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Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

While the pace of traumatic brain injury (TBI) research has accelerated, the treatment options remain limited. Clinical trials are yet to yield successful treatment options, leading to innovative strategies to overcome the severe debilitating consequences of TBI. Stem cells may act as a potential treatment option. They have two key characteristics, the ability of self-renewal and the ability to give rise to daughter cells, which in the case of neural stem cells (NSCs) includes neurons, astrocytes and oligodendrocytes. They respond to the injury environment providing trophic support and have been shown to differentiate and integrate into the host brain. In this review, we introduce the notion of an NSC and describe the two neurogenic niches in the mammalian brain. The literature supporting the activation of an NSC in rodent models of TBI, both in vivo and in vitro, is detailed. This endogenous activation of NSCs may be augmented by exogenous transplantation of NSCs. Delivery of NSCs to assist the host nervous system has become an attractive option, with either fetal or adult NSC. This has resulted in cognitive and functional improvement in rodents, and current animal studies are using human NSCs. While no NSC clinical trials are currently ongoing for TBI, this review touches upon other neurological diseases and discuss how this may move forward into TBI., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The innate immune response contributes to the inflammatory activity after traumatic brain injury (TBI). In the present study we identify macrophage-inducible C-type lectin (mincle) as a pattern recognition receptor that contributes to innate immunity in neurons after TBI. Here we report that mincle is activated by SAP130 in cortical neurons in culture, resulting in production of the inflammatory cytokine TNF. In addition, mincle and SAP130 are elevated in the brain and cerebrospinal fluid of humans after TBI and the brain of rodents after fluid percussion brain injury. Thus, these findings suggest the involvement of mincle to the pathology of TBI. Importantly, blocking mincle with a neutralizing antibody against mincle in cortical neurons in culture treated with SAP130 resulted in inhibition of mincle signaling and decreased TNF production. Therefore, our findings identify mincle as a contributor to the inflammatory response after TBI.

Traumatic brain injury (TBI) is a substantial public health problem. The discovery of progressive, ongoing damage to the brain by means of complex molecular mechanisms which follow the initial injury has raised the possibility of targeted therapeutic intervention. Despite a substantial investment in trials testing dozens of therapeutics in humans, however, to date none has demonstrated robust efficacy. Deficiencies in the design of human clinical trials is likely to explain many translational failures, at least in part. Here we review secondary injury mediators and key trials which have targeted them. We provide a thorough discussion of putative reasons why trials thus far have failed and suggestions for the design of future clinical studies. Important insights from the IMPACT study are also presented in detail; in addition to providing critical insights for future trial design and analysis it suggests that reanalysis of completed studies may reveal inappropriately discarded treatments. Unfortunately limited resources are available for translational research and it is difficult to procure funds needed for well-resourced, large and definitive studies. History suggests, however, that investing in studies that are unlikely to provide a definitive answer only serves to increase required investment as they tend to mandate further study., (© 2015 Elsevier B.V. All rights reserved.)

Objective: As the aged population is rapidly growing globally, geriatric traumatic brain injury (TBI) becomes an increasing problem. There are higher mortality and poorer functional outcome in the geriatric TBI population (≥65 years) compared with younger groups despite neurosurgical interventions. Therefore, current treatment priorities and cost-effectiveness should be critically examined. We evaluated the benefit of surgical management in the elderly (≥65 years) after TBI., Methods: A total of 3194 patients with confirmed TBI were enrolled from 1998 to 2011, in the Japan Neurotrauma Data Bank. Retrospective analysis was conducted from the Japan Neurotrauma Data Bank on 888 (28%) patients (≥65 years) who did and did not undergo surgery. In particular, the effect of low Glasgow coma scale (GCS) (3-5) was compared with outcome with and without surgery., Results: Of all the patients 65 years of age and over, 478 (54%) were given surgical management (craniectomy, craniotomy, or burr-hole evacuation). This group of patients had significantly more favorable outcome at 6 months (18% vs. 7%) and less mortality (62% vs. 81%). However, within this surgical group, patients with initial GCS scores of 3-5 had significantly more unfavorable outcome (96% vs. 79%) and more mortality (87% vs. 57%) compared with those with GCS scores of 6-15., Conclusions: We confirmed that age is a major determinant of outcome after TBI. In addition, we found that neurosurgical management is associated with the improvement of the prognosis and a decrease in the rate of mortality in geriatric TBI. However, surgical management was not shown to be an effective treatment in elderly patients with GCS scores of 3-5., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Trauma is a major risk factor for venous thromboembolism (VTE). Traumatic brain injury (TBI) is generally considered to further increase the VTE risk, which should prompt routine thromboprophylaxis. However, the associated risk for intracranial hemorrhage often delays anticoagulants. We test the hypothesis that TBI associated with polytrauma results in a higher rate of VTE than polytrauma without TBI., Methods: From August 2011 to June 2013, a prospective observational trial with informed consent was performed in 148 intensive care unit (ICU) patients with a Greenfield Risk Assessment Profile score of 10 or greater., Results: Demographics, Greenfield Risk Assessment Profile scores, the incidence of polytrauma, and mortality were similar, but TBI patients had worse Injury Severity Scores (ISS) (32 vs. 22), longer ICU lengths of stay (21 days vs. 12 days), more hypercoagulable thromboelastogram values on admission (94% vs. 79%), more received unfractionated heparin prophylaxis (65% vs. 36%), and the prophylaxis start date was more than a day later (all p < 0.05). Nevertheless, the VTE rate with TBI was similar to that without TBI (25% vs. 26%, p = 0.507). Furthermore, VTE occurred at similar time points after ICU admission with and without TBI. In both groups, about 30% of the VTEs were detected within 2 days of ICU admission and 50% of the VTEs occurred within 10 days of admission despite chemical and mechanical thromboprophylaxis., Conclusion: In complex polytrauma patients who survived to ICU admission and who were prescreened for high VTE risk, TBI did not further increase the risk for VTE. The most likely explanation is that no single risk factor is necessary or sufficient for VTE development, especially in those who routinely receive chemical and mechanical thromboprophylaxis., Level of Evidence: Epidemiologic study, level III.

