in the ventromedial and dorsolateral prefrontal cortex, anterior cingulate, and motor cortices across the groups was compared. There is a significant thinning of gray matter in all four cortical areas compared with controls, with greater thinning in some areas in patients with DAI compared with those without. Comparing the thickness of individual cortical layers, thinning of different layers in the four cortical areas was found, with greater thinning seen with DAI in some cortical areas. In this regard, there is variability between cortical areas and subject groups.33 Additionally, there is a greater loss of large pyramidal and nonpyramidal neurons with a more severe score on the GOS from all four cortical regions, with the greatest loss of neurons in the prefrontal cortex of patients with DAI. Further, there is a reduced density of neurons across all subject groups. This analysis suggests a loss of neuron cell bodies in cortical areas of the moderate to severely traumatized brains. No neuronal number assessments were made in deeper brain structures such as the hippocampus, or in brains with mTBI. For explosive blast TBI, to evaluate the presence of neuronal injury, magnetic resonance spectroscopic imaging (MRSI) studies have proven useful: MRSI studies focus on the measurement of millimolar concentrations of low-molecularweight molecules. These molecules include N-acetyl-acetate (NAA) a compound found only in neurons,34 choline, a trimethylamine that is associated with membrane damage and repair35 and creatine, both phosphorylated and unphosphorylated forms of phosphocreatine, the primary buffer for ATPrequiring processes.27 Reductions in NAA are typically interpreted as reflecting neuronal loss or injury. In contrast, choline increases are seen in diseases that result in axonal damage.27 Recently, MRSI studies done in veterans exposed to an explosive blast and with a history of self-reported memory impairment found significant reductions in the ratio of NAA
de Lanerolle et al.
to choline (Ch) and NAA/Cr in the anterior hippocampus. Metabolite ratio reductions in the right hippocampus were more extensive than in the left. Hippocampal volume measurements revealed that the right hippocampus was 20% smaller than the left. These findings suggest neuronal injury in the hippocampus. These changes were independent of comorbidities such as posttraumatic stress disorder (PTSD) and depression.27,36,37 These hippocampal changes in mTBI were associated with reductions in visual memory.36 As a means of confirming that such reductions in metabolite ratios were indeed associated with neuronal injury, swine exposed to pure blast pressure waves were studied with MRSI at 2 weeks, 1 month, and 8 months postblast. At the 8-month time point, statistically significant decreases in the NAA/Ch ratio were observed in the hippocampus, but not in the thalamus, basal ganglia, or cortex. Neuropathological studies performed at 8 months postblast and neuron density estimates revealed a significant decrease in neurons in hippocampus area CA1 compared with controls (15%), with an almost significant decrease in area CA4 (32 and unpublished data). Thus, even mTBI is associated with neuronal injury in functionally critical areas, but the injury to the brain may not be as extensive as in moderate to severe trauma.
Microglial Activation There have been few pathological studies that have examined the activation of microglia in human TBI brains. Studies of diffuse axonal injury in moderate to severe impact CHI TBI have reported the presence of small clusters of microglia in the white matter.6 Smith and colleagues38 have reported on the expression of activated astrocytes in 99 TBI patients, 57 of whom survived for < 12 months, and 42 for longer terms. Of this population, 37 had severe TBI (GCS 8), 3 with moderate TBI (GCS 9–12) and 3 with mTBI (GCS 13–15). In 11 of these cases, TBI appears to be moderate or severe, but there is no clear indication to confirm this. Patients were compared with age-matched controls without TBI or other neurologic disease. The study seemed to focus on the severe to mTBI groups as a whole, with little indication of differences in the mild group. Immunohistochemistry for activated microglia was performed with two antibodies: anti-CD68, which recognizes microglia with phagocytic function; and anti-CR3/43, which recognizes microglia with class II MHC. The expression of microglia in the hippocampus, inferior temporal gyrus, corpus callosum, and cingulate gyrus was studied.38 They found that the postmortem interval and period of formalin fixation had no influence on immunostaining for these markers. CR3/ 34 immunostaining revealed that survivors > 1 year had lower expression levels than < 1-year survivors and controls, whereas CD68 immunostains failed to show any statistical differences between > 1-year survivors, < 1-year survivors and controls. In general, microglial activation is thought to decrease from control levels in the first 24 hours, then increase to a maximum around 3 hours and then decrease again, with greater activation seen in those with DAI compared with those without. The expression of activated microglia or a surrogate maker for them has not been studied in humans who have suffered Seminars in Neurology
Vol. 35
No. 1/2015
15
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Neuropathology of Traumatic Brain Injury
Neuropathology of Traumatic Brain Injury
de Lanerolle et al.
