The usefulness of diffusion tensor imaging in detection of diffuse axonal injury in a patient with head trauma

Diffuse axonal injury is the predominant mechanism of injuries in patients with traumatic brain injury. Neither conventional brain computed tomography nor magnetic resonance imaging has shown sufficient sensitivity in the diagnosis of diffuse axonal injury. In the current study, we attempted to demonstrate the usefulness of diffusion tensor imaging in the detection of lesion sites of diffuse axonal injury in a patient with head trauma who had been misdiagnosed as having a stroke. A 44-year-old man fell from a height of about 2 m. Brain magnetic resonance imaging (32 months after onset) showed leukomalactic lesions in the isthmus of the corpus callosum and the left temporal lobe. He presented with mild quadriparesis, intentional tremor of both hands, and trunkal ataxia. From diffusion tensor imaging results of 33 months after traumatic brain injury onset, we found diffuse axonal injury in the right corticospinal tract (centrum semiovale, pons), both fornices (columns and crus), and both inferior cerebellar peduncles (cerebellar portions). We think that diffusion tensor imaging could be a useful tool in the detection of lesion sites of diffuse axonal injury in patients with head trauma.     

Unilateral acute foot drop due to diffuse axonal injury after head trauma

Acute foot drop due to diffuse axonal injury (DAI) has not been previously described in the literature. In this report, we present a patient with unilateral acute foot drop caused by a DAI lesion after head trauma.     

Correlation of survival time with size of axonal swellings in diffuse axonal injury

Widespread damage to axons in the white matter of the brain is a well-recognised consequence of non-missile head injury. This diffuse axonal injury is characterised by a gradual swelling of the axon associated with an accumulation of cellular organelles and proteins. We have investigated the relationship between the size of the swellings of the damaged axon with survival time in post-mortem brain tissue. Sixty-six cases of head injury with known length of post-traumatic survival were selected for study, and immunohistochemistry for β-amyloid precursor protein (βAPP) was carried out. The minimum diameter of the βAPP-immunolabelled damaged axons was measured in micrometers using the IBAS image analysis system. There was a strong, positive and significant relationship between the mean size of axonal swelling and survival time which plateaued at around 85 h post injury. With longer survival times the situation becomes more complex. βAPP immunolabelling of damaged axons can contribute evidence about trauma and post-injury survival time in the forensic setting but should always be assessed with other evidence. Received: 13 June 1996 / Revised: 18 July 1997, 20 October 1997, 4 November 1998 / Accepted: 5 January 1999     

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.     

Ultrastructural evidence of axonal shearing as a result of lateral acceleration of the head in non-human primates

Summary The concept of shearing of axons at the time of non-impact injury to the head was first suggested in the middle of this century. However, no experimental model of diffuse axonal injury (DAI) has provided morphological confirmation of this concept. Evidence from experiments on invertebrate axons suggests that membrane resealing after axonal transection occurs between 5 and 30 min after injury. Thus, ultrastructural evidence in support of axonal shearing will probably only be obtained by examination of very short-term survival animal models. We have examined serial thin sections from the corpus callosum of non-human primates exposed to lateral acceleration of the head under conditions which induce DAI. Tearing or shearing of axons was obtained 20 and 35 min after injury, but not at 60 min. Axonal fragmentation occurred more frequently at the node/paranode but also in the internodal regions of axons. Fragmentation occurred most frequently in small axons. Axonal shearing was associated with dissolution of the cytoskeleton and the occurrence of individual, morphologically abnormal membranous organelles. There was no aggregation of membranous organelles at 20 and 35 min but small groups did occur in some axons at 60 minutes. We suggest that two different mechanisms of injury may be occurring in non-impact injury to the head. The first is shearing of axons and sealing of fragmented axonal membranes within 60 min. A second mechanism occurs in other fibres where pertubation of the axon results in axonal swelling and disconnection at a minimum of 2 h after injury.Supported by NIH grant number NS-08803-21, the Wellcome Trust, the Royal Society, London and the Institute of Neurological Sciences, University of Glasgow. Part of this work was presented at the Ist International Neurotrauma Symposium, Fukishima, Japan and the IVth European Meeting of Neuropathology, Berlin Dedication: The authors would like this work to be a tribute to Professor J. H. Adams upon his retiral. His research into diffuse axonal injury inspired the authors to undertake this study.     

