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PubMed1992

Traumatically induced axonal injury: pathogenesis and pathobiological implications.

This work reviews the pathobiology of traumatically induced axonal injury. Drawing upon literature gleaned from the experimental and clinical setting, this review attempts to emphasize that, other than the most destructive insults, traumatic brain injury does not typically cause direct mechanical disruption of the axon. Rather, this review documents that with traumatic injury focal, subtle axonal change occurs, and that over time, such change leads to impaired axoplasmic transport, continued axonal swelling, and ultimate disconnection. The initial intra-axonal events that trigger the above described sequence of reactive axonal change are considered with focus on the possibility of either traumatically altered axolemmal permeability, direct cytoskeletal damage/perturbation, or more overt metabolic/functional disturbances. Not only does this review focus on the sequence of traumatically induced axonal change, but also, it considers its attendant consequences in terms of Wallerian degeneration and subsequent deafferentation. The concept that traumatically induced diffuse axonal injury leads to diffuse deafferentation is emphasized together with its pathobiological implications for morbidity and recovery. The potential for either adaptive or maladaptive neuroplasticity subsequent to such diffuse deafferentation is considered in the context of mild, moderate and severe traumatic brain injury.

Animals↗

PubMedDate not supplied

Neuropathology of the vegetative state after head injury.

A detailed neuropathological study of patients identified clinically after head injury as either severely disabled (SD, n = 30) or vegetative (VS, n = 35) has been carried out to determine the nature and frequency of the various pathologies that form the basis of these clinical states. Patients who were SD were older (SD median 49.5 yrs vs. VS median 38 yrs, p = .04), more likely to have a lucid interval (SD 31% vs. VS 9%, p = .03), and to have had an acute intracranial haematoma (SD 70% vs. VS 26%, p < .001). SD patients less often had severe, Grades (2 or 3) of traumatic diffuse axonal injury (SD 30% vs. VS 71%, p = .001) and less often had thalamic damage (SD 37% vs. VS 80%, p < .001). Similar features of both focal and diffuse damage were present in some SD and VS cases with both groups having considerable damage to white matter and to the thalamus. It is concluded that the principal structural basis of both SD and VS is diffuse traumatic axonal injury (DAI) with widespread damage to white matter and changes in the thalami. However, both ischaemic brain damage and the vascular complications of raised intracranial pressure contributed to the clinical signs and symptoms.

Adolescent↗

PubMed2002

[Finite element analysis of DAI animal model caused by nonimpact with half bound head in cats].

This study sought to make a biomechanical analysis of the diffuse axonal injury(DAI) animal model caused by nonimpact with half bound head in cats. A three-dimensional finite element model of cat's head was established. The head of an anesthetized cat was scanned in 2 mm section. The nods and element meshes were signed out according to the geometry of every section. The geometric data were put into the computer and the element mesh body of cat's head was established in vizi CAD system. The maximum stress, minimum stress and von Mises stress were calculated by Super SAP (93ed) finite elemental software when the force was loaded on the right or left side of model in zero section. The analysis showed that the maximum stress appeared in the anterior and posterior loaded point and extended to cranial base in the cranial shell. There was high stress in the brain surface also. Because of cerebellar tentorium, cerebral falx, petrosal bone and sellar process, the stress did not decrease equivalently while approaching the deep brain, but it was distributed in cerebral-cerebellar peduncles, brain stem, corpus callosum and basal ganglia area at high values. The results suggest that the stress caused by rotational force is widespreadly and unequivalently distributed in brain tissue, which is mainly effected by the cerebellar tentorium, cerebral falx and the irregular geometric forms of cranial bone.

Animals↗

PubMed2004

Marked increase of beta-amyloid(1-42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury.

