Extensive traumatic axonal injury of brain due to violence: A case report.

RATIONALE: Many studies using diffusion tensor imaging (DTI) have demonstrated traumatic axonal injury (TAI) in patients whose conventional brain magnetic resonance imaging (MRI) results are negative following head trauma. Injury mechanism for TAI in these patients has been mainly associated with motor vehicle accident, whereas very little is known about TAI by violence. PATIENT CONCERNS: A 42-year-old male patient presented after experiencing head trauma due to violence. His face was hit several times by 2 men, and 1 of the men kicked the right side of the patient's head, after which the patient's left parietal area hit the ground while falling. After the head trauma, he felt mild motor weakness of the left upper and lower extremities and had mild articulation difficulty, cognitive dysfunction including memory impairment, and excessive daytime sleepiness. DIAGNOSES: The patient was diagnosed as TAI. INTERVENTIONS: Clinical assessments and DTI were performed at 10 days after the head trauma. OUTCOMES: He showed mild left hemiparesis (5/4), mild dysarthria, mild cognitive abnormality (Clinical Dementia Rating: 0.5) and mild abnormality on the Epworth Sleepiness Scale (score: 12; cut-off score: 10, maximum score: 24). DTI showed the following configurational abnormalities: right corticospinal tract narrowing, left corticobulbar tract narrowing, discontinuations in the anterior portion of both cingula, discontinuation of the left fornical crus, non-reconstruction of the right dorsolateral prefronto-thalamic tract, and narrowing in both lower ventral ascending reticular activating systems. LESSONS: Extensive TAI of various neural tracts was demonstrated by performing DTI of a patient with head trauma due to violence. Analysis of the neural tracts via DTI can be useful in detection of TAI in patients who show various neurological features following head trauma due to violence.

Thalamic atrophy and dysfunction in patients with mild-to-moderate traumatic diffuse axonal injury: a short-term and mid-term MRI study.

Disrupted white matter structure has been established in patients with diffuse axonal injury (DAI), but morphological changes in gray matter and local intrinsic activity in the short and midterm (before 6 months) have not been documented in DAI patients. We hypothesized that regionally selective atrophy observed in deep gray matter in the short-term and mid-term periods in patients with mild-to-moderate DAI, local atrophy, and/or dysfunction would be related to clinical characteristics. We evaluated the changes in regional density and synchronization in 18 DAI patients separately using Diffeomorphic Anatomical Registration through Exponentiated Lie algebra-enhanced voxel-based morphometry and regional homogeneity (ReHo). Compared with the controls, DAI patients showed a decreased density in the bilateral thalami and decreased ReHo values in the ventral anterior and ventral lateral nuclei of the bilateral thalami. Pearson's correlation analysis showed that decreased density in the bilateral thalami was correlated negatively with time since injury and decreased ReHo values in the ventral anterior and ventral lateral nuclei of the bilateral thalami were associated with a worsened motor assessment scale. These findings suggest that mild-to-moderate traumatic DAI within the short and midterm could lead to thalamic atrophy and that dysfunction in the bilateral thalami is associated with declining motor function. This study could potentially provide complementary evidence as an important element in longitudinal studies.

Profiling biomarkers of traumatic axonal injury: From mouse to man.

Traumatic brain injury (TBI) poses a major public health problem on a global scale. Its burden results from high mortality and significant morbidity in survivors. This stems, in part, from an ongoing inadequacy in diagnostic and prognostic indicators despite significant technological advances. Traumatic axonal injury (TAI) is a key driver of the ongoing pathological process following TBI, causing chronic neurological deficits and disability. The science underpinning biomarkers of TAI has been a subject of many reviews in recent literature. However, in this review we provide a comprehensive account of biomarkers from animal models to clinical studies, bridging the gap between experimental science and clinical medicine. We have discussed pathogenesis, temporal kinetics, relationships to neuro-imaging, and, most importantly, clinical applicability in order to provide a holistic perspective of how this could improve TBI diagnosis and predict clinical outcome in a real-life setting. We conclude that early and reliable identification of axonal injury post-TBI with the help of body fluid biomarkers could enhance current care of TBI patients by (i) increasing speed and accuracy of diagnosis, (ii) providing invaluable prognostic information, (iii) allow efficient allocation of rehabilitation services, and (iv) provide potential therapeutic targets. The optimal model for assessing TAI is likely to involve multiple components, including several blood biomarkers and neuro-imaging modalities, at different time points.

