Severe Diffuse Traumatic Brain Injury Research Articles

The effect of Riluzole on neurological outcomes, blood-brain barrier, brain water and neuroinflammation in traumatic brain injury

BackgroundRiluzole (RLZ) is a potent anticonvulsant drug that reveals neuroprotective effects on neurological disease by inhibiting the release of glutamate and increasing its uptake. This study aims to investigate the potential neuroprotective effects of Riluzole in a rat model with acute severe traumatic brain injury (TBI). Materials and MethodsIn this study, seven groups of male Wistar rats were investigated including Sham, Intact, TBI, Saline (TBI + intraperitoneal (i.p) injection of normal saline), TBI + i.p injection of Riluzole in 2,4 and 8 mg/kg doses (RLZ 2, RLZ 4 and RLZ 8 groups), induction of severe diffuse TBI performed by weight dropping Marmarou model, and evaluation of short-term neurological deficits by using veterinary coma scale (VCS), beam-balance and beam-walk tasks. Histopathological changes in neural tissue were evaluated by using hematoxylin and eosin staining and light microscopy. Evaluation of blood-brain barrier (BBB) permeability was performed by using the Evans Blue method 6 h after traumatization. Brain water content assessment was performed by using the wet-dry method and the level of IL-1β and IL-10 was determined by using an enzyme-linked immunosorbent assay (ELISA). ResultsTreatment with Riluzole improves neurological function, VCS score, and vestibulomotor function, reduces pathological changes of neural tissue, brain edema, and level of IL-1β, and increases IL-10 concentration in CSF compared to the saline group (p < 0.0001). Treatment with 4 and 8 mg/kg of Riluzole reveals a significant therapeutic effect on consequences of TBI. This effect was enhanced by an increase in the dose of Riluzole from 4 to 8 mg/kg, but no significant changes were seen after administration of 2 mg/kg of Riluzole. ConclusionRiluzole can reduce the first and second phase of TBI damage by lowering inflammation, brain edema, histopathological destruction, BBB permeability, level of IL- 1β, and increasing IL-10 in CSF; it is highly suggested to use Riluzole in further studies and human trials, and also to consider it as a therapeutic compound in the treatment of traumatic brain injury.

Decompressive Craniectomy for the Treatment of Severe Diffuse Traumatic Brain Injury: A Randomized Controlled Trial.

Background Severe traumatic brain injury (TBI) is one of the leading public health problems across the world. TBI is associated with high economic costs to the healthcare system specially in developing countries. Decompressive craniectomy is a procedure in which an area of the skull is removed to increase the volume of intracranial compartment. There are various techniques of decompressive craniectomy used that include subtemporal and circular decompression, and unilateral or bilateral frontotemporoparietal decompression. Objective The aim of this study was to compare the outcome of decompressive craniectomy for the management of severe TBI versus conservative management alone at the Department of Neurosurgery, Abbasi Shaheed Hospital, Karachi, Pakistan. Methods The study (randomized controlled trial) was conducted from February 1, 2014, till June 30, 2017. Results A total of 136 patients were included after following the inclusion criteria. They were randomly assigned to two groups, making it 68 patients in each study group. There were 89 males and 47 females. All the patients received standard care recommended by the Brain Trauma Foundation. The mortality rate observed at 6 months in decompressive craniectomy was 22.05%, while among conservative management group, it was 45.58%. Difference in mortality of both groups at 6 months was significant. Total 61.76% (42) of patients from decompressive craniectomy group had a favorable outcome (Glasgow outcome scale: 4-5) at 6 months. While among conservative management group, total 35.29% (24) had a favorable outcome (Glasgow outcome scale: 4-5). Difference in Glasgow outcome scale at 6 months of both groups was significant. Conclusion In conclusion, decompressive craniectomy is simple, safe, and better than conservative management alone.

Clinical Value of Bilateral Balanced Frontotemporoparietal Decompressive Craniectomy in Severe Diffuse Traumatic Brain Injury.