mTBI. Though ligands exist (e.g., translocator protein) for PET imaging of microglial and astrocyte activation associated with inflammation, such studies are unavailable for TBI cases. Microglial activation was examined in a swine model of explosive blast mTBI.32 Immunostaining for microglia performed with two markers, CD68 and ionized calcium-binding adaptor molecule 1 (Iba-1), showed the same pattern of staining. Morphologically recognizable activated microglia (more numerous, enlarged nuclei and somata, increased processes and some with rod-like shape) are seen in the central white matter and corpus callosum of explosive blast exposed animals, even though injured axons were not seen in these areas. The hippocampus and superior frontal cortex did not show activated microglia. There was no morphologic evidence of activated phagocytic microglia (cells with shortened processes that are rounded or ameboid) even in white matter areas in which other signs of microglial activation were noted. This is consistent with the absence of axonal injury in these areas.32 In general, activated microglia are interpreted as evidence of an inflammatory response, releasing several factors including pro- and anti-inflammatory cytokines, chemokines, and other molecules, modulating secondary injury and recovery after injury.2,39 However, recent research shows that microglia participate in a wide variety of functions, some in conjunction with innate immune mechanisms leading to neural network reorganization.40 The role activated microglia play in traumatic brain injury remains an important area of research.
Astrocyte Activation Astrocytes are an important cellular component of the brain and play an important role in normal neural function as well as influencing brain injury and recovery. Experimental animal studies have found that astrocyte activation is a prominent feature of CHI TBI. Controlled cortical impact-induced brain injury in mice produced not only neuronal damage, but also astrogliosis.41,42 In a study of swine exposed to explosive blast pressure waves, glial fibrillary acidic protein (GFAP) immunostaining revealed a significant increase in activated astrocytes in the hippocampus and cortical gray and white matter in the parasagittal cortices, including the cingulate gyri, superior, middle and inferior frontal gyri, and corpus callosum. The density of activated astrocytes in the hippocampus of blastexposed animals was higher than in controls, and in animals with repeat blast exposure higher than with a single exposure. The activated astrocytes are found in areas they are not normally found or at best weakly expressed, such as in gray matter. The new astrocytes have a distinctive stellate appearance, with the processes of adjacent astrocytes not overlapping and maintaining a tiled appearance,32 in contrast to astrocytes that are seen in areas of dense neuronal injury where their processes interdigitate. Such a pattern of astrogliosis has not been reported in human patients with mTBI, although increased GFAP is reported in athletes with chronic traumatic encephalopathy (CTE) consequent to multiple traumatic experiences. Seminars in Neurology
Vol. 35
No. 1/2015
Cerebrovascular Injury following PHI and CHI Cerebrovascular injury and hemorrhage commonly accompany PHI and severe head trauma resulting from head impact or an explosive blast. Armonda and coworkers43,44 report that a significant number of patients with severe TBI resulting from a blast or high-velocity gunshot wounds to the head develop some form of vascular injury—pseudoaneurysms, subarachnoid hemorrhage, and other hemorrhages (epidural, subdural, intraventricular hemorrhages), with a significantly large number showing traumatic cerebral vasospasm (TCV). Traumatic cerebral vasospasm is the reduction in the normal caliber of a blood vessel by smooth muscle contraction, resulting in increased blood flow velocity.43 Traumatic cerebral vasospasm is associated with both blunt and penetrating brain injury in 30 to 40% of cases (studies summarized in43). A low GCS score and the presence of subarachnoid hemorrhage are strongly predictive of TCV. Ischemic damage is also significantly high ( 90%) in a group of 635 patients with fatal, nonmissile head injury, and survival times of 1 hour to 14 years.45 At the cellular level, an ischemic cascade results in free radical release, which results in the breakdown of neuronal membranes that trigger an inflammatory response, the release of excitotoxic amino acids (glutamate), an increase in intracellular calcium, and eventually neuronal death.46 Ischemic brain damage is believed to be an important cause of mortality.45 Cerebrovascular injury is less common in mTBI. Head computed tomography examinations of patients with mild or minor complicated TBI were typically negative on the first day after the event.47 In approximately 20% of cases that were subsequently positive, the abnormalities were subtle, seen as petechial hemorrhages, mild edema, and/or small contusions.48,49 In another study of mTBI patients, although DAI was found in 29%, none had evidence of hemosiderin, suggesting that they were all nonhemorrhagic lesions. In a subgroup of 32%, dilated perivascular (Virchow-Robin) spaces were detected, and were commonly located in the parietal subcortical white matter.50 In an experimental model of mild TBI produced in swine exposed to pure blast pressure waves in three operationally relevant scenarios, no evidence of hemorrhage was observed, even 8 months postblast (32 and unpublished findings). However, in an experimental study of nonhuman primates to lateral head acceleration, subtle cellular evidence of vascular changes were reported.51 Three types of changes in cellular morphology were observed: (1) ultrastructural evidence of lucency and enlargement of perivascular astrocyte foot processes; (2) development of microvilli on the luminal endothelial surface; and (3) numerical changes in the number of pinocytotic vesicles, a component of transendothelial transport. Some of these changes resolved over time.