The changing “epidemiology” of pediatric head injury and its impact on the daily clinical practice

Aim  This article focuses on the developments that occurred during the last two decades in the management of pediatric head injury. It describes the changes in incidence, various advancements in diagnosis, management, prognosis, prevention and strategies required for better outcome, and control of head injury. Materials and methods  Thorough evaluation of various papers, research, and our experience revealed that in developed countries, there has been a decreasing trend in head trauma incidence and trauma-related deaths as compared to developing countries. Results  This is mainly attributed to the widespread implementation of preventive measures. The development in imaging facilities, better characterization and grading of severe trauma (see, for example, diffuse axonal injury), an advanced understanding of the pathophysiology of secondary brain injury, endocrinological disturbances, predictive factors of outcome, development in neurophysiological monitoring, management advances in critical care units, implementation of safely measures, etc. have brought a significant change in overall outcome and profile of pediatric head injury Conclusion  The further developments in field of brain plasticity, stem cell, rehabilitation, evolution of new drugs, preventive community measures, and global policies to deal with head trauma are expected to play a major role in days to come. The development of future pediatric trauma centers based on current evolutions (in order to achieve a good outcome), global and emphatic preventions of trauma will be required to establish equilibrium between developed and developing countries.     

The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats

Experimental models of traumatic brain injury have been developed to replicate selected aspects of human head injury, such as contusion, concussion, and/or diffuse axonal injury. Although diffuse axonal injury is a major feature of clinical head injury, relatively few experimental models of diffuse traumatic brain injury (TBI) have been developed, particularly in smaller animals such as rodents. Here, we describe the pathophysiological consequences of moderate diffuse TBI in rats generated by a newly developed, highly controlled, and reproducible model. This model of TBI caused brain edema beginning 20 min after injury and peaking at 24 h post-trauma, as shown by wet weight/dry weight ratios and diffusion-weighted magnetic resonance imaging. Increased permeability of the blood-brain barrier was present up to 4 h post-injury as evaluated using Evans blue dye. Phosphorus magnetic resonance spectroscopy showed significant declines in brain-free magnesium concentration and reduced cytosolic phosphorylation potential at 4 h post-injury. Diffuse axonal damage was demonstrated using manganese-enhanced magnetic resonance imaging, and intracerebral injection of a fluorescent vital dye (Fluoro-Ruby) at 24-h and 7-day post-injury. Morphological evidence of apoptosis and caspase-3 activation were also found in the cerebral hemisphere and brainstem at 24 h after trauma. These results show that this model is capable of reproducing major biochemical and neurological changes of diffuse clinical TBI.     

Traumatic brain axonal injury produces sustained decline in intracellular free magnesium concentration

Decline in brain intracellular free magnesium concentration following experimental traumatic brain injury has been widely reported in a number of studies. However, to date, these studies have been confined to focal models of brain injury and temporally limited to the immediate 8-h period post-trauma. Recently, a new model of impact-acceleration brain injury has been developed which produces nonfocal diffuse axonal injury more typical of severe clinical trauma. The present study has used phosphorus magnetic resonance spectroscopy and the rotarod motor test to characterise magnesium homeostasis and neurologic outcome over a period of 8 days after induction of severe impact-acceleration injury in rats. Severe impact-acceleration induced injury resulted in a highly significant and sustained decline in intracellular free magnesium concentration that was apparent for 4 days post-trauma with recovery to preinjury levels by day six. There were no significant changes in pH or ATP concentration at any time point post-injury. All animals demonstrated a significant neurologic deficit over the assessment period. The extended period of magnesium decline after severe diffuse brain trauma suggests that repeated administration may be required for pharmacotherapies targeted at restoring magnesium homeostasis.     

直线加速度所致的猫弥漫性轴突损伤

目的：为了解直线加速度在颅脑损伤特别是在弥漫性轴突损伤（ＤＡＩ）中的作用。方法：用一套撞击装置对２６只猫进行实验。结果：直线加速度可以导致几乎所有类型的颅脑损伤，包括颅骨骨折、蛛网膜下腔出血、硬膜下血肿、硬膜外血肿、脑挫伤、脑干损伤，特别是ＤＡＩ。ＤＡＩ的特征性改变－轴突回缩球在２４小时内死亡的动物脑标本中看不到，２４小时后可见到，７２小时则多而典型，７天时仍然存在。结论：凡能使脑的神经纤维受到广泛剪力和（或）张力的任何形式的外部作用均可产生ＤＡＩ。     

弥漫性轴突损伤胆碱能纤维改变的实验研究

目的通过大鼠弥漫性脑损伤模型观察海马及乳头体内的轴突损伤,了解轴突损伤后上述结构中胆碱酯酶纤维的变化,探讨轴突损伤与伤后记忆功能障碍的相关性.方法用Marmarou介绍的落体打击装置致伤动物,对海马和乳头体区脑组织进行胆碱酯酶(AChE)纤维染色.结果该模型较好地模拟了轴突损伤的表现,简便实用.在这个模型中轴突损伤的最常见部位为桥脑基底部和小脑上脚,其次为大脑半球白质、海马和乳头体.海马结构内含有大量胆碱酯酶阳性染色纤维.与对照组相比中,损伤10天海马CA1区,CA3区,齿状回分子层和乳头体内纤维密度明显低于对照组大鼠(P＜0.01).结论大鼠损伤后海马区和乳头体内胆碱酯酶阳性纤维明显减少,这可能是弥漫性轴突损伤病人记忆功能损害的原因.     

Traumatically induced axonal damage without concomitant change in focally related neuronal somata and dendrites

Summary Traumatic head injury has long been associated with the genesis of reactive axonal change, which many believe to be a major factor in influencing neurological outcome. Although much significance has been attached to such a traumatically induced axonal change, little information exists as to whether such a reactive change occurs as an isolated event or rather as an event associated with concomitant focal tissue damage, possibly involving related neuronal somal and dendritic elements. This issue was critically assessed in mechanically brain-injured cats in which the anterograde axonal transport of horseradish peroxidase was employed to detect reactive axonal change. Following such traumatically induced reactive axonal change over a 21-day post-traumatic period, altered axons were consistently observed within the red, vestibular and reticular nuclei and any evidence for concomitant change within the related neuronal somal and dendritic elements was assessed using light and electron microscopy. Typically, such axonal change occurred without any evidence of focally related somatic or dendritic alteration. Isolated examples of reactive axons approximating neurons undergoing chromatolysis were observed. However, such neuronal chromatolytic change appeared not to be a primary response to trauma, but rather a response secondary to severence of these neurons' axonal projections. The results of this study demonstrate that, in mild to moderate head injury, reactive axonal change does occur in isolation from other forms of focal parenchymal abnormality. This finding, therefore, emphasizes the concept that the number of axons damaged is most likely related to the magnitude of any ensuing neurological abnormality.Supported by NIH grants NS 12587 and NS 20193 designated as a Javits Neuroscience Investigator Award     

A method to quantitate axonal injury

The quantitation of diffuse axonal injury provides a more objective approach to the assessment of tissue damage in head injuries. The method designed in this study takes into account the anisotropy and structural inhomogeneity of the brain, and the distribution of lesions in diffuse axonal injury. The number of counts required for the statistical analysis is inversely proportional to the square of the desired accuracy, specified as the percentage of the mean value of the axonal balloons since the true mean is unknown from the outset. The number of fields are examined using an indexed-squares graticule in 10 different areas of the brain. Silver-stained sections from the brains of head injured patients that survived longer than 12 h must be used with this method. Difficulties may arise when patients of different survival times are compared since it takes some time for the axonal balloons to develop. A correlation with the survival time can be established with the quantitative data collected. The morphometric principles and the statistical rationale on which this methodology is based are briefly presented.     

A preliminary histopathological study of the effect of agmatine on diffuse brain injury in rats

The present study evaluates the effects of agmatine on histopathological damage following traumatic injury using a clinically relevant model of diffuse brain injury. A total of 27 male Sprague-Dawley rats weighing 200-225g were anaesthetised and subjected to head trauma using Marmarou's impact-acceleration model. The rats were then separated into two main groups: one was treated with agmatine and the other with saline for up to 4 days immediately after head trauma. Rats from both groups were killed 1, 3 or 8 days post-injury. The brains were examined histopathologically and scored according to the axonal, neuronal and vascular changes associated with diffuse brain injury. There were no significant differences between the groups at 1day or 3 days after trauma, but evaluation after 8 days revealed a significant improvement in the group treated with agmatine. Our data indicate that agmatine has a beneficial effect in diffuse brain injury and should be trialled for therapeutic use in the management of this condition.     