Thalamocortical Sensorimotor Circuit Damage Associated with Disorders of Consciousness for Diffuse Axonal Injury Patients.

The relationship of structural and functional brain damage and disorders of consciousness (DOC) for diffuse axonal injury (DAI) is still not fully explored. We employed diffusion tensor imaging (DTI) and resting-state fMRI (RS-fMRI) to examine the changes of resting activations and white matter (WM) integrity for DAI with DOC. WM damages were observed in the body and genu of the corpus callosum, right external capsule (EC) and superior corona radiate (SCR), left superior cerebellar peduncle (SCP) and posterior thalamic radiation (PTR). The RS-fMRI revealed augmented amplitude of low-frequency fluctuation (ALFF) in the anterior cingulate cortex, hippocampus, insula, amygdala and putamen, and reduced ALFF in the precuneus, thalamus, pre-central and post-central gyri. Correlation analysis identified positive associations between the Glasgow Coma Scale (GCS) and activation of the precuneus and between GCS and DTI measurements in the left PTR and SCP, but a negative correlation was found between GCS and activation of the thalamus. Cross modality association analyses indicated that activations of the amygdala and postcentral gyrus were correlated with DTI measurements of the right EC and left PTR respectively. These results implicate that the WM damages in thalamocortical sensorimotor circuit and aberrant brain activity responding to self-awareness and sensation are critical factors to DOC, which expand the current understanding of the neural mechanisms underlying DAI.

Hypothalamic-amygdalar-brainstem volume reduction in a patient with narcolepsy secondary to diffuse axonal injury.

A 17-year-old male with diffuse axonal injury (DAI) was referred to our psychiatric clinic with a diagnosis of depression. However, further investigation indicated that he had narcolepsy without cataplexy secondary to DAI. We assessed regional volume alterations in the patient; MRI analysis showed a significant decrease in the volume of the hypothalamus, left amygdala, and brainstem. Our findings add to further understanding of the structural basis of secondary narcolepsy, and may provide basis for future neuroimaging studies on sleep disturbances in traumatic brain injury (TBI).

Deafferentation in thalamic and pontine areas in severe traumatic brain injury.

PURPOSE: Severe traumatic brain injury (TBI) is characterized mainly by diffuse axonal injuries (DAI). The cortico-subcortical disconnections induced by such fiber disruption play a central role in consciousness recovery. We hypothesized that these cortico-subcortical deafferentations inferred from diffusion MRI data could differentiate between TBI patients with favorable or unfavorable (death, vegetative state, or minimally conscious state) outcome one year after injury. METHODS: Cortico-subcortical fiber density maps were derived by using probabilistic tractography from diffusion tensor imaging data acquired in 24 severe TBI patients and 9 healthy controls. These maps were compared between patients and controls as well as between patients with favorable (FO) and unfavorable (UFO) 1-year outcome to identify the thalamo-cortical and ponto-thalamo-cortical pathways involved in the maintenance of consciousness. RESULTS: Thalamo-cortical and ponto-thalamo-cortical fiber density was significantly lower in TBI patients than in healthy controls. Comparing FO and UFO TBI patients showed thalamo-cortical deafferentation associated with unfavorable outcome for projections from ventral posterior and intermediate thalamic nuclei to the associative frontal, sensorimotor and associative temporal cortices. Specific ponto-thalamic deafferentation in projections from the upper dorsal pons (including the reticular formation) was also associated with unfavorable outcome. CONCLUSION: Fiber density of cortico-subcortical pathways as measured from diffusion MRI tractography is a relevant candidate biomarker for early prediction of one-year favorable outcome in severe TBI.