To explore the clinical value of bilateral balanced frontotemporoparietal decompressive craniectomy (bbDC) in severe diffuse traumatic brain injury by comparison to the unilateral frontotemporoparietal decompressive craniectomy (uDC). Twenty three patients with severe diffuse traumatic brain injury from April 2015 to December 2019 were selected, including 10 cases underwent bbDC (bilateral group) and 13 cases underwent uDC (unilateral group). Compared with the postsurgical intracranial pressure (ICP), cerebral perfusion pressure, cerebral blood flow volume, postsurgical imaging score, the occurrence of complications as well as the 6 month outcome (Glasgow Outcome Scale, GOS) of two groups. 1. The postsurgical ICP was lower in the bbDC group than in the uDC group, while the postsurgical CCP and cerebral blood flow volume were higher in the bbDC group than in the uDC group. 2. Postsurgical imaging scores of the bbDC group were lower, indicating that the decompression effect of bbDC was more exhaustive than that of the uDC group. 3. The incidence of intraoperative acute cerebral bulging was lower in bbDC group than in uDC group. 4. The bbDC could effectively reduce the proportion of patients with the worst prognosis (dead+vegetative state). For patients with severe, diffuse traumatic brain injury combined with bilateral or unilateral pupil dilation, bilateral balanced decompression craniotomy is an effective method, which should be performed as soon as possible. As compared to unilateral decompression, the decompression effect on the brainstem is more thorough; the incidence of acute cerebral bulging, postoperative incisional hernia, and postoperative cerebral infarction involving a large area are reduced. ICP can be better controlled, cerebral perfusion pressure and cerebral blood flow increases, improving the patient's survival rate, quality of life, and prognosis.

Morphine attenuates neuroinflammation and blood-brain barrier disruption following traumatic brain injury through the opioidergic system

Endogenous opiates are suggested to have a role in the pathophysiology of traumatic brain injury (TBI). Furthermore, administration of opioidergic agents in TBI injured animals have been shown to affect the brain injury and provide neuroprotection post-TBI. This study aims to investigate the potential neuroprotective effects of morphine through inhibition of neuroinflammatory pathways in acute severe TBI. Male Wistar rats were divided into seven groups (24 rats per group): Sham, Vehicle (TBI + intraperitoneal (i.p) injection of normal saline), TBI + i.p injection of morphine in 1, 5 and 10 mg/kg doses (MOR 1, MOR 5 and MOR 10 groups), TBI + morphine (5 mg/kg i.p) + Naloxone (NAL + MOR), and TBI + morphine (5 mg/kg i.p) + Naltrindole (NALT + MOR). A severe diffuse TBI model (weight dropping Marmarou model) was used to induce TBI in rats. The veterinary coma scale (VCS), beam-walk, and beam-balance tasks were used to assess short-term neurological deficits. Histolopathological changes of brain tissue was evaluated using light microscopy and hematoxilin and eosin staining. Blood-Brain barrier (BBB) disruption was evaluated by the Evans Blue method 6 h post-injury. Brain water content and cerebrospinal fluid (CSF) content of IL-1β and IL-10 were assessed by the wet-dry method and enzyme-linked immunosorbent assay (ELISA), respectively. Morphine (1 and 5 mg/kg doses) attenuated BBB leakage, improved VCS score, pathological changes of brain tissue, and vestibulomotor function compared to the vehicle group (p < 0.0001). Only 5 mg/kg morphine attenuated brain edema (p < 0.0001). Furthermore, 1 and 5 mg/kg morphine significantly changed CSF concentration of IL-1β and IL-10 compared to the vehicle group (p < 0.0001). Inhibition of opioid receptors by naloxone and naltrindole abolished morphine neuroprotective effects (p < 0.0001 vs. MOR 5 group). This study suggests that morphine administration inhibits TBI-mediated neuroinflammation via opioid receptors and improves neurobehavioral function following TBI, which provides a potential therapeutic opportunity in the treatment of traumatic brain injury.

Physiotherapy in children hospitalized with traumatic brain injury in a South African tertiary paediatric hospital.