Severe traumatic brain injury (TBI) may result in widespread damage to axons, termed diffuse axonal injury. Alzheimer's disease (AD) is characterised by synaptic and axonal degeneration together with senile plaques (SP). SP are mainly composed of aggregated beta-amyloid (Abeta), which are peptides derived from the amyloid precursor protein (APP). Apart from TBI in itself being considered a risk factor for AD, severe head injury seems to initiate a cascade of molecular events that are also associated with AD. We have therefore analysed the 42 amino acid forms of Abeta (Abeta1-42) and two soluble forms of APP (alpha-sAPP and ss-sAPP) in ventricular cerebrospinal fluid (VCSF) and Abeta(1-42) in plasma from 28 patients in a serial samples 0-11 days after TBI. The levels of alpha-sAPP, ss-sAPP and Abeta(1-42) were determined using ELISA assays. After TBI, there was a significant stepwise increase in VCSF-Abeta(1-42) up to 1173 % from day 0-1 to day 5-6 and in VCSF-beta-sAPP up to 2033 % increase from day 0-1 to day 7-11. There was also a slight but significant increase of VCSF-beta-sAPP from day 0-1 to day 5-6 and day 7-11. By contrast, the plasma- Abeta(1-42) level is unchanged after injury. The marked increase in VCSFAbeta(1-42) implies that increased Abeta expression may occur as a secondary phenomenon after TBI with axonal damage. The unchanged level of plasma-Abeta(1-42) in contrast to the marked increase in VCSF-Abeta(1-42) after severe TBI, supports the suggestion that plasma Abeta(1-42) does not reflect Abeta metabolism in the central nervous system (CNS).

Adult↗

PubMed1989

Clinicoradiological and therapeutic considerations in severe diffuse traumatic brain injury in children.

Forty-one children with severe head injuries and diffuse brain lesions were selected from a consecutive series of 62 children in traumatic coma (21 focal mass lesions) and studied. According to the CT pattern, two main types of intracranial lesions were considered: diffuse axonal injury (DAI) and diffuse brain swelling (DBS). High mortality, due to secondary increases of intracranial pressure (ICP), correlated well with the patterns of severe DBS, absence of perimesencephalic cisterns, and obliteration of the ventricles. However, children with normal CTs, and/or obvious shearing injuries indicative of DAI, had favorable outcomes; there was no mortality if increased ICP was not present. We conclude that although there does not seem to be any routine indications for ICP monitoring in children with pure DAI, early ICP monitoring and aggressive management of increasing ICP should be considered in comatose children with DBS, especially when associated with subarachnoid hemorrhage and respiratory or circulatory failure.

Adolescent↗

PubMed1988

Prospective comparative study of intermediate-field MR and CT in the evaluation of closed head trauma.

Forty patients with closed head trauma were evaluated prospectively with CT and intermediate-field-strength MR imaging to compare the diagnostic efficacies of the two techniques. Traumatic lesions were detected in 38 patients. The severity of injury, as determined by the Glascow Coma Scale, ranged from 3 to 14. The sensitivities of CT and MR were calculated for all subgroups of lesions: (1) hemorrhagic and nonhemorrhagic intraaxial lesions (diffuse axonal injury, cortical contusion, subcortical gray-matter injury, primary brainstem injury); (2) extraaxial hematomas (subdural, epidural); and (3) diffuse hemorrhage (subarachnoid, intraventricular). CT and MR (T1- and T2-weighted) studies were both highly and comparably sensitive in the detection of hemorrhagic intraaxial lesions. MR scans, however, were much more sensitive in detecting nonhemorrhagic lesions. cortical contusions and diffuse axonal injury constituted 91.9% of all intraaxial lesions. The sensitivities of the imaging techniques for this combined group of lesions were (1) nonhemorrhagic lesions (CT = 17.7%, T1-weighted MR = 67.6%, T2-weighted MR = 93.3%); (2) hemorrhagic lesions (CT = 89.8%, T1-weighted MR = 87.1%, T2-weighted MR = 92.5%). MR was also significantly better in detecting brainstem lesions (CT = 9.1%, T1-weighted MR = 81.8%, T2-weighted MR = 72.7%). The sensitivities of the diagnostic studies in the detection of extraaxial hematomas were CT = 73.2%, T1-weighted MR = 97.6%, T2-weighted MR = 90.5%). Intraventricular hemorrhage was consistently seen with all three imaging studies, but subarachnoid hemorrhage was detected much more frequently with CT. In summary, MR has clear advantages over CT in evaluating closed head trauma. Although its sensitivity in detecting hemorrhagic lesions is similar to that of CT, it is much better than CT in detecting nonhemorrhagic lesions, which are more prevalent. MR is more useful than CT in classifying primary and secondary forms of injury and directing treatment. CT's one advantage over MR is its ability to more rapidly assess unstable patients who may need surgery.

