Shoji Yokobori

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), S100β, 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), S100β, 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.

Acute Diagnostic Biomarkers for Spinal Cord Injury: Review of the Literature and Preliminary Research Report

OBJECTIVE Many efforts have been made to create new diagnostic technologies for use in the diagnosis of central nervous system injury. However, there is still no consensus for the use of biomarkers in clinical acute spinal cord injury (SCI). The aims of this review are (1) to evaluate the current status of neurochemical biomarkers and (2) to discuss their potential acute diagnostic role in SCI by reviewing the literature. METHODS PubMed (http://www.ncbi.nlm.nih.gov/pubmed) was searched up to 2012 to identify publications concerning diagnostic biomarkers in SCI. To support more knowledge, we also checked secondary references in the primarily retrieved literature. RESULTS Neurofilaments, cleaved-Tau, microtubule-associated protein 2, myelin basic protein, neuron-specific enolase, S100β, and glial fibrillary acidic protein were identified as structural protein biomarkers in SCI by this review process. We could not find reports relating ubiquitin C-terminal hydrolase-L1 and α-II spectrin breakdown products, which are widely researched in other central nervous system injuries. Therefore, we present our preliminary data relating to these two biomarkers. Some of biomarkers showed promising results for SCI diagnosis and outcome prediction; however, there were unresolved issues relating to accuracy and their accessibility. CONCLUSION Currently, there still are not many reports focused on diagnostic biomarkers in SCI. This fact warranted the need for greater efforts to innovate sensitive and reliable biomarkers for SCI.

Optimal range of global end-diastolic volume for fluid management after aneurysmal subarachnoid hemorrhage: a multicenter prospective cohort study.

Objectives:Limited evidence supports the use of hemodynamic variables that correlate with delayed cerebral ischemia or pulmonary edema after aneurysmal subarachnoid hemorrhage. The aim of this study was to identify those hemodynamic variables that are associated with delayed cerebral ischemia and pulmonary edema after subarachnoid hemorrhage. Design:A multicenter prospective cohort study. Setting:Nine university hospitals in Japan. Patients:A total of 180 patients with aneurysmal subarachnoid hemorrhage. Interventions:None. Measurements and Main Results:Patients were prospectively monitored using a transpulmonary thermodilution system in the 14 days following subarachnoid hemorrhage. Delayed cerebral ischemia was developed in 35 patients (19.4%) and severe pulmonary edema was developed in 47 patients (26.1%). Using the Cox proportional hazards model, the mean global end-diastolic volume index (normal range, 680–800 mL/m2) was the independent factor associated with the occurrence of delayed cerebral ischemia (hazard ratio, 0.74; 95% CI, 0.60–0.93; p = 0.008). Significant differences in global end-diastolic volume index were detected between the delayed cerebral ischemia and non–delayed cerebral ischemia groups (783 ± 25 mL/m2 vs 870 ± 14 mL/m2; p = 0.007). The global end-diastolic volume index threshold that best correlated with delayed cerebral ischemia was less than 822 mL/m2, as determined by receiver operating characteristic curves. Analysis of the Cox proportional hazards model indicated that the mean global end-diastolic volume index was the independent factor that associated with the occurrence of pulmonary edema (hazard ratio, 1.31; 95% CI, 1.02–1.71; p = 0.03). Furthermore, a significant positive correlation was identified between global end-diastolic volume index and extravascular lung water (r = 0.46; p < 0.001). The global end-diastolic volume index threshold that best correlated with severe pulmonary edema was greater than 921 mL/m2. Conclusions:Our findings suggest that global end-diastolic volume index impacts both delayed cerebral ischemia and pulmonary edema after subarachnoid hemorrhage. Maintaining global end-diastolic volume index slightly above normal levels has promise as a fluid management goal during the treatment of subarachnoid hemorrhage.

Neuroprotective effect of preoperatively induced mild hypothermia as determined by biomarkers and histopathological estimation in a rat subdural hematoma decompression model.