严重头外伤后植物状态4例尸检报告

目的:探讨严重头外伤病人植物状态的原因。方法:对4例植物状态死者尸检观察。结果:4例尸检均可见脑及脑干弥漫性水肿,全部病例皮质及半数病例丘脑及豆状核有大灶性梗塞、出血,以及弥漫性轴索损害。结论:脑及脑干弥漫性水肿,广泛性缺血性损害及弥漫性轴索损害是严重头外伤后植物状态的形态学基础,致皮质间及皮质与丘脑间联系中断。     

Posttraumatic infarction in the territory supplied by the lateral lenticulostriate artery after minor head injury

Background Occlusion of the intracranial arteries due to blunt head traumas has been less frequently observed in patients with minor head injuries.Case report A 4-year-old boy presented with speech disturbance 2 h after minor head injury. An initial computed tomography (CT) scan showed a questionable finding of a focal punctate high density in the left basal ganglia. Hemiparesis developed on the right limbs 8 h post-injury, and a subsequent CT scan revealed a discrete low-density change around the focal high density. Diffusion-weighted images revealed a clearly demarcated high-signal intensity lesion in similar area on T2-weighted and fluid-attenuated inversion recovery sequences images, compatible with infarcted tissues on the territory supplied by the lateral lenticulostriate artery. His hemiparesis improved gradually, and by post-trauma day 10 he was able to walk briefly without assistance. He was discharged on foot at post-trauma day 14.Discussion and conclusion Children with minor head trauma who have normal findings on initial CT scan may rarely have basal ganglionic infarction resulting from arterial spasm or thromboembolism of the perforating arteries. Hospital admission and careful observation should be considered for patients with minor head injury and persistent neurologic deficits despite normal CT findings. Magnetic resonance study is valuable for the evaluation of posttraumatic infarction, differentiating from hemorrhagic diffuse axonal injuries.     

Trauma and impaired consciousness

This article discusses brain trauma and impaired consciousness. It reviews the various states of impaired consciousness related to trauma, with an historical and current literature viewpoint. The causes and pathophysiology of impaired consciousness in concussion, diffuse axonal injury, and focal brain lesions are discussed and management options evaluated.     

Low signal intensity and increased anisotropy on magnetic resonance imaging in the white matter lesion after head trauma: unrecognized findings of diffuse axonal injury

We report on a four-year-old girl with head trauma caused by a motor vehicle accident. She presented with delirium, oculomotor palsy and ptosis in her left eye, left hemiparesis, and pyramidal signs in all extremities. Computed tomography on the day of admission showed diffuse cerebral edema with right-sided predominance. Magnetic resonance images on day 3 of admission showed lesions of diffuse axonal injury and contusion in the corpus callosum and right occipital and bilateral temporal lobes. There was a low-intensity lesion in the white matter of the right hemisphere on T2-weighted images, fluid-attenuated inversion recovery, T2()-weighted images, apparent diffusion coefficient maps and diffusion-weighted images. This low-intensity lesion disappeared by day 7, and a transient brain atrophy in the right hemisphere appeared on day 28. The low signal intensity in the cerebral white matter was apparently different from that associated with contusion and typical diffuse axonal injury, and might represent a late-onset accumulation of non-heme iron and free radicals in the white matter after head trauma.     

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

The immature brain in the first several years of childhood is very vulnerable to trauma. Traumatic brain injury (TBI) during this critical period often leads to neuropathological and cognitive impairment. Previous experimental studies in rodent models of infant TBI were mostly concentrated on neuronal degeneration, while axonal injury and its relationship to cell death have attracted much less attention. To address this, we developed a closed controlled head injury model in infant (P7) mice and characterized the temporospatial pattern of axonal degeneration and neuronal cell death in the brain following mild injury. Using amyloid precursor protein (APP) as marker of axonal injury we found that mild head trauma causes robust axonal degeneration in the cingulum/external capsule as early as 30 min post-impact. These levels of axonal injury persisted throughout a 24 h period, but significantly declined by 48 h. During the first 24 h injured axons underwent significant and rapid pathomorphological changes. Initial small axonal swellings evolved into larger spheroids and club-like swellings indicating the early disconnection of axons. Ultrastructural analysis revealed compaction of organelles, axolemmal and cytoskeletal defects. Axonal degeneration was followed by profound apoptotic cell death in the posterior cingulate and retrosplenial cortex and anterior thalamus which peaked between 16 and 24 h post-injury. At early stages post-injury no evidence of excitotoxic neuronal death at the impact site was found. At 48 h apoptotic cell death was reduced and paralleled with the reduction in the number of APP-labeled axonal profiles. Our data suggest that early degenerative response to injury in axons of the cingulum and external capsule may cause disconnection between cortical and thalamic neurons, and lead to their delayed apoptotic death.