Physical impairments following traumatic brain injury (TBI) may limit participation in daily living. Physiotherapy could assist in managing these limitations, however, there is a paucity of literature on the physiotherapy management of children in the acute phase of TBI. To describe the characteristics, course and outcome of children hospitalized with TBI, with specific reference to the role of physiotherapy. A retrospective folder review of all children (n = 130, median 5.37 years [IQR 1.88-7.88]) admitted in 2016 with a primary diagnosis of TBI was conducted at a tertiary paediatric hospital. Most cases presented with mild TBI (66.2%). The most common cranial manifestation of the TBI was brain bleeds (80%) and most occurred as a result of road traffic accidents (50%, including both pedestrian and motor vehicle accidents). Physiotherapy was administered in 35 cases (26.9%), with functional interventions, such as mobilizations out of bed, the most common form of therapy (71.4%). Children involved in road traffic accidents, presenting with severe diffuse TBI, resulting in altered tone and coordination problems, admitted to intensive care, monitored with an intracranial pressure or Licox monitor, and receiving occupational therapy and/or been followed up by dieticians, were more likely to receive physiotherapy. The duration of hospitalization (median 4 days [IQR 2-9]) was associated with infections, severity of TBI, presence of an intracranial monitoring, and parietal lobe injury. This is the first study in South Africa investigating standard physiotherapy care in children admitted with TBI. Physiotherapy was provided in a small portion of children and appeared to be well tolerated. However, due to the limited information recorded in the physiotherapy notes, results of this study need to be confirmed in larger, more well-documented studies before generalizations can be made.

Patient Outcomes at Twelve Months after Early Decompressive Craniectomy for Diffuse Traumatic Brain Injury in the Randomized DECRA Clinical Trial.

Functional outcomes at 12 months were a secondary outcome of the randomized DECRA trial of early decompressive craniectomy for severe diffuse traumatic brain injury (TBI) and refractory intracranial hypertension.In the DECRA trial, patients were randomly allocated 1:1 to either early decompressive craniectomy or intensive medical therapies (standard care). We conducted planned secondary analyses of the DECRA trial outcomes at 6 and 12 months, including all 155 patients.We measured functional outcome using the Glasgow Outcome Scale-Extended (GOS-E). We used ordered logistic regression, and dichotomized the GOS-E using logistic regression, to assess outcomes in patients overall and in survivors. We adjusted analyses for injury severity using the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model.At 12 months, the odds ratio (OR) for worse functional outcomes in the craniectomy group (OR 1.68; 95% confidence interval [CI]: 0.96-2.93; p = 0.07) was no longer significant. Unfavorable functional outcomes after craniectomy were 11% higher (59% compared with 48%), but were not significantly different from standard care (OR 1.58; 95% CI: 0.84-2.99; p = 0.16). Among survivors after craniectomy, there were fewer good (OR 0.33; 95% CI: 0.12-0.91; p = 0.03) and more vegetative (OR 5.12; 95% CI: 1.04-25.2; p = 0.04) outcomes.Similar outcomes in survivors were found at 6 months after injury. Vegetative (OR 5.85; 95% CI: 1.21-28.30; p = 0.03) and severely disabled outcomes (OR 2.49; 95% CI: 1.21-5.11; p = 0.01) were increased.Twelve months after severe diffuse TBI and early refractory intracranial hypertension, decompressive craniectomy did not improve outcomes and increased vegetative survivors.

Myelin water imaging of moderate to severe diffuse traumatic brain injury.

Traumatic axonal injury (TAI), a signature injury of traumatic brain injury (TBI), is increasingly known to involve myelin damage. The objective of this study was to demonstrate the clinical relevance of myelin water imaging (MWI) by first quantifying changes in myelin water after TAI and then correlating those changes with measures of injury severity and neurocognitive performance. Scanning was performed at 3 months post-injury in 22 adults with moderate to severe diffuse TBI and 30 demographically matched healthy controls using direct visualization of short transverse component (ViSTa) MWI. Fractional anisotropy (FA) and radial diffusivity (RD) were also obtained using diffusion tensor imaging. Duration of post-traumatic amnesia (PTA) and cognitive processing speed measured by the Processing Speed Index (PSI) from Wechsler Adult Intelligence Scale-IV, were assessed. A between-group comparison using Tract-Based Spatial Statistics revealed that there was a widespread reduction of apparent myelin water fraction (aMWF) in TBI, consistent with neuropathology involving TAI. The group difference map of aMWF yielded topography that was different from FA and RD. Importantly, aMWF demonstrated significant associations with PTA (r = −0.564, p = .006) and PSI (r = 0.452, p = .035). In conclusion, reduced myelin water, quantified by ViSTa MWI, is prevalent in moderate-to-severe diffuse TBI and could serve as a potential biomarker for injury severity and prediction of clinical outcomes.

