Abstracts from The 10 th International Neurotrauma Symposium (INTS) April 27–30,2011 Shanghai,China

O1 Sports-Related Head and Cranio-Maxillofacial Injuries in Japan: A Retrospective Study of 187 Patients.

Background: The number of sports-related head and cranio-maxillofacial injuries is increasing because of the large number of people who engage in sports activities. Local and national culture defines the types and frequencies of sports-related injuries that occur. The aim of this study was to investigate the spectrum of sports-related brain injuries in Japan, present the etiologies in different sports, and to suggest protective measures.

Methods: The study was carried out retrospectively using medical records from 1960 for hospitalized patients who suffered brain and cranio-maxillofacial injuries between 1996 and 2009 at our university hospitals. The factors evaluated were: type of sport involved, age, sex, mechanism of injury, and mode of treatment.

Results: One hundred eighty-seven patients (9.5%) had brain and cranio-maxillofacial injuries due to sports injuries. The male:female ratio was 45:4, and the highest incidence of injury was in the 10- to 20-year-old age group. The most common were cranio-maxillofacial fractures (54.5%), followed by cerebral concussions (25.9%). The majority of cranio-maxillofacial fractures were mandible fractures (24.5%), followed by blowout fractures (13.3%). Boxing, soccer, and baseball players were at highest risk of injury, and the main mechanism of injury was impact against another player (54.0%). In all, 41.7% needed surgical treatment.

Conclusions: A clearer understanding of the etiology and extent of all sports-related head and cranio-maxillofacial injuries would be useful to support the increasing need for preventive and protective measures.

O2 Experience with Brain Tissue Monitoring in 127 Children with Severe Traumatic Brain Injury.

Background: Experience with continuous brain tissue oxygen (PbtO₂) monitoring has grown steadily over the last few years in adult traumatic brain injury (TBI), but less experience has been achieved in pediatric TBI. In this paper we review our experience with PbtO₂ monitoring in 127 children with severe TBI.

Methods: Data were examined from a prospectively-collected TBI registry at the Red Cross Children's Hospital, a university-affiliated pediatric hospital. PbtO₂ monitors (Licox, Integra Neurosciences, Plainsboro Township, NJ) were usually placed in right frontal white matter, along with a parenchymal intracranial pressure (ICP) monitor (Codman, Raynham, MA). In the initial part of the series data were collected from hourly observations, and in the later part of the series with a high-frequency system (50 Hz) using ICMPlus software (Cambridge University, Cambridge, U.K.).

Results: There were 127 children with severe TBI (mean age 6.3 ± 3.7 years), the majority of whom were injured in motor vehicle accidents. Continuous PbtO₂ monitoring was found to be safe and feasible. Small focal hematomas at the site of entry of the ICP/PbtO₂ monitors were rare (1%) and clinically insignificant. Placement with bolts was possible (Codman double-lumen), even in young children, and were more reliable than burrhole insertion, which was associated with suboptimal catheter tip placement and dislodging of the catheter. PbtO₂ was sensitive to changes in ICP, blood pressure, systemic oxygenation, carbon dioxide, and hemoglobin. PbtO₂ had a complex relationship with ICP; and negative relationships were most common, but positive relationships were also seen with apparent hyperemia and blood pressure changes when autoregulation was impaired. From pooled data, the correlation between ICP and PbtO₂ was weak (r = 0.055). The relationship with cerebral perfusion pressure (CPP) was also complex, given the many variables affecting PbtO₂. From pooled data, PbtO₂ was reduced below CPP by 40 mm Hg. PbtO₂ was very sensitive to systemic changes in arterial oxygenation and carbon dioxide by provocative testing. PbtO₂ was also very sensitive to blood pressure changes, even when autoregulation was relatively strong.

Conclusion: PbtO₂ monitoring is safe and feasible in children with severe TBI. It demonstrates sensitive real-time responses to local and systemic factors, and has variable relationships with ICP and CPP, presumably determined by inter-individual variability, and the dynamic and multifactorial nature of TBI.

O3 Experience with Local Cerebral Blood Flow Monitoring Combined with Intracranial Pressure and Brain Oxygen Monitoring in Children with Traumatic Brain Injury.

Background: Focal tissue monitoring in traumatic brain injury (TBI) has both advantages and limitations. Currently there are no data on local cerebral blood flow (CBF) monitoring in children with TBI. In this article we examine our experience with a local tissue probe based on the thermal diffusion method.

Methods: The CBF probe (Hemedex, Cambridge, MA) was placed in the same region of the brain as the brain tissue oxygen probe (Licox, Integra Neurosciences, Plainsboro Township, NJ), usually in the relatively uninjured right frontal white matter. The monitor was calibrated every 25 min for general monitoring and before all physiological tests. Data were collected using a high-frequency software system (ICMPlus; Cambridge University, Cambridge, U.K.) at 50 Hz. The responses of the monitor to temporary increases in the inspired fraction of oxygen, changes in carbon dioxide tension, and changes in blood pressure (pressure autoregulation) were recorded.

Results: Local CBF was monitored in 12 children with TBI. In general, monitored CBF mirrored changes in brain tissue oxygen (PbtO₂) in response to local and systemic variables. When pressure autoregulation was tested, local CBF tended to increase in most cases when blood pressure was increased, regardless of the status of autoregulation, similarly to the changes seen in PbtO₂, and likely reflecting small microvascular changes. When the fraction of inspired oxygen (Fio ₂) was increased from baseline to 100% for 15 min (26 tests in 12 patients), CBF was stable in most patients (mean change −8.3 ± 34%); decreased CBF tended to be associated with concurrent CO₂ changes during the test. In general, CBF was sensitive to changes in CO₂, and paralleled the changes in PbtO₂. Local CBF was also sensitive to changes in ICP, similarly to the PbtO₂ changes. Relative values of CBF appeared to be more useful than absolute values, which tended to vary between calibrations. There no were complications associated with monitoring in any of the patients.

Conclusion: Continuous local CBF monitoring is feasible in children with TBI. Relative values of monitoring appear to be sensitive to local and systemic physiological changes, but absolute values appear to be less reliable at present.

O4 Correlative Study of Plasma Hemopexin and Oxidative Stress in Patients with Hemorrhagic Stroke.

Background: Hemin toxicity may partly contribute to brain damage caused by hemorrhagic stroke. The natural defense against extracellular heme is primarily provided by hemopexin (HPX), a plasma and neuronal glycoprotein with high binding affinity to heme. The most important role of HPX is to protect cells from oxidative stress. We investigate the correlation between plasma HPX and oxidative injury and prognosis of patients with hemorrhagic stroke.

Methods: In all, we included 105 hemorrhagic stroke patients, aged 57.45 ± 7.85 years, who were admitted to our department from January to October 2010. The patients were divided into three groups (severe, moderate, and mild brain injury), according to Glasgow Coma Scale (GCS) score as assessed on admission. Plasma HPX was detected by Western-blot at 1, 2, 3, 5, 7, and 14 days after hemorrhagic stroke. The level of oxidative injury was also detected, including NADPH, glutathione, and superoxide dismutase (SOD). The GCS scores of these patients were assessed at the same time point as HPX, and GOS scores were assessed again 3 months later.

Results: Plasma HPX levels in the moderate and mild brain injury groups began to decrease significantly.

Conclusion: These results suggest that HPX may protect the central nervous system from oxidative stress in hemorrhagic stroke patients, but these defenses are not sufficient to cope with hemin, and thus we may strive to induce HPX expression to help protect these patients against hemin toxicity.

O5 Surgical Treatment of Post-Traumatic Epilepsy.

Background: Post-traumatic epilepsy is estimated to constitute 5% of all cases of epilepsy and over 20% of cases of symptomatic epilepsy. Patients whose post-traumatic epilepsy does not respond to medication may undergo surgery to remove the epileptogenic focus. The aim of the present study was to investigate the surgical effects of post-traumatic epilepsy.

Methods: From July 2003 to December 2008, 65 patients with late post-traumatic epilepsy were included. Of these 65 patients, 48 were male and 17 were female, and their mean age was 21.5 ± 3.2 years (range 12–38 years). Inclusion criteria were: (1) diagnosis of previous traumatic brain injury confirmed by clinical data, including head computed tomography or magnetic resonance imaging (MRI); (2) persistent seizures more than once a month over 18 months despite appropriate pharmacological treatment (at least two drugs, appropriate to seizure type, at adequate doses, and with adequate compliance); and (3) epileptic foci were located by ictal electroencephalogram (EEG) and MRI. The type of surgical procedure and scope of resection were examined according to the injured brain region, epileptogenic zone, and the seizure type. Areas of scar tissue in the injured brain regions were recorded, and areas of encephalomalacia focus were resected. Multiple subpial transections or cortical searing, anterior temporal lobe resection, and amygdalohippocampectomy were the most commonly performed procedures. Intracranial EEG monitoring was performed during surgery and post-operatively. Patients were followed-up at 2 and 6 years. In all 4 cases were simple localized seizures, 6 cases were complex localized seizures, and the rest were complex generalized seizures. By brain region, the frontal lobe was affected in 12 cases (8 left and 4 right), the parietal lobe in 5 patients (2 left and 3 right), the temporal lobe in 22 cases (10 left and 12 right), and the parietal lobes in 23 cases (14 left and 9 right). Also, 4 cases had skull defects. Scar tissue recordings and resection of encephalomalacia foci were performed in 8 patients, and anterior temporal lobe resection and amygdalohippocampectomy were performed in 57 patients.

Results and Conclusions: In the follow-up period, I level of Engle Rating was achieved in 54 cases, II level in 6 cases, and III level in 5 cases. Surgical procedure is an effective method to eliminate seizures of patients with late post-traumatic epilespsy. There are several types of surgical operations that can be used. Not only the injured brain tissue, but the anterior temporal lobe, hippocampus, and amygdala can be epileptogenic zones, and thus targets of these procedures.

O6 Diagnosis and Treatment of Children with Liquid Epidural Hematoma.

Methods: Eight patients (7 male and 1 female, mean age 8 years) with liquid epidural hematomas who had surgery were retrospectively analyzed. There were 3 road accident cases, 2 cases were wounded in falls, 1 case was a combat injury, and 2 cases were fall injuries. All cases had fractures at the injury site, and 5 had soft tissue swelling of the scalp. In 2 cases drainage of the hematoma was done via subperiosteal aspiration, 1 case underwent keyhole surgery, and 2 cases had standard craniotomy. These were the characteristics of diagnosis and treatment of children with epidural hematoma: (1) they displayed a definite history of head injury; (2) they displayed the clinical manifestations of epidural hematoma; (3) computed tomography (CT) scans showed epidural spindle hematomas, but because the hematomas were liquid, they were easily deformed, and when the intracranial pressure was high, the hematoma was half-moon shaped, similarly to a subdural hematoma, but the dura mater was clearly seen, and thus the hematoma had not broken into the cortical sulci; (4) they often had scalp soft tissue swelling due to epidural hematomas associated with skull fractures and subperiosteal hematomas or hemorrhages; (5) a liquefaction zone grew thusly: first, an ectoentad liquefaction zone of subperiosteal hematoma formed, and often liquefaction was obvious at the site of the fracture, often due to tissue effusion at the site of fracture. Then the entoectad liquefaction zone grew due to cerebrospinal fluid overflow through the damaged dura, and often liquefaction was obvious at the site where the dura was damaged; (6) the CT value of liquid epidural hematoma was often less than 40 HU, (the value of blood coagulation is between 40 and 80 HU), and most were between 20 and 25 HU; (7) there were signs of compressive subperiosteal hematoma, which should be distinguished from epidural hematoma in the absorption period. The latter always appeared after injured or found hematoma more than 1 week, and CT scan can find the liquefaction often from around, formed a complete liquefaction cycle, later stage formation a very uniform low density, and the scalp soft tissue was not swelling, or swelling subsided.

O7 Tranexamic Acid in the Treatment of Traumatic Intracranial Hemorrhage: A Randomized, Double-Blinded, Placebo-Controlled Trial.

Background: Traumatic brain injury (TBI) is commonly accompanied by intracranial bleeding that can worsen after hospital admission. Tranexamic acid (TXA) has been shown to reduce bleeding in elective surgery, and there is evidence that short courses of TXA can reduce re-bleeding in spontaneous intracranial hemorrhage. We aimed to determine the effectiveness and safety of TXA in preventing progressive intracranial hemorrhage in TBI.

Methods: We enrolled 238 patients more than 16 years of age with moderate to severe TBI (post-resuscitation Glasgow Coma Scale [GCS] score 4–12), who had a computed tomography (CT) scan within 8 h of injury, and in whom there was no immediate indication for surgery. We excluded patients if they had a coagulopathy or a serum creatinine level above 2 mg/dL. The treatment was 2 g of TXA. The primary outcome was progressive intracranial hemorrhage (PIH), which was defined as an intracranial hemorrhage seen on the second CT scan that was not seen on the first CT scan, or an intracranial hemorrhage seen on the first scan that had expanded by 25% or more in any dimension (height, length, or width) on the second scan.

Results: PIH was present in 16 (14%) of 115 patients allocated to TXA, and in 28 (25%) of 114 patients allocated to placebo [RR = 0.57 (95% CI 0.32,0.99)]. The relative risk of death from all causes in patients allocated to TXA compared with placebo was 0.69 (0.35 to 1.39), and the relative risk for unfavorable outcome on the Glasgow Outcome Scale was 0.76 (0.46 to 1.27). There was no evidence of increased risk of thromboembolic events in those allocated to TXA.

Conclusion: TXA may reduce PIH in TBI. Large clinical trials are needed to assess the effects of TXA on death and disability after TBI.

O8 Pathogenetic Mechanisms for Neuroprotection by Neurosteroids in Traumatic Brain Injury.

Background: Today the role of gender differences is becoming increasingly clear. There are many recent in vitro and in vivo studies related to new molecular mechanisms that reveal the influence of neurosteroids on the pathophysiology and outcome of traumatic brain injury (TBI). These mechanisms are independent of hormone exposure, but can be the result of the genetic complement of the cell. The study goal was to compare hormonal and cytokine profiles and clinical manifestations in TBI patients according to gender differences, as well as some markers of different molecular pathways of cell death.

Methods: In all, 69 males (8 patients died) and 17 females (1 patient died) with a Glasgow Coma Scale (GCS) score ≤ 8 at admission, in four age ranges (15–29, 30–44, 45–59, and 60–74 years) were included. For each gender group the sex hormones (progesterone, estradiol, testosterone, luteinizing hormone, and follicle-stimulating hormone), cytokines (interleukin-6 [IL-6], soluble interleukin-2 receptor [sIL-2R], and erythropoietin), ferritin (an oxide stress marker) were analyzed with immunochemiluminescent analysis. Also, hemodynamic patterns were evaluated by transpulmonary thermodilution (PiCCO).

Results: We found significantly higher levels of IL-6, sIL-2R, ferritin, and CRP in females. The significantly higher levels of ferritin seen in males compared with females was one of the most interesting findings, as this indicates that different pathways of cell apoptosis and cell death characterize male and female brain ischemia, particularly the predominance of the NO/PARP/AIF mitochondrial pathway for males, and the cytochrome C/caspase pathway for females.

Conclusions: Our data are useful for molecular genetic investigations to study the impact of genetic features inherent to gender differences, and to find the most effective neuroprotective agents.

O9 Sulforaphane Suppresses Atp-Induced Inflammation via the NRF2/ARE Pathway in Primary Rat Neurons.

Background: Inflammation plays an important role in the pathogenesis of secondary damage after neurotrauma. Previous studies have shown treatment of spinal cord injured rats with sulforaphane (SUL), an activator of the Nrf2/ARE pathway, significantly increased levels of Nrf2 and downstream signaling, and decreased levels of inflammatory cytokines. The role of this study was to investigate the precise molecular mechanisms of the anti-inflammatory effects of Nrf2 on neurons.

Methods: Primary rat neurons were used, and 1 mM ATP was added for 45 min to induce inflammation in neurons. Cells were pretreated without SUL, or with SUL (10 or 20 μM) for 2 h. Immunoblotting was performed to detect levels of Nrf2 and downstream signaling, and cytokines and phospho-IκBα.

Results: SUL increased levels of Nrf2 and downstream signaling, and attenuated the ATP-induced increase of caspase-1, IL-1β, and TNF-α in rat primary neurons, in a concentration-dependent manner. Moreover, treatment with SUL significantly inhibited phosphorylation of IκBα, which indicates that the anti-inflammatory effect of Nrf2 is regulated by inactivation of NF-κB.

Conclusion: This study shows that activation of the Nrf2/ARE pathway is neuroprotective against ATP-induced inflammation in primary rat neurons. SUL may be a candidate agent to reduce inflammation following neurotrauma.

O10 Transcription Factor NRF2 Protects the Spinal Cord from Inflammation Produced by Spinal Cord Injury.

Background: Inflammation plays an important role in the pathogenesis of secondary damage after spinal cord injury (SCI). Previous studies have suggested that nuclear factor-erythroid 2-related factor 2 (Nrf2), a pleiotropic transcription factor, may play a key role in modulating inflammation in a variety of experimental models. This study evaluated the neuroprotective role of Nrf2 in the inflammatory response after SCI in mice.

Methods: Nrf2-deficient (Nrf2^–/–) and wild-type (Nrf2^+/+) mouse spinal cord compression injury was induced by the application of vascular clips (force of 10g) to the dura. Sulforaphane (SFN) was used to activate Nrf2 after SCI. Inflammatory cytokines, NF-κB activity, histological injury score, counts of dying neurons in grey matter, water content of the impaired spinal cord, and Basso open-field motor scores (BMS) were assessed to determine the extent of SCI-mediated damage.

Results: The results showed that SFN activated Nrf2 in impaired spinal cord tissue, improved hindlimb locomotor function as assessed by BMS scores, and reduced inflammatory damage, histological injury, numbers of dying neurons, and spinal cord edema caused by SCI. Nrf2^–/– mice demonstrated more severe neurological deficits and spinal cord edema after SCI, and did not benefit from the protective effect of SFN.

Conclusions: Taken together, our results suggest that Nrf2 may represent a strategic target for SCI therapies.

O11 Transcription Factor NRF2 is Neuroprotective After Spinal Cord Injury in Mice.

Background: Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional factor for antioxidant response element (ARE)-regulated genes. After spinal cord injury (SCI), the Nrf2-ARE pathway is activated in the spinal cord.

Methods: To explore the function of Nrf2 in SCI, we compared the motor and neurological responses of Nrf2 knockout (KO) and wild-type (WT) mice to spinal cord compression injury induced by the application of vascular clips (force of 10g) to the dura.

Results: As assessed by the Basso open-field motor score and footprint analysis, KO mice developed more severe hindlimb weakness than WT mice 4 days after SCI, and the difference persisted for at least 4 weeks. KO mice also showed smaller spinal motor-evoked potentials (MEPs) than WT mice 4 weeks after SCI. Morphological tests revealed that KO mice underwent more severe neuronal death and spinal cord edema when measured 2 days after SCI than WT mice. In correlation with the neurological deficits, the release of inflammatory cytokines such as TNF-α, IL-6, and IL-1β, and NF-κB activity in the spinal cord of KO mice were all higher than in WT mice, whereas antioxidant and detoxifying enzyme expression, and other types of enzyme activities, including those of NADPH, quinone oxidoreductase 1, and glutathione S-transferase-α1, were all lower in KO mice 24 h after SCI.

Conclusions: Taken together, our results suggest that Nrf2 plays a neuroprotective role in the inflammatory response after SCI in mice.

O12 Erythropoietin Ameliorates Axonal Damage, Attenuates Macrophage Infiltration, and Restores Motor Function in a Combined Model of Traumatic Axonal Injury and Hypoxia.

Background: Diffuse brain injury is the predominant form of traumatic brain injury (TBI), which in combination with hypoxia is associated with exacerbated secondary damage and worse neurological outcomes. Erythropoietin (EPO) is neuroprotective in focal TBI; however, its therapeutic effect has never been investigated in a diffuse TBI-hypoxia paradigm. In this study we examined whether EPO improves neurological outcomes, reduces axonal pathology, and attenuates neuroinflammation in rats following traumatic axonal injury (TAI) with or without post-traumatic hypoxia.

Methods: TAI was produced in rats by dropping a 450-g weight from 2 m, and hypoxia was induced by ventilation with 14% oxygen for 30 min after TAI. The rats were administered recombinant human EPO-alpha (5000 IU/kg IP) or vehicle, at 1 and 24 h post-injury. Motor function was assessed using the rotarod test (0–30 rpm) up to 14 days post-injury. Brain tissue was collected at 1, 7, and 14 days, and immunohistochemistry was performed for axonal pathology (neurofilament 200), and macrophage/microglial activation/infiltration (CD68).

Results: TAI + hypoxia + EPO rats showed significant improvement on the rotarod test by 5 days (24.3 ± 2.2 rpm) compared to TAI + hypoxia + vehicle animals (14.6 ± 1.8 rpm), while a pronounced decrease was detected in the TAI + hypoxia + EPO rats at both 7 days (27.2 ± 8.4 versus 18.5 ± 7.3 rpm), and 14 days post-injury (144.8 ± 33 versus 92.1 ± 44.8 rpm). No differences in inflammatory cell numbers were detected between TAI + vehicle and TAI + EPO treatments at either 7 days (54 ± 20.1 versus 169.9 ± 58), or 14 days post-injury (112.2 ± 51.1 versus 59.7 ± 15.7).

Conclusions: These preliminary results demonstrate that EPO provides neuroprotection only in TAI animals with additional hypoxic insult. EPO reduces axonal pathology and macrophage infiltration following TAI + hypoxia in the corpus callosum and brainstem, the most vulnerable regions in this TAI model. These benefits may be due to the recognized hypoxic induction of the EPO receptor, which will be investigated in future studies.

O13 Neuroprotection of Emodin on Blast-Induced Traumatic Brain Injury in Rats.

Background: Blast-induced traumatic brain injury (bTBI) has been the predominant cause of neurotrauma in recent military conflicts, and it is also emerging as a potential threat in civilian terrorism. We observed the neuroprotective effects of emodin on bTBI in rat.

Methods: Seventy-eight adult Sprague-Dawley rats were randomly divided into three groups: a normal control group, an injury-only group, and an emodin treatment group. There were six observational time points for each group: 6 and 12 h, and 1, 3, 5, and 7 days, with 6 rats for each time point. bTBI was induced in all but the normal controls, and emodin was given 30 min after injury (10 mg/kg/d IP injection). After injury, the behaviors of the rats were recorded. Levels of neuron-specific enolase (NSE) in the serum and brain water content were measured at the different time points. Also, the numbers of NSE-immunohistochemistry-reactive cells were counted in the cortex.

Results: The levels of NSE in serum and the brain water content of the injury and the emodin treatment groups were higher than pre-injury levels at most time points (p < 0.01), they peaked at 24 h post-injury, and then they declined, but were still higher than pre-injury levels at 5 days. The numbers of NSE-immunohistochemistry-reactive cells in the cortex were significantly decreased. The emodin group had a similar tendency to the control group, but the animals had an earlier peak, at 12 h post-injury, and returned to normal levels at 3 days post-injury.

Conclusion: These findings demonstrate that emodin has protective effects on the injured brain in rats with bTBI.

O14 Manipulating Microglia and Macrophages to Promote Repair of the Injured Spinal Cord.

Following traumatic or ischemic/reperfusion injury to the spinal cord or brain, macrophages derived from resident microglia and infiltrating blood monocytes accumulate in the affected area. Collectively, these cells exert diverse and conflicting effects on neurons and glia. Indeed, microglia/macrophages can cause neuronal cell death, axonal injury, and demyelination, but can also promote neuron survival, axon regeneration, remyelination, and revascularization. Over the past few years, we have used a number of strategies to manipulate resident and recruited macrophages in an effort to understand their seemingly paradoxical functions, specifically in the context of rodent models of traumatic spinal cord injury (SCI). Data will be presented showing that SCI elicits CNS macrophages with a distinct molecular phenotype, one that simultaneously favors cell killing and axon growth/regeneration. Newer data will also be presented to show that it is possible to manipulate the lesion microenvironment and/or the CNS macrophages such that the natural course of inflammation progresses to favor tissue repair without concomitant cell killing. In this context, preliminary applications of therapeutic gene transfer and bioengineering will be discussed.

O15 Neurotraumatology in Japan and Asia.

The era of modern neurosurgery in Japan began in 1877, when Professor S. Sato first operated on patients with gunshot wounds during the civil war. Thereafter, the first operated case of epidural hematoma was reported in 1905. Before the CT era, the incidence and number of patients suffering from injuries in traffic accidents peaked in 1970, during a period of rapid economic development, and the first domestic Society of Neurotrauma was founded in 1967. This society was succeeded by the Japan Society of Neurotraumatology (JSNT), which was founded as the Japan Society of Neurosurgery in 1977. This society has been active with several multicenter projects. In 2008, the Asia Oceania Neurotrauma Society (AONTS) was founded, with members from Japan, Taiwan, China, and Korea, and the Second Congress was held in March, 2010, with participants from 21 countries from around the world. The fruits of the major projects of the JNTS and AONTS will be presented with future perspectives.

O16 Early Decompressive Craniectomy for Patients with Severe Traumatic Brain Injury and Refractory Intracranial Hypertension (DECRA): A Prospective Randomized Clinical Trial.

Even in high-volume neurotrauma centers, fewer than 50% of patients with severe traumatic brain injury (TBI) become long-term independently-living survivors. Those patients who develop refractory intracranial hypertension despite the best current management have even fewer favorable outcomes. Decompressive craniectomy is a surgical treatment option for severe TBI patients that decreases intracranial pressure, but its impact on long-term neurological function has not been established. Uncontrolled case series and a case-control study suggest benefit. The Brain Trauma Foundation Guidelines (3rd ed., 2007) classify decompressive craniectomy, along with all other surgical therapies for TBI patients, as a Level III option. Favorable reports from case series have encouraged increasing clinical use of decompressive craniectomy, despite the fact that no randomized trials have been conducted, and the benefits and complications remain unstudied. The DECRA trial is a prospective randomized trial of 155 patients from Australia, New Zealand, and Saudi Arabia. Group allocation was concealed, and outcome assessments were conducted by blinded assessors using structured telephone questionnaires. The primary outcome was patient neurological function on the Glasgow Outcomes Scale-Extended at 6 months post-injury. DECRA commenced recruitment in 2003, and the last patient was enrolled in April 2010. After the first 80 patients were enrolled, an interim analysis was conducted and baseline balance for all key demographic factors was confirmed. Final patient outcome assessments will be conducted in November 2010, and this will be followed by database lock and data analysis. The Cochrane Injuries Group confirms that DECRA is the first prospective randomized trial of any surgical therapy for adults with severe TBI. It is one of few randomized trials of any medical or surgical therapies for severe TBI patients. The full DECRA study results will be presented.

O17 Early Nervous System Dysfunction Due to Non-Organic Craniocerebral Explosion Shock Injury in Rats: An Experimental Study.

Background: We studied the impact of explosion shock not causing organic craniocerebral injury on nervous system function in rats.

Methods: Ninety Sprague-Dawley adult male rats (300–350 g/rat) were randomly divided into three groups: an explosion shock model non-organic craniocerebral injury group (explosive distance 10 cm), a sonic intervention injury group, and a normal control group. An electric detonator with the equivalent of 400 mg of TNT was used in the explosion group. The sonic intervention group was subjected to the same type of injury as the animals in the explosion group. The respiration, heart rate, and limb activity of the animals were observed on post-injury days 1, 2, 3, 5, and 7.The brain electrical signals were analyzed using Lempel-Ziv complexity [C(n)].The rats were put to death on the 7th day, and the water content of the brain and the microscopic pathomorphological changes were assessed.

Results: The rats in the three groups survived for more than 7 days. The water content of the brains did not increase markedly, and no microscopic pathomorphological changes took place. Transient respiratory arrest occurred in 36.7% (11/30) of the rats in the explosion group, their mean time of respiratory recovery was 3.5 sec, and extremity convulsions occurred in 46.7% (14/30; mean duration 4.2 sec). Transient respiratory arrest occurred in 20% (6/30) of the rats in the sonic intervention group, and the mean time of respiratory recovery was 2.7 sec. Extremity convulsions occurred in 20% (6/30; mean duration 3.3 sec). The rates of transient respiratory arrest were higher in the explosion group than in the sonic intervention group, and there was a significant difference between them (p < 0.05). The C(n) was highest in the control group, and dropped rapidly in the explosion group.

Conclusions: Explosion shock causes nervous system dysfunction and leads to a series of physiological and behavioral changes, while not causing organic brain damage, thus suggesting that explosion shock causes nervous system dysfunction and non-organic brain injury.

O18 Severe Head Injuries Among Judo Players in Japan: A 27-Year Survey of Junior and Senior High School Students.

Background: Sports-related head injuries remain a common clinical problem. We are seeking ways to protect against fatal brain injuries in sports players, although prevention is the best way to do so. In the present study, we investigated the incidence and profiles of judo-induced head injuries in Japan.

Methods: Over the 27-year period from 1983–2009, 108 students died as a result of judo-related accidents in Japanese junior and senior high schools. The data were collected from the records of the National Agency for the Advancement of Sports and Health (NAASH), and the types of judo throws and brain lesions were analyzed.

Results: Review of the records revealed that the annual number of student deaths was 4. Among the 108 dead students, 46 (42.6%) were in the first grade of senior high school, and 18 (16.7 %) were in the second grade of senior high school and the first grade of junior high school. The incidence of fatalities was significantly higher in beginners. Seventy cases (64%) out of the 108 died from brain injury, followed by cardiac failure and/or asphyxia. Among the brain-injured students, 65% had acute subdural hematomas. The leading type of throw used prior to death was the Oozotogari (major outer reaping) in 15 patients, followed by the Seoinage (the shoulder throw), and the Taiotoshi (body drop), with 6 cases each.

Conclusions: These results suggest that Judo beginners should have adequate protective training, such as the Ukemi (protective technique), before fighting. Also, the use of safety devices should be considered to prevent fatal brain injuries in judo students.

O19 The Neural Basis of Impaired Self-Awareness After Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) frequently impairs self-awareness. This limits recovery and the response to rehabilitation. The neural basis for this impairment has been unclear, but spatial neglect following stroke often results from damage to the right lateralized fronto-parietal network. Impairments of self-awareness can be studied by identifying patients who do not consistently monitor their own actions, which we refer to as “performance neglect.” Here we used complementary functional imaging and structural connectivity analyses to investigate: (1) whether patients with impaired self-awareness fail to activate attentional networks following errors; and (2) whether this performance neglect is associated with structural disconnection of distributed brain networks secondary to diffuse axonal injury.

Methods: We studied 38 TBI patients with varying levels of self-awareness. Two patient groups, with high- and low-performance neglect, were defined behaviorally, based on their ability to correct errors, and they were compared to a third group of controls. We used functional magnetic resonance imaging (MRI) to investigate the neural response to errors on a version of the stop-signal task. This paradigm uses an adaptive staircase procedure to control error rate, allowing performance to be equated across groups. We then used diffusion tensor imaging to study white matter integrity following TBI. A voxel-based approach (Tract-Based Spatial Statistics) was used to identify any group differences in fractional anisotropy and mean diffusivity.

Results: All three groups made similar numbers of errors on the stop-signal task, demonstrating that the patients were able to perform the task accurately. However, patients with high and low levels of performance neglect showed different neural responses to errors. Patients with behavioral evidence of performance neglect showed significantly less activation of the right lateralized fronto-parietal attentional network. In contrast, patients without evidence of performance neglect showed greater activation within the same network, particularly within the right middle frontal gyrus. Diffusion tensor imaging analysis demonstrated that patients with performance neglect had more evidence of white matter disruption (lower fractional anisotropy) within the corpus callosum and parafalcine white matter tracts.

Conclusion: Impaired self-awareness following TBI is associated with abnormally low brain activation to errors within a right lateralized attentional network. This may result from the disconnection of distributed brain networks produced by diffuse axonal injury.

O20 Diffuse Injury and Focal Mass Lesion are Associated with Different Biomarker Profiles After Severe Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) is a heterogeneous disorder with different forms of presentation. The Marshall computed tomographic (CT) classification identifies groups of patients with TBI, based on morphological abnormalities on CT scan. These macroscopic structural damages are associated with diverse cellular vulnerability patterns, as well as different pathophysiological mechanisms at the microscopic level that cannot be visualized. Therefore, new surrogate markers for these processes are needed. The aim of this study was to investigate different biomarkers in comparison with morphological abnormalities on the CT scan as assessed by the Marshall classification.

Methods: The study recruited 81 patients with severe TBI, defined by a Glasgow Coma Scale (GCS) score of ≤ 8, from four trauma centers. A control group included healthy blood donors (n = 167). Serum samples for analysis of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were obtained at the time of hospital admission, and every 6 h thereafter. Demographic data, clinical variables, and the category of the Marshall classification were recorded.

Results: The mean serum levels of UCH-L1 and GFAP were elevated 11.3-fold (UCH-L1), and 28.7-fold (GFAP) compared to controls in the first 24 h post-injury.

Conclusion: Although, conventional classification of TBI with CT findings differentiates between focal and diffuse injury, our results showed that better discrimination may be obtained by making use of blood biomarkers. The current data are consistent with the hypotheses that measurement of UCH-L1 and GFAP may provide independent data about the specific types of cellular damage and pathomechanisms involved in primary injury, which may have an impact on management decisions of these critically ill patients.

O21 Role of Serum Biomarkers in Individuals in Coma or Vegetative State After Traumatic Brain Injury.

Background: Several studies have shown that blood biomarker levels in the acute and subacute phases after traumatic brain injury (TBI) may be diagnostic and prognostic tools in addition to clinical indices. However, the role of brain damage biomarkers in the chronic phase after TBI has not been examined. The purpose of our study was to evaluate serum concentrations of two brain-specific biomarkers—microtubule-associated protein-2 (MAP-2) and glial fibrillary acidic protein (GFAP)—in patients in coma or vegetative state following severe TBI, and to analyze their relationships with clinical characteristics.

Methods: We analyzed 28 adult post-acute TBI patients. Mean interval from injury was 2.73 months (SD ± 2.03 months). One hundred seventy-six healthy blood donors served as controls. Serum MAP-2 and GFAP levels were measured by quantitative ELISA on admission in the rehabilitation department. Data collected included demographic and clinical variables. Basal level of consciousness was assessed using the level of cognitive functioning (LCF), and functional baseline was measured with the Disability Rating Scale (DRS).

Results: Patients had MAP-2 levels significantly higher than controls (0.06 ± 0.009 versus 0.0009 ± 0.0008 ng/mL). MAP-2 concentrations in serum are significantly associated with consciousness, and are not influenced by time of sample withdrawal. These data suggest that MAP-2 may be a promising serum marker with valuable implications for clinical care and rehabilitative programs in patients with coma or vegetative state due to TBI.

O22 The Incidence and Implications of Acute Kidney Injury in Patients with Traumatic Brain Injury.

Background: Information on the incidence of acute kidney injury in patients with traumatic brain injury (TBI) is very limited, although acute kidney injury contributes to morbidity, mortality, and resource use. We performed the first dedicated investigation of the incidence of acute kidney injury in patients with moderate and severe TBI, and assessed the association of acute kidney injury with risk factors and outcomes in these patients.

Methods: We studied all TBI patients over 16 years of age admitted to the two designated trauma hospitals in the state of Victoria, Australia, from January 1 to December 31, 2008. Patients were included if they had head trauma and presented with a Glasgow Coma Scale score < 13. Prospectively collected data from the hospital trauma registries, intensive care units, and pathology databases, were analyzed retrospectively. The extensively validated RIFLE criteria were used to categorize renal function.

Results: The incidence of acute kidney injury was 9.2% (19/207). Patients who developed acute kidney injury were older, had higher severity of illness, and a lower Glasgow Coma Scale score. Overall, 42.1% of these patients died in hospital, compared with 18.1% of patients without acute kidney injury. In a univariate linear regression analysis, age, severity of illness, and admitting hospital were associated with acute kidney injury. After multivariable logistic regression, the occurrence of acute kidney injury was associated with age (neurotrauma can simultaneously protect brain and kidney and decrease the incidence of acute kidney injury). Erythropoietin and prophylactic hypothermia are two such treatments. Indeed the multi-center randomized controlled EPO-TBI and POLAR trials, which are respectively investigating the benefits of erythropoietin and early and sustained hypothermia for neurological outcomes, also assess the effect of these interventions on the kidneys. These trials have recently commenced recruitment in Australia.

O23 A New Multiple Cerebral Concussion Model was Developed and the Histopathology Changes were Observed After Injury in Rats.

Background: The goal of this study was to develop a new model for multiple cerebral concussion (MCC) in rats and observe the histopathological changes of neural axons and myelin sheath in cerebral cortex, dorsal hippocampus, and brainstem reticular formation areas post-injury.

Methods: A new three-times impact model (3MCC) was achieved using a metallic pendulum-striker concussive device, delivering one impact each day, for a total of 3 days. Forty-eight male Sprague-Dawley rats were randomly divided into six 3MCC groups: 1, 2, 4, 8, 16, and 24 days post-injury. One control group was used. Each group had 8 animals. The rats were killed with 4% paraformaldehyde at each time point. Then pyknotic degenerating neurons were observed and counted, and axons and myelin sheaths were stained with the Bielschowsky and Weil method, and the diameter of the axons and the grey value of the myelin sheaths were measured using an optical microscope.

Results: The pyknotic degeneration of neurons was observed in the cerebral cortex, dorsal hippocampus, dentate gyrus, and brainstem reticular formation after 3MCC. The damage to neurons in the 2-day group peaked, and was more severe than in the 8-day and 16-day groups. In some axons pathological changes in the brainstem were observed, including axonal swelling, misalignment, disconnection, and axonal retraction bulbs. The axon diameters in the brainstem were increased and there were significant differences from the 2-day and 4-day groups (p < 0.05) compared with controls. Myelin sheaths in the brainstem showed swelling, degeneration, and destaining after injury. The grey values in all except the 24-day group were significantly different compared with controls (p < 0.05), and reached peaks in the 2-day and 4-day groups.

Conclusion: Some neuron and neurofiber pathological changes exist in the cerebral cortex, dorsal hippocampus, and brainstem reticular formation after 3MCC in rats.

O24 A Study of the Quantitation of Brain Microglia Cells of Pure Cerebral Concussion and Multiple Cerebral Concussions in Rats.

Background: To establish pure cerebral concussion (PCC) and multiple cerebral concussion (MCC) rat models, and observe the changes in microglia (MIG) by cell count after injury, so as to understand the neurobiological mechanisms of PCC and MCC.

Methods: The PCC or MCC model was duplicated using a metallic pendulum-striker concussive device. Ninety-six female and male Sprague-Dawley rats were randomly divided into 12 groups: PCC 1-, 2-, 4-, 8-, 16-, and 24-day groups, and MCC 1-, 2-, 4-, 8-, 16-, and 24-day groups; one control group was used. Each group had eight animals. Each animal was sacrificed and fixed with 4% paraformaldehyde at each time point. The frozen sections were staining with hematoxylin and eosin (HE) and Nissl for microglia cell counts in the following areas: PFC, Pir, Cpu, AcbC, BST, RSA, CA1-4, upper and lower dentate gyrus, LD, white matter of brainstem, and prerubral region.

Results: The numbers of MIG cells in most areas and time points of both PCC and MCC rats were increased compared with control animals after injury, all except the PFC and hippocampus. The quantity of MIG in MCC animals was more increased than in PCC rats in the following areas: AcbC, Pir, Cpu, BST, RSA, CA1-4, LD, and lower dentate gyrus.

Conclusion: The numbers of microglia in both PCC and MCC animals were increased after injury, and then gradually lowered. MCC animals had more damage than PCC animals.

O25 The Association Between Apolipoprotein E and Traumatic Brain Injury Severity and Functional Outcome.

Background: Traumatic brain injury (TBI) can result in significant disability, but outcomes are variable. The impact of known predictors accounts for a limited proportion of the variance seen in outcomes. Apolipoprotein E genotype has been investigated as an additional source of variability in injury severity and outcome, with mixed findings reflecting variable methodology and generally limited sample sizes. This study aimed to examine whether possession of the apolipoprotein E e4 allele was associated with greater acute injury severity and poorer long-term outcome following TBI.

Methods: Apolipoprotein E genotype was determined for 648 patients with TBI, who were prospectively followed-up for a mean of 1.9 years post-injury.

Results: The hypotheses that e4 carriers would have lower Glasgow Coma Scale scores and longer post-traumatic amnesia durations were not supported. Prediction of worse Glasgow Outcome Scale-Extended scores for e4 carriers was supported. Results indicate that the apolipoprotein E e4 allele may be associated with poorer long-term outcomes, but not acute injury severity. Possible mechanisms include differential effects of the e4 allele on inflammatory and cellular repair processes, and/or amyloid deposition.

O26 Sleep Distrurbance and Melatonin Levels Following Traumatic Brain Injury.

Background: Sleep disturbances commonly follow traumatic brain injury (TBI) and contribute to ongoing disability. However, there are no conclusive findings regarding specific changes to sleep quality and sleep architecture measured using polysomnography. Possible causes of the sleep disturbances include disruption of circadian regulation of sleep-wakefulness, psychological distress, and a neuronal response to injury. We investigated sleep-wake disturbances and their underlying mechanisms in a TBI patient sample.

Methods: This was an observational study comparing 23 TBI patients (429.7 ± 287.6 days post-injury), and 23 age- and gender-matched healthy volunteers, on polysomnographic sleep measures, salivary dim light melatonin onset (DLMO) time, and self-reported sleep quality, anxiety, and depression.

Results: TBI patients reported higher rates of anxiety and depressive symptoms and sleep disturbance than controls. TBI patients showed decreased sleep efficiency (SE), and increased wake after sleep onset (WASO). Although no significant group differences were found in sleep architecture, when anxiety and depression scores were controlled for, TBI patients showed higher amounts of slow-wave sleep. No differences in self-reported sleep timing or salivary DLMO time were found. However, TBI patients showed significantly lower levels of evening melatonin production. Melatonin level was significantly correlated with REM sleep, but not SE or WASO.

Conclusions: Reduced evening melatonin production may indicate disruption to circadian regulation of melatonin synthesis. The results suggest that there are at least two factors contributing to sleep disturbances in TBI patients. We propose that elevated depression is associated with reduced sleep quality, and increased slow-wave sleep is attributed to the effects of mechanical brain damage.

O27 A Perfusion FMRI Study of the Neural Correlates of Working Memory Deficits in Traumatic Brain Injury.

Background: Regional cerebral blood flow (CBF) is closely coupled to regional neural activity, and can be noninvasively quantified using arterial spin labeled (ASL) perfusion fMRI. The present study used ASL perfusion fMRI to characterize tonic changes of CBF associated with working memory deficits in traumatic brain injury (TBI) compared to control participants.

Methods: Twenty-one individuals with moderate to severe TBI, and 18 demographically-matched healthy control participants were included. An amplitude-modulated continuous ASL technique was used at 3 Tesla. All participants completed one resting perfusion scan and one task perfusion scan. Each scan lasted approximately 6 min. During the task scan, they performed a visual letter 2-back verbal working memory task.

Results: Compared to controls, individuals with TBI showed significantly lower accuracy (d-prime, p < 0.005) and response speed (reaction time, p < 0.005). Voxel-wise whole-brain analysis demonstrated that both groups activated the fronto-parietal cortical network known to be involved in performing the 2-back task. A group (control or TBI) × task (2-back or rest) interaction effect was identified in the bilateral occipital cortices (BA 18), after controlling for the task performance level (d-prime). A subsequent ROI analysis confirmed that while these areas were deactivated during the task in controls, the same areas tended to be activated in TBI. These areas were also found to be disproportionately hypoperfused in TBI patients during the resting session. Regression analyses with the performance level (d-prime) as the predictor revealed that higher accuracy was associated with a task-related CBF increase in the left superior parietal (BA7) and posterior intraparietal cortices (BA 7/39) in control participants. However, in individuals with TBI, higher performance was correlated with a task-related CBF decrease in the bilateral anterior cingulate cortex (BA 24).

Conclusion: ASL perfusion fMRI demonstrated tonic cortical CBF changes associated with working memory dysfunction in chronic survivors of moderate to severe TBI. Compared to controls, individuals with TBI demonstrated altered patterns of task-related activation, and altered correlations between performance and CBF change.

O28 Cerebral Metabolic Effects of Strict Normoglycemia Versus Current Clinical Glycemic Control Following Severe Brain Injury.

