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"Brain hemorrhage"
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Key Role of Sulfonylurea Receptor 1 in Progressive Secondary Hemorrhage after Brain Contusion
An important but poorly understood feature of traumatic brain injury (TBI) is the clinically serious problem of spatiotemporal progression (“blossoming”) of a hemorrhagic contusion, a phenomenon we term progressive secondary hemorrhage (PSH). Molecular mechanisms of PSH are unknown and efforts to reduce it by promoting coagulation have met with equivocal results. We hypothesized that PSH might be due to upregulation and activation of sulfonylurea receptor 1 (SUR1)-regulated NCCa-ATP channels in capillary endothelial cells, predisposing to oncotic death of endothelial cells and catastrophic failure of capillary integrity. Anesthetized adult male rats underwent left parietal craniectomy for induction of a focal cortical contusion. The regulatory subunit of the channel, SUR1, was prominently upregulated in capillaries of penumbral tissues surrounding the contusion. In untreated rats, PSH was characterized by progressive enlargement of the contusion deep into the site of cortical impact, including corpus callosum, hippocampus, and thalamus, by progressive accumulation of extravasated blood, with a doubling of the volume during the first 12 h after injury, and by capillary fragmentation in penumbral tissues. Block of SUR1 using low-dose (non-hypoglycemogenic) glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in the size of the necrotic lesion and in preservation of neurobehavioral function. Antisense oligodeoxynucleotide against SUR1, administered after injury, reduced both SUR1 expression and PSH, consistent with a requirement for transcriptional upregulation of SUR1. Our findings provide novel insights into molecular mechanisms responsible for PSH associated with hemorrhagic contusions, and point to SUR1 as a potential therapeutic target in TBI.
Journal Article
Progression of Traumatic Intracerebral Hemorrhage: A Prospective Observational Study
Preliminary evidence has shown that intracerebral hemorrhages, either spontaneous (sICH) or traumatic (tICH) often expand over time. An association between hemorrhage expansion and clinical outcomes has been described for sICH. The intent of this prospective, observational study was to characterize the temporal profile of hemorrhage progression, as measured by serial computed tomography (CT) scanning, with the aim of better understanding the natural course of hemorrhage progression in tICH. There was also a desire to document the baseline adverse event (AE) profile in this patient group. An important motive for performing this study was to set the stage for subsequent studies that will examine the role of a new systemic hemostatic agent in tICH. Subjects were enrolled if they had tICH lesions of at least 2 mL on a baseline CT scan obtained within 6 h of a head injury. CT scans were repeated at 24 and 72 h. Clinical outcomes and pre-defined AEs were documented. The data showed that 51% of the subjects demonstrated an increase in tICH volume, and that most of the increase occurred early. In addition, larger hematomas exhibited the greatest expansion. Thromboembolic complications were identified in 13% of subjects. This study demonstrates that tICH expansion between the baseline and 24-h CT scans occurred in approximately half of the subjects. The earlier after injury that the initial CT scan is obtained, the greater is the likelihood that the hematoma will expand on subsequent scans. The time frame during which hemorrhagic expansion occurs provides an opportunity for early intervention to limit a process with adverse prognostic implications.
Journal Article
Early Hemorrhagic Progression of Traumatic Brain Contusions: Frequency, Correlation with Coagulation Disorders, and Patient Outcome: A Prospective Study
The focus of this paper is to identify and quantify risk factors for early hemorrhagic progression of brain contusions (HPC) in patients with traumatic brain injury (TBI) and to evaluate their impact on patients' outcome. Further, based on abnormal values in routine blood tests, the role of trauma-induced coagulopathy is analyzed in detail. Therefore, a prospective study of 153 TBI patients was completed at one institution between January 2008 and June 2012. The collected data included demographics, initial Glasgow Coma Scale pupillary response, initial and 6 h follow-up computed tomography scan findings, coagulation parameters (international normalized ratio, partial thromboplastin time, platelet count, fibrinogen, D-dimer and factor XIII), as well as outcome data using the modified Rankin score at discharge and after one year. The overall rate of early HPC within the first 6 h was 43.5%. The frequency of coagulopathy was 47.1%. When analyzing for risk factors that independently influenced outcome in the form of mRS ≥4 at both points, the following variables appeared: elevated D-dimer level (≥10,000 μg/L), HPC, and initial brain contusions ≥3 cm. Patients sustaining early HPC had a hazard ratio of 5.4 for unfavorable outcome at discharge (p=0.002) and of 3.9 after one year (p=0.006). Overall, patients who developed early HPC were significantly more likely to be gravely disabled or to die. Unfavorable neurological outcome after an isolated TBI is determined largely by early HPC and coagulopathy, which seem to occur very frequently in TBI patients, irrespective of the severity of the trauma.
