Anti-high mobility group box-1 antibody therapy for traumatic brain injury.

OBJECTIVE: High mobility group box-1 (HMGB1) plays an important role in triggering inflammatory responses in many types of diseases. In this study, we examined the involvement of HMGB1 in traumatic brain injury (TBI) and evaluated the ability of intravenously administered neutralizing anti-HMGB1 monoclonal antibody (mAb) to attenuate brain injury. METHODS: Traumatic brain injury was induced in rats or mice by fluid percussion. Anti-HMGB1 mAb or control mAb was administered intravenously after TBI. RESULTS: Anti-HMGB1 mAb remarkably inhibited fluid percussion-induced brain edema in rats, as detected by T2-weighted magnetic resonance imaging; this was associated with inhibition of HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression, and improvement of motor function. In contrast, intravenous injection of recombinant HMGB1 dose-dependently produced the opposite effects. Experiments using receptor for advanced glycation end product (RAGE)(-/-) , toll-like receptor-4 (TLR4)(-/-) , and TLR2(-/-) mice suggested the involvement of RAGE as the predominant receptor for HMGB1. INTERPRETATION: Anti-HMGB1 mAb may provide a novel and effective therapy for TBI by protecting against BBB disruption and reducing the inflammatory responses induced by HMGB1.

An analysis of T2 mapping on brain tumors.

PURPOSE: Vasogenic edema on glioblastoma multiforme (GBM) or a metastatic brain tumor (METS) may have different T2 relaxation time values because it involves an increased water component. In this study, we assessed the diagnostic utility of T2 mapping techniques in distinguishing GBM from METS. MATERIALS AND METHODS: We studied a glioblastoma (GBM) patient and a metastatic brain tumor (METS) patient who had not undergone previous surgery or treatment. All MR imaging was carried out using a 3.0-T whole-body unit, and axial T2 maps were generated with five TEs (TE = 20, 40, 60, 80, and 100 ms). Data were analyzed by using image processing and analysis software. RESULTS: The T2 map of a GBM case showed that the -peritumoral area at a T2 relaxation time of 120-160 ms is prominent compared with the area at 210-240 ms. In contrast, the peritumoral area at 210-240 ms was prominent compared with the area at 120-160 ms in a METS case. CONCLUSION: The distribution of T2 relaxation time in the peritumoral area shows different patterns in glioblastomas and metastatic brain tumors.

Evaluation of the stage of hemorrhage using optical diffuse reflectance spectroscopy: an in vivo study.

Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke. Estimation of the stage of hemorrhage allows clinicians to know when the hemorrhage occurred, even in unconscious patients, enabling decisions to be made about the optimal management and treatment strategy. After ICH, oxidative denaturation of the hemoglobin progresses, and deoxyhemoglobin is gradually converted to methemoglobin. MRI has been used to estimate the stage of hemorrhage by evaluating the status of hemoglobin. However, there is currently no bedside device that can be used for the measurement of hemoglobin derivatives in patients with hematomas. The aim of the present study was to investigate the validity of using optical diffuse reflectance spectroscopy (ODRS) for bedside evaluation of the stage of hemorrhage. An ICH model was generated in adult Sprague-Dawley male rats by stereotactically injecting 50 µl of autologous blood into the right caudate nucleus. To analyze the hemoglobin derivatives in the hematomas, ODRS measurement was performed for the rats in vivo. In all rats, we found increased absorption at around 630 nm, which indicated the formation of methemoglobin. In conclusion, the results of the present study suggest that ODRS allows clinicians to more easily evaluate the stage of hemorrhage at the patient's bedside.

The effect of hydrogen gas on a mouse bilateral common carotid artery occlusion.

In recent studies, molecular hydrogen selectively reduced the levels of hydroxyl radicals in vitro and exerted a therapeutic anti-oxidant activity in a rat middle cerebral artery occlusion model. The aim of this study was to investigate the effect of hydrogen gas on a mouse bilateral common carotid artery occlusion (BCCAO) model. Male C57BL/6J mice were subjected to transient BCCAO with a nontraumatic aneurysm clip. The mice were divided into three groups: sham, BCCAO, and BCCAO treated with 1.3 % hydrogen gas. Cerebral blood flow (CBF) in the cortex was measured sequentially for both hemispheres with a non--invasive and noncontact laser Doppler blood perfusion imager during the procedure. Vital signs were also recorded. Oxidative stress evaluated by measuring the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), neuronal injury in the hippocampal CA1 sector, and brain water content were assessed 24 h after ischemia. The hydrogen gas treatment had no significant effect on vital signs or CBF values. However, the reduction of the expression of 8-OHdG, the decrease in the neuronal injury in the hippocampal CA1 sector, and the attenuation in brain water content were observed in hydrogen-treated mice. In conclusion, hydrogen gas might be effective in a mouse BCCAO model.

