Utility of Early Magnetic Resonance Imaging to Enhance Outcome Prediction in Critically Ill Children with Severe Traumatic Brain Injury.

BACKGROUND: Many children with severe traumatic brain injury (TBI) receive magnetic resonance imaging (MRI) during hospitalization. There are insufficient data on how different patterns of injury on early MRI inform outcomes. METHODS: Children (3-17 years) admitted in 2010-2021 for severe TBI (Glasgow Coma Scale [GCS] score < 9) were identified using our site's trauma registry. We used multivariable modeling to determine whether the hemorrhagic diffuse axonal injury (DAI) grade and the number of regions with restricted diffusion (subcortical white matter, corpus callosum, deep gray matter, and brainstem) on MRI obtained within 7 days of injury were independently associated with time to follow commands and with Functional Independence Measure for Children (WeeFIM) scores at the time of discharge from inpatient rehabilitation. We controlled for the clinical variables age, preadmission cardiopulmonary resuscitation, pupil reactivity, motor GCS score, and fever (> 38 °C) in the first 12 h. RESULTS: Of 260 patients, 136 (52%) underwent MRI within 7 days of injury at a median of 3 days (interquartile range [IQR] 2-4). Patients with early MRI were a median age of 11 years (IQR 7-14), 8 (6%) patients received cardiopulmonary resuscitation, 19 (14%) patients had bilateral unreactive pupils, the median motor GCS score was 1 (IQR 1-4), and 82 (60%) patients had fever. Grade 3 DAI was present in 46 (34%) patients, and restricted diffusion was noted in the corpus callosum in 75 (55%) patients, deep gray matter in 29 (21%) patients, subcortical white matter in 23 (17%) patients, and the brainstem in 20 (15%) patients. After controlling for clinical variables, an increased number of regions with restricted diffusion, but not hemorrhagic DAI grade, was independently associated with longer time to follow commands (hazard ratio 0.68, 95% confidence interval 0.53-0.89) and worse WeeFIM scores (estimate ß - 4.67, 95% confidence interval - 8.33 to - 1.01). CONCLUSIONS: Regional restricted diffusion on early MRI is independently associated with short-term outcomes in children with severe TBI. Multicenter cohort studies are needed to validate these findings and elucidate the association of early MRI features with long-term outcomes in children with severe TBI.

Establishing a 3-Tesla Magnetic Resonance Imaging Method for Assessing Diffuse Axonal Brain Injury in Rats.

Traumatic brain injury (TBI) significantly contributes to death and disability worldwide. However, treatment options remain limited. Here, we focus on a specific pathology of TBI, diffuse axonal brain injury (DABI), which describes the process of the tearing of nerve fibers in the brain after blunt injury. Most protocols to study DABI do not incorporate a specific model for that type of pathology, limiting their ability to identify mechanisms and comorbidities of DABI. In this study, we developed a magnetic resonance imaging (MRI) protocol for DABI in a rat model using a 3-T clinical scanner. We compared the neuroimaging outcomes with histologic and neurologic assessments. In a sample size of 10 rats in the sham group and 10 rats in the DABI group, we established neurological severity scores before the intervention and at 48 h following DABI induction. After the neurological evaluation after DABI, all rats underwent MRI scans and were subsequently euthanized for histological evaluation. As expected, the neurological assessment showed a high sensitivity for DABI lesions indicated using the ß-APP marker. Surprisingly, however, we found that the MRI method had greater sensitivity in assessing DABI lesions compared to histological methods. Out of the five MRI parameters with pathological changes in the DABI model, we found significant changes compared to sham rats in three parameters, and, as shown using comparative tests with other models, MRI was the most sensitive parameter, being even more sensitive than histology. We anticipate that this DABI protocol will have a significant impact on future TBI and DABI studies, advancing research on treatments specifically targeted towards improving patient quality of life and long-term outcomes.

A study on the application of diffuse axonal multi-axis general evaluation for brain injury assessment in small overlap barrier crash test.