Journal Article
Simvastatin-Mediated Upregulation of VEGF and BDNF, Activation of the PI3K/Akt Pathway, and Increase of Neurogenesis Are Associated with Therapeutic Improvement after Traumatic Brain Injury
This study was undertaken to evaluate the effect of simvastatin, a cholesterol-lowering agent, on the Akt-mediated signaling pathway and neurogenesis in the dentate gyrus (DG) of the hippocampus in rats after traumatic brain injury (TBI). Adult male Wistar rats were divided into three groups: (1) sham group (n = 8); (2) saline control group (n = 40); and (3) simvastatin-treated group (n = 40). Controlled cortical impact (CCI) injury was performed over the left parietal lobe. Simvastatin was administered orally at a dose of 1 mg/kg starting at day 1 after TBI and then daily for 14 days. Bromodeoxyuridine (BrdU) was injected intraperitoneally into rats. A modified Morris Water Maze (WM) task was performed between 31 and 35 days after treatment to test spatial memory (n = 8/group). Animals were sacrificed at 1, 3, 7, 14, and 35 days after treatment (n = 8/group/time point). Western blot was utilized to investigate the changes in the Akt-mediated signaling pathway. Enzyme-linked immunosorbent assay (ELISA) analyses were employed to measure vascular endothelial growth factor (VEGF) and brain-derived neurotrophin factor (BDNF) expression. Immunohistochemical and fluorescent staining were performed to detect the BrdU- and neuronal nuclei (NeuN)/BrdU-positive cells. Our data show that simvastatin treatment increases phosphorylation of v-akt murine thymoma viral oncogene homolog (Akt), glycogen synthase kinase-3β (GSK-3β), and cAMP response element-binding proteins (CREB); elevates the expression of BDNF and VEGF in the DG; increases cell proliferation and differentiation in the DG; and enhances the recovery of spatial learning. These data suggest that the neurorestorative effect of simvastatin may be mediated through activation of the Akt-mediated signaling pathway, subsequently upregulating expression of growth factors and inducing neurogenesis in the DG of the hippocampus, thereby leading to restoration of cognitive function after TBI in rats.
Journal Article
Traumatic Brain Injury-Associated Coagulopathy
Traumatic injury is a common cause of coagulopathy, primarily due to blood loss and hemodilution secondary to fluid resuscitation. Traumatic injury-associated coagulopathy often follows a course of transition from hyper- to hypocoagulable state exemplified in disseminated intravascular coagulation. The incidence of coagulopathy is significantly higher in patients with traumatic brain injury (TBI), especially those with penetrating trauma compared to injury to the trunk and limbs. This occurs despite the fact that patients with isolated TBI bleed less and receive restricted volume load of fluids. TBI-associated coagulopathy is extensively documented to associate with poor clinical outcomes, but its pathophysiology remains poorly understood. Studies in the past have shown that brain tissue is highly enriched in key procoagulant molecules. This review focuses on the biochemical and cellular characteristics of these molecules and pathways that could make brain uniquely procoagulant and prone to coagulopathy. Understanding this unique procoagulant environment will help to identify new therapeutic targets that could reverse a state of coagulopathy with minimal impacts on hemostasis, a critical requirement for neurosurgical treatments of TBI.
Journal Article
Revisiting Grade 3 Diffuse Axonal Injury: Not All Brainstem Microbleeds are Prognostically Equal
Background
Recovery of functional independence is possible in patients with brainstem traumatic axonal injury (TAI), also referred to as “grade 3 diffuse axonal injury,” but acute prognostic biomarkers are lacking. We hypothesized that the extent of dorsal brainstem TAI measured by burden of traumatic microbleeds (TMBs) correlates with 1-year functional outcome more strongly than does ventral brainstem, corpus callosal, or global brain TMB burden. Further, we hypothesized that TMBs within brainstem nuclei of the ascending arousal network (AAN) correlate with 1-year outcome.