Adolescent↗

PubMed2002

Neuropathological investigation of cerebral white matter lesions caused by closed head injury.

In order to ascertain whether there is widespread axonal disruption of cerebral white matter in the so-called 'diffuse axonal injury' (DAI), a type of closed head injury, proposed by Adams et al. the author investigated his own cases clinicopathologically. Twenty-six male autopsied cases of head injury, aged between 19 and 84, 15 of which had sustained road traffic accidents, were examined; the others were due to falling from heights and so on. The study group all belonged to non-missile head injuries and included 12 cases of diffuse brain injury, as well as 14 cases of focal brain injury, according to the classification of Gennarelli et al. The survival time ranged from 2 h to 21 years. Formalin-fixed brains were cut coronally so as to make paraffin-embedded hemispheric sections. Then these sections were stained conventionally (HE, Bodian, Kluver-Barrera and Holzer) and immunohistochemically (GFAP) to assess axonal decrease, myelin pallor and gliosis by the use of light microscopy. In the 13 chronic cases that died more than 1 month after the accidents, the intensities of gliosis, myelin pallor and axonal decrease tended to correlate with each other. In the 13 acute cases who died less than 1 month after their accident, the degree of axonal decrease in white matter seemed to correlate with the severity of myelin pallor. Regardless of types of trauma, however, axonal retraction balls, the so-called hallmark of DAI, were found only with myelin pallor suggesting the presence of brain swelling after the injury. Therefore these findings indicate that it may be difficult to accept the notion of DAI, that is, the presence of axonal retraction balls without brain swelling. In addition, diffuse vascular injury (2 cases) as well as rarefaction of subcortical white matter (6 cases) were presented and their pathogenesis individually discussed based on a literature review.

Adult↗

PubMedDate not supplied

Usefulness of diffusion tensor imaging for evaluation of motor function in patients with traumatic brain injury: three case studies.

OBJECTIVES: To determine whether diffusion tensor imaging (DTI) can detect diffuse axonal injury, and to evaluate the association of DTI findings with motor function in patients with traumatic brain injury. DESIGN: Three case studies. SETTING: An inpatient rehabilitation unit in Korea. PARTICIPANTS: Three patients with traumatic brain injury in whom conventional neuroimaging showed normal-appearing white matter. MAIN OUTCOME MEASURES: Patients were studied with DTI. Fractional anisotropy (FA) was measured from 3 different anatomic locations on both sides of the corticospinal tract. Motor function was evaluated using the motoricity index. RESULTS: Fractional anisotropy tended to be reduced in normal-appearing corticospinal tracts that were remote from the involved segment. Diffusion tensor imaging showed reduction of FA in areas consistent with motor dysfunction. CONCLUSION: Fractional anisotropy of the corticospinal tract may be used in the detection of diffuse axonal injury. The association between decreased motoricity index and decreased FA suggests that DTI may be useful in evaluating patients with traumatic brain injury.

Adult↗

PubMed2005

[The clinical utility of MR diffusion tensor imaging and spatially normalized PET to evaluate traumatic brain injury patients with memory and cognitive impairments].

We detected and compared abnormal brain areas using both MR diffusion tensor imaging (DTI) and easy Z score imaging system (eZIS) of FDG-PET for traumatic brain injury patients with memory and cognitive impairments. Twenty normal subjects and eighteen diffuse axonal injury patients with memory and cognitive impairments were studied with DTI and eZIS of 18F-FDG-PET. DTI contained fractional anisotorophy (FA) analysis and the tractography for the corpus callosum. After PET imaging was performed, statistical analysis using eZIS was undergone with followed processing steps, including smoothing, normalization and z transformation with respect to normal database. Z score map was superimposed on 3D MRI brain. Group analysis was performed using SPM. In diffuse axonal injury patients, the decline of FA was observed around the corpus callosum in comparison with normal subjects and the reduction of glucose metabolism was shown in the cingulated association. These results suggest that the reduction of metabolism within the cingulated cortex indicated deprived neuronal activation caused by the impaired neuronal connectivity that was revealed with DTI. Furthermore, the metabolic abnormalities within the cingulated cortex may be responsible for memory and cognitive impairments. DTI and spatially normalized PET have a role in neuroimaging interpretation for patients with memory and cognition impairments because its 3D better visualization allows objective and systematic investigation.