Object: Mass lesions from traumatic brain injury (TBI) often require surgical evacuation as a life-saving measure and to improve outcomes, but optimal timing and surgical technique, including decompressive craniectomy, have not been fully defined. The authors compared neurosurgical approaches in the treatment of TBI at 2 academic medical centers to document variations in real-world practice and evaluate the efficacies of different approaches on postsurgical course and long-term outcome., Methods: Patients 18 years of age or older who required neurosurgical lesion evacuation or decompression for TBI were enrolled in the Co-Operative Studies on Brain Injury Depolarizations (COSBID) at King's College Hospital (KCH, n = 27) and Virginia Commonwealth University (VCU, n = 24) from July 2004 to March 2010. Subdural electrode strips were placed at the time of surgery for subsequent electrocorticographic monitoring of spreading depolarizations; injury characteristics, physiological monitoring data, and 6-month outcomes were collected prospectively. CT scans and medical records were reviewed retrospectively to determine lesion characteristics, surgical indications, and procedures performed., Results: Patients enrolled at KCH were significantly older than those enrolled at VCU (48 vs 34 years, p < 0.01) and falls were more commonly the cause of TBI in the KCH group than in the VCU group. Otherwise, KCH and VCU patients had similar prognoses, lesion types (subdural hematomas: 30%-35%; parenchymal contusions: 48%-52%), signs of mass effect (midline shift ≥ 5 mm: 43%-52%), and preoperative intracranial pressure (ICP). At VCU, however, surgeries were performed earlier (median 0.51 vs 0.83 days posttrauma, p < 0.05), bone flaps were larger (mean 82 vs 53 cm(2), p < 0.001), and craniectomies were more common (performed in 75% vs 44% of cases, p < 0.05). Postoperatively, maximum ICP values were lower at VCU (mean 22.5 vs 31.4 mm Hg, p < 0.01). Differences in incidence of spreading depolarizations (KCH: 63%, VCU: 42%, p = 0.13) and poor outcomes (KCH: 54%, VCU: 33%, p = 0.14) were not significant. In a subgroup analysis of only those patients who underwent early (< 24 hours) lesion evacuation (KCH: n = 14; VCU: n = 16), however, VCU patients fared significantly better. In the VCU patients, bone flaps were larger (mean 85 vs 48 cm(2) at KCH, p < 0.001), spreading depolarizations were less common (31% vs 86% at KCH, p < 0.01), postoperative ICP values were lower (mean: 20.8 vs 30.2 mm Hg at KCH, p < 0.05), and good outcomes were more common (69% vs 29% at KCH, p < 0.05). Spreading depolarizations were the only significant predictor of outcome in multivariate analysis., Conclusions: This comparative-effectiveness study provides evidence for major practice variation in surgical management of severe TBI. Although ages differed between the 2 cohorts, the results suggest that a more aggressive approach, including earlier surgery, larger craniotomy, and removal of bone flap, may reduce ICP, prevent cortical spreading depolarizations, and improve outcomes. In particular, patients requiring evacuation of subdural hematomas and contusions may benefit from decompressive craniectomy in conjunction with lesion evacuation, even when elevated ICP is not a factor in the decision to perform surgery.

Objective: Severe traumatic brain injury (TBI) is a dynamic neuropathologic process in which a substantial proportion of patients die within the first 48-hours. The assessment of injury severity and prognosis are of primary concern in the initial management of severe TBI. Supplemental testing that aids in the stratification of patients at high risk for deterioration may significantly improve posttraumatic management in the acute setting., Methods: This retrospective study assessed the utility of both single-marker and multimarker models as predictive indicators of acute clinical status after severe TBI. Forty-four patients who sustained severe TBI (admission Glasgow Coma Scale [GCS] score ≤ 8) were divided into two cohorts according to a dichotomized clinical outcome at 72 hours after admission: Poor status (death or GCS score ≤ 8) and improved status (GCS score improved to >8). Threshold values for clinical status prediction were calculated for serum S-100B, matrix metalloproteinase-9, and plasma D-dimer, upon admission and at 24 hours after TBI by the use of receiver operating characteristic analysis. Performance characteristics of these single-marker predictors were compared with those derived from a multimarker logistic regression analysis., Results: Biomarkers with the greatest predictive value for poor status at 72 hours included serum S-100B on admission, as well as plasma D-dimer and serum S-100B at 24 hours, for which, associations were strongly significant. Multimarker analysis indicated no substantial improvement in prediction accuracy over the best single predictors during this time frame., Conclusion: In conjunction with other clinical, physical, and radiologic evidence, blood-derived biochemical markers may serve to enhance prediction of early clinical trends after severe TBI., (Copyright © 2014. Published by Elsevier Inc.)

Traumatic brain injury (TBI) is still the worldwide, leading cause of mortality and morbidity in young adults. The prognosis of TBI patients is strongly affected by secondary brain damage including mitochondrial dysfunctions. In many basic and clinical studies, mitochondrial dysfunctions, including the opening of mitochondrial permeability transition (mPT) pore, and treatments including cyclosporine A (CsA) have been studied. These evidences suggest an important role for mitochondria as therapeutic targets for neuroprotection after TBI. This review summarizes the data about normal and pathological mitochondrial function after TBI, TBI pathobiology relating to mitochondrial dysfunction and therapeutic strategies including drug treatment. This review also mentioned about glucose, lactate, and pyruvate metabolisms in TBI, including the "astrocyte-neuron lactate shuttle (ANLS)" hypothesis. Mitochondrial pathophysiology in TBI is still unclear. Thus, the pharmacological treatment in TBI patient is still challenging. This review could help further understanding of this topic. Hopefully, this could help further development and innovation for drug therapies in TBI.

Background: After traumatic brain injury (TBI), catecholamines (CAs) may be needed to maintain adequate cerebral perfusion pressure (CPP), but there are no recommended alternative vasopressor therapies. This is an interim report of the first study to test the hypothesis that arginine vasopressin (AVP) is a safe and effective alternative to CAs for the management of CPP in patients with severe TBI., Methods: Since 2008, all TBI patients requiring intracranial pressure monitoring at this Level 1 trauma center have been eligible for a randomized trial to receive either CA or AVP if vasopressors were required to maintain CPP greater than 60 mm Hg., Results: To date, 96 patients have been consented and randomized. Demographics, vital signs, and laboratory values were similar. As treated, 60 required no vasopressors and were the least severely injured group with the best outcomes. Twenty-three patients received CA (70% levophed, 22% dopamine, 9% phenylephrine) and 12 patients received AVP. The two vasopressor groups had similar demographics, but Injury Severity Score (ISS) and fluid requirements on intensive care unit Day 1 were worse in the AVP versus the CA groups (all p < 0.05) before treatment. These differences indicate more severe injury with accompanying hemodynamic instability. Nevertheless, adverse events were not increased with AVP versus CA. Trends favored AVP versus CA, but no apparent differences were statistically significant at this interim point. There was no difference in mortality rates between CA and AVP., Conclusion: These preliminary results suggest that AVP is a safe and effective alternative to CA for the management of CPP after TBI and support the continued investigation and use of AVP when vasopressors are required for CPP management in TBI patients., Level of Evidence: Therapeutic study, level II.

Object: Simultaneous traumatic brain injury (TBI) and aortic injury has been considered unsurvivable for many years because treatments such as sedation and blood pressure goals conflict for these 2 conditions. Additionally, surgical interventions for aortic injury often require full anticoagulation, which is contraindicated in patients with TBI. For these reasons, and due to the relative rarity of aortic injury/TBI, little data are available to guide treating physicians., Methods: A retrospective review was performed on all simultaneous TBI and aortic injury cases from 2000 to 2012 at a university-affiliated, Level I trauma center. Patient demographics, imaging studies, interventions, and outcomes were analyzed. Traumatic brain injury/aortic injury cases treated with endovascular stenting were specifically studied to determine trends in procedure timing, use of anticoagulation, and neurological outcome., Results: Thirty-three patients with concurrent TBI and aortic injury were identified over a 12-year period. The median patient age was 44 years (range 16-86 years) and the overall mortality rate after imaging diagnosis was 46%. All surviving patients were awake and neurologically functional at discharge, and 83% were discharged home or to rehabilitation facilities. Patients who died had a higher Injury Severity Scale score (p = 0.006). Severe TBI (p = 0.045) or hemodynamic instability (p = 0.015) upon arrival to the hospital was also correlated with increased mortality rates. Thirty-three percent of aortic injury/TBI patients (n = 11) underwent endovascular stenting, and 7 of these patients received intravenous anticoagulation therapy at the time of surgery. Six of these 7 anticoagulation-treated patients experienced no significant progression on postoperative brain CT, whereas 1 patient died of hemodynamic instability prior to undergoing further imaging., Conclusions: Simultaneous TBI and aortic injury is a rare condition with a historically poor prognosis. However, these results suggest that many patients can survive with a good quality of life. Technological advances such as endovascular aortic stenting may improve patient outcome, and anticoagulation is not absolutely contraindicated after TBI.