Traumatic axonal injury: the prognostic value of lesion load in corpus callosum, brain stem, and thalamus in different magnetic resonance imaging sequences.

The aim of this study was to explore the prognostic value of visible traumatic axonal injury (TAI) loads in different MRI sequences from the early phase after adjusting for established prognostic factors. Likewise, we sought to explore the prognostic role of early apparent diffusion coefficient (ADC) values in normal-appearing corpus callosum. In this prospective study, 128 patients (mean age, 33.9 years; range, 11-69) with moderate (n = 64) and severe traumatic brain injury (TBI) were examined with MRI at a median of 8 days (range, 0-28) postinjury. TAI lesions in fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and T2*-weighted gradient echo (T2*GRE) sequences were counted and FLAIR lesion volumes estimated. In patients and 47 healthy controls, mean ADC values were computed in 10 regions of interests in the normal-appearing corpus callosum. Outcome measure was the Glasgow Outcome Scale-Extended (GOS-E) at 12 months. In patients with severe TBI, number of DWI lesions and volume of FLAIR lesions in the corpus callosum, brain stem, and thalamus predicted outcome in analyses with adjustment for age, Glasgow Coma Scale score, and pupillary dilation (odds ratio, 1.3-6.9; p = <0.001-0.017). The addition of Rotterdam CT score and DWI lesions in the corpus callosum yielded the highest R2 (0.24), compared to all other MRI variables, including brain stem lesions. For patients with moderate TBI only the number of cortical contusions (p = 0.089) and Rotterdam CT score (p = 0.065) tended to predict outcome. Numbers of T2*GRE lesions did not affect outcome. Mean ADC values in the normal-appearing corpus callosum did not differ from controls. In conclusion, the loads of visible TAI lesions in the corpus callosum, brain stem, and thalamus in DWI and FLAIR were independent prognostic factors in patients with severe TBI. DWI lesions in the corpus callosum were the most important predictive MRI variable. Interestingly, number of cortical contusions in MRI and CT findings seemed more important for patients with moderate TBI.

Whole-brain proton MR spectroscopic imaging of mild-to-moderate traumatic brain injury and correlation with neuropsychological deficits.

Changes in the distribution of the magnetic resonance (MR)-observable brain metabolites N-acetyl aspartate (NAA), total choline (Cho), and total creatine (Cre), following mild-to-moderate closed-head traumatic brain injury (mTBI) were evaluated using volumetric proton MR spectroscopic imaging (MRSI). Studies were carried out during the subacute time period following injury, and associations of metabolite indices with neuropsychological test (NPT) results were evaluated. Twenty-nine subjects with mTBI and Glasgow Coma Scale (GCS) scores of 10-15 were included. Differences in individual metabolite and metabolite ratio distributions relative to those of age-matched control subjects were evaluated, as well as analyses by hemispheric lobes and tissue types. Primary findings included a widespread decrease of NAA and NAA/Cre, and increases of Cho and Cho/NAA, within all lobes of the TBI subject group, and with the largest differences seen in white matter. Examination of the association between all of the metabolite measures and the NPT scores found the strongest negative correlations to occur in the frontal lobe and for Cho/NAA. No significant correlations were found between any of the MRSI or NPT measures and the GCS. These results demonstrate that significant and widespread alterations of brain metabolites occur as a result of mild-to-moderate TBI, and that these measures correlate with measures of cognitive performance.

Combination of Mn(2+)-enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve.