PURPOSE: Head injury criterion (HIC) companied by a rotation-based metric was widely believed to be helpful for head injury prediction in road traffic accidents. Recently, the Euro-New Car Assessment Program utilized a newly developed metric called diffuse axonal multi-axis general evaluation (DAMAGE) to explain test device for human occupant restraint (THOR) head injury, which demonstrated excellent ability in capturing concussions and diffuse axonal injuries. However, there is still a lack of comprehensive understanding regarding the effectiveness of using DAMAGE for Hybrid Ⅲ 50th percentile male dummy (H50th) head injury assessment. The objective of this study is to determine whether the DAMAGE could capture the risk of H50th brain injury during small overlap barrier tests. METHODS: To achieve this objective, a total of 24 vehicle crash loading curves were collected as input data for the multi-body simulation. Two commercially available mathematical dynamic models, namely H50th and THOR, were utilized to investigate the differences in head injury response. Subsequently, a decision method known as simple additive weighting was employed to establish a comprehensive brain injury metric by incorporating the weighted HIC and either DAMAGE or brain injury criterion. Furthermore, 35 sets of vehicle crash test data were used to analyze these brain injury metrics. RESULTS: The rotational displacement of the THOR head is significantly greater than that of the H50th head. The maximum linear and rotational head accelerations experienced by H50th and THOR models were (544.6 ± 341.7) m/s2, (2468.2 ± 1309.4) rad/s2 and (715.2 ± 332.8) m/s2, (3778.7 ± 1660.6) rad/s2, respectively. Under the same loading condition during small overlap barrier (SOB) tests, THOR exhibits a higher risk of head injury compared to the H50th model. It was observed that the overall head injury response during the small overlap left test condition is greater than that during the small overlap right test. Additionally, an equation was formulated to establish the necessary relationship between the DAMAGE values of THOR and H50th. CONCLUSION: If H50th rather than THOR is employed as an evaluation tool in SOB crash tests, newly designed vehicles are more likely to achieve superior performance scores. According to the current injury curve for DAMAGE and brain injury criterion, it is highly recommended that HIC along with DAMAGE was prioritized for brain injury assessment in SOB tests.

Role of integrin and its potential as a novel postmortem biomarker in traumatic axonal injury.

Traumatic axonal injury (TAI) accounts for a large proportion of the mortality of traumatic brain injury (TBI). The diagnosis of TAI is currently of limited use for medicolegal purposes. It is known that axons in TAI are diffusely damaged by secondary processes other than direct head injury. However, the physiopathological mechanism of TAI is still elusive. The present study used RGD peptide, an antagonist of the mechanotransduction protein integrin, to explore the role of integrin-transmitted mechanical signalling in the pathogenesis of rat TAI. The rats were subjected to a linearly accelerating load, and changes in beta-amyloid precursor protein (ß-APP) expression, skeleton ultrastructure, skeleton protein neurofilament light (NF-L), and α-tubulin in the brainstem were observed, indicating that RGD could relieve the severity of axonal injury in TAI rats. In addition, the expression of ß-integrin was stronger and centralized in the brainstem of the deceased died from TAI compared to other nonviolent causes. This study examined the pathophysiology and biomechanics of TAI and assessed the role of integrin in the injury of microtubules and neurofilaments in TAI. Thus, we propose that integrin-mediated cytoskeletal injury plays an important role in TAI and that integrin has the potential as a biomarker for TAI.

The Relationship Between Cortical Morphological and Functional Topological Properties and Clinical Manifestations in Patients with Posttraumatic Diffuse Axonal Injury: An Individual Brain Network Study.

To evaluate the altered network topological properties and their clinical relevance in patients with posttraumatic diffuse axonal injury (DAI). Forty-seven participants were recruited in this study, underwent 3D T1-weighted and resting-state functional MRI, and had single-subject morphological brain networks (MBNs) constructed by Kullback-Leibler divergence and functional brain networks (FBNs) constructed by Pearson correlation measurement interregional similarity. The global and regional properties were analyzed and compared using graph theory and network-based statistics (NBS), and the relationship with clinical manifestations was assessed. Compared with those of the healthy subjects, MBNs of patients with DAI showed a higher path length ([Formula: see text]: P = 0.021, [Formula: see text]: P = 0.011), lower clustering ([Formula: see text]: P = 0.002) and less small-worldness ([Formula: see text]: P = 0.002), but there was no significant difference in the global properties of FBNs (P: 0.161-0.216). For nodal properties of MBNs and FBNs, several regions showed significant differences between patients with DAI and healthy controls (HCs) (P < 0.05, FDR corrected). NBS analysis revealed that MBNs have more altered morphological connections in the frontal parietal control network and interhemispheric connections (P < 0.05). DAI-related global or nodal properties of MBNs were correlated with physical disability or dyscognition (P < 0.05/7, with Bonferroni correction), and the alteration of functional topology properties mediates this relationship. Our results suggested that disrupted morphological topology properties, which are mediated by FBNs and correlated with clinical manifestations of DAI, play a critical role in the short-term and medium-term phases after trauma.