Methods
Using a prospective outcome database of patients treated for moderate-to-severe traumatic brain injury at an inpatient rehabilitation hospital, we retrospectively identified 39 patients who underwent acute gradient-recalled echo (GRE) magnetic resonance imaging (MRI). TMBs were counted on the acute GRE scans globally and in the dorsal brainstem, ventral brainstem, and corpus callosum. TMBs were also mapped onto an atlas of AAN nuclei. The primary outcome was the disability rating scale (DRS) score at 1 year post-injury. Associations between regional TMBs, AAN TMB volume, and 1-year DRS score were assessed by calculating Spearman rank correlation coefficients.
Results
Mean ± SD number of TMBs was: dorsal brainstem = 0.7 ± 1.4, ventral brainstem = 0.2 ± 0.6, corpus callosum = 1.8 ± 2.8, and global = 14.4 ± 12.5. The mean ± SD TMB volume within AAN nuclei was 6.1 ± 18.7 mm
3
. Increased dorsal brainstem TMBs and larger AAN TMB volume correlated with worse 1-year outcomes (
R
= 0.37,
p
= 0.02, and
R
= 0.36,
p
= 0.02, respectively). Global, callosal, and ventral brainstem TMBs did not correlate with outcomes.
Conclusions
These findings suggest that dorsal brainstem TAI, especially involving AAN nuclei, may have greater prognostic utility than the total number of lesions in the brain or brainstem.
Journal Article
Time Course of Post-Traumatic Mitochondrial Oxidative Damage and Dysfunction in a Mouse Model of Focal Traumatic Brain Injury: Implications for Neuroprotective Therapy
In the present study, we investigate the hypothesis that mitochondrial oxidative damage and dysfunction precede the onset of neuronal loss after controlled cortical impact traumatic brain injury (TBI) in mice. Accordingly, we evaluated the time course of post-traumatic mitochondrial dysfunction in the injured cortex and hippocampus at 30 mins, 1, 3, 6, 12, 24, 48, and 72 h after severe TBI. A significant decrease in the coupling of the electron transport system with oxidative phosphorylation was observed as early as 30 mins after injury, followed by a recovery to baseline at 1 h after injury. A statistically significant (P < 0.0001) decline in the respiratory control ratio was noted at 3 h, which persisted at all subsequent time-points up to 72 h after injury in both cortical and hippocampal mitochondria. Structural damage seen in purified cortical mitochondria included severely swollen mitochondria, a disruption of the cristae and rupture of outer membranes, indicative of mitochondrial permeability transition. Consistent with this finding, cortical mitochondrial calcium-buffering capacity was severely compromised by 3h after injury, and accompanied by significant increases in mitochondrial protein oxidation and lipid peroxidation. A possible causative role for reactive nitrogen species was suggested by the rapid increase in cortical mitochondrial 3-nitrotyrosine levels shown as early as 30 mins after injury. These findings indicate that post-traumatic oxidative lipid and protein damage, mediated in part by peroxynitrite, occurs in mitochondria with concomitant ultrastructural damage and impairment of mitochondrial bioenergetics. The data also indicate that compounds which specifically scavenge peroxynitrite (ONOO) or ONOO−derived radicals (e.g. ONOO− + H+ → ONOOH → †NO2 + †OH) may be particularly effective for the treatment of TBI, although the therapeutic window for this neuroprotective approach might only be 3 h.
Journal Article
Early brain biomarkers of post-traumatic seizures: initial report of the multicentre epilepsy bioinformatics study for antiepileptogenic therapy (EpiBioS4Rx) prospective study
BackgroundTraumatic brain injury (TBI) causes early seizures and is the leading cause of post-traumatic epilepsy. We prospectively assessed structural imaging biomarkers differentiating patients who develop seizures secondary to TBI from patients who do not.DesignMulticentre prospective cohort study starting in 2018. Imaging data are acquired around day 14 post-injury, detection of seizure events occurred early (within 1 week) and late (up to 90 days post-TBI).ResultsFrom a sample of 96 patients surviving moderate-to-severe TBI, we performed shape analysis of local volume deficits in subcortical areas (analysable sample: 57 patients; 35 no seizure, 14 early, 8 late) and cortical ribbon thinning (analysable sample: 46 patients; 29 no seizure, 10 early, 7 late). Right hippocampal volume deficit and inferior temporal cortex thinning demonstrated a significant effect across groups. Additionally, the degree of left frontal and temporal pole thinning, and clinical score at the time of the MRI, could differentiate patients experiencing early seizures from patients not experiencing them with 89% accuracy.Conclusions and relevanceAlthough this is an initial report, these data show that specific areas of localised volume deficit, as visible on routine imaging data, are associated with the emergence of seizures after TBI.
Journal Article