PURPOSE: To evaluate manganese (Mn(2+))-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) as tools for detection of axonal injury and regeneration after intravitreal peripheral nerve graft (PNG) implantation in the rat optic nerve (ON). MATERIALS AND METHODS: In adult Fischer rats, retinal ganglion cell (RGC) survival was evaluated in Flurogold (FG) back-filled retinal whole mounts after ON crush (ONC), intravitreal PNG, and intravitreal MnCl(2) injection (150 nmol) at 0 and 20 days post lesion (dpl). MEMRI and echo-planar DTI (DTI-EPI) was obtained of noninjured ON one day after intravitreal MnCl(2) injection, and at 1 and 21 dpl after ONC, intravitreal PNG, and intravitreal MnCl(2) injections given at 0 and 20 dpl. GAP-43 immunohistochemistry was performed after the last MRI. RESULTS: ONC reduced RGC density in retina by 94% at 21 dpl compared to noninjured ON without MnCl(2) injections. Both intravitreal PNG and intravitreal MnCl(2) injections improved RGC survival in retina, which was reduced by 90% (ONC+MnCl(2)), 82% (ONC+PNG), and 74% (ONC+PNG+MnCl(2)) compared to noninjured ON. DTI-derived parameters (fractional anisotropy [FA], mean diffusivity, axial diffusivity lambda( parallel), and radial diffusivity lambda( perpendicular)) were unaffected by the presence of Mn(2+) in the ON. At 1 dpl, CNR(MEMRI) and lambda( parallel) were reduced at the injury site, while at 21 dpl they were increased at the injury site compared to values measured at 1 dpl. GAP-43 immunoreactive axons were present in the ON distal to the ONC injury site. CONCLUSION: MEMRI and DTI enabled detection of functional and structural degradation after rat ON injury, and there was correlation between the MRI-derived and immunohistochemical measures of axon regeneration.

[Effect of Chinese medicine Huishen granule on cognitive outcome following diffuse axonal injury: experiment with rats].

OBJECTIVE: To investigate the influence of Chinese medicine Huishen granule (HG) containing ginseng, grassleaved sweet flag rhizome, pilose deer antler, etc, on learning and memory functions in diffuse axonal injury (DAI) and the mechanisms thereof. METHODS: Impact acceleration method was used to establish DAI Wistar rat models. Twenty model rats were randomly divided into 2 equal groups, the DAI+HG group treated with gastric perfusion of HG 3 times a day since 24 h after the establishment of model for 14 days, and the DAI group without treatment. Ten rats underwent sham operation as controls. Fourteen days after the injury, Morris water maze (MWM) test was used to detect the rat's abilities of learning and memory for continuous 5 days. The changes of escape latency in acquisition of the task, the percentage of time spent in target quadrant, and the number of crossing the point of original platform in probe test were recorded. At day 20 after the-operation, the rats were subjected to long-term potentiation (LTP) recording in hippocampus to measure the percentage of slope and baseline of excitatory post-synaptic potential (EPSP). Two rats from each group were killed 24 h, 14 d, and 20 d after the operation with their brains taken out, HE and immunohistochemical staining were employed to exam the brain lesion at 24 h, day 14 and 20 post-injury. RESULTS: The escape latency of the DAI group was (32.8+/-4.6) s, significantly longer than those of the DAI+HG and sham operation groups [(20.3+/-0.7) and (16.8+/-0.8) s respectively, both P<0.05]. The target quadrant staying time percentage and number of platform location crossings of the DAI group were (36.4+/-3.2)% and 4.5+/-0.6 respectively, both significantly less than those of the DAI+HG and sham operation groups [(46.0+/-2.4)% and 6.8+/-0.8, and (46.9+/-2.1)% and 8.1+/-0.8 respectively, all P<0.05]. The LTP level of the DAI group was (101.4+/-3.3)%, significantly lower than those of the DAI+HG and sham operation groups [(116.3+/-6.7)% and (117.9+/-2.8)% respectively, both P<0.05]. No significant differences in the parameters were found between the DAI+HG and sham operation groups (all P>0.05). Classical pathological changes of DAI occurred in the brains of the DAI and DAI+HG groups at the time point of 24 h, and mitigated partly at the time points of day 14 and 20. CONCLUSION: The learning and memory impairment of DAI was ameliorated significantly with the treatment of Chinese medicine HG, owing to the recuperation of synaptic plasticity in hippocampal area.

Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin.