Decompressive Craniectomy in Diffuse Traumatic Brain Injury: An Industrial Hospital Study.

Context:High intracranial pressure is the most frequent cause of mortality and disability after severe traumatic brain injury (TBI) which is treated by first-line therapeutic measures. When these measures fail, second-line therapies are started. Among second-line therapies, decompressive craniectomy (DC) has been used. It improves the functional outcome in these patients.Aim:This study aims to analyze the clinicoradiological factors associated with the prognosis of severe TBI in patients undergoing DC.Settings and Design:It was a retrospective case series study from April 2014 to March 2016.Subjects and Methods:A total of 85 patients (admitted at Tata Main Hospital, Jamshedpur) with severe diffuse TBI with clinical and radiological evidence of intracranial hypertension who were refractory to first-tier therapies and required DC were included in our study. Cases excluded were patients with age <10 years and polytrauma patients.Results:Out of 85 cases, 55 were males, and thirty were females (male:female = 1.8:1) with the age ranging from 17 to 68 years. Road traffic accident was the leading cause of injury in 69.5% cases. A total of 49 (58%) patients were of Glasgow coma scale (GCS) 4–6 whereas 36 (42%) patients had GCS 7–8. Computed tomography (CT) scan brain was classified as per Marshall CT classification. Bifrontotemporal DC was done in 29% cases, and unilateral frontotemporoparietal craniectomy was done in 71%.Conclusions:Patients with younger age, early surgical intervention, better preoperative GCS score, and with low Marshall CT score have better prognosis.

Is Intracranial Pressure Monitoring of Patients With Diffuse Traumatic Brain Injury Valuable? An Observational Multicenter Study.

Although intracranial pressure (ICP) monitoring of patients with severe traumatic brain injury (TBI) is recommended by the Brain Trauma Foundation, any benefits remain controversial. To evaluate the effects of ICP monitoring on the mortality of and functional outcomes in patients with severe diffuse TBI. Data were collected on patients with severe diffuse TBI (Glasgow Coma Scale [GCS] score on admission <9 and Marshall Class II-IV) treated from January 2012 to December 2013 in 24 hospitals (17 level I trauma centers and 7 level II trauma centers) in 9 Chinese provinces. We evaluated the impact of ICP monitoring on 6-month mortality and favorable outcome using propensity score-matched analysis after controlling for independent predictors of these outcomes. ICP monitors were inserted into 287 patients (59.5%). After propensity score matching, ICP monitoring significantly decreased 6-month mortality. ICP monitoring also had a greater impact on the most severely injured patients on the basis of head computed tomography data (Marshall computed tomography classification IV) and on patients with the lowest level of consciousness (GCS scores 3-5). After propensity score matching, monitoring remained nonassociated with a 6-month favorable outcome for the overall sample. However, monitoring had a significant impact on the 6-month favorable outcomes of patients with the lowest level of consciousness (GCS scores 3-5). ICP monitor placement was associated with a significant decrease in 6-month mortality after adjustment for the baseline risk profile and the monitoring propensity of patients with diffuse severe TBI, especially those with GCS scores of 3 to 5 or of Marshall computed tomography classification IV.

The effect of gene therapy with the APOE3 Gene on structural and functional manifestations of secondary hippocampal damages in experimental traumatic brain injury

to study the efficiency of gene therapy following traumatic brain injury (TBI) by evaluating the influences of liposomal transfection of the brain tissue by APOE3-containing plasmid vector on the structural and functional manifestations of development of secondary brain injuries after acute experimental TBI in the rats of different age. Severe diffuse TBI in rats was inflicted under overall anesthesia by free load weighing 450 g, falling from a 1.5 m elevation. The mixture of DOTAP liposome and 25 μg of plasmid vector pCMV·SPORT6 with cDNA of APOE3 gene was infused intraventricularly using ALZET osmotic pumps. Combined morphological, electron microscopic, immunohistochemical and morphometric studies of СА1 hippocampal region were conducted in rats at days 5 and 10 following TBI and gene therapy after investigation of motor functions (using composite neurological motor score) and cognitive functions in Morris water maze. Significant changes in the morphofunctional state of hippocampus, as well as in the neurological and cognitive functions were shown on the model of severe TBI in the adult and old Wistar rats. Gene therapy, specifically cationic-liposome mediated APOE3 gene transfer to the CNS cells by plasmid vector, decreased a TBI-induced death of neurons and improved qualitative composition of neuronal population, normalized neuron-glial relations, decreased gliosis and microglial activation, axonal damage, myelin destruction and lipofuscin accumulation, all these having age-related peculiarities. After gene therapy observed in the animal brain was a lower intensity of the processes of apoptosis and a decrease of its rate in old animals. The above changes were accompanied with a more fast and expressed regress of neurological and cognitive disturbances typical for TBI. Administration of plasmid vector after TBI resulted in an increase of survival rate of old animals vs. old animals which got no gene therapy. APOE3 gene therapy has therapeutic potential in the treatment of severe TBI.