Background: In this era of cost containment, the value of routine repeat head computed tomography (CT) in patients with mild TBI (mTBI) and no interval neurologic change has been challenged. The purpose of this study was to test the hypothesis that routine repeat head CT provides critical information after mTBI even with no neurologic change., Methods: From January 1996 to May 2010, records from all patients admitted to our Level I trauma center with an arrival Glasgow Coma Scale (GCS) score of 13 to 15 and at least one head CT were retrospectively reviewed., Results: In 360 patients with mTBI and positive initial head CT finding, the most common abnormalities were subarachnoid hemorrhage (64%), intraparenchymal hemorrhage (57%), and subdural hemorrhage (40%). Scans were repeated in 8 ± 6 hours; 11% were recalled, 59% remained stable, but 30% showed injury progression. Those patients with worsening repeat head CT finding had higher Injury Severity Score (ISS), were more likely to be intubated and require craniotomy, had longer stay, and had higher mortality (all p < 0.001). On multiple logistic regression, altered GCS score (odds ratio, 3.1-4.0), ISS (odds ratio, 1.1), and presence of mass effect (odds ratio, 2.0) were independently associated with worsening repeat head CT finding. In patients receiving a neurosurgical operative intervention, 32% to 59% had no clinical decline before the worsening repeat CT finding., Conclusion: After mTBI, worsening of repeat head CT finding is seen in a third of patients and is associated with worse outcomes. A substantial fraction of patients who require operative intervention will have no clinical changes in the first 8 hours, supporting the value of repeat head CT within this time frame., Level of Evidence: Care management study, level III.

Traumatic brain injury (TBI) treatment is now focused on the prevention of primary injury and reduction of secondary injury. However, no single effective treatment is available as yet for the mitigation of traumatic brain damage in humans. Both chemical and environmental stresses applied before injury have been shown to induce consequent protection against post-TBI neuronal death. This concept termed "preconditioning" is achieved by exposure to different pre-injury stressors to achieve the induction of "tolerance" to the effect of the TBI. However, the precise mechanisms underlying this "tolerance" phenomenon are not fully understood in TBI, and therefore even less information is available about possible indications in clinical TBI patients. In this review, we will summarize TBI pathophysiology, and discuss existing animal studies demonstrating the efficacy of preconditioning in diffuse and focal type of TBI. We will also review other non-TBI preconditioning studies, including ischemic, environmental, and chemical preconditioning, which maybe relevant to TBI. To date, no clinical studies exist in this field, and we speculate on possible future clinical situations, in which pre-TBI preconditioning could be considered.

Primary Objective: To review basic elements to be considered in the development of effective neurotrauma care systems in low- and middle-income countries. Neurotrauma occurs more frequently in developing countries. The survival rate among neurotrauma patients depends in large part on the degree of sophistication of the trauma system., Research Design: A critical review of the literature was undertaken., Results: In developing countries, there are difficulties in fully integrating the resources for care if the local and regional trauma systems are poorly structured. Factors like inadequate emergency and neurointensive care, low compensation compared with elective procedures or high medico-legal risks may result in a lack of interest from the few available neurosurgeons to be fully integrated in neurotrauma care. Appropriate structuring of trauma systems according to countries needs and their functionality is a key element that would facilitate the optimal use of resources for integral neurotrauma care., Conclusions: In order to implement an efficient trauma system, organization of low cost resources such as trauma registries and quality control programmes are required. The participation of medical associations in legislative and government processes is also an important factor for the appropriate development and organization of an effective trauma system in under-privileged areas.

Object: Traumatic brain injury (TBI), the third most common CNS pathology, plagues 5.3 million Americans with permanent TBI-related disabilities. To evaluate injury severity and prognosis, physicians rely on clinical variables. Here, the authors seek objective, biochemical markers reflecting molecular injury mechanisms specific to the CNS as more accurate measurements of injury severity and outcome. One such secondary injury mechanism, the innate immune response, is regulated by the inflammasome, a molecular platform that activates caspase-1 and interleukin-1β., Methods: The authors investigated whether inflammasome components were present in the CSF of 23 patients with TBI and whether levels of inflammasome components correlate with outcome. The authors performed an immunoblot analysis of CSF samples from patients who suffered TBI and nontrauma controls and assessed the outcomes 5 months postinjury by using the Glasgow Outcome Scale. Data were analyzed using Mann-Whitney U-tests and linear regression analysis., Results: Patients with severe or moderate cranial trauma exhibited significantly higher CSF levels of the inflammasome proteins ASC, caspase-1, and NALP-1 than nontrauma controls (p < 0.0001, p = 0.0029, and p = 0.0202, respectively). Expression of each protein correlated significantly with the Glasgow Outcome Scale score at 5 months postinjury (p < 0.05). ASC, caspase-1, and NALP-1 were significantly higher in the CSF of patients with unfavorable outcomes, including death and severe disability (p < 0.0001)., Conclusions: NALP-1 inflammasome proteins are potential biomarkers to assess TBI severity, outcome, and the secondary injury mechanisms impeding recovery, serving as adjuncts to clinical predictors.

Background: Patients with tangential gunshot wounds (TGSWs) commonly present with a good Glasgow Coma Scale score and without a history of loss of consciousness. Typically, the bullet does not breach the skull, however, there is a considerable force directed into the brain, and these patients are best treated as sustaining a moderate-to-severe blunt head injury. These patients require observation and repeat imaging. Physicians should be aware of this entity as these patients can deteriorate in a delayed fashion., Objectives: The authors present a case of a TGSW to the head in a neurologically intact patient. The initial post-injury computed tomography (CT) scan showed a very small subdural hematoma (SDH) with no overlying fracture of the skull. A delayed CT scan performed 4 h after arrival to the Emergency Department and 6 h after injury demonstrated an increase in size of the SDH, new traumatic subarachnoid hemorrhage, and bilateral cerebral contusions. Clinically, the patient showed worsening of her neurological examination. She underwent aggressive non-surgical treatment for increased intracranial pressure with almost complete recovery., Conclusion: Although patients with TGSWs are typically in good condition upon presentation, these injuries are not always trivial, and these patients should have, at minimum, a non-contrast brain CT scan to evaluate underlying damage to the brain and skull. In addition, a delayed CT scan and close observation on a neurosurgical service are indicated., (Published by Elsevier Inc.)