Periventricular leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [beta-amyloid precursor protein (beta-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis. Using beta-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages, a finding consistent with others. Interestingly, GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. We conclude that diffuse axonal injury, as determined by apoptotic marker fractin, occurs in PVL and that its cause likely includes primary ischemia and trophic degeneration secondary to corticothalamic neuronal damage.

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.

Perisomatic thalamic axotomy after diffuse traumatic brain injury is associated with atrophy rather than cell death.

Morbidity and mortality associated with traumatic brain injury (TBI) stem from diffuse axonal injury (DAI) throughout subcortical and brainstem white matter and subcortical nuclei. After midline fluid percussion brain injury, DAI in the thalamus includes perisomatic axotomy and resembles human post-traumatic pathology where the degree of morbidity correlates with thalamic damage. After axotomy, acute somatic perturbations resolve and appear compatible with cell survival; however, the long-term fate of neurons in an area with perisomatic axotomy is unknown. From brain-injured and uninjured rats at 1, 7 and 28 days after injury (injury, n = 5/group; sham, n = 4), alternate sections were immunostained for amyloid precursor protein (APP) to detect perisomatic axotomy or Giemsa stained for quantification of neuronal number, neuronal density, regional volume, and neuronal nuclear volume using design-based stereology. One day postinjury, APP-immunoreactive axons were identified consistently within the perisomatic domains of thalamic neurons of the ventral basal complex. Bilateral systematic-random quantification of the ventral basal complex indicated a significant reduction in neuronal density (number per mm, but not number alone) at 1 week after injury, compared with sham and 1 day postinjury. Furthermore, by 1 day and persisting through 1 week after injury, the mean neuronal nuclear volume was atrophied significantly compared with sham. Therefore, diffuse TBI results in early perisomatic axonal injury followed by neuronal atrophy in the ventral basal complex, without gross degeneration. Enduring atrophy in thalamic relays could underlie circuit disruption responsible for post-traumatic morbidity.

Neurotrophic factors attenuate microvascular permeability disturbances and axonal injury following trauma to the rat spinal cord.

Alterations of the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI) and leakage of serum proteins induce vasogenic edema and cell damage. The possibility that two members of the neurotrophin family, BDNF or IGF-1 induce neuroprotection by attenuating the BSCB permeability following trauma was examined in a rat model. Repeated topical application of BDNF or IGF-1 (0.1 1microg, 0.5 microg or 1 microg in 10 microl) onto the spinal cord 30 min before SCI or 2, 5, 10 or 30 min thereafter significantly attenuated BSCB permeability to Evans blue and iodine. In the neurotrophin treated rats. edema formation, degradation of MBP, and myelin vesiculation were much less frequent compared to the untreated traumatised rats. The protective effect of BDNF and IGF-1 was most pronounced at the high dose (1 microg in 10 microl) given either 30 min before or within 10 min after SCI. The observations suggest that early intervention with neurotrophins in high doses following trauma (within 10 min) attenuates disturbances of the fluid microenvironment of the spinal cord. This indicates that BSCB opening plays an important role in SCI induced myelin vesiculation and cord pathology.

The structural basis of moderate disability after traumatic brain damage.

The objective was to discover the nature of brain damage in survivors of head injury who are left with moderate disability. Macroscopic and microscopic examination was carried out on the brains of 20 persons who had died long after a head injury that had been treated in a neurosurgical unit. All had become independent but had various disabilities (moderate disability on the Glasgow outcome scale) Most deaths had been sudden, which had led to their referral from forensic pathologists. Post-traumatic epilepsy was a feature in 75%. An intracranial haematoma had been evacuated in 75%, and in 11 of the 15 with epilepsy. Diffuse axonal injury was found in six patients, five of the mildest type (grade 1) and one of grade 2. No patient had diffuse thalamic damage but one had a small focal ischaemic lesion in the thalamus. No patient had severe ischaemic brain damage, but three had moderate lesions which were bilateral in only one. No patient had severe cortical contusions. In conclusion, the dominant lesion was focal damage from an evacuated intracranial haematoma. Severe diffuse damage was not found, with diffuse axonal injury only mild and thalamic damage in only one patient.