[Primary injuries of corpus callosum vessels in craniocerebral injuries]. / Pervichnye povrezhdeniya sosudov mozolistogo tela pri cherepno-mozgovoi travme.

The aim of the scientific work is to establish morphological characteristics of hemorrhages in the corpus callosum as a marker of primary vascular injuries in diffuse axonal injury (DAI) in relation to the goals and objectives of forensic examination. Changes in the structures of corpus callosum were analyzed in 45 corpses of persons with traumatic brain injury who died in hospital from DAI diagnosed according to clinical and instrumental data within 24 hours after the trauma. The changes were characterized by rectic hemorrhages (haemorrhagia per rhexin) in combination with successively developing vascular, tissue, and cellular post-traumatic reactions. These changes were not observed in the control group. The following morphological characteristics of hemorrhages were established: small focal, elongated, clearly contoured hemorrhages of different sizes, up to 4 mm long, up to 0.8 mm wide, unidirectional at an angle from the lower to upper surface of the sagittal corpus callosum section, at least three, grouped in limited areas sized up to 1.5 × 1.0 cm without clear borders. The detected hemorrhages and the course of changes give reason to consider them the result of primary traumatic effects, making them a diagnostic marker of DAI.

Axonal Injury Partially Mediates Associations Between Increased Left Ventricular Mass Index and White Matter Damage.

BACKGROUND AND PURPOSE: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-ß, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure. METHODS: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE-ε4 positive, LV mass index 51.4±8.1 g/m2, NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE-ε4. In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations. RESULTS: Among all participants, LV mass index was unrelated to CSF biomarkers (P>0.33). LV mass index interacted with MCI (P=0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE-ε4 carriers (P=0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage. CONCLUSIONS: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE-ε4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage.

Center of mass and anatomical coordinate system definition for sheep head kinematics, with application to ovine models of traumatic brain injury.

Pathological outcomes of traumatic brain injury (TBI), including diffuse axonal injury, are influenced by the direction, magnitude, and duration of head acceleration during the injury exposure. Ovine models have been used to study injury mechanics and pathological outcomes of TBI. To accurately describe the kinematics of the head during an injury exposure, and better facilitate comparison with human head kinematics, anatomical coordinate systems (ACS) with an origin at the head or brain center of mass (CoM), and axes that align with the ovine Frankfort plane equivalent, are required. The aim of this study was to determine the mass properties of the sheep head and brain, and define an ACSvirtual for the head and brain, using anatomical landmarks on the skull with the aforementioned origins and orientation. Three-dimensional models of 10 merino sheep heads were constructed from computed tomography images, and the coordinates of the head and brain CoMs, relative to a previously reported sheep head coordinate system (ACSphysical ), were determined using the Hounsfield unit-mass density relationship. The ACSphysical origin was 34.8 ± 3.1 mm posterosuperior of the head CoM and 43.7 ± 1.7 anteroinferior of the brain CoM. Prominent internal anatomical landmarks were then used to define a new ACS (ACSvirtual ) with axes aligned with the Frankfort plane equivalent and an origin 10.4 ± 3.2 mm from the head CoM. The CoM and ACSvirtual defined in this study will increase the potential for comparison of head kinematics between ovine models and humans, in the context of TBI.

Segmented 3D Echo Planar Acquisition for Rapid Susceptibility-Weighted Imaging: Application to Microhemorrhage Detection in Traumatic Brain Injury.