Background: Pathological waves of spreading mass neuronal depolarisation arise repeatedly in injured, but potentially salvageable, grey matter in 50-60% of patients after traumatic brain injury (TBI). We aimed to ascertain whether spreading depolarisations are independently associated with unfavourable neurological outcome., Methods: We did a prospective, observational, multicentre study at seven neurological centres. We enrolled 109 adults who needed neurosurgery for acute TBI. Spreading depolarisations were monitored by electrocorticography during intensive care and were classified as cortical spreading depression (CSD) if they took place in spontaneously active cortex or as isoelectric spreading depolarisation (ISD) if they took place in isoelectric cortex. Investigators who treated patients and assessed outcome were masked to electrocorticographic results. Scores on the extended Glasgow outcome scale at 6 months were fitted to a multivariate model by ordinal regression. Prognostic score (based on variables at admission, as validated by the IMPACT studies) and spreading depolarisation category (none, CSD only, or at least one ISD) were assessed as outcome predictors., Findings: Six individuals were excluded because of poor-quality electrocorticography. A total of 1328 spreading depolarisations arose in 58 (56%) patients. In 38 participants, all spreading depolarisations were classified as CSD; 20 patients had at least one ISD. By multivariate analysis, both prognostic score (p=0·0009) and spreading depolarisation category (p=0·0008) were significant predictors of neurological outcome. CSD and ISD were associated with an increased risk of unfavourable outcome (common odds ratios 1·56 [95% CI 0·72-3·37] and 7·58 [2·64-21·8], respectively). Addition of depolarisation category to the regression model increased the proportion of variance in outcome that could be attributed to predictors from 9% to 22%, compared with the prognostic score alone., Interpretation: Spreading depolarisations were associated with unfavourable outcome, after controlling for conventional prognostic variables. The possibility that spreading depolarisations have adverse effects on the traumatically injured brain, and therefore might be a target in the treatment of TBI, deserves further research., Funding: US Army CDMRP PH/TBI research programme., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Authors of several studies have studied biomarkers and computed tomography (CT) findings in the acute phase after severe traumatic brain injury (TBI). However, the correlation between structural damage as assessed by neuroimaging and biomarkers has not been elucidated. The aim of this study was to investigate the relationships among neuronal (Ubiquitin carboxy-terminal hydrolase L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarker levels in serum, neuroradiological findings and outcomes after severe TBI., Methods: The study recruited patients from four neurotrauma centers. Serum samples for UCH-L1 and GFAP were obtained at the time of hospital admission and every 6 hours thereafter. CT scans of the brain were obtained within 24hrs of injury. Outcome was assessed by Glasgow Outcome Scale (GOS) at discharge and at 6 months., Results: 81 severe TBI patients and 167 controls were enrolled. The mean serum levels of UCH-L1 and GFAP were higher (p < 0.001) in TBI patients compared to controls. UCH-L1 and GFAP serum levels correlated significantly with Glasgow Coma Scale (GCS) and CT findings. GFAP levels were higher in patients with mass lesions than in those with diffuse injury (2.95 ± 0.48 ng/ml versus 0.74 ± 0.11 ng/ml) while UCH-L1 levels were higher in patients with diffuse injury (1.55 ± 0.18 ng/ml versus 1.21 ± 0.15 ng/ml, p = 0.0031 and 0.0103, respectively). A multivariate logistic regression showed that UCH-L1 was the only independent predictor of death at discharge [adjusted odds ratios 2.95; 95% confidence interval, 1.46-5.97], but both UCH-L1 and GFAP levels strongly predicted death 6 months post-injury., Conclusions: Relationships between structural changes detected by neuroimaging and biomarkers indicate each biomarker may reflect a different injury pathway. These results suggest that protein biomarkers could provide better characterization of subjects at risk for specific types of cellular damage than that obtained with neuroimaging alone, as well as provide valuable information about injury severity and outcome after severe TBI.

Background: Traumatic brain injury (TBI) generates regional alterations in cerebral metabolism, leading to the potential evolution of persistent metabolic dysfunction. In the case of penetrating, firearm-related TBI, the pathophysiological mechanisms underlying these acute-phase metabolic derangements are not entirely understood-hindering the potential effectiveness of therapeutic intervention. The use of cerebral microdialysis to monitor biochemical alterations that occur, post-TBI, provides critical insight into the events that perpetuate neurological deterioration., Methods: Cerebral microdialysis was used to monitor alterations in the brain tissue chemistry of a 22-year-old female patient who sustained a penetrating gunshot wound to the head. Extracellular glucose, lactate, pyruvate, and lactate pyruvate ratio (LPR) were monitored over the course of the first-week post-injury., Results: Analysis of the microdialysate revealed sustained elevations in LPR with peaks in excess of those seen in patients who have sustained permanent ischemic injury. This interval of persistently elevated LPR was followed by a spontaneous reduction of values, to levels below the defined threshold for metabolic crisis, over a period of several days., Conclusions: Microdialysis studies may significantly improve the understanding of the metabolic alterations that occur in patients who sustain a variety of forms of neurotrauma. Ultimately, monitoring these variations in brain tissue chemistry will improve the insight into the neuropathological mechanisms underlying penetrating traumatic brain injury, and enhance the therapeutic approach of these patients.

Epidermal growth factor (EGF) is a known mitogen for neural stem and progenitor cells (NS/NPCs) in the central nervous system (CNS). In vitro, EGF maintains NS/NPCs in the proliferative state, whereas in the normal rodent brain it promotes their proliferation and migration in the subventricular zone (SVZ). Additionally, EGF administration can augment neuronal replacement in the ischemic-injured adult striatum. Recently we found that the SVZ and the hippocampus display an injury-induced proliferative response following traumatic brain injury (TBI) that is linked to increased EGF expression. As adult neurogenesis is associated with cognitive function, we hypothesized that post-TBI administration of EGF could affect neurogenesis and cognitive recovery. Adult rats were intraventricularly infused with EGF or vehicle for 7 days following TBI. 5-Bromo-2-deoxyuridine (BrdU) was administered to label proliferating cells and the animals were sacrificed at 1 or 4 weeks post-injury. Using immunohistochemistry and stereology, we found that at 1 week post-injury, compared to vehicle-infused animals EGF-infused animals had significantly more BrdU-positive cells in the SVZ and hippocampus concomitant with enhanced EGF receptor expression. At 4 weeks post-injury, the number of BrdU-positive cells in the hippocampus was similar in both groups, suggesting that EGF does not support long-term survival of newly generated cells. Furthermore, we found that the EGF-induced proliferative population differentiated preferentially toward astroglial phenotype. Nevertheless, animals treated with EGF showed significant improvement in cognitive function, which was accompanied by reduced hippocampal neuronal cell loss. Collectively, the data from this study demonstrate that EGF exerts a neuroprotective rather than neurogenic effect in protecting the brain from injury.