A better mild traumatic brain injury model in the rat.

The primary pathology associated with mild -traumatic brain injury (TBI) is selective axonal injury, which may characterize the vast majority of blast-induced TBIs. Axonal injuries in cases of mild TBI have been considered to be the main factors responsible for the long-lasting memory or attentional impairment in affected subjects. Among these axonal injuries, recent attention has been focused on the cingulum bundle (CB). Furthermore, recent studies with diffusion tensor MR imaging have shown the presence of injuries of the CB in cases of mild TBI in humans. This study aimed to provide a better laboratory model of mild TBI.Sprague-Dawley rats were subjected to mild TBI using laser-induced shock waves (LISW) (sham, 0.5 J/cm(2), or 1.0 J/cm(2); n = 4 per group). Bodian-stained brain sections 14 days after LISW at 0.5 J/cm(2) or 1.0 J/cm(2) showed a decrease in the CB axonal density compared with the sham group, whereas there were no differences in the axonal density of the corpus callosum.The present study shows that this model is capable of reproducing the histological changes associated with mild TBI.

Adiponectin and traumatic brain injury.

Adiponectin, a circulating adipose-derived hormone regulating inflammation and energy metabolism, has beneficial actions on cardiovascular disorders. Recent studies have suggested that adiponectin might be a potential molecular target for ischemic stroke therapy; however, little is known about the effects of adiponectin on traumatic brain injury. The present study examined the immunoactivity of adiponectin.Adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury using the Dragonfly device. Immuno-histochemical studies showed that the adiponectin expression was increased in the cerebral cortex at 24 h after injury and in the hippocampus at 72 h after injury. Our findings suggest that adiponectin might participate in the pathophysiological process occurring after traumatic brain injury.

Traumatic hematoma of the posterior fossa.

Posterior fossa injury is rare, occurring in less than 3 % of head injuries. We retrospectively reviewed patients' clinical and radiological findings, management, and outcomes. The aim of the present study was to investigate the features of posterior fossa hematoma, including posterior fossa epidural hematoma (EDH), posterior fossa subdural hematoma (SDH), and intracerebellar hematoma. From January 1995 to January 2009, 4,315 patients with head trauma were hospitalized at our institution. The -present study focused on 41 patients (1.0 %) with traumatic hematomas of the posterior fossa. Eighteen patients had EDH, 10 patients had SDH, and 17 patients had intracerebellar hematomas. In each type of injury, occipital bone fractures were seen in many patients, and hematoma enlargement was often observed within a few days of the injury. In addition, a high frequency of associated lesions and a high poor outcome rate were features of intracerebellar hematomas and -posterior fossa SDH. The present study suggests that repeat CT imaging and careful management are necessary until the lesion is stabilized, and patients showing lesions with mass effects should therefore be immediately treated with surgery.

Traumatic basal ganglia hematomas: an analysis of 20 cases.

Twenty patients with traumatic basal ganglia hematoma (TBGH) were studied. Of the 20 patients, 16 were male and 4 were female, with an age range of 4-89 years (mean, 54.4 years). The causes of injury were traffic accidents in 12 patients and falls in 8. The mean admission GCS score was 7.5. Skull fractures were revealed in five patients (25 %). The hematoma was found in the putamen in 15 patients (80 %), the thalamus in 4, and the caudate in 1. The mean hematoma volume was 10.7 mL. The CT findings indicated focal contusions in 9 patients, subdural hematoma in 5, intraventricular hemorrhage in 4, subarachnoid hemorrhage in 10, and diffuse axonal injury in 5. Six patients (30 %) underwent surgery. The final outcomes were poor: 7 patients (35 %) died, 1 was in a vegetative state, 4 experienced severe disabilities, and 8 patients (40 %) made a favorable recovery. The statistical analysis identified the GCS score and midline shift as prognostic factors.Our study revealed interesting characteristics of TBGH, including a high frequency of putaminal involvement, a low frequency of skull fractures, a high frequency of associated intracranial lesions, and a high poor outcome and mortality rate.

Cerebrospinal fluid congestion in the perioptic space.