OBJECT In patients who have sustained a traumatic brain injury (TBI), hypothermia therapy has not shown efficacy in multicenter clinical trials. Armed with the post hoc data from the latest clinical trial (National Acute Brain Injury Study: Hypothermia II), the authors hypothesized that hypothermia may be beneficial in an acute subdural hematoma (SDH) rat model by blunting the effects of ischemia/reperfusion injury. The major aim of this study was to test the efficacy of temperature management in reducing brain damage after acute SDH. METHODS The rats were induced with acute SDH and placed into 1 of 4 groups: 1) normothermia group (37°C); 2) early hypothermia group, head and body temperature reduced to 33°C 30 minutes prior to craniotomy; 3) late hypothermia group, temperature lowered to 33°C 30 minutes after decompression; and 4) sham group, no acute SDH (only craniotomy with normothermia). To assess for neuronal and glial cell damage, the authors analyzed microdialysate concentrations of GFAP and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) by using a 100-kD probe. Fluoro-Jade B-positive neurons and injury volume with 2,3,5-triphenyltetrazolium chloride staining were also measured. RESULTS In the early phase of reperfusion (30 minutes, 2.5 hours after decompression), extracellular UCH-L1 in the early hypothermia group was significantly lower than in the normothermia group (early, 4.9 ± 1.0 ng/dl; late, 35.2 ± 12.1 ng/dl; normothermia, 50.20 ± 28.3 ng/dl; sham, 3.1 ± 1.3 ng/dl; early vs normothermia, p < 0.01; sham vs normothermia, p < 0.01, analyzed using ANOVA followed by a post hoc Bonferroni test). In the late phase of reperfusion (> 2.5 hours after decompression), extracellular GFAP in the early hypothermia group was also lower than in the normothermia and late hypothermia groups (early, 5.5 ± 2.9 ng/dl; late, 7.4 ± 3.4 ng/dl; normothermia, 15.3 ± 8.4 ng/dl; sham, 3.3 ± 1.0 ng/dl; normothermia vs sham; p < 0.01). The number of Fluoro-Jade B-positive cells in the early hypothermia group was significantly smaller than that in the normothermia group (normothermia vs early: 774,588 ± 162,173 vs 180,903 ± 42,212, p < 0.05). Also, the injury area and volume were smaller in the early hypothermia group in which hypothermia was induced before craniotomy and cerebral reperfusion (early, 115.2 ± 15.4 mm(3); late, 344.7 ± 29.1 mm(3); normothermia, 311.2 ± 79.2 mm(3); p < 0.05). CONCLUSIONS The data suggest that early, preoperatively induced hypothermia could mediate the reduction of neuronal and glial damage in the reperfusion phase of ischemia/reperfusion brain injury.

Time course of recovery from cerebral vulnerability after severe traumatic brain injury : A microdialysis study

BACKGROUND The aim of this study was to evaluate the time course of recovery from cerebral vulnerability, using microdialysis (MD) technique and cerebral vascular autoregulation measurement, to clarify the appropriate timing of subsequent major surgical procedures, and to minimize the possibility of secondary brain injury in patients with severe traumatic brain injury (STBI). METHODS In 3,470 MD samples of 25 patients with STBI, cerebral extracellular biomarkers (glucose, lactate, pyruvate, glycerol, and glutamate) were measured. In addition, to estimate cerebral vascular autoregulaton, the pressure reactivity index (PRx) was calculated with intracranial pressure (ICP) and mean arterial pressure. The data with ICP, cerebral perfusion pressure (CPP), and PRx were collected hourly for 7 days after injury and they were compared with MD biomarkers daily. RESULTS During the study period, the average ICP and CPP remained stable and were within the threshold of STBI treatment guidelines. After injury, the extracellular glucose concentration decreased, and the levels of glycerol, glutamate, and lactate/pyruvate ratio (LPR), which indicate cerebral ischemia and neural cell damage, increased. On the fourth day after injury, the extracellular glucose concentration improved, and the value of LPR decreased. The average PRx decreased daily and became negative on the fifth day after injury. CONCLUSION Our results indicated that cerebral vascular autoregulation would recover on the fourth day after STBI, and cerebral perfusion might be increased by recovery of autoregulation. Thus, subsequent nonemergent surgery should be performed at least 4 days after STBI to prevent secondary brain injury. In addition, we should keep in mind that the cerebral vulnerability might persist for 4 days after suffering STBI.

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.

Global end-diastolic volume is associated with the occurrence of delayed cerebral ischemia and pulmonary edema after subarachnoid hemorrhage.

Predictive variables of delayed cerebral ischemia (DCI) and pulmonary edema following subarachnoid hemorrhage (SAH) remain unknown. We aimed to determine associations between transpulmonary thermodilution–derived variables and DCI and pulmonary edema occurrence after SAH. We reviewed 34 consecutive SAH patients monitored by the PiCCO system. Six patients developed DCI at 7 days after SAH on average; 28 did not (non-DCI). We compared the variable measures for 1 day before DCI occurred (DCI day −1) in the DCI group and 6 days after SAH (non-DCI day −1) in the non-DCI group for control. The mean value of the global end-diastolic volume index (GEDI) for DCI day −1 was lower than that for non-DCI day −1 (676 ± 65 vs. 872 ± 85 mL/m2, P = 0.04). Central venous pressure (CVP) was not significantly different (7.8 ± 3.1 vs. 9.4 ± 1.9 cm H2O, P = 0.45). At day −1 for both DCI and non-DCI, 11 patients (32%) had pulmonary edema. Global end-diastolic volume index was significantly higher in patients with pulmonary edema than in those without this condition (947 ± 126 vs. 766 ± 81 mL/m2, P = 0.02); CVP was not significantly different (8.7 ± 2.8 vs. 9.2 ± 2.1 cm H2O, P = 0.78). Although significant correlation was found between extravascular lung water (EVLW) measures and GEDI (r = 0.58, P = 0.001), EVLW and CVP were not correlated (r = 0.03, P = 0.88). Thus, GEDI might be associated with DCI occurrence and EVLW accumulation after SAH. ABBREVIATIONS 95% CI — 95% confidence interval AUC — area under the receiver operating characteristic curve CO — cardiac output CVP — central venous pressure DCI — delayed cerebral ischemia EVLW — extravascular lung water EVLWI — extravascular lung water index GEF — global ejection fraction GEDV — global end-diastolic volume GEDI — global end-diastolic volume index ITBV — intrathoracic blood volume ITTV — intrathoracic thermal volume PVPI — pulmonary vascular permeability index SAH — subarachnoid hemorrhage SVRI — systemic vascular resistance index

Preconditioning for Traumatic Brain Injury

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.

Targeted temperature management in traumatic brain injury

Traumatic brain injury (TBI) is recognized as the significant cause of mortality and morbidity in the world. To reduce unfavorable outcome in TBI patients, many researches have made much efforts for the innovation of TBI treatment. With the results from several basic and clinical studies, targeted temperature management (TTM) including therapeutic hypothermia (TH) have been recognized as the candidate of neuroprotective treatment. However, their evidences are not yet proven in larger randomized controlled trials (RCTs). The main aim of this review is thus to clarify specific pathophysiology which TTM will be effective in TBI.Historically, there were several clinical trials which compare TH and normothermia. Recently, two RCTs were able to demonstrate the significant beneficial effects of TTM in one specific pathology, patients with mass evacuated lesions. These suggested that TTM might be effective especially for the ischemic-reperfusional pathophysiology of TBI, like as acute subdural hematoma which needs to be evacuated. Also, the latest preliminary report of European multicenter trial suggested the promising efficacy of reduction of intracranial pressure in TBI.Conclusively, TTM is still in the center of neuroprotective treatments in TBI. This therapy is expected to mitigate ischemic and reperfusional pathophysiology and to reduce intracranial pressure in TBI. Further results from ongoing clinical RCTs are waited.

Glucose and oxygen metabolism after penetrating ballistic-like brain injury

Traumatic brain injury (TBI) is a major cause of death and disability in all age groups. Among TBI, penetrating traumatic brain injuries (PTBI) have the worst prognosis and represent the leading cause of TBI-related morbidity and death. However, there are no specific drugs/interventions due to unclear pathophysiology. To gain insights we looked at cerebral metabolism in a PTBI rat model: penetrating ballistic-like brain injury (PBBI). Early after injury, regional cerebral oxygen tension and consumption significantly decreased in the ipsilateral cortex in the PBBI group compared with the control group. At the same time point, glucose uptake was significantly reduced globally in the PBBI group compared with the control group. Examination of Fluorojade B-stained brain sections at 24 hours after PBBI revealed an incomplete overlap of metabolic impairment and neurodegeneration. As expected, the injury core had the most severe metabolic impairment and highest neurodegeneration. However, in the peri-lesional area, despite similar metabolic impairment, there was lesser neurodegeneration. Given our findings, the data suggest the presence of two distinct zones of primary injury, of which only one recovers. We anticipate the peri-lesional area encompassing the PBBI ischemic penumbra, could be salvaged by acute therapies.