Tau Expression and Chronic Traumatic Encephalopathy A meta-analysis of 15 case-controlled studies of patients with TBI estimated that 50% of those who suffered loss of consciousness were at increased risk of Alzheimer-type dementia.52 Additionally, the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology) study found that the
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
16
Neuropathology of Traumatic Brain Injury
17
blast pressure. Thus, the evidence that explosive blast results in CTE is weak. Studies of a large animal model (swine) exposed to pure blast pressure did not show any hyperphosphorylated tau or β-amyloid, even as late as 8 months postblast.
Comparisons Despite the many studies being done on the neuropathology of TBI in animal models, the neuropathology of human TBI remains incompletely understood. However, even with the limited data available, it can be discerned that there are similarities and differences between the neuropathology resulting from the differing TBI etiologies. Penetrating head injury and moderate to severe CHI are more likely than mTBI to cause disruption in the cerebral vasculature. Bissett46 identified some points for comparison. Penetrating injuries from missiles may cause petechial and linear hemorrhages. With the destruction of the vasculature, contusions and hemorrhages form rapidly, and edema may begin as early as 30 minutes after injury.46,62 Stab wound injuries lead to hemorrhage and related mass effect, whereas gunshot wounds result in cerebral edema.46,62 At the cellular level, an ischemic cascade similar to that with nonpenetrating closed head trauma can occur.45 Unlike CHI, PHI can cause bleeding that results in hypovolemic hypotension, hemorrhagic shock, and cardiopulmonary arrest.46,62 In contrast to PHI and moderate or severe CHI, mTBI is associated with little or no vascular injury, and rarely even petechial hemorrhages are observed. Axonal injury occurs in PHI and is similar to classical DAI6 described in moderate to severe CHI. It is unclear from the literature if such a pattern is also present in impact mTBI. On the contrary, the distributional pattern of injured axons in explosive blast mTBI is likely (on the basis of animal experiments) to be quite different, and is found at the interface of brain parenchyma and cerebrospinal fluid periventricularly. Studies are unavailable to confirm this pattern in human mTBI. Glial fibrillary acidic protein-positive astrocyte activation and proliferation is increased in models of mTBI, where the astrocytes retain a more normal tiled appearance rather than the morphology associated within regions of neuronal injury, where they have long intertwining processes that form a glial scar. Such scars are more common in moderate and severe TBI. Reactive astrocytes in mTBI may play a role in inflammatory processes by releasing a variety of inflammatory molecules.63 Microglial activation appears to be limited in mTBI compared with severe and moderate TBI in animal models. However, the expressions of activated astrocytes and microglia have not been investigated in mTBI in humans. In summary, the review of studies on the neuropathology of TBI suggests that the pathological profiles of severe and moderate CHI may differ from mTBI, as the former shows extensive neuronal injury while mTBI may have limited neuronal injury but increased glial activation. Furthermore, the neuropathology of mTBI resulting from explosive blast may have a distinctive neuropathological profile. Seminars in Neurology
Vol. 35
No. 1/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
odds ratio for dementia after head trauma with loss of consciousness was double that for TBI without loss of consciousness.53 Moderate and severe head injury, but not mTBI, were associated with an increased risk of Alzheimer disease (AD).54 Multiple mTBIs, such as in professional athletes, are associated with a clinical entity described as chronic traumatic encephalopathy (CTE), formerly called “punch drunk” or dementia pugilistica. Chronic traumatic encephalopathy was recently suggested to also be present in veterans exposed to explosive blast.55 The pathological signs of CTE are thought to resemble those in AD.56 McKee et al57 reviewed 48 published cases of neuropathologically verified CTE as well as three of their own