Recent attention has been paid to the -cerebrospinal fluid (CSF) dynamics between the intracranial subarachnoid space (SAS) and the SAS around the optic nerve (ON-SAS). We experienced three patients who had an expanded ON-SAS associated with mass lesions extending into the optic canal, and studied their MRI findings after decompressive surgery. In all three patients, decompressive surgery of the optic canal resulted not only in the disappearance of the expanded ON-SAS, but also in improvement of the visual function. The present study may indicate that normalization of the ON-SAS can be considered to be the achievement of "effective" decompression. Therefore, we suggest that, in patients with an expanded ON-SAS associated with mass lesions, the state of the ON-SAS should be evaluated by pre- and postoperative MRI, in addition to the degree of tumor resection.

Surgical results after primary decompressive craniectomy in poor-grade aneurysmal subarachnoid hemorrhage.

It is well known that patients with poor-grade aneurysmal subarachnoid hemorrhage (SAH) have poor outcomes owing to significant mass effect and brain stem compression. On the other hand, decompressive craniectomy (DC) has shown efficacy in reducing morbidity and mortality in patients with intracranial hypertension. Here, we study the efficacy of DC in poor-grade SAH with attention to surgical outcome. A total of 38 consecutive patients with poor-grade SAH was treated in our hospital between 1 August 2005 and 30 July 2010. Among these 38 patients, we involved 15 patients with DC in the present study. We retrospectively reviewed medical charts and radiological findings. Glasgow Outcome Scale score on discharge showed good response in 1 (6.7 %), moderate disability in 6 (40.0 %), severe disability in 4 (28.1 %), vegetative state in 2 (1.3 %), and death in 2 (13.3 %). In particular, 3 grade IV patients (50.0 %) had a favorable outcome. Recent several experimental studies also indicated that DC significantly improves outcome owing to increased perfusion pressure or reduced intracranial pressure. We suggest that the DC provided the efficacy in reducing mortality in poor-grade SAH patients.

Decompressive craniectomy with hematoma evacuation for large hemispheric hypertensive intracerebral hemorrhage.

Hemispheric hypertensive intracerebral hemorrhage (ICH) has a high mortality rate. Decompressive craniectomy (DC) has generally been used for the treatment of severe traumatic brain injury, aneurysmal subarachnoid hemorrhage, and hemispheric cerebral infarction. However, the effect of DC on hemispheric hypertensive ICH is not well understood. To investigate the effects of DC for treating hemispheric hypertensive ICH, we retrospectively reviewed the clinical and radiological findings of 21 patients who underwent DC for hemispheric hypertensive ICH. Eleven of the patients were male and 10 were female, with an age range of 22-75 years (mean, 56.6 years). Their preoperative Glasgow Coma Scale scores ranged from 3 to 13 (mean, 6.9). The hematoma volumes ranged from 33.4 to 98.1 mL (mean, 74.2 mL), and the hematoma locations were the basal ganglia in 10 patients and the subcortex in 11 patients. Intraventricular extensions were observed in 11 patients. With regard to the complications after DC, postoperative hydrocephalus developed in ten patients, and meningitis was observed in three patients. Six patients had favorable outcomes and 15 had poor outcomes. The mortality rate was 10 %. A statistical analysis showed that the GCS score at admission was significantly higher in the favorable outcome group than that in the poor outcome group (P = 0.029). Our results suggest that DC with hematoma evacuation might be a useful surgical procedure for selected patients with large hemispheric hypertensive ICH.

Is decompressive craniectomy a risk factor for ventriculomegaly?

OBJECTIVE: Decompressive craniectomy (DC) is an established therapeutic option following severe traumatic brain injury (TBI). However, several delayed complications of DC have been reported, including ventriculomegaly, which can lead to poor patient outcomes. Nevertheless, ventriculomegaly can occur after TBI even without DC. The aim of the present study was to investigate the influence of DC on ventriculomegaly. MATERIAL AND METHODS: Adult male Sprague-Dawley rats (300-400 g) were subjected to lateral fluid percussion injury using a fluid percussion device. Rats were randomly divided into four groups: sham, craniectomized without trauma (D group), traumatized without DC (FPI group), and craniectomized immediately after trauma (FPI + D group). On day 28 of recovery, ventricular volumes were measured by image analysis. RESULTS: There was no significant difference in ventricular size between the sham group and the D group animals or between the FPI group and the FPI + D group animals. CONCLUSION: These data suggest that DC may not be a risk factor for ventriculomegaly after TBI.

Hydrocephalus following decompressive craniectomy for ischemic stroke.