Background: Hyperglycemia in critically ill patients is associated with increased morbidity and mortality, and there is a strong relationship between high plasma glucose and poor outcome in head-injured patients. Glucose, however, is the main substrate for a cerebral oxidative metabolism, and low extracellular brain glucose levels are related to worse outcome following severe traumatic brain injury (TBI). Despite the general agreement on the need for glycemic control, safe levels of plasma glucose are not known and require further evaluation. This study aimed to prospectively compare the parameters of cerebral energy metabolism between TBI patients who receive either an intensive glycemic control protocol, or a routine glycemic control protocol.

Methods: This is a single-center prospective, randomized, cross-over study. Sixteen patients with severe TBI requiring neuromonitoring including cerebral microdialysis and insulin treatment for hyperglycemia were recruited. All patients received 24 h of treatment with insulin to achieve strict normoglycemia (glucose 4–7 mmol/L), and 24 h of a standard insulin regimen to maintain glucose below 10 mmol/L. Microdialysis parameters were measured hourly. The non-parametric paired Wilcoxon rank test was used to compare the differences between routine and intensive glycemic control periods. Evaluated parameters included cerebral extracellular glucose, lactate, pyruvate, lactate-to-pyruvate ratio (L:P), lactate-to-glucose ratio (L:G), glutamate, and glycerol.

Results: Median [IQR] levels of extracellular cerebral glucose during strict glucose control were significantly lower compared to the conventional insulin regimen (1.08 [0.45–1.42] mmol/L versus 1.40 [0.60–1.87] mmol/L; p = 0.001). Low cerebral glucose concentrations below 0.5 mmol/L were observed on average in 28.2% of those on strict glucose control, and in 13% receiving conventional treatment (p = 0.012). Nevertheless, concentrations of extracelular lactate and the L:P ratio were significantly lower during strict glucose control compared to conventional treatment (p = 0.017 and p = 0.02, respectively).

Conclusions: Cerebral extracellular glucose levels are affected by the plasma level of glucose. Strict normoglycemia (4–7 mmol/L) can lead to a higher percentage of extremely low glucose levels in the injured brain. On the other hand, our data suggest that better values of cerebral energy metabolism parameters (lower L:P ratio and lactate) were observed during periods of strict glucose control. Possible explanations for the findings will be discussed.

O29 Biomarkers in Serum After Experimental Diffuse and Focal Traumatic Brain Injury in Rats.

Background: Traumatic brain injury (TBI) biomarkers would be highly valuable in the diagnosis of various forms of TBI, and also in the evaluation and treatment of TBI patients, and may even provide prediction of the outcome of the future impairments of the patients. Here we analyzed brain and serum samples derived from rodent models of rotational and penetration TBI by reverse phase protein microarray (RPPM).

Methods: The first model is a controlled penetration of 2-mm-thick needle-shaped object, which is accelerated with a bullet from an air gun or a pendulum (pen-TBI). In the second model we produce diffuse axonal injury. The animal is subjected to high-speed sagittal rotation acceleration (rot-TBI). A total of 48 animals were used, grouped into normal controls, sham-operated, and injured animals. The rats were sacrificed at days 1, 3, and 14 post-injury, and serum samples were analyzed for Tau, NF200, MBP, N-cadherin, NSE, and S100B.

Results: We found an increase in all proteins measured in both rotational and penetrating TBI. However, there were distinct temporal patterns of expression of protein markers in each TBI model. The results of tau and NF200 appear consistent with the injury mechanism in DAI (i.e., initial axonal distention followed by a secondary axotomy). The NSE and S100B showed a biphasic pattern in focal penetrating injury (pen-TBI), indicating a secondary injury.

Conclusion: This information can be used to form a palette of biomarkers that can improve and contribute to diagnostic and therapeutic tools in TBI management.

O30 Principal Component Analysis of Cerebral Parenchymal Cytokine Expression Following Traumatic Brain Injury.

Background: The central nervous system (CNS) has long been regarded as an immunologically privileged site. Pre-clinical studies have repeatedly demonstrated that resident CNS cells both produce and respond to soluble inflammatory mediators (i.e., cytokines). We sought to characterize the cerebral inflammatory response to trauma in humans using cerebral microdialysis. Principal component analysis (PCA) is a method for reducing large numbers of variables into principal components that summarize the sources of variation within the dataset.

Methods: We have utilized cerebral microdialysis in 12 patients to assay a panel of 42 cytokines throughout 5 days of monitoring. The same cytokines were measured in arterial and jugular venous blood. Statistical analysis was performed using multivariate analysis, including PCA, followed by partial least squares discriminant analysis (PLS-DA). SIMCA-P + version 12 (Umetrics, Umea, Sweden) was used to identify principal components which accounted for the majority of the variation within the dataset.

Results: All 42 cytokines were recovered from the human brain following TBI. A subset of cytokines had parenchymal concentrations more than 10-fold those found in serum, including IL-1β, IL-1ra, IL-6, IL-8, IP-10, and TNF. A temporal profile was built for each of the cytokines, demonstrating that certain cytokines peaked on day 1 (e.g., IL-1β), certain cytokines peaked on day 2 (e.g., IL-1ra), and some cytokines peaked on day 3 (e.g., IP-10) following injury. Multivariate analysis revealed a small group of cytokines to be responsible for the majority of the variation in cytokine responses between patients, including IL6, IL-1β, and TNF.

Conclusions: Cerebral microdialysis is capable of recovering a range of cytokines from the human brain and characterizing their temporal profile. These cytokines are produced in a defined temporal sequence following injury, and a subset of these cytokines is responsible for the majority of the variations in response seen between patients. Interestingly, these cytokines have been strongly implicated in the pathophysiology of TBI in rodent models. This provides direct empirical evidence for the production of cytokines within the CNS.

O31 Endovascular Treatment Strategy for Traumatic Carotid-Cavernous Fistulas.

Objective: To evaluate endovascular treatment outcome for traumatic carotid-cavernous fistulas (TCCFs).

Methods: We retrospectively studied 628 consecutive cases of TCCF who were treated by a variety of different techniques and embolization methods in our department between January 1980 and August 2009. Of the 628 patients with TCCFs, 571 cases were treated through transarterial embolization including with muscle (4 cases), coils (13 cases), detachable balloons (522 cases), and microcoils (32 cases); 25 cases were treated through transvenous embolization, including embolization through ophthalmic veins with microcoils (12 cases), NBCA (1 case), and through femoral venous-superior (inferior) petrosal sinus with microcoils (2 cases); and 32 cases were treated by the combination of transarterial embolization with detachable balloons, and transvenous embolization with microcoils. In all, 369 patients were followed-up from 6 months to 27 years.

Results: In all cases, the symptoms related to the TCCF regressed after treatment and did not recur during follow-up. All of the 628 patients were cured. Temporary cerebral ischemia occurred in 4 patients and pseudoaneurysm in 2 patients. TCCFs recurring in 5 patients from 1 to 2 months after embolization were cured by re-embolization with NBCA and silk suture.

Conclusions: Endovascular embolization through a transarterial approach with detachable balloons is the optimal method to treat TCCFs. However, if this technique fails, treatment with a variety of newer embolic agents, as well as newer microcatheters and guidewires, has greatly facilitated treatment by transvenous embolization via different venous routes.

O32 APOE Isoforms Affect Early Apoptosis After Experimental Traumatic Brain Injury in Neuronal/Glial Co-Cultures via Modification of Delayed Rectifier K + Currents.

Background: The purpose of this study was to elucidate the mechanisms mediating the effects of apolipoprotein E (APOE) alleles on early apoptosis in an ex vivo model of brain trauma by measuring the delayed rectifier K + current [IK(DR)].

Methods: Eukaryotic expression vectors carrying individual APOE alleles (ɛ2, ɛ3, and ɛ4) were transfected into neural stem cells (NSCs) derived from APOE-knockout mice. An ex vivo neuronal/glial co-culture model of mechanical injury was designed using a controlled razor blade scratch. Flow cytometry and patch clamp recording were used to analyze the associations of the APOE genotypes with early cell apoptosis and IK(DR).

Results: Early apoptosis following injury was identified in all groups. Early apoptosis at 24 h was higher than at 6 h and 12 h in each group (significant differences among the groups were found before injury). Furthermore, increases of IK(DR) were observed in all groups after injury. The amplitude of the IK(DR) increase in the APOEɛ4-transfected group was significantly lower compared with all other groups (p < 0.05). Our results not only provide experimental support for previous clinical findings, they also suggest that APOEɛ4 can exert an inhibitory effect on IK(DR) following injury, resulting in reduced K + efflux, which in turn aggravates intracellular Ca2 + overload. The inhibitive effect on the magnitude of IK(DR) may be one mechanism by which APOEɛ4 adversely affects the outcome of traumatic brain injury.

O33 Endovascular Treatment of Intracranial Pseudoaneurysms.

Background: The goal of this study was to explore the diagnosis and treatment of intracranial pseudoaneurysms.

Methods: The data from 7 patients with intracranial pseudoaneurysms treated with cover stents were analyzed retrospectively.

Results: Once the site of intracranial pseudoaneurysms was precisely determined by angiographic technique, a cover stent was introduced and advanced to the site. Satisfactory results were obtained in these patients.

Conclusion: A cover stent is the optimal option for the treatment of patients with intracranial pseudoaneurysms.

O34 Management and Prognosis for 127 Patients with Traumatic Bifrontal Contusions.

Background: With the aggravation of edema and possible hemorrhagic contusion enlargement, those with bifrontal contusions may deteriorate rapidly or even die due to central brain herniation. Close monitoring and proper treatment are important for the best outcomes.

Methods: From January 2003 to August 2009, 102 males and 25 females with bifrontal contusions were reviewed retrospectively (age 7–81 years, average 47 years). Upon admission, severe brain injury (GCS score 3–5) was present in 36 cases (28.3%), moderate injury (GCS score 9–12) in 38 cases (29.9%), and mild injury (GCS score 13–15) in 53 cases (41.7%). Of these, 64 patients were treated non-operatively. In the 63 patients who accepted surgery, 39 cases underwent ICP monitoring, and 24 cases had no ICP monitoring.

Results: There were no distinct differences in GCS scores upon admission (average 8.62–8.91), and at discharge (average 11.32–10.45), between the ICP operation group and the non-ICP operation group. Length of ICU stay was much shorter in the ICP operation group (15.67 ± 8.72 days) than in the non-ICP operation group (25.32 ± 18.78 days). Length of hospital stay was also much shorter in the ICP operation group (18.94 ± 8.92 days) than in the non-ICP operation group (34.29 ± 22.64 days). Length of osmolar therapy with mannitol was 14.11 ± 6.65 days in the ICP operation group, which also was much shorter than in the non-ICP operation group. In all, 29 ICP operation patients and 19 non-ICP operation patients were followed-up with the Glasgow Outcome Scale 6 months later. Average GOS scores were 4.21 and 3.32 for the two groups, respectively (p = 0.025), indicating better outcomes in the ICP operation group than the non-ICP operation group.

Conclusion: ICP monitoring was important for patients with moderate and severe bifrontal contusions, and contribute to better prognoses.

O35 Disease Burden of Traumatic Brain Injury in Eastern China.

Traumatic brain injury (TBI) is a major cause of disability, morbidity, and mortality among trauma patients, and is responsible for a significant proportion of all traumatic deaths. The loss of human potential and the long-term impairments and disabilities associated with TBI create a tremendous impact on the family and society, and cost society millions of dollars each year. The WTO reported that the cost of road traffic accidents accounted for 1.5% of GNP in China. Lifetime medical care costs of head injuries occurring in the United States in 1985 were estimated to total $4.5 billion, including $3.5 billion in hospital costs alone. The newest report showed that in the United States the direct and indirect medical costs totaled $56 billion each year. In the United States from 1997 to 1999, the cost of acute inpatient care for TBI ranged from $8189 dollars for moderate TBI to $33,537 dollars for critical TBI. But in China, recent efforts to estimate the costs of acute inpatient care for TBI have been few, and have been limited to small samples, survivors, or patients admitted to rehabilitation. Here we first conducted a large, prospective cohort study involving a representative sample to estimate the demographic profiles and cost of hospitalization of TBI patients in eastern China, which is the most developed area in China, with a population estimated to be 373.3 million, or 28.7% of the total population. The influence of demographic characteristics (e.g., age, sex, and payer type), health system factors (e.g., hospital size, location, and type), and injury severity, on total hospital charges and LOS were also analyzed.

O36 The Research of the Applied Value of NT-pro-BNP After Traumatic Brain Injury.

Background: In this study we evaluated the value of plasma N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in the assessment of the severity of traumatic brain injury (TBI) and increased intracranial pressure (ICP).

Methods: From January 2009 to December 2009, 63 TBI patients admitted to our neurosurgery department were studied. Clinical data such as sex, age, Glasgow Coma Scale (GCS) score at admission, mechanism of injury, ICP values, inpatient days, and intensive care unit (ICU) days were collected. The patients were subsequently divided into mild TBI patients (GCS score 13–15; n = 14), moderate TBI patients (GCS score 9–12; n = 24), and severe TBI patients (GCS score 3–8; n = 25). The sample was analyzed using an electrochemiluminescence immunoassay.

Results: NT-pro-BNP levels were increased significantly in the severe TBI patients compared to moderate TBI patients, as well as to mild TBI patients (F = 12.590 compared to patients without elevated ICP; 520.220 ± 153.5037 pg/mL, n = 5 versus 221.945 ± 142.7059 pg/mL, n = 40; p < 0.01). NT-pro-BNP levels correlate with GCS score and the number of ICU days.

Conclusions: The higher the early plasma NT-pro-BNP level, the more difficult to control the ICP after TBI. NT-pro-BNP levels drawn immediately upon admission appear to be a potential predictor for the severity of TBI and the degree of intracranial hypertension, and may help us to predict and intervene in those with increased ICP early.

O37 Management of Traumatic Brain Injury in China.

Traumatic brain injury (TBI) is one of the leading causes of death from traumatic injury, and is the fifth highest killer in China overall, and the highest killer of young adults. Since the founding of the People's Republic of China in 1949, there have been significant developments in the field of TBI management. Thanks to the establishment of neurosurgery centers and postgraduate training programs, today most Chinese medical facilities including district hospitals have neurosurgical specialists, are equipped with CT scanners, and have established neurosurgery departments. Recent data show that there are now approximately 10,000 neurosurgeons in China, most of whom are caring for or have cared for TBI patients. In addition, the number of CT scanners has reached 4000, and most Chinese hospitals including a significant number of county and village health centers have them. This suggests that the diagnosis of TBI can be made without referring patients to large medical institutions. Multi-center clinical trials, such as investigations of sodium valproate and nimodipine, have affected medical interventions in TBI. In 2009, China published its own guidelines for the surgical management of TBI. Despite this great progress, there are several means by which we can improve the quality of TBI treatment in China: (1) head injury prophylaxis has somehow been overlooked; (2) techniques associated with neurointensive care need to be improved; (3) the training system for young neurosurgeons should be more systematic and further improved. Basic research on brain injury and regenerative medicine could cast light on new means of TBI management.

O38 Diagnosis and Critical Care for Concurrent Central Diabetes Insipidus with Cerebral Salt-Wasting Syndrome in Traumatic Brain Injury Patients.

Background: Having a poor prognosis, concurrent diabetes insipidus (CDI) and cerebral salt-wasting syndrome (CSW) rarely appear in patients with neurologic disorders, especially for neurotrauma patients, who are complicated clinically and difficult to diagnose. Inaccurate and late diagnosis, similarly to inappropriate treatment, will lead to serious negative outcomes. Deep understanding of the characteristics of CDI combined with CSW are very important in making the correct diagnosis, as well as for prompt and appropriate treatment.

Methods: Six neurotrauma patients, who suffered concurrent CDI and CSW, were reviewed retrospectively for clinical characteristics. Four male and two female patients were included who suffered traffic accidents or falls (age 28–52 years, average 36.8 years; Glasgow Coma Scale [GCS] scores were 5–15 on emergency admission).

Results: The most outstanding characteristic was massive polyuria, ranging from 7210–10,000 mL/d, and rising from 550 mL to more than 1000 mL in 1 h in one case, which could not be controlled by vasopressin. The second was high urinary sodium levels and high pro-BNP levels without cardiac dysfunction, which led to much higher urine osmolarity than serum osmolarity. However, normal serum sodium levels and urine specific gravities were found in most of these patients. With intensive monitoring of central venous pressure, physiologic saline and hypertonic saline were mainly transfused to correct massive sodium and water losses. Simultaneously, desmopressin for water resorption and cortisone acetate to encourage urine sodium retention were also important. One patient died from brain herniation and multiple organ failure, one was in a vegetative state due to pons demyelination after a rapid sodium transfusion, and four other patients were discharged with a GCS score of 15.

Conclusion: A deeper recognition of CDI combined with CSW, and a higher diagnostic rate, may result in better outcomes.

O39 Impact of Electrophysiology Monitoring on the Management of Comatose Patients with Traumatic Brain Injury.

Background: To assess the effect of electrophysiology monitoring, including continuous electroencephalography (cEEG), somatosensory-evoked potentials (SEP), and brainstem auditory-evoked potentials (BAEP), on the management of comatose patients with traumatic brain injury, particularly in the setting of the intensive care unit.

Methods: This was a retrospective cohort study done in medical and neuroscience intensive care units and neurological wards. Eighty-four consecutive cEEG monitoring studies were performed on 47 individual inpatients. Outcome measures included mortality, Glasgow Outcome Scale (GOS) scores, epileptiform electroencephalographic abnormalities, and changes in antiepileptic drug, sedation, and other medical therapy based on the electrophysiological findings.

Results: Electrophysiological findings led to specific clinical management changes in 26 out of 47 inpatients. These included detection of epileptiform electroencephalographic abnormalities in 4 cases, initiating or escalating antiseizure medications in 3 patients due to seizure detection, demonstrating that a specific event (subtle movement or vital sign change) was not a seizure in 4 cases, obtaining urgent neuroimaging in 2 cases, confirming brainstem injury in 12 cases, and brain death in 1 case that led to a clinical change. In the remaining 21 patients, electrophysiological monitoring ruled out the presence of non-convulsive seizures, but did not lead to a specific change in clinical management.

Conclusions: The findings of electrophysiological monitoring resulted in changes in management, including modification of anti-seizure medications, obtaining neuroimaging, and the use of other medications, for over half of our comatose TBI patients.

O40 Validating the Incidence of Coagulopathy and Disseminated Intravascular Coagulation in Patients with Traumatic Brain Injury: Analysis of 242 Cases.

Background: Our goal was to estimate the incidence of coagulopathy and disseminated intravascular coagulation (DIC) in traumatic brain injury (TBI) patients, and to investigate its relationship to patient outcome.

Methods: This was a prospective observational study. From January 2007 to June 2009, 242 consecutive adult TBI patients seen in three independent hospitals were recruited. Glasgow Coma Scale (GCS) score on admission, platelet counts (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D-dimer (D-DT), and DIC scores were recorded for each case on admission. Clinical outcome was measured according to the Glasgow Outcome Scale (GOS) at 3 months post-injury. Statistical analysis was carried out using Student's t-test, one-way analysis of variance (ANOVA), and Tukey's test.

Results: Coagulation abnormalities were present in approximately 50% of TBI patients. Prolonged PT and increased D-DT and FIB levels were seen in patients with more severe brain injury and poorer outcomes, and these findings were statistically significant.

Conclusions: Coagulation changes, particularly the occurrence of DIC, may occur within 6 h after TBI and are more pronounced in patients with severe injuries and poor outcomes. PT, D-DT levels, and more comprehensively DIC scores, may be useful prognostic indicators in TBI patients.

O41 The Clinical Applications of Titanium Mesh Multi-Point Forming in Craniocerebral Trauma Patients.

Background: Here we summarized the skull defect cases caused by craniocerebral trauma in our hospital in the past 5 years to research the clinical applications of titanium mesh multi-point forming in craniocerebral trauma patients.

Methods: In all, 273 patients suffering from skull defects caused by craniocerebral trauma have been treated in our hospital in the past 5 years, and 179 patients were treated with multi-point forming technology by titanium mesh shaping. The following aspects were analyzed: the differences in irritation of soft tissue between different repair materials, the difficulty of shaping, anesthesia and surgery time, shaping satisfaction, and postoperative complications.

Results: Because of the use of multi-point forming technology, the average titanium mesh shaping time in cranioplasty is only 5 min, no subcutaneous hydrops or rejections occur, and titanium mesh is reliable and patients like its appearance. The surgical procedure is simple, and it can greatly reduce the shaping time, anesthesia time, and operative time, reduce the risk of surgery, and greatly reduce the chances of postoperative infection and hydrops. The multi-point forming technology reduces the difficulty of the work of neurological surgeons, and can decrease postoperative complications. It can significantly improve the patient's quality of life, and reduces the use of titanium screws, saving operative costs.

Conclusion: The multi-point forming technology with titanium mesh shaping is much better than other skull repair technologies. It creates huge economic and social benefits, so it should be widely used.

O42 Diffuse Axonal Injury Analysis.

Abstract Not Available

O43 Delayed Traumatic Intracranial Hematoma Clinical Analysis.

Delayed traumatic intracerebral hematoma (DTICH) may occur during surgery or the postoperative and conservative course of treatment after traumatic brain injury. In the period from 1993–1998, we treated 35 patients with DTICH. Among them, 9 patients died, 3 had severe disability, 1 had mild disability, and 23 were cured. Through the comprehensive analysis of the mechanism, CT images, clinical manifestations, and treatment and prognosis of DTICH, we found that DTICH is closely related to cerebral contusion, and the dehydrating agent should be used with caution. Statistical analysis indicated that the surgical removal of hematoma before hernia formation could reduce mortality significantly.

O44 The Added Value of Ordinal Analysis in Clinical Trials in Traumatic Brain Injury.

Background: In clinical trials for traumatic brain injury (TBI), the ordinal five-point Glasgow Outcome Scale (GOS) is commonly collapsed into two categories: unfavorable versus favorable outcome. Simulation studies have shown that exploiting the ordinal nature of the GOS increases the chances of detecting treatment effects. The objective of this study was to quantify the benefits of ordinal analysis in the real-life situation of a large TBI trial.

Methods: We used data from the CRASH trial, which investigated the efficacy of corticosteroids in TBI patients (n = 9554). We applied two techniques for ordinal analysis: proportional odds analysis, and the sliding dichotomy approach, for which the GOS was dichotomized at different cut-off points according to baseline prognostic risk. These approaches were compared to dichotomous analysis. The information density in each analysis was indicated by a Wald statistic. All analyses were adjusted for baseline characteristics.

Results: Dichotomous analysis of the 6-month GOS showed a non-significant treatment effect (OR = 1.09, 95% CI 0.98,1.21, p = 0.096). Ordinal analysis with proportional odds regression or sliding dichotomy showed highly statistically significant treatment effects (OR 1.15, 95% CI 1.06,1.25, p = 0.0007, and OR 1.19, 95% CI 1.08,1.30, p = 0.0002, respectively), with 2.05-fold and 2.56-fold higher information density compared to the dichotomous approach, respectively.

Conclusions: Analysis of the CRASH trial data confirmed that ordinal analysis of outcome substantially increases statistical power. We recommend that future clinical TBI trials adopt ordinal analyses. This will permit detection of smaller treatment effects.

O45 Differential Response to Injury and Immunophilin Ligand Treatment in Unmyelinated and Myelinated Axons.

Background: Prior evidence suggests that unmyelinated and myelinated axons exhibit different degrees of conduction deficits after traumatic brain injury (TBI), and show different capacities for functional recovery. To obtain morphological correlates of post-injury axonal dysfunction, ultrastructural assessments were made of corpus callosum axons between 3 h and 15 days following TBI in adult rats. In addition, the efficacy of cyclosporin-A (CsA) and FK506 to prevent fiber dysfunction was assessed.

Methods: At 3 h, 1 day, or 15 days after midline fluid percussion injury, ultrastructural stereological procedures quantified the number and cross-sectional areas of intact (non-degenerating) axon profiles, and areas bounded by myelin, in sagittal sections from genu, middle, or splenium regions. To assess immunophilin ligand neuroprotection, rats underwent injury, as above, and were treated at 15 min or 1 h post-injury with FK506 (3 mg/kg IV), or CsA (20 mg/kg IP). At 1 day post-injury, evoked compound action potentials (CAPs) were acquired in brain slice electrophysiology, separately quantifying unmyelinated and myelinated callosal CAP signals.

Results: In all, 5054 unmyelinated and 1953 myelinated axons were assessed, to estimate injury-induced changes in fiber density and caliber. Mean area of unmyelinated axons decreased post-injury, falling to a maximum of 23% below sham levels at 15 days. Myelinated axon caliber was not significantly altered, although a decrease in the periaxonal (submyelin) space was observed. Neither the mean density of intact myelinated nor that of unmyelinated axons was significantly altered by injury. Treatment with either CsA or FK506 protected against TBI-induced suppression of myelinated CAPs, when given at 15 min post-injury, but not at 1 h. Neither drug prevented post-injury suppression of unmyelinated CAPs.

Conclusions: Stereological assessments did not reveal significant TBI-related changes in the density of intact axons in the corpus callosum, suggesting that electrophysiological observations of suppressed callosal CAPs are not due to loss of axons, but more likely reflect sublethal pathology affecting axonal conduction. The present ultrastructural findings provide possible morphological correlates of this pathology, including reduced cross-sectional area of unmyelinated axons and constriction of the periaxonal space in myelinated fibers. The selective neuroprotective benefit of CsA and FK506, for myelinated but not unmyelinated axons, may reflect different levels of mitochondrial pathology, or calcineurin activity, in the two fiber types. The present findings, that fiber type strongly determines post-traumatic axonal pathology and treatment response, may have implications in the development of therapeutic interventions.

O46 Progressive Epidural Hematomas in Patients with Head Trauma: Incidence, Outcome, and Risk Factors.

Background: Progressive epidural hematoma (PEDH) after head injury is often observed on serial computed tomography (CT) scans, but its significance is uncertain. In this study, patients in whom two CT scans were obtained within 24 h of injury were analyzed to determine the incidence, risk factors, and mortality impact of PEDH.

Methods: The diagnosis of PEDH was determined by comparing the first and subsequent repeat CT scans. We prospectively reviewed 412 patients with head trauma to determine the incidence and timing of PEDH, and to evaluate the effects of demographics, admission Glasgow Coma Scale (GCS) score, the presence of coagulopathy, hypotension, skull fracture, and decompression craniotomy, and the timing of the first CT scan, on the development of PEDH after trauma. Multivariate logistic regression analysis was used to identify independent risk factors.

Results: PEDH was found in 9.22% of patients overall. The mortality rates were not significantly higher in patients with EDH than those without PEDH, when matched for admission GCS score. Decompressive craniotomy (OR 0.283, 95% CI 0.113,0.646), time from injury to first CT scan (OR 0.400, 95% CI 0.179,0.814), coagulopathy (OR 0.336, 95% CI 0.145,0.797), and hypotension (OR 0.357, 95% CI 0.164,0.792), were each independent predictors of PEDH.

Conclusions: Early progressive epidural hematoma occurs in almost 9.22% of head-injured patients who undergo CT scanning at least two times within the first 24 h of injury. Low systolic BP, the presence of coagulopathy, decompression craniotomy, and a shorter time interval between injury and the first CT scan appear to be key determinants of PEDH. PEDH has no significant impact on mortality and GOS score. Early repeated CT scanning is indicated in patients with non-surgically-treated hemorrhage revealed on the first CT scan.

O47 Serum Albumin and Retinol-Binding Protein Levels at 24 Hours After Trauma as Predictors of Outcome in Traumatic Brain Injury: Analysis of 138 Cases.

Background: Serum visceral proteins levels have long been associated with disease severity and outcome in various clinical settings, but not in traumatic brain injury (TBI). Recognizing its importance, we attempted to analyze the sensitivity of visceral proteins in reflecting stress state after TBI, and to establish a predictive model of outcome, by investigating serum prealbumin (PA), retinol-binding protein (RBP), albumin (ALB), and total protein (TP) levels, of patients with TBI.

Methods: The serum PA, RBP, ALB, and TP levels within 12 h post-injury were detected in 138 patients with acute TBI, and a comparative analysis combined with GCS scores was performed. The relationship to the prognosis was analyzed by multiple logistic regression analysis.

Results: Compared with the normal control group, the levels of serum visceral proteins were decreased significantly in patients with TBI (p < 0.01). The abnormal percentage of PA was 39.13%, RBP was 51.45%, ALB was 17.39%, and TP was 30.43%, and the abnormal levels were significantly lower than the normal range. The difference between such abnormal percentages was statistically significant (F = 37.683, p = 0.001). The levels of serum RBP, ALB, and TP in the severe injury group were significantly lower than those in the mild injury group (p < 0.05, p < 0.01, and p < 0.01, respectively). The logistic regression equation suggested that the levels of albumin and prealbumin seen within 12 h after injury correlated with prognosis, and that the lower the levels, the worse the prognosis.

Conclusions: Compared with traditional testing, ALB, PA, and RBP are more sensitive in reflecting the stress state caused by TBI as negative acute phase proteins.

O48 A Prospective Clinical Study of Routine Repeat Computed Tomography After Traumatic Brain Injury.

Background: Controversy over the need to perform routine repeat computed tomography (CT) scans on patients with traumatic brain injury (TBI) persists. Our aim was to discuss this issue and to identify the conditions under which this approach is necessary.

Methods: The sample, consisting of 103 patients who suffered TBI but were not surgically treated, was divided into two groups: the routine-repeat CT group (n = 53), and the non-routine-repeat CT group (n = 50). We compared patients with respect to age, score on the Glasgow Coma Scale (GCS) upon arrival at the emergency room, number of hours between the first CT scan and injury, blood coagulation function at admission, length of stay at the neurological intensive care unit (neuro-ICU-LOS), length of hospital stay (LOS), GCS score at discharge, and hospital charges. t-Tests and logistic regression analyses were used to analyze the relationships among factors. Patients in the routine-repeat CT group were divided into three groups according to GCS score to determine the need for routinely repeated CT scans.

Results: The results revealed statistically significant differences between the two groups in terms of neuro-ICU-LOS and LOS (p < 0.01). No significant differences emerged with respect to hospital charges and GCS scores at discharge (p > 0.05). The logistic regression analysis showed that age, fibrin degradation products (FDP), International Normalized Ratio (INR), and D-dimer concentration (DD), constituted risk factors for progressive hemorrhage (OR > 1, p < 0.05). Lower GCS scores, number of hours between the first CT scan and the injury (HCT1), and levels of platelet count (PLT), were associated with a greater likelihood of developing progressive hemorrhage.

Conclusion: In general, the routine-repeat CT group fared better than did the non-routine-repeat CT group. Routinely repeated CTs were minimally effective among those with mild TBI, whereas this procedure demonstrated a significant effect on patients with moderate and severe TBI.

O49 Endostatin is Increased in Cerebrospinal Fluid After Severe Traumatic Brain Injury.

Background: Cerebral ischemia and hypoxia are the most common secondary injuries following severe traumatic brain injury (TBI), and have a direct impact on the prognosis of the patients. Angiogenesis is an important pathophysiological response to trauma and ischemia, and is modulated by pro-angiogenic and anti-angiogenic factors. Increased expression of pro-angiogenic factors in blood has been detected in patients with TBI, but fewer studies have focused on the expression of anti-angiogenic factors after TBI. Recent experimental studies have suggested that endostatin (ES) might play an important role in the secondary brain injury and angiogenesis seen following TBI. The aim of this study was to explore the dynamic change of cerebrospinal fluid (CSF) endostatin in patients with severe TBI.

Methods: ES levels were measured serially for 1 week after hospitalization by using the enzyme-linked immunosorbent assay (ELISA) method in the CSF of 30 patients with severe TBI, and comparative analysis combined with GCS scores on admission and the short-term and long-term prognosis of the patients were performed. ROC curves were used to appraise the value of CSF ES levels in predicting the prognosis of patients with severe head injury.

Results: Compared with the normal control group, the CSF levels of ES in the patients with severe head injury were increased markedly on days 3, 5, and 7 post-trauma (CSF ES levels on days 5 and 7 after injury had predictive value in the short-term and long-term prognosis of patients with severe head injury). The best threshold values were ≥ 86.72 pg/mL and ≥ 67.29 pg/mL, respectively.

Conclusion: ES levels in CSF of patients with severe TBI increased markedly within 1 week after injury, and its dynamic change may have some effect on the classification of brain injury severity and the assessment of prognosis.

O50 The Research of Early Enteral Nutritional Support in Head Injury.

Background: Here we discuss the clinical characteristics and therapeutic effects of early enteral nutrition (EN) in the recovery from severe head injury.

Methods: Seventy-eight cases of severe head injury were randomly divided into a treatment group (n = 40) and a control group (n = 38).GCS score was used to assess the patient's condition. After a nasogastric (jejunal) tube was inserted within 24 h, nutritive fiber was started at 48 h after injury in the treatment group. The control group received conventional therapy. The levels of prealbumin, blood glucose, hemoglobin, and serum albumin, the lymphocyte count and nitrogen balance, and the incidence of complications and prognosis were assessed on days 7 and 14, and we compared the clinical and nutritional characteristics within and between groups.

Results: The nutrition of the patients in the treatment group was more significantly improved than that in the control group. The blood glucose of the patients in the treatment group was significantly lower than that in the control group. Lymphocyte count, serum protein, albumin, and nitrogen balance values were also all superior to those in the control group (p < 0.05). Arm muscle circumference and triceps skinfold thickness of the treatment group were significantly better than those in the control group (p < 0.05). In the treatment group, the nutritional parameters were superior to those in the control group, and complications were less common than those seen in the control group (p < 0.05). According to the Glasgow Outcome Scale and the Oxford Handicap Scale, their prognoses were markedly improved compared with controls (p < 0.05).

Conclusions: Early enteral nutritional support is imperative to the recovery of severe head-injured patients. Establishing standards of practice and nutritional protocols will assure that patients receive optimal nutrition assessment and intervention in a timely manner.

O51 Operative Strategy for Craniofacial Injury: An Experience with 2000 Cases.

Background: Our goal was to assess the operative strategies used in craniofacial injuries.

Methods: In all, 2000 cases of craniofacial injury were retrospectively reviewed, including clinical manifestations, CT scans, operative methods, results, complications, and follow-up results.

Results: The traumatic mechanisms of our 2000 cases included traffic accidents, falling, and fighting. Among these, 671 cases were transferred to our hospital from another hospital. At admission 109 cases complained of loss of sight on one side, 128 cases had otorrhea, and 397 cases had rhinorrhea. CT scans showed that 378 cases had intracranial hematomas (epidural hematomas in 200 cases, subdural hematomas in 197 cases, and intracerebral hematomas in 173 cases); 1485 cases had cranial vault fractures, 1543 cases had cranial base fractures, 1439 cases had orbital fractures, 467 cases had zygomatic fractures, 1165 cases had maxillary fractures, 741 cases had mandibular fractures, and 619 cases had nasoethmoid fractures. Cranio-orbital injury occurred in 375 cases, cranio-orbital-nasoethmoid injury in 461 cases, cranio-orbital-maxillary injury in 138 cases, cranio-maxillary injury in 743 cases, cranio-maxillary-mandiblular injury in 197 cases, and cranio-orbital-nasoethmoid-maxillary-mandibular injury in 84 cases. Of these, 1317 cases were treated by two-specialist cooperation, 599 cases received therapy that required three-specialist cooperation, and 84 cases received therapy that required four-specialist cooperation. Also, 1329 cases received one-stage surgery for their trauma, and 671 received two-stage surgery. Within 2 postoperative weeks, 34 cases had died, all resulting from severe cerebral damage. Also, 53 cases suffered infections requiring antibiotic therapy. The cause of the infections may be related to nasosinus injury; 51 cases showed CSF leakage, and among these, 41 cases were cured with conservative methods, and 12 cases required repeated debridement.

Conclusion: Operative procedures and the order of treatment of craniofacial injuries should be determined by various specialists. If the operation is planned in one stage, the neurosurgical operation should be undertaken first. Incorrect management of the nasosinus membrane is the main cause of postoperative infection.

O52 Wide Optic Nerve Canal Decompression for the Treatment of Blindness Resulting from an Indirect Optic Nerve Injury.

Background: We endeavored to investigate the efficacy of wide decompression of the optic canal for treating blindness resulting from an indirect optic nerve injury.

Methods: Forty-three patients with blindness resulting from an indirect optic nerve injury were retrospectively reviewed for preoperative vision, preoperative image, operative video, postoperative vision acuity, complications, and follow-up results.

Results: The 43 patients included 37 males and 6 females, with an age range from 15–41 years old (average 31.8 years). On preoperative examination, all patients presented with blindness in the involved eye. Six patients had an optic canal fracture. During the operation, a compression of the optic canal from a bony fragment was found in 1 patient, and an optic nerve sheath hematoma was found in another patient. After the operation, 6 patients developed CSF rhinorrhea, but recovered with conservative therapy. At the 6-month follow-up, vision was improved to 3/60 in 3 patients, 5 patients could count fingers, 3 patients could see hand motions, and 3 patients retained light perception in the afflicted eye. The vision in other patients remained non-perceptive to light.

Conclusion: Although the prognosis for blindness resulting from an indirect optic injury is poor, some patients have a chance to recover with sufficient decompression of the traumatized optic nerve. Poor results of this procedure may be related to the severity of the primary optic nerve injury.

O53 Mechanisms Underlying Cell Death After Brain Injury.

Traumatic brain injury (TBI) is a highly complex disorder characterized by multiple interacting cell death mechanisms, including apoptosis, necrosis, autophagy, and innate immune responses. The molecular regulators of these pathways are interconnected; numerous death stimuli are capable of activating multiple pathways, and several pathways share genes that are critical for their prospective execution. Here, we examined apoptosis, necrosis, autophagy, and inflammasome activation in rats subjected to moderate TBI via a parasagittal fluid-percussion brain insult. We show that caspases in both the intrinsic and extrinsic apoptotic pathways, and the tumor necrosis factor (TNF) ligand-receptor system, play essential roles in apoptosis after TBI. Moreover, excitotoxicity induced after TBI is linked to autophagy through protein interactions between NR2B signaling intermediates and the autophagic protein beclin 1 in membrane raft microdomains. Lastly, vigorous innate immune inflammatory responses initiated by TBI involve activation of inflammasomes, and the production of interleukin-1β, that contribute to secondary cell death. The complexity and diversity of the cell death mechanisms induced after TBI points to the development of neuroprotective strategies that target upstream regulators that modulate multiple injury mechanisms.

O54 A Novel Model of Traumatic Brain Injury that Shows Graded Brain Damage and Behavioral Deficits.

Background: Animal models of traumatic brain injury (TBI) are essential for testing novel hypotheses and therapeutic interventions. Unfortunately, no single model has been able to reproduce the entire spectrum of these injuries. Dominant models currently used by investigators to examine focal injuries include the closed head injury (CHI), fluid percussion injury (FPI), and controlled cortical impact (CCI) injury models. CHI is produced by weight-dropping, and induces obvious brain damage and functional deficits. However, the force used may cause skull fracture and high mortality. The CCI model utilizes a rigid, piston-like impactor to produce a graded TBI. Because of the softness of the brain tissue, tip plunge imitates a penetration brain injury, and does not cause diffuse brain deformation and distinct functional deficits. In this study, we combined advantages of both the CHI and CCI models, and developed a new model of TBI that produces graded brain injury and functional deficits in mice.

Methods: C57BL/6 mice (age 10 weeks, weight 20 g) were divided into four groups based on impact depth: sham, 0.5 mm, 1.0 mm, and 1.5 mm from the surface of the skull. A midline craniotomy (5-mm diameter) was performed extending 2 mm anteriorly and 3 mm posteriorly from the bregma, centered over the sagittal suture. The skull flap was left in place and stabilized with adhesive, allowing for direct impact of the exposed skull without producing fractures. A bilateral cortical impact on the surface of the skull flap was performed using an electromagnetic impactor (tip diameter 3 mm, speed 3 m/sec, and dwell time 50 msec). Following injury, the mice were subjected to a variety of cognitive and behavioral tests, and 4 weeks later they were sacrificed for histopathological examination.

Results: Our results showed that the injury significantly decreased the neuroscore and increased foot drops in a severity-dependent manner, suggesting that our TBI model can produce graded motor deficits. In addition, Morris water maze testing showed increased latency to locate the hidden platform in a severity-dependent manner, suggesting that our model can produce graded memory deficits. Furthermore, adhesive removal testing showed significant increases in time-to-contact and time-to-remove the adhesive tape from the paw in a severity-dependent manner, indicating graded somatosensory and motor deficits. Histological analysis showed a clear gradation in brain tissue damage following graded brain injuries.

Conclusion: These findings collectively suggest that the current model may offer a sensitive, reliable, and clinically relevant model for the assessment of therapeutic strategies for TBI.

O55 Traumatic Brain Injury in the Elderly: Experience in Tertiary Critical Care Center in Japan.

Background: The geriatric population is rapidly increasing in Japan, and treatment of traumatic brain injury (TBI) in the elderly has been a significant topic of discussion.

Methods: Elderly TBI patients aged 75 years or older who were admitted to our tertiary critical center between 2005 and 2009 were retrospectively reviewed. Their outcome was assessed by the Glasgow Outcome Scale (GOS) at 3 months.

Results: Fifty patients (25 men and 25 women) were aged 75 years or older (range 75–93 years; mean 80.8 years). They accounted for 11.6% of all TBI patients admitted during the same time period. The mechanism of injury was traffic accidents in 13 (9 were pedestrians), falls in 27, and unknown in 10 patients. Twenty-six of them had Glasgow Coma Scale scores of 8 or less, and 11 showed pupillary abnormalities (9 had anisocoria; 2 were bilaterally fixed and dilated). Their predominant CT findings were acute subdural hematoma in 38 (13 had pure subdural hematoma), cerebral contusion in 29, traumatic subarachnoid hemorrhage in 22, and acute epidural hematoma in 11 (duplicated lesions included). Most of them had chronic diseases: hypertension in 21, diabetes mellitus in 14, ischemic heart disease in 8, cerebral infarction in 6, dementia in 6, ventriculoperitoneal shunt in 5, and chronic renal failure with hemodialysis in 4 patients. Eighteen of were taking antiplatelet medications and one an anticoagulant. Twenty-seven patients underwent 43 neurosurgical operations: 26 craniotomies (including 7 decompressive craniectomies) and 5 burr-hole operations for hematoma evacuation, 3 contusion necrotomies, and 9 ICP had sensor placement. Their outcome was good recovery in 5, moderate disability in 10, severe disability in 23, and death in 2. Seventeen patients had a “talk and deteriorate” clinical course, and 6 of them died. Of 12 deaths, only 1 died of extracerebral complications.

Conclusion: Management of comorbidities is essential in the treatment of elderly TBI patients. Although they have worse mortality and functional outcome than non-elderly patients, early surgical intervention for pure subdural hematoma may be effective to minimize brain damage.

O56 Development of a Neurotrauma Unit in a Level I Apex Trauma Center in New Delhi.

The Jai Prakash Narain Apex Trauma Centre was conceptualized to cater to the increasing need to treat trauma in India, and it became fully functional in 2007. Neurotrauma services offered include a dedicated neurotrauma intensive care unit, routine intraparenchymal ICP monitoring, and mobile CT to care for head injury patients. The management of such cases begins with a trauma team posted in the emergency department trained in ATLS services, shifting patients to surgery/ICU within 30 min of arrival, and efficient management of hypotension/hypoxia to help prevent secondary brain injury. All severe head injury patients undergo routine intraparenchymal ICP monitoring, and undergo surgical intervention if ICP is > 20 mm Hg for over 1 h, regardless of CT findings, as we have noted a late rise in ICP, even with normal a CT scan, and confirm intracranial hypertension with intraoperative findings. An average of four mobile CT scans per patient are done in the neurotrauma ICU, around the clock. Average scan time is 12.3 min, and the scans can be seen on consoles from anywhere in hospital, thus increasing the comfort level of the surgeon, and expediting decision making in these critically-injured patients with altered cerebral hemodynamics. Mobile CT is especially useful in patients who are on hemodynamic support and ventilators. The mortality rate for severe head injury in our center was reduced from 40% to 22%, with the institution of ICU protocols, ICP monitoring, and the use of dedicated neurointensivists. We encourage prophylactic early percutaneous tracheostomies and percutaneous gastro/jejunostomy in severe cases.

Conclusions: We believe a neuroICU is different from a general ICU, and that it needs dedicated neurointensivists, critical care physicians, and rigorous protocols for better outcomes. The mobile CT scanner is an indispensable tool in the modern era for the management of head injury patients in a busy trauma center.

O57 Age-Related Differential Apoptotic Response After Traumatic Brain Injury.

Background: Apoptotic cell death plays an important role, contributing to the secondary insults seen following traumatic brain injury (TBI). This study investigated the level of apoptosis and the temporal and spatial changes of proteins that are related to apoptosis, with particular interest in the changes seen following aging and TBI in the dentate gyrus of the hippocampus.

Methods: Male Sprague-Dawley rats aged 28 days (juvenile) and 22 months (aged) were used. Animals were subjected to a moderate lateral fluid percussive injury and sacrificed at 2 days post-injury. For proteomic study, one group of injured rats and age-matched sham animals were perfused with ice-cold PBS, and the ipsilateral dentate gyrus was dissected and homogenized, followed by 2D gel and mass spectrographic analysis. For TUNEL and immunofluorescence staining, another group of rats was perfused and the brains were dissected and snap frozen. Coronal brain sections were sliced with a cryostat and processed for TUNEL staining and immunofluorescence double and triple labeling to identify cell types undergoing apoptosis.

Results: Proteomic studies have revealed normal aging and TBI-related changes of three apoptotic-related proteins, including hippocalcin (P23k), acidic nuclear phosphoprotein pp32 (LANP), and heat-shock protein 27 (Hsp27). Coupled with the changes in the levels of these apoptotic proteins, we also found age- and injury-related TUNEL-labeling changes in the dentate gyrus. We found that in sham animals, juvenile animals had more TUNEL-labeled apoptotic cells compared to aged brains, with the majority of these cells located in the subgranular zone of the dentate gyrus. The apoptotic cells expressed early neuronal marker PSA-NCAM, indicating that they were newly-generated immature neurons. In contrast, in the injured animals, compared to juveniles, aged rats had much higher numbers of TUNEL-labeled cells, located mostly in the granular cell layer, that were NeuN-labeled mature neurons. Fluorescence triple labeling revealed that many apoptotic cells were engulfed by microglial cells.

Conclusion: Taken together, our results revealed differential apoptotic cell responses following aging and TBI, and this may contribute to the differential cognitive recovery observed in the two age groups.

Supported by NS055086.

O58 Experimental Studies of Transplantation of Human Amnion Membrane Mesenchymal Stem Cells for Cerebral Ischemia-Reperfusion Injury in Rats.

Background: An established mouse ischemia-reperfusion model was used to assess the actions and related mechanisms of cerebral ischemia injuries via different pathways of transplanting hAMSCs.

Methods: Using a modified suture method, the rat models of middle cerebral artery occlusion-reperfusion were established. hAMSCs were transplanted by ventriculus lateralis cerebri and tail vein after 24 h of cerebral ischemia. Neurological Severity Score (NSS) was evaluated at 1 week and 4 weeks after cerebral ischemia. Immunofluorescence studies were carried out for detecting expression of BrdU-positive cells. The volume of cerebral infarction was assessed 1 week after cerebral ischemia. The results were evaluated for the different transplanted pathways.

Results: hAMSCs transplanted via different pathways promote local survival and differentiation that greatly improve animal nerve function. The results showed that the transplanting pathway from the ventriculus lateralis cerebri has better effects than from tail vein.

Conclusion: hAMSCs effectively promote animal nerve function.

O59 Detection of Cerebrovascular Autoregulation in Patients After Traumatic Brain Injury.

Background: We investigated the state of cerebrovascular autoregulation (CA) in patients with craniocerebral trauma, as well as its clinical significance.

Methods: CA was studied within 24 h and on day 6 in 22 patients after craniocerebral trauma, using transcranial doppler combined with a carotid compression test.

Results: Impaired CA was demonstrated in 13 (81.3%) of 16 patients with severe head injury within 24 h, which positively correlated with prognosis, while 2 (33.3%) of 6 cases had moderate craniocerebral trauma. The state of CA varies with time after injury, and was restored after 6 days.

Conclusions: Assessing the state of CA reveals the compensatory capacity of cerebral tissue after craniocerebral trauma, which provides guidance for clinical treatment and prognosis.

O60 Minocycline Does Not Affect Neurogenesis, But Improves Neurological Outcome Following Focal Traumatic Brain Injury in Mice.

Background: Neurogenesis is stimulated following brain injury, and potentially contributes to tissue repair; however, this response may be limited by elevated levels of inflammatory cytokines produced by reactive microglia. Therefore, we investigated whether treatment with the anti-inflammatory drug minocycline could attenuate accumulation of reactive phagocytic microglia, enhance specific stages of neurogenesis, and improve neurological outcomes in a closed head injury (CHI) model of focal traumatic brain injury (TBI).

Methods: Adult C57BL/6 mice were subjected to: CHI + minocycline (day 1: 45 mg/kg, days 2–7 or 2–14: 22.5 mg/kg IP twice/day); CHI + vehicle; and sham-operated + vehicle controls. BrdU (days 1–4: 200 mg/kg IP) was administered to label proliferating cells. Neurological outcome was assessed using the Neurological Severity Score (NSS), and a ledged beam task was done at multiple time points for up to 6 weeks. Brains were collected at 1 and 6 weeks (n = 6–7). BrdU- and DCX-immunolabeled cells were quantified in the dentate gyrus (DG) and subventricular zone (SVZ), to assess cell proliferation/survival and neuronal differentiation, respectively. Neuronal and glial maturation/survival at 6 weeks in the DG and pericontusional cortex was determined by BrdU co-labeling with NeuN and GFAP.

Results: Minocycline reduced neurological dysfunction from 24 h to 6 weeks following trauma (p < 0.05 versus vehicle controls), and tended to decrease F4/80 + microglia at 1 week (p = 0.083). BrdU-labeled and Dcx-labeled cells were increased in the SVZ and DG of traumatized mice at 1 and 6 weeks compared to shams (p < 0.05). Also, the percentages of new neurons and astrocytes at 6 weeks post-injury were no different with minocycline treatment (p > 0.05).

Conclusion: This study demonstrates that minocycline does not affect precursor proliferation, neuronal differentiation, or new cell survival after experimental TBI. However, minocycline treatment was associated with improved neurological outcome, which may be due to its anti-inflammatory actions.

O61 The Temporal Profiles in Serum Concentrations of the Biomarker S100B in the First 48 Hours After Traumatic Brain Injury Correspond to Outcome

Background: Traumatic brain injury (TBI) is one of the leading causes of death and disability. An early and accurate assessment of the affected patient suffering from TBI is important to promptly decide upon treatment strategies. Serum levels of the protein S100B are elevated in patients suffering from TBI, and has been proposed as a good addition to other clinical variables when calculating outcome. Different temporal patterns of the serum levels of S100B have been shown. The aim of this study was to analyze the different patterns, with a focus on outcome and other factors related to co-morbidity in patients suffering from TBI.

Methods: In all, 265 patients suffering from TBI admitted to the neuro-intensive care unit, having three consecutive serum samples of S100B within the first 72 h after trauma were included.

Results: S100B AUC, S100 peak serum level, and increasing serum levels of S100B significantly presence of traumatic subarachnoid hemorrhage, early cerebral ischemia and signs of increasing intracranial hematomas are statistically significant (p < 0.05) to high and increasing levels of S100B. Using a multi-nomial logit regression analysis, increased age (p < 0.01), early cerebral ischemia (p < 0.05), and increased S100B AUC statistically significantly affected mortality (p < 0.01)

Conclusion: The temporal profile of S100B is unique for every patient after TBI, and statistically correlates with S100B AUC, one of the factors that correlates strongly with mortality and morbidity, and thereby may promptly provide the physician with an important tool in clinical decision-making.

O62 Management of Pediatric Head Injuries in Australia and New Zealand: Triggers for Head CT Scans in a Survey of Senior Physicians.

Background: Multicenter clinical decision rules (CDR) for children with head injuries have been developed, in particular the Canadian Assessment of Tomography for Childhood Head Injury rule (CATCH), the Children's Head Injury Algorithm for the Prediction of Important Clinical Events (CHALICE), and the Prediction Rule for Clinically-Important Traumatic Brain Injury by the Pediatric Emergency Care Applied Research Network (PECARN). Prior to national implementation of one of these CDRs, we set out to determine the current CT head triggers after head injuries as reported by senior pediatric emergency department (PED) physicians in Australia and New Zealand.

Methods: An anonymous piloted survey was distributed to PED physicians at PREDICT sites in Australia and New Zealand. Based on standardized scenarios we elicited history- and examination-based triggers for head CTs for head injuries. These were compared with the recommendations in the CATCH, CHALICE, and PECARN CDRs. Clinical practice guidelines (CPGs) from each site were also reviewed.

Results: Surveys were collected in December, 2010, with a response rate of 93% (130/140). No indication for head CT was identified by 100% of survey participants, and each CDR included several indications not supported by many respondents. Approximately 10% of participants identified the following published indications by patient history: GCS score of 14, more than one episode of emesis, fall greater than 3 feet or 5 stairs, definite amnesia, or any loss of consciousness. Examination findings of depressed skull fracture, skull-base fracture, or focal neurology were triggers for CTs for > 90% of respondents. Prolonged loss of consciousness, abnormal behavior, and amnesia were CT triggers for only ∼ 50% of participants. Eighty percent of respondents thought that indications for head CT in younger children were different, specifically regarding behavior change, GCS, and fontanelle assessment. Eight different CPGs for head injury care were used at the 13 PREDICT sites; 77% included indications for head CT, but were highly variable between sites, and CPGs were not explicitly based on published CDRs.

Conclusions: There is marked variation in the management of pediatric head injuries as reported by ED physicians in Australia and New Zealand, and when compared to published CDRs from Europe and North America. These findings reflect the complex nature of decision making surrounding head CT use in children. Ideally, the major published head injury CDRs should be prospectively validated in the Australasian setting.

O63 Guideline-Based Management of Severe Head Injury in Japan.

In the era of EBM and guidelines, several guidelines for the management of severe head injury were developed in United States and European countries. The aim of this study was to introduce the Japanese guidelines and compare them with the guidelines used in other countries. The Japanese guidelines for the management of severe head injury were developed in 2000 by the Task Force of the Japan Society of Neurotraumatology, based on a combination of committee consensus and critical literature review of the publications over the past 10 years. The Japanese guidelines updated in 2006 were intended to be more practical recommendations, also focusing on topics not addressed in the U.S. guidelines, such as operative indications and methods, and management of craniofacial injuries and pediatric and geriatric head injury patients. The scale of recommendations used in these guidelines were: (1) be appropriate, (2) be often to do, (3) tend to do, (4) may be done, (5) be desirable, and (6) be not recommended. In the Japanese guidelines, the majority of literature was categorized as class II or III, and the indications for ICP monitoring and the ICP treatment threshold are appropriate to the level of the grade of the recommendation. The actual recommendations in Japanese guidelines are quite similar to those of Western countries. Reports on the application of these guidelines indicate their positive effect on the results of the management of severe head injury. The value of the Japanese guidelines lies in widespread use, not only in university hospitals, but also in smaller general hospitals, for the basic management of head injury. The Japanese guideline-based management of patients with severe head injury promotes quality care and improves outcomes following head injury in Japan. The third revised edition will be published in 2011.

O64 A New Tracheal Cannula Used in Severe Craniocerebral Injury.

Abstract Not Available

O65 A Combined Clinical and MRI Approach for Outcome Prediction in Mild Traumatic Brain Injury Patients with Negative CT Scans.

Background: The purpose of this study was to predict outcome at 6 months for mild traumatic brain injury (mTBI) patients with negative head computed tomography (CT) scans, by combining clinical and magnetic resonance imaging (MRI) findings.

Methods: We included 800 mTBI patients treated between June 2007 and June 2010 in a neurosurgical intensive care unit in Tai-zhou, China, that underwent an MRI scan of the brain using T1, T2, and FLAIR sequences in 15.12% (65) of 430 patients with negative head CT scans. Outcome was assessed at 6 months post-trauma using the Glasgow Outcome Scale-Extended (GOSE), divided into unfavorable (GOSE score 1–6) and favorable (GOSE score 7–8) outcome groups. The predictive value of several variables was determined using Fisher's exact test. Symptom assessment was done using the Rivermead Post-Concussion Questionnaire (RPQ), which was performed at 1 week post-trauma. To compare the RPQ scores between the MRI-negative group (n = 45) and the MRI-positive group (n = 23), a Wilcoxon rank statistic was used.

Results: At follow-up, of 65 patients who underwent an MRI scan of the brain, 16 (24.62%) had an unfavorable outcome, but surgical intervention was not required for all patients. Extracranial injuries, skull fractures, the location of the force, alcohol intoxication, and positive MRI findings were associated with an unfavorable outcome. Furthermore, the total number of lesions, frontal lobe lesions, and lesions exceeding 1 cm in diameter, were important predictors of the poor outcome in terms of positive MRI findings. In addition, the RPQ scores were significantly higher in the MRI-positive group than in the MRI-negative group.

Conclusions: These data suggest that MRI associated with clinical assessment improves outcome prediction in mTBI patients with negative head CT scans. Complete RPQ scores should be done acutely in mTBI patients with a negative head CT scan to determine whether to require further MRI, particularly if symptoms and signs become more severe.

O66 The Supratentorial Approach to Posterior Fossa Epidural Hematoma.

Background: Posterior fossa epidural hematoma (PFEDH) is a rare entity with a higher mortality than its supratentorial counterparts. Prompt surgical evacuation provides an excellent chance of recovery. Previous surgical approaches involved a wide unilateral or bilateral suboccipital craniectomy, which required relatively large craniotomies and resulted in skull defects. The improvements seen in surgical techniques and diagnostic imaging, as well as the introduction of new surgical instruments, enable us to treat PFEDH through a supratentorial approach. In the present study, we conducted a retrospective study of 23 PFEDH patients treated using a supratentorial approach, and focused on the technical aspects, indications, and effects of this approach.

Methods: Twenty-three patients presenting with PFEDH at West China Hospital between January 2006 and August 2009 that were treated with supratentorial approach were included in this study. The hospital records of these patients were analyzed retrospectively.

Results: In all 23 patients treated with surgery, no patients died, and no residual hematomas were found after operation. During the follow-up of 6 months, all 23 patients had excellent recovery. The length of the surgical procedure was significantly reduced compared to standard techniques.

Conclusion: Supratentorial approach craniectomy can evacuate a PFEDH excellently, and achieves the purpose of minimally-invasive surgery with good results.

O67 Spinal Cord Injury and Neuroinflammation.

Abstract Not Available

O68 Effects of Progesterone on Behavioral Outcome Following Diffuse Axonal Injury in Rats.

Background: The aim of this study was to investigate the effect of progesterone on spatial learning ability and behavior in DAI rat models, and to attempt to examine the underlying mechanisms.

Methods: An impact acceleration method was used to establish DAI in a Wistar rat model (Marmarou's model). Animals were randomly assigned to one of three groups (n = 10/group): sham (SHAM) controls, vehicle (DAI + DMSO), and progesterone (DAI + PROG). The PROG group received 16 mg/kg PROG. The initial IP injection was at 1 h post-injury, followed by subcutaneous injections at 6 h, 24 h, and every day after injury for 5 consecutive days. Modified Neurological Severity Score (mNSS) was performed from day 1 post-injury to assay the rats' behavior and continued for 7 days. From day 14 post-injury, Morris water maze (MWM) testing was used to assess the rats' spatial learning ability for another 5 days. On day 20 post-injury, the rats were subjected to long-term potentiation (LTP) recording in the hippocampus to measure the percentage of slope and baseline of excitatory post-synaptic potentials (EPSP). In addition, serial magnetic resonance imaging scanning and hematoxylin and eosin staining (H&E) was conducted to examine the brain lesions at 24 h, and 7, 14, and 20 days post-injury. Immunohistochemical staining (IHC) with the primary antibody of beta-amyloid precursor protein was implemented to confirm the DAI model.

Results: The rats in the DAI + DMSO group displayed significantly longer escape latency than those in the DAI + PROG and SHAM operation groups (both p < 0.05). The target quadrant staying time percentage and number of platform location crossings of the DAI + DMSO group were significantly less than those of the DAI + PROG and SHAM groups (both p < 0.05). An increase in mNSS scores was observed after the initial injury, while there was a significant improvement after progesterone administration compared to the DAI + DMSO group (p < 0.05). The LTP level of the DAI + DMSO group was lower than that of the DAI + PROG and SHAM groups (both p < 0.05). No significant differences in the other parameters were found between the DAI + PROG and SHAM groups.

Conclusion: Marmarou's DAI model is successfully established, with a significant impairment in the rats' spatial learning ability, behavior, and electrophysiological parameters. The short-term application of progesterone significantly ameliorates the injury-related symptoms, and induces recuperation of synaptic plasticity in the hippocampal area.

O69 Treatment of Traumatic Vertebral Arteriovenous Fistulas with Cross-Over Technique.

Abstract Not Available

O70 Small Applied Electric Fields Guide Human Neural Stem Cell Migration in Vitro.

Background: Electric stimulation has recently been recognized as a powerful mechanism to guide cell migration during wound healing, regeneration, and development. Effectively directed migration of human neural stem cells (h-NSCs) is critical for normal development and wound healing in the human central nervous system (CNS). Here, we aimed to characterize h-NSC migration in small applied electric fields (EFs) in vitro.

Methods: We derived h-NSCs from human embryonic stem cells (h-ESCs) and maintained their phenotype. EF-directed migration of h-NSCs was investigated with a time-lapse imaging system.

Results: Without EFs, h-NSCs displayed random migration. With EFs (field strength: 16, 50, 100, and 300 mV/mm), the cells showed electrotaxis towards the cathode. With increasing field strength the migration directedness and distance to the cathode were significantly increased. Additionally, the track speed of h-NSCs was accelerated in an EF of 300 mV/mm. We conclude that h-NSCs demonstrate a robust electrotaxis towards the cathode.

Conclusion: Applied EFs could be a novel and effective cue to guide h-NSCs to sites of CNS injury, and may contribute to improved therapies for CNS repair.

Supported by California Institute of Regenerative Medicine (RB1-01417).

O71 Decompressive Craniectomy for Traumatic Brain Injury.

Background: The goal of this study was to evaluate the outcome of TBI with decompressive craniectomy.

Methods: This was a prospective study of 165 victims of TBI who had undergone decompressive craniectomy between 2000 and 2010. There were 19 children, and the youngest patient was 6 years old. ICP monitoring was done in only 108 cases. Patients with dilated pupils had undergone emergency decompressive craniectomy. The most common CT scan feature was compressed lateral vent. Post-operative CT was done on days 1, 3, and 5 to assess the progress. Twenty-five patients had undergone surgery within 24 h of hospitalization. The ICP in these patients was not measured before performing decompressive craniectomy. A late decompressive craniectomy (i.e., after 24 h and within 6 days) was performed in 140 patients with ICP > 35 mm Hg, or a unilateral or bilateral absence of pupillary reflexes, besides abnormalities on CT scan. Large decompressive craniectomy (>12 cm in diameter) was done in all cases with opening of the dura. Duraplasty was done in 111 cases. Bifrontal craniectomy was done in 90 patients with massive global swelling. Cranioplasty was done 6–20 weeks later.

Results: Twenty-six percent had good outcomes. Five patients could resume their former occupations and another 11 had to change jobs. Mild deficits were seen in 17 patients, and 21% remained in a vegetative state. Overall 53% patients died. Those with young age and early surgery had better outcomes. Children with severe head injury presenting with decorticate posturing and treated by unilateral decompressive craniectomy showed good recovery; 15.8% needed reoperation, and all of them had hemicraniectomy for mass lesions such as development of contusion/brain swelling with herniation. Hemorrhagic contusion expansion was observed in 40%. Subdural hygromas developed early after decompressive surgery. Twenty patients needed a ventriculoperitoneal shunt for hydrocephalus, and 1 patient presented with brain abscess 53 days after the operation. The progress of one patient is illustrated.

Conclusion: Decompressive craniectomy needs to be individualized. Young age and early surgery are useful predictors of better outcome. It is important to recognize that poor neurological status on presentation does not always indicate irreversible brain damage. Judicious use of decompressive craniectomy combined with neuro-intensive care offers the potential to save lives with acceptable functional outcomes.

O72 Fracture of the Carotid Artery Canal: Report of Two Cases.

Background: Fracture of the carotid artery canal is a rare type of basal fracture. In most conditions, the lowest slices of CT scans often are above the level of the carotid canal, so fracture of the carotid artery canal may not be seen. Therefore we rarely make the diagnosis of carotid canal fracture, and know little about the clinical manifestations and therapy for it. We present imaging and clinical features in 2 patients with fracture of the carotid artery canal.

Methods: Two cases that had tardive massive cerebral infarction after severe head injury were studied with CT scans and clinical features. We analyzed the imaging findings, with attention paid to the reason for the massive cerebral infarction. In addition, we analyzed all the therapeutic procedures for each patient.

Results: In both patients, the fracture of the carotid artery canal was located on the right side. The massive cerebral infarction happened after the operation, and by chance on the right side. DSA was performed in one patient. We did not find any obstruction of the main artery, and only some tiny arteries were seen on DSA. Both of them were managed with vasodilators, but this was in vain. One died of failure of the brainstem, and the other died in the bleeding of reperfusion.

Conclusions: Fracture of the carotid artery canal can be diagnosed via CT scan. However, it is unsure whether the fracture of the carotid artery canal induces massive cerebral infarction. It is certain that as a complication of fracture of the carotid artery canal, massive cerebral infarction may occur. More attention and better therapeutic measures should be given to fractures of the carotid artery canal.

O73 Guiding Neuronal Migration and Nerve Growth Electrically.

Exogenously applied electric stimulation regulates neurite growth and neuronal migration. Electrical stimulation, with either AC or DC fields, may regulate the cell cycle, division, and migration of many types of cells. We report that small applied electric fields (EFs) affect polarization, neurite growth, and migration of NSCs. EFs guide migration of neurons, neuronal stem/progenitor cells (NSCs), and stem cells toward the cathode. Several signaling pathways that may be involved in EF-guided behaviors have been identified. Injury to the peripheral nerves and central nervous system induce endogenous EFs. Exploiting the existence of the endogenous EFs and application of EFs may be a useful approach in guiding neurite growth, migration of NSCs, and may help repair damaged nerve tissues.

O74 Clinical Studies of the Utility of Serum Biomarkers for the Diagnosis, Prognosis, and Management of Traumatic Brain inJury.

Background: While traumatic brain injury (TBI) is a major challenge for civilian and military medicine, there are no simple, non-invasive tests approved by the FDA for diagnosis of acute central nervous system injury. These injuries can occur in civilian medical populations presenting to emergency rooms, and those exposed to sports concussions. In combat environments, blast explosion-associated overpressure can also cause brain injury (OBI) that could be pathologically distinct from civilian TBI and sports concussion. Banyan has initiated clinical studies in civilian TBI in emergency rooms and sports concussion settings. In addition, we have ongoing studies of markers of blast-related TBI in military personnel exposed to repeated low-level blasts during training.

Methods: We have conducted Pilot and Feasibility Studies of mild, moderate, and severe TBI to examine the relationships between our lead biomarker candidates (UCH-L1 and GFAP) and measures of acute injury magnitude (GCS and CTMRI) and outcome, including GOS-E and neuropsychological measures. These studies are being conducted in preparation for initiation of a Pivotal Trial in 2011 to seek FDA approval of biomarkers for acute diagnosis of TBI. Feasibility studies are also examining the potential utility of other biomarkers, including alpha-spectrin breakdown products (SBDPs) and markers of dendritic and synaptic damage. Separate clinical research studies are examining the potential utility of candidate biomarkers to detect OBI experienced by special forces breachers exposed to blast during training. Biomarker levels were determined by ELISAs of serum samples taken at various times after exposure to TBI or OBI.

Results: Pilot and preliminary studies indicate that UCH-L1 and GFAP are sensitive and specific biomarkers of the magnitude of acute TBI. Other studies indicate that serum-based biomarkers such as GFAP, UCH-L1, and SBDPs can improve outcome prediction following TBI. Plans for the upcoming pilot trial for FDA approval of biomarkers will also be reviewed. Data will be presented on planned studies of biomarkers of sports concussion. Data presented separately by Dr. Wang in the Phase I Breachers Study demonstrate that UCH-L1, GFAP, and SBDP-150 are correlated with post-exposure neurologic symptoms and automated neuropsychological assessments.

Conclusion: Extensive pilot and feasibility clinical studies have provided strong evidence that UCH-L1, GFAP, and other biomarkers, can be sensitive and specific biomarkers of acute injury and predictors of outcome. Biomarkers could also have promise for the diagnosis of OBI and sports concussion.

O75 Diverse Vascular Responses to Experimental Traumatic Brain Injury: Evidence for Traumatic Brain Injury Model-Linked Variation.

Background: At present, there are multiple models used to study traumatic brain injury (TBI). Currently, most assume that all these models generate similar injury to the brain and its vasculature, with the result that the observations made in these models are often lumped together for interpretation and discussion in the scientific community.

Methods: To explore the potential that two similar injury models can elicit different vascular responses, male adult Sprague-Dawley rats were anesthetized with sodium pentobarbital and subjected to either impact acceleration injury (IAI) or lateral fluid percussion brain injury (LFPI). These animals were equipped with cranial windows for evaluation of pial arteriolar reactivity to known vasodilators.

Results: If untreated, both IAI and LFPI caused sustained cerebral vascular abnormalities. If treated with delayed hypothermia for a duration of 1 h, there was partial protection in animals subjected to IAI, with little or no protection seen in the LFPI model. In terms of autoregulation, the regulatory ability of pial arterioles was compromised in animals subjected to IAI, but they were completely paralyzed following LFPI. In chronic experiments, cerebral vascular function in untreated animals following LFPI remained impaired up to 6 weeks of survival. In contrast, untreated animals following IAI spontaneously recovered over 6 weeks. Equally important, differences in vascular protection were noted regarding the route of drug administration (i.e., systemic [IV or IP] versus topical application) in these models.

Conclusion: Findings from this study clearly demonstrate that LFPI consistently delivered more severe damage to the cerebral vasculature than that occurring with IAI. In view of other variables, such as age and gender, the results of this investigation suggest that findings from different injury models cannot be lumped together and discussed interchangeably without appropriate consideration.

O76 Evidence for Neuronal Atrophy as Well as Cell Death Following Diffuse Brain Injury.

Background: Our understanding of the neuronal somatic response to traumatic injury is limited. To date, most information has been derived from those neuronal changes observed in contusional and pericontusional domains, which are of limited relevance to abnormalities induced by diffuse injury. In this presentation, we review the potential for neuronal perturbation in response to diffuse brain injury involving axotomy and/or primary neuronal somatic injury.

Methods: Adult mice, rats, and micropigs were subjected to mild to moderate central fluid percussion brain injury, which produced diffuse axonal injury (DAI) without contusion. The animals were followed from days to months post-injury, when they were processed for the qualitative and quantitative assessment of neuronal somatic perturbation via the use of multiple bioimaging approaches. YFP-H mice were used to assess the burden of DAI and its implications for the related neuronal somata. In rats and micropigs, similar assessments were performed, employing antibodies targeting β-APP, as well as other markers of axonal and neuronal somatic injury. Additionally, in the injured rats, small-molecular-weight extracellular tracers were used to assess the potential for injury-induced mechanoporation and neuronal injury/death.

Results: Through these approaches, we routinely observed that DAI did not result in neuronal cell death. Rather, in all cases, DAI led to neuronal atrophy that persisted over 1 month post-injury. Such atrophic changes were best visualized in YFP-expressing transgenic mice, in which the axotomized neurons could be readily followed over time. However, despite the overall utility of YFP expression, the parallel use of various antibodies targeting axon perturbation (APP) yielded similar results in the injured rats and micropigs. While DAI-related atrophy predominated with mild injury, moderate injury also resulted in the scattered poration of non-axotomized neurons, which over time revealed a progression to either necrotic or autophagic cell death.

Conclusion: These findings generated from multiple species subjected to diffuse brain injury clearly illustrate that the resulting DAI does not lead to neuronal death. Rather, such axotomy consistently sets the stage for atrophy that may lead to neuronal recovery. Further, with more moderate injury, scattered non-axotomized neurons reveal poration of their cell membranes that can trigger cell death. Collectively these findings illustrate the diversity and complexity of the neuronal responses to diffuse injury, while suggesting that their potential therapeutic modulation will present multiple challenges.

O77 Neuroproteomics and Systems Biology-Based Protein Biomarker Discovery and Validation for Traumatic and Blast Brain Injury.

Background: Traumatic brain injury (TBI) is a major problem in civilian and military medicine. Yet there are no simple non-invasive diagnostics for acute brain injury. In combat environments, blast explosion-associated overpressure also causes brain injury (OBI) that could have pathology that is distinct from traditional TBI. Our goal is to use a proteomics and systems biology platform to discover and then validate novel biofluid-based biomarker assays for the diagnosis, prognosis, and management of TBI and OBI patients.

Methods: oth a rat model of TBI (controlled cortical impact) and a novel rat model of OBI (overpressure wave-induced brain injury) were employed. Injured brain tissues (versus controls) were subjected to a cation ion exchange-polyacrylamide gel electrophoresis (CAX-APGE)/tandem mass spectrometry differential proteomics platform to identify differentially expressed protein markers. Systems biology analysis will then be applied to assist biomarker analysis and selection. Top candidate biomarkers were first validated by immunoassays in animal models. This was followed by validation in human TBI and OBI patients.

Results: Rat TBI models and OBI models, respectively, generated over 62 and 113 candidate biomarkers that were up- or downregulated. These candidates were subjected to systems biology analysis, which identified converging hot spots and neuro-pathways that are associated with TBI and OBI. A number of top candidate biomarkers (e.g., UCH-L1, GFAP, SBDPs, MAP2, and CNPase) are first validated by immunoblotting or ELISA using biofluids (CSF and blood) from the animal models. This is followed by validation in human TBI and OBI. For TBI, we employed severe, moderate, and mild TBI patients, versus normal and CSF controls. Thus far, UCH-L1, GFAP, SBDPs, and MAP2 show strong promise as diagnostic biomarkers for TBI. For OBI, we are studying breacher trainees who are subjected to controlled explosions during their 2-week training program. Data obtained from our Phase I breacher study showed that the biomarkers UCH-L1, GFAP, and SBDP150 are correlated with post-exposure neurological symptomatology and Automated Neuropsychological Assessment Metrics (ANAM) results.

Conclusion: Proteomic and systems biology platforms are suitable tools to discover and select novel protein biomarker candidates for both TBI and blast overpressure brain injury. Such biomarkers should show brain specificity and must be validatable in both animal models and ultimately human subjects suffering from TBI or OBI.

O78 Advanced MRI Detection of Blast-Related Traumatic Brain Injury.

Blast-related traumatic brain injury (TBI) is a common injury sustained by U.S. military personnel in Iraq and Afghanistan. The majority of blast-related TBI is mild or concussive, without detectible intracranial pathology on CT or conventional MRI. We hypothesized that traumatic axonal injury, not detected on conventional neuroimaging, is a primary pathophysiological process underlying blast-related TBI. To test this hypothesis, we used an advanced MRI method called diffusion tensor imaging (DTI), which is more sensitive to traumatic axonal injury than conventional MRI. We enrolled a cross-sectional cohort of 63 active-duty U.S. military personnel who presented to Landstuhl Regional Medical Center (LRMC) with signs and/or symptoms of blast-related TBI. Controls were 21 U.S. military personnel presenting to LRMC with blast exposure and other injuries. All subjects were scanned at LRMC in the first 90 days after injury. In individual subject analyses, 17 of the 63 TBI patients (27%) had clear evidence of white matter abnormalities on DTI that were consistent with traumatic axonal injury. Specifically, relative anisotropy, a DTI marker of brain white matter integrity, was reduced in two or more brain regions in each of these 17 subjects. Reductions were defined as at least 2 standard deviations below the mean of the 21 control subjects. By chance, no more than 1 of 63 normal subjects would be expected to have two or more such reductions in nine independent regions. This may be useful in assisting triage decisions, improving diagnostic accuracy, and aiding therapeutic development.

O79 Retrospective Analysis of Risk Factors for Outcome in Traumatic Brain Injury with Multiple Injuries

Background: Patients with traumatic brain injury (TBI) with multiple injuries have a worse outcome than those with isolated TBI. The contribution of different body parts and their degree of injury to this increased mortality is unknown, and the situation is confounded by the presence of complications. The purpose of this study was to investigate the role of seven separate risk factors to the mortality and early outcome from isolated TBI.

Methods: In all, 2465 patients were enrolled in the study over a period of 3 years 5 months, and 41.62% were defined as TBI with multiple injuries. Two categories of risk factors were defined: factors such as gender and age at trauma, and factors such as different body parts and degree of injury. Glasgow Outcome Scale scores at discharge, therapy, and complications were compared for TBI with multiple injuries and isolated TBI.

Results: The mortality for those with TBI with multiple injuries was almost twice that of their isolated TBI counterparts (11.31% versus 5.28%, p < 0.01), even for those with mild to moderate TBI (Glasgow Coma Scale score 9–15). Among the survivors of multiple injuries, more patients had a poor functional outcome (Glasgow Outcome Scale score of 2 or 3) at hospital discharge than the isolated group (p < 0.01). Risk factors associated with high mortality were Glasgow Coma Scale score, age, and degree of injury to lung (regression coefficients were 1.728, 0.762, and 0.746, respectively; p < 0.01).

Conclusion: The mortality of TBI is higher in TBI with multiple injuries than that of isolated TBI. Although complications or type of head injury may partly account for this increased mortality, Glasgow Coma Scale score, age, and degree of injury to lung are important risk factors leading to the high mortality seen in TBI with multiple injuries.

O80 Quantitative Correlation of Brain Strain with Traumatic Axonal Injury Using a Combined Computer and Experimental Model of Rat Head-Impact Acceleration-Induced Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) is caused by local tissue deformation at the time of trauma, leading to neurological dysfunction. Finite element (FE) modeling of TBI is an effective approach to quantify the local mechanical responses and to define injury thresholds. A combined experimental and computer modeling approach was used in this study to establish the relationships between tissue level strain response and axonal pathology in a rodent impact-acceleration model of TBI.

Methods: The FE model of the adult Sprague-Dawley rat head was developed based on the geometry acquired from MicroCT and T2-weighted MRI (4.7 Tesla) scans. The head model has over 990,000 3D elements, and consists of the scalp, skull, dura, arachnoid-pia, gray and white matter of the cerebrum and cerebellum, ventricles, corpus callosum (cc), brainstem with pyramidal tract (py) and medial lemniscus, cervical spine, and facial tissues. The rest of the spine and the full body were also meshed to mimic spinal-brainstem stretching during impact. Thirteen different mechanical properties were used to represent the regional heterogeneities and the anisotropies of brain tissues/white matter tracts. The validated rat head model was applied to simulate 2.25-m (n = 8) and 1.25-m (n = 8) drop height impact acceleration experiments conducted on anesthetized rats. The strain response level calculated at every element at 200 μm³ resolution in various white matter tissues was related to axonal pathology assessed and quantified by β-APP and RMO14 immunochemistry.

Results: The average principal strain was 0.15 in the entire cc (range 0.07–0.24), and 0.19 in the entire py (range 0.09–0.33) from 2.25-m head impact. The average strain of 0.08 in the cc and 0.10 in the py with 1.25-m impact was significantly lower (9.85/200 μm³ and 2.0/200 μm³, respectively) in the live anesthetized rats. The model also predicted high strain in the medial lemniscus and pyramidal decussation.

Conclusion: An anatomically detailed FE model of a rat head/body enabled a thorough analysis of the biomechanical response at tissue/cellular levels in an in vivo TBI model. The correlation of tissue strain with histopathology in white matter tracts may lead to the development of thresholds for traumatic axonal injury. These tissue level thresholds can be translated to a FE human head model, thereby improving the utility of a human head model for assessing various severities of TBI.

O81 Assessing Injury Predictors for Traumatic Axonal Injury in a Rodent Head Impact Acceleration Model.

Background: A modified Marmarou impact acceleration model was developed to study the kinematics of the rat head, determine the severity of traumatic axonal injury (TAI), and to assess injury predictors for severe TAI.

Methods: Thirty-one anesthetized male Sprague-Dawley rats (375–425 g were impacted with a 450-g mass from either 1.25- or 2.25-m drop height. Linear and angular responses of the head were measured with an accelerometer and angular rate sensor, and the impact was captured by high-speed video. Latency to surface righting was assessed post-TBI. At 24 h post-TBI the rats were perfused and 13–15 brain sections spaced at 0.48 mm through the corpus callosum (CC) were processed for β-APP immunocytochemistry. Over 370 injury maps of TAI in the entire CC were constructed to determine the total TAI in the CC for each rat. Peak and average head linear and angular accelerations, HIC, and Power Index were assessed as predictors of TAI. Injury predictors were assessed using logistical regression and ROC analysis.

Results: The average impact velocity at 1.25-m and 2.25-m drop heights was 4.54 ± 0.06 m/sec and 6.13 ± 0.06 m/sec, respectively. The average linear acceleration, head angular velocity, and surface righting time in the 1.25-m group were 154 ± 46 g, 91 ± 29 rad/sec, and 16.22 ± 2.96 min, which were significantly less than those in the 2.25-m group (293 ± 156 g, 122 ± 51 rad/sec, and 24.03 ± 7.14 min). Head peak linear acceleration (666 ± 165 g for the 1.25-m group and 902 ± 514 g for the 2.25-m group) was not significantly different between groups. The TAI count in the 1.25-m group (21 ± 14) was significantly less than in the 2.25-m group (154 ± 208). Logistical regression showed that the occurrence of severe TAI was best predicted by the average linear acceleration, followed by the Power Index, and time to surface righting. The estimated average linear acceleration levels were 210, 265, and 320 g, for 25%, 50%, and 80% probability of severe TAI. The combination of average linear acceleration plus time to surface righting achieved an area under the ROC curve of 0.949, compared to 0.889 for average linear acceleration and 0.823 for time to surface righting. The optimal specificity and sensitivity of the two combined predictors for severe TAI were 88.9% and 90.9%, respectively.

Conclusions: Rat head kinematics were characterized for two impact velocities, and TAI maps were constructed through the CC. Injury levels and biomechanical and behavioral responses of the rats were determined, and their correlation with the TAI in CC was assessed.

O82 Histological Assessment and Quantification of Axonal Injury in the Corpus Callosum and Pyramidal Tract.

Background: Traumatic axonal injury (TAI) involves two distinct changes in the affected axons: neurofilament compaction (NFC) due to alterations in neurofilament side arms, and impaired axoplasmic transport (IAT), leading to retraction balls. NFC can be investigated by RMO-14 antibodies targeting specific locations on side arms, whereas IAT can be visualized by using antibodies for β-amyloid precursor protein (β-APP), which is found in the accumulated axoplasm.

Methods: Anesthetized rats were impacted on the vertex of the helmeted skull with a 450-g mass from drop heights of 1.25 m (8 rats) and 2.25 m (8 rats), using a modified Marmarou impact acceleration device. The rats were perfused 24 h post-impact, and NFC and IAT were assessed in the corpus callosum (cc) and pyramidal tract (py), using RMO-14 and β-APP antibody immunocytochemistry. In the cc, every 12th coronal section was analyzed for IAT using β-APP, for a total of 13–15 sections. Adjacent sections were stained and analyzed for NFC using RO-14. In the py, 5 sagittal sections from 0–1000 μm were selected and analyzed for IAT, and the adjacent sections were analyzed for NFC. Each stained section was observed at 100 × magnification and photographed. All serial photomicrographs from a given section were photomerged, resulting in 13–15 panoramic digital images for the cc, and 5 panoramic digital images for the py. A 200 × 200-mm grid system was digitally superimposed on each composite image, and the number of damaged axons was counted within each grid by utilizing the cell counter function in ImageJ software.

Results: TAI was more prominent in the py than in the cc. At 2.25 m, the total TAI count (β-APP and RMO-14) in the cc averaged 197 ± 111 SEM, and in the py averaged 1060 ± 319 SEM. At 1.25 m, the total TAI count in the cc averaged 30 ± 6.5 SEM, and in the py 208 ± 157 SEM. Total TAI counts in the py were significantly higher than in the cc. A correlation between total TAI and surface righting time was also observed.

Conclusions: A technique was developed to successfully quantify two distinct changes to axonal pathology after TBI for two major axonal fiber systems. TAI count was greater at 2.25 m than at 1.25 m, TAI density was greater in the py tracts than in the cc, and β-APP-stained axons were more prominent than RMO14.

O83 Correlations of Severity and Extent of Brain Strain with Clinical Symptoms and Pathology of Diffuse Brain Injury.

Background: Understanding the anatomical features of the neuropathology and severity of traumatic brain injury in relation to local tissue strain/deformation may lead to the development of injury thresholds for injury prevention. This study was designed to relate proposed rotational parameters to localized strain measures for mild to severe diffuse brain injuries (DBI).

Methods: The Wayne State University finite element model of the human head was exercised to predict strain responses in brain regions for a set of loading conditions. Input head motions were those posited to cause severe cerebral concussion (SCC; AIS3), and mild to severe diffuse axonal injury (DAI; AIS4, AIS5). The effects of coronal, sagittal, and transverse loading directions were compared. The severity and extent of the affected brain regions were compared based on tissue strain damage criteria to assess the risk of DBI as a result of mechanical loading.

Results: Early strains were seen at the surface, while later higher strains occurred in the white matter, brainstem, and deep gray matter. In moderate and severe DAI, multiple cortical layers also experienced high strain. The high strains were located in the thalamus, midbrain, upper brainstem, and hippocampus for coronal loading; in the corpus callosum, caudate, dorsal pons, and fronto-parietal cortex for sagittal loading; and in the corpus callosum, cingulum, thalamus, peri-ventricular area, and internal capsule for transverse loading. In SCC, 30% of the brain volume had strains > 0.35 and 0.50. In mild to severe DAI, at strain > 0.35, the affected brain volume ranged from 45–85%, and the affected volume with > 0.5 strain was 20–45%, and included involvement of the brainstem. The affected brain volume was the greatest as the head rotated about the z-axis.

Conclusions: Correlations of brain strain and injury location allow a reliable injury predictor for estimating the DBI risk, and thus the degree of clinical symptoms and pathological abnormalities. Together with our previous study of mild and classical concussion, 0.35 brain strain appears to be a good indicator for concussive injury (AIS1–3). For DAI, 0.50 strain with 20% brain volume could be a predictor for mild DAI, and if the strain increased to a volume of 30% with involvement of upper brainstem region, then moderate DAI would occur. Severe DAI could be expected when > 40% of brain structures experience strain of > 0.5. These proposed strain criteria can be used to assess risk and outcome for the entire spectrum of diffuse brain injury.

O84 Exploration of the Effect of Microsurgery on the Treatment of Contusion and Laceration of the Brain: An Analysis of 236 Cases.

Background: Our goal was to discuss the effect of microsurgery for the treatment of cerebral contusion and laceration.

Methods: We analyzed 236 cases of microsurgery for patients with cerebral contusion and laceration performed in our department from January 2005 through October 2010. We compared midline displacement, rebleeding rate, encephaledema volume, rate of postoperative cerebral infarction, improvement in GCS scores at 3 days post-surgery, and hydrocephalus at 3 months post-surgery, with 160 similar cases operated using standard procedures (non-microsurgery).

Results: Among the 236 cases of microsurgery, we had 162 cases with good postoperative GOS scores, 36 cases of moderate handicap, 18 cases of severe handicap, 4 cases of vegetative survival, and 16 cases of death. Compared with the standard-operated group, for the microsurgery group, midline displacement was faster, rates of rebleeding were lower, the incidence of cerebral infarction was lower, GCS improvement was faster, the incidence of encephaledema was lower, and the incidence of post-operative hydrocephalus was lower. There was a remarkable difference seen with statistical analysis (p < 0.05).

Conclusion: Microsurgery is conducive to improved treatment of cerebral contusion and laceration, reducing complications and improving quality of life.

O85 Characterising the Effects of Amyloid Precursor Protein Knockout on Outcome Following Traumatic Brain Injury.

The amyloid precursor protein (APP) is known to increase following traumatic brain injury (TBI). It has been hypothesized that this increase in APP may be deleterious to outcome due to the production of neurotoxic Abeta. Conversely, others have suggested that this upregulation may be beneficial, as cleavage of APP via the alternative non-amyloidogenic pathway produces the soluble alpha form of APP (sAPPalpha), which is known to have neuroprotective and neurotrophic functions. Indeed, our previous studies have shown that treatment with sAPPalpha following diffuse TBI in rats reduced apoptotic cell death and axonal injury and improved motor outcome. However, it is not yet known whether endogenous APP plays a similar beneficial role following TBI. In order to investigate this, the outcome of APP-knockout mice was compared to that of APP-wild-type mice following two types of TBI: a focal lesion induced by a controlled cortical impact injury, and a diffuse lesion caused by a weight drop model. Following both types of injury, APP^–/– mice showed impaired spatial memory compared to APP^+/+ mice, with a significantly increased latency to locate a previously learned escape hole in the Barnes maze on all days tested post-injury. After the diffuse injury, APP^–/– mice had a small but significant rotarod motor deficit compared to APP^+/+ mice, whereas after focal injury APP^–/– mice demonstrated significantly more footfaults on the ledged beam than APP^+/+ mice on days 2–5 post-injury. These deficits correlated with increased neuronal injury, with APP-knockout mice having significantly more degenerating hippocampal neurons than APP-wild-type mice, as detected with Fluoro Jade staining, at 24 h following the focal injury. This corresponded with a decrease in the number of surviving hippocampal neurons in APP-knockout mice at 7 days post-injury. The improved outcome seen in APP-wild-type mice compared to APP-knockout mice suggests that the upregulation of APP seen post-injury may be a protective response.

O86 Neuroprotection in Traumatic Brain Injury.

Traumatic brain injury (TBI) is the leading cause of death in those under age 40 years, and represents a major healthcare problem worldwide. In the last decade, dozens of compounds and treatment strategies have been tested, yet none of them proved effective at decreasing the burden of disease. We aim to analyze and present contemporary literature data, as well as the most recent results, in order to highlight the importance of multi-targeted approaches that simultaneously inhibit necrotic and apoptotic pathways. Results of the application of the poly(ADP-ribose) polymerase (PARP) inhibitor L-2286 indicate that this substance significantly decreases the density of diffusely injured axons, and leads to improved functional outcome in an impact acceleration model of TBI. Similar results were obtained with the application of the pituitary adenylate cyclase-activating polypeptide (PACAP) in various models of TBI. Potential clinical application of complex neuroprotective strategies, including early therapeutic hypothermia in conjunction with immunophilins, PACAP, and PARP-inhibition, as well as estrogen analogues, is also discussed. The future of neuroprotection is not only based on the development of such treatment strategies, but also on the appearance of novel endpoints in preclinical and clinical studies, including the introduction of TBI-specific biomarkers and more sensitive imaging tools.

O87 Effect of Recombinant Human Erythropoietin on Survivin Expression in Brain Tissues After Traumatic Brain Injury in Rats.

Background: To explore the r-HuEPO-adjustable effect on survivin expression after traumatic brain injury (TBI) in rats, and understand the mechanisms of neuroprotection by r-HuEPO.

Methods: Seventy-eight adult Wistar rats were randomly divided into a sham operation group (n = 6), a TBI group (n = 36), and an r-HuEPO group (n = 36). The experimental TBI model was established by the modified Feeney method. Samples were obtained after injury for measuring apoptosis of neuronal cells by Epics XL Flow Cytometry, and assessing the expressions of survivin and NF-κB proteins by immunochemical method.

Results: Compared to the sham group, the number of apoptotic cells, and survivin NF-κB-immunopositive cells were all increased significantly after TBI (p < 0.01). r-HuEPO significantly increased the expression of survivin and NF-κB, but decreased apoptotic rates.

Conclusion: Increased expression of NF-κB by r-HuEPO might be one of the mechanisms in regulating survivin level, inhibiting neuronal apoptosis, and exerting a neuroprotective function.

O88 Temporal Changes in Traumatic Brain Injury Detected by Diffusion Tensor Imaging.

Background: It is becoming clear that many of the sequelae of traumatic brain injury (TBI) are not just a direct consequence of the acute event, but represent a dynamic process. However, data on the temporal pattern of changes remain incomplete, but may be important to define therapeutic windows. Diffusion tensor imaging (DTI) is a promising imaging modality for TBI.

Methods: Ten patients (median Glasgow Coma Scale score 5) underwent MRI on a minimum of three occasions: within the first 48 h of injury (scan 1), at approximately 6 weeks post-injury (scan 2), and at least 6 months post-injury (scan 3). Of these, seven also had a scan at least 1 year post-injury (scan 4). Regions of interest were manually drawn in MNI125 space. ROIs selected included the anterior corpus callosum, the posterior corpus callous, frontal white matter, and posterior white matter. The DTI data were normalized and mean FA for the different ROIs were calculated. For the seven who had two scans after 6 months, the change in FA in the posterior corpus callosum was correlated with the change in motor latency.

Results: In all ROIs at all time points the patient FA was significantly lower than the controls. FA continued to decrease from the first scan to a nadir at scan 3, from which FA subsequently approached but did not return to normal. The patterns of change for the ROIs were consistent among all patients when their individual data were assessed. All patients improved their motor latency between scans 3 and 4. This change was significantly correlated with the change in FA in the anterior and posterior corpus callosum (r = 0.736, p = 0.036 and r = –0.607, p = 0.024, respectively). This is the first study to show evidence of a consistent pattern of temporal change in FA in multiple ROIs post-traumatic brain injury. FA was low immediately following TBI, and appeared to worsen for several weeks, with a nadir at approximately 6 months. When patients were followed up past the simonth time point, there appeared to be an increase in FA, which correlated with improved motor function and may indicate recovery.

Conclusion: These data provide further insight into the late pathophysiology, may help select appropriate patients for clinical trials, and provide a framework that allows DTI to be used as an imaging biomarker of therapy response.

O89 The Rescueicp Decompressive Craniectomy Study.

Background: The RESCUEicp study (randomised evaluation of surgery with craniectomy for uncontrollable elevation of ICP) aims to provide Class I randomized evidence as to whether decompressive craniectomy is effective for the management of patients with raised and refractory ICP following traumatic brain injury.

Methods: It was an international multicenter randomized trial comparing decompressive craniectomy with medical management. Patients (n = 50 for the pilot phase, n = 400 for the main study) with TBI and raised ICP (>25 mm Hg) refractory to initial treatment measures are eligible for the study. The protocol will be presented. Patients are randomized to one of two arms: continuation of optimal medical management (including barbiturates), versus surgery (decompressive craniectomy). The inclusion criteria are: TBI, age 10–65 years, and abnormal CT scan, and the exclusion criteria are: bilateral fixed and dilated pupils, bleeding diathesis, and devastating injury not expected to survive 24 h. Outcome is assessed using the Glasgow Outcome Score-Extended, and the SF-36 quality of life questionnaire, at 6 months, 1 year, and 2 years, with additional surrogate endpoints (ICP control and length of stay in ICU).

Results: Over 280 patients have been recruited to date from the U.K. and international centers. The study is ongoing.

Conclusion: Randomizing patients with TBI to decompressive craniectomy versus optimal medical management is feasible. Whether this operation is effective and safe remains to be seen. We would welcome more participation of more centers.

O90 Radiological Abnormalities Following Decompressive Craniectomy for Post-Traumatic Intracranial Hypertension.

Background: Recent years have seen renewed interest in the use of decompressive craniectomy (DC) as a means of controlling refractory intracranial hypertension after TBI. This is termed secondary DC. In our unit, secondary DC is used as a last-tier therapy in the context of an ICP/CPP-driven protocol (see www.rescueicp.com for details). We reviewed a series of consecutive patients who underwent secondary DC, in order to establish the incidence and type of radiological sequelae, including complications.

Methods: This was a retrospective single-center study. All patients who underwent a secondary DC for TBI in our unit over a 2-year period were included in this study. Secondary DCs were identified by searching operating theatre registers. CT scans performed within the first post-operative week were defined as early, and CT scans performed after the first week were defined as delayed.

Results: Sixteen eligible patients with pre- and post-operative imaging were identified. Median age was 37.5 years (range 18–59 years). Review of pre-operative CT scans revealed diffuse injury (Marshall grades 2–4) in 11 patients (68%). Median time from injury to DC was 2 days (range 0.5–9 days). Nine patients underwent a bifrontal craniectomy (56%), and the rest a unilateral hemicraniectomy (44%). Review of early post-operative imaging (n = 15, performed at a median of 3.5 days post-operatively) revealed brain herniation (>1 cm outside the outline of the outer table) in 20% of the cases (2 hemicraniectomies and 1 bifrontal DC). Hemorrhagic contusions (n = 10) expanded in 2 cases (20%) following DC, while they remained stable in size in 8 cases (80%). There was one case of a new extra-axial hematoma (>1 cm). No CT scans showed evidence of ventriculomegaly. Review of delayed imaging (n = 10; performed at a median of 18 days post-operatively) revealed ventriculomegaly in 4 patients (40%). Three of them eventually required a VP shunt. Seven patients (70%) had evidence of extra-axial (subdural or subgaleal) hypodense collections (>1 cm) following DC. Three collections required drainage (30%): 2 contralateral subdural hygromas following hemicraniectomy, and 1 subgaleal collection after bifrontal DC.

Conclusion: Secondary DC is associated with a significant number of radiological abnormalities on CT scanning. Until further evidence regarding the efficacy of DC in improving outcomes is available, it should be used as part of ICP/CPP-driven therapeutic protocols, and ideally in the context of a randomized trial.

O91 Interaction Between Brain Chemistry and Physiology After Traumatic Brain Injury: Impact of Autoregulation and Microdialysis Catheter Location.

Background: Bedside monitoring of cerebral metabolism in head injury with microdialysis is gaining wider clinical acceptance. The objective of this study was to examine the relationship between the fundamental physiological neuromonitoring modalities intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygen (PbtO₂), and cerebrovascular pressure reactivity index (PRx), with cerebral chemistry as assessed with microdialysis, with particular focus on the lactate:pyruvate (LP) ratio as a marker of energy metabolism.

Methods: Prospectively collected observational neuromonitoring data from 97 patients with TBI requiring neurointensive care management and invasive cerebral monitoring were analyzed. A linear mixed model analysis was used to account for individual patient differences.

Results: Perilesional tissue chemistry exhibited a significant independent relationship with ICP, PbtO₂, and CPP thresholds, with increasing LP ratio in response to decreases in PbtO₂ and CPP, and increases in ICP. The relationship between CPP and chemistry depended on the state of the PRx. Within the studied physiological range, tissue chemistry only changed in response to increasing ICP or a drop in PbtO below 1.33 kPa (10 mm Hg). In agreement with previous studies, significantly higher levels of cerebral lactate (pted relationships between established physiological variables and biochemistry. Decreases in perfusion and oxygenation were associated with deteriorating neurochemistry, and these effects were more pronounced in perilesional tissue and when cerebrovascular reactivity was impaired.

O92 Expression of Adenoviral-Mediated BDNF Genes in Spinal Cord.

Background: Brain-derived neurotrophic factor (BDNF) is the second member of the neurotrophic factor (NTF) family in the brain and spinal cord. BDNF is mainly synthesized by brain tissue, and is to able to maintain the central nervous system and neuronal survival, and promotes the growth of nerve axon basic protein. However, BDNF expression is small in the normal central nervous system. In injured spinal cord tissue, a partial increase in expression of BDNF can promote functional recovery of spinal cord neurons, but also affects the expression of instability with shorter processing time. In this study recombinant replication defective adenoviral vectors encoding BDNF gene (AdBDNF), jointly with adenoviral vector with CTLA4Ig gene (AdCTLA4Ig), were transferred into the spinal cord parenchyma of rat lumbar tissues, in order to study the adenovirus-mediated CTLA4Ig gene and BDNF gene co-expression.

Methods: The rats were randomly divided into three groups (n = 30 each): a normal control group (A group), without adenovirus import; an experimental control group (B group; Ad0 + AdBDNF transfer group, each 1 μL); and an experimental group (C group; AdCTLA4Ig + AdBDNF transfer group, each 1 μL). At seven different time points within 5 weeks post-injection of the B and C groups, and at all time points in A group, lumbar enlargement of the spinal cord was removed, cut into 40-μm-thick cross-sections and stained for immunohistochemistry of the BDNF- and count-positive cells. Determination of immunoreactive products was determined via optical density (OD). Immunofluorescence staining of AdCTLA4Ig was done, and PCR was used to monitor groups B and C for virus, and RT-PCR was used to detect BDNF gene expression in the rat spinal cords.

Results: In groups B and C the BDNF-positive staining cells, and immunoreactive products as assessed with OD, were significantly increased, and the expression was higher than that seen in the normal group (A group), and in group C the difference was significant (p < 0.05). PCR detection showed that the expression of adenovirus gradually decreased, and in group C was the lowest. RT-PCR detection showed that during peak periods of BDNFmRNA expression, group C was the highest. At the different time points compared, BDNFmRNA expression was significantly different (p < 0.05).

Conclusion: BDNF has the ability of aggregation, and the AdV-mediated CTLA4Ig gene enhances the intensity of BDNF gene expression.

O93 Neuroprotective Effects of Progesterone and Dextromethorphan in a Rodent Model of Penetrating Ballistic-Like Brain Injury.

Background: This study evaluated the potential beneficial effects of progesterone (PROG) and dextromethorphan (DM) on neurofunctional outcome following penetrating ballistic-like brain injury (PBBI) in rats.

Methods: Anesthetized rats were prepared for stereotactic insertion of the PBBI probe, and a calibrated water-pressure pulse was used to rapidly (<40 msec) expand the probe's elastic tubing into an elliptical balloon equivalent to 10% of total rat brain volume. PROG (10 mg/kg IV) was administered at 30 min and 6 h post-injury, and continued once per day out to 5 days post-PBBI. DM (10 mg/kg IV) was administered at 30 min, 2 h, 4 h, and 6 h post-injury, and continued once per day out to 5 days post-PBBI. Neurological assessments were made using a neuroscore exam (24 h–7 days post-injury), motor assessments were made using a rotarod test (7 and 10 days post-injury), and cognitive assessments were made using the Morris water maze task (MWM; 13–17 days post-injury).

Results: Both PROG and DM showed neuroprotective efficacy on PBBI-induced neurological and motor deficits, but only DM (not PROG) showed significant neuroprotective efficacy against PBBI-induced cognitive impairments in the MWM task.

Conclusion: These initial results are promising, particularly with regard to the severity of damage incurred in the PBBI model. Further research to establish the full dose-response curve for PROG and DM in the PBBI model is ongoing.

O94 Recovery from Glutamate and Energy Metabolism Alterations After Mild Traumatic Brain Injury.

Background: Various neuroimaging techniques now offer the possibility of detecting subtle functional, anatomical, or physiological abnormalities after mild traumatic brain injury (mTBI), and hence may complement traditional clinical assessments in predicting and monitoring morbidity. Here we present our recent studies on brain metabolism after mTBI as measured by proton magnetic resonance spectroscopy (1H-MRS).

Methods: MR spectroscopic imaging was used to assess gray and white matter neurometabolite levels, including the sum of the glutamate and glutamine (Glx) concentrations, and the sum of the creatine and phosphocreatine (Cr) concentrations, across a supraventricular slice in 30 individuals with semi-acute mTBI and 30 matched controls.

Results: There were no significant group differences on clinical measures of attention, memory, working memory, processing speed, and executive skills, though the mTBI group reported significantly more somatic, cognitive, and emotional symptoms. Within 3 weeks of injury (mean 13 days), white matter Cr and Glx were elevated in the mTBI group, while gray matter Glx was reduced. While N-acetylaspartyl groups (NAA) were not significantly lower in the TBI group, NAA was positively associated with days post-injury during the semi-acute period of recovery. Seventeen mTBI patients returned for a follow-up evaluation (mean 120 days post-injury). A significant group by time interaction indicated significant recovery in the mTBI group for gray matter Glx, and trends in white matter Cr and Glx. An estimate of pre-morbid intelligence predicted the magnitude of neurometabolite normalization over the follow-up interval.

Conclusions: In the absence of cognitive dysfunction detectable by clinical measures, mTBI subjects demonstrated a pattern of altered glutamate and energy metabolism that tended to normalize within 3 months, and moreover, appeared distinct from the changes reported for more severe TBI. Glutamate is converted to glutamine in astrocytes after uptake from the synaptic cleft, and glutamate receptors have also been found on oligodendrocytes, where they may be involved in signaling for myelination. As such, depressed gray matter Glx after mTBI may reflect perturbed glutamatergic transmission, while higher white matter Glx may be related to repair. Similarly, higher levels Cr in white matter may be a response to the higher energy demands of repair. Finally, the relationship between pre-morbid intelligence and metabolic normalization may indicate that biological factors underlying intelligence may also be associated with a more rapid recovery. These findings and tentative hypotheses warrant further exploration in pre-clinical models of injury.

O95 Experimental Observations of Craniocerebral Contracoup Injury.

Background: Our purpose was to develop an animal model of craniocerebral contrecoup injury, and to characterize the neuropathological features produced by this TBI model.

Methods: The experimental device consisted of a horizontal impactor and a suspension framework. A 1.75-kg impact to the head was designed to strike the animal's occiput. The suspension framework was used to simulate the post-impact movement of the experimental animals along the impact direction. A total of 36 anesthetized rabbits were divided into two groups. In group A, the impactor directly stroke the animal's occiput. In group B, the animal's head was covered by a plastic helmet fixed at the parieto-occipital region, and the impactor struck the helmeted head. The animal's head in group B was subjected to angular acceleration with limited linear motion. Group A was divided into three subgroups (n = 8/group), with impact velocities of 6, 9, and 12 m/sec. Group B was divided into two subgroups (n = 6/group), for impact velocities of 9 and 12 m/sec. An overall craniocerebral injury scale was devised according to the physiopathological symptoms/signs: respiratory disturbances, convulsions, and pupil shifting. Intracranial pressure was measured at the cisterna magna, occiput, frontal copular part, and pavimentum cerebri epidurally.

Results: The injury patterns produced by the model included the contrecoup contusion and subdural hemorrhage in the basilar region. In group A at impact velocities of 6 and 9 m/sec, the animals suffered a mild and a moderate craniocerebral injury, respectively. Both the mild and moderate injury included the contrecoup contusion and/or contrecoup cerebral hemorrhage. At 12 m/sec, the animals suffered a severe to very severe injury with skull fracture. However, the contrecoup injury severity was similar for animals in the 12-m/sec and 9-m/sec impact groups. The intracranial pressure data were correlated with contrecoup injury severities. In group B, at 9 m/sec impact the animals sustained diffuse axonal injury rather than contrecoup contusion. At 12 m/sec, the craniocerebral injury was moderate; however, the contrecoup contusion was only mild. The injury patterns sustained by the animals suggested that angular acceleration alone was not major mechanism responsible for craniocerebral contrecoup injury.

Conclusion: A new animal model was developed that was capable of producing repeatable, clinically-relevant, features of craniocerebral contrecoup injury. The injury probably arises from a combination of the stress wave concentration on the basilar surface, and the negative pressure at the contrecoup site. Future studies will include finite element analysis of stress/strain responses within the brain.

O96 Cervical Facet Pain: Biomechanics, Neuroanatomy, and Neurophysiology.

Background: The purpose of this study is to investigate the biomechanics, neuroanatomy, and neurophysiology of cervical facet pain.

Methods: A comprehensive search of international and Chinese journals related to cervical facet pain was conducted. Eighty-six studies were found and reviewed in this article.

Results: (1) Considering all data from biomechanical testing using human volunteers, head-neck preparations, and motion segments, it is possible that a critical distraction of the facet joint may be required for its painful capsular injury. Meanwhile, numerical simulations have demonstrated that axial compression can cause loosening of cervical facet ligaments, and make it easier for the facet joint capsule and other soft tissues to be injured. (2) An extensive distribution of small nerve fibers and free and encapsulated nerve endings exists in the cervical facet joint capsule, including nerves containing substance P, a putative neuromodulator of pain. (3) High-threshold mechanoreceptors appear to be nociceptors that signal impending tissue damage, and low-threshold slowly-adapting mechanoreceptors may sense joint position, while low-threshold fast-adapting units may sense joint movement. (4) Sensitization and excitation of nerves in the cervical facet joint and surrounding muscle occur when the joint is inflamed or exposed to certain chemicals that are released during injury and inflammation. (5) Marked reduction in nerve activity occurs in facet tissue injected with lidocaine and hydrocortisone.

Conclusion: It is suggested that the facet joint capsule is a source of neck pain, and that the pain may arise from large strains in the joint capsule that cause pain receptors to fire.

O97 Effect of Whole-Body Deep Hypothermic Circulatory Arrest on Expression of Smad2 and Smad4 in Cortex Neurons of Rats.

Background: We sought to investigate the effect of deep hypothermic circulatory arrest (DHCA) on expression of Smad2 and Smad4 in cortex neurons of rats.

Methods: Forty SD rats were divided randomly into three groups: deep hypothermic circulatory arrest (DHCA) group (n = 12), normal temperature circulatory arrest (NTCA) group (n = 12), and normal animal control (NC) group (n = 12); the next four rats were used as blood donors for other rats. The animal model of closed-chest DHCA was established in rats by means of external cannulation. In the DHCA group, 10 min of circulatory arrest was induced after the temperature of the rectum was lowered to 20°C by external circulation and body surface cooling. In the NTCA group 10 min of circulatory arrest was induced at normal temperature. In the NC group, 10 min of external circulation without circulatory arrest or deep hypothermia was performed. The cerebral cortices were removed and dissociated after external circulation, and then Smad2 and Smad4 were measured using immunohistochemistry, and the results were analyzed with SPSS 11.0.

Results: The level of Smad4 expression in the DHCA and the NTCA groups were much higher than that in the NC group (p < 0.05). The level of Smad4 expression of the DHCA group was much higher than that of the NTCA group (p < 0.05). The level of Smad2 expression of the DHCA group and the NTCA group was much higher than that of the NC group (p < 0.05). The level of Smad2 expression of the DHCA group was much higher than that of the NTCA group (p < 0.05).

Conclusion: Ischemia can induce the expression of Smad2 and Smad4, while deep hypothermia may increase Smad2 and Smad4 expression. Deep hypothermia may have a protective effect against brain injury due to ischemia and anoxia, and the increasing expression of Smad2 and Smad4 may be among the mechanisms of the protective effects of deep hypothermia.

O98 Effect of Whole Body Deep Hypothermic Circulatory Arrest on Expression of Nestin and HIF-1A in Cortex Neurons of Rats.

Background: To detect the expression of nestin and HIF-1α (hypoxia-inducible factor-1α) in cortex neurons of rats subjected to deep hypothermic circulatory arrest (DHCA), or normal temperature circulatory arrest (NTCA).

Methods: Forty SD rats were divided randomly into three groups: DHCA group (n = 12), NTCA group (n = 12), and normal control (NC) group (n = 12); the next four rats were used as the blood donors for all rats. The animal model of closed-chest DHCA was established in rats by means of external cannulation. In the DHCA group, 10 min of circulatory arrest was performed after the temperature of the rectum was lowered to 20°C by external circulation and body surface cooling. In the NTCA group, 10 min of circulatory arrest was performed at normal temperature. In the NC group, 10 min of external circulation without circulatory arrest or deep hypothermia was performed. Cerebral cortexes were removed and dissociated, and were analyzed with immunohistochemistry for nestin and HIF-1α. Data were analyzed using SPSS 11.0.

Results: The levels of nestin expression in the DHCA and NTCA groups were much higher than those in the NC group (p < 0.05). The level of nestin expression of the DHCA group was much higher than that of the NTCA group (p < 0.05). The levels of HIF-1α expression of the DHCA and NTCA groups were much higher than those of the NC group (p < 0.05). The level of HIF-1α expression of the DHCA group was much higher than that of the NTCA group (p < 0.05).

Conclusion: Ischemia can induce the expression of HIF-1α and nestin, while deep hypothermia may increase HIF-1α and nestin expression. Deep hypothermia could be protective in the brain after ischemia, and increasing expression of HIF-1α and nestin may be among the mechanisms of its protective effects.

O99 Activation of Hypoactive NMDA Receptors Provides Neuroprotection.

Background: Traumatic brain injury (TBI) triggers a transient increase in glutamate efflux in the brain. It was suggested that activation of the NMDA receptor (NMDAR) mediates delayed excitotoxic neuronal death following TBI. Numerous studies showing that NMDAR antagonists reduce cell death and improve outcomes in animal models support this notion. Yet all clinical trials with NMDA antagonists have not only failed, but some have even led to detrimental outcomes. In recent years we showed that NMDAR are hypoactive from hours to days after TBI, and that their activation by a full agonist (NMDA) or the co-agonist D-cycloserine (DCS) is neuroprotective. Here we further extended this notion to a mouse model of LPS-induced neuroinflammation, and examined whether NMDAR are also hypoactive in this global inflammation model, LPS-mice display cognitive impairments, and whether such impairments can be reversed by DCS.

Methods: Male mice were subjected to TBI using a weight-drop device, and administered 10 mg/kg (IP) DCS or vehicle 24 or 72 h later. Functional recovery was assessed up to 60 days using the Neurological Severity Score (NSS), and cognitive function was assessed using the novel object recognition test (ORT). For the model of neuroinflammation, mice were injected intracerebrally with saline or lipopolysaccharide (LPS; 10 μg in 2 μL). Then 24 h later DCS was injected (IP), and memory function was assessed using ORT between 2 and 30 days post-LPS. The animals were killed after 8 days and their brains were processed for electrophysiological recording of hippocampal LTP and in vitro quantitative autoradiography with [3H]PK11195, an established marker of microgliosis. Statistical analysis was performed by one-way ANOVA (NORT), or two-way ANOVA by treatment and region (autoradiography), followed by Fisher's PLSD post-hoc test.

Results: NSS were significantly greater than in vehicle in all groups in which treatment was begun at 24 h or 72 h post-TBI. Additional doses given on days 2 and 3 post-injury did not further improve recovery. Mice treated with DCS also showed improved memory function in the ORT paradigm. In the LPS-induced neuroinflammation model, significant and long-lasting deficits in object recognition and in LTP were found. These were restored by DCS, which also reduced the extent of neuroinflammation ([3H]PK11195 binding).

Conclusions: Activation of the NMDAR by its co-agonist DCS is a novel therapeutic modality for TBI and LPS-induced neuroinflammation. Due to its wide use in humans and well-established safety profile, its translation into clinical trials is warranted.

O100 Stretchable Neural Chips for the Study of Traumatic Brain Injury.

Traumatic brain injury (TBI), caused by acceleration or a blow to the head, results in deformation of the brain tissue, and based on studies of TBI biomechanics it is generally believed that stretch is the primary mechanism of cell and tissue damage after TBI. Brain tissue is a viscoelastic material, and its biological response to trauma has been found to be dependent on the dynamic properties of how large (strain) and how fast (strain rate) the brain tissue is being stretched. Although many previous studies have shown that post-traumatic neuronal death plays an important role in the damage to brain function seen after TBI, dysfunction or re-organization of neuronal cells and networks may also contribute to the post-traumatic dysfunction of the brain. At a cellular level, the correlate of macroscopic changes in behavior and function is the alteration of neuronal electrophysiology. Electrophysiological studies in animal models of TBI have yielded mechanistic insights into the causes of post-injury neuropathology. However, few previous studies have quantified changes in brain electrophysiological function in response to precisely controlled and verified mechanical stimuli simulating head injuries of differing severities. We developed stretchable neural chips, which were incorporated into our in vitro TBI model, to make electrophysiological recordings before, during, and after mechanical injury, for functional (electrophysiological) measurement and analysis. The chips were elastically stretchable and capable of undergoing large, biaxial, 2D stretch, while simultaneously recording neuronal activity from multiple sites. By culturing tissue directly on the SMEA, serial analyses of neuronal network function over extended periods could be possible. The mechanical strain or severity of the stretch can be accurately controlled to generate mild to severe damage to the tissue. The actual deformation of the tissue was verified by high speed video. The SMEAs were capable of chronic and simultaneous multi-site recording of extracellular signals from brain slice cultures before and after controlled deformation. Unlike single-electrode recordings, the long-range connectivity of neural networks can be studied with these arrays, due to their capability of simultaneous multisite recording, providing additional insights into neuronal information processing and function within neural circuits. Moreover, drugs can be applied to the tissue with its electrophysiological activity being monitored, which is more convenient than in vivo models for high-content screening of novel drug treatments and development of related therapeutics.

O101 CRASH-2: Antifibrinolytic Treatment in Traumatic Brain Injury.

Background: Tranexamic acid (TXA) reduces bleeding in surgical patients and reduces mortality due to bleeding in trauma patients. We assessed its effect on intracranial hemorrhage in patients with TBI.

Methods: A randomized placebo-controlled trial was conducted in a subset of 270 patients participating in the CRASH-2 trial. Patients fulfilling the CRASH-2 trial inclusion criteria (adult trauma patients with, or at risk of, significant bleeding within 8 h of injury), who also had TBI, were randomly allocated to TXA (loading dose 1 g over 10 min, then infusion of 1 g over 8 h), or matching placebo. The primary outcome was the occurrence of intracranial hemorrhage growth between a CT scan at hospital admission, and a second scan 24–48 h later, adjusting for Glasgow Coma Scale score, age, time from injury to the CT scans, and initial hemorrhage volume. Randomization was balanced by center, with an allocation sequence based on a block size of eight generated by a random number generator. All investigators were masked to treatment allocation. All analyses were by intention to treat, and adopted a Bayesian approach, assuming no prior knowledge of the effect of TXA. The study is registered as ISRCTN86750102. In all, 133 patients were allocated to TXA, and 137 were allocated to placebo, of whom 123 (92%) and 126 (92%), respectively, provided information on the primary (imaging) outcome. All patients provided information on clinical outcomes.

Results: The analysis suggested that TXA was likely to be associated with a reduction in hemorrhage growth (adjusted difference −3.8 mL; 95% C.I. 11.5,3.9), fewer focal ischemic lesions (adjusted odds ratio 0.54; 95% C.I. 0.20,1.46), and fewer deaths (adjusted odds ratio 0.49; 95% C.I. 0.22,1.06).

Conclusion: TXA has the potential to reduce hemorrhage growth and deaths without increasing cerebral ischemia in patients with TBI. These results from our innovative analysis provide strong grounds for therapeutic optimism, and suggest further clinical trials are fully justifiable.

O102 Progesterone Induces Angiogenesis and Neuroprotection in Aged Traumatic Brain Injury Rats.

Background: Progesterone treatment promotes neuroprotective effects in young adult animals after traumatic brain injury (TBI), by reducing oxygen free radicals, repairing the blood–brain barrier, and enhancing the immunological system. The circulating endothelial progenitor cell (EPC) plays an important role in angiogenesis and vasculogenesis. Progesterone regulation of angiogenesis and circulating EPCs in aged animals has not been investigated. This study tests the hypothesis that the administration of progesterone induces neuroprotection and promotes EPC-related angiogenesis in aged TBI rats.

Methods: Aged (20-month-old) male 90 rats were subjected to a moderate unilateral parietal cortical contusion injury, while the other groups were sham-injured controls, receiving vehicle (DMSO), or not (n = 45/group). The progesterone was administered at a dose of 16 mg/kg within 1 h post-TBI, and subsequent daily injections were given for another 14 days (n = 45/group). Neurological functional tests and immnunostaining were performed. Blood circulating EPCs were identified by flow cytometry.

Results: A significant improvement in neurological function was confirmed by the modified Neurological Severity Score (mNSS), and improvements were seen in spatial learning ability as assessed by the Morris water maze, and long-term potentiation in CA1 of the hippocampus. The level of circulating EPCs was significantly increased in the progesterone treatment group, which continually persisted at a higher level than that in control subjects for at least 21 days post-TBI. Both CD34 and CD31 are undifferentiated endothelial cell markers, while vWF is the differentiated endothelial cell marker. We found that CD34-positive cell numbers and vessel density as measured by CD31 and vWF were significantly increased in the injured cortical tissue and in the hippocampus in the progesterone treatment group compared to controls.

Conclusions: The data indicate that progesterone treatment improves neurological functional outcomes after TBI, and facilitates EPC-related angiogenesis in the injured brain after TBI in aged rats.

O103 Effects of Atorvastatin on Angiogenesis and Neural Regeneration in Traumatic Brain Injury in Rats.

Background: Administration of statins has been proven to promote neural functional improvement in rats after stroke, independent of their capability to reduce cholesterol. However, the mechanism of the effect of statins on neural regeneration remains to be clarified, and few have reported about the effects of statins on TBI. Since statins were reported to promote angiogenesis in several previous reports, statin-induced angiogenesis and neurofunctional protection in TBI was hypothesized.

Methods: The fluid-percussion TBI Wistar rat model was established, and atorvastatin (1 mg/kg/d) was given orally at 1 h after TBI, and then repeated at 2, 24, 48, 72, 144, and 296 h post-injury. Normal control rats received only saline with the same frequency. Modified Neurological Severity Scores (mNSS) testing was utilized to evaluate the behavioral response to TBI and the atorvastatin treatment. The spatial learning ability was assayed in the Morris water maze, and long-term potentiation in the CA1 of the hippocampus was measured to see if the communication between the hippocampus and other parts of the brain was affected by atorvastatin administration. The rats were then sacrificed at day 25 after TBI, and the brain samples were processed for immunohistochemical staining to measure the vessel density as measured by vWF staining.

Results and Conclusion: Atorvastatin administration was confirmed to induce a significant reduction in impairment in neurological function after TBI, which was believed to correlate with angiogenesis induction, but the details of this mechanism remain to be further elucidated.

O104 Improvement on Spatial Learning in the Morris Water Maze Following Recombinant Adenovirus Vector-Mediated Hes1 in the Adult Mouse Hippocampus After Fluid Percussion Injury.

Background: Recent studies have demonstrated that neurogenesis occurs in both developing and adult brains, and the subgranular zone of the hippocampal dentate gyrus is one area where neural stem cells exist in the adult brain. Here we examined the efficacy of organization and injection of a recombinant adenovirus-expressing hairy and enhancer of split homolog 1(Hes1) in the mouse dentate gyrus, and the mouse spatial learning function in the Morris water maze (MWM) after fluid percussion injury.

Methods: Gene transfection-induced Hes1 overexpression in the adult mouse hippocampus was performed using recombinant adenovirus vectors. Three days after viral injection, Ad-Hes1 could be detected by green fluorescent protein (GFP) microscopy and Western blotting. Its effects on mouse spatial learning in the MWM was observed at 21 days post-injury.

Results: In the treatment group, infected cells were detected in the subgranular zone of the hippocampal dentate gyrus by observing green fluorescence, and the treatment successfully led to substantial elevations of hippocampal Hes1 levels as observed by Western blot. In addition, its effect on spatial learning (1 month after fluid percussion injury) was positive. The adenovirus-induced Hes1-overexpressing mice performed well above control levels.

Conclusions: These results demonstrate that the gene Hes1 can be efficiently introduced into neural stem cells, which exist in the subgranular zone of the hippocampal dentate gyrus in adult mice. Furthermore, adenovirus-directed infection can lead to hippocampal Hes1 elevation, which significantly improves cognitive performance on the MWM after fluid percussion injury in adult mice.

O105 Altered Expression of the Voltage-Gated Sodium Channel A-Subunit Following Fluid Percussion Traumatic Brain Injury in Rats.

Background: Traumatic brain injury (TBI) triggers excess activation of voltage-gated sodium channels (VGSC). Most studies of experimental TBI have focused on VGSC's key role in excitotoxic damage and the neuroprotective effect of VGSC blockers after TBI. Few have explored the mRNA and protein expression pattern of VGSC after TBI. We hypothesized that the effect of TBI on VGSC may start at a genetic level. Possible alterations of VGSC alpha-subunit mRNA and protein expression induced by TBI were determined in the hippocampus of the rat.

Methods: The mRNA and protein levels of Nav1.1, Nav1.2, Nav1.3, and Nav1.6, in the bilateral hippocampus following lateral fluid percussion brain injury (2–72 h post-TBI) were measured using RT-PCR and immunoblot techniques.

Results: The mRNA and the protein of Nav1.1 and Nav1.2 were significantly downregulated in hippocampus (p < 0.01) at early stages post-TBI. In contrast, the mRNA and protein of Nav1.3 and Nav1.6 were significantly upregulated (p < 0.01). Our data suggest that TBI may induce significant alterations in VGSC alpha-subunit expression in the hippocampus of the rat at early stages after the primary injury. As a reaction to TBI, VGSC regulates its expression in particular ways, according to the type of alpha-subunit.

O106 Different Expression of Hes1 and Its Effect on Adult Neurogenesis in the Mouse Hippocampus After Traumatic Brain Injury.

Background: Neurogenesis takes place in the subgranular zone of the hippocampal dentate gyrus throughout the entire lifespan of the rodent, and can be modulated by physiological and pathological events. Endogenous neural progenitor cells (NPCs) play a beneficial role in cognitive recovery following traumatic brain injury (TBI). However, the detailed regulatory mechanisms behind neurogenesis are still unclear. As a nuclear protein that was also one of the important effector molecules of the Notch signaling pathway, Hes1 protein is a negative transcriptional factor that plays a crucial role in the regulation of NPCs. Therefore, the aim of the present study was to investigate the different expression of Hes1 in the mice hippocampus, and its effect on adult neurogenesis after TBI.

Methods: TBI models were established by lateral fluid percussion injury (FPI). All mice were randomly signed to two groups: mice subjected to lateral fluid FPI (group TBI), and mice treated by identical surgical procedures without receiving the fluid pulse (group NC). The expression of Hes1 was analyzed by Western blot, and the TBI-induced neurogenesis was determined by immunofluorescence labeling and confocal microscopic detection. Cognitive function following TBI was assessed with the Morris water maze.

Results: The expression of hippocampal Hes1 increased at 1 day post-TBI. Then its expression began to decrease at day 3, and reached a nadir at day 7. Along with the expression changes of hippocampal Hes1, neurogenesis (BrdU-labeled), which occurred in the hippocampal SGZ, increased at first, and subsequently the newly-generated cells differentiated into dentate granular neurons (BrdU/NeuN); however, cognitive deficits persisted.

Conclusions: These results demonstrate that Hes1 plays an important role in neurogenesis after TBI, and that the process is involved in endogenous adult neurogenesis. First, the increase of Hes1 was required for quiescent adult NPCs to resume proliferation. Then, a reduction in Hes1 can induce the newly-generated cells to differentiate into dentate granular neurons, which may take part in the repair of neurological functions. However, endogenous neurogenesis can only repair neurological functions to a certain extent, not completely.

O107 The Expression of Survivin, A Key Component of the WNT/Beta-Catenin Signaling Pathway, Contributes to Traumatic Brain Injury-Induced Adult Neurogenesis in the Mice Hippocampus.

Background: Enhancing endogenous neurogenesis has been suggested as a treatment for traumatic brain injury (TBI); however, the factors that trigger adult neurogenesis after TBI remain elusive. The two neurogenic regions, the subgranular zone (SGZ) and the subventricular zone (SVZ), maintain relatively quiescent states, but they are active while receiving intrinsic and/or extrinsic stimulation via the activation of relevant signals.

Methods: A total of 105 adult C57BL/6 mice and 3e mice used for immunofluorescence staining were administered BrdU, before the brains were removed and underwent survivin/BrdU double-label staining (n = 3 at each time point). In addition, both survivin/BrdU/NeuN and survivin/BrdU/GFAP triplex labeling were performed at 5 days after TBI. Sham-operated tissue was also used for Q-PCR (n = 6), Western blot (n = 6), and immunofluorescence staining (n = 3).

Results: The 3e, we showed that survivin is mainly expressed in astrocytes by comparing the co-localization of survivin/BrdU/GFAP and survivin/BrdU/NeuN triplex immunofluorescence staining.

Conclusion: The expression of survivin, an anti-apoptotic protein, increased in a time-dependent manner in the SGZ of the hippocampus after TBI, and was affected by the changes seen in the newly-generated neuronal cells in this area. The findings strengthen the connection between the expression of survivin and adult neurogenesis after TBI, while also suggesting that the upregulation of survivin may represent a new class of effective treatment for TBI.

O108 Rna Interference in the Hippocampus Demonstrates the Role of the Hes1 Gene in Adult Neurogenesis.

Background: Recent studies show that regulation of the expression of Hes1 is important to maintain neural stem cells, and to regulate the fate of embryonic stem cells during the development of the central nervous system. Moreover, upregulation of Hes1 expression was required for quiescent adult fibroblasts to resume proliferation. Therefore, the aim of the present study was to verify the feasibility and efficiency of RNA interference (RNAi) in vivo, and the role of Hes1 in endogenous adult neurogenesis.

Methods: We injected small interfering RNAs (siRNAs) directly into the hippocampus of wild-type mice, knocking down expression of Hes1. The optimal siRNA was selected by quantitative real-time PCR. The expression level of Hes1 after RNAi was analyzed by Western blot at 1, 2, 3, and 10 days post-injection, and endogenous adult neurogenesis was determined by immunofluorescence labeling and confocal microscopic detection. Cognitive function following RNAi was estimated using the Morris water maze.

Results: The expression of hippocampal Hes1 began to decrease at 1 day, and reached a nadir 3 days after injection. Along with the downregulation of Hes1, adult neurogenesis (BrdU), which occurs in the SGZ, correspondingly was reduced at 3 days. Differentiated cells in the dentate granular neurons (BrdU/NeuN) were significantly increased, but the newly-generated cells were not increased at 10 days post-injection. In addition, there was no obvious difference in the learning potential of the two groups of mice.

Conclusions: Our findings indicate that the Hes1 gene plays an important role in adult neurogenesis. Reduction of Hes1 caused newly-generated cells to differentiate into dentate granular neurons, but the amount of newly-generated cells did not increase, and the increase in differentiated cells in the hippocampus did not significantly improve mouse learning potential. More generally, we established a model in which injection of siRNA into the adult mouse hippocampus yields specific gene knockdown, and this may be useful for investigating in vivo genes that are involved in neurogenesis and behavioral plasticity.

O109 A Study of Adult Neurogenesis for Repairing Cognitive Function After Different Graded Traumatic Hippocampal Injury.

Background: Endogenous neurogenesis exists in the adult mammal brain, and the hippocampus is a typical region possessing this capacity. The consequences of hippocampal injury are manifested as learning and memory deficits. The existence of neural progenitor cells in this area may contribute to cognitive recovery following traumatic brain injury (TBI) through proliferative reaction and re-establishing synaptic contacts. We tested the capability of adult endogenous neurogenesis to repair cognitive function, and observed the regenerative status of neural progenitor cells after different graded traumatic hippocampal injuries to assess the significance of endogenous neurogenesis in the repair of injury.

Methods: Forty-five Wistar rats were randomly divided into mildly- and severely-injured groups and a control group, which were subjected to different grades of lateral fluid percussion damage to the hippocampus. Cognitive function was tested at 8–12, 29–33, and 57–61 days post-injury using the Morris water maze, and brain immunofluorescence staining was performed at 7 and 61 days post-injury using the biomarkers BrdU and NeuN in order to examine the proliferative response and maturational fate of newly-generated cells.

Results: At 8–12 and 29–33 days post-injury the mild group and the severe group displayed significant cognitive deficits compared to the control group, but at 57–61 days post-injury there was no apparent difference between the mild group and the control group, whereas the severe group still showed more cognitive deficits compared to the other two groups. At 7 days post-injury, the injured animals displayed enhanced cell proliferation compared with the control group. At 61 days post-injury, the number of newborn neurons in the mild group was greater than that of the other two groups, and the control group had the greatest proportion of newly-generated neurons, as characterized by double labeling of BrdU with NeuN.

Conclusion: Our experiment demonstrates that TBI may be a stimulating factor for the proliferation of progenitor cells in the adult hippocampus, but more serious brain trauma is not accompanied by more newly-generated cells, and endogenous neurogenesis can only repair brain function to certain extent. The mature hippocampus can restore cognitive function through endogenous neurogenesis after mild trauma. With severe trauma, however, the microenvironment of neurogenesis is changed, which inhibits new cell generation and leads to incomplete injury repair and brain dysfunction, requiring further medical treatment.

O110 Effect of PACAP on Traumatic Brain Injury in Rats Through the TLR4/NF-KB Pathway.

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) has demonstrated neuroprotective effects against focal cerebral ischemia, traumatic brain injury, and Parkinson's disease. However, the underlying molecular mechanisms remain unclear. The aim of the present study was to investigate the effect of exogenous PACAP on the toll-like receptor 4 (TLR4)- and nuclear factor-kappa B (NF-κB)-related signaling pathway on secondary brain injury in rats after traumatic brain injury (TBI).

Methods: The SD rats were randomly divided into four groups (n = 8): a normal group, a sham group, a vehicle + TBI group, and a PACAP + TBI group. A right parietal cortical contusion was produced by weight-drop injury. PACAP was administered intracerebroventricularly at a dose of 1 μg/5 μL at 20 min before TBI. Brain samples were extracted at 24 h post-trauma.

Results: Light microscopy and electron microscopy indicated that the brain tissue around the injured cortex had edema, hemorrhage, inflammatory cell infiltration, and swollen neurons showing degeneration, and the neurons were in disarray in the hippocampus. Apoptotic neurons was also observed. Oligodendrocytes, astrocytes, and activated microglia were increased around the injured cortex and hippocampus. Pretreatment with PACAP markedly attenuated the injury, inhibited the protein expression of TLR4 and MyD88 in the injured cortex and hippocampus, but did not significantly change the expression of TLR4 and MyD88 in the striatum. Pretreatment with PACAP inhibited the expression of NF-κB and p-IκB, increased the expression of IκB, and decreased the Bax:Bcl-2 protein ratio. Meanwhile, we analyzed the expression of the TLR4- and NF-κB-related signaling pathway in the uninjured cortex, hippocampus, and striatum. There was no significant alterations seen in any group.

Conclusion: Pretreatment with PACAP may protect against TBI via attenuating the TLR4/NF-κB-mediated secondary inflammatory response following TBI.

O111 Surgical Strategies for Severe Brain Contusion and Laceration.

Background: The purpose of our study was to elaborate and evaluate the surgical strategies for severe brain contusion and laceration. Depending on the location and severity of injury, as well as the principles of decompression and brain protection, surgical treatments of severe brain contusion and laceration were classified into four types: type I, simple decompressive craniectomy, without resection of the contusion and laceration focus; type II, resection of the contusion and laceration focus combined with decompressive craniectomy; type III, safe cerebral lobe resection combined with decompressive craniectomy, without resection of the contusion and laceration focus; and type IV, contusion and laceration focus resection only, without decompression.

Methods: We retrospectively analyzed 140 cases of severe brain contusion and laceration treated with surgery. The cases were classified as follows: 44 patients (31.4%) operated with type I; 52 patients (7.1%) operated with type II; 36 patients (25.7%) operated with type III; and 8 patients (5.8%) operated with type IV. Glasgow Outcome Scale (GOS) scores were measured after > 6 months of follow-up. For GOS results, favorable recovery and moderate disability were defined as favorable outcomes. The complications and therapeutic effects of the different groups were analyzed and compared.

Results: The 6-month follow-up data showed that the outcomes in the types I, II, and III groups were better than those of the type IV group (p < 0.05). However, the favorable outcome rates of types I and III were still higher than that of type II. Our data show that severe brain contusion and laceration can be treated with different surgical strategies according to the location and severity of injury. Surgical strategies based on reductions of intracranial pressure and protection of brain function will achieve better therapeutic effects than other strategies.

Conclusion: Simple decompressive craniectomy and safe cerebral lobe resection combined with decompressive craniectomy are recommended as the preferred surgical strategies for severe brain contusion and laceration.

O112 Transarterial Embolization of Traumatic Carotid-Cavernous Fistulas with Ethylene Vinyl Alcohol Copolymer (ONYX).

Background: Here we summarize the preliminary experience and effectiveness of treating traumatic carotid-cavernous fistulas (TCCFs) with ethylene vinyl alcohol copolymer (Onyx).

Methods: In 11 patients with 12 traumatic carotid-cavernous fistulas, we covered the fistulas with balloons, and super selected the cavernous sinus through the fistula, then embolized the fistulas with pure Onyx or a combination of coils or detachable balloons.

Results: The patient with the bilateral TCCFs received secondary treatment, in light of the changes seen in cerebral blood flow after the primary treatment of one side. Angiographic control revealed that all of the fistulas were obliterated at the end of treatment, and all patients had good patency of the internal carotid arteries. Clinical examination showed varying resolution of the signs and symptoms of carotid cavernous fistulas, with no new neurological signs, and the postoperative visual acuity of 4 patients totally recovered. No recurrent fistulas were shown at 7 months follow-up by DSA or MRA in 3 cases.

Conclusion: Transarterial embolization of complicated traumatic carotid-cavernous fistulas with ethylene vinyl alcohol copolymer (Onyx), assisted by balloons, appears to be effective and safe.

O113 Hydrogen-Rich Saline Provides Protection Against Traumatic Brain Injury in Rats.

Background: Hydrogen has been proven to be a novel antioxidant through its selective reduction of the hydroxyl radical. This study was conducted to explore whether treatment with hydrogen-rich saline would limit the extent of injury seen following experimental traumatic brain injury.

Methods: Experimental TBI was induced in rats by a cryogenic injury model. Hydrogen-rich saline or placebo (physiologic saline) was injected IP immediately after, and at 24 and 48 h after injury. Forty-eight hours after injury brain water content was measured with the wet-dry method, and blood–brain barrier (BBB) breakdown was evaluated by assay of Evans blue extravasation. Furthermore, the extent of cerebral damage was also assessed.

Results: Administration of hydrogen-rich saline markedly improved recovery from motor dysfunction compared with the placebo group (p < 0.05). Brain edema was significantly reduced in the cortex of the hydrogen-treated group relative to that seen in the placebo-treated group (p < 0.05). BBB breakdown was significantly lower in the hydrogen-treated group than in the placebo-treated group (p < 0.05). Hydrogen treatment reduced injury volume significantly compared to the placebo group (p < 0.05).

Conclusion: This preliminary study has demonstrated that hydrogen-rich saline might afford significant neuroprotection in an experimental TBI model, and may hold promise for future clinical applications.

O114 Experimental Study of Hypertonic Sodium Chloride Hydroxyethl Starch-40 Injection for Cryogenic Brain Edema in Rats.

Background: Here we explore the therapeutic effect of hypertonic sodium chloride hydroxyethyl starch-40 injection (HSH) on cryogenic brain injury in rats.

Methods: In our model, we used dosages of 2, 4, and 8 mL/kg, compared with mannitol and normal saline (both 4 mL/kg dosage), and the optimal dosage to treat brain edema on the basis of intracranial pressure (ICP) and cerebral water content was evaluated.

Results: HSH decreased ICP after cryogenic brain injury, and maintained it at a lower level. Different dosages of HSH had different acting times in maintaining ICP. The data indicated that the 2-mL/kg HSH group induced less reduction in ICP than the other three treatment groups, and that there was no difference between the 4-mL/kg HSH group and the 8-mL/kg HSH group in decreasing ICP. The cerebral water content of the normal side of the treatment groups was significantly decreased compared to that of the sham group, but there was no significant difference between them on the injured side.

Conclusion: HSH has a similar therapeutic effect to MNT on cryogenic brain edema in rats, and there is a dose-effect relationship. An ideal HSH dosage of 4 mL/kg is recommended to treat brain edema.

O115 Endovascular Treatment of Traumatic Aneurysms: A Review of 37 Cases.

Background: Traumatic aneurysm is considered an unusual but dangerous complication after head trauma, and it is an easily missed diagnosis. Endovascular treatment has been considered an efficient method to treat these aneurysms. We performed this retrospective study to evaluate the feasibility, effectiveness, and safety of endovascular treatment for traumatic aneurysms.

Methods: Between March 2000 and October 2010, 37 patients with 37 traumatic aneurysms received endovascular treatment at our institution. We retrospectively collected and analyzed the data for these patients, including demographics, morphologic features of the aneurysms, treatment results, and follow-up.

Results: There were 11 cases of traumatic dissecting aneurysms, 8 located in the cervical segment of the carotid artery, and 3 located in the vertebral artery. There were 26 cases of traumatic pseudoaneurysms, 2 located in the pericallosal artery, 3 located in the supraclinoid segment of the carotid artery and 17 located in the cavernous segment, 2 located in the basal artery, and 2 located in the middle meningeal artery; 7 of the 26 pseudoaneurysms developed into carotid cavernous fistulas after the rupture of the aneurysms. The patients received coil or stent angioplasty, or stent-assisted embolization or onyx embolization, parent artery occlusion, or membrane-covered stent implantation. All of the cases with dissecting aneurysms had vessel reconstruction. Of the 26 pseudoaneurysms, complete occlusion was achieved in 17, a residual neck remained in 7, and 2 had parent artery occlusion. Procedure-related complications occurred in 1 patient, leading to no permanent effect. The MRS score at discharge was 0–2 in 31 patients and 3–6 in 6 patients. The angiographic follow-up results of 29 patients (mean 13.6 months) showed 4 with recurrence and retreatment, 1 with parent artery occlusion, and the other 24 remained stable or improved. The clinical follow-up (mean 33.5 months) demonstrated neurologic deterioration or rebleeding.

Conclusions: Our preliminary experience demonstrates that interventional treatment for traumatic aneurysms is feasible and efficacious. However, its long-term safety should be further evaluated by larger case series and more adequate follow-up.

O116 Clinical Analysis of Mild Hypothermia Combined with Hyperbaric Oxygen for Traumatic Cerebral Infarction.

Background: Here we discuss the mechanisms and clinical manifestations of traumatic cerebral infarction (TCI), and the therapeutic effect of mild hypothermia combined with hyperbaric oxygen on TCI.

Methods: Sixty patients with TCI were randomly divided into a mild hypothermia combined with hyperbaric oxygen treatment group, and a control group, with 30 patients in each group. The therapeutic effects of the two groups were statistically analyzed according to the GOS prognostic scoring system 6 months after injury.

Results: The good recovery rate was 53.33% in the mild hypothermia combined with hyperbaric oxygen treatment group, and 26.67% in the control group. There was a significant difference between the two groups.

Conclusion: Mild hypothermia combined with hyperbaric oxygen treatment can improve cerebral microcirculation and the hemorheological index of the cerebral infarction area, and is effective in improving outcomes and reducing disability in patients with TCI.

O117 The Diagnosis and Treatment of Traumatic Intracranial Aneurysms.

Background: Traumatic intracranial aneurysms (TICA) are rare, but the mortality and morbidity rates for patients harboring these aneurysms are much higher than those with true aneurysms. We present 7 cases of TICA and discuss their clinical characteristics, diagnosis, and treatment options.

Methods: We studied 7 patients with TICA in our hospital from September 2005 to August 2009. We retrospectively collected data for traumatic causes, related symptoms of TICA, diagnostic methods for TICA, and Glasgow Outcome Score at discharge.

Results: Our 7 patients were all injured in traffic accidents. The symptoms of TICA were as follows: 2 patients suffered from recurrent SAH after closed head injury, and 5 patients had severe nasal bleeding after TBI and skull base fracture. The mean duration from diagnosis to our hospital was 41 days. One patient was diagnosed with CT angiography, 1 with transcranial doppler, and 5 with DSA. Two aneurysms involved the distal anterior cerebral artery, and 5 involved the internal carotid artery at the level of the skull base. All patients were treated with endovascular embolization.

Conclusion: TICA usually occurs as a consequence of severe head trauma. Early diagnosis with cerebral angiography and prompt treatment are essential. For most TICA cases endovascular therapy is the first option.

O118 Contributing Factors and Treatment of Infection Complicated by Malignant Encephalocele After Bone Flap Decompression.

Background: The purpose of our study was to elaborate and discuss the contributing factors and comprehensive treatment of infection complicated by malignant encephalocele after bone flap decompression.

Methods: We performed a retrospective analysis of 9 cases of craniocerebral injury or spontaneous intracranial hemorrhage who received emergent bone flap decompression and later developed infection complicated with malignant encephalocele.

Results: The region and surgical type of decompression was incorrect in 6 cases, and intracranial encapsulated hydrops was not drained in time in 3 cases. Bacterial cultures of CSF or incisional secretions were positive in 7 cases, and the bacterial strains were consistent with the sputum cultures. All cases underwent surgery after anti-infection and other treatment. The surgical treatment included local debridement, duraplasty with pedicle fascia flap, scalp defect repair with shift flap, and drainage of hydrops. All 9 cases were cured.

Conclusion: Incorrect decompression region and unrelieved intracranial hypertension are the main causes of malignant encephalocele. Infection is probably the result of local bacterial spread after incision disruption. Once infection develops from the encephalocele, surgery is needed in most cases. Choice of correct surgical type is the key means of preventing these infections.

O119 Right Median Nerve Stimulation in Post-Traumatic Coma.

Background: Reduced state of consciousness remains one of the major consequences of severe traumatic brain injury. To date, little progress has been made in its alleviation, even though a great deal of attention has been given to the issue. The question on every neurosurgeon's mind is what a physician can do to help coma patients and their families when lives are saved through intensive medical intervention. To investigate safe and efficient coma awakening strategies is among the targets of severe brain injury treatment.

Methods: In this clinical trial, we applied the right median nerve stimulation (RMNS) technique in patients suffering from coma at the acute stage following primary brainstem injury. Eighty-seven patients were recruited into this multi-center clinical trial, and were randomly divided into treatment and control groups. In the treatment group, RMNS was used as the coma awakening method during the NICU period, and data including intracranial pressure, Glasgow Coma Scale score, and vital signs were taken daily for patients in both groups. Patients received RMNS treatment 8 h per day for 2 weeks, and were followed-up for 3 months.

Results: The initiation of RMNS was at 9.2 ± 1.36 days in the treatment group. RMNS showed no significant relationship with changes in ICP values, regardless of variations in intracranial status. At the end of 2 weeks of treatment, the mean GCS scores of the treatment group were significantly higher compared with controls (p < 0.01). Three-month follow-up showed that more patients regained consciousness in the treatment group, and GOS scores were higher compared with controls (p < 0.05).

Conclusions: RMNS exhibits potential therapeutic value for patients with long-term coma and those in a vegetative state. The present study is the first to report the application of RMNS in patients with acute traumatic coma resulting from primary brainstem injury. Clinical data indicate that RMNS is a safe method to increase arousal of brain structures, even in patients who are still under NICU treatment, and the GCS and GOS data indicate that RMNS can hasten the recovery of decreased consciousness and improve prognosis, at least in those with primary brainstem injury.

O120 Endovascular Treatment of Traumatic Carotid-Cavernous Sinus Fistulas.

Background: Here we summarize the endovascular methods for the treatment of traumatic carotid-cavernous sinus fistulas (TCCF).

Methods: Fifty-six TCCF patients were admitted to our department from August 2000 to August 2010, and endovascular embolization techniques and outcomes of the treatments were analyzed retrospectively.

Results: Patients were treated by the detachable balloon technique in 36 cases, microcoil fistula embolization in 3 cases, cavernous sinus embolization with coils alone or coils combined with Onyx in 8 cases (transarterial approach in 4 cases and transvenous approach in 4 cases), stent graft technique in 6 cases, and internal carotid artery occlusion with balloon in 4 cases. All 56 cases were cured, and the rate of internal carotid artery patency was 92.9% (52/56). There were no complications during the procedures, except for re-treatment with balloon due to early deflation in 1 case. After embolization, all patients were followed up for 3–36 months. Two patients had pseudoaneurysms, and one was embolized by coils for obvious symptoms, and the other asymptomatic pseudoaneurysm was not treated.

Conclusion: Although the detachable balloon technique is the first choice of treatment for TCCF, microcoils and Onyx are good alternative treatments when the orifice of the fistula is too small to allow entry of the balloon. Stent grafting is a useful tool for TCCF. Further research and development are needed to optimize stent graft technology for the cerebrovascular system.

O121 A Clinical Investigation of the Mechanism of Growing Skull Fractures in Children.

Background: Many theories have been offered to explain growing skull fractures (GSFs), such as dural tears, arachnoid herniation, increased intracranial pressure, bone absorption due to ischemia of the fracture line, and delayed or ceased bone growth. These theories, however, are limited by certain inadequacies. In this prospective study, we sought to uncover the mechanisms of GSFs, and their treatment methods in children.

Methods: Ten patients with GSFs who received treatment at our hospital between November 2000 and October 2009 were retrospectively analyzed. The age at injury, duration from the time of injury to the appearance of the GSF, fracture width, and imaging characteristics were analyzed. Cranioplasty was carried out, while duraplasty was not performed.

Results: The age at injury ranged from 7–21 months, and the age at surgery ranged from 3–5 years. The injuries included 4 fall injuries and 6 automobile collision injuries. All were linear skull fractures. The duration from the time of injury to the appearance of a GSF was <1 month in 4 cases and <2 months in 6 cases. Six patients had frontal bone fractures, 2 had parietal bone fractures, and 2 had occipital bone fractures. The fracture width ranged from 1.5–3.0 cm. The growing fractures became stationary just after onset, without further progression. CT revealed 4 cases of encephalocele underneath the fracture, and 6 cases of encephalomalacia due to brain contusion. Follow-up ranged from 6 months to 7 years. Titanium plate fixation was stable, without loosening or displacement. There were no skull deformities in any patient.

Conclusion: GSFs usually occur in young children. The rapid growth of the brain in young children produces an outward expansion force, which plays a crucial role in GSF development. It is possible that the current theories such as dural tear, arachnoid herniation, increased intracranial pressure, bone absorption due to ischemia of the fracture line, and delayed or ceased bone growth, only constitute secondary causes.

O122 Improved Neurite Outgrowth on Central Nervous System Myelin Substrate by Sirna-Mediated Knockdown of NGR.

Background: The purpose of this study was to investigate the in vitro effect of short interfering RNAs (siRNA) against NgR on neurite outgrowth in an inhibitory substrate.

Methods: Three siRNA sequences directed against NgR were designed and cerebellar granule cells were transfected. Reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence double staining were used to screen for the most efficient sequence of siRNA against NgR. The most efficient sequence of siRNA NgR was transfected into cerebellar granule cells grown on CNS myelin substrate, and compared with scrambled sequence-transfected cells and non-transfected cells.

Results: The results showed that NgR mRNA decreased notably at 24 and 48 h, and recovered by 96 h after transfection with siRNA NgR sequence 1 (p < 0.05). NgR immunoreactivity was also markedly reduced 24 and 48 h after transfection of siRNA sequence 1 compared with before transfection (p < 0.05). The immunoreactivity of NgR recovered after 72 h of post-transfection. In contrast, neurite growth on the myelin substrate was greatly improved within 72 h after transfection with siRNA sequence 1, compared with the scrambled sequence-transfected group or the non-transfected group (p < 0.05).

Conclusion: We conclude that siRNA-mediated knockdown of NgR significantly inhibits NgR expression, thereby improving neurite outgrowth in vitro.

O123 Treatment Strategies for Penetrating Orbito-Cranial Injuries: Two Case Reports and Literature Review.

Background: Here we report two cases of penetrating orbito-cranial injuries. One case was operated by early surgical debridement. The other patient experienced a third operation for cellulitis in the orbit, brain abscess, and subperiosteal abscess present after two operations. We discuss key points of treatment of penetrating orbito-cranial injuries and infectious complications.

Methods: The relationship of preoperative evaluation and treatment strategies with curative effect is analyzed in a case of early debridement. At the same time, the treatment process and operative strategy of another patient with cellulitis of the orbit, brain abscess, and subperiosteal abscess, are also discussed. The second patient initially experienced debridement for orbito-cranial penetrating wounds, followed by resection of a right frontal brain abscess, and then was transferred to our hospital for the third operation.

Results: The first patient experienced early complete debridement, foreign body excision, optic canal and supraorbital split decompression, and cranium reconstruction at the same time, and his wound was healed at phase 1. Follow-up has been for 11 months post-surgery. He had good recovery of eyesight, eye movement, and satisfactory appearance, and with no postoperative complications. The second patient experienced one operation for puncture drainage of brain abscesses, surgical debridement, and drainage of intraorbital and frontal subperiosteal abscesses, and was cured with good recovery without relapse at 10 months follow-up.

Conclusion: The treatment of penetrating orbito-cranial wounds is complicated, and they can cause brain injury, accompanied by ocular trauma, cranial nerve and vascular injury, and may lead to orbito-cranial deformities and nerve dysfunction. Thus treatment is very difficult. Once infectious complications occur, they are difficult to handle and may directly endanger life. The ideal treatment of penetrating orbit-cranial wounds includes early thorough debridement, effective hemostasis, and skull base reconstruction, in order to recover a satisfactory appearance and to prevent complications. Early complete debridement is the key, and often requires multidisciplinary cooperation.

O124 Analysis of Risk Factors Related to Early Post-Traumatic Seizure in Patients with Open-Head Injury.

Background: The risk of early post-traumatic seizure in open-head injury is high, and seizures may aggravate damage to the brain. Thus the prevention and therapy of early post-traumatic seizures in open-head injury is important. We aimed to investigate the risk factors for early post-traumatic seizure in open-head injury, and prophylaxis of the seizures.

Methods: We identified 91 patients treated in the Shanghai Institute of Neurosurgery from September 2006 to September 2009. We obtained data on open-head injuries and early post-traumatic seizures in these patients, and analyzed the clinical data retrospectively.

Results: In all, 13 patients with open-head injuries suffered early post-traumatic seizures. Chi-square testing found that age, severity of injury, contusion, intracerebral hematoma, traumatic subarachnoid hemorrhage, depressed fracture, and lesions in the parietal lobe had significant effects (age, OR = 7.719; contusion, OR = 28.590; traumatic subarachnoid hemorrhage, OR = 8.244; intracerebral hematoma, OR = 24.344).

Conclusion: Early post-traumatic seizures should be controlled promptly in patients with open-head injury, and anti-epileptic drugs should be used prophylactically in patients at high risk.

O125 A Case Report of Cerebral Salt-Wasting Syndrome.

The cerebral salt-wasting syndrome (CSWS) was first proposed in 1950. The syndrome, which is easily confused with SIADH, is often seen in those with brain trauma and craniopharyngeal canal tumors. Damage to the hypothalamo-hypophyseal system is the cause of SIADH, and antidiuretic hormone induces water retention, and then dilutional hyponatremia. On the other hand, CSWS is due to the competitive inhibition of the antidiuretic hormone receptor by atrial natriuretic peptide or brain natriuretic peptide, resulting in the loss of sodium. If a brain trauma patient undergoing routine treatment appears to have hyponatremia without gastrointestinal decompression, vomiting, or overhydration, a diagnosis of CSWS should be considered. The diagnostic criteria include: basic disease of the central nervous system; hyponatremia (20 mmol/L); urinary production > 1800 mL/d; hypovolemia; and dehydration. Our report concerns on a patent with CSWS after skull reconstruction. Regarding clinical treatment, expanding blood volume is most important, and limitation of water intake is absolutely essential. The hypertonicity natrium is commonly used. One should bear in mind that overly fast natrium infusion will lead to demyelinating disease, so careful monitoring is needed. Electrolyte disturbances can be rectified after the correct therapy has been given.

O126 Can Early Decompressive Craniectomy Improve Patient Outcomes in Traumatic Brain Injury?

Background: Decompressive craniectomy (DC) is an important method for managing severe traumatic brain injury (TBI). At present, controversy about this procedure exists, especially about the optimum operative time frame for patients with TBI. We analyzed the effect of early DC as a first-tier therapy for intracranial hypertension in the management of TBI.

Methods: A prospective study was performed at the First Affiliated Hospital, College of Medicine, Zhejiang University. From January 2008 to December 2009, 25 patients who underwent early DC were included in the study, and 19 patients who underwent late DC as a second-tier therapy for intracranial hypertension were included as a control group.

Results: The 30-day mortality rate after surgery was 16% in the study group, and the overall mortality rate was 20% at 6-months follow-up. A total of 52% of patients (13 patients) had good outcomes (GOS score 4 or 5), and 7 patients remained in a severely disabled or vegetative state (GOS score 2 or 3). In the control group 4 patients died, and 12 had good outcomes at 6-months follow-up. The remaining 3 patients had poor outcomes (GOS score 2 or 3). The study group was well matched with the control group (there were no differences in patient demographics and trauma severity between the two groups). However, the outcomes in the study group were no better than those in the control group, as evaluated by the 6-month GOS score.

Conclusion: Early DC as a first-tier therapy for intracranial hypertension did not improve patient outcome compared with late DC for managing TBI. A well-designed prospective study is necessary for a thorough investigation.

O127 The Analysis of the Cause of Death in Severe Craniocerebral Trauma.

Background: We sought to analyze the cause of death in severe craniocerebral trauma, to summarize the experiences, and to assess measures of prevention and cure.

Methods: Seventy-six patients with severe craniocerebral trauma were analyzed retrospectively for their characteristics, courses of cure, associated injuries, and causes of death.

Results: The main causes of death early were the primary and secondary central failures and hemorrhagic shock from associated injuries. The main causes of delayed death were cerebral herniation due to progressing intracranial hematoma and intracranial hypertension, the failure of brainstem function, and lung infections.

Conclusion: Timely pre-hospital care, close patient observation, early and appropriate neurosurgery, and prevention of complications are important in successfully treating severe craniocerebral trauma.

O128 Decompressive Craniectomy or not: Experience of 41 Patients with Severe Traumatic Brain Injury.

Background: The effectiveness of decompressive craniectomy (DC) has been well documented for the treatment for severe traumatic brain injury (TBI), but related complications frequently occur. The indications for DC are re-examined and discussed in this study.

Methods: From October 2008 to May 2009, 41 patients aged 18 to 75 years with severe traumatic brain injury were included and divided into a DC group (DC, n = 15), and a non-DC group (NDC, n = 26), according to intraoperative conditions. Postoperative intracranial pressure, complications, need for a second operation, and outcomes were compared between the two groups.

Results: The mean preoperative GCS score in DC group was significantly lower than that in NDC group (p < 0.05). In the DC group, two patients had seizures post-surgery, and another developed cerebrocele during follow-up, and the patients in the NDC group had no seizure, delayed hematoma, CSF fistula, cerebrocele, or infection. Eight patients in the DC group and two in the NDC group died. Patients in the NDC group had significantly lower mortality and better prognoses (p < 0.05).

Conclusion: Decompressive craniectomy is necessary to manage fulminant intracranial hypertension or intraoperative brain swelling. After total removal of the hematoma and necrotized neural tissue, it is safe to replace the bone flap. Decompressive craniectomy does not necessarily lead to better outcomes.

O129 Successful Treatment of Intracranial Infection by Acinetobacter Baumannii by Continuous Lumbar Cisterna Drainage and Intrathecal Colistin.

Background: Here we explore the effect of the treatment of intracranial infection by Acinetobacter baumannii with continuous lumbar cisterna drainage and intrathecal colistin.

Methods: We cured 23 patients of intracranial infection with Acinetobacter baumannii using continuous lumbar cisterna drainage and intrathecal colistin.

Results: In 23 patients with intracranial infection with A. baumannii, 2 died of central failure, 1 patient died of multiple organ failure, and 1 patient required discharge in treatment. Nineteen patients were clinically cured, and the cure rate was 82.6%. These 19 patients were followed-up for 1–6 months, and none of them had repeat intracranial infection.

Conclusion: The treatment of intracranial infection by Acinetobacter baumannii with continuous lumbar cisterna drainage and intrathecal colistin is safe and effective. It is valuable in reducing mortality and complications, and in improving prognosis.

O130 Clinical Research on Three-Dimensional Shaping Titanium Mesh to Repair Skull by Digitized Imaging.

Background: Here we explore the clinical application in cranioplastic surgery of three-dimensional shaping titanium mesh by utilizing digitized imaging.

Methods: The operative time, post-operative complications, and satisfaction with shaping of 47 patients with skull defects were analyzed after cranioplastic surgery.

Results: There were no incision infections, subcutaneous effusions, or titanium mesh depressions after surgery. The patients were satisfied with their outcomes and post-operative appearances.

Conclusion: Three-dimensional shaping titanium mesh by utilizing digitized imaging has many advantages, such as a simple and convenient surgical process, few complications, and natural curves and physiological shape post-cranioplasty.

O131 Clinical Analysis of 46 Cases of Epidural Hematoma with Minimally-Invasive Puncture Treatment.

Background: Here we investigate the clinical efficacy of minimally-invasive puncture and drainage in treating epidural hematoma.

Methods: A retrospective chart review of 46 consecutive patients with epidural hematoma was recruited from January 2007 to October 2010. All subjects without local fractures or large blood vessels adjacent to or across the sinus were included. The examination and treatment were performed at 3–5 days post-injury. CT located the center of the hematoma, and it was aspirated by injection of 2–4 million U urokinase after local anesthesia with 2% lidocaine, and it was assessed once per day for hematoma dissolution, drainage, and other treatment. Repeat CT scans were done on post-operative days 1, 3, and 5, and the drainage needle was removed when the hematoma was completely or mostly (more than 90%) absorbed. Routine antibiotics were given to prevent post-operative infection.

Results: At 3–5 days after surgery, the hematoma was completely drained in 34 patients (74%), and 12 patients (26%) still had small quantities present (≤5 mL). Forty-six patients had favorable outcomes according to GOS status when followed-up for 1–1.5 months.

Conclusions: Minimally-invasive puncture and drainage, which can minimize injury and attain favorable outcomes, is an effective approach for the treatment of epidural hematoma.

O132

Abstract Withdrawn

Pengcheng Wang Hao Peng People's Hospital of Hainan Province, Haikou, Hainan, China O133

Analysis of Treatment Measures for Acute Encephalocele.

Background: Patients with brain injury are susceptible to acute encephalocele, and its attendant difficult treatment and high mortality rate. Here we analyze the causes of acute encephalocele in patients receiving surgery for brain injury, to ascertain the most reasonable treatment for these patients, to improve treatment of these patients, and to reduce rates of disability and death.

Methods: This was a retrospective analysis of 33 patients with craniocerebral injury who had acute encephalocele between January 2008 and October 2010 in our hospital. We assess the measures used in these patients, and summarize the results achieved.

Results: According to GOS scores, good recovery was seen in 5 cases, moderate disability in 6 cases, severe disability in 4 cases, vegetative state in 3 cases, and death in 15 cases. The mortality rate was 45.5%, and the severe disability rate was 21.2%.

Conclusion: Delayed intracranial hematoma post-surgery was the main cause of acute encephalocele in these patients, often due to rapid swelling, but timely treatment can achieve good results. Low blood pressure and cerebral perfusion pressure and extensive brain injuries are also important preoperatively, often causing gradual encephalocele formation, with poor outcomes. In the event of encephalocele during surgery, an immediate CT is needed to clarify the diagnosis, followed by craniotomy to remove the hematoma and the bone plate for decompression, thus reducing secondary brain injury and mortality.

Pengcheng Wang Hao Peng People's Hospital of Hainan Province, Haikou City, Hainan, China

O134 Clinical Analysis of 170 Cases of Chronic Subdural Hematoma in the Elderly with Minimally-Invasive Puncture Treatment.

Background: Here we investigate the clinical efficacy of minimally-invasive puncture and drainage in treating chronic subdural hematoma in the elderly.

Methods: A retrospective chart review of 170 consecutive patients with epidural hematoma was recruited from January 2007 to October 2010. After a CT scan to locate the hematoma, the thickness of hematoma was determined, and the scalp was drilled after 2% lidocaine local anesthesia. The hematoma was drained until the liquid was clear, and the drain was removed. Conventional antibiotics were used to prevent infection post-surgery, and a CT scan was done at 1 month post-surgery.

Results: All patients improved and the drainage probes were removed in less 3 days, and average hospital stay was 5 days. CT scans indicated that the hematoma was gone, there were no recurrences, and all recovered completely by 1 month.

Conclusions: Minimally-invasive puncture and drainage, which can minimize injury and yields favorable outcomes, is an effective approach in the treatment of chronic subdural hematoma in the elderly.

Wangpengcheng Hao Peng People's Hospital of Hainan Province, Haikou City, Hainan, China

O135 Delayed Epidural Hematoma in the Temporal Lobe Leading to Brain Herniation After Minor Injury.

Background: In this paper we discuss delayed epidural hematoma after minor injuries caused by brain herniation in the temporal lobe and clinical features and treatment experience.

Methods: This was a retrospective analysis of 38 patients from January 2008 to November 2010 with epidural hematoma after minor injuries caused by brain herniation in the temporal lobe. In all, 27 males and 11 females were included; 26 cases were traffic injuries, 10 cases were combat injuries, and 2 cases were fall injuries; GCS score was 13 for 5 cases, 14 for 6 cases, and 15 for 27 cases at admission; 2 cases had no epidural hematoma on initial CT done 0.5–2 h post-injury; hematoma was less than 5 mL for 8 cases, 5–9 mL for 17 cases, and 10–20 mL for 11 cases; partial skull fractures were present in 7 cases. Unilateral mydriasis was seen in 5 cases, and bilateral mydriasis in 2 cases at 3 h post-injury; unilateral mydriasis was seen in 13 cases, and bilateral mydriasis in 7 cases at 3–6 h post-injury; unilateral mydriasis was seen in 8 cases, and bilateral mydriasis in 3 cases at 6–12 h post-injury. All 38 cases had craniotomy to remove the hematoma, 24 cases for decompression surgery to remove bone, and 31 patients were found to have linear fractures of the frontotemporal or temporparietal areas in surgery.

Results: The evaluation results for GOS at discharge: good recovery for 29 cases (76.3%), moderate disability for 7 cases (18.4%), severe disability for 2 cases (5.3%), and no deaths. Large cerebral infarction was seen in 9 cases, and small cerebral infarction in 4 cases; subdural effusion was seen in 16 patients after surgery.

Conclusion: Delayed epidural hematoma in the temporal lobe was often caused by local fractures, and linear fractures are not easily found on preoperative CT scans. Patients with frontotemporoparietal injury with normal CTs taken early after injury (within 2 h), and those with only small epidural hematomas, should be closely observed, and CT should be repeated if patients are found to be bleeding or the hematoma grows. In these cases surgical treatment should be immediate to prevent secondary brain injury.

Wang Maode Li Ruichun Xu Gaofeng Xie Wanfu Zhang Zhonglin Bao Gang First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shanxi, China

O136 Maxillofacial Osseous Reconstruction in a One-Stage Operation Combined with Craniotomy for Moderate Craniocerebral Injury.

Background: Here we evaluate the practicality of maxillofacial osseous reconstruction in a one-stage operation combined with craniotomy for moderate craniocerebral injury.

Methods: Nine patients suffered from frontal and/or temporal lobe contusions (GCS score < 13, mean 11.7), and maxillofacial fractures (including the ethmoid bone, nasal bone, lacrimal bone, and frontal and maxillary sinuses). They were treated in our department between January 2009 and October 2010. All of the patients underwent craniotomy for intracranial hematoma clearance at 12 h after admission. Five patients (mean GCS score 11.9) among them received maxillofacial osseous reconstruction in a one-stage operation. The other four (mean GCS score 11.4) received maxillofacial osseous reconstruction 4 weeks after the craniotomy.

Results: All the patients were restored postoperatively to a condition of GCS score > 14 within 2 weeks. The four patients receiving maxillofacial reconstruction 4 weeks after craniotomy found that the reconstructive surgery did not go smoothly because of the scar tissue arising from the surface of the bone fragments. This phenomenon was not seen in those receiving one-stage operation of maxillofacial reconstruction. As confirmed by 3D CT reconstruction of the skull, the 5 patients who underwent the one-stage operation had good results, and none had complications. However, the outcomes in the other 4 patients were not satisfactory. Moreover, cerebrospinal fluid leakage took place in two of them after the reconstructive surgery.

Conclusion: Although the primary purpose of the treatment of craniocerebral injury is to save lives, maxillofacial osseous reconstruction in a one-stage operation can yield good results, with good cosmetic and functional outcomes, and also avoids the economic and mental burdens of a second-stage surgery. It is essential to put forward treatment guidelines detailing the use of a one-stage combined craniotomy and maxillofacial osseous reconstruction for moderate craniocerebral injury.

Wang Maode Wang Wei Wang Tuo Li Qi Chen Wei Du Chang Wang Li Kuo First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shanxi, China

O137 Lumbar Drainage for Treating Refractory Central Nervous System Infection Induced by Open Craniocerebral Injury: Report of 7 Cases.

Background: Here we evaluate the validity of lumbar drainage in the treatment of open craniocerebral injury-induced refractory central nervous system infection.

Methods: Seven patients with open craniocerebral injury, who were diagnosed with CNS infection by CSF laboratory test and culture, were treated with systemic administration of antibiotics for 5–7 days. However, the CNS infection was not cured, and even worsened. Lumbar drainage combined with systemic administration was performed in all cases. The clinical data were studied to evaluate the treatment effectiveness.

Results: The CSF culture showed that there were 3 cases of Staphylococcus epidermidis, 1 of Staphylococcus aureus, 1 of Enterococcus faecium, 1 of Enterobacter cloacae, and 1 of filamentous fungus. Drug sensitivity testing showed that most organisms were sensitive to ceftriaxone and vancomycin, and all gram-positive cocci were sensitive to linezolid. The body temperature and CSF white blood cell count improved 2–5 days after lumbar drainage. Six of the 7 patients with refractory CNS infection were cured 9–15 days after lumbar drainage, and the patient infected with filamentous fungus died 18 days after drainage.

Conclusion: Patients with open craniocerebral injury sometimes sustain CNS infection, which can be cured by systemic administration of sensitive antibiotics. When the infection becomes severe and refractory, lumbar drainage should be performed to drain the infectious CSF. In our experience, such a combined therapy is effective.

Guo Xiaoye He Huilan Wang Juan Zhao Xin Wu Yuanyuan Sun Yaping Yu Yuanyuan Wang Maode First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shanxi, China

O138 Examination of Different Rehabilitation Exercise Methods in Patients with Severe Head Injury.

Background: Here we examine the efficacy of different early rehabilitation training methods for patients with severe head injury.

Methods: Eighty patients with severe head injury were randomly divided into 2 groups: 40 patients for the rehabilitation group were treated by traditional rehabilitation training methods, combined with a T-shaped boot designed by the authors; 40 patients for the control group were treated using traditional rehabilitation training methods only. Rehabilitation training was performed for 30 min three times per day. Patient motor function was evaluated using the Brunnstrom Rating Scale, and ADL were evaluated by the Barthel Rating Scale.

Results: When the patients were discharged, the neurological function recovery in the rehabilitation group was superior to that in control group, and had fewer complications as well.

Conclusion: Traditional rehabilitation training combined with a T-shaped boot designed by the authors improve neurological function recovery in patients with severe head injury.

Gui-huai Wang Bo Han Ya-juan Tang Beijing Tiantan Hospital, Capital University of Medical Sciences, Beijing, China

O139 Syringoperitoneal Shunting for Delayed Post-Traumatic Syringomyelia: Report of 5 Cases and Literature Review.

Post-traumatic syringomyelia (PTS) is a rare and intricate complication of spinal cord injury commonly seen in male adults. Symptoms are often delayed until several years after spinal cord injury. Pain and sensory or motor deficits are the chief complaints. Without effective intervention, the course of disease is likely further deterioration. Syringoperitoneal shunting (SPS), an effective operative treatment, has been clinically widely applied. We describe five cases diagnosed with PTS in our department: three patients that suffered traffic or fall accidents with compression fractures, one that suffered an intravertebral anesthesia injury, and another that sustained a stab wound. Their intervals between spinal trauma and syringomyelia were 14, 21, 16, 13, and 6 years. In three cases, the level of the lesion was located at L1, in one case at T12, and in another at T6, where every syrinx extended cranially to the bulb. The main symptom was progressive neurological deterioration. They all had SPS and postoperative follow-up. Short-term results indicated that SPS was a good treatment choice for PTS. Long-term follow-up studies are needed to more objectively assess the therapy.

Yang Liu Li Xue Hong Quan Song Zhen Pei Liu Min General Hospital of Shenyang Military Region, PLA, Shenyan, China

O140 Curative Effect of Autologous Transplantation of Mesenchymal Stem Cells on Cold-Induced Brain Injury in Rats.

Background: Here we explore the curative effect of autologous transplantation of bone mesenchymal stem cells (MSCs) on severe brain injury induced by cold.

Methods: After MSCs from Wistar rats were proliferated, they were labeled with BrdU in vitro. The BrdU-marked autologous MSCs were injected into the internal carotid arteries of rats with severe brain injury induced by cold. Sixty-four rats were divided into four groups: group A, rats receiving routine treatment; group B, rats treated by autologous transplantation of MSCs; group C, rats treated by autologous transplantation of MSCs, GM1, and Salvia miltiorrhiza injection; group D, rats treated by papaverine injection before MSCs were autologously transplanted.

Results: The BrdU-labeled MSCs were observable in the injured brain areas. The amount of BrdU-positive cells in the injured brain area in groups B, C, and D, and the indicators of neural function in group B, were significantly more than those in group A (p < 0.05).

Conclusion: Autologous MSCs labeled with BrdU can migrate into the injured brain area after injection into the internal carotid artery and the cerebral ventricular system, and exert a curative effect in rats with cold-induced severe brain injury.

Tao Tang Di Fan Zhenquan Song Mingguang Zhao General Hospital of Shenyang Military Region, Shenyang, China

O141 Expression and Significance of VEGF During the Early Period Following Craniocerebral Missile Wounds in Canines.

Background: Here we investigate the regularity of VEGF expression early after craniocerebral missile wounds in canines, and its correlation with cerebral lesions.

Methods: We sampled at different periods and in different regions after wounding, assessed VEGF expression with immunohistochemical staining, and analyzed the correlation with cerebral edema.

Results: At 30 min after wounding, endothelial cell swelling, tight junction opening, organelle degeneration, and edema surrounding blood vessels could be seen. Water content increased continuously (p < 0.01). Increases in VEGF expression were also seen (p < 0.01). The induction and expression of VEGF in the contusion area and concussion area of the trajectory and the brainstem are an early stage reaction to injury.

Conclusion: VEGF is closely related with acute cerebral edema.

Di Fan Zaihua Xu Zhenquan Song Tao Tang General Hospital of Shenyang Military Region, Shenyang, China

O142 Experimental Study: Secondary Injury in Penetrating Craniocerebral Gunshot Wounds.

Background: Here we investigate the role of TNF-α, COX-2, caspase-3, and NF-κB/Rels in secondary injury after penetrating craniocerebral gunshot wounds.

Methods: Fourteen dogs were divided into two groups: group A, a modified model (n = 9), operated by removal of the frontotemporoparietal skull before being shot in the frontal lobe directly into the coronal gyrus; and group B, a control group (n = 5) that was operated only. The velocity and pellet weight of the projectile from the Dongfeng-SS03 pistol used were 190–210 m/sec and 2.60 ± 0.05 g. Thiopentone (25 mg/kg) was injected as anesthesia before tracheal intubation. The pistol was fixed at a distance of 20 cm from the dog's head. The target point was 2.5–3.0 cm behind the zygomatic process. The angle of incidence was 90 degree to the sagittal surface. Six hours after shooting, three brain tissue areas were removed, which were 0.5–2.0, 2.0–4.0, and more than 4.0 cm from the target point in groups A and B; those from group A were marked as group A1, A2, and A3. All samples were kept in formalin for immunohistochemical study, and in liquid nitrogen for Western blotting and polymerase chain reaction study. GAPDH was used as an internal reference.

Results: On IHC, TNF-α and COX-2 protein showed positive staining in the cytoplasm, and the level of expression ascended gradually from A3 to A1. The immunopositive rates in group A were higher than those in group B (p < 0.01). Caspase-3-positive staining was detected in the cytoplasm and nucleus, and group A2 and A3 were different from group B (p < 0.01). On Western blotting the relative amounts of TNF-α, COX-2, and caspase-3 protein in group A were higher than those in group B (p < 0.05). A difference in COX-2 levels between group A1 and A2 was also seen. On PCR the relative amounts of TNF-α, P65, P52, COX-2, and caspase-3 mRNA in group A were higher than those in group B (p < 0.01). It also showed differences among A1, A2, and A3. Moreover, P65 and COX-2 levels ascended gradually from A3 to A1.

Conclusion: TNF-α, P65, P52, COX-2, and caspase-3 are all involved in the mechanism of secondary injury in penetrating craniocerebral gunshot wounds. The role of P65 in secondary injury is more important than that of P52. The neuron degeneration induced by COX-2 may be more important than the neuron apoptosis induced by caspase-3 in secondary injury.

Zhiqing Li Guobiao Liang Haifeng Zhang Chunyong Yu Jun Lin xu Gao Jun Chen Peng Cao General Hospital of Shenyang Military Region, Shenyang, China

O143 Endovascular Treatment of Traumatic Carotid-Cavernous Fistula by an Arterial Approach: Clinical Analysis of 142 Cases.

Background: Here we evaluate the effects of endovascular therapy by an arterial approach for traumatic carotid-cavernous fistula.

Methods: All patients with carotid-cavernous fistula (CCF) were diagnosed by cerebral angiography. In all, 142 cases were treated with a detachable balloon. Patients failing balloon therapy underwent Jostent graft stent angioplasty.

Results: In all, 135 cases were successfully treated with detachable balloon, and 7 were successfully treated with Jostent graft stent angioplasty after failed with detachable balloon therapy. Two cases went on to oculomotor palsy and one to abducens nerve palsy, and they were released between 1 week and 12 days. Four cases with detachable balloon therapy recurred in 3 h to 2 weeks and received re-treatment, and there were no recurrences in patients treated with Jostent graft stents.

Conclusion: Transarterial therapy is an effective method to treat CCF. For those patients not suitable for detachable balloon treatment, blocking of the corresponding carotid artery may be employed after confirming that there is compensation by the circle of Willis. Jostent graft stent angioplasty can only be applied to those patients who have suitable anatomic conditions at the carotid siphon.

Wenjianfeng Qiansuokai Ninety-Fourth Hospital of PLA, NanChang, Jiangxi, China

O144 Effect of Early Hyperbaric Oxygenation Therapy with a Ventilator on the Incidence of Stress Ulcer in Severely Brain-Injured Patients.

Background: We explored the preventive effect of hyperbaric oxygenation therapy on the incidence of stress ulcers induced in severely brain-injured patients.

Methods: In all, 108 severely brain-injured patients (Glasgow Coma Scale score 3–8) were randomly divided into a hyperbaric treatment group and a control group. The control group's patients received omeprazole to prevent or to treat the stress ulcer, while the hyperbaric oxygen group received early hyperbaric oxygenation therapy with a ventilator.

Results: The incidence of stress ulcers was lower in the HBO group compared than in the control group (p < 0.05).

Conclusion: The incidence of stress ulcer may be higher if the brain injury is more severe or if the GCS score is lower. Early hyperbaric oxygenation therapy may help reduce the incidence of stress ulcers and the high mortality rate due to stress ulcers in severely brain-injured patients.

Chen Lei Wu Hai-Bo Ding Sheng-Hao Bao Ying-Hui Gao Guo-Yi Pan Yao-Hua Liang Yu-Min Jiang Ji-Yao Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

O145 Dynamic Changes in Intracranial Pressure After Decompressive Craniectomy in Patients with Deadly Intracranial Pressure Following Severe Tramuatic Brain Injury.

Background: Uncontrollable intracranial pressure (ICP) following severe traumatic brain injury (TBI) is a major cause of death and disability. Decompressive craniectomy (DC) has been widely used for patients with uncontrolled ICP, but some controversy remains. This study focused on the dynamic changes in ICP seen after DC in patients with deadly ICP following severe TBI, and investigate the effect on outcome.

Methods: From December 2007 to December 2010, 12 consecutive patients with severe TBI with GCS scores ≤ 8 were prospectively managed by DC. Before DC, a burr-hole was made, an ICP probe was inserted, and the initial ICP was recorded. Then routine DC was performed and the ICP was recorded after removal of the bone flap, opening of the dura, duroplasty, and closure of the scalp. ICP monitoring was continued post-surgery. The Glasgow Outcome Scale (GOS) was used to evaluate the initial neurological outcome at discharge. All data for these patients were reviewed and the relationships between ICP and outcome were analyzed.

Results: All 12 patients received unilateral or bilateral decompressive craniectomy with duroplasty. Mean initial ICP was 40.6 ± 14.7 mm Hg before craniectomy. The ICP decreased significantly to 24.1 ± 9.7 mm Hg (p < 0.05) after bone flap removal, and continued to decrease to 5.4 ± 4.3 mm Hg (p < 0.05) after opening of the dura. After duroplasty and closure of the scalp, the ICP increased slightly, but was still lower than the initial ICP. At discharge, six patients (50%, GOS 5) had good recovery, one patient (8.3%, GOS 3) had severe disability, three patients (25.0%, GOS 2) were in a vegetative state, and two patients (16.7%, GOS 1) had died.

Conclusion: Our initial results indicate that greater decreases in ICP may be obtained after dural opening during DC, and that this may contribute to improvements in outcomes.

Liang Yu-Min Bao Ying-Hui Gao Guo-Yi Pan Yao-Hua Ding Sheng-Hao Chen Lei Jiang Ji-Yao Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

O146 Primary Decompressive Craniectomy for Patients with Transtentorial Herniation Following Severe Traumatic Brain Injury.

Background: From January 2004 to March 2010, primary decompressive craniectomy(DC) was performed prospectively on 36 patients with transtentorial herniation secondary to severe traumatic brain injury. In this study we retrospectively analyzed the outcomes of these 36 patients.

Methods: The initial Glasgow Coma Scale (GCS) score of all patients was ≤ 8, and unilateral or bilateral dilation of the pupils was confirmed before surgery. All patients underwent unilateral or bilateral frontotemporoparietal decompressive craniectomy followed by duraplasty, and the accompanying hematomas were also evacuated during surgery. The intracranial pressure (ICP) before, during, and after DC was measured, and ICP monitoring was continued post-surgery. Using the ICP and mean blood pressure, the corresponding cerebral perfusion pressure (CPP) was calculated. Follow-up was continued at least for 6 months, and Glasgow Outcome Scale (GOS) scores were used to evaluate the neurological outcomes.

Results: The mean ICP was 38.5 ± 8.5 mm Hg, and it significantly decreased to 18.8 ± 2.8 mm Hg. Immediate reductions in ICP and for significant decreases of ICP and prevention of secondary brain injury, dural opening, and duraplasty were necessary.

Conclusion: The improvement in CPP seen after early primary DC may contribute to more satisfactory outcomes in patients with transtentorial herniation following severe TBI.

Liang Yu-Min Gao Guo-Yi Bao Ying-Hui Pan Yao-Hua Ding Sheng-Hao Chen Lei Tang Chao Tang Hai-Bo Jiang Ji-Yao Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

O147 Traumatic Bilateral Epidural Hematomas.

In this study we retrospectively analyzed the outcome of traumatic bilateral epidural hematomas (TBEDHs) in 40 patients. The data for these patients were retrospectively reviewed from September 2000 through September 2010. Among 40 cases, hematomas were on either side of midline in 33 cases, and at different sides of midline in 7 cases. In 18 cases TBEDHs were confirmed on initial CT scanning after injury, and the other 22 cases were progressive and were confirmed by operation or repeated CT scanning. All hematomas were evacuated after diagnosis, and venous bleeding was confirmed in 33 cases. According to the Glasgow Outcome Scale (GOS), 35 cases recovered well, 3 cases became moderately disabled, 1 case was severely disabled, and 1 case died on discharge. Our data show that the majority of TBEDHs were caused by anteroposterior forces and were mainly due to venous bleeding. Good recovery is possible if early diagnosis and management are obtained.

Weiping Li Qiusheng Zhang Meng Zhang Hengzhou Lin First Affiliated Hospital of Shenzhen University, Shenzhen, China

O148 Effect of Intracranial Pressure and Cerebral Perfusion Pressure on Brain Tissue Oxygen Pressure and Prognosis in Patients with Severe Craniocerebral Injury.

Background: Here we discuss the effect of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) changes on brain tissue oxygen pressure (PbtO₂) and prognosis after severe craniocerebral injury.

Methods: We observed the changes in CCP, ICP, prognosis, and PbtO₂, in 96 cases of severe craniocerebral injury, and then compared their relationships.

Results: There was a negative correlation between PbtO₂ and ICP when ICP was between 25 and 50 mm Hg (r = −0.693), placerate the major venous sinuses, and affect craniocervical stability. Early neurological deficits were diagnosed in 51 patients, and 23 patients had permanent neurological deficits. Nine patients died within 3 days of intensive care treatment.

Conclusion: Injury to the skull base can lead to catastrophic outcomes such as meningitis, brain abscess, neurological deficits, brain hemorrhage, and death. Each of these injuries will need an individual strategy. Decisions regarding the timing of surgery and the sequence of the surgical procedures must be made with great care. Modern surgical techniques and recent technologies, including repair of cerebrospinal fluid leakage, functional preservation of the olfactory nerves in frontobasal trauma, optic nerve decompression, decompression of the superior orbital fissure, facial nerve reconstruction, interventional technique for intravascular repair of vascular injuries, and recent developments in brainstem implants, all contribute significantly to improve outcomes and enhance the quality of life of these patients.

Su Ning Zhang Lei Wang Kai Hui Hao Cao Bao-ping Chen Xiao-yan Li Juan Luo Peng Fei Zhou Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China

O149 The Notch Signaling Pathway Mediates Neuroprotective Effects in Mouse Cortical Neurons After Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) in humans leads to neuronal death and neurological dysfunction. Reducing the necrosis and apoptosis of neurons can improve the survival rate after TBI. Notch signaling contributes to a variety of cell-fate decisions during development. Our aim was to investigate whether Notch activation could influence the apoptosis of neurons after TBI in vitro.

Methods: Cultured cortical neurons were injured by physical damage. Western blot and immunohischemistry were used to examine the activation of Notch, Notch intracellular domain (NICD), and caspase-3.

Results: Neurons exhibited substantially increased levels of NICD and caspase-3. Furthermore, blockage of the Notch pathway by a γ-secretase inhibitor significantly reduced the NICD induced by TBI. The apoptosis of neurons was also reduced.

Conclusion: These data suggest that the Notch signaling pathway may mediate the survival of neurons after TBI.

Zhang Lei Liu Wei Fei Zhou Su Ning He Yalong He Xiaosheng Cheng Guang Qu Yan Wang Kai Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China

O150 Homer Gene Expression Induced by Diffuse Axonal Injury in Neurons of Rats.

Background: Homer protein, a newly-found member of the post-synaptic density (PSD) protein family, plays an important role in neuronal synaptic activity. Our previous study showed that Homer1a may provide neuroprotection in injured neurons.

Methods: In this study, the expression and significance of three isoforms of the Homer1 gene (Homer1a, 1b, and 1c) in neurons after diffuse axonal injury (DAI) in vivo were investigated by immunohischemistry, Western blot, and real-time RT-PCR. DAI was produced by accelerated lateral head rotation.

Results: It was shown that Homer1a was not expressed in the neurons of the normal control and sham-operated groups, but was overexpressed in the neurons of the DAI group from 30 min to 72 h after DAI. However, both Homer1b and 1c were constitutively expressed in the neurons of all three groups (p > 0.05). In addition, unlike Homer1b/c, the expression of Homer1a was different in different anatomic sites (hippocampus, cortex, and brainstem). Moreover, Homer1a was found to be expressed only in the cytoplasm of the neurons, not in the nuclei.

Conclusion: Our results indicate that after DAI, the dynamically-expressed Homer1a and constitutively-expressed Homer1b/c may play important roles in the development of DAI.

Fei Zhou Zhang Lei Liu Wei Zhao Yong-geng Su Ning Wang Kai Chen Tao Li Dong Hui Hao Xijing Hospital, Fourth Military Medical University, Xi'an, China

O151 Homer1A Regulates Expression of Glutamate and GABA in an Oxygen Glucose Deprivation-Exposed Neuron Model in Rats.

Homer, one of the newly-discovered scaffold proteins, is concentrated in the excitatory synapses, in which the short-form Homer1a proteins antagonize the long-form Homer proteins that adapt glutamate receptors to the sources of calcium influx and release. In the present study, it was shown that Homer1a not only evoked Ca²⁺ release to adjust the expression of glutamate and to protect injured neurons, but it also regulated the expression of GABA to protect against oxygen glucose deprivation-exposed neuronal damage through modulating the distribution and function of GABA receptors. It was shown that Homer1a protein may play an important role in the protection of neurons, by altering the balance between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA.

Fei Zhou Zhang Xiang Gao Da-kuan Liu Wei-ping Li Bing Luo An-fu Jiang Xiao-fan He Xiao-sheng Zang Lei Xijing Hospital, Fourth Military Medical University, Xi'an, China

O152 A Retrospective Study of the Diagnoses and Treatment of 4462 Cases of Severe Traumatic Brain Injury.

Background: Here we analyze and summarize the diagnostic and treatment modalities used in order to increase the cure rate and survival rate for patients with severe traumatic brain injury (STBI).

Methods: A retrospective study was made of the diagnoses and treatments of 4462 cases of STBI. There were 3298 male and 1164 female patients in this group. The most frequent cause of injury was traffic accidents (35. 5%). Closed head injuries occurred in 3654 (81.9%), cases and open-head injuries in 808 (18.1%) cases. The most common clinical manifestations were unconsciousness and changes in pupils and vital signs. In this group, 1158 cases (26.0%) were found to have injuries to other organs, and 1356 cases (30.4%) had other complications. All of the cases underwent first aid, surgery, or conventional treatment. Emphasis was placed on the treatment of secondary insults.

Results: Surgery was done in 3023 cases (67.7%), with a mortality rate of 17.9%, and conventional treatment was done in 1439 cases (32.3%), with a mortality rate of 23.7%.There were 2462 cases (55.2%) with fair recovery, 508 cases (11.4%) with mild disability, 339 cases (7.6%) with severe disability, 272 cases (6.1%) in a vegetative state, and 881 cases (19.7%) of death in this group on discharge according to the Glasgow Outcome Scale.

Conclusion: Active diagnoses and treatments, strict rules for medication, and prevention and treatment of secondary insults may be the keys to higher cure rates and lower morbidity rates in those with STBI.

Zhang Lei Su Ning Cao Bao-ping Wang Kai Hui Hao Li Bing Zhou Chui-bing Ji Xi-tuan Fei Zhou Xijing Hospital, the Fourth Military Medical University, Xi'an, Shan'xi, China

O153 Ulinastatin Attenuates Cerebral Ischemic Neuroinjury Via AQP4- and NKCC1-Mediated Anti-Edema Action.

Background: Both AQP4 and NKCC1 have been shown to exert anti-edema effects associated with cerebral ischemic injury in vitro and in vivo, and the human urinary trypsin inhibitor ulinastatin (UTI) plays a role in the regulation of apoptosis, and is thought to have potential therapeutic applications. The aim of this study was to investigate the potential neuroprotective role of UTI against cerebral ischemic edema induced by middle cerebral artery occlusion (MCAO) in rats, and the underlying mechanism.

Methods: Adult male BALB/c mice weighing 25–30 g were subjected to 1 h MCAO and pretreated with vehicle (0.9% isotonic saline), UTI alone, or UTI plus bumetanide (a specific NKCC1 inhibitor), or TGN-020 (a specific AQP4 inhibitor), at 1–7 days after MCAO. Neurological deficit scores (NDS) and brain water content were assessed at 24 h, 72 h, and 7 days after MCAO. Neuronal apoptosis and autophagy, and AQP4, NKCC1, activated caspase-3, cathepsin B, and beclin1 expression were also determined at 24 h and 7 days after MCAO.

Results: The administration of UTI to mice with MCAO-induced acute ischemic edema resulted in significant decreases both in the levels of apoptosis and water content of the brain, increased autophagy in the acute phase of ischemic edema (24 h and 72 h), and decreased autophagy in the chronic phase of ischemic edema (7 days). Meantime, AQP4, NKCC1, and activated caspase-3 expression were decreased, and the expression of cathepsin B and Beclin1 were increased, at 24 h and 72 h after MCAO. However, the expression of AQP4 and NKCC1 were increased, and cathepsin B and beclin1 expression were decreased, at 7 days after ischemic edema. Furthermore, the neuroprotective effect of UTI was partly blocked by the AQP4 inhibitor TGN-020 and the NKCC1 inhibitor bumetanide.

Conclusions: In summary, these data suggest that UTI has neuroprotective effects against ischemic edema in vivo via AQP4- and NKCC1-mediated apoptotic and autophagic action, and that this protection may be associated with regulated activation of AQP4 and NKCC1.

Chen Tao Liu WenBo Chao XiaoDong Qu Yan Zhang Lei Luo Peng Xie KeLiang Huo JunLi Fei Zhou Xijing Hospital, the Fourth Military Medical University, Xi'an, Shan'xi, China

O154 Neuroprotective Effect of Osthole Against Oxygen and Glucose Deprivation in Rat Cortical Neurons: Involvement of the MAPK Pathway.

Osthole, a bioactive simple coumarin derivative extracted from many medicinal plants such as Cnidium monnieri (L.) Cusson, exerts a broad spectrum of pharmacological activities, and is considered to have potential therapeutic applications. The aim of this study was to investigate the potential neuroprotective role of osthole against ischemic injury in vitro, as well as the potential mechanism. Cultured cortical neurons were exposed to oxygen and glucose deprivation (OGD) for 4 h, followed by 24 h of reperfusion. Osthole exhibited remarkable neuroprotection in a dose-dependent manner, and the effect required the presence of osthole during both the OGD and reperfusion phases. Western blot was used to examine the activation of three members of the mitogen-activated protein kinase (MAPK) family: extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 kinase (p38). We found that osthole prolonged activation of ERK1/2 and prevented activation of JNK. Furthermore, we investigated the effects of MAPKs inhibitors on osthole-induced protection. The results demonstrated that the protection by osthole was partly reversed by PD98059, a selective inhibitor of ERK1/2, but was further enhanced by the JNK inhibitor SP600125. In addition, osthole-induced reductions in neuronal apoptosis were abrogated by the ERK1/2 inhibitor PD98059, whereas neuronal necrosis was further decreased by the JNK inhibitor SP600125. In summary, these data suggested that osthole has neuroprotective effects against ischemic injury in vitro via its anti-apoptotic and anti-necrotic activities, and that the protection may be associated with prolonged activation of ERK1/2 and suppression of JNK activity.

Hui Hao Zhang Lei Wang Kai Su Ning Qu Yan Zhou Chui-bing Li Bing Fei Zhou Xijing Hospital, the Fourth Military Medical University, Xi'an, Shan'xi, China

O155 Neuroprotective Effect of Hyperbaric Oxygen Preconditioning Against Cerebral Ischemic Injury in the Rat: Involvement of Noth1 and Homer1A.

Background: Here we investigate the expression of notch-1 and holmer1a proteins in the ischemic penumbra after cerebral ischemia/reperfusion in mice preconditioned with hyperbaric oxygen.

Methods: Sixty male LACA mice (20–25 g) were randomly divided into a hyperbaric oxygen pretreatment group (HBOP-group, group A), a non-HBOP group (group B), and a control group (group C), with 20 mice in each group. The mice in group A were pretreated with five consecutive HBOP sessions (2.5 absolute atmospheric pressure, 100% O₂, 1 h, once per day). The mice in group B were treated with five consecutive non-HBOP sessions (hyperbaric oxygen chamber, 1 absolute atmospheric pressure, air, 1 h, once per day). The mice in group C were normally fed. At 24 h after the last pretreatment, 15 mice from each group were subjected to ischemia using an MCAO model for 2 h, and then reperfusion for 24 h. Then 15 mice from each group were sacrificed and assessed for notch-1 and homer-1a proteins by Western blot. The other 5 mice were subjected to Morris water maze testing after 5 days of feeding to assess cognitive functions.

Results: Upon comparison of the mice in the non-HBOP pretreatment group and the control group, the expression of notch-1 and holmer1a proteins were higher (lower) in the HBOP group (p < 0.05). Morris water maze results were better in the HBOP group than in the others. The other two groups were no different on Morris water maze testing.

Conclusion: The expression of notch-1 and holmer1a proteins were higher (lower) in the HBOP group than the non-HBOP group and the control group. Hyperbaric oxygen therapy may promote improved abilities in mice after ischemia-reperfusion injury.

Wang Kai Zhang Lei Su Ning Hui Hao Chen Xiao-yan Li Juan Qu Yan Zhen Hai-ning Fei Zhou Xijing Hospital, the Fourth Military Medical University, Xi'an, Shan'xi, China

O156 Mild Hypothermia Effect on Autophagy in Rats After Subarachnoid Hemorrhage.

Background: Here we studied the effects of mild hypothermia on autophagy in rats after subarachnoid hemorrhage injury.

Methods: Thirty-six SD rats were randomly divided into a sham-operation group, a mild hypothermia group, and a normothermia group. An SAH model was used to produce subarachnoid hemorrhage injury. Therapeutic hypothermia was achieved 30 min after injury by surface cooling, and was maintained for 4 h. The expression of brain cathepsin B and beclin1 were detected by Western blot and real time RT-PCR. Electron microscopy and flow cytometry were performed to analyze autophagy.

Results: The expression of rat brain cathepsin B and beclin1 in the mild hypothermia group was much higher than that in the normothermia group at 3 h. Mild hypothermia increased autophagy in the acute phase of subarachnoid hemorrhage.

Conclusion: Mild hypothermia can downregulate the expression of cathepsin B and beclin1 in the acute phase of injury, and may play a protective role in subarachnoid hemorrhage.

Baiyun Liu Xu Feifan Li Jingsheng Song Shengjun Beijing Neurosurgical Institute Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

O157 Surgical Management of a Penetrating Orbitocranial Injury Reaching the Brainstem: A Case Report.

We treated a patient with a penetrating orbitocranial injury reaching the brainstem. A sharpened wooden comb handle was accidentally introduced at the inner canthus of the left eye. It passed along the medial border of the globe transorbitally and went through the superior orbital fissure into the cavernous sinus, then continued through the ipsilateral cavernous segment of the internal carotid artery, reaching the brainstem. On admission, the patient was conscious with a GCS score of 15. His left ocular motility was restricted and the injured eye had only light perception. His pupils were round and the ratio of left:right pupil was 4:2, light reflex, OD(+), and OS(dull). CT and MRI of the head showed a well-defined low-density abnormality in the left optic canal, passing through the midbrain to the pons, and a low-intensity structure in the left cavernous sinus and pons with an ipsilateral internal carotid artery occlusion, respectively. Under general anesthesia, a frontotemporal orbitozygomatic craniotomy was performed to expose the stump of the wooden fragment. After pulling apart the frontotemporal lobes, the foreign body was clearly seen between the cavernous sinus and pons above the skull base. Finally, with the help of a temporary interruption of the left common carotid artery, the entire fragment was carefully removed. Though there was some bleeding after the extraction, effective hemostasis was performed immediately. The patient's post-operative course was uneventful, but the initial neurologic deficit of the patient remained fixed. A 1-year follow-up visit showed that the patient's left ocular motility had recovered, and the MRI displayed a carotid-cavernous fistula (CCF). Penetrating and perforating periorbital puncture wounds by wooden fragments are not rare, but ones that reach the brainstem are extremely rare. This case was notable due to the complicated patient condition and difficult surgical treatment. Long-term follow-up for changes in the CCF are needed.

Jiangjiyao Yumin Liang Yinghui Bao Guoyi Gao Shanghai Renji Hospital, Shanghai, China

O158 Efficacy of Standard Craniectomy for Refractory Intracranial Hypertension with Cerebral Contusion.

Background: Refractory intracranial hypertension caused by massive cerebral contusion, intracerebral/subdural hematoma, and brain edema, remain prognostic factors in patients with traumatic brain injury. Surgical decompression for refractory intracranial hypertension after severe head injury remains controversial. Which type of decompressive craniectomy should be performed (standard trauma craniectomy [STC] or limited craniectomy [LC]) is still a matter of debate.

Methods: A few years ago, we devised an RCT to compare the efficacy of the two types of decompressive craniectomy in 486 patients with severe traumatic brain injury (GCS < 8) with refractory intracranial hypertension at five medical centers in China. The patients were randomly divided into two groups: patients receiving STC (n = 241) got a unilateral frontotemporoparietal bone flap (12 × 15 cm), and patients receiving LC (n = 245) received a routine temporoparietal scalp flap (6 × 8 cm). Refractory intracranial hypertension caused by unilateral massive frontotemporoparietal contusion, intracerebral/subdural hematoma, and brain edema was confirmed by CT scan in all 486 cases.

Results: At 6-month follow-up, according to the Glasgow Outcome Scale (GOS), 96 cases in the STC group had favorable outcomes (39.8%), and the other 145 cases had unfavorable outcomes (60.2%). However, only 70 cases in the LC group had favorable outcomes (28.6%), and the other 175 cases had unfavorable outcomes (71.4%; p < 0.05). More recently, we found that bilateral STC yielded satisfactory outcomes in 37 patients with bilateral cerebral contusions with refractory intracranial hypertension. We conclude that STC significantly improves the outcomes of those with severe traumatic brain injury with refractory intracranial hypertension due to unilateral frontotemporoparietal contusion with or without intracerebral or subdural hematomas.

Conclusion: This indicates that STC, but not LC, should be recommended for these patients.

Sheng Wang Jincao Chen Quan Niu Hong Heping Wang Yibo Ou Zhengwei Li Ting Lei Tongji Hospital, Tongji Medical School, Huazhong University of Sciences and Technology, Wuhan, Hubei, China

O159 Regional Biochemical Changes in Diffuse Axonal Injury in Rats: A Microdialysis Study.

Background: In this study we explored the regional biochemical changes seen following diffuse axonal injury (DAI), and studied the potential of microdialysis in monitoring the concentration changes in glucose, lactate, and glutamate in extracellular fluid (ECF).

Methods: SD rats were divided into two groups: a control group and a DAI group. Microdialysis was applied to monitor the changes in glucose, lactate, and glutamate in the ECF.

Results: The lowest values of cerebral ECF glucose seen on microdialysis in the DAI group were reduced (32 ± 9%) below baseline values. In this group the values of cerebral ECF glucose had returned to baseline by 120 min. The values of cerebral ECF glucose in the DAI group were much lower than in the control group at several different time points (p < 0.05). The levels of cerebral ECF lactate seen on microdialysis were elevated (385 ± 35%) above baseline levels after DAI. The cerebral ECF lactate levels in the DAI group were higher than those in the control group at several different time points (p < 0.05). Glutamate levels in the ECF were also higher than those of the control group (p < 0.01), and though they fluctuated, they were still above baseline. The peak concentrations of glucose and lactate correlated with brain water content.

Conclusion: Microdialysis is an ideal method for dynamic sampling of neurochemical substances in the extracellular space following DAI. Increased lactate and decreased glucose may indicate accelerated glycolysis post-DAI. The changes in lactate, glucose, and glutamate in the cerebral ECF following DAI are important biochemical parameters that can be used to determine the severity of DAI and to predict outcomes.

Lyeth Bruce University of California–Davis, Davis, California

O160 Neuropeptide Modulation in Traumatic Brain Injury.

Traumatic brain injury (TBI) leads to a rapid and excessive increase in glutamate concentration in the extracellular milieu, which is strongly associated with excitotoxicity and neuronal degeneration. This article presents studies that examine an abundant peptide neurotransmitter, N-acetylaspartylglutamate (NAAG), found in the mammalian brain, that acts as a potent and selective agonist of subtype 3 mGluR (mGluR3). NAAG is released by neurons and hydrolyzed into NAA and glutamate by a specific peptidase released by astrocytes. We hypothesize that NAAG may play a significant role in modulating glutamate excitotoxicity if its rapid hydrolysis can be inhibited. We hypothesize that NAAG could confer protection in the traumatized brain by several mechanisms. First, NAAG reduces excessive glutamate release by activation of presynaptic mGluR3 autoreceptors. Also, by inhibiting the hydrolysis of NAAG into NAA and glutamate, a secondary source of synaptic glutamate could be diminished. Second, activation of mGluR3 on astrocytes increases the expression of glutamate transporters, thereby facilitating removal of excess glutamate from the synapse. Third, the NAAG hydrolysis product, NAA, may contribute to Na⁺ overload in astrocytes as a result of NAA-Na⁺ co-transport into astrocytes. Overload of [Na⁺]i can initiate astrocyte pathology that subsequently impacts negatively on surrounding neurons. Mechanistic and pre-clinical studies are presented that test the effectiveness of these compounds in models of TBI and TBI complicated by secondary insults. This research will provide new and important insights into glutamate excitotoxicity, and examine important dynamics of neuron-astrocyte interactions in TBI pathophysiology. This research will also provide clinically relevant information about potential pharmacological agents for the treatment of human head injury.

Zhuang Zhiye Huan Jian Cepero Maria L. Liebl Daniel J. The Miami Project to Cure Paralysis and Department of Neurosurgery, University of Miami School of Medicine, Miami, Florida

O161 Ephrinb3 Regulates the Release of Gliotransmitters in Astrocytes.

Background: Astrocytes are believed to regulate synaptic functions by the release of gliotransmitters. Here we investigated whether ephrins and Eph receptors mediate the release of glutamate, glutamine, and D-serine from astrocytes.

Methods: Primary astrocyte cultures were prepared from neonatal CD-1 mice. EphrinB protein fragments (EBPF) were generated by a pET32a expression system contained in a thioredoxin solubility tag. Glutamate, glutamine, and D-serine measurements were performed by using chemiluminescence, fluorescence, or high-performance liquid chromatography assays. Lentivirus was applied to express wild-type or mutant serine racemase (SR) with a V5 tag. cDNA of mutant SR with replacement of lysine-56 with glycine (SRK56G) was made using the GeneTailor^™ site-directed mutagenesis system.

Results: Astrocytes are known to release gliotransmitters to regulate neuronal transmission, but the environmental factors that influence these responses are poorly defined. We observed significant dose-dependent increases in glutamate, glutamine, and D-serine levels in wild-type astrocyte cultures stimulated for 15 min with ephrinB1 and ephrinB3. These increases were attenuated in the absence of EphB3 and/or EphA4, high-affinity receptors that preferentially bind ephrinB3, suggesting that multiple astrocyte-derived Ephs mediate these responses. SR is an important enzyme that converts L-serine to D-serine, and increased L/D-serine levels can lead to enhanced glutamine and glutamate production through the elimination of water and the production of pyruvate. We observed a significant increase in pyruvate following ephrinB3 stimulation, which could be blocked with lentivirus that expresses dominant-negative-SR (DN-Lenti-SR), whereas wild-type SR (WT-Lenti-SR) led to increased pyruvate, glutamate, and D-serine release.

Conclusion: EphrinB3 can regulate glutamate, glutamine, and D-serine release from astrocytes, especially via activation of EphB3 and/or EphA4. This leads to enhanced SR activity and pyruvate levels, which results in increased production and release of gliotransmitters.

Sandro Krieg Trabold Sonanini Plesnila Technical University Munich, Klinikum rechts der Isar, Munich, Germany

O162 Therapeutic Window of Arginine Vasopressin V1A Receptor Inhibition After Traumatic Brain Injury.

Background: We recently showed that arginine vasopressin (AVP) V1a receptors mediate brain edema formation following stroke and TBI. The therapeutic window for the application of V1a receptor antagonists following TBI, however, is thus far unknown. Therefore, we evaluated the efficacy of AVP V1a receptor inhibition when given at increasing intervals post-TBI.

Methods: Male C57/BL6 mice were traumatized under isoflurane anesthesia by controlled cortical impact (CCI). A single dose of 40 ng/g body weight of the specific AVP V1a receptor antagonist SR49059 was applied intracerebroventricularly 5 min, and 1, 3, or 6 h after TBI. Twenty-four hours later, brain water content, intracranial pressure (ICP), contusion volume, plasma sodium, and neurological outcomes were assessed. Moreover, we assessed body weight, contusion volume, motor function, and general neurological status using the Neurological Severity Score (NSS) for 7 consecutive days post-trauma.

Results: Central V1a receptor inhibition 5 min post-CCI showed the best effect on brain edema development (80.6 ± 0.39% versus 81.7 ± 0.24% in controls; p < 0.05), ICP (15.2 ± 0.9 mm Hg versus 22.1 ± 2.4 mm Hg in controls; p < 0.05), and contusion volume (30.2 ± 1.2 mm³ versus 35.3 ± 1.3 mm³ in controls; p < 0.05) at 24 h after trauma, as well as on beam walk assessment and weight loss at 7 days post-TBI. Application 3 h later also showed decreased brain edema, whereas treatment after 1 and 6 h had no effects.

Conclusion: Inhibition of AVP V1a receptors reduces secondary brain damage; however, the therapeutic window in mice is relatively short. This may reflect the rather rapid development of brain edema in this species, and/or fast activation of the AVP system following TBI. Since human brain swelling usually occurs significantly more slowly than that in rodents, central inhibition of AVP V1a receptors may nevertheless represent a novel molecular target for treating TBI.

Sandro Krieg Trabold Sonanini Plesnila Technical University Munich, Klinikum rechts der Isar, Munich, Germany

O163 Arginine Vasopressin V1A and V2 Receptors for Secondary Brain Damage After Experimental Traumatic Brain Injury.

Background: Arginine vasopressin (AVP) is known to regulate endothelial water transport (e.g., in the kidney), and as we showed recently in the brain, following cerebral ischemia. The current study aimed to investigate the role of AVP V1a and V2 receptors in brain edema formation and secondary brain damage following traumatic brain injury (TBI).

Methods: Under isoflurane anesthesia, male C57/BL6 mice underwent CCI, and were given specific AVP V1a or V2 receptor inhibitors systemically or intracerebroventricularly (ICV) 5 min after trauma. Blood pressure, cerebral blood flow (CBF), brain water content, intracranial pressure (ICP), contusion volume, plasma sodium levels, and neurological outcome were evaluated 24 h later. Moreover, reaction of the cerebral vasculature upon V1a and V2 receptor inhibition were assessed via intravital fluorescence microscopy, and cerebral V1a and V2 receptor mRNA expression was measured 3, 6, and 24 h post-TBI.

Results: A centrally administered AVP V1a receptor antagonist did not affect CBF or blood pressure, but reduced brain edema formation dose-dependently by up to 68%, resulting in ICP attenuation of 46% 24 h after TBI. Consequently, contusion growth was diminished by 47%. Systemic AVP V1a receptor inhibition did not reduce secondary brain damage, but did completely prevent the short-lasting but severe post-traumatic increase seen in blood pressure. ICV inhibition of V2 receptors reduced brain edema by 41% 24 h after trauma, but failed to influence ICP and lesion growth at any dosage. At 3 h after trauma, cerebral V1a receptor mRNA expression was increased 2.4-fold, while V2 receptor mRNA levels did not change until expression dropped to 0.21-fold 24 h after TBI.

Conclusion: Post-traumatic brain edema formation and the subsequent development of secondary brain damage are mediated by AVP and its V1a receptors. Hence, central inhibition of AVP V1a receptors may represent a novel strategy for the treatment of TBI.

Li Zhiqiang Quan Zhe Shen Dongqing Chen Ming Cao Jianhui Dai Xinlian Ruixing Liu Ying Wu Bin Central Hospital of Fengxian District, Shanghai, China

O164 The Clinical Analysis of Patients with Severe Traumatic Brain Injury Treated by Re-Operation.

Background: Here we analyze the relating factors of patients with severe traumatic brain injury who were treated by re-operation, and evaluate the effect of re-operation on outcomes of such patients.

Methods: From December 2005 to November of 2010, 51 patients with severe traumatic brain injury received re-operations secondary to increasing ICP. The data of all these patients were reviewed retrospectively. The Glasgow Outcome Scale (GOS) was used to evaluate the neurological outcome at discharge.

Results: Among these 51 patients, the cause of re-operation was secondary edema in 12 cases, progressive hematomas in 26 cases, incorrect initial operation in 5 cases, and large areas of cerebral infarction in 8 cases. The second operations were performed on the same locations in 14 cases, in a nearby area in 9 cases, expanded decompressive craniectomies were done in 12, and on the contralateral side in 16 cases. At discharge, GOS scores were 1, 2, 3, 4, and 5, in 10, 2, 4, 6, and 29 patients, respectively.

Conclusion: The main causes for re-operations were as diverse as the types of brain injuries. Prompt management of such patients should yield good recovery if secondary brain injuries can be controlled.

Yan Edwin Frugier Tony Lim Chai Tan May Rosenfeld Jeffrey Walker David Guillemin Gilles Morganti-Kossmann Cristina National Trauma Research Institute, Alfred Hospital, Melbourne, Australia

O165 Enhanced Activation of the Kynurenine Pathway and Increased Neurotoxin Quinolinic Acid Production After Traumatic Brain Injury.

Background: The kynurenine pathway (KP) metabolizes the essential amino acid tryptophan, plays an important role in neuroinflammation, and is responsible for the production of the neurotoxin quinolinic acid (QUIN) in various neurological diseases. However, KP has not been adequately explored after traumatic brain injury (TBI) in humans.

Methods: Human ventricular CSF was collected daily for 6 days from 26 severe TBI patients. The samples were analyzed for tryptophan metabolites by HPLC or GC-MS. Patient neurological outcomes were assessed using Glasgow Outcome Scale-Extended (GOSE). Brain tissue was collected from TBI victims and analyzed for gene expression of the enzymes regulating the KP.

Results: One of the end products of the KP is the neuroprotectant kynurenic acid (KYNA), which was significantly increased between days 2 (150.0 ± 35.5 nM) and 5 (218.4 ± 53.5 nM), compared to controls (83.4 ± 16.0 nM), and did not change in TBI brain samples, indicating that the increase seen in KYNA may be due to the elevation of its precursor kynurenine (on average TBI = 217.8 ± 133.9 nM, control = 82.7 ± 11.2 nM). In comparison, the other end product of KP is the neurotoxin QUIN, which gradually increased post-TBI, with normal levels seen at day 0 (25.2 ± 7.3 nM), and significant elevations seen between days 1 (89.7 ± 41.6 nM) and 5 (291.1 ± 102.6 nM), compared with controls (16.6 ± 9.7 nM). pGOSE obtained at 6 months post-TBI.

Lijun Hou Hai (co-first author) Jin Chengguang Pan Chao Li Changzheng Hospital, Second Military Medical University, Shanghai, China

O166 Skull-Base Trauma.

Background: The management of skull-base trauma continues to be a major challenge, even for experienced multidisciplinary teams. This article provides the neurosurgeon's perspective in the management of such trauma, using a 10-year retrospective analysis of patients sustaining skull-base trauma.

Methods: Retrospective analysis covering a period of 10 years (from 2000 to 2010) and 180 patients was performed.

Results: Skull-base fractures was found in 152 patients (66 of the anterior, 59 of the middle, and 27 of the posterior skull base), and 78% of patients had a concomitant intracranial injury. Damage to the anterior fossa including the paranasal sinuses may produce CSF leakage, and damage to olfactory nerves, optic nerves, and orbital contents. Fractures may affect the carotid canal, injure the internal carotid artery, and result in carotid-cavernous fistulas. Trauma to the petrous bone may cause facial palsy and deafness, and CSF leakage with otorrhea. Trauma to the posterior fossa may lacerate the major venous sinuses, and affect cranio-cervical stability. Early neurological deficits were diagnosed in 51 patients, and 23 patients had permanent neurological deficits. Nine patients died within 3 days of intensive care treatment.

Conclusions: Injury to the skull base can lead to catastrophic outcomes, such as meningitis, brain abscess, neurological deficits, brain hemorrhage, and death. Each of these injuries will need an individual strategy. Decisions regarding the timing of surgery and the sequence of the surgical procedures must be made with great care. Modern surgical techniques and recent technologies, including repair of cerebrospinal fluid leakage, functional preservation of the olfactory nerves in frontobasal trauma, assisted optic nerve decompression, decompression of the superior orbital fissure, facial nerve reconstruction, interventional technique for intravascular repair of vascular injuries, and recent developments in brainstem implants, all contribute significantly to improve outcomes and enhance the quality of life of these patients.

Lingsma H.F. Steyerberg E.W. Roozenbeek B. Habbema J.D.F. Maas A.I.R. Department of Public Health, Center for Medical Decision Making, Erasmus MC, Rotterdam, The Netherlands; Department of Neurosurgery, Antwerp University Hospital, Edegem, Belgium

O167 Comparative Effectiveness Research: What Can It Bring to the Field of Traumatic Brain Injury?

A patient has a right to expect the best possible care, and the health professional has a duty to provide it. But what is best? Even the most evidence-based practice guidelines have limited recommendations that are supported by high-quality evidence. Although there may be studies that indicate that a treatment is efficacious relative to placebo, there frequently are few that directly compare the different available alternatives, or that have examined their impacts in populations of the same age, sex, and ethnicity, or with the same co-morbidities as the patient. Comparative effectiveness research (CER) aims to fill this knowledge gap. Randomized controlled trials are designed to demonstrate efficacy, and the study population and setting may differ in important ways from those in which the interventions will be used. In contrast, CER intends to measure the benefits and harms of an intervention in ordinary settings and broader populations, and therefore is more relevant to policy evaluation and the healthcare decisions of providers and patients. In traumatic brain injury (TBI), there are many unanswered questions, despite the many clinical trials that have been performed in the last few decades. These questions are directly related to decisions that have to made every day in clinical practice, such as intracranial pressure management, timing of intracranial surgery, and organization of acute trauma care. There are some unique features of TBI that make CER a very feasible approach to answer such questions. First, there are large between-center differences, and between-country differences, in both outcomes and management. These could be considered worrisome, but provide a major opportunity to compare alternative interventions or strategies that all are possible best practices. Second, very well-performing prognostic models are available for TBI. This is important, since studying the effects of treatment in observational data always carries a risk of confounding. High-quality, externally-validated models provide the possibility to adjust for patient characteristics that affect outcome. Third, advanced statistical models are available to analyze differences between centers. Fourth, there is the development of common data elements, with the aim to standardize data collection and coding of variables. The common data elements are starting to be applied in clinical studies, which will provide a wealth of uniformly-collected, comparable observational data. CER has the potential to provide answers to the unanswered questions in TBI treatment. These answers can directly inform decision making in clinical practice, and thus improve care for TBI patients.

Li Xiangdong Hui Weining Hui Guozhen The First Hospital Affiliated to Suzhou University, Suzhou, China

O168 Study of the Correlation of Thrombin Around the Hematoma with Brain Cell Apoptosis and Brain Edema After Intracerebral Hemorrhage in Rats.

Background: Here we study the development of thrombin (TB) following experimental intracerebral hemorrhage (ICH) in rats, analyze the correlation between TB and brain cell apoptosis, and characterize the brain edema around the hematoma.

Methods: A total of 105 adult male Sprague-Dawley (SD) rats were randomly divided into three treatment groups: an ICH group, a physiological saline group, and a normal control group. Each of the three groups was randomly divided into 7 time points: 6 h, 12 h, 24 h, 48 h, 3 days, 5 days, and 7 days. An ICH rat model was constructed using a stereotactical injection technique. Thrombin-anti-thrombin (TAT) complex in brain tissue surrounding the hematoma was detected by an ELISA assay, the apoptotic rate of brain cells was analyzed by flow cytometry, the brain moisture level was assessed with a dry-wet weighing technique, and the morphological changes were observed with a transmission electron microscope.

Results: After 6 h, the ICH model was constructed successfully by injection of autologous arterial blood. Our results showed that the concentration of TAT and the apoptosis rate of brain cells around the hematoma in the ICH group were significantly higher than those in the physiological saline group or normal control group (p < 0.05); they reached their maximum (p < 0.01) 48 h after the ICH model was constructed, and began declining 3 days later (p < 0.01), but were still higher than in the other two groups (p < 0.01) at the 7-day time point. Six hours after the ICH model was completed, the brain moisture level around the hematoma in the ICH group was significantly higher than that of the other two groups (p < 0.05). The brain moisture level reached its maximum 3 days later (p < 0.01), and eventually began decreasing 7 days after the model was made (p < 0.01); the rate was still significantly higher than in the other two groups (p < 0.01). There was a significant correlation between the concentration of TAT and the rate of apoptosis of brain cells, as well as between the concentration of TAT and the brain moisture level, in the ICH group (r = 0.627 and 0.315, respectively; both p < 0.01). Using an electron microscope we observed brain cell apoptosis, significant brain edema around capillary vessels, and nerve fiber demyelination. These changes were significantly greater in the ICH group than in the other two groups.

Conclusion: Following ICH, the concentration of TB, the apoptotic rate of brain cells, and the brain moisture level around the hematoma, all increased. The symptoms were time phase-dependent and lasted beyond 1 week. TB may result in the apoptosis of brain cells with brain edema (vasogenic brain edema). Removing the hematoma surgically as early as possible should ameliorate secondary brain injury caused by TB.

Muresanu Dafin F. University CFR Hospital, Cluj Napoca, Romania

O169 Pleiotropic Multimodal Treatment Paradigm in Traumatic Brain Injury: Concept and Clinical Results.

The old concept that neuroprotection means suppressing pathophysiological processes, and the idea that a single molecule might be effective in clinical practice, are obsolete today, and represent the root cause of treatment failure. TBI's effects on the brain are traditionally conceived as a linear sum of independent pathophysiological processes (excitotoxicity, inflammation, apoptosis, and oxidative stress) that generate the pathological cascades seen in acute and chronic disorders. The pathway approach has produced a very detailed understanding of the molecular changes in the post-lesional brain, but it possesses blind spots that are critically related to the failure of pharmacological neuroprotection in TBI. This has generated a simplistic way of understanding the concepts of all attempts at clinical neuroprotection. The idea that a system is a linear sum of its component parts is called “superposition,” and the associated approach is called “reductionism.” Every lesion in the nervous system initially triggers an endogenous neuroprotective reaction, followed by an endogenous repair process, combining neurotrophicity, neuroprotection, neuroplasticity, and neurogenesis, overlapping and acting under genetic control to generate endogenous defense activity (EDA), which continually counteracts pathophysiological processes. All of these biological processes are initiated and regulated by biological molecules. Neurotrophic factors are probably the best example in this respect. They are acting in a pleiotropic neuroprotective way against pathological cascades. The same molecules, due to a complex genetically-regulated process, are able to further regulate neurotrophicity, neuroplasticity, and neurogenesis. Therefore, they have not only pleiotropic neuroprotective activity, but also have multimodal mechanisms of action. Besides the concept of pleiotropic multimodal molecules, this presentation will give an overview of particular aspects regarding the therapeutic effects for brain protection and recovery after TBI.

Morganti-Kossmann Cristina Semple Bridgette Yan Edwin Frugier Tony Hellewell Sarah Bye Nicole National Trauma Research Institute, Alfred Hospital; Department of Surgery, Alfred, Monash University, Melbourne, Australia; Department of Neurological Surgery, University of California–San Francisco, San Francisco, California

O170 Modulation of the Immune Response by Traumatic Brain Injury.

Since the early 1990s the role of brain inflammation elicited in response to traumatic injury (TBI) has received increasing attention, providing evidence for both beneficial and detrimental functions. In our laboratory emphasis is given to differences in immune responses induced by focal and diffuse TBI in rodents and humans, in relation to tissue damage. These distinct forms of brain injury are characterized by lesion formation in focal TBI, abundantly infiltrated by leukocytes and cell death, while diffuse TBI produces a widespread axonal pathology in white matter, co-localizing with macrophage accumulation in the absence of overt cell death. In focal TBI, we identified the chemokine network as a driver of secondary brain damage. Deletion of the macrophage chemokine MCP-1, or the neutrophil chemokine-receptor CXCR2, confers neuroprotection by reducing leukocyte accumulation, lesion volume, and cell death, resulting in altered cytokine cascades and improved outcome. In addition, a novel immunomodulatory role for MCP-1 was discovered in cultured glia, which strongly depends on the concentration of the inflammatory stimulus. This provides the basis for future pharmacological studies targeting selective inflammatory networks. Key work in a diffuse rat TBI model demonstrated that a hypoxic insult exacerbates neuroinflammation, axonal swelling/disconnection, and motor deficit. Similarly, in TBI patients, hypoxia prolongs cytokine release in cerebrospinal fluid and blood injury marker levels, thus supporting epidemiological data reporting that the combination of diffuse brain injury and hypoxia is associated with worse outcomes. In accordance with previous data showing aggravated deficits in cytokine-knockout mice after TBI, we recently demonstrated that robust anti-inflammatory treatment with high doses of minocycline only provided transient amelioration of function, whereas a prolonged treatment at low doses sustained recovery, thus corroborating an unequivocal beneficial function of neuroinflammation. Improved outcome with low-dose minocycline was not mediated by enhanced neurogenesis, as the proliferation, differentiation, and survival of neural progenitor cells remained unaffected. Therefore we speculate that neurogenesis induced after TBI cannot be increased by suppressing neuroinflammation, but can be by providing a favorable environment via administration of factors such as erythropoietin and BDNF, which are known to enhance neurogenesis. Overall these studies indicate that mild immunosuppression is the key for effective neuroprotection, but not its abolishment. This hypothesis stems from these findings: (1) anti-inflammatory treatment with low-, but not with a high-dose treatment delivers sustained neuroprotection; (2) targeting specific inflammatory/chemokine networks may be more efficacious than broad immunosuppression; and (3) providing the injured brain with cytokine-induced neurotrophins may support repair by enhancing neurogenesis.

Hovda David A. Departments of Neurosurgery and Molecular and Medical Pharmacology, University of California–Los Angeles, Los Angeles, California

O171 Altered Brain Metabolism Without Ischemia.

Since the landmark paper published by Graham and associates in 1989, it has been thought that cerebral ischemia is a common, if not fundamental, component of the pathophysiology of human traumatic brain injury (TBI). Over the last few years investigators have begun to debate this issue as to whether “classic” cerebral ischemia is a common feature of TBI, or if it needs to be redefined in terms of metabolic demands. For years, neuroscientists thought that the human brain was quiescent in terms of energy demands after TBI, given that patients were commonly in a state of coma and seemed unresponsive. An increase in energy demand was thought to only occur after TBI when a second insult occurred (e.g., seizure or hypoxia). This lecture will address the cerebral metabolic changes that occur following TBI. Changes in the roles for basic cellular fuels, and the need to understand and appreciate energy crisis in the absence of frank cerebral ischemia, will both be presented. Utilizing multi-imaging modalities, and neurochemical and neurophysiological measurements, an appreciation of where we stand in our understanding of the temporal and regional aspects of the metabolic changes occurring after TBI will be presented.

Maas Andrew I.R. Lingsma Hester Roozenbeek, on behalf of the IMPACT study group Bob Department of Neurosurgery, Antwerp University Hospital, Edegem, Belgium; Department of Public Health, Center for Medical Decision Making, Erasmus MC, Rotterdam, The Netherlands

O172 The Impact of Impact: Recommendations for Trial Design, Prognosis. and Standardization.

Background: Clinical trials in TBI pose complex methodological challenges due to the heterogeneity of TBI populations, the lack of mechanistic early end-points, and the insensitivity of outcome measures. The IMPACT studies aimed to develop recommendations for improving the design and analysis of trials in TBI.

Methods: The IMPACT study group was initiated in 2003 as an international collaborative venture supported by the U.S. National Institutes of Health, involving methodological, statistical, and clinical expertise. Access was granted to individual patient data of initially eight randomized controlled trials and three observational studies including a total of 9205 patients. During the continuation funding period (2007–2011) more studies were included, providing access to data for over 40,000 patients. Relevant variables from the individual studies were extracted and merged to form a database for exploring concepts to improve the design of clinical trials. Prognostic analyses and identification of robust covariates formed the cornerstone for extensive simulation studies, addressing selection and prognostic targeting of enrollment, covariate adjustment, and ordinal approaches to the analysis.

Results: These are the summary recommendations resulting from the simulation studies. (1) Inclusion criteria should be as broad as is compatible with the current understanding of the mechanisms of the intervention under evaluation. (2) The statistical analysis should incorporate pre-specified covariate adjustment. The statistical analysis should use an ordinal approach, using either sliding dichotomy or proportional odds methodology. These recommendations can increase statistical power by 40–50%, thus enhancing chances for detecting clinically relevant treatment effects. Subsequent explorations of data from a trial with a treatment effect have proven their validity. Besides fulfilling the primary objective of the study, the IMPACT studies have yielded additional contributions. Prognostic models were developed according to state-of-the-art methodological insights, including external validation. These have numerous applications besides those related to trial design, and include classification by prognosis, and benchmarking for assessment of the quality of health care delivery. The IMPACT studies have also been instrumental in initiating the process of standardization of data collection and coding of variables in TBI: the common data elements. This standardization is crucial to future research, and is essential for studies using comparative effectiveness research, and for meta-analyses across individual patient data. IMPACT results and publications are available at: www.tbi-impact.org.

Conclusion: The IMPACT studies have yielded important contributions to the field of TBI, including recommendations for improving trial design, validated prognostic models, and proposals for standardization of data collection.

Gasparovic Charles Yeo Ronald A. Merideth Flannery Ruhl David Doezema David Mayer Andrew R. The Mind Research Network, Albuquerque, New Mexico; Department of Neurology, University of New Mexico School of Medicine, Albuquerque, New Mexico; Department of Emergency Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Department of Psychology, University of New Mexico, Albuquerque, New Mexico

O173 Recovery from Glutamate and Energy Metabolism Alterations After Mild Traumatic Brain Injury.

Background: Various neuroimaging techniques now offer the possibility of detecting subtle functional, anatomical, or physiological abnormalities after mild traumatic brain injury (mTBI), and hence may complement traditional clinical assessments in predicting and monitoring morbidity. Here we present our recent studies of brain metabolism after mTBI, as measured by proton magnetic resonance spectroscopy (1H-MRS).

Methods: MR spectroscopic imaging was used to assess gray and white matter neurometabolite levels, including the sum of the glutamate and glutamine (Glx) concentrations, and the sum of the creatine and phosphocreatine (Cr) concentrations, across a supraventricular slice in 30 individuals with semi-acute mTBI and 30 matched controls.

Results: There were no significant group differences on clinical measures of attention, memory, working memory, processing speed, and executive skills, though the mTBI group reported significantly more somatic, cognitive, and emotional symptoms. Within 3 weeks of injury (mean 13 days), white matter Cr and Glx were elevated in the mTBI group, while gray matter Glx was reduced. While N-acetylaspartyl groups (NAA) were not significantly lower in the TBI group, NAA was positively associated with days post-injury during the semi-acute period of recovery. Seventeen mTBI patients returned for a follow-up evaluation (mean 120 days post-injury). A significant group × time interaction indicated significant recovery in the mTBI group for gray matter Glx, and trends in white matter Cr and Glx. An estimate of pre-morbid intelligence predicted the magnitude of neurometabolite normalization over the follow-up interval.

Conclusions: In the absence of cognitive dysfunction detectable by clinical measures, mTBI subjects demonstrated a pattern of altered glutamate and energy metabolism that tended to normalize within 3 months, and moreover appeared distinct from the changes reported for more severe TBI. Glutamate is converted to glutamine in astrocytes after uptake from the synaptic cleft, and glutamate receptors have also been found on oligodendrocytes, where they may be involved in signaling for myelination. As such, the depressed gray matter Glx seen after mTBI may reflect perturbed glutamaturgic transmission, while higher white matter Glx may be related to repair. Similarly, higher levels Cr of in white matter may be a response to the higher energy demands of repair. Finally, the relationship between pre-morbid intelligence and metabolic normalization may indicate that biological factors underlying intelligence may also be associated with a more rapid recovery. These findings and tentative hypotheses warrant further exploration in pre-clinical models of injury.

Sofroniew Michael V. Department of Neurobiology, University of California–Los Angeles, Los Angeles, California

O174 Astrogliosis After Spinal Cord Injury.

Reactive astrogliosis and scar formation are prominent features of spinal cord injury and other CNS insults. Genetic tools are now enabling the molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. This presentation will examine findings from our and other laboratories indicating that reactive astrogliosis is a complex, multifaceted process, comprising numerous potential cellular and molecular changes with a wide range of potential effects regulated by different signaling molecules. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon, but instead is a finely-gradated continuum of changes that occur in context-dependent ways regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Although reactive astrocytes have often been regarded as uniformly detrimental to clinical outcome, it is now clear that reactive astrogliosis, including scar formation, can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. In addition, increasing evidence points towards the potential that reactive astrogliosis may play either primary or contributing roles in a wide variety of CNS disorders, via loss of normal astrocyte functions or gain of abnormal effects. A better understanding of astrocyte signaling mechanisms and the mechanisms of reactive astrogliosis has the potential to open the door to identifying many molecules that might serve as novel therapeutic targets for a wide range of neurological disorders including spinal cord injury.

Chiu Wen-Ta Taipei Medical University, Taipei, China

O175 Neurotrauma Research in Taiwan.

The incidence, disability, and mortality rates of neurotrauma are high in most countries, while their social and economic costs are paid by health systems worldwide. Taking into account the high frequency of motor vehicle accidents, natural disasters, and conflicts in all countries, neurotrauma research has been cited as the highest priority worldwide by the U.S. National Institutes of Health and Department of Defense, as well as the World Health Organization. The Center for Neurotrauma Research (CNR) has been a TMU research platform for 23 years. This innovative neuroscience group has completed 96 projects and has published 233 scientific papers over the past 5 years. It maintains the world's largest database on traumatic brain injury (TBI), with more than 170,000 cases. In order to tackle this serious problem, stepwise approaches for TBI were implemented from 1991 to 2007. Step 1 was to collect a nationwide TBI registry in order to identify the risk factors and determinants. We found that the major cause of TBI in Taiwan was motorcycle-related injury, and very few motorcyclists wear helmets. Step 2 was to launch the implementation of the helmet use law on June 1, 1997. A rapid decline in TBI hospitalizations and deaths was demonstrated soon thereafter. Step 3 was to enroll in international collaborations with the Global Spine and Head Injury Prevention Project (Global SHIP Project) groups for TBI. The comparative results thus obtained could be used to develop preventive strategies for developing countries. Step 4 was to implement clinical research studies of TBI, which included studies on propofol, hyperbaric oxygen therapy, and brain parenchymal oxygen monitoring. Step 5 was to develop guidelines for the management of severe TBI in Taiwan. Through a 2-year period of review, discussion, and integration, a nine-chapter guideline was published in June 2007. In summary, CNR experience and process for management of TBI in Taiwan can be used as a reference for other developing countries.

Poster Presentation Abstracts

Alexandrova Evgeniya Tenedieva Valeriya Zaitsev Oleg Zakharova Nataliya Potapov Alexander Vorobyov Yuriy Burdenko Neurosurgery Institute, Moscow, Russia

P1 Plasma Catecholamine Monitoring and Consciousness Recovery in Patients after Severe Traumatic Brain Injury.

Background: Progress made in intensive care and neurosurgery has led to increased rates of survival in patients after severe traumatic brain injury (sTBI) with prolonged coma and post-comatose consciousness disorders. Depressed consciousness duration correlates with mental recovery outcome. Shortening of duration of unconsciousness/depressed consciousness and its abatement are the main unsolved problems in the treatment of TBI patients. Post-traumatic unconsciousness is a clinical manifestation of disconnection between the brainstem, subcortical structures, and cortex, particularly the frontal lobes. It is known that the frontal cortex is involved in modulation of sympathetic nervous system activity, which is the main source of plasma norepinephrine (NE) and dopamine (DA) levels. Here we compare the NE and DA (catecholamines, CA) level changes with the stages of consciousness recovery in patients after sTBI (GCS ≤ 7).

Methods: In this study we enrolled 61 patients (36 men and 12 women), both with (n = 43, group 1) and without (n = 18, group 2) deep brain structure damage (basal ganglia, thalamus, or corpus callosum) from 12–56 (32 ± 11) years old. Group 1 consisted of 18 patients with bilateral frontal lobe damage and 25 patients without bilateral frontal lobe damage. The extent and localization of brain damage was verified by MRI/CT in all patients. Consciousness levels were staged using the following criteria: eye opening only ± tracking (stage 1), obeying commands ± attempts to speak (stage 2), and answers questions ± orientation (stage 3). Plasma CA levels were evaluated by HPLC.

Results: Two variants of catecholamine dynamics were found: (1) CA-dissociation, with oppositely directed NA and DA level changes, was observed in unconsciousness (stage 1); and (2) CA-association, with unidirectional NA and DA level changes followed by unconsciousness regression (stages 2–3). CA-dissociation periods were observed in stage 3 (which was accompanied by psychomotor agitation) in patients with injury to two frontal lobes and deep brain structure damage. DA levels increased in group 1 (p = 0.04), and decreased in group 2 (p = 0,04) patients just before third stage achievement. CA-dissociation was negatively correlated with the velocity, quality of consciousness recovery, and outcome, as evaluated by Glasgow Outcome Scale (p < 0.05).

Conclusion: In this study we found that plasma NA and DA dynamics in patients with traumatic deep brain structure damages are different from patients without damage to these structures. Bilateral frontal lobe damage can also contribute to plasma CA levels. Perhaps these results can be used in the adjustment of specific (dopaminergic, norepinephrinergic, and cholinergic) pharmacotherapy for consciousness recovery.

Gurkoff Gene Shahlaie Kriarash Lyeth Bruce Muizelaar Paul Berman Robert University of California–Davis, Davis, California

P2 Delivery of a VGCC Blocker through the Cisterna Magna Improves Cognitive Function in a Rodent Model of Traumatic Brain Injury.

Background: One of the complications of pharmacotherapy is that systemically administered agents are often accompanied by side effects. Previously we have demonstrated that the cone-snail-derived omega-conotoxin ziconotide (Prialt), a potent N-type voltage-gated calcium channel blocker, could reduce cell death and behavioral dysfunction associated with traumatic brain injury in the rodent. Clinical trials of systemically-delivered ziconotide were halted due to side effects related to hypotension. However, ziconotide was recently approved for intrathecal administration in humans for relief of intractable pain. These studies have been designed to determine whether ziconotide, when delivered centrally via direct injection into the cisterna magna, will improve outcomes from traumatic brain injury without the side effects observed following systemic injection.

Methods: Adult male Sprague-Dawley rats (350–400 g) were administered saline or 150 or 500 ng of ziconotide into the cisterna magna 30 min prior to moderate fluid percussion injury. Additionally a control group was administered saline into the cisterna magna 30 min prior to a sham injury. Motor behavior was assessed using the beam walk, rotarod, and inclined plane, on days 1, 3, 5, 7, and 12 post-injury. Cognitive performance was assessed using the Morris water maze on days 11–15 post-injury. All animals were perfused on day 15 immediately following water maze training. Brains will be analyzed for cell death.

Results: We now demonstrate that 150–500 ng of ziconotide delivered directly to the cisterna magna 30 min prior to moderate lateral fluid percussion injury significantly improves motor and cognitive behavioral outcome in the first 2 weeks post-injury. Specifically, injured animals receiving ziconotide had a reduction in latency on the beam walk and increased time spent on the rotarod as measured over the first week post-injury. Additionally, animals receiving ziconotide had a reduction in latency to find the escape platform in the Morris water maze on days 11–15 post-injury.

Conclusion: These data demonstrate that centrally delivered ziconotide can improve outcome following a moderate traumatic brain injury in the rat. These findings are particularly exciting, as delivery of pharmacotherapy such as ziconotide centrally through the cisterna magna of a patient suffering a severe TBI may improve delivery of drug to target, while at the same time reducing complications from peripheral side effects.

Jun Jia Xiao-feng Shi Tian-an Zhong Yong Yin Yu Ye Li-zhi Yi Shenzhen Longgang Central Hospital, Shenzhen, China

P3 Mild Hypothermia Treatment for Patients with Severe Head Injury and Analysis Of S-100B Protein in Sera.

Background: Here we try to confirm brain protection by mild hypothermia by detecting changes in concentrations of S-100B protein in the serum of patients with severe head injury, and study the possible mechanism behind its effect.

Methods: We included 100 persons in normal health as a control group, and took serum samples to assess the concentration of S-100B protein in serum. We also included 100 patients with severe head injury (GCS score ≤ 8), who were divided into two groups: mild hypothermia (50 cases) and normal temperature (50 cases). We took serum samples at different time points post-injury to detect the concentration of S-100B protein in serum, and compared them.

Results: The S-100B protein concentration was not influenced by age or sex. The concentrations of S-100B protein in serum were markedly different between the control group and the normal temperature group (p < 0.05).

Conclusion: S-100B protein has high sensitivity and specificity in the diagnosis of severe head injury, and it is a effective biochemical indicator. Thus we deduce that treatment with mild hypothermia can protect brain tissue.

Rafols Jose Reynolds Christian Kreipke Christian Wayne State University, Detroit, Michigan

P4 Diffuse Axonal Injury and Endothelin: A Coupling of Concurrent Pathologies?

Background: Two common pathologies associated with traumatic brain injury (TBI) are diffuse axonal injury (DAI) and hypoperfusion of the microcirculation from enhanced contractility of reacting microvessels. Over the past decade our laboratory has focused its attention on strategies to mitigate TBI-induced hypoperfusion through the use of endothelin receptor antagonism. Selective antagonism of the endothelin receptor A (ETrA) was previously shown to decrease both the hypoperfusion and the extent of cell injury as assessed by Fluoro Jade staining, and also ameliorates cognitive behavioral (radial arm maze) deficits following TBI. However, recently we have uncovered a potentially novel consequence of selective ETrA blockade—a decrease in the extent of DAI.

Methods: In order to confirm this observation, TBI was induced in adult (400–450 g) male Sprague-Dawley rats using a modified model of diffuse TBI (after Marmarou's weight impact/acceleration model). Shortly after impact, animals were given a 1.0 mg/kg IV injection of BQ123, a selective ETrA antagonist. At 24 and 48 h post-TBI, coronal brain sections through the rostro-caudal extent of the corpus callosum were collected, and morphometric analyses of beta amyloid precursor peptide (β-APP)-stained retraction bulbs resulting from DAI were counted.

Results: Compared to control (non-TBI and sham operated) animals, ETrA antagonism significantly reduced (>30%) the number of retraction bulbs in the corpus callosum, with this reduction temporally coinciding with both improved histopathological (Fluoro Jade staining in layers II–III of the sensorimotor cortex), and behavioral (radial arm maze) outcomes.

Conclusions: While the precise mechanism is currently unknown, the results suggest that improving CBF via ETrA blockade can ameliorate TBI-induced DAI. Alternatively, endothelin (which is known to be upregulated after TBI), via the ETrA, could directly impact the pathophysiology of DAI. Future studies should be performed to determine whether dysregulation of ETrA signaling may be part of the molecular cascade leading to DAI.

Hu Jian-Guo Zhou Jian-Sheng Zhang Yu-Xin Zhao Bao-Ming Ma Shan-Feng Lü He-Zuo Center Laboratory, Anhui Key Laboratory of Tissue Transplantation, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China

P5 Transplantation of OLIG2-Expressing Neural Stem Cells and Adoptive Immunotherapy of Myelin Basic Protein-Activated T Cells Promotes Remyelination and Functional Recovery after Spinal Cord Injury.

Background: Neural stem cell transplantation is a major focus of current research in the treatment of spinal cord injury (SCI). However, it is important to promote the transplanted neural stem cells (NSCs) to differentiate into OLs and neurons at the lesion site. Previous studies have shown that Olig2 overexpression can promote the differentiation of cultured NSCs into mature OLs. Moreover, it has been reported that myelin basic protein-activated T cells (MBP-T) can produce neurotrophic factors, improve the SCI local microenvironment, and be neuroprotective. Therefore, we propose that a combination of Olig2-modified NSC transplantation and MBP-T cell adoptive immunotherapy may have complementary roles in the treatment of SCI. In this study, MBP-T cells, which can express IFN-γ, IL-10, and IL-13 after activation in vitro, were passively immunized to spinal-cord-injured rats within 1 day after SCI. The NSCs, which were infected with lentivirus expressing green fluorescent protein (GFP-NSCs), or Olig2 (lig2-GFP-NSCs), were transplanted into the injured spinal cord 9 days after injury. The fate of the transplanted cells was tracked by GFP fluorescence after transplantation at different time points.

Results: After adoptive immunotherapy, the transferred MBP-T cells (CD4-positive) could be detected in injured spinal cord from 3 days to 4 weeks. The infiltration of the MBP-T cells was correlated with, and the differentiation of resident microglia and/or infiltrating blood monocytes was moved toward, an alternatively-activated anti-inflammatory (M2) macrophage phenotype. From 2–7 weeks after transplantation, the grafted NSCs could be seen to survive and integrate into the injured spinal cord. At 2 weeks, the survival of grafted NSCs increased fivefold in MBP-T cell-transferred rats compared to vehicle-treated ones. The engrafted GFP-NSCs mostly differentiated into astrocytes, but not OLs and neurons. However, the percentage of MBP-positive OLs increased 12-fold in Olig2-GFP-NSC-engrafted rats compared with GP-NSC-engrafted ones. Immunofluorescence analyses showed that the grafted Olig2-GFP-NSCs could form central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in animals that received Olig2-GFP-NSC transplantation and MBP-T cell adoptive immunotherapy was significantly increased compared with all other groups. In the combined MBP-T cell and Olig2-GFP-NSC group, a significant decrease in spinal cord lesion volume, along with increases in spared myelin, were found compared to the other groups. Such histological improvement correlated well with an increase in behavioral recovery.

Conclusion: Thus combined treatment with Olig2-modified NSC transplantation and MBP-T cell adoptive immunotherapy can enhance remyelination and facilitate functional recovery after traumatic SCI.

Magnoni Sandra Guenzani Silvia Esparza Thomas J. Holtzman David M. Zipfel Greg J. Carrabba Giorgio Gotti Miriam Brody David L. Stocchetti Nino Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy

P6 TAU Elevations in the Brain Extracellular Space Correlate with Reduced Amyloid-B Levels and Predict Adverse Clinical Outcomes after Severe Traumatic Brain Injury.

Background: Axonal injury is believed to be a major determinant of adverse outcomes following traumatic brain injury. However, it has been difficult to acutely assess the severity of axonal injury in human TBI patients. We hypothesized that microdialysis-based measurements of the brain extracellular fluid levels of tau and neurofilament light chain, two low-molecular-weight axonal proteins, could be helpful in this regard.

Methods: To test this hypothesis, 100-kDa cutoff microdialysis catheters were placed in 16 patients with severe TBI at two neurological/neurosurgical intensive care units. The catheters were placed in normal-appearing brain tissue with no lesions at CT scan, or in morphologically-damaged brain tissue adjacent to contusions.

Results: Tau levels in the microdialysis samples were highest early and fell over time in the majority of patients. Initial tau levels were more than threefold higher in patients with microdialysis catheters placed in pericontusional regions than in patients without focal CT abnormalities (p = 0.0048). Tau levels and neurofilament light-chain levels were positively correlated (r = 0.65, p = 0.0084). Neurofilament light-chain levels were also higher in patients with pericontusional catheters (p = 0.04). Interestingly, initial tau levels showed a strong inverse correlation with initial amyloid-β levels measured in the same samples (r = 0.87; tau 7519 pg/mL, and amyloid-β < 639 pg/mL). Importantly, high initial tau levels correlated with worse clinical outcomes, as assessed using the Glasgow Outcome Scale at 6 months after injury (r = 0.63, p = 0.02).

Conclusions: Taken together, our data add support for the hypothesis that axonal injury as expressed by high interstitial levels of tau may be related to long-term impairments following traumatic brain injury. Microdialysis-based measurement of tau levels in the brain extracellular space may be a useful method to assess the severity of axonal injury acutely in the intensive care unit. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings, and to determine whether this approach provides added value when combined with clinical and radiological data.

Xiaojie Lu Yasuo Ding Wuxi No.2 Hospital, Wuxi, China

P7 Validity and Reliability of a Chinese Version of Sport Concussion Assessment Tool 2 in Mild Traumatic Brain Injury Patients.

Background: We introduced Sport Concussion Assessment Tool 2 (SCAT2) in China, and evaluated the validity and reliability of the Chinese version in patients with mTBI.

Methods: The first step was the translation and back-translation of the instrument by experts in the relevant disciplines, including a neurosurgeon, a psychologist, a nurse specialist, and a Chinese language teacher. Then a cross-sectional study of 135 patients was tested to compare the consistency of their reports of traumatic brain injury (TBI) across instruments, in a brief follow-up interview, and on three surveys, including the Quarterly Survey, the Computerized TBI Questionnaire, and the Neurobehavioral Symptom Inventory.

Results: Participants who screened positive on the Chinese version of SCAT2 generally provided consistent information about probable TBI in the follow-up interview.

Conclusion: The Chinese version of SCAT2 is a culturally specific mTBI assessment instrument. It can satisfy conventional criteria and is valuable in clinical practice, and in the screening of mTBI populations.

Wang Haifeng Ge Pengfei Chen Dawei Qi Bin Chen Bo Yang Fuwei Huang Chuanjiang Luo Yinan Fu Shuanglin First Affiliated Bethune Hospital of Jilin University, Changchung, China

P8 Protective Effects of Ginsenoside RB1 on Neuronal Death and Brain Edema after Traumatic Brain Injury.

Background: Currently there are no pharmacological treatments available for traumatically induced neuronal death and brain edema. Evidence indicates that ginsenoside Rb1 has protective effects on neuronal death induced by transient ischemia. Therefore we examined its effects on neuronal death and brain edema after traumatic brain injury.

Methods: A rat lateral fluid percussion brain injury model was used in this study. The rats were divided into a sham group, a vehicle-treated group, and an Rb1 group. The ginsenoside Rb1 was administered at 4 h after traumatic brain injury. The rats in each group were sacrificed at 6, 12, 24, and 72 h after brain injury. Neuronal apoptosis was evaluated by TUNEL, and brain water content was assessed using the wet-dry method. Immunostaining and Western blot analysis were used for assaying the expression of apoptosis-related proteins Bcl-2 and Bax, and edema-related proteins AQP1, AQP4, occluding, and claudin-5.

Results: Compared with the vehicle-treated group, TUNEL labeling showed that the apoptotic cells in the GRb1 group decreased significantly from 24 to 72 h; the number of Bcl-2-positive neurons was significantly increased in the GRb1 group from 12 to 72 h, while the number of Bax-positive neurons was significantly smaller. Western blot analysis showed that Rb1 significantly increased the expression level of Bcl-2, and decreased the level of Bax, from 12 to 72 h. The brain water content was decreased significantly in the Rb1 group at 24 and 72 h. Western blot analysis showed that the average AQP4 expression levels in contused areas of rats receiving Rb1 were significantly decreased, and Rb1 also attenuated the expressional reduction of occludin and claudin-5 at lesion sites from 12 to 72 h.

Conclusion: Ginsenoside Rb1 prevents the ischemic neuronal death induced by traumatic brain injury, and the mechanism is related to an increase in the expression of anti-apoptotic proteins, and modulation of the expression of brain-edema related proteins.

Zhang Zhiqun Finger Isaac Gurkoff Gene Shabashvili Arseniy Zoltewicz Susie Wang Kevin Center of Innovative Research, Banyan Biomarkers Inc., Alachua, Florida

P9 Utilization of Fluorescently-Tagged Calpain and Caspase Inhibitors to Study Necrotic and Apoptotic Neural Injury.

Extensive data from experimental and human TBI studies have shown that calpain-1,2 (calpain), and caspase-3, two cell death-linked cysteine proteases, are prominently involved in neuronal injury in TBI. During acute neuronal necrosis, the calpains are overactivated, while caspase-3 is strictly activated in delayed apoptosis. Importantly, only the activated calpain and caspase forms are susceptible to binding and inactivation by their respective small molecule pharmacological inhibitors. Therefore, we argue that one could exploit pathology-dependent binding of inhibitor molecules to calpain and caspase proteases for use as imaging probes to study neuronal necrotic and apoptotic cell death phenotypes. In this study, fluorescently-tagged calpain and caspase inhibitors have been synthesized and tested in cell-based assays and neuronal mechanical injury models to evaluate their uptake, distribution, and responses to neurotoxic challenges. Exposure of human SH-SY5Y neuroblastoma cells to fluorescently-tagged calpain and caspase inhibitors led to selective labeling of cells that had morphological and biochemical changes characteristic of calcium ionophore-induced necrosis or camptothecin-induced apoptosis, respectively. A strong correlation between the activation of calpain or caspases or their target-related breakdown products of alpha II-spectrin biomarker and the intensity of fluorescence was observed. Furthermore, a calpain inhibitor probe showed strong signals and exhibited high selectivity following mechanical injury in rat neuronal culture. Therefore, it is anticipated that the fluorescently-labeled calpain and caspase inhibitors developed here could be novel and useful tools in studying pathology-dependent proteolysis and cell death phenotypes following acute and delayed neuronal injury.

Zhang Yi Guan Zhen Huang Kun Popovich Phillip G. Center for Brain and Spinal Cord Repair, Department of Neuroscience, The Ohio State University, Columbus, Ohio

P10 Detection of Spontaneous Autonomic Dysreflexia in a Mouse Model of Spinal Cord Injury.

Background: High-level spinal cord injury (SCI) causes profound immunological impairment via unknown mechanisms. After high-level SCI (above T5), sensory input to the spinal cord can elicit hyper-reflexic activation of spinal sympathetic preganglionic neurons. The resultant phenomenon, referred to as autonomic dysreflexia (AD), is characterized by markedly increased blood pressure (BP), with a paradoxical decrease in heart rate (HR). Here we tested the hypothesis that recurrent spontaneous AD occurs after high-level SCI in mice, and is associated with impaired immune function.

Methods: To identify the onset, frequency, and duration of AD episodes, implantable telemetric probes were used to continuously measure BP and HR in conscious, freely moving SCI mice. Complete spinal transections were made at the T3 (T3Tx; high-level SCI) or T9 (T9Tx; mid-level SCI) spinal level. Sham mice received a laminectomy without SCI. Beginning at 5 days post-injury (dpi), data were accumulated 24 h/d until 35 dpi. A MATLAB algorithm was created to automatically detect episodic sustained (>30 sec) spikes in BP (>10 mm Hg), with a corresponding decrease in HR. Post-hoc analyses of these data subdivided AD events as mild, moderate, or severe (>30 mm Hg, severe AD; > 20 mm Hg, moderate AD; > 10 mm Hg, mild AD).

Results: Spontaneous sustained AD occurred only in T3Tx mice. The frequency of mild AD events was stable, increasing in number slowly as a function of time. In contrast, the frequency of moderate and severe events (∼5–10 events/d) increased more rapidly in two distinct phases. Phase I occurred within 7 dpi, likely due to loss of descending modulation of sympathetic outflow from the spinal cord. Phase II started at 14 dpi, with the number of dysreflexic events increasing from ∼10 to ∼25/d over a period of 3 weeks. The magnitude of the changes in BP and HR caused by spontaneous AD is equivalent to or greater than that caused by intentional colon distension or other noxious stimuli presented below the level of injury. These aberrant physiological changes, found only in T3Tx mice, were associated with profound splenic atrophy. In the spleen, CD45R + B lymphocytes and CD3 + T lymphocytes were reduced in T3Tx mice.

Conclusion: Recurrent spontaneous AD is a natural consequence of high-level SCI. In SCI mice, the frequency of AD events increases over time and predicts the onset of immune suppression. Studies to test a cause-effect relationship between spontaneous AD and level-dependent post-SCI immune dysfunction are ongoing.

Du Zhuoying Jin Yi Hu Jin Gao Liang Wu Xuehai Wu Xing Zhou Liangfu Huashan Hospital of Fudan University, Shanghai, China

P11 Long-Term Outcome After Early Surgical Optic Nerve Decompression for Traumatic Optic Nerve Injury.

Background: Here we evaluate the effectiveness of early surgical decompression for traumatic optic neuropathy.

Methods: Between 2006 and 2008, 35 patients diagnosed with traumatic optic neuropathy received surgical optic nerve decompression within 24 h of onset. The visual acuity of 24 patients was no light perception, and of the remaining 11 was light perception. The surgical decompression was performed via a transcranial extradural approach. The bony optic canal was drilled open in all patients, and the optic sheath was slit open in 26 patients. Visual acuity was assessed and recorded up to 24 months after surgery.

Results: Recovery was seen in 29 patients immediately after surgery, 10/24 patients with no light perception, and 8/11 patients with residual light perception preoperatively, recovered to effective visual acuity within 3 months after surgery. Two patients were reported to have continuous recovery over 24 months. Surgical complications included transient CSF leakage during surgery (1 patient), transient visual decrease (1 patient), and cerebral infection (1 patient). No major complications were seen in the current study.

Conclusion: Early surgical optic nerve decompression is effective for visual preservation after traumatic optic neuropathy.

Hong-Zhi Gao Guang-Rong Ji Wei-Peng Hu Jun-Yan Chen Ling Lin The Second Affiliated Hospital of Fujian Medical University, Fuzhou, China

P12 Changes in Plasma Ghrelin Concentration and their Effect on Gastrointestinal Function in Patients with Acute Traumatic Brain Injury.

Background: Ghrelin, a 28-amino-acid gut brain peptide, including non-acyl and acyl ghrelin, performs a variety of functions, ranging from endocrine and metabolic actions related to energy homeostasis, to gastrointestinal function and cell protection, to modulation of inflammation. Energy imbalance and functional dyspepsia are often found in patients with traumatic brain injury (TBI), especially in severe TBI patients.

Objective: Here we measured plasma total ghrelin, acyl ghrelin, and other gut brain peptides such as leptin and melatonin in patients with acute TBI, to assess the relationship between these peptides and functional dyspepsia and negative energy balance after acute TBI.

Methods: Plasma concentrations of total ghrelin, acyl ghrelin, leptin, melatonin, and glucose, and white blood cell counts were measured in the first 6–48 h and at the 7th and 30th days after acute TBI in 60 patients with severe, moderate, and mild injury based on GCS scores, and in 20 normal controls.

Results: Plasma concentrations of total ghrelin in all patients with acute brain injury was decreased at 6–48 h (p < 0.05; 478.61 ± 201.71 pg/mL), and at 7 days (641.03 ± 256.07 pg/mL) after injury compared to controls (910.26 ± 314.45 pg/mL), whereas no marked changes in acyl ghrelin, leptin and melatonin levels were seen. In the severe group, total ghrelin was still at low levels (572.58 ± 198.53 pg/mL) compared to controls (p < 0.05), and all patients had weight loss and difficult defecation. Total ghrelin was negatively correlated with white blood cell counts (p < 0.05) in first 6–48 h post-injury, and became positively correlated after 7 days, with no correlations seen between ghrelin and plasma glucose.

Conclusion: The decreased total ghrelin (non-acyl) levels in plasma seen after acute TBI caused reduced appetite, and at least in part, accelerated the development of functional dyspepsia and negative energy balance. Our data also support the hypothesis that the regulating systems for non-acyl ghrelin and acyl ghrelin are different. These results suggest that non-acyl ghrelin and its agonists may represent a potential therapeutic agent in severe TBI patients to improve their nutritional state.

Schwarzmaier Susanne Terpolilli Cole Plesnila Kolaus Department of Neurodegeneration, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Neurosurgery, Ludwig-Maximilians University, Munich, Germany

P13 Inhibition of Endothelial Nos After Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) is associated with a multitude of alterations resulting in secondary brain damage. NO synthases (NOS) are suspected to be involved in these mechanisms. Administration of the NOS inhibitor VAS203 has been shown to have beneficial effects after CCI. However, the mechanisms underlying this effect cannot be fully explained by inhibition of inducible NOS (iNOS), which is upregulated only after injury. Hence we next investigated the effect of VAS203 on one of the constitutive NOS, the endothelial NOS (eNOS), in order to determine whether increased activity of eNOS might be involved in secondary brain damage.

Methods: C57/BL6 mice (n = 12) were intubated and ventilated under continuous control of end-tidal CO₂. Subsequently a cranial window was prepared. After baseline recordings, the animals were subjected to controlled cortical impact (CCI; 6 m/sec, 0.5 mm). At 30 min after CCI, either VAS203 or control NaBP were administered. The lumens of arterioles and venules were visualized in vivo by administration of FITC-dextrane. Vessel diameters were monitored by intravital microscopy (IVM), both before and up to 2.5 h after CCI.

Results: Values of both end-tidal CO₂ and MABP where within the physiological range throughout the experiment. Arteriolar diameter was stable during baseline monitoring. By contrast, after CCI, it increased to 108.2 ± 2.7% or 109.8 ± 6.5% of baseline. Administration of NaPB had a small but not significant constrictive effect on arteriolar diameter. Administration of VAS203, however, resulted in significant vasoconstriction (92.2 ± 2.1% of baseline, or to 85.3% of post-traumatic diameter in cerebral arterioles). No significant effect of VAS203 or NaBP was seen in sham-operated animals.

Conclusion: VAS203 completely inhibited the arteriolar dilation that occurs after CCI, and this vasodilation is likely induced by increased activity of eNOS after TBI. The vasoconstrictive effect did not induce a reduction in CBF. However, it resulted in a reduction of post-traumatic ICP, which may be due to a restoration of cerebral compliance. Thus the acute effect of VAS203 on ICP can be explained by the inhibition of post-traumatically increased eNOS activity.

Lee Darrin Gurkoff Gene Schwartzkroin Philip Berman Robert Muizelaar Jan Paul Lyeth Bruce University of California–Davis, Davis, California

P14 Hyperexcitability and Epileptogenesis Following Traumatic Brain Injury and Secondary Hypoxia.

Background: Traumatic brain injury frequently results in and is complicated by hypoxia. These factors individually have been associated with the development of new-onset seizures; however, it is unknown how consecutive injuries affect seizure susceptibility. The aim of this study was to examine the effects of traumatic brain injury and secondary hypoxia on hyperexcitability and epileptogenesis.

Methods: In this study, 42 adult male Sprague-Dawley rats (300–350 g) underwent either a fluid percussion injury (FPI, n = 23) or a sham injury (n = 19), followed by implantation of a contralateral amygdala electrode. After injury and electrode implantation, the rodent either underwent 30 min of hypoxia (Fio ₂ 11%), or 30 min of normoxia. Subsequently, each animal underwent a rapid kindling protocol for 14 days beginning on post-procedure day 2. Behavioral and electrographic seizure duration, as well as Racine classification staging, were recorded. Hyperexcitability was tested in a different group of animals using flurothyl gas exposure. Six rodents received either FPI (n = 3) or sham injury (n = 3) followed by flurothyl exposure on post-procedure days 2 and 16. Seizure duration and onset were recorded.

Results: In the kindling study, behavioral and electrographic seizure duration was recorded each day in the four groups (FPI and normoxia, FPI and hypoxia, sham and normoxia, and sham and hypoxia). There was no significant difference among the four arms. Onset to stage 5 seizures demonstrated a trend towards an increased seizure threshold in the FPI and normoxia (12.0 ± 1.4 days), FPI and hypoxia (11.2 ± 0.6 days), and sham and hypoxia (11.6 ± 1.1 days) arms, relative to the sham and normoxia arm (8.7 ± 1.1 days). While 85.7% of sham and normoxia and 87.5% of sham and hypoxia animals developed stage 5 seizures, only 66.7% of FPI and normoxia and 70.0% of FPI and hypoxia animals developed them. In the flurothyl study on post-injury day 2, FPI animals developed stage 5 seizures later than sham animals (799.5 ± 37.02 seconds versus 596.7 ± 53.7 seconds; p < 0.05). By post-injury day 16, there was no difference in time to onset of stage 5 seizures.

Conclusion: Following fluid percussion injury or FPI followed by secondary hypoxia, there is a higher seizure threshold in the acute phase after FPI; however, seizure threshold returns to baseline 14 days after insult.

Phillips Linda Black Raiford Harris Lesley Reeves Thomas Virginia Commonwealth University, Richmond, Virginia

P15 White Matter Neuroprotection and the Role of Matrix Metalloproteinases.

Background: Traumatic brain injury (TBI) produces profound white matter (WM) pathology, resulting in structural and functional axonal damage. Prior studies identified compounds that protect against this traumatic axonal injury (TAI). Among the most promising are the immunosuppressants cyclosporine-A (CsA) and FK-506, as well as the antibiotic minocycline. These drugs target different cellular pathways to stabilize axonal integrity: mitochondrial release of cytochrome c, calcineurin activity, and the immune response. Our studies with corpus callosum showed that TBI alters expression and activity of matrix metalloproteinases 2 and 9 (MMP 2 and 9), enzymes contributing to blood–brain barrier (BBB) permeability and axonal pathobiology. While FK-506 and minocycline can target the MMP response in other brain pathologies, it is not known if these neuroprotective drugs differentially affect MMPs in injured CC. Here we report results comparing the effects of CsA, FK-506, and minocycline, on MMP2,9 activity following TBI.

Methods: Rats were subjected to moderate central fluid percussion TBI and allowed to survive 1 or 3 days post-injury. Published protocols identified as protective against TAI were applied for each drug: CsA (20 mg/kg IP at 15 min post-injury), FK-506 (3 mg/kg IV at 30 min pre-injury), and minocycline (45 mg/kg IP at 30 min and 6 h post-injury). Effects of treatment on callosal MMP2,9 were assessed using gelatin zymography, focusing on 1 day post-injury for the CsA and minocycline groups, and 3 days post-injury for FK-506-treated animals. At sacrifice, the entire callosum was dissected free and protein extracts prepared. Enzyme activity was measured densitometrically and expressed as percentages of paired controls.

Results: Callosal zymograms identified both pro and active forms of MMP9 and pro MMP2. We observed differential post-injury drug effects on MMP 2,9. At 1 day, CsA had no effect on the activity of either gelatinase. By contrast, minocycline increased activity of pro MMP9 (31%), attenuated active MMP9 (24%), but failed to change the MMP2 signal. In animals treated with FK-506, at 3 days MMP2 enzyme activity was attenuated (28%), but neither form of MMP9 was affected.

Conclusion: Taken together, these results show that individual agents facilitating WM protection differentially affect MMP pathways influencing axonal stabilization. This influence may occur during acute injury periods, when the BBB is vulnerable, or in later post-injury stages, where matrix organization mediates the extent of axonal recovery. Gelatinase's role appears to be multifaceted during this period, involving different enzymes at different stages of the response.

Wu Yuxiang Lv Xiaohua Zeng Shaoqun

P16 Fine Structure Difference of Nerve Fibers in Ventral and Dorsal Roots.

Abstract not Available

Dong Jirong Cai Xuejian Wang Yuhai Shi Zhonghua Liu Bin Cai Sang 101st Hospital of PLA, WuXi, China

P17 Studies of Tentorium Cerebelli Incisions in the Treatment of Tentorial Herniation.

We aim to explore safer and more convenient operative methods of tentorium cerebelli incision in the treatment of severe and very severe brain injury complicated by tentorial herniation. There were 236 severe and very severe head-injury patients with uncal herniations in our hospital from July 1994 to October 2010, who had received craniotomy to evacuate hematomas by removal of a large bone flap, in addition to tentorium cerebelli incision. We chose conventional U-shaped skin incisions for cases with temporal, temporoparietal, or temporoparietal-occipital hematomas or contusions. For frontal or frontotemporal hematomas or contusions we used a modified Kelly's question mark skin incision. We followed the original route to the upper margin of the mastoid process, from the ear rear to anterior along the hairline. The end point of the modified incision was 1.0 cm into the upper zygomatic arch before the tragus. Appropriate positions and specially-designed hooked scalpels were used in these operations. There were 91 cases with GCS scores 3–5, and 145 cases of scores 6–8 before the operations. Ninety-two cases (38.9%) survived in good condition, 51 cases (21.6%) had moderate disability, 41 cases (17.4%) had severe deficits, 23 cases (9.7%) were vegetative, and 29 cases (12.3%) died. It may improve prognosis by using a safer and more manageable operative procedure for tentorium cerebelli incisions for cerebral herniations.

Dong Jirong Xu Qinyi Cai Xuejian Wang Biao Wang Yuhai Shi Zhonghua Liu Bin Hu Xu

P18 Management of Dissymmetric Bilateral Frontal Contusions with a Unilateral Approach for Cerebral FALX Incision with Endoscopic Assistance.

Abstract not Available

Xiao-chuan Sun Li Jiang Xiao-hong Yin Cheng Yin Wei Dan Ke Liu The First Hospital Affiliated to Chongqing Medical University, Yuanjiagang, China

P19 The Influence of Apolipoprotein E Polymorphisms on the Electrical Activity of the Brain After Mild/Moderate Traumatic Brain Injury.

Background: The aim of this study was to investigate the influence of apolipoprotein E gene (APOE) polymorphisms on the electrical activity of the brain at the acute stage of mild/moderate traumatic brain injury.

Methods: The clinical data of 112 patients with mild/moderate traumatic brain injury were collected and the APOE genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The electrical activity of the brain in each patient was recorded by EEG two times within a week after injury. Qualitative and quantitative methods were used to determine the variations of electrical activity of the brain. Chi-square testing, analysis of variance, and logistic regression analyses via SPSS version 11.5 were performed to analyze the relationships among APOE genotypes, electroencephalographic data, and clinical data.

Results: Among 112 patients, the distributions of APOE genotypes and allleles matched the Hardy-Weinberg law. Twelve out of 22 patients with AOEɛ4 (54.5%) presented with deteriorated EEGs, which was significantly higher than the rate in patients without APOEɛ4 (16 of 90 patients, 17.8%, p = 0.000). Comparison of the first and second EEGs demonstrated that the slow waves in patients with APOEɛ4 significantly increased (p = 0.0098), while the slow waves in patients with APOEɛ2 and APOEɛ3 decreased (p < 0.05). The reduction of slow waves in APOEɛ2 carriers was more obvious than that seen in APOEɛ3 carriers (p = 0.0249). Logistic regression analyses showed that APOEɛ4 was a risk factor for EEG deterioration after traumatic brain injury.

Conclusion: APOEɛ4 is a risk factor for EEG deterioration during the acute stage after mild/moderate traumatic brain injury. However, APOEɛ2 appears beneficial for the recovery of electrical activity of the brain.

Li Jiang Xiao-chuan Sun Cheng Yin Shuai Zhou The First Hospital Affiliated to Chongqing Medical University, Yuanjiagang, China

P20 Effect of Exogenous APOE on Intracellular Calcium Levels After Injury.

Background: APOE genotype influences the outcome of TBI via unclear mechanisms, and it has also long been known that calcium plays a key role in the pathophysiology of TBI-induced cell death. The purpose of this study was to explore the effect of exogenous APOE on intracellular calcium after injury in vitro.

Methods: Astrocytes from APOE knock-out mice were isolated and cultured in order to avoid interference with APOE generated by the cells themselves, and astrocyte transection models were established. Recombinant human apoE4, recombinant human apoE3, and wild-type mouse apoE, were added to culture media, which formed three study groups (namely group 4, group 3, and group 2), and group 1 without any added apoE was used as a control. Intracellular calcium was labeled by fluorescent probe fluo-3, and the intracellular calcium levels were determined for individual cells using laser scanning confocal microscopy 2 h after injury.

Results: At 2 h after injury, intracellular calcium levels of the astrocytes in group 4 were significantly higher than those of the other groups, while intracellular calcium levels of the astrocyte in group 3 were the lowest. (intracellular calcium levels: group 4 > group 1 > group 2 > group 3).

Conclusion: Exogenous apoE4 induces higher intracellular calcium loads post-injury, suggesting that APOE may affect the outcome of TBI through isoform-specific influences on intracellular calcium levels.

Xiao-chuan Sun Xiao-hong Yin Li Jiang Wei Dan Cheng Yin The First Hospital Affiliated to Chongqing Medical University, Yuanjiagang, China

P21 The Different Effects of APOE Genotypes Incited by Traumatic Brain Injury on Electroencephaograms in the Acute Stage.

Background: The purpose of this study was to investigate the differences in brain electrical activity among patients with different APOE genotypes (APOEɛ2, APOEɛ3, or APOEɛ4) in the acute stage of TBI.

Methods: In this study we recruited 118 patients admitted within 3 days after suffering mild or moderate traumatic brain injury, and 40 normal adults as controls. APOE genotyping was performed using PCR-RFLP. Electroencephalography was performed in the patients after admission, and in all the control subjects. Quantitative electroencephalographic data from the TBI patients and normal adults were collected and analyzed by professionals.

Results: The quantitative EEG data among APOEɛ2, APOEɛ3, and APOEɛ4 carriers, and the normal subjects had no statistically significant differences (p = 0.097). In 118 patients with mild/moderate traumatic brain injury, there were significant differences in the quantitative data among APOEɛ2, APOEɛ3, and APOEɛ4 carriers (p = 0.008). Compared with APOEɛ3 carriers, the energy value of slow waves was higher in patients with APOEɛ4, and lower in patients with APOEɛ2.

Conclusion: The isoform-specific influence of APOE on brain electrical activity is indistinct in the physiological state, but can be induced by TBI. APOEɛ4 exerts negative effects on brain electrical activity, while APOEɛ2 appears to protect brain function.

Hai-tao Wu Xiao-chuan Sun Li Jiang Yong Jiang Cheng Yin Hai-jian Xia The First Hospital Affiliated to Chongqing Medical University, Yuanjiagang, China

P22 APOE Isoform-Specific Influence on NF-KB Expression of Astrocytes After Injury.

Background: Previous studies have demonstrated the association of APOE polymorphisms with pathological evolution in the early phase of traumatic brain injury and outcomes post-TBI. However, the mechanisms via which APOE influences TBI prognosis are not clear. The aim of this study was to investigate the correlation between APOE polymorphisms and the NF-κB levels of astrocytes in the early stage after injury in vitro.

Methods: The CDS region of three APOE alleles was obtained by reverse transcription polymerase chain reaction (RT-PCR), then the recombinant plasmid pEGFP-N1-APOE was constructed and identified by sequencing. Astrocytes were separated from APOE gene knock-out mice, and identified by immunocytochemistry. The recombinant plasmids containing the three APOE alleles (APOE ɛ2, APOE ɛ3, and APOE ɛ4) were respectively transfected into the isolated astrocytes with lipofectamine 2000. Injury was produced by scratch injury to a monolayer of confluent astrocytes. RT- PCR was used to detect the expression of NF-κB mRNA at 12, 24, and 48 h post-injury. Western blot analysis was used to detect the expression of NF-κB protein as well.

Results: The expression of NF-κB was observed at the 12th hour post-injury, but there was no statistically significant difference among the three groups (p < 0.05). The expression was increased at the 24th hour post-injury. Compared with the other two groups, APOE ɛ4-transfected astrocytes expressed higher levels of NF-κB (p < 0.05). At the 48th hour post-injury, the expression of NF-κB was increased further, and statistically significant differences were seen between APOE ɛ4 and the other two groups (p < 0.05).

Conclusion: This study suggests that APOE ɛ4 carriers may have poorer outcomes due to more severe inflammatory responses in the early phase post-injury.

Xue-yuan Wang Shu-yuan Yang Graduate School of Tianjin Medical University, Tianjin, China

P23 In-Depth Exploration of Cerebrospinal Fluid from Patients with Traumatic Brain Injury by Combinatorial Peptide Ligand Libraries: A Pilot Study.

Background: The performance of combinatorial peptide ligand libraries was investigated for the removal of the most abundant proteins in cerebrospinal fluid (CSF) from patients with traumatic brain injury (TBI).

Methods: CSF samples were obtained from 10 patients with TBI. The commercially available hexapeptide ligand library (HLL) ProteoMiner was used to treat the CSF samples, in which proteins compete for binding sites on bead-bound peptide hexamers with different binding properties. Two-dimensional electrophoresis (2-DE) was performed on the concentrated crude CSF, the ProteoMiner flow-through, and the bound fractions, to visually examine the effect of the sample preparation.

Results: The high-abundance proteins albumin, IgG heavy chains, Ig light chains, serotransferrin, α1-antitrypsin, apolipoprotein A-1, and transthyretin, were the main proteins found in the flow-through fraction. The total number of spots in the 2-DE gel of the bound fraction was 1527, whereas 1246 spots were observed on the 2-DE gel of the flow-through fraction. After enrichment of low-abundance proteins, the number of spots increased by ∼ 23%.

Conclusions: The use of the ProteoMiner and 2-DE enabled detection of many new protein spots, and increased resolution and improved intensity of low-abundance proteins compared with the precipitation technique. Combinatorial peptide ligand libraries may be used as a tool for screening low-abundance biomarkers in human CSF in order to prevent additional injuries resulting from secondary events in the post-traumatic period of TBI.

Nelson Neta Paluy Vadim BHR Pharma, LLC, Herndon, Virginia

P24 Synapse^® Study BHR-100-301: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study to Investigate the Efficacy and Safety of Progesterone in Patients with Severe Traumatic Brain Injury.

Background: Numerous pre-clinical studies have demonstrated that progesterone has beneficial effects in TBI via multiple mechanisms. In a pilot and two Phase 2 studies conducted in moderate-to-severe TBI patients, progesterone showed promising efficacy, resulting in improved functional outcomes and mortality with an acceptable safety profile. BHR Pharma, LLC (supported by Besins Healthcare) has launched the SyNAPSe^® Phase 3 trial to evaluate BHR-100 progesterone lipid infusion in 1180 severe TBI patients (Glasgow Coma Scale score 4–8).

Methods: Subjects are entered into the SyNAPSe study following proxy consent or per local country consent regulations, and are then randomized in a 1:1 ratio to BHR-100 or placebo. Randomization is conducted centrally, stratified by region. Subjects are treated initially with a loading dose of 0.71 mg/kg/h of BHR-100 or placebo IV for the first hour, followed by a continuous maintenance infusion of 0.5 mg/kg/h, for a total of 120 h/5 days. The infusion must be initiated within 8 h of the brain injury, as confirmed by CT scan. The primary end-point is the Glasgow Outcome Scale (GOS) score as assessed at 6-months post-injury. Secondary end-points include the GOS-Extended, mortality, and the quality of life measure SF-36. The trial is registered at www.clinicaltrials.gov [ID NCT01143064].

Results: To date, the study has received approval in 15 countries and 43 sites in the U.S., Europe, and Asia, and have received investigational review board/ethics committee approval to conduct the trial. Most of the additional 100 sites will be approved by May 2011. The study currently is under review in the People's Republic of China. An interim analysis is planned once 400 subjects (200 in each arm) have completed the 6-month assessment.

Conclusion: BHR-100 is a promising candidate as a neuroprotectant for severe TBI patients. Successful completion of the SyNAPSe Phase 3 study may lead to the approval and registration of BHR-100 as the first such drug to have positive outcomes in the acute treatment of these patients.

Takeuchi Satoru Nawashiro Hiroshi Sato Shunichi Kawauchi Satoko Shima Katsuji National Defense Medical College, Saitama, Japan

P25 A Better Mild Traumatic Brain Injury Model in the Rat.

Background: dentification of mild traumatic brain injury (TBI) is quite challenging. The primary pathology associated with mild TBI is selective axonal injury, which may characterize the vast majority of blast-induced TBI. Axonal injuries in mild TBI have been considered as the main factors responsible for the long-lasting memory or attentional impairment. Among these axonal injuries, recent attention has been focused on the cingulum bundle (CB), because the CB connects the anterior thalamic nuclei with the hippocampal region, and is involved in attention, emotions, spatial orientation, and memory. Furthermore, recent studies with diffusion tensor MR imaging have shown injuries to the CB in mild TBI in humans. This study aimed to make a better laboratory model of mild TBI.

Methods: Sprague-Dawley rats were subjected to mild TBI, using laser-induced shockwaves (LISW) (sham, 0.5 J/cm², or 1.0 J/cm²; n = 4 per group). The mechanism of the effect of LISW is as follows: (1) a 32-nm nanosecond laser pulse was irradiated onto a laser target (laser-absorbing material) on the head, (2) plasma is formed, and (3) expansion of the plasma is accompanied by a shockwave. T-maze and radial-arm maze testing were performed for behavior observations. Fourteen days after LISW, axonal densities were quantified by assessing light transmittance of digital images of Bodian silver staining, using the software program Image J (freely downloadable from rsb.info.nih.gov).

Results: Macroscopic examination of the brains showed no abnormalities of the cerebral cortex in all groups. Bodian-stained brain sections 14 days after LISW at 0.5 J/cm² or 1.0 J/cm² showed a statistically significant decrease in CB axonal density compared with the sham group.

Kobayashi Hiroaki Otani Naoki Nawashiro Hiroshi Shima Katsuji Suzuki Shinaya Uenoyama Maki National Defense Medical College, Division of Environmental Medicine, National Defense Medical College Research Institute, Japan

P26 Effects of Hydrogen Gas in a Mouse Cold Induced Brain Injury Model.

Background: Hydrogen gas (H₂) is an antioxidant agent that reduces hydroxyl radical. H₂ exposure improved conditions in a model of rat brain reperfusion injury. We investigated the effect of H₂ gas in a mouse cold induced brain injury model.

Methods: Male C57BL6/J mice (10–12 weeks old) were anesthetized by 2.0–2.5% isoflurane. After a midline scalp incision, cold-induced brain injury was produced. A cotton bud was soaked in liquid nitrogen, and put onto the skull for 15 sec. The target was 3 mm lateral and 3 mm dorsal from the bregma. After cold injury, the mice were immediately put in a chamber, and mixed gas (1.3% H₂, 30% oxygen, and 68% nitrogen) was supplied continuously for 6 h on day 1. On day 2 and day 3, the mice were exposed to the mixed gas for 6 h each day. Mice without H₂ treatment were exposed to room air. After the third day of mixed gas exposure, the mice were sacrificed at 48 h after injury. Evaluations were made of (1) injury volume, (2) blood–brain barrier (BBB) breakdown, (3) brain edema, and (4) behavioral testing at 48 h after injury.

Results: H₂ therapy reduced injury volume and improved behavioral testing. However, H₂ therapy intensified BBB breakdown and increased brain edema.

Conclusion: H₂ treatment is probably effective for mouse cold-induced brain injury; however, H₂ therapy has unfavorable effects against traumatic brain injury.

Cai Qiang Chen Qianxue Chen Zhibiao Wu Liquan Wang Long

P27 Microsurgical Treatment for Traumatic Intracerebral Hematoma in the Sylvian Fissure Region.

Abstract not Available

Wang Long Chen Qianxue Xu Haitao Huang Shulan Chen Zhibiao Tian Daofeng Cai Qiang Wu Liquan Qi Xuchen Renmin Hospital of Wuhan University, Wuhan, China

P28 The Diagnosis and Treatment of Sigmoid Sinus Thrombosis Following Closed Craniocerebral Injury.

Background: Here we discuss the diagnostic tools and principles of treatment of sigmoid sinus thrombosis following closed craniocerebral injury.

Methods: We performed a SCI search for articles on sigmoid sinus thrombosis following closed craniocerebral injury that were published between 1995 and January 2010. We found 7 articles including 15 patients, and we added our own case to this series. The clinical conditions, diagnostic methods, principles of treatment, and prognosis were analyzed using data from these cases.

Results: The GCS scores of the 16 patients with sigmoid sinus thrombosis following closed craniocerebral injury were between 13 and 15. They had symptoms such as terrible headaches and vomiting. The mean age was 20.9 years. There were 12 right sigmoid thrombosis patients and 4 left, with 12 cases combined with thrombosis of the transverse sinus or jugular vein. Five patients were treated with anticoagulation, 10 cases by observation, and 1 patient received surgery.

Conclusion: One should have a high suspicion of sigmoid sinus thrombosis when one finds ambiguous intracranial hypertension symptoms following closed craniocerebral injury. The diagnosis can be verified by CTA or MR venography, though sometimes digital subtraction angiography must be used. Most cases require only observation, though some may need anticoagulation and monitoring.

Wu Yongchao Zou Zhenwei Zheng Qixin Union Hospital, Huazhong University of Science and Technology, Wuhan, China

P29 Biocompatibility and Bioactivity of Functionalized Self-Assembling Nanofiber Scaffolds for Dorsal Root Ganglion Neurons.

Background: Here we assess the biocompatibility and bioactivity of the functionalized designer self-assembling nanofiber scaffolds IKVAV-NS and FGL-NS for dorsal root ganglion neurons.

Methods: Two functional motifs, IKVAV from laminin and FGL from NCAM (neural cell adhesion molecule), were chosen to functionalize the widely used non-bioactive self-assembling scaffold RADA-16. IKVAV and FGL were added to the C-termini of RADA-16. Then the characterization of these functionalized materials was tested using atomic force microscopy (AFM) and a rheometer. The biocompatibility and bioactivity of these scaffolds were examined for adhesion, neurite growth, and migration of dorsal root ganglion (DRG) neurons.

Results: The functionalized molecules could self-assemble to build nanofiber scaffolds (IKVAV-NS and FGL-NS). The fiber diameter of the FGL-NS was 38.2 ± 2.7 nm, and the length of the fibers was as long as several hundred nanometers. The diameter of the nanofibers of IKVAV-NS was 24.9 ± 2.3 nm. Hydrogel formation of IKVAV-NS and FGL-NS were further confirmed using rheological tests. Both IKVAV-NS and FGL-NS were non-cytotoxic. Importantly, these novel self-assembling peptide scaffolds could promote adhesion, neurite sprouting, and migration into the 3D scaffold of DRG neurons. The DRG neuron survival rates of cells cultured on IKVAV-NS and FGL-NS at 7 days were 89.2% and 90.1%, respectively. The average neurite length of the DRG neurons was 74.9 ± 5.68 μm on RADA-16, 140.27 ± 10.27 μm on FGL-NS, and 120.36 ± 11.47 μm on IKVAV-NS. Maximal DRG neurite length was 298.43 ± 38.02 μm on RADA-16, 553.63 ± 36.83 μm on FGL-NS, and 496.35 ± 42.83 μm on IKVAV-NS.

Conclusion: The novel designer peptide scaffolds containing the IKVAV and FGL motifs had excellent biocompatibility and bioactivity and could be used for neuronal regeneration.

Guang Hou Ji Li GuoPing Sichuan University West China Hospital, Sichuan, China

P30 The Application of CT Subarachnoid Opacification in Post-Traumatic Hydrocephalus.

Background: Here we evaluate the value of CT subarachnoid opacification (CTSO) in the diagnosis and treatment of post-traumatic hydrocephalus (PTH).

Methods: CTSO was performed on 66 patients with enlarged ventricles on normal CT/MR to diagnose hydrocephalus and confirm the obstructive level. Patients required different treatments according to CTSO: conservative treatment to delay CSF absorption, L-P (lumbaro-peritoneal) shunts to ventricular-spinal subarachnoid communicating hydrocephalus, V-P (ventriculo-peritoneal) shunts to ventricular-spinal subarachnoid noncommunicate.

Results: Two patients (2/66) were confirmed with delayed CSF absorption, and on follow-up CSF absorption had returned to normal 1 year later; 42 (42/66) had L-P shunts; and 22 patients (22/66) had V-P shunts. All of the patients' ventricles became smaller and clinical manifestations improved.

Conclusion: CTSO is simple and effective in the diagnosis of PTH, and can be used both in diagnosis and typing. CTSO is better than normal CT, MRI, and RCFS (radionuclide cerebrospinal fluid scintigraphy), and easy to perform.

Kreipke Christian Rafols Jose Reynolds Christian Kuhn Donald Armstead William Wayne State University, Detroit, Michigan

P31 ETRA Antagonism and Traumatic Brain Injury: Towards a Clinical Trial.

Background: Traumatic brain injury results in multiple pathologies, including a significant reduction in cerebral blood flow. Our combined laboratories have shown that endothelin-1 plays a major role in the induction of hypoperfusion.

Methods: Therefore, using a rodent model of diffuse traumatic brain injury, we sought to test the effects of IV administration of various selective and non-selective endothelin receptor antagonists on CBF (as measured using arterial spin labeling MRI), cellular injury (as measured using Fluoro-Jade labeling), and behavioral outcome (as measured using a radial arm maze spatial learning task) following TBI.

Results: Our results indicate that ETrA antagonism causes a decrease both in hypoperfusion and cellular injury, and improves behavioral outcomes. Conversely, ETrB antagonism did not improve any measure of outcome at any dose given. Furthermore, mixed ETrA/B antagonism did not improve outcome.

Conclusion: These data suggest that specific TrA antagonists may be effective in ameliorating the deleterious effects of TBI.

Tong Wusong Ping Zheng Yi-jun Guo Junfa Xu Wen-jin Yang Gao-yi Li Bin He Jing-song Zeng Hui Yu Pudong New Area People's Hospital, Shanghai, China

P32 Prognosis Analysis and Risk Factors Related to Progressive Intracranial Hemorrhage in Patients with Acute Traumatic Brain Injury.

Background: This study aimed to investigate the risk factors related to progressive intracranial hemorrhage (PIH) in patients with traumatic brain injury (TBI).

Methods: A cohort of 498 TBI patients was retrospectively reviewed, and 139 (27.91%) patients suffered from PIH as confirmed by CT scan. Data included gender, age, mechanism of injury, Glasgow Coma Scale (GCS) score at admission, time from injury to the first CT, the signs on the initial CT scan, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen (Fg), thrombin time (TT), platelets (PLT) and D-dimer (D-D) values. The clinical factors were compared between PIH and non-PIH patients.

Results: The differences between PIH and non-PIH patients were significant for age, GCS at admission, the signs on the initial CT scan (fracture, subarachnoid hemorrhage, brain contusion, and primary hematoma), PT, Fg, and D-D values, and abnormal plasma D-D values were the most important predictors of PIH (p < 0.01).

Conclusion: For patients with an initial CT scan showing subarachnoid hemorrhage, brain contusion, or primary hematoma, with abnormal D-D levels, an earlier CT scan and dynamic coagulation test should be performed in order to detect PIH as early as possible, so medical intervention can be prompt.

Greer John McGinn Melissa M. Povlishock John T. Virginia Commonwealth University School of Medicine, Richmond, Virginia

P33 Diffuse Traumatic Brain Injury Induces A Heterogeneous Axonal Response with Evidence of Reactive Sprouting in a Subset of Injured Fibers.

Background: Diffuse axonal injury (DAI) is a consistent component of traumatic brain injury (TBI), and is associated with much of its morbidity. Though much is known about the pathobiology underlying DAI, our understanding of this phenomenon is incomplete, due in part to the research community's heavy reliance upon immunohistochemical markers of axonal injury. To circumvent this, we have employed a model of central fluid percussion injury (cFPI), combined with a transgenic mouse strain (YFP-H), to perform an early and detailed morphological assessment of DAI in layer 5 pyramidal neurons.

Methods: Adult YFP-H mice (25–30 g) were subjected to cFPI and sacrificed at 15 min, 30 min, 1 h, 3 h, 6 h, 12 h, and 24 h post-TBI, and the brain tissue was analyzed with routine fluorescence and confocal microscopy, along with parallel ultrastructural analyses.

Results: Utilizing this approach, YFP-positive axonal swellings were observed as early as 15 min post-injury. Additionally, at both 15 min and 1 h post-injury, multifocal sites of injury along the same axonal fiber were observed in many cases. While most of the swellings at these early time points maintained continuity with their distal axonal segments, by 24 h post-injury, the majority of injured axons displayed clear disconnections. With disconnection, two distinct populations of axotomized YFP-positive neurons emerged, becoming most readily identifiable by 24 h post-injury. One YFP-positive neuronal population exhibited classical rounded swellings, which consistently labeled positive for APP (a marker of axonal injury and impaired axonal transport). In contrast, a second population displayed truncated proximal axonal segments lacking APP immunoreactivity, many of which displayed evidence of injury-induced reactive sprouting. Quantitative analysis of the damaged axonal profiles revealed that the truncated, sprouting axonal population seen at 24 h post-injury constituted 41.8% of the remaining YFP-positive axonal segments. This was comparable to the percentage of YFP-positive fibers that remained capped with axonal swellings (39.3%).

Conclusion: These findings related to the pathogenesis and fate of DAI underscore the heterogeneity of the cellular/axonal responses seen following diffuse brain injury. Further, these studies conducted in YFP mice also illustrate the need for caution when interpreting data based solely on immunohistochemical markers of axonal injury, that may fail to identify the total population of injured fibers. Lastly, our observation that some reactive axons sprout suggests the potential for regeneration, although it is unknown if this regeneration leads to adaptive or maladaptive repair.

Lu hua Jiang Yun-zhao Wang Qi-hong Wuxi Third People's Hospital, Wuxi, P.R. China; Huashan Hospital, Shanghai, P.R. China

P34 Gradual Decompression for Traumatic Malignant Intracranial Hypertension.

Background: Decompressive craniectomy (DC) for the treatment of malignant intracranial hypertension due to traumatic brain injury is a generally accepted practice. However, the conventional DC procedure remains controversial, because of the increase in brain edema, massive intraoperative brain swelling, and contralateral space-occupying hematomas, which may cause post-ischemic luxury perfusion, one of the main factors related to unfavorable outcomes. We have developed a novel gradual decompression technique in DC to avoid an abrupt and uncontrolled decompression.

Methods: Since 2007, 51 patients (GCS score 30 mm Hg for 30 min) were treated with surgical decompression in our hospital. We have changed our technique for DC by using a series of gradual decompressive steps, which consists of emergency burr-hole evacuation, creating numerous small dural openings and removing clots, enlarging fenestration in the frontal and the temporal basal regions to treat brain contusion, and performed an augmentation duraplasty in all 51 patients. Outcomes in the 51 patients treated with this technique were compared to 50 patients treated with a conventional decompression and durotomy between 2003 and 2006.

Results: By using this novel operating technique, the outcomes of these treated patients were GOS > 3 in 37% (19 of 51), and the mortality rate was 25% (13 of 51). In comparison, the outcomes of the control group were poor. Outcomes showed GOS > 3 in 12% (6 of 50), and the mortality rate was 78% (39 of 50).

Conclusion: Our results suggest that gradual decompression may prevent a sudden increase in cerebral blood volume and reduce the rate of post-ischemic luxury perfusion. A randomized controlled trial is required to substantiate these findings.

Jiang Yun-zhao Lu hua Lan Qing Wuxi Third People's Hospital, Wuxi, China; Second Affiliated Hospital of Soochow University, Jiangsu, China

P35 Gradual and Controlled Decompression for Brain Swelling due to Severe Head Injury.

Background: Patients with uncontrollable intracranial hypertension due to post-traumatic brain swelling (BS) most often either die or survive in an extremely disabled state. Decompressive craniectomy (DC) with dural augmentation may be the best way to assist these patients. However, the efficacy of DC for functional outcome remains controversial. One of the factors contributing to poor outcomes may be intraoperative brain extrusion. We have adopted a new surgical technique called “gradual and controlled decompression” (GCD) for unilateral acute post-traumatic BS, which can prevent and control massive intraoperative brain swelling (IOS).

Methods: In the past 3 years, we have applied GCD in the treatment of unilateral acute post-traumatic BS associated with thin subdural hematomas. The GCD procedure includes: (1) emergency burr-hole evacuation and drainage; (2) creating numerous small dural openings and removing clots; (3) making a U-shaped discontinuous dural small incision around the circumference of the craniotomy; (4) enlarging the fenestration in the frontal and the temporal basal regions to treat brain contusion; (5) performing an augmentation duroplasty through the discontinuous small opening with dural prosthetic substances; and (6) excising temporal muscle, fascial release, and galeatomy. Outcome was assessed 6 months after injury using the Glasgow Outcome Scale (GOS).

Results: This technique has been employed in 12 patients suffering from unilateral acute post-traumatic BS. The mean GCS score at presentation was 6, with a range of 3–11. Through gradual stepwise decompression, IOS was well prevented and controlled, and an expanded duroplasty was performed successfully in all cases. The outcome was favorable (GOS score of 4 or 5) in 5 patients, unfavorable (GOS score of 3) in 2 patients, vegetative state in 2 patients, and 3 patients died.

Conclusions: This new surgical approach can prevent severe extrusion of the brain through the craniotomy defect, and allow the gradual and gentle release of the subdural space. Further clinical studies should be conducted to assess the impact of this new technique on morbidity and mortality rates.

Liu Gang Detloff Megan R. Miller Kassi N. Santi Lauren Houle John D. Spinal Cord Research Center Department of Neurobiology and Anatomy Drexel University College of Medicine, Philadelphia, Pennsylvania

P36 Exercise-Induced Modulation of Microrna-21 and 199A Affects the PTEN/MTOR Pathway in the Lumbar Spinal Cord After Spinal Cord Injury in Rats.

Background: Injured axons in the spinal cord exhibit a poor regenerative response, leading to devastating consequences. Recent studies emphasizing the intrinsic changes within the damaged neuron and its axon have identified the PTEN/mTOR signaling pathway as a critical regulator of protein synthesis and process outgrowth in the damaged CNS. As researchers develop effective strategies for axonal regeneration, it is important to evaluate changes in spinal cord networks below the spinal cord injury (SCI), so that they are receptive for regenerating axons. Exercise (Ex) is a non-invasive therapy for SCI that yields anatomical, electrophysiological, and biochemical plasticity within the segmental spinal cord. MicroRNAs (miRs) are a class of small, non-coding RNAs that regulate mRNA expression and translation into protein. The purpose of this experiment was to determine whether miRs are important signaling regulators of intrinsic neuronal plasticity in the lumbar cord, and whether they can be modulated by Ex.

Methods: Adult, female Sprague-Dawley rats received complete T10 transection. Rats were assigned to the following groups: Tx10d, Tx10d + Ex, Tx10d + Ex + rapamycin, Tx31d, and Tx31d + Ex (n = 5/group). Ex groups received 60 min of Ex on motorized bicycles 5 days/week starting 5 days post injury (dpi). The expression of miRs, their target genes, and downstream effectors involved in the PTEN/mTOR gene pathway were probed via Q-PCR at 10 and 31 dpi.

Results: We show that Ex elevated expression of miR21 and decreased expression of miR199a-3p. These changes in miR expression correlated with changes in the expression of their target genes (i.e., PTEN expression decreased while mTOR expression increased with Ex). Western blotting and immunohistochemistry for activated S6, a downstream effector of mTOR, revealed a significant increase in phosphorylated S6 levels within intermediate grey neurons in rats receiving Ex. Rapamycin treatment of exercised rats reduced p-S6 levels.

Conclusions: These results suggest that Ex is an effective therapeutic strategy to maintain segmental spinal cord neurons below the SCI to receive regenerating axons by acting on multiple miRs and their targets.

Corrigan Frances Pham Ch Vink Robert Masters Colin Blumbergs Peter Cappai Roberto Van den Heuvel Corinna University of Adelaide, Adelaide, S.A., Australia

P37 Sappalpha Rescues Deficits in Amyloid Precursor Protein Knockout Mice Following Traumatic Brain Injury.

The amyloid precursor protein (APP) is upregulated following traumatic brain injury (TBI), and this is thought to be a protective response due to the actions of its metabolite, sAPPalpha. Indeed, our previous work has shown that APP^–/– mice were significantly more impaired following TBI than their APP^+/+ counterparts. Although this is most likely due to a lack of sAPPalpha, it is unknown which region within this peptide is responsible for its neuroprotective properties. sAPPalpha consists of up to six domains, with the beneficial actions of sAPPα linked to the D1 and D6a domains, which have been shown to promote neurite outgrowth in vitro. This study investigated whether the D1 or D6a domains of sAPPalpha could rescue deficits in APP knockout mice following a focal TBI. Following injury, treatment with either the D1 or D6a domains was as effective as the full length sAPPalpha peptide at rescuing both motor and cognitive deficits following TBI, as tested on the ledged beam and Barnes maze, respectively. Thus, although untreated APP^–/– mice made significantly more footfaults on days 2–5 post-injury on the ledged beam than APP^+/+ mice, those treated with the D1 or D6a domains were not significantly different from injured APP^+/+ mice on all days tested post-injury. Similarly, without treatment, APP^–/– mice took significantly longer to locate a previously learned escape hole on the Barnes Maze than APP^+/+ mice on days 2, 4, and 6 post-injury. However, treatment with either the D1 or D6a domains resulted in a significant improvement, such that the animals were no longer different from the APP^+/+ mice. This improvement seen in APP^–/– mice treated with the D1 or D6a domains corresponded with a decrease in neuronal injury. At 24 h post-injury, APP^–/– mice had significantly more degenerating neurons within the CA region of the hippocampus than APP^+/+ mice, as detected with Fluoro Jade staining. Treatment with either the D1 or D6a domains of sAPPalpha meant that these APP^–/– mice no longer had significantly more dying neurons than APP^+/+ mice. As such this study has identified two regions within sAPPalpha that provide its neuroprotective activity following TBI.

Szellár Dóra Mezősi Emese Bajnok László Czeiter Endre Kovács Noémi Simon Mária Büki András Department of Neurosurgery Psychiatry and Endocrinology, Medical Faculty of Pécs University, Pécs, Hungary

P38 Traumatic Brain Injury-Associated Hypopituitarism in Light of Long-Term Follow-Up.

A growing body of evidence indicates that traumatic brain injury (TBI) might be complicated by Hypopituitarism, further exacerbating existing impairments in physical, cognitive, and psychosocial functioning. There are conflicting data on the onset of post-TBI hypopituitarism and the necessary duration of follow-up. This analysis of the Pécs TBI Database aimed to reveal the occurrence of pituitary hypofunction in survivors of severe TBI as long as 5 years post-injury. The Database contains data from 430 closed-head injury cases with post-resuscitation Glasgow Coma Scale (GCS) scores under 9, collected between 2002 and 2010. Patients treated between March 2004 and December 2007 were selected for endocrine check-up. We have analyzed 59 patients (median age 38.4 years, range 6–75 years) with post-injury time varying between 3 and 70 months, and 20 of these cases were followed for more than 3 years. Endocrine tests included thyroid function, cortisol and ACTH levels, prolactin, sex hormone concentrations, GH–IGF-I axis, and posterior pituitary function evaluation. Additional stimulatory tests were performed if data indicated pituitary hypofunction (insulin, arginine, glucagon, and TRH tests). Endocrine abnormalities were detected in 52.5% of our patients. Growth hormone (GH) deficiency was the most frequent abnormality detected, in up to 35.5% of patients. In 15% of cases endocrine abnormalities affected multiple axes (primarily GH deficiency + hypogonadism). In six cases followed from our previous cohort, we found a new onset of hypopituitarism (4 with GH-deficiency, 2 with hypogonadism) following a normal endocrine lab test with more than 12-, and injury with more than 18 months in each case. One case developed hypogonadism 4 years post-injury, following three normal tests. Our data indicate that a small number of patients may suffer from de novo hypopituitarism with late onset post-injury; however, the efficacy and indications for long-term endocrine follow-up requires further study.

Chan Julie Phillips Linda Virginia Commonwealth University, Richmond, Virginia

P39 Glial Osteopontin: Role in Successful Regrowth During Trauma-Induced Plasticity.

Background: Osteopontin (OPN) is a highly phosphorylated acidic protein that acts as an immune molecule in the extracellular matrix during wound repair. Recent studies indicate that OPN is a key molecule in the regulation of inflammatory neurodegenerative diseases such as Parkinson's disease and multiple sclerosis. Its role in the CNS is further described as a modulator of axonal growth and myelin reformation after crush injury. In light of increasing evidence supporting OPN's facilitation of growth in the CNS after injury, we have examined OPN's role in trauma-induced synaptic plasticity. Recent data from our lab show an increase in transcript and protein levels in tissue extracts following unilateral entorhinal cortex lesion (UEC). Specifically, these increases in OPN occur in areas where synaptic organization takes place, suggesting OPN's involvement in axonal growth and dendritic reformation. Multiple cell types are likely involved in this reorganization process, but OPN distribution during plasticity remains unclear.

Methods: To further examine OPN's role after TBI, we explored the localization of OPN during reactive synaptogenesis utilizing confocal imaging and specific cellular antibodies. Following UEC in adult male rats, hippocampal OPN was examined at 2, 7, and 15 days post-injury, specifically in the deafferented dentate. Further probing for cellular localization in reactive glial populations included specific antibodies for microglia and astroglia.

Results: We found strong OPN localization in granule cell bodies, as well as molecular layer (ML) cell body and diffuse neuropil staining. Following injury, there was a shift in OPN distribution from the granule cell bodies toward the dendritic ML, a finding most prominent in the acute recovery phase at 2 days post-injury. Previous literature describes the co-localization of OPN with microglia early in wound repair, and astroglia at later intervals following injury. Our co-localization studies showed OPN-positive cells in microglia early after injury, but no clear localization in astroglia was present at any survival interval. Interestingly, the shift in distribution of OPN into the ML is consistent with morphological changes seen in deafferented dendrites, and the change in glial OPN at early post-injury stages is associated with reactive microglia.

Conclusion: Taken together, OPN's role in repair after trauma is likely linked to the acute immune response, potentially contributing to early debris clearance and conditioning of the deafferented environment for successful synaptic regeneration.

Jian Lin Xiao-Peng Zhang Guo-Liang Wang Wei-Min Wang Guangzhou General Hospital, Guangzhou Command, PLA, Guangzhou, China

P40 The Therapeutic Effects of Continuous Thoracic Epidural Anesthesia for Intractable Cushing's Ulcer After Severe Brain Injury.

Background: Here we study the clinical application of continuous thoracic epidural anesthesia (CTEA) for patients with intractable Cushing's ulcer after severe brain injury.

Methods: Thirty-eight patients with severe brain injury with GCS scores ≤ 8 suffered from intractable Cushing's ulcers. They were treated by continuous thoracic epidural anesthesia (CTEA), with 0.5% lidocaine or 0.25% bupivacaine to block the great splanchnic nerve for 5 days. The therapeutic effects in these patients were observed clinically, and five of them were followed with gastroscopic examination.

Results: Rapid hemostasis and improved gastric dynamics were observed in all patients. The symptoms of Cushing's ulcer disappeared, and gastric function recovered simultaneously after CTEA for 5 days. Vasodilatation and rapid healing of the gastric mucosa were confirmed in the five patients by gastroscopic examination.

Conclusion: CTEA is a convenient and effective adjunct therapeutic method for treating intractable Cushing's ulcer.

Lund Stine Borgen Skandsen Toril Moen Kent Gøran Hara Sozaburo Bliksås Andreas Vik Anne Norwegian University of Science and Technology/St. Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway

P41 Patients with Moderate Head Injury: From the Acute Phase to Long-Term Outcome.

Background: Patients with moderate head injury are heterogeneous regarding injury severity and clinical presentation. In this study we describe injury-related characteristics and 1-year outcome in a cohort of patients with moderate head injury admitted to a trauma center. Methods: During a 5-year period (2004–2009), 130 out of 136 patients with moderate head injury according to the Head Injury Severity Scale (HISS), admitted to a level 1 trauma center, were included in this study,. Variables from the acute phase were collected prospectively, and 1-year outcome was assessed with the Glasgow Outcome Scale-Extended (GOSE).

Results: Median age was 44 years (range 1–92 years, 20% were above 65 years), and median admission GCS score was 13 (range 5–15). Eighteen percent had a normal initial CT scan, and worst CT Marshall score was 1 in 19% and 2 in 50%. A mass lesion requiring surgery was found in 12%, while 22% had either an intraparenchymal ICP transducer or an external ventricular drain inserted. Median Injury Severity Scale (ISS) score was 20 (range 1–50), and 30% underwent other surgical interventions. Most of the patients (84%) were admitted to intensive care units. A majority of the patients were discharged to their home (41%), local hospital (36%), or to further rehabilitation (16%). One year after injury, two-thirds (65%) had a good recovery (GOSE score 7–8), 24% were moderately disabled (GOSE score 5–6), and 7% were severely disabled (GOSE score 3–4). A majority (97%) of the patients with moderate head injury lived at home; however, only 60% of those working before the injury (n = 50) had returned to work within 1 year.

Conclusions: One fourth of the patients with moderate head injury required neurosurgical intervention, and 12% developed a mass lesion requiring surgery. Most of the patients were discharged to home, and two-thirds of the patients had a good recovery. However, only 60% of the patients were back to work 1 year after the injury.

Yong Wang Qing-Hua Liang Hang Chen Henan Provincial People's Hospital, Zhengzhou, China

P42 The Early Diagnosis and Treatment of Intracranial Traumatic Pseudoaneurysm: A Report of 8 Cases.

Background: Here we investigate the imaging features and treatments of intracranial traumatic pseudoaneurysms.

Methods: From 2003 to 2010, data from 8 patients with intracranial traumatic pseudoaneurysms were collected. Their clinical characteristics and imaging features were analyzed retrospectively. Three cases were treated by clipping the neck of the aneurysm, and 5 cases were treated by endovascular treatment, including parent vessel occlusion using a detachable balloon in four, and pseudoaneurysm embolization using NBCA in one.

Results: Four aneurysms were located on the internal carotid artery, three on the pericallosal artery, and one on the middle meningeal artery. Three cases were associated with skull-base fractures involving the intracranial course of the ICA, and three cases with interhemispheric subdural hematomas. Good therapeutic efficacy was achieved in five patients, poor efficacy in two patients, and one died. Seven patients underwent follow-up at 6 months to 4 years, and no rebleeding was seen in them.

Conclusion: Early angiographic diagnosis with skull-base fractures involving the intracranial course of the ICA, or with interhemispheric subdural hematoma is necessary. Early clipping of the neck of the aneurysm or endovascular treatment play an important role in preventing secondary hemorrhage, and decreasing morbidity and mortality.

Murray Lynnette Cooper D. Jamie Rosenfeld Jeffrey Arabi Yaseen Davies Andrew Ponsford Jennie Seppelt Ian Wolfe Rory The Alfred Hospital, Prahran, Victoria, Australia

P43 Optimizing Follow-Up and Outcome Assessments in Traumatic Brain Injury Trials.

Background: Traumatic brain injury studies predominantly use an assessment of neurological function some time after hospital discharge as the primary end-point. Recent studies have followed-up patients at 6 months after injury, with variable loss to follow up. We have established an outcome process that minimizes loss to follow-up and maximizes the quality of the outcome assessment.

Methods: The DECRA trial is a prospective randomized trial of 155 patients from Australia, New Zealand, and Saudi Arabia. Patients with severe traumatic brain injury and refractory intracranial hypertension were randomly assigned to receive either a decompressive craniectomy, or to continue with standard medical management. The primary outcome was patient neurological function assessed using the Glasgow Outcome Scale-Extended (GOSE) at 6 months after injury. Patients were tracked following hospital discharge by the research coordinators at each participating site. The GOSE assessments were conducted by three blinded assessors using structured telephone questionnaires. The assessment teams were each led by an experienced assessor. Two assessors were located in Australia and one assessor was in Saudi Arabia. The assessors were trained using a prepared training package of examples and self-testing exercises. The chief assessor reviewed the outcome assessments performed by the other assessors. Any complex assessments were referred to an assessment panel for a consensus decision.

Results: DECRA commenced recruitment in 2003, and the last patient was enrolled in April 2010. Research coordinators successfully tracked all surviving patients, which resulted in a 100% follow-up rate for the primary study outcome measure.

Conclusion: We have successfully completed a prospective randomized controlled trial with zero loss to follow-up for the primary outcome measure of GOSE at 6 months. Assessments were reviewed by the chief assessor, and a consensus panel if required, to ensure consistency of the assessments.

Murray Lynnette Cooper Jamie Rosenfeld Jeffrey Arabi Yaseen Davies Andrew Ponsford Jennie Seppelt Ian Wolfe Rory The Alfred Hospital, Prahran, Victoria, Australia

P44 Optimizing the Consent Process in Severe Traumatic