cases, and classified CTE as a distinct disease state. Histopathologically, they identify neuronal loss and gliosis in the hippocampus, substantia nigra, and cerebral cortex, with mammillary bodies, medial thalamus, locus ceruleus, and nucleus accumbens also susceptible to neuronal loss. Chronic traumatic encephalopathy is classified as a neurodegenerative tauopathy. Tauopathy is a condition associated with hyperphosphorylated tau proteins that aggregate to form neurofibrillary tangles (NFTs). Tau immunohistochemical localization studies show that the protein tangles in CTE are similar to those in AD.58 However, the distribution of tau protein is different in CTE compared with AD. In CTE the tau protein is distributed in multiple foci, often dense in superficial layers (layers II and III) of the cortex and usually around blood vessels. This is in contrast to AD, where tau protein is less dense and preferentially located in deeper layers V and VI.59 β-amyloid is not commonly seen in CTE. Goldstein et al60 reported on postmortem examination of four men (22–45 years of age) with a history of exposure to explosive blast. Two were comorbid with PTSD and had a prior history of mTBI at an early age, whereas the other two had no PTSD and only one with a previous history of concussion. Their brains were compared with brains of subjects without a history of explosive blast exposure and athletes with history of head impact. The scope of the study was narrow, with the focus mostly on the expression of phosphorylated and nonphosphorylated tau proteins. In the subjects with explosive blast exposure and/or impact, perivascular foci of tau-immunoreactive neurofibrillary tangles (NFTs) and glial tangles in the inferior frontal, dorsolateral frontal, parietal and temporal cortices, particularly near sulcal depth, were reported. Phosphorylated tau immunoreactive dystrophic axons and NFTs were also found in the superficial layers of the frontal and parietal cortices and the hippocampus. Tau immunoreactive degenerating axons, axon retraction bulbs, and axon dystrophy were observed in subcortical white matter adjacent to cortical tau pathology and perivascular areas. Immunoreactive activated clusters of microglia were also reported in subcortical white matter underlying focal tau pathology, but not in unaffected brain regions. Commenting on the Goldstein study,60 Tsao61 points out some limitations. Three of the four patients studied had a previous medical history of concussion, and the fourth had injuries severe enough to cause concussion. Therefore, it is possible that the phosphorylated tau deposition seen in these patients was due to secondary head impact and not explosive
de Lanerolle et al.
Neuropathology of Traumatic Brain Injury
de Lanerolle et al.
References
23 Mott FW. The microscopic examination of the brains of two men
1 Teasdale G, Jennett B. Assessment of coma and impaired con2
3 4
5
6
7
8
9
10 11
12
13
14
15
16
17
18
19
20
21
22
sciousness. A practical scale. Lancet 1974;2(7872):81–84 Smith C. Review: the long-term consequences of microglial activation following acute traumatic brain injury. Neuropathol Appl Neurobiol 2013;39(1):35–44 Blennow K, Hardy J, Zetterberg H. The neuropathology and neurobiology of traumatic brain injury. Neuron 2012;76(5):886–899 Blumbergs PC, Reilly P, Vink R. Trauma. In: Love S, Jouis DN, Ellison DW, eds. Greenfields Neuropathology. London, UK: Edward Arnold; 2008:733–832 Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ. Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury. J Neurotrauma 1995;12(4):565–572 Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI, McLellan DR. Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology 1989;15(1):49–59 Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, Roberts GW. Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett 1993;160(2):139–144 Hortobágyi T, Wise S, Hunt N, et al. Traumatic axonal damage in the brain can be detected using beta-APP immunohistochemistry within 35. min after head injury to human adults. Neuropathol Appl Neurobiol 2007;33(2):226–237 Geddes JF, Whitwell HL, Graham DI. Traumatic axonal injury: practical issues for diagnosis in medicolegal cases. Neuropathol Appl Neurobiol 2000;26(2):105–116 Cammermeyer J. The importance of avoiding “dark” neurons in experimental neuropathology. Acta Neuropathol 1961;1:245–270 Jortner BS. The return of the dark neuron. A histological artifact complicating contemporary neurotoxicologic evaluation. Neurotoxicology 2006;27(4):628–634 Oehmichen M, Meissner C, König HG. Brain injury after gunshot wounding: morphometric analysis of cell destruction caused by temporary cavitation. J Neurotrauma 2000;17(2):155–162 Oehmichen M, Meissner C, König HG. Brain injury after survived gunshot to the head: reactive alterations at sites remote from the missile track. Forensic Sci Int 2001;115(3):189–197 Oehmichen M, Meissner C, König HG, Gehl H-B. Gunshot injuries to the head and brain caused by low-velocity handguns and rifles. A review. Forensic Sci Int 2004;146(2-3):111–120 Koszyca B, Blumbergs PC, Manavis J, et al. Widespread axonal injury in gunshot wounds to the head using amyloid precursor protein as a marker. J Neurotrauma 1998;15(9):675–683 Bakir A, Temiz C, Umur S, Aydin V, Torun F. High-velocity gunshot wounds to the head: analysis of 135 patients. Neurol Med Chir (Tokyo) 2005;45(6):281–287, discussion 287 Adams JH, Graham DI, Scott G, Parker LS, Doyle D. Brain damage in fatal non-missile head injury. J Clin Pathol 1980;33(12): 1132–1145 Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ. Staining of amyloid precursor protein to study axonal damage in mild head injury. Lancet 1994;344(8929):1055–1056 Stevens MC, Lovejoy D, Kim J, Oakes H, Kureshi I, Witt ST. Multiple resting state network functional connectivity abnormalities in mild traumatic brain injury. Brain Imaging Behav 2012;6(2):293–318 Ling G, Eklund J, Bandak FA. Blast brain injury from explosive blast: description and clinical management. In: Grafman J, Salazar AM, eds. Handbook of Clinical Neurology. Amsterdam: Elsevier; 2015 Cramer F, Paster S, Stephenson C. Cerebral injuries due to explosion waves, cerebral blast concussion; a pathologic, clinical, and electroencephalographic study. Archives Neurol Psychiatr 1949; 61:1–20 Hirsch AE, Ommaya AK. Head injury caused by underwater explosion of a firecracker. Case report. J Neurosurg 1972;37(1): 95–99
Seminars in Neurology
Vol. 35
No. 1/2015
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39 40 41
42
43
44
dead of commotio cerebri (shell shock) without visible external injury. J R Army Med Corps 1917;29:662–677 Murthy JM, Chopra JS, Gulati DR. Subdural hematoma in an adult following a blast injury. Case report. J Neurosurg 1979;50(2): 260–261 Taber KH, Warden DL, Hurley RA. Blast-related traumatic brain injury: what is known? J Neuropsychiatry Clin Neurosci 2006; 18(2):141–145 Taber KH, Hurley RA. Update on mild traumatic brain injury: neuropathology and structural imaging. J Neuropsychiatry Clin Neurosci 2013;25(1):1–5 Hetherington HP, Bandak A, Ling G, Bandak F. Advances in imaging explosive blast mild traumatic brain injury. In: Grafman J, Salazar AM, eds. Handbook of Clinical Neurology. Netherlands: Elsevier; 2015: In press Davenport ND, Lim KO, Armstrong MT, Sponheim SR. Diffuse and spatially variable white matter disruptions are associated with blast-related mild traumatic brain injury. Neuroimage 2012;59(3): 2017–2024 Mac Donald CL, Johnson AM, Cooper D, et al. Detection of blastrelated traumatic brain injury in U.S. military personnel. N Engl J Med 2011;364(22):2091–2100 Morey RA, Haswell CC, Selgrade ES, et al. Effects of chronic mild traumatic brain injury on white matter integrity in Iraq and Afghanistan war veterans. Hum Brain Mapp 2013;34(11): 2986–2999 Peskind ER, Petrie EC, Cross DJ, et al. Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war Veterans with persistent post-concussive symptoms. Neuroimage 2011;54(Suppl 1):S76–S82 de Lanerolle NC, Bandak F, Kang D, et al. Characteristics of an explosive blast-induced brain injury in an experimental model. J Neuropathol Exp Neurol 2011;70(11):1046–1057 Maxwell WL, MacKinnon M-A, Stewart JE, Graham DI. Stereology of cerebral cortex after traumatic brain injury matched to the Glasgow outcome score. Brain 2010;133(Pt 1):139–160 Urenjak J, Williams SR, Gadian DG, Noble M. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993;13(3):981–989 Brooks WM, Friedman SD, Gasparovic C. Magnetic resonance spectroscopy in traumatic brain injury. J Head Trauma Rehabil 2001;16(2):149–164 de Lanerolle NC, Hamid H, Kulas J, et al. Concussive brain injury from explosive blast. Ann Clin Transl Neurol 2014;1(9): 692–702 Hetherington HP, Hamid H, Kulas J, et al. MRSI of the medial temporal lobe at 7T in explosive blast mild traumatic brain injury. Magn Reson Med 2014;71:1358–136710.1002/mrm.24814 Smith C, Gentleman SM, Leclercq PD, et al. The neuroinflammatory response in humans after traumatic brain injury. Neuropathol Appl Neurobiol 2013;39(6):654–666 Loane DJ, Byrnes KR. Role of microglia in neurotrauma. Neurotherapeutics 2010;7(4):366–377 Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science 2013;339(6116):156–161 Garman RH, Jenkins LW, Switzer RCI III, et al. Blast exposure in rats with body shielding is characterized primarily by diffuse axonal injury. J Neurotrauma 2011;28(6):947–959 Kernie SG, Erwin TM, Parada LF. Brain remodeling due to neuronal and astrocytic proliferation after controlled cortical injury in mice. J Neurosci Res 2001;66(3):317–326 Armonda RA, Bell RS, Vo AH, et al. Wartime traumatic cerebral vasospasm: recent review of combat casualties. Neurosurgery 2006;59(6):1215–1225, discussion 1225 Ling G, Bandak F, Armonda R, Grant G, Ecklund J. Explosive blast neurotrauma. J Neurotrauma 2009;26(6):815–825
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
18
Neuropathology of Traumatic Brain Injury
46 47
48
49
50
51
52
53 54
common in fatal non-missile head injury. J Neurol Neurosurg Psychiatry 1989;52(3):346–350 Blissitt PA. Care of the critically ill patient with penetrating head injury. Crit Care Nurs Clin North Am 2006;18(3):321–332 Bigler ED, Maxwell WL. Neuropathology of mild traumatic brain injury: relationship to neuroimaging findings. Brain Imaging Behav 2012;6(2):108–136 Iverson GL, Lovell MR, Smith S, Franzen MD. Prevalence of abnormal CT-scans following mild head injury. Brain Inj 2000;14(12): 1057–1061 Smits M, Hunink MG, van Rijssel DA, et al. Outcome after complicated minor head injury. AJNR Am J Neuroradiol 2008;29(3): 506–513 Orrison WW, Hanson EH, Alamo T, et al. Traumatic brain injury: a review and high-field MRI findings in 100 unarmed combatants using a literature-based checklist approach. J Neurotrauma 2009; 26(5):689–701 Maxwell WL, Whitfield PC, Suzen B, et al. The cerebrovascular response to experimental lateral head acceleration. Acta Neuropathol 1992;84(3):289–296 Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry 2003; 74(7):857–862 Guo Z, Cupples LA, Kurz A, et al. Head injury and the risk of AD in the MIRAGE study. Neurology 2000;54(6):1316–1323 Plassman BL, Havlik RJ, Steffens DC, et al. Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 2000;55(8):1158–1166
19
55 Miller G. Neuropathology. Blast injuries linked to neurodegenera-
tion in veterans. Science 2012;336(6083):790–791 56 Lakis N, Corona RJ, Toshkezi G, Chin LS. Chronic traumatic enceph-
57
58
59
60
61
62
63
alopathy - neuropathology in athletes and war veterans. Neurol Res 2013;35(3):290–299 McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 2009;68(7):709–735 Schmidt ML, Zhukareva V, Newell KL, Lee VM, Trojanowski JQ. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer’s disease. Acta Neuropathol 2001;101(5): 518–524 Hof PR, Delacourte A, Bouras C. Distribution of cortical neurofibrillary tangles in progressive supranuclear palsy: a quantitative analysis of six cases. Acta Neuropathol 1992;84(1):45–51 Goldstein LE, Fisher AM, Tagge CA, et al. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 2012;4(134): 134ra60 Tsao JW. Comment on “chronic traumatic encephalopathy in blastexposed military veterans and a blast neurotrauma mouse model”. Sci Transl Med 2012;4(157):157le7, author reply 157lr5 Campbell GA. The pathology of penetrating wounds of the brain and its enclosures. In: Aarabi B, Kaufman HH, eds. Missile wounds of the head and neck. Park Ridge, IL: American Association of Neurological Surgeons; 1999:73–89 Ahmed F, Gyorgy A, Kamnaksh A, et al. Time-dependent changes of protein biomarker levels in the cerebrospinal fluid after blast traumatic brain injury. Electrophoresis 2012;33(24): 3705–3711
Seminars in Neurology
Vol. 35
No. 1/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
45 Graham DI, Ford I, Adams JH, et al. Ischaemic brain damage is still
de Lanerolle et al.
Copyright of Seminars in Neurology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