Numerous studies on hydrocephalus after decompressive craniectomy (DC) for severe traumatic brain injury have been reported, whereas there have been only two reports on DC for hemispheric cerebral infarction. Here, we present the clinical details of 23 patients who underwent DC for hemispheric cerebral infarction and the incidence of hydrocephalus following DC. Of the 23 patients, 13 were male and 10 were female, with an age range from 34 to 75 years (mean, 60.8 years). The areas of hemispheric infarctions were those of the middle cerebral arteries in 12 patients and of the internal carotid arteries in 11 patients. The mean preoperative GCS score was 6. Nineteen patients (82.6 %) underwent cranioplasty. Pre-cranioplasty hydrocephalus was observed in 11 (47.8 %) patients. Four patients who had precranioplasty hydrocephalus were transferred or died without cranioplasty, and post-cranioplasty hydrocephalus occurred in 7 (36.8 %). Only one patient underwent a shunt procedure after cranioplasty. We consider that the explanation for the discrepancies between our study and the previous studies might lie in the definition of hydrocephalus and the indications for shunting.

A suitable formula for estimating the volume gained by decompressive craniectomy in malignant hemispheric infarction.

Decompressive craniectomy (DC) improves the survivability and functional outcome in patients with malignant hemispheric infarction (MHI). The decompressive effect of DC depends on the decompressive volume (DV). The value of the formulas for estimating DV has not been reported to date. We have investigated the value of the formulas to estimate DV in patients with MHI. We analyzed the head CTs of six patients who underwent DC for MHI. We examined 1/2ABC, 1/3ABC, π/6ABC, and 2/3Sh formulas to determine the formula that gives the closest estimation of DV compared with computer-assisted volumetric analysis (gold standard). The mean volume values of the gold standard, 1/2ABC, 1/3ABC, π/6ABC, and 2/3Sh formulas were 100.2, 102.4, 68.3, 105.2, and 109.2 mL respectively. Spearman's correlation coefficient was assessed for DV obtained by each of the four different formulas relative to the gold standard. These were as follows: 1/2ABC = 0.8095 (p < 0.05), 1/3ABC = 0.8095 (p < 0.05), π/6ABC = 0.7381 (p < 0.05), and 2/3Sh = 0.4524 (p > 0.05). In conclusion, the 1/2ABC formula is the most useful and the closest estimation of DV in patients with MHI after DC.

Targeted increase in cerebral blood flow by transcranial near-infrared laser irradiation.

BACKGROUND AND OBJECTIVE: Brain function is highly dependent on cerebral blood flow (CBF). The precise mechanisms by which blood flow is controlled by NIR laser irradiation on the central nervous system (CNS) have not been elucidated. In this study, we examined the effect of 808 nm laser diode irradiation on CBF in mice. STUDY DESIGN/MATERIALS AND METHODS: We examined the effect of NIR irradiation on CBF at three different power densities (0.8, 1.6 and 3.2 W/cm(2)) and directly measured nitric oxide (NO) in brain tissue during NIR laser irradiation using an amperometric NO-selective electrode. We also examined the contribution of NO and a neurotransmitter, glutamate, to the regulation of CBF by using a nitric oxide synthase (NOS) inhibitor, N(g)-nitro-L-arginine methyl ester hydrochloride (L-NAME), and an N-methyl-D-aspartate (NMDA) receptor blocker, MK-801, respectively. We examined the change in brain tissue temperature during NIR laser irradiation. We also investigated the protection effect of NIR laser irradiation on transient cerebral ischemia using transient bilateral common carotid artery occlusion (BCCAO) in mice. RESULTS: We showed that NIR laser irradiation (1.6 W/cm(2) for 15-45 minutes) increased local CBF by 30% compared to that in control mice. NIR laser irradiation also induced a significant increase in cerebral NO concentration. In mice that received L-NAME, NIR laser irradiation did not induce any increase in CBF. Mice administered MK-801 showed an immediate increase but did not show a delayed additional increase in local CBF. The increase in brain tissue temperature induced by laser irradiation was estimated to be as low as 0.8 degrees C at 1.6 W/cm(2), indicating that the heating effect is not a main mechanism of the CBF increase in this condition. Pretreatment with NIR laser irradiation improved residual CBF and reduced the numbers of apoptotic cells in the hippocampus. CONCLUSION: Our data suggest that NIR laser irradiation is a promising experimental and therapeutic tool in the field of cerebral circulation research.

[The characteristics of blast traumatic brain injury].