BACKGROUND: Susceptibility-weighted imaging (SWI) provides superior image contrast of cerebral microhemorrhages (CMBs). It is based on a three-dimensional (3D) gradient echo (GRE) sequence with a relatively long imaging time. PURPOSE: To evaluate whether an accelerated 3D segmented echo planar imaging SWI is comparable to GRE SWI in detecting CMBs in traumatic brain injury (TBI). STUDY TYPE: Prospective. SUBJECTS: Four healthy volunteers and 46 consecutive subjects (38.0 ± 14.4 years, 16 females; 12 mild, 13 moderate, and 7 severe TBI). FIELD STRENGTH/SEQUENCE: A 3 T scanner/3D gradient echo and 3D segmented echo planar imaging (segEPI). ASSESSMENT: Brain images were acquired using GRE and segEPI in a single session (imaging time = 9 minutes 47 seconds and 1 minute 30 seconds, respectively). The signal-to-noise ratio (SNR) calculated from healthy volunteer thalamus and centrum semiovale were compared. CMBs were counted by three raters blinded to diagnostic information. STATISTICAL TESTS: A t-test was used to assess SNR difference. Pearson correlation and Wilcoxon signed-rank test were performed using CMB counts. The intermethod agreement was evaluated using Bland-Altman method. Intermethod and interrater reliabilities of image-based diffuse axonal injury (DAI) diagnoses were evaluated using Cohen's kappa and percent agreement. P ≤ 0.05 was considered statistically significant. RESULTS: Thalamus SNRs were 16.9 ± 2.2 and 16.5 ± 3 for GRE and segEPI (P = 0.84), respectively. Centrum semiovale SNRs were 25.8 ± 4.6 and 21.1 ± 2.7 (P = 0.13). The correlation coefficient of CMBs was 0.93, and differences were not significant (P = 0.56-0.85). For DAI diagnoses, Cohen's kappa was 0.62-0.84 and percent agreement was 85%-94%. DATA CONCLUSION: CMB counts on segEPI and GRE were highly correlated, and DAI diagnosis was made equally effectively. segEPI SWI can potentially replace GRE SWI in detecting TBI CMBs, especially when time constraints are critical. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Diffuse axonal injury has a characteristic multidimensional MRI signature in the human brain.

Axonal injury is a major contributor to the clinical symptomatology in patients with traumatic brain injury. Conventional neuroradiological tools, such as CT and MRI, are insensitive to diffuse axonal injury (DAI) caused by trauma. Diffusion tensor MRI parameters may change in DAI lesions; however, the nature of these changes is inconsistent. Multidimensional MRI is an emerging approach that combines T1, T2, and diffusion, and replaces voxel-averaged values with distributions, which allows selective isolation of specific potential abnormal components. By performing a combined post-mortem multidimensional MRI and histopathology study, we aimed to investigate T1-T2-diffusion changes linked to DAI and to define their histopathological correlates. Corpora callosa derived from eight subjects who had sustained traumatic brain injury, and three control brain donors underwent post-mortem ex vivo MRI at 7 T. Multidimensional, diffusion tensor, and quantitative T1 and T2 MRI data were acquired and processed. Following MRI acquisition, slices from the same tissue were tested for amyloid precursor protein (APP) immunoreactivity to define DAI severity. A robust image co-registration method was applied to accurately match MRI-derived parameters and histopathology, after which 12 regions of interest per tissue block were selected based on APP density, but blind to MRI. We identified abnormal multidimensional T1-T2, diffusion-T2, and diffusion-T1 components that are strongly associated with DAI and used them to generate axonal injury images. We found that compared to control white matter, mild and severe DAI lesions contained significantly larger abnormal T1-T2 component (P = 0.005 and P < 0.001, respectively), and significantly larger abnormal diffusion-T2 component (P = 0.005 and P < 0.001, respectively). Furthermore, within patients with traumatic brain injury the multidimensional MRI biomarkers differentiated normal-appearing white matter from mild and severe DAI lesions, with significantly larger abnormal T1-T2 and diffusion-T2 components (P = 0.003 and P < 0.001, respectively, for T1-T2; P = 0.022 and P < 0.001, respectively, for diffusion-T2). Conversely, none of the conventional quantitative MRI parameters were able to differentiate lesions and normal-appearing white matter. Lastly, we found that the abnormal T1-T2, diffusion-T1, and diffusion-T2 components and their axonal damage images were strongly correlated with quantitative APP staining (r = 0.876, P < 0.001; r = 0.727, P < 0.001; and r = 0.743, P < 0.001, respectively), while producing negligible intensities in grey matter and in normal-appearing white matter. These results suggest that multidimensional MRI may provide non-invasive biomarkers for detection of DAI, which is the pathological substrate for neurological disorders ranging from concussion to severe traumatic brain injury.