Accidents, Traffic↗

PubMed2006

Deficits in predictive smooth pursuit after mild traumatic brain injury.

Given that even mild traumatic brain injury (TBI) may produce extensive diffuse axonal injury (DAI), we hypothesized that mild TBI patients would show deficits in predictive smooth pursuit eye movements (SPEM), associated with impaired cognitive functions, as these processes are dependent on common white matter connectivity between multiple cerebral and cerebellar regions. The ability to predict target trajectories during SPEM was investigated in 21 mild TBI patients using a periodic sinusoidal paradigm. Compared to 26 control subjects, TBI patients demonstrated decreased target prediction. TBI patients also showed increased eye position error and variability of eye position, which correlated with decreased target prediction. In all subjects, average target prediction, eye position error and eye position variability correlated with scores related to attention and executive function on the California Verbal Learning Test (CVLT-II). However, there were no differences between TBI and control groups in average eye gain or intra-individual eye gain variability, or in performance on the Wechsler Abbreviated Scale of Intelligence (WASI), suggesting that the observed deficits did not result from general oculomotor impairment or reduced IQ. The correlation between SPEM performance and CVLT-II scores suggests that predictive SPEM may be a sensitive assay of cognitive functioning, including attention and executive function. This is the first report to our knowledge that TBI patients show impaired predictive SPEM and eye position variability, and that these impairments correlate with cognitive deficits.

Adolescent↗

PubMed2006

Postinjury administration of pituitary adenylate cyclase activating polypeptide (PACAP) attenuates traumatically induced axonal injury in rats.

Pituitary adenylate cyclase activating polypeptide (PACAP) has several different actions in the nervous system. Numerous studies have shown its neuroprotective effects both in vitro and in vivo. Previously, it has been demonstrated that PACAP reduces brain damage in rat models of global and focal cerebral ischemia. Based on the protective effects of PACAP in cerebral ischemia and the presence of common pathogenic mechanisms in cerebral ischemia and traumatic brain injury (TBI), the aim of the present study was to investigate the possible protective effect of PACAP administered 30 min or 1 h postinjury in a rat model of diffuse axonal injury. Adult Wistar male rats were subjected to impact acceleration, and PACAP was administered intracerebroventricularly 30 min (n = 4), and 1 h after the injury (n = 5). Control animals received the same volume of vehicle at both time-points (n = 5). Two hours after the injury, brains were processed for immunohistochemical localization of damaged axonal profiles displaying either beta-amyloid precursor protein (beta-APP) or RMO-14 immunoreactivity, both considered markers of specific features of traumatic axonal injury. Our results show that treatment with PACAP (100 microg) 30 min or 1 h after the induction of TBI resulted in a significant reduction of the density of beta-APP-immunopositive axon profiles in the corticospinal tract (CSpT). There was no significant difference between the density of beta-APP-immunopositive axons in the medial longitudinal fascicle (MLF). PACAP treatment did not result in significantly different number of RMO-14-immunopositive axonal profiles in either brain areas 2 hours post-injury compared to normal animals. While the results of this study highlighted the complexity of the pathogenesis and manifestation of diffuse axonal injury, they also indicate that PACAP should be considered a potential therapeutic agent in TBI.

Amyloid beta-Protein Precursor↗

PubMed2005

Mild axonal stretch injury in vitro induces a progressive series of neurofilament alterations ultimately leading to delayed axotomy.