With the increase in terrorist activity in recent times, the number of blast injuries has also increased in civilian and military settings. In a recent war, the number of patients who suffered blast traumatic brain injury (bTBI) increased, so treatment of bTBI is currently a very important issue. Blast injury is complicated and can be divided into 4 categories: primary, secondary, tertiary, and quaternary. Primary blast injury results from exposure to blast waves; secondary blast injury is trauma caused by fragments of explosive devices; tertiary blast injury is the result of collision with objects; and quaternary blast injury is the result of exposure to toxic and other substances. Blast waves mainly injure air-containing organs such as the lung, bowel, and ear. The brain may also be affected by blast waves. From the clinical perspective, hyperemia and severe cerebral edema occur frequently in patients who sustain significant bTBI. Penetrating or closed head injury caused by the explosion may be associated with vasospasm and pseudoaneurysm formation. Mild traumatic brain injury during war can be associated with posttraumatic stress disorder. To elucidate the mechanism of bTBI, many research works using animal models and computer analysis are underway. Such studies have so far shown that blast waves can cause damage to the brain tissue and cognitive deficits; however, detailed investigations on this topic are still required. Treatment of bTBI patients may require clinical knowledge and skills related to intensive care, neurology, and neurosurgery. Moreover, further research is required in this field.

[Diagnostic efficacy and pitfalls of a 64-raw multislice computed tomography scan for mild head injuries in children].

The aim of this study is to analyze the usefulness of 64-raw multislice computed tomography (CT) scans and bone images of three-dimensional CT (3D-CT) scans for evaluation of mild head injuries in children. Thirteen children (9 boys and 4 girls, less than or equal to 15 years old) with mild head injury were included in the study. Head CT scans obtained within 24 hours after injury. All children had no episodes of loss of consciousness, amnesia, epilepsy, vomiting, and no neurological abnormality on arrival at hospital. We detected 9 positive findings on CT scans, which looked like fracture lines at the frontal bone in 7 cases. The bone images of CT axial views revealed a true fracture in one case in which a skull X-ray could not demonstrate a fracture line, but, other positive findings turned out to be a diploic vein surrounded by a thin bone cortex. All false positive findings were detected in the patients under the age of 6. By the 3D-reconstructive CT scan, it is easier to detect not only the intracranial lesions but also the cranial fracture. But, the diploic vein is apt to be misdiagnosed as the fracture line, especially in patients under the age of 6.

"Phosphene": early sign of vascular compression neuropathy of the optic nerve.

BACKGROUND: Phosphenes, flashes of light, are a visual phenomenon experienced by patients with ophthalmological disease and normal individuals. CASE REPORT: We report here a 68-year-old woman in whom phosphenes appeared in the left visual field due to compression of the right optic nerve by an aneurysm of the anterior communicating artery. RESULTS: The symptom decreased dramatically after clipping of the aneurysm. CONCLUSION: Phosphenes may be an important early sign of vascular compression neuropathy of the optic nerve.

Up-regulation of L type amino acid transporter 1 after spinal cord injury in rats.

BACKGROUND: L-type amino acid transporter 1 (LAT1) is proposed to be a major nutrient transporter at the blood brain barrier. LAT1 requires the heavy chain of 4F2 cell surface antigen (4F2hc) for functional expression. METHODS: We investigated the expression of this heterodimeric transporter after traumatic spinal cord injury in rat by using immunohistochemical and western blot analyses. FINDINGS: LAT1 immunoreactivities were up-regulated in the capillary endothelia in close to the injury epicenter 24 hours after injury. It reached a peak at 48 hours after injury, and thereafter decreased. 4F2hc was abundant and unchanged all through the time course after SCI. Western blot analysis under reductive and non-reductive conditions showed that LAT1 and 4F2hc were conjugated as a heterodimeric transporter and the functional regulation was dependent on the light chain, LAT1. CONCLUSIONS: We suggest that LAT1 may be transiently upregulated as part of the tissue-repair process after traumatic contusion injury in the spinal cord.

Pilomyxoid astrocytoma of the fourth ventricle in an adult.

Pilomyxoid astrocytomas have been identified as a variant of pilocytic astrocytoma. They are listed as a novel clinico-pathological entity in the 2007 World Health Organisation (WHO) classification of tumours of the central nervous system. This tumour corresponds to a WHO grade II neoplasm whereas pilocytic astrocytoma corresponds to WHO grade I. We have encountered an infratentorial tumour with pilomyxoid features in an adult. A 25 year old man presented with tinnitus and hyperacusis. Brain MRI revealed a mass occupying the fourth ventricle. We performed partial resection, but no adjuvant therapy was given. The staining index for the anti-Ki-67 monoclonal antibody MIB-1 was less than 1% in this patient. Pilomyxoid astrocytomas are not limited to the hypothalamic/chiasmatic region in children. Additional knowledge and recognition of this entity is necessary to improve treatment of pilomyxoid astrocytoma.