The therapeutic influence of epsilon3 isoform of apolipoprotein E on pathophysiological mechanisms of secondary brain injury evolution after experimental traumatic brain injury

Purpose. To test the therapeutic potential of apolipoprotein E isoform epsilon3, whose synthesis in nerve tissue was induced by means of gene therapy, in an experimental traumatic brain injury (TBI) model, and to substantiate its mechanism of therapeutic action based on current literature data.Methods. To determine structural and functional changes associated with severe diffuse TBI, adult male Wistar rats were subjected to weight drop impact acceleration injury and evaluated at day 10 after trauma. A mixture of DOTAP liposomes and 25 µg of recombinant plasmid pCMV-APOE3 cDNA was infused intraventicularly immediately after TBI using ALZET osmotic pumps. The hippocampal CA1 regions were analyzed by means of light and electron microscopy, morphometry, immunocytochemical and confocal analysis using markers selective for neurons (NeuN) and astrocytes (GFAP). The neurofunctional outcome was assessed in an open field test.Results. The research data have shown that cationic liposome-mediated APOE3 gene transfer has a beneficial effect on hippocampal structure and ultrastructure, diminishes neuronal loss and severity of diffuse axonal injury, gliosis and microglial reaction, as well as aids regression of posttraumatic stress and anxiety.Conclusion. According to literature data, possible mechanisms of apoE therapeutic action are (1) normalization of neural cellular lipid component, (2) its role in regulating reactive gliosis and inflammatory response of CNS to injury, (3) antioxidant effects of apolipoprotein E, (4) regulation of cell death mechanisms, (5) influence of apolipoprotein E on differential gene expression and regulation of genomic response of CNS cells to injury

DECRA...Where do we go from here?