We report a new model of transient axonal stretch injury involving pressurized fluid deflection of bundles of axons, resulting in a transient 1-6% increase in original axon length to investigate the slow progression of axonal alterations that are characteristic of diffuse axonal injury (DAI). We found no discernable difference in axon bundle morphology or cytoskeletal neurofilament protein arrangement between unstretched and stretched axonal bundles at 24 h post-injury. However, by 48 h post-injury, there was a stereotypical response of stretched axons involving characteristic neurofilament alterations that bear similarities to in vivo neuronal responses associated with DAI that have been reported previously. For instance, neurofilament protein immunoreactivity (SMI-312) was increased in axons contained within 51% of all injured axon bundles at 48 h compared to surrounding unstretched axon bundles, suggestive of neurofilament compaction. Furthermore, axonal bundle derangement occurred in 25% of injured axon bundles, with individual fibres segregating from each other and becoming undulating and wavy. By 72 h post-stretch, 70% of injured axon bundles underwent secondary axotomy, becoming completely severed at the site of initial stretch injury. While these results suggest a temporal series of stereotypical responses of axons to injury, we were able to distinguish very clear differences between mildly (100-103% increase in original axonal length) injured and strongly injured (106%+) axons. For instance, mildly injured axons developed increased neurofilament immunoreactivtity (SMI-312) within 48 h, and the marked development of ring-like neurofilament immunoreactive structures within axonal bundles, which were rarely axotomized. Conversely, at more severe strain levels increased neurofilament immunoreactivity was less apparent, while axons often became distorted and disorganised within axonal bundles and eventually became completely disconnected. Almost no ring-like neurofilament structures were observed in these severely injured axonal bundles. This suggests that axons do not respond in a stereotypical manner to a transient stretch insult, and indeed that variable degrees of stretch injury activate different responses within axons, with dramatically different outcomes. Hence, it is possible that the cytoskeletal characteristics that we have used in this study may be useful parameters for discriminating between mildly and severely injured axons following TBI.

Animals↗

PubMed2006

Use of advanced neuroimaging techniques in the evaluation of pediatric traumatic brain injury.

Advanced neuroimaging techniques are now used to expand our knowledge of traumatic brain injury, and increasingly, they are being applied to children. This review will examine four of these methods as they apply to children who present acutely after injury. (1) Susceptibility weighted imaging is a 3-dimensional high-resolution magnetic resonance imaging technique that is more sensitive than conventional imaging in detecting hemorrhagic lesions that are often associated with diffuse axonal injury. (2) Magnetic resonance spectroscopy acquires metabolite information reflecting neuronal integrity and function from multiple brain regions and provides sensitive, noninvasive assessment of neurochemical alterations that offers early prognostic information regarding the outcome. (3) Diffusion weighted imaging is based on differences in diffusion of water molecules within the brain and has been shown to be very sensitive in the early detection of ischemic injury. It is now being used to study the direct effects of traumatic injury as well as those due to secondary ischemia. (4) Diffusion tensor imaging is a form of diffusion weighted imaging and allows better evaluation of white matter fiber tracts by taking advantage of the intrinsic directionality (anisotropy) of water diffusion in human brain. It has been shown to be useful in identifying white matter abnormalities after diffuse axonal injury when conventional imaging appears normal. An important aspect of these advanced methods is that they demonstrate that 'normal-appearing' brain in many instances is not normal, i.e. there is evidence of significant undetected injury that may underlie a child's clinical status. Availability and integration of these advanced imaging methods will lead to better treatment and change the standard of care for use of neuroimaging to evaluate children with traumatic brain injury.

Body Water↗

PubMed1995

Pontomedullary rent. A specific type of primary brainstem traumatic injury.

Pontomedullary rent is a primary injury to the brainstem that may occur in high-speed accidents. We present a series of 13 autopsies with complete or partial pontomedullary rent documented over a 12-year period. Of the 13 cases, seven had associated basal skull fractures and three had fractures of the cervical spine. In five patients, the rent was an isolated traumatic lesion of the brain. While pontomedullary rents are mostly caused by traumatic craniocervical hyperextension, some authors feel that these rents could be a form of diffuse axonal injury caused by angular acceleration of the head. In this study, two patients had documented features of diffuse axonal injury. More than one mechanism of injury could therefore be involved. Pontomedullary rents could be underdiagnosed, as partial rent is compatible with survival and, when there are no associated fractures, these tears may be attributed to artifactual damage occurring during removal of the brain at autopsy.