Ketogenic diet protects myelin and axons in diffuse axonal injury.

BACKGROUND: Ketogenic diet (KD) has been identified as a potential therapy to enhance recovery after traumatic brain injury (TBI). Diffuse axonal injury (DAI) is a common type of traumatic brain injury that is characterized by delayed axonal disconnection. Previous studies showed that demyelination resulting from oligodendrocyte damage contributes to axonal degeneration in DAI. AIM: The present study tests a hypothesis that ketone bodies from the ketogenic diet confers protection for myelin and attenuates degeneration of demyelinated axon in DAI. METHODS: A modified Marmarou's model of DAI was induced in adult rats. The DAI rats were fed with KD and analyzed with western blot, transmission electron microscope, ELISA test and immunohistochemistry. Meanwhile, a co-culture of primary oligodendrocytes and neurons was treated with ketone body ß-hydroxybutryate (ßHB) to test for its effects on the myelin-axon unit. RESULTS: Here we report that rats fed with KD showed an increased fatty acid metabolism and ketonemia. This dietary intervention significantly reduced demyelination and attenuated axonal damage in rats following DAI, likely through inhibition of DAI-induced excessive mitochondrial fission and promoting mitochondrial fusion. In an in vitro model of myelination, the ketone body ßHB increased myelination significantly and reduced axonal degeneration induced by glucose deprivation (GD). ßHB robustly increased cell viability, inhibited GD-induced collapse of mitochondrial membrane potential and attenuated death of oligodendrocytes. CONCLUSION: Ketone bodies protect myelin-forming oligodendrocytes and reduce axonal damage. Ketogenic diet maybe a promising therapy for DAI.

Prognosticating outcome using magnetic resonance imaging in patients with moderate to severe traumatic brain injury: a machine learning approach.

INTRODUCTION: Over the last decade advancements in computer processing have enabled the application of machine learning (ML) to complex medical problems. Convolutional neural networks (CNN), a type of ML, have been used to interrogate medical images for variety of purposes. In this study, we aimed to investigate the potential application of CNN in prognosticating patients with traumatic brain injury (TBI). METHODS: Patients with moderate to severe TBI and evidence of diffuse axonal injury (DAI) were selected retrospectively. A CNN model was developed using a training subgroup and a holdout subgroup was used as a testing dataset. We reported the model characteristics including area under the receiver operating characteristic curve (AUC). RESULTS: We included a total of 38 patient, of which we generated 725 MRI sections. We developed a CNN model based on a modified AlexNet architecture that interpreted the brain stem injury to generate outcome predictions. The model was able to predict GOS outcomes with a specificity of 0.43 and a sensitivity of 0.997. It showed an AUC of 0.917. CONCLUSION: The utilization of machine learning MRI analysis for prognosticating patients with TBI is a valued method that require further investigation. This will require multicentre collaboration to generate large datasets.