In the United States, about two million head injuries of all types (including skull and facial fractures) occur each year (175 to 200 per 100,000 population), with the annual cost around $80 billion dollars. It has been a year since the results of the randomized Decompressive Craniectomy (DECRA) trial were published on March 25 in the New England Journal of Medicine,New Engl J Med. Published online March 25, 2011. Since then, it has stirred up controversy in a number of circles amongst our colleagues. Over a period of eight years, the DECRA trial, identified 155 patients from 3478 screened, with severe diffuse TBI and intracranial hypertension refractory to first-tier therapies. These 155 were randomly assigned to either early decompressive craniectomy or standard of care therapy. Patients in the craniectomy group, were found to have less time with intracranial pressures above the treatment threshold (20 mm.hg.), fewer interventions for elevations in intracranial pressure (ICP), and shorter lengths of stay (l.o.s), in the intensive care unit (ICU). Unfortunately however, patients that underwent decompressive hemi-craniectomy had worse scores on the Extended Glasgow Outcome Scale than those receiving standard care and ultimately greater risk of an unfavorable outcome. Rates of death at 6 months were similar in the craniectomy group (19%) vs. the standard-care group (18%). The authors concluded that in adults with severe diffuse traumatic brain injury and refractory intracranial hypertension, early bifrontotemporoparietal decompressive craniectomy[8] decreased intracranial pressure and the length of stay in the ICU but was associated with more unfavorable outcomes.[5] Their conclusions have raised a lot of eyebrows and significant criticism including senior members from the Section on Neurotrauma,[11] which had 5 major objections ranging from 1.) the Study's use of a small subset of patients with traumatic brain injury no (mass lesions); This clearly indicates a small and restricted subset of patient's with traumatic brain injury. 2.) An uncommon choice of operative technique(bifrontal procedures), thus limiting the procedural efficacy for lowering intracranial pressure), 3.) a long accrual time (over which theoretical differences in treatment might have evolved); 4.) differences in study groups (significantly more patients with bilaterally unreactive pupils were included in the surgical group, 5.) minimal mean elevations in intracranial pressure leading up to randomization (median for both groups during the 12 hours before randomization at the upper limit of normal, 20 mm Hg). Since this study seems to focus primarily on intracranial pressure, it is also important to point out, that most Neurosurgeons and Neuro-intensivists that manage traumatic brain injury would rarely if ever entertain decompressive craniectomy in patients with an ICP of 20 mm Hg for such brief duration. Studies recording ICP following head injury show that thresholds of 25 mm Hg determine outcome,[1,12] It follows, most likely, that patients who will benefit from decompression are those with intractable intracranial hypertension above 25 mm Hg. In a sense, the author's aggressive approach may be justified in order to decompress the brain as soon as possible, but in those patients with diffuse injury without mass lesions, many Specialists would use medical therapy for a longer period, leaving decompressive craniectomy as a last resort. The trial's criteria for craniectomy simply does not give current first tier protocols enough time to optimize management of ICP.[2,3,12] What this study does suggest is that the normalization of ICP achieved with decompressive craniectomy may not be the key to managing patients with diffuse, severe traumatic brain injury. When ICP and cerebral perfusion pressure(CPP) are normalized, patients with severe traumatic brain injury often have severe cerebral hypoxia, with reduced oxygen tension in brain tissue, which may explain their poor outcome[6] This has been shown in studies of hyperventilation and TBI.[7,9] Strategies to improve cerebral oxygenation suggest the benefit of multimodality monitoring for these patients. Brain ischemia/hypoxia is a key factor in Neurologic outcome following severe traumatic brain injury, Unfortunately, no concomitant measurements of cerebral blood flow (CBF), brain tissue oxygenation(Pbt02), microdyalisis or bio-markers were used while ICP was increasing.[7,9,10] Multi-modality monitoring should be seriously considered whenever we want to properly assess the value of an aggressive surgical approach such as decompressive hemi-craniectomy.[4,10,12] Unfortunately, the DECRA study leaves us with little evidence that aggressive Neurosurgical intervention aimed at reducing ICP, improves outcome. In closing, I would caution the readers not to close the door on this topic but rather, support work which will help define the optimal clinical setting for this procedure. We await the results of the other ongoing trial of craniectomy for head injury called the Randomized Evaluation of Surgery with Craniectomy for uncontrollable Elevation of Intracranial Pressure(RESCUEicp), which has several differences in their design as compared to DECRA.

Clinical Trials in Decompressive Craniectomy After Severe Diffuse Traumatic Brain Injury

C m t d i o r q T he recently published results of the DECRA (DEcompressive CRAniectomy) trial (7) have stimulated much discussion about the role of decompressive surgery in the etting of severe traumatic brain injury (TBI). Although decomressive craniectomy after severe diffuse TBI has been shown to educe intracranial pressure (ICP) and thereby facilitate mainteance of cerebral perfusion, the optimal timing, target population, nd effect on survivor outcome of decompression remain topics f debate. Recent studies have attempted to answer these uestions, but there is still a paucity of evidence and no concluive recommendation for lifesaving surgery in the setting intraranial hypertension after TBI. Even guidelines on ICP thresholds or hypertension and refractory hypertension are vague, usually iven as a range from 20–25 mg (3). In addition, using simple hresholds without consideration of true ICP burden is problemtic. The field of neurosurgery requires evidence-based answers o these questions now more than ever, as trauma is a leading ause of death in the first 40 years of life worldwide, with almost 0% of incidents involving the head (1).