Adolescent↗

PubMed1998

On the field evaluation of athletic head injuries.

This article reviews the diagnosis and management of athletic-related head injury. Cerebral concussion, diffuse axonal injury, brain contusion, and the spectrum of intracranial hematoma is discussed. Emphasis is placed on the need to evaluate when it is prevented from further participation.

Athletic Injuries↗

PubMed1998

Axonal cytoskeletal changes after nondisruptive axonal injury. II. Intermediate sized axons.

Earlier studies of axonal cytoskeletal responses to stretch injury in the guinea pig optic nerve, a model of nondisruptive axonal injury such as occurs in human diffuse axonal injury, have demonstrated different cytoskeletal responses between the smallest and largest axons. But these form only approximately 3% of the total number of axons in the optic nerve. It was then posited that the pathology described in the latter axons may not be representative of the pathology in the majority of axons after stretch injury. In order to test this hypothesis, we carried out a quantitative, morphological analysis of structural changes in the cytoskeleton of intermediate (axonal diameter of 0.5-2.0 mM) sized axons at 4 h after stretch injury. Neurofilaments in axons up to 1.00 microm in diameter increased in number and in axons up to 1.50 microm diameter were compacted. This did not occur in larger axons (diameter of 1.51-2.00 microm) in the present study. However, there was focal compaction of neurofilaments in some of the larger fibers at sites where the integrity of the axolemma was lost. The response by microtubules to stretch injury differed from that of neurofilaments in that there was an increased spacing between microtubules and a loss of their number in axons of >1.51 microm diameter. We provide quantitative, morphological evidence (a) that the neurofilamentous cytoskeleton of different sized axons responds in different ways to stretch and (b) that the response by microtubules differs from that of neurofilaments.

Animals↗

PubMed1991

CT appearance of shearing injuries of the brain.

Shearing injuries, also called diffuse axonal injuries, are a special kind of severe head trauma, usually caused by a motor vehicle accident, in which disruption of white matter axons takes place. Twelve cases of shearing injuries were diagnosed by computed tomography (CT). The typical CT findings were small hemorrhagic lesions in the cerebral white matter, most often in cerebral hemispheres and internal capsules. In most patients, hemorrhagic foci were multiple. Single lesions were found in only two patients. Features of brain edema were found in eight of ten early studies, and subarachnoidal hemorrhage only in three. Two patients also had subdural hematomas. CT appearance of the shearing injuries is characteristic, especially in connection with clinical data indicating a history of head trauma and severe state of the patient.

Accidents, Traffic↗

PubMed2002

Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability.

BACKGROUND: Although in situ pathological studies and in vivo magnetic resonance (MR) investigations have shown that axonal injury can be significant in the early stages of multiple sclerosis (MS), diffuse axonal injury is generally considered a secondary event. Cerebral axonal damage can be specifically assessed in vivo by measuring levels of brain N-acetylaspartate (NAA, a specific index of axonal integrity detected by MR spectroscopy). Other new MR measurements such as magnetization transfer ratio (MTr) or computed estimation of brain volume can provide less specific indexes of tissue damage. OBJECTIVE: To determine whether diffuse axonal and tissue injury is present in patients with definite MS who do not show clinically significant disability. METHODS: We measured brain NAA levels (normalized to creatine [Cr]), MTr values, and cerebral volumes in patients with definite MS who had low T2-weighted MR imaging lesion volumes and no clinical disability, and also in age-matched healthy control subjects. RESULTS: Values of central brain NAA/Cr and MTr in normal-appearing white matter were significantly lower in the MS patients than in controls (P<.001). In contrast, total brain volumes were not significantly different between these groups. Similar results were found for MS patients with early disease (duration, <3 years) and with a particularly low cerebral T2-weighted MR imaging lesion load (< or = 2 cm(3)). CONCLUSIONS: Cerebral NAA/Cr and MTr values are diffusely decreased in MS patients with early disease, low demyelinating lesion load, and no significant disability. This suggests that axonal and/or tissue injury begins very early in the course of MS and might be at least partially independent of cerebral demyelination.

Adolescent↗