Approximately 350,000 individuals in the US are affected annually by severe and moderate traumatic brain injuries (TBI) that may result in long-term disability. This rate of injury has produced approximately 3.3 million disabled survivors in the US alone. There is currently no specific treatment available for TBI other than supportive care, but aggressive prehospital resuscitation, rapid triage, and intensive care have reduced mortality rates. With the recent demonstration that neurogenesis occurs in all mammals (including man) throughout adult life, albeit at a low rate, the concept of replacing neurons lost after TBI is now becoming a reality. Experimental rodent models have shown that neurogenesis is accelerated after TBI, especially in juveniles. Two approaches have been followed in these rodent models to test possible therapeutic approaches that could enhance neuronal replacement in humans after TBI. The first has been to define and quantify the phenomenon of de novo hippocampal and cortical neurogenesis after TBI and find ways to enhance this (for example by exogenous trophic factor administration). A second approach has been the transplantation of different types of neural progenitor cells after TBI. In this review the authors discuss some of the processes that follow after acute TBI including the changes in the brain microenvironment and the role of trophic factor dynamics with regard to the effects on endogenous neurogenesis and gliagenesis. The authors also discuss strategies to clinically harness the factors influencing these processes and repair strategies using exogenous neural progenitor cell transplantation. Each strategy is discussed with an emphasis on highlighting the progress and limiting factors relevant to the development of clinical trials of cellular replacement therapy for severe TBI in humans.

Object: Dysregulation of water homeostasis induces cerebral edema. Edema is a major cause of morbidity and mortality following traumatic brain injury (TBI). Aquaporin-1 (AQP-1), a water channel found in the brain, can function as a transporter for CO2 across the cellular membrane. Additionally, AQP-1's promoter contains a glucocorticoid response element. Thus, AQP-1 may be involved with edema-related brain injury and might be modulated by external conditions such as the pH and the presence of steroids. In this study, the authors investigated the hypotheses that: 1) AQP-1 participates in brain water homeostasis following TBI; 2) secondary injury (for example, acidosis) alters the expression of AQP-1 and exacerbates cerebral edema; and 3) corticosteroids augment brain AQP-1 expression and differentially affect cerebral edema under nonacidotic and acidotic conditions., Methods: Anesthetized Sprague-Dawley rats were subjected to moderate to severe TBI (2.5-3.5 atm) or surgery without injury, and they were randomized to receive a 3-mg/kg bolus of intravenous dexamethasone within 10 minutes after injury or surgery, a 3-mg/kg bolus of dexamethasone followed by 1-mg/kg maintenance doses every 8 hours for 24 hours, or saline boluses at similar time intervals. A second group of animals was subjected to respiratory acidosis with target arterial blood pH 6.8-7.2 for 1 hour following the surgery or injury. To evaluate selective blockage of AQP-1, some animals received a single intraperitoneal dose of HgCl2 (0.3-30.0 mmol/L) within 30 minutes of injury or surgery. At 4 or 24 hours postinjury, animals were killed and their brains were harvested for mRNA, protein, or water content analyses., Results: The authors demonstrated elevated cerebral edema levels at 4 and 24 hours following TBI. Dexamethasone administration within 1 hour of TBI attenuated the cerebral edema under nonacidotic conditions but worsened it under acidotic conditions. Selective blockage of AQP-1 channels with HgCl2 attenuated the edematous effects of corticosteroids and acidosis. Reverse transcriptase polymerase chain reaction and immunohistochemical analyses demonstrated a paucity of AQP-1 in the cerebral cortices of the uninjured animals. In contrast, AQP-1 mRNA and protein levels were higher in the cerebral cortices of animals that sustained a TBI., Conclusions: These findings implicate an important, modifiable role for AQP-1 in water homeostasis within the CNS following TBI.

Introduction: Intracranial pressure (ICP) has become a cornerstone of care in adult and pediatric patients with traumatic brain injury (TBI)., Discussion: Despite the fact that continuous monitoring of ICP in TBI was described almost 60 years ago, there are no randomized trials confirming the benefit of ICP monitoring and treatment in TBI. There is, however, a large body of clinical evidence showing that ICP monitoring influences treatment and leads to better outcomes if part of protocol-driven therapy. However, treatment of ICP has adverse effects, and there are several questions about ICP management that have yet to be definitively answered, particularly in pediatric TBI. This review examines the history and evolution of ICP monitoring, pathophysiological concepts that influence ICP interpretation, ongoing controversies, and the place of ICP monitoring in modern neurocritical care.

Cyclosporin A (CsA) has recently been proposed for use in the early phase after traumatic brain injury (TBI), for its ability to preserve mitochondrial integrity in experimental brain injury models, and thereby provide improved behavioral outcomes as well as significant histological protection. The aim of this prospective, randomized, double-blind, dual-center, placebo-controlled trial was to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of CsA in patients with severe TBI. Fifty adult severe TBI patients were enrolled over a 22-month period. Within 12 h of the injury patients received 5 mg/kg of CsA infused over 24 h, or placebo. Blood urea nitrogen (BUN), creatinine, hemoglobin, platelets, white blood cell count (WBC), and a hepatic panel were monitored on admission, and at 12, 24, 36, and 48 h, and on days 4 and 7. Potential adverse events (AEs) were also recorded. Neurological outcome was recorded at 3 and 6 months after injury. This study revealed only transient differences in BUN levels at 24 and 48 h and for WBC counts at 24 h between the CsA and placebo patients. These modest differences were not clinically significant in that they did not negatively impact on patient course. Both BUN and creatinine values, markers of renal function, remained within their normal limits over the entire monitoring period. There were no significant differences in other mean laboratory values, or in the incidence of AEs at any other measured time point. Also, no significant difference was demonstrated for neurological outcome. Based on these results, we report a good safety profile of CsA infusion when given at the chosen dose of 5 mg/kg, infused over 24 h, during the early phase after severe head injury in humans, with the aim of neuroprotection.

Here we investigated the incidence of cortical spreading depolarizations (spreading depression and peri-infarct depolarization) after traumatic brain injury (TBI) and their relationship to systemic physiologic values during neurointensive care. Subdural electrode strips were placed on peri-contusional cortex in 32 patients who underwent surgical treatment for TBI. Prospective electrocorticography was performed during neurointensive care with retrospective analysis of hourly nursing chart data. Recordings were 84 hr (median) per patient and 2,503 hr in total. In 17 patients (53%), 280 spreading depolarizations (spreading depressions and peri-infarct depolarizations) were observed. Depolarizations occurred in a bimodal pattern with peak incidence on days 1 and 7. The probability of a depolarization occurring increased significantly as a function of declining mean arterial pressure (MAP; R(2) = 0.78; p < 0.001) and cerebral perfusion pressure (R(2) = 0.85; p < 0.01), and increasing core temperature (R(2) = 0.44; p < 0.05). Depolarization probability was 7% for MAP values of >100 mm Hg but 33% for MAP of < or =70 mm Hg. Temperatures of < or =38.4 degrees C were associated with a 21% depolarization risk, compared to 63% for >38.4 degrees C. Intracranial pressures were higher in patients with depolarizations (18.3 +/- 9.3 vs. 13.5 +/- 6.7 mm Hg; p < 0.001). We conclude that depolarization phenomena are a common cortical pathology in TBI. Their association with lower perfusion levels and higher temperatures suggests that the labile balance of energy supply and demand is an important determinant of their occurrence. Monitoring of depolarizations might serve as a functional measure to guide therapeutic efforts and their blockade may provide an additional line of defense against the effects of secondary insults.