Anesthesia Literature Review

Anesthesia Literature Review

Brain energy depletion in a rodent model of diffuse traumatic brain injury is not prevented with administration of sodium lactate

Lactate has been identified as an alternative fuel for the brain in situations of increased energy demand, as following a traumatic brain injury (TBI). This study investigates the effect of treatment with sodium lactate (NaLac) on the changes in brain energy state induced by a severe diffuse TBI. Rats were assigned to one of the eight groups (n = 10 per group): 1—sham, normal saline; 2—TBI, normal saline; 3—TBI, hypertonic saline; 4—TBI, 100 mM NaLac, 5—TBI, 500 mM NaLac; 6—TBI, 1280 mM NaLac; 7—TBI, 2000 mM NaLac and 8-TBI-500 mM NaLac + magnesium sulfate. Cerebrums were removed 6 h after trauma. Metabolites representative of the energy state (ATP, ATP-catabolites), N-acetylaspartate (NAA), antioxidant defenses (ascorbic acid, glutathione), markers of oxidative stress (malondialdehyde, ADP-ribose) and nicotinic coenzymes (NAD +) were measured by HPLC. TBI induced a marked decrease in the cerebral levels of ATP, NAA, ascorbic acid, glutathione and NAD + and a significant rise in the content of ATP-catabolites, malondialdehyde and ADP-ribose. These alterations were not ameliorated with NaLac infusion. We observed a significant reduction in cerebral NAD +, an essential co-enzyme for mitochondrial lactate-dehydrogenase that converts lactate into pyruvate and thus replenishes the tricarboxylic acid cycle. These results suggest that the metabolic pathway necessary to consume lactate may be compromised following a severe diffuse TBI in rats.

Decompressive Craniectomy in Diffuse Traumatic Brain Injury

It is unclear whether decompressive craniectomy improves the functional outcome in patients with severe traumatic brain injury and refractory raised intracranial pressure. From December 2002 through April 2010, we randomly assigned 155 adults with severe diffuse traumatic brain injury and intracranial hypertension that was refractory to first-tier therapies to undergo either bifrontotemporoparietal decompressive craniectomy or standard care. The original primary outcome was an unfavorable outcome (a composite of death, vegetative state, or severe disability), as evaluated on the Extended Glasgow Outcome Scale 6 months after the injury. The final primary outcome was the score on the Extended Glasgow Outcome Scale at 6 months. Patients in the craniectomy group, as compared with those in the standard-care group, had less time with intracranial pressures above the treatment threshold (P<0.001), fewer interventions for increased intracranial pressure (P<0.02 for all comparisons), and fewer days in the intensive care unit (ICU) (P<0.001). However, patients undergoing craniectomy had worse scores on the Extended Glasgow Outcome Scale than those receiving standard care (odds ratio for a worse score in the craniectomy group, 1.84; 95% confidence interval [CI], 1.05 to 3.24; P=0.03) and a greater risk of an unfavorable outcome (odds ratio, 2.21; 95% CI, 1.14 to 4.26; P=0.02). Rates of death at 6 months were similar in the craniectomy group (19%) and the standard-care group (18%). In adults with severe diffuse traumatic brain injury and refractory intracranial hypertension, early bifrontotemporoparietal decompressive craniectomy decreased intracranial pressure and the length of stay in the ICU but was associated with more unfavorable outcomes. (Funded by the National Health and Medical Research Council of Australia and others; DECRA Australian Clinical Trials Registry number, ACTRN012605000009617.).

Influence of liposome-mediated APOE3 gene transfection of brain tissue on diffuse axonal injury, caused by traumatic brain injury, in experiment

The goal of study was to estimate the structural damage of axons in rats with severe traumatic brain injury (TBI), and the possibilities of such disorders correction by means of gene therapy that launches the synthesis of e3 isoform of apolipoprotein E in brain tissue. Severe diffuse TBI in rats was inflicted under overall anesthesia by free load weighing 450 g, falling from a 1.5 m elevation. The mixture of DOTAP liposome and 25 µg of plasmid vector pCMV•SPORT6 with cDNA of APOE3 gene was infused intraventricularly using ALZET osmotic pumps. Severe experimental TBI is characterized by the damage of hippocampal cytoarchitectonics with destructive-dystrophic changes of all brain elements (neurons, glia, capillaries). The distinguishing feature of this damage is diffuse axonal injury exhibited by pronounced changes of axonal cytoskeleton, axonal edema and deformity, mitochondrial destruction and serious damage to myelin sheathes. The liposome-mediated brain tissue transfection with plasmid vector carrying the gene of e3 isoform of apolipoprotein E has a positive therapeutic effect after TBI including the decrease of diffuse axonal injury.