Diffuse Axonal Injury Grade on Early MRI is Associated with Worse Outcome in Children with Moderate-Severe Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is the leading cause of death and disability in children, but effective tools for predicting outcome remain elusive. Although many pediatric patients receive early magnetic resonance imaging (MRI), data on its utility in prognostication are lacking. Diffuse axonal injury (DAI) is a hallmark of TBI detected on early MRI and was shown previously to improve prognostication in adult patients with TBI. In this exploratory study, we investigated whether DAI grade correlates with functional outcome and improves prognostic accuracy when combined with core clinical variables and computed tomography (CT) biomarkers in pediatric patients with moderate-severe TBI (msTBI). METHODS: Pediatric patients (≤ 19 years) who were admitted to two regional level one trauma centers with a diagnosis of msTBI (Glasgow Coma Scale [GCS] score < 13) between 2011 and 2019 were identified through retrospective chart review. Patients who underwent brain MRI within 30 days of injury and had documented clinical follow-up after discharge were included. Age, pupil reactivity, and initial motor GCS score were collected as part of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. Imaging was reviewed to calculate the Rotterdam score (CT) and DAI grade (MRI) and to evaluate for presence of hypoxic-ischemic injury (MRI). The primary outcome measure was the Pediatric Cerebral Performance Category Scale (PCPCS) score at 6 months after TBI, with favorable outcome defined as PCPCS scores 1-3 and unfavorable outcome defined as PCPCS scores 4-6. The secondary outcome measure was discharge disposition to home versus to an inpatient rehabilitation facility. RESULT: Of 55 patients included in the study, 45 (82%) had severe TBI. The most common mechanism of injury was motor vehicle collision (71%). Initial head CT scans showed acute hemorrhage in 84% of patients. MRI was acquired a median of 5 days after injury, and hemorrhagic DAI lesions were detected in 87% of patients. Each 1-point increase in DAI grade increased the odds of unfavorable functional outcome by 2.4-fold. When controlling for core IMPACT clinical variables, neither the DAI grade nor the Rotterdam score was independently correlated with outcome and neither significantly improved outcome prediction over the IMPACT model alone. CONCLUSIONS: A higher DAI grade on early MRI is associated with worse 6-month functional outcome and with discharge to inpatient rehabilitation in children with acute msTBI in a univariate analysis but does not independently correlate with outcome when controlling for the GCS score. Addition of the DAI grade to the core IMPACT model does not significantly improve prediction of poor neurological outcome. Further study is needed to elucidate the utility of early MRI in children with msTBI.

Is Diffuse Axonal Injury Different in Adults and Children? An Analysis of National Trauma Database.

BACKGROUND: Diffuse axonal injury (DAI) is typically associated with significant mechanisms of injury and the effects of acceleration-deceleration forces on brain tissues. The prognosis of DAI remains a matter of active investigation, but little is known about outcome differences between adult and pediatric populations with DAI. METHODS: We performed a retrospective cohort study involving blunt trauma patients with DAI between the years 1997 and 2018 from the Israeli National Trauma Registry. The patients were divided to pediatric (age <15 years) and adult (age >15 years) groups, with subsequent comparison of demographics and outcomes. RESULTS: Diffuse axonal injury was identified in 1983 patients, including 469 pediatric victims (23.6%) and 1514 adults (76.4%). Adults had higher Injury Severity Score (20.5% vs 13.2%, P = 0.0004), increased mortality (17.7% vs 13.4%, P < 0.0001), longer hospitalizations (58.4% vs 44.4%, P < 0.001), and higher rehabilitation need rates (56.4% vs 41.8%, P < 0.0001). Associated extracranial injuries were also more common in adults, particularly to the chest. CONCLUSIONS: Pediatric patients with DAI have improved outcomes and fewer associated injuries than adult counterparts.

[Expert errors in formulating a forensic diagnosis and conclusions in cases of diffuse axonal brain damage]. / Ekspertnye oshibki pri formulirovanii sudebno-meditsinskogo diagnoza i vyvodov v sluchayakh diffuznogo aksonal'nogo povrezhdeniya mozga.

The study objective is to review expert errors in the wording of a post-mortem diagnosis and expert conclusions in cases of traumatic brain injury with diffuse axonal brain damage. We reviewed 50 corpse examinations of those who died from a traumatic brain injury with diffuse axonal brain damage. A retrospective analysis of the results of expert examinations, the structure of the post-mortem forensic diagnosis, and the validity of expert conclusions showed that expert errors were made in 30% of cases. In 93% of cases, the errors were epistemological due to the lack of a scientifically based methodological approach to the expert opinion on a particular mechanism for the development of traumatic brain injury with diffuse axonal brain damage; and lack of professional expertise. A case is provided demonstrating the most common expert errors in the examination of this type of traumatic brain injury.