Following severe traumatic brain injury (TBI), a complex interplay of pathomechanism, such as exitotoxicity, oxidative stress, inflammatory events, and mitochondrial dysfunction occurs. This leads to a cascade of neuronal and axonal pathologies, which ultimately lead to axonal failure, neuronal energy metabolic failure, and neuronal death, which in turn determine patient outcome. For mild and moderate TBI, the pathomechanism is similar but much less frequent and ischemic cell death is unusual, except with mass lesions. Involvement of mitochondria in acute post-traumatic neurodegeneration has been extensively studied during the last decade, and there are a number of investigations implicating the activation of the mitochondrial permeability transition pore (mPTP) as a "critical switch" which determines cell survival after TBI. Opening of the mPTP is modulated by several factors occurring after a severe brain injury. Modern neuroprotective strategies for prevention of the neuropathological squeal of traumatic brain injury have now begun to address the issue of mitochondrial dysfunction, and drugs that protect mitochondrial viability and prevent apoptotic cascade induced by mPTP opening are about to begin phase II and III clinical trials. Cyclosporin A, which has been reported to block the opening of mPTP, showed a significant decrease in mitochondrial damage and intra-axonal cytoskeletal destruction thereby protecting the axonal shaft and blunting axotomy. This review addresses an important issue of mPT activation after severe head injury, its role in acute post-traumatic neurodegeneration, and the rationale for targeting the mPTP in experimental and clinical TBI studies.

Stem/progenitor cells reside throughout the adult CNS and are actively dividing in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. This neurogenic capacity of the SVZ and DG is enhanced following traumatic brain injury (TBI) suggesting that the adult brain has the inherent potential to restore populations lost to injury. This raises the possibility of developing strategies aimed at harnessing the neurogenic capacity of these regions to repair the damaged brain. One strategy is to enhance neurogenesis with mitogenic factors. As basic fibroblast growth factor (bFGF) is a potent stem cell mitogen, we set out to determine if an intraventricular administration of bFGF following TBI could affect the levels of injury-induced neurogenesis in the SVZ and DG, and the degree to which this is associated with cognitive recovery. Specifically, adult rats received a bFGF intraventricular infusion for 7 days immediately following TBI. BrdU was administered to animals daily at 2-7 days post-injury to label cell proliferation. At 1 or 4 weeks post-injury, brain sections were immunostained for BrdU and neuronal or astrocytic markers. We found that injured animals infused with bFGF exhibited significantly enhanced cell proliferation in the SVZ and the DG at 1 week post-TBI as compared to vehicle-infused animals. Moreover, following bFGF infusion, a greater number of the newly generated cells survived to 4 weeks post-injury, with the majority being neurons. Additionally, animals infused with bFGF showed significant cognitive improvement. Collectively, the current findings suggest that bFGF-enhanced neurogenesis contributes to cognitive recovery following TBI.

Introduction: Patients with traumatic brain injury commonly receive phenytoin for seizure prophylaxis. Due to the non-linear pharmacokinetics of phenytoin and narrow therapeutic window, phenytoin concentrations are monitored to ensure efficacy and prevent toxicity. Because phenytoin is hepatically metabolized, polymorphisms within cytochrome P450 enzymes can affect phenytoin concentrations., Methods: We report a case of a 53-year-old Asian female admitted to the neuroscience intensive care unit after suffering a traumatic brain injury. Phenytoin was subsequently administered for seizure prophylaxis., Results: Four days after being initiated on phenytoin, the patient remained lethargic, and phenytoin toxicity was suspected. Lab values revealed a free phenytoin concentration of 4.4 mg/l, and phenytoin was discontinued. Upon further investigation, it was found that the patient was a cytochrome P450 2C9 poor metabolizer. Causes of the patient's toxic phenytoin concentration such as drug interactions, decreased albumin, and lab error were excluded. The cause of her elevated phenytoin concentration was determined to be hepatic polymorphism., Conclusion: This case reveals the clinical significance of genetic polymorphisms and the effect on phenytoin dosage requirements. Because pharmacogenomic testing is expensive and not readily available, routine monitoring of phenytoin concentrations is warranted. Further, established polymorphisms should be documented to prevent toxicity of drugs metabolized by similar pathways.

Objective: Perfluorocarbon emulsions have been shown to improve outcomes in stroke models. This study examined the effect of Oxycyte, a third-generation perfluorocarbon emulsion (04RD33; Synthetic Blood International, Inc., Costa Mesa, CA) treatment on cognitive recovery and mitochondrial oxygen consumption after a moderate lateral fluid percussion injury (LFPI)., Methods: Adult male Sprague-Dawley rats (Harlan Bioproducts for Science, Indianapolis, IN) were allocated to 4 groups: 1) LFPI treated with a lower dose of Oxycyte (4.5 mL/kg); 2) LFPI with a higher dose of Oxycyte (9.0 mL/kg); 3) LFPI with saline infusion; and 4) sham animals treated with saline. Fifteen minutes after receiving moderate LFPI or sham surgery, animals were infused intravenously with Oxycyte or saline within 30 minutes while breathing 100% O2. Animals breathed 100% O2 continuously for a total of 4 hours after injury. At 11 to 15 days after LFPI, animals were assessed for cognitive deficits using the Morris water maze test. They were sacrificed at Day 15 after injury for histology to assess hippocampal neuronal cell loss. In a parallel study, mitochondrial oxygen consumption values were measured by the Cartesian diver microrespirometer method., Results: We found that injured animals treated with a lower or higher dose of Oxycyte had significant improvement in cognitive function when compared with injured saline-control animals (P < 0.05). Moreover, injured animals that received either dose of Oxycyte had significantly less neuronal cell loss in the hippocampal CA3 region compared with saline-treated animals (P < 0.05). Furthermore, a lower dose of Oxycyte significantly improved mitochondrial oxygen consumption levels (P < 0.05)., Conclusion: The current study demonstrates that Oxycyte can improve cognitive recovery and reduce CA3 neuronal cell loss after traumatic brain injury in rats.

Objective and Importance: Cortical spreading depolarizations (CSD) are waves of mass tissue depolarization that mediate progressive development of cortical infarction in animal models and occur in approximately 50% of patients with acute brain injury. Here we performed multi-modal cerebral monitoring to investigate pathologies associated with CSD occurrence in a case of severe traumatic brain injury., Clinical Presentation: A 20 years old male suffering severe traumatic brain injury from a fall had extensive frontal subdural and intraparenchymal hemorrhage with mass effect. Craniectomy was performed for hematoma evacuation and decompression., Intervention: During surgery, a subdural electrocorticography (ECoG) electrode strip, along with microdialysis and PtiO2 probes, was placed beside injured cortex for CSD monitoring. Within 13-81 hours post-injury, 34 CSD occurred. CSD incidence increased during spontaneous hyperthermia and decreased during induced normothermia. Periods of CSD activity were also associated with low brain glucose (<0.10 mmol/l), elevated glutamate (>40 mmol/l) and lactate/pyruvate (>40), and PtiO2<10 mmHg. CSD caused progressive deterioration of ECoG activity only in regions with infarction at follow-up on day 27., Conclusion: Repetitive mass tissue depolarizations accompanied a negative course of hemorrhagic lesion progression in the presence of ischemic conditions after traumatic brain injury. Whether as cause or effect, CSD may represent an inherent component of progressive metabolic failure leading to tissue death, and temperature appears to be an important factor influencing their occurrence. Continuous ECoG is a valuable tool for monitoring subclinical events such as CSD and seizures and for translational research in acute brain injury mechanisms and therapeutics.

Following severe traumatic brain injury (TBI), increasing oxygen delivery to the brain has been advocated as a useful strategy to reverse mitochondrial dysfunction and improve neurological outcome. However, this might also promote overproduction of free radicals, responsible for lipid peroxidation and hence brain cell damage. Therefore, a method for monitoring this potential adverse effect in humans is desirable. Glycerol, an end product of phospholipid breakdown, easily detectable in the human brain by means of microdialysis, might represent a reliable indicator of free radical-induced cell membrane damage. Brain microdialysates were collected from 24 adult male Sprague-Dawley rats over a 3-hour period following sham operation (n=6), chemical brain injury via administration of Fenton's reagent (n=6), a powerful hydroxyl radical generator, and lateral fluid percussion injury (FPI; n=12). In the FPI animals, post-traumatic i.v. administration of either normal saline or the free radical scavenger Tempol (10 mg/kg, followed by an infusion of 30 mg/kg/h over 3 h) was carried out to evaluate the effect of blockade of free radical generation. Samples were analyzed for the presence of glycerol and the marker of hydroxyl radical (OH.) by generation of 2,3-DHBA (dihydroxybenzoic acid). Brain tissue staining with TTC (2,3,5-triphenyltetrazoium chloride) was performed for lesion size assessment. Rats subjected to either Fenton's reagent administration or FPI exhibited significantly higher levels of glycerol as compared with shams (p=0.05). However, when the FPI was followed by Tempol administration, concentration of both glycerol and 2,3-DHBA decreased significantly (p=0.05). Furthermore, TCC staining revealed a significant reduction of secondary brain tissue damage in Tempol-treated animals (p=0.05). Our data suggest that injury-induced increases in microdialysate glycerol levels are a valid indicator of free radical activity, and their amelioration following Tempol treatment accords with less histological damage in response to FPI.

Object: Hyperbaric oxygen (HBO2) has been shown to improve outcome after severe traumatic brain injury, but its underlying mechanisms are unknown. Following lateral fluid-percussion injury (FPI), the authors tested the effects of HBO2 treatment as well as enhanced normobaric oxygenation on mitochondrial function, as measured by both cognitive recovery and cellular adenosine triphosphate (ATP) levels., Methods: Adult male Sprague-Dawley rats were subjected to moderate lateral FPI or sham injury and were allocated to one of four treatment groups: 1) FPI treated with 4 hours of normobaric 30% O2; 2) FPI treated with 4 hours of normobaric 100% O2; 3) FPI treated with 1 hour of HBO2 plus 3 hours of normobaric 100% O2; and 4) sham-injured treated with normobaric 30% O2. Cognitive outcome was assessed using the Morris water maze (MWM) on Days 11 to 15 after injury. Animals were then killed 21 days postinjury to assess hippocampal neuronal loss. Adenosine triphosphate was extracted from the neocortex and measured using high-performance liquid chromatography. The results showed that injured animals treated with HBO2 or normobaric 100% O2 alone had significantly higher levels of cerebral ATP as compared with animals treated using normobaric 30% O2 (p < or = 0.05). The injured animals treated with HBO2 had significant improvements in cognitive recovery, as characterized by a shorter latency in MWM performance (p < or = 0.05), and decreased neuronal loss in the CA2/3 and hilar regions as compared with those treated with 30% or 100% O2, (p < or = 0.05)., Conclusions: Both hyperbaric and normobaric hyperoxia increased cerebral ATP levels after lateral FPI. In addition, HBO2 treatment improved cognitive recovery and reduced hippocampal neuronal cell loss after brain injury in the rat.

The hippocampus is particularly vulnerable to traumatic brain injury (TBI), the consequences of which are manifested as learning and memory deficits. Following injury, substantive spontaneous cognitive recovery occurs, suggesting that innate repair mechanisms exist in the brain. However, the underlying mechanism contributing to this is largely unknown. The existence of neural stem cells in the adult hippocampal dentate gyrus (DG) and their proliferative response following injury led us to speculate that neurogenesis may contribute to cognitive recovery following TBI. To test this, we first examined the time course of cognitive recovery following lateral fluid percussion injury in rats. Cognitive deficits were tested at 11-15, 26-30 or 56-60 days post-injury using Morris Water Maze. At 11-15 and 26-30 days post-injury, animals displayed significant cognitive deficits, which were no longer apparent at 56-60 days post-TBI, suggesting an innate cognitive recovery at 56-60 days. We next examined the proliferative response, maturational fate and integration of newly generated cells in the DG following injury. Specifically, rats received BrdU at 2-5 days post-injury followed by Fluorogold (FG) injection into the CA3 region at 56 days post-TBI. We found the majority of BrdU+ cells which survived for 10 weeks became dentate granule neurons, as assessed by NeuN and calbindin labeling, approximately 30% being labeled with FG, demonstrating their integration into the hippocampus. Additionally, some BrdU+ cells were synaptophysin-positive, suggesting they received synaptic input. Collectively, our data demonstrate the extensive anatomical integration of new born dentate granule neurons at the time when innate cognitive recovery is observed.

With the hope of replacing neurons lost in traumatic brain injury (TBI), experimental models are being used to investigate TBI-induced neurogenesis. Although selectively vulnerable to TBI, the neurogenic hippocampus may have the unique ability to replace damaged neurons locally. Injury may also activate signaling pathways that induce neuroblasts from the subventricular zone to migrate to areas of focal cortical damage. Additionally, there is some evidence for local activation of latent neural progenitor cells in the injured neocortex itself. Each of these themes is discussed, with emphasis on the possibility of future therapeutic intervention.

We provide a critical analysis of the value of S100B as a marker of brain damage and possible therapeutic implications. The early assessment of the injury severity and the consequent prognosis are of major concern for physicians treating patients suffering from traumatic brain injury (TBI). A reliable indicator to accurately determine the extent of the brain damage has to meet certain requirements: (i) to originate in the central nervous system (CNS) with no contribution from extracerebral sources; (ii) a passive release from damaged neurons and/or glial cells without any stimulated active release; (iii) a lack of specific effects on neurons and/or glial cells interfering with the initial injury; (iv) an unlimited passage through the blood-brain barrier (BBB). The measurement of putative biochemical markers, such as the S100B protein, has been proposed in this role. Over the past decade, numerous studies have reported a positive correlation of S100B serum levels with a poor outcome following TBI. However, some studies raise doubt whether the serum measurement of S100B is a valid biochemical marker of brain damage. We summarize the specific properties of S100B and analyze whether they support or counteract the necessary requirements to designate this protein as an indicator of brain damage. Finally, we report recent experimental findings suggesting a possible therapeutic potential of S100B.

Background: In previous studies, it has been shown that intravenous lactate therapy can improve brain neurochemistry, adenosine triphosphate (ATP) generation and outcome after traumatic brain injury (TBI) in rats. In this study, we examined: (1) four L-lactate concentrations to determine the optimal therapeutic dose post TBI in terms of cognitive function; (2) ATP production after TBI for the L-lactate concentration found to be the optimal dose; (3) the possible production of lactic acidosis with the highest L-lactate concentration tested., Methods: Thirty minutes following a fluid percussion injury (FPI) over the left cerebral hemisphere, the animals received an intravenous infusion of 10, 28, 100, or 280 mM L-lactate (n = 10 for each group) for 3 h at a rate of 0.65 ml/h. Shams and control injured animals received a saline infusion. At 11-15 days post injury, cognitive deficits were examined using the Morris Water Maze (MWM) test. Three groups of rats were used for ATP analysis: shams, injured + saline infusion, and injury + the optimal lactate dose as determined by the MWM (n = 4/group). Additionally, a group receiving 280 mM L-lactate (n = 5) and one receiving a saline infusion (n = 3) were monitored for arterial blood variables and blood pressures., Findings: In the MWM test, only the 100 mM L-lactate-treated injured animals showed a significant reduction in cognitive deficits when compared to saline-treated injured animals (p

Objective: Failure of energy metabolism after traumatic brain injury may be a major factor limiting outcome. Although glucose is the primary metabolic substrate in the healthy brain, the well documented surge in tissue lactate after traumatic brain injury suggests that lactate may provide an energy need that cannot be met by glucose. We hypothesized, therefore, that administration of lactate or the combination of lactate and supraphysiological oxygen may improve mitochondrial oxidative respiration in the brain after rat fluid percussion injury. We measured oxygen consumption (VO2) to determine what effects glucose, lactate, oxygen, and the combination of lactate and oxygen have on mitochondrial respiration in both injured and uninjured rat brain tissue., Methods: Anesthetized Sprague-Dawley rats were intubated and ventilated with either 0.21 or 1.0 fraction of inspired oxygen (FIO2). Brain tissue from acute sham animals was subjected in vitro to 1.1 mM, 12 mM and 100 mM concentrations of glucose and L-lactate. In another group, injury (fluid percussion injury of 2.5 +/- 0.02 atmospheres) was induced over the left hemisphere. The VO2 of mug amounts of brain tissues were measured in a microrespirometry system (Cartesian diver)., Results: The VO2 was found to be independent of glucose concentrations, but dose-dependent for lactate. Moreover, the lactate dependent VO2s were all significantly higher than those generated by glucose. Injured rats on FIO2 0.21 had brain tissue VO2 rates that were significantly lower than those of shams or preinjury levels. In injured rats treated with FIO2 1.0, the reduction in VO2 levels was prevented. Injured rats that received an intravenous infusion of 100 mM lactate had VO2 rates that were significantly higher than those obtained with FIO2 1.0. Combined treatment further boosted the lactate generated VO2 rates by approximately 15%., Conclusion: Glucose sustains mitochondrial respiration at a low level "fixed" rate because, despite increasing its concentration nearly 100-fold, it cannot up-regulate VO2 after fluid percussion injury. Lactate produces a dose-dependent VO2 response, possibly enabling mitochondria to meet the increased energy needs of the injured brain.

Severe traumatic brain injury (TBI) leads to an immunocompromised state responsible for an increased morbidity and mortality. Our understanding of the mechanisms responsible for this brain damage is incomplete. Damage maybe mediated by a complex cascade of neuroinflammation, and cytokine activation. In addition, translocation and accumulation of T cells in the brain parenchyma could take place and be related to detrimental effects. Our aims in this prospective randomized pilot study, were to detect the early effect of severe TBI upon cell-mediated immunity, to verify if early immunologic impairment correlates with neurologic outcome, and finally, to test the effect of early administration of iv infusion of cyclosporin A upon cell-mediated immunologic function. Forty-nine patients with severe TBI were studied. Thirty-six of these patients received a 24-h intravenous infusion of Cyclosporin A, or two 24-h infusions of the drug. 10 patients were in the placebo group. Three patients, not enrolled in the cyclosporin trial, were studied only for the relationship between cellular immunity, neurological outcome, and infection rate. T cell counts and microbiological cultures were performed in all patients. Sixty-five percent of patients demonstrated reduced T lymphocyte counts on admission. Furthermore, reduction of T cell numbers was related with significantly worse neurologic outcome and an increase in pulmonary infection. There was no significant difference between the placebo and CsA treated patients for the studied immunological parameters, or for incidence of infection. We also observed sequestration/diapedesis of T cells into the brain parenchyma, around contusions, after human TBI and we speculate that this could be responsible for further brain damage.

Object: The edema associated with brain swelling after traumatic brain injury (TBI) has been thought to be vasogenic in origin, but the results of previous laboratory studies by the authors have shown that a cellular form of edema is mainly responsible for brain swelling after TBI. In this study the authors used magnetic resonance (MR) imaging techniques to identify the type of edema that occurs in patients with TBI., Methods: Diffusion-weighted MR imaging was used to evaluate the apparent diffusion coefficient (ADC) in 44 patients with TBI (Glasgow Coma Scale Score < 8) and in eight healthy volunteers. Higher ADC values have been associated with vasogenic edema, and lower ADC values with a predominantly cellular form of edema. Regional measurements of ADC in patients with focal and diffuse injury were computed. The water content of brain tissue was also assessed in absolute terms by using MR imaging to measure the percentage of water per gram of tissue. Cerebral blood flow (CBF) was measured using stable Xe-computerized tomography (CT) studies to rule out ischemia as a cause of cellular edema. The mean ADC value in the healthy volunteers was 0.82 +/- 0.05 x 10(-3) mm2/second. The ADC values in the patients with diffuse brain injury without swelling were close to the mean for the healthy volunteers. In contrast, the patients with brain swelling had increased brain water content and low ADC values (mean 0.74 +/- 0.05 x 10(-3) mm2/second). The ADC values correlated with CT classifications. In all patients with low ADC values, the CBF values were outside the range for ischemia., Conclusions: The brain swelling observed in patients with TBI appears to be predominantly cellular, as signaled by low ADC values in brain tissue with high levels of water content.

Traumatic brain injury (TBI) remains a major public health problem, and there is a great medical need for a pharmacological treatment that could improve long-term outcome. The excitatory neurotransmitter, glutamate, has been implicated in processes leading to neurodegeneration. Traxoprodil (CP-101,606) is a novel and potent glutamate receptor antagonist that is highly selective for the NR2B subunit of the NMDA receptor; it has been shown to be neuroprotective in animal models of brain injury and ischemia. A randomized, double-blind, placebo-controlled study was therefore conducted to assess the efficacy and safety of a 72-h infusion of traxoprodil compared to placebo in subjects with computed tomography scan evidence of severe TBI (GCS 4-8). A total of 404 males and non-pregnant females, aged 16-70, were treated within 8 h of injury. At baseline, subjects were stratified by motor score severity. The results showed that a greater proportion of the traxoprodil-treated subjects had a favorable outcome on the dichotomized Glasgow Outcome Scale (dGOS) at 6 months (delta 5.5%, OR 1.3, p = 0.21, 95% CI:[0.85, 2.06]) and at last visit (delta 7.5%, OR 1.47, p = 0.07, 95% CI:[0.97, 2.25]). The mortality rate with traxoprodil treatment was 7% less than with placebo treatment (OR 1.45, p = 0.08, 95% CI:[0.96, 2.18]). Differences between treatment groups were more pronounced in the severest subset (delta 11.8% for the dGOS at last visit and delta 16.6% for mortality). Traxoprodil was well tolerated. Although these results are intriguing, no definitive claim of efficacy can be made for traxoprodil for the treatment of severe TBI.