Substance P is Associated with the Development of Brain Edema and Functional Deficits after Traumatic Brain Injury

Brain edema and swelling is a critical factor in the high mortality and morbidity associated with traumatic brain injury (TBI). Despite this, the mechanisms associated with its development are poorly understood and interventions have not changed in over 30 years. Although neuropeptides and neurogenic inflammation have been implicated in peripheral edema formation, their role in the development of central nervous system edema after brain trauma has not been investigated. This study examines the role of the neuropeptide, substance P (SP), in the development of edema and functional deficits after brain trauma in rats. After severe diffuse TBI in adult male rats, neuronal and perivascular SP immunoreactivity were increased markedly. Perivascular SP colocalized with exogenously administered Evans blue, supporting a role for SP in vascular permeability. Inhibition of SP action by administration of the neurokinin-1 (NK1) antagonist, N-acetyl-L-tryptophan, at 30 mins after trauma attenuated vascular permeability and edema formation. Administration of the NK1 antagonist also improved both motor and cognitive neurologic outcomes. These findings suggest that SP release is integrally linked to the increased vascular permeability and edema formation after brain trauma, and that treatment with an NK1 receptor antagonist reduces edema and improves neurologic outcome.

Midline brain injury in the immature rat induces sustained cognitive deficits, bihemispheric axonal injury and neurodegeneration

Infants and children less than 4 years old suffer chronic cognitive deficits following mild, moderate or severe diffuse traumatic brain injury (TBI). It has been suggested that the underlying neuropathologic basis for behavioral deficits following severe TBI is acute brain swelling, subarachnoid hemorrhage and axonal injury. To better understand mechanisms of cognitive dysfunction in mild-moderate TBI, a closed head injury model of midline TBI in the immature rat was developed. Following an impact over the midline suture of the intact skull, 17-day-old rats exhibited short apnea times (3–15 s), did not require ventilatory support and suffered no mortality, suggestive of mild TBI. Compared to un-injured rats, brain-injured rats exhibited significant learning deficits over the first week post-injury ( p < 0.0005), and, significant learning ( p < 0.005) and memory deficits ( p < 0.05) in the third post-injury week. Between 6 and 72 h, blood–brain barrier breakdown, extensive traumatic axonal injury in the subcortical white matter and thalamus, and focal areas of neurodegeneration in the cortex and hippocampus were observed in both hemispheres of the injured brain. At 8 to 18 days post-injury, reactive astrocytosis in the cortex, axonal degeneration in the subcortical white matter tracts, and degeneration of neuronal cell bodies and processes in the thalamus of both hemispheres were observed; however, cortical volumes were not different between un-injured and injured rat brains. These data suggest that diffuse TBI in the immature rat can lead to ongoing degeneration of both cell soma and axonal compartments of neurons, which may contribute, in part, to the observed sustained cognitive deficits.

Frontal Hypoactivation on Functional Magnetic Resonance Imaging in Working Memory after Severe Diffuse Traumatic Brain Injury

Working memory is frequently impaired after traumatic brain injury (TBI). The present study aimed to investigate working memory deficits in patients with diffuse axonal injury and to determine the contribution of cerebral activation dysfunctions to them. Eighteen patients with severe TBI and 14 healthy controls matched for age and gender were included in the study. TBI patients were selected according to signs of diffuse axonal injury on computed tomography (CT) and without any evidence of focal lesions on MRI clinical examination. Functional magnetic resonance (fMRI) was used to assess brain activation during n-back tasks (0-, 2-, and 3-back). Compared to controls, the TBI group showed significant working memory impairment on the Digits Backwards (p=0.022) and Letter-Number Sequencing subtests from the WAIS-III (p<0.001) under the 2-back (p=0.008) and 3-back (p=0.017) conditions. Both groups engaged bilateral fronto-parietal regions known to be involved in working memory, although patients showed less cerebral activation than did controls. Decreased activation in TBI patients compared to controls was observed mainly in the right superior and middle frontal cortex. The correlation patterns differed between patients and controls: while the control group showed a negative correlation between performance and activation in prefrontal cortex (PFC), TBI patients presented a positive correlation in right parietal and left parahippocampus for the low and high working memory load, respectively. In conclusion, severe TBI patients with diffuse brain damage show a pattern of cerebral hypoactivation in the right middle and superior frontal regions during working memory tasks, and also present an impaired pattern of performance correlations.