[Morphological markers of pathophysiological changes in the neuronal processes in the acute post-traumatic period of diffuse axonal injury]. / Morfologicheskie markery patofiziologicheskikh izmenenii otrostkov neironov v ostrom posttravmaticheskom periode diffuznogo aksonal'nogo povrezhdeniya mozga.

The purpose of the study was to establish morphological markers of pathophysiological changes in the neuronal processes of in the acute (up to 36 hours) post-traumatic period of diffuse axonal injury (DAI) for the purposes of expert practice. Histological examination of the body of corpus callosum of the corpses of 66 persons dead from DAI and of 25 persons dead from various non-violent and violent causes, excluding head trauma, was performed (control group). Morphological markers of specific pathophysiological changes in the neuronal process were established by light microscopy with the use of immunohistochemical examination in acute period DAI. Uneven contours of the processes suggested displacement of cytoskeletal elements, areas of vacuolization of the cytoplasm of the processes suggested violation of intracellular transport caused by a change of permeability with preserved integrity of the process shell without mechanical separation of the process, uneven thickness (3.9 ± 1.6 µm) of the processes, varicose and cone-shaped thickening of them was a manifestation of focal edema of the neuronal process and compression of the cytoskeleton as a result of ion-enzymatic disorders, uneven coloration, areas of fragmentary compaction of neurofilaments indicated the zones of deformation and compression of the cytoskeleton, zones of granular-lumpy decay and fibrillolysis of neurofilaments indicated destruction of the cytoskeleton. Changes in the neuronal processes are a manifestation of a polyethological general pathological process and are not a differential diagnostic criterion of DAI.

[Methodology for forensic diagnosis of diffuse axonal injury]. / Metodologiya sudebno-meditsinskoi diagnostiki diffuznogo aksonal'nogo povrezhdeniya golovnogo mozga.

An original methodological approach for forensic diagnostics of diffuse axonal injury (DAI) was developed based on the comprehensive study results. The approach is based on the algorithm of expert actions, including utilizing the developed rational methods set to identify pathognomonic morphological features using accessible and effective histological techniques. Also, the approach includes ways of analysis and estimation of these features. The proposed methodological approach aims to provide an objective diagnosis of this type of traumatic brain injury (TBI) and establish the age of its acute post-traumatic period. The known and generally accepted definitions of DAI and TBI are clarified.

[Problems of forensic diagnosis of diffuse axonal brain injury in the acute post-traumatic period]. / Problemy sudebno-meditsinskoi diagnostiki ostrogo perioda diffuznogo aksonal'nogo povrezhdeniya golovnogo mozga.

The article refers to actual problems of forensic diagnostics of diffuse axonal brain injury in the acute post-traumatic period, that is of particular importance in the case of head trauma in conditions of non-evidence. To solve the existing problems, it is necessary to conduct a comprehensive study aimed at improving the diffuse axonal brain injury examination by developing a unified methodological approach to running the forensic medical diagnostics of this form of traumatic brain injury and determining the duration of the acute (up to three days) post-traumatic period.

[Clinical presentation and gross appearance of diffuse axonal injury in the early post-injury period]. / Klinicheskaya i makroskopicheskaya kharakteristika diffuznogo aksonal'nogo povrezhdeniya mozga v ostrom posttravmaticheskom periode.

The objective of the study was to investigate and characterize the clinical presentation, and establish macroscopic diagnostic signs of diffuse axonal injury (DAI) in the early (up to 3 days) post-injury period. In DAI, coma develops immediately after head injury and persists for 3 days post-injury until death. The coma is accompanied by dominant primary stem neurological symptoms, hemodynamic and respiratory disturbances and does not progress to a vegetative state. Lifetime computed tomography reveals cerebral hemorrhage in 40.5% of cases. We established the macroscopic signs of head injury in DAI. For the postmortem diagnosis of DAI, a detailed macroscopic appearance of pathognomonic cerebral hemorrhages is given, which are most frequently (67.5%) localized in the corpus callosum (CC), namely in the area from its genu to the middle of the trunk (97%). A rational, improved scheme of excision of CC trunk areas for the histological study is proposed.

Diffuse axonal injury predicts neurodegeneration after moderate-severe traumatic brain injury.

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials.