Injury-Transplantation Interval-Dependent Amelioration of Axonal Degeneration and Motor Deficit in Rats with Penetrating Traumatic Brain Injury.

Penetrating traumatic brain injury (pTBI) is increasingly survivable, but permanently disabling as adult mammalian nervous system does not regenerate. Recently, our group demonstrated transplant location-dependent neuroprotection and safety of clinical trial-grade human neural stem cell (hNSC) transplantation in a rodent model of acute pTBI. To evaluate whether longer injury-transplantation intervals marked by chronic inflammation impede engraftment, 60 male Sprague-Dawley rats were randomized to three sets. Each set was divided equally into two groups: 1) with no injury (sham) or 2) pTBI. After either 1 week (groups 1 and 2), 2 weeks (groups 3 and 4), or 4 weeks after injury (groups 5 and 6), each animal received 0.5 million hNSCs perilesionally. A seventh group of pTBI animals treated with vehicle served as the negative control. All animals were allowed to survive 12 weeks with standard chemical immunosuppression. Motor capacity was assessed pre-transplant to establish injury-induced deficit and followed by testing at 8 and 12 weeks after transplantation. Animals were euthanized, perfused, and examined for lesion size, axonal degeneration, and engraftment. Compared to vehicle, transplanted groups showed a trend for reduced lesion size and axonal injury across intervals. Remote secondary axonal injury was significantly reduced in groups 2 and 4, but not in group 6. The majority of animals showed robust engraftment independent of the injury-transplant time interval. Modest amelioration of motor deficit paralleled the axonal injury trend. In aggregate, pTBI-induced remote secondary axonal injury was resolved by early, but not delayed, hNSC transplantation.

Assessing fetal human neural stem cells tumorigenicity potential in athymic rats with penetrating traumatic brain injury (pTBI).

Traumatic brain injuries (TBI) often produce disability in survivors due to unresolved inflammation and progressive neurodegeneration. The central nervous system in mammals is incapable of self-repair. Two decades of preclinical studies and clinical trials have provided insights into TBI pathophysiology that could be utilized to develop clinically relevant therapy. Our laboratory recently reported efficacy of clinical trial grade fetal human neural stem cells (hNSCs) in immunosuppressed rats with penetrating traumatic brain injury (pTBI). Next, in compliance with the United States Food and Drug Administration (USFDA) guidance, this study explores safety by assessing the tumorigenicity potential of intracranial hNSC transplants in athymic rats with pTBI. First, the maximum tolerated dose (MTD) was determined. Then, forty athymic pTBI rats were randomized to either: Group A. pTBI + vehicle or Group B. pTBI + hNSCs at MTD one week after injury with 6-months survival, sufficient time to uncover transplant associated tumorigenicity. A board-certified Pathologist examined hematoxylin-eosin (H&E), Ki67 immunostained brain and spinal cord, serial sections along with several abnormal peripheral masses for evidence of lesion, transplant, and oncogenesis. There was no evidence of transplant derived tumors or oncogenic tissue necrosis. Consistent with athymic literature, the lesion remained unchanged even after robust hNSC engraftment. This safety study supports the conclusion that hNSCs are safe for transplantation in pTBI. The differences in lesion expansion between immunosuppressed and athymic rats in the presence of hNSCs suggests an unexpected role for thymus derived cells in resolution of trauma induced inflammation.

Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial.

BACKGROUND: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome. METHODS: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. RESULTS: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. CONCLUSIONS: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

EphB3 interacts with initiator caspases and FHL-2 to activate dependence receptor cell death in oligodendrocytes after brain injury.

Clinical trials examining neuroprotective strategies after brain injury, including those targeting cell death mechanisms, have been underwhelming. This may be in part due to an incomplete understanding of the signalling mechanisms that induce cell death after traumatic brain injury. The recent identification of a new family of death receptors that initiate pro-cell death signals in the absence of their ligand, called dependence receptors, provides new insight into the factors that contribute to brain injury. Here, we show that blocking the dependence receptor signalling of EphB3 improves oligodendrocyte cell survival in a murine controlled cortical impact injury model, which leads to improved myelin sparing, axonal conductance and behavioural recovery. EphB3 also functions as a cysteine-aspartic protease substrate, where the recruitment of injury-dependent adaptor protein Dral/FHL-2 together with capsase-8 or -9 leads to EphB3 cleavage to initiate cell death signals in murine and human traumatic brain-injured patients, supporting a conserved mechanism of cell death. These pro-apoptotic responses can be blocked via exogenous ephrinB3 ligand administration leading to improved oligodendrocyte survival. In short, our findings identify a novel mechanism of oligodendrocyte cell death in the traumatically injured brain that may reflect an important neuroprotective strategy in patients.

Human neural stem cell transplant location-dependent neuroprotection and motor deficit amelioration in rats with penetrating traumatic brain injury.

BACKGROUND: Penetrating traumatic brain injury induces chronic inflammation that drives persistent tissue loss long after injury. Absence of endogenous reparative neurogenesis and effective neuroprotective therapies render injury-induced disability an unmet need. Cell replacement via neural stem cell transplantation could potentially rebuild the tissue and alleviate penetrating traumatic brain injury disability. The optimal transplant location remains to be determined. METHODS: To test if subacute human neural stem cell (hNSC) transplant location influences engraftment, lesion expansion, and motor deficits, rats (n = 10/group) were randomized to the following four groups (uninjured and three injured): group 1 (Gr1), uninjured with cell transplants (sham+hNSCs), 1-week postunilateral penetrating traumatic brain injury, after establishing motor deficit; group 2 (Gr2), treated with vehicle (media, no cells); group 3 (Gr3), hNSCs transplanted into lesion core (intra); and group 4 (Gr4), hNSCs transplanted into tissue surrounding the lesion (peri). All animals were immunosuppressed for 12 weeks and euthanized following motor assessment. RESULTS: In Gr2, penetrating traumatic brain injury effect manifests as porencephalic cyst, 22.53 ± 2.87 (% of intact hemisphere), with p value of <0.0001 compared with uninjured Gr1. Group 3 lesion volume at 17.44 ± 2.11 did not differ significantly from Gr2 (p = 0.36), while Gr4 value, 9.17 ± 1.53, differed significantly (p = 0.0001). Engraftment and neuronal differentiation were significantly lower in the uninjured Gr1 (p < 0.05), compared with injured groups. However, there were no differences between Gr3 and Gr4. Significant increase in cortical tissue sparing (p = 0.03), including motor cortex (p = 0.005) was observed in Gr4 but not Gr3. Presence of transplant within lesion or in penumbra attenuated motor deficit development (p < 0.05) compared with Gr2. CONCLUSION: In aggregate, injury milieu supports transplanted cell proliferation and differentiation independent of location. Unexpectedly, cortical sparing is transplant location dependent. Thus, apart from cell replacement and transplant mediated deficit amelioration, transplant location-dependent neuroprotection may be key to delaying onset or preventing development of injury-induced disability. LEVEL OF EVIDENCE: Preclinical study evaluation of therapeutic intervention, level VI.

Subdural hematoma decompression model: A model of traumatic brain injury with ischemic-reperfusional pathophysiology: A review of the literature.

The prognosis for patients with traumatic brain injury (TBI) with subdural hematoma (SDH) remains poor. In accordance with an increasing elderly population, the incidence of geriatric TBI with SDH is rising. An important contributor to the neurological injury associated with SDH is the ischemic damage which is caused by raised intracranial pressure (ICP) producing impaired cerebral perfusion. To control intracranial hypertension, the current management consists of hematoma evacuation with or without decompressive craniotomy. This removal of the SDH results in the immediate reversal of global ischemia accompanied by an abrupt reduction of mass lesion and an ensuing reperfusion injury. Experimental models can play a critical role in improving our understanding of the underlying pathophysiology and in exploring potential treatments for patients with SDH. In this review, we describe the epidemiology, pathophysiology and clinical background of SDH.

Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI.

Traumatic brain injury (TBI) is the largest cause of death and disability of persons under 45 years old, worldwide. Independent of the distribution, outcomes such as disability are associated with huge societal costs. The heterogeneity of TBI and its complicated biological response have helped clarify the limitations of current pharmacological approaches to TBI management. Five decades of effort have made some strides in reducing TBI mortality but little progress has been made to mitigate TBI-induced disability. Lessons learned from the failure of numerous randomized clinical trials and the inability to scale up results from single center clinical trials with neuroprotective agents led to the formation of organizations such as the Neurological Emergencies Treatment Trials (NETT) Network, and international collaborative comparative effectiveness research (CER) to re-orient TBI clinical research. With initiatives such as TRACK-TBI, generating rich and comprehensive human datasets with demographic, clinical, genomic, proteomic, imaging, and detailed outcome data across multiple time points has become the focus of the field in the United States (US). In addition, government institutions such as the US Department of Defense are investing in groups such as Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug-screening consortium to address the barriers in translation. The consensus from such efforts including "The Lancet Neurology Commission" and current literature is that unmitigated cell death processes, incomplete debris clearance, aberrant neurotoxic immune, and glia cell response induce progressive tissue loss and spatiotemporal magnification of primary TBI. Our analysis suggests that the focus of neuroprotection research needs to shift from protecting dying and injured neurons at acute time points to modulating the aberrant glial response in sub-acute and chronic time points. One unexpected agent with neuroprotective properties that shows promise is transplantation of neural stem cells. In this review we present (i) a short survey of TBI epidemiology and summary of current care, (ii) findings of past neuroprotective clinical trials and possible reasons for failure based upon insights from human and preclinical TBI pathophysiology studies, including our group's inflammation-centered approach, (iii) the unmet need of TBI and unproven treatments and lastly, (iv) present evidence to support the rationale for sub-acute neural stem cell therapy to mediate enduring neuroprotection.

New astroglial injury-defined biomarkers for neurotrauma assessment.

Traumatic brain injury (TBI) is an expanding public health epidemic with pathophysiology that is difficult to diagnose and thus treat. TBI biomarkers should assess patients across severities and reveal pathophysiology, but currently, their kinetics and specificity are unclear. No single ideal TBI biomarker exists. We identified new candidates from a TBI CSF proteome by selecting trauma-released, astrocyte-enriched proteins including aldolase C (ALDOC), its 38kD breakdown product (BDP), brain lipid binding protein (BLBP), astrocytic phosphoprotein (PEA15), glutamine synthetase (GS) and new 18-25kD-GFAP-BDPs. Their levels increased over four orders of magnitude in severe TBI CSF. First post-injury week, ALDOC levels were markedly high and stable. Short-lived BLBP and PEA15 related to injury progression. ALDOC, BLBP and PEA15 appeared hyper-acutely and were similarly robust in severe and mild TBI blood; 25kD-GFAP-BDP appeared overnight after TBI and was rarely present after mild TBI. Using a human culture trauma model, we investigated biomarker kinetics. Wounded (mechanoporated) astrocytes released ALDOC, BLBP and PEA15 acutely. Delayed cell death corresponded with GFAP release and proteolysis into small GFAP-BDPs. Associating biomarkers with cellular injury stages produced astroglial injury-defined (AID) biomarkers that facilitate TBI assessment, as neurological deficits are rooted not only in death of CNS cells, but also in their functional compromise.

Amelioration of Penetrating Ballistic-Like Brain Injury Induced Cognitive Deficits after Neuronal Differentiation of Transplanted Human Neural Stem Cells.

Penetrating traumatic brain injury (PTBI) is one of the major cause of death and disability worldwide. Previous studies with penetrating ballistic-like brain injury (PBBI), a PTBI rat model revealed widespread perilesional neurodegeneration, similar to that seen in humans following gunshot wound to the head, which is unmitigated by any available therapies to date. Therefore, we evaluated human neural stem cell (hNSC) engraftment to putatively exploit the potential of cell therapy that has been seen in other central nervous system injury models. Toward this objective, green fluorescent protein (GFP) labeled hNSC (400,000 per animal) were transplanted in immunosuppressed Sprague-Dawley (SD), Fisher, and athymic (ATN) PBBI rats 1 week after injury. Tacrolimus (3 mg/kg 2 days prior to transplantation, then 1 mg/kg/day), methylprednisolone (10 mg/kg on the day of transplant, 1 mg/kg/week thereafter), and mycophenolate mofetil (30 mg/kg/day) for 7 days following transplantation were used to confer immunosuppression. Engraftment in SD and ATN was comparable at 8 weeks post-transplantation. Evaluation of hNSC differentiation and distribution revealed increased neuronal differentiation of transplanted cells with time. At 16 weeks post-transplantation, neither cell proliferation nor glial lineage markers were detected. Transplanted cell morphology was similar to that of neighboring host neurons, and there was relatively little migration of cells from the peritransplant site. By 16 weeks, GFP-positive processes extended both rostrocaudally and bilaterally into parenchyma, spreading along host white matter tracts, traversing the internal capsule, and extending ∼13 mm caudally from transplantation site reaching into the brainstem. In a Morris water maze test at 8 weeks post-transplantation, animals with transplants had shorter latency to platform than vehicle-treated animals. However, weak injury-induced cognitive deficits in the control group at the delayed time point confounded benefits of durable engraftment and neuronal differentiation. Therefore, these results justify further studies to progress towards clinical translation of hNSC therapy for PTBI.

EphrinB3 restricts endogenous neural stem cell migration after traumatic brain injury.

Traumatic brain injury (TBI) leads to a series of pathological events that can have profound influences on motor, sensory and cognitive functions. Conversely, TBI can also stimulate neural stem/progenitor cell proliferation leading to increased numbers of neuroblasts migrating outside their restrictive neurogenic zone to areas of damage in support of tissue integrity. Unfortunately, the factors that regulate migration are poorly understood. Here, we examine whether ephrinB3 functions to restrict neuroblasts from migrating outside the subventricular zone (SVZ) and rostral migratory stream (RMS). We have previously shown that ephrinB3 is expressed in tissues surrounding these regions, including the overlying corpus callosum (CC), and is reduced after controlled cortical impact (CCI) injury. Our current study takes advantage of ephrinB3 knockout mice to examine the influences of ephrinB3 on neuroblast migration into CC and cortex tissues after CCI injury. Both injury and/or ephrinB3 deficiency led to increased neuroblast numbers and enhanced migration outside the SVZ/RMS zones. Application of soluble ephrinB3-Fc molecules reduced neuroblast migration into the CC after injury and limited neuroblast chain migration in cultured SVZ explants. Our findings suggest that ephrinB3 expression in tissues surrounding neurogenic regions functions to restrict neuroblast migration outside the RMS by limiting chain migration.

Microdialysis as Clinical Evaluation of Therapeutic Hypothermia in Rat Subdural Hematoma Model.

Cerebral microdialysis (MD) is a fine laboratory technique which has been established for studying physiological, pharmacological, and pathological changes in the experimental studies of traumatic brain injury (TBI). This technique has also been well translated and widely applied to clinical bedside monitoring to provide pathophysiological analysis in severe TBI patients. The MD technique is thus well suited for straightforward translation from basic science to clinical application.In this chapter, we describe our evaluation of MD method in acute subdural hematoma (ASDH) rat model. With 100 kDa cut-off microdialysis membrane, we could measure several biomarkers such as ubiquitin carboxy hydrolase L1 (UCH-L1), a neuronal marker and glial fibrillary acidic protein (GFAP), and a glial marker in extracellular fluid. In this experiment, we could detect that the peak of extracellular UCH-L1 in the early hypothermia group was significantly lower than in the normothermia group. Also, in the late phase of reperfusion (>2.5 h after decompression), extracellular GFAP in the early hypothermia group was lower than in the normothermia. These data thus suggested that early, preoperatively induced hypothermia could mediate the reduction of neuronal and glial damage in the reperfusion phase of ischemia/reperfusion brain injury.Microdialysis allows for the direct measurement of extracellular molecules in an attempt to characterize metabolic derangements before they become clinically relevant. Advancements in technology have allowed for the bedside assay of multiple markers of ischemia and metabolic dysfunction, and the applications for traumatic brain injury have been well established. As clinicians become more comfortable with these tools their widespread use and potential for clinical impact with continue to rise.

Wooden Foreign Body in the Skull Base: How Did We Miss It?

BACKGROUND: Timely detection of intraorbital and skull base wooden foreign bodies is crucial. Wooden foreign bodies are difficult to detect on imaging. The radiologist may fail to identify wooden foreign bodies on two thirds of initial scans and can miss them in almost one third of total cases. CASE DESCRIPTION: A 66-year-old woman sustained a penetrating injury through the left upper eyelid with a small tree branch. The branch was immediately removed in the field, and she was provided with prompt medical care at a local hospital. Initial computed tomography (CT) scan diagnosis was "posttraumatic sinusitis," and this was treated empirically with vancomycin and piperacillin/tazobactam. On the eighth day after injury, she developed progressive swelling and pain of her eyelid with left trigeminal/supraorbital numbness and complete left ophthalmoplegia. A new CT scan showed an open "track" from the region of the left upper orbit/superior rectus to the contralateral sphenoid sinus, which raised suspicion for a retained foreign body. Further imaging confirmed the suspicion. Endoscopic sinus surgery was performed with extraction of the wooden object and evacuation of the left orbital infection. CONCLUSIONS: This case indicates that intraorbital and skull base wooden foreign bodies are elusive, demanding a high index of suspicion from both clinicians and radiologists to identify retained material in the setting of ocular or sinus trauma. For better identification of wooden foreign bodies, bone windows on CT should have a width of -1000 Hounsfield units with a soft tissue window level of -500 Hounsfield units.

Moderate Traumatic Brain Injury: The Grey Zone of Neurotrauma.

Moderate traumatic brain injury (MTBI) is poorly defined in the literature and the nomenclature "moderate" is misleading, because up to 15 % of such patients may die. MTBI is a heterogeneous entity that shares many aspects of its pathophysiology and management with severe traumatic brain injury. Many patients who ''talk and died'' are MTBI. The role of neuroimaging is essential for the proper management of these patients. To analyze all aspects of the pathophysiology and management of MTBI, proposing a new way to categorize it considering the clinical picture and neuroimaging findings. We proposed a different approach to the group of patients with Glasgow Coma Scale (GCS) ranging from 9 through 13 and we discuss the rationale for this proposal. Patients with lower GCS scores (9-10), especially those with significant space-occupying lesions on the CT scan, should be managed following the guidelines for severe traumatic brain injury, with ICU observation, frequent serial computed tomography (CT) scanning and ICP monitoring. On the other hand, those with higher range GCS (11-13) can be managed more conservatively with serial neurological examination and CT scans. Given the available evidence, MTBI is an entity that needs reclassification. Large-scale and well-designed studies are urgently needed.

Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III.

BACKGROUND AND PURPOSE: The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography-based planimetry (CTP). METHODS: In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. RESULTS: In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r(2)=0.93) than with site-ABC (r(2)=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm(3); CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. CONCLUSIONS: ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.

Direct observation during surgery shows preservation of cerebral microcirculation in patients with traumatic brain injury.

OBJECTIVE: To describe the alterations of the cortical microcirculation of the brain (blood flow and vessel density) in TBI patients who and compare them with a control group. METHODS: Prospective and observational study in a third-level university hospital. Cortical microcirculation in the brain was directly observed using sidestream dark-field (SDF) imaging in 14 patients who underwent surgery: 5 subdural hematomas (SDH) and 9 parenchymal lesions (contusions/hematomas). In this last set of patients, images were recorded in the "pericontusional" areas and in the "surrounding" brain (areas that were as far from the lesion as the craniotomy allowed). These patients were compared to five patients who underwent craniotomy for a disease that did not affect the cortex. RESULTS: There were fewer "pericontusional" images that could be analyzed due to the presence of subarachnoid hemorrhage. The proportion or perfused vessels was similar in all groups: control 99.5% ± 1.3%; SDH 98.6% ± 2.4%; "pericontusional" area 98.2% ± 2.4%; "surrounding" area 98.4% ± 2.5% (p = 0.145). The perfused vessel density index was smaller in the "pericontusional" area: control 6.5 ± 1.6 l/mm; SDH 6.5 ± 2.5 l/mm; "pericontusional" area 5.4 ± 2.6 l/mm; "surrounding" 6.6 ± 2.1 l/mm (p = 0.07). CONCLUSIONS: Although the analysis of pericontusional zone was difficult, there were fewer vessels than in the controls and there was no change in the flow. In the surrounding zone and in patients with SDH, we did not document alterations in the microcirculation. Direct imaging of cerebral microcirculation in TBI patients showed that despite serious brain injury the cerebral microcirculation was remarkably well preserved.

Evidence to support mitochondrial neuroprotection, in severe traumatic brain injury.

Traumatic brain injury (TBI) is still the leading cause of disability in young adults worldwide. The major mechanisms - diffuse axonal injury, cerebral contusion, ischemic neurological damage, and intracranial hematomas have all been shown to be associated with mitochondrial dysfunction in some form. Mitochondrial dysfunction in TBI patients is an active area of research, and attempts to manipulate neuronal/astrocytic metabolism to improve outcomes have been met with limited translational success. Previously, several preclinical and clinical studies on TBI induced mitochondrial dysfunction have focused on opening of the mitochondrial permeability transition pore (PTP), consequent neurodegeneration and attempts to mitigate this degeneration with cyclosporine A (CsA) or analogous drugs, and have been unsuccessful. Recent insights into normal mitochondrial dynamics and into diseases such as inherited mitochondrial neuropathies, sepsis and organ failure could provide novel opportunities to develop mitochondria-based neuroprotective treatments that could improve severe TBI outcomes. This review summarizes those aspects of mitochondrial dysfunction underlying TBI pathology with special attention to models of penetrating traumatic brain injury, an epidemic in modern American society.

Microdialysis in the neurocritical care unit.

Effective monitoring is critical for neurologically compromised patients, and several techniques are available. One of these tools, cerebral microdialysis (MD), was designed to detect derangements in cerebral metabolism. Although this monitoring device began as a research instrument, favorable results and utility have broadened its clinical applications. Combined with other brain monitoring techniques, MD can be used to estimate cerebral vulnerability, to assess tissue outcome, and possibly to prevent secondary ischemic injury by guiding therapy. This article reviews the literature regarding the past, present, and future uses of MD along with its advantages and disadvantages in the intensive care unit setting.

Biomarkers for the clinical differential diagnosis in traumatic brain injury--a systematic review.

Rapid triage and decision-making in the treatment of traumatic brain injury (TBI) present challenging dilemma in "resource poor" environments such as the battlefield and developing areas of the world. There is an urgent need for additional tools to guide treatment of TBI. The aim of this review is to establish the possible use of diagnostic TBI biomarkers in (1) identifying diffuse and focal brain injury and (2) assess their potential for determining outcome, intracranial pressure (ICP), and responses to therapy. At present, there is insufficient literature to support a role for diagnostic biomarkers in distinguishing focal and diffuse injury or for accurate determination of raised ICP. Presently, neurofilament (NF), S100ß, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1) seemed to have the best potential as diagnostic biomarkers for distinguishing focal and diffuse injury, whereas C-tau, neuron-specific enolase (NSE), S100ß, GFAP, and spectrin breakdown products (SBDPs) appear to be candidates for ICP reflective biomarkers. With the combinations of different pathophysiology related to each biomarker, a multibiomarker analysis seems to be effective and would likely increase diagnostic accuracy. There is limited research focusing on the differential diagnostic properties of biomarkers in TBI. This fact warrants the need for greater efforts to innovate sensitive and reliable biomarkers. We advocate awareness and inclusion of the differentiation of injury type and ICP elevation in further studies with brain injury biomarkers.

Preoperative-induced mild hypothermia attenuates neuronal damage in a rat subdural hematoma model.

Post-traumatic hypothermia has been effective for traumatic brain injury in the laboratory setting. However, hypothermia has not shown efficacy in clinical trials. With the results of a recent clinical trial, we hypothesized that hypothermia might reduce neuronal damage in acute subdural hematoma (ASDH) by blunting the effects of reperfusion injury. Twenty rats were induced with ASDH and placed into one of four groups. The normothermia group was maintained at 37 °C throughout. In the early hypothermia group, brain temperature was reduced to 33 °C 30 min prior to craniotomy. In the late hypothermia group, brain temperature was lowered to 33 °C 30 min after decompression. The sham group had no ASDH and underwent only craniotomy with normothermia. For estimation of glial and neuronal cell damage, we analyzed serum and microdialysate (using a 100kD probe) concentrations of: glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl--terminal hydrolase -L1 (UCH-L1). Hypothermia induced early significantly reduced the concentration of MD UCH-L1. In conclusion, hypothermia induced early may reduce neuronal cell damage in the reperfusion injury, which was induced after ASDH removal. MD UCH-L1 seems like a good -candidate for a sensitive microdialysate biomarker for -neuronal injury and outcome.

Neuromonitoring with microdialysis in severe traumatic brain injury patients.

BACKGROUND: Neuromonitoring with microdialysis has the potential for early detection of metabolic derangements associated with TBI. METHODS: 1,260 microdialysis samples from 12 TBI patients were analyzed for glucose, -lactate, pyruvate, lactate/pyruvate ratio (LPR), and lactate/glucose ratio (LGR). Analytes were correlated with the Glasgow Coma Scale (GCS) before surgery and with the Glasgow Outcome Scale (GOS) at the time of discharge. The patients were divided into two groups for GCS: 3-6 and 7-9, and for GOS 1-3 and 4-5. Chi-squared test was performed for correlations. RESULTS: Glucose, lactate levels, and LGR were high in TBI patients with GCS 3-6 (p < 0.0001). Pyruvate level was lower in patients with GCS 7-9 (p < 0.001). LPR was higher in patients with GCS 3-6 (p < 0.05). High glucose, lactate level (p < 0.001), and LPR (p < 0.01) was observed in patients with GOS 1-3. Pyruvate level was low in patients with GOS 1-3 (p < 0.001). LGR was higher in patient with better outcome (GOS 4-5). CONCLUSION: After craniotomy extracellular glucose and lactate were good "biomarkers" of cerebral damage in TBI patients. We consider that high extracellular lactate and low glucose is an indicator of severe neurological damage and poor outcome, because of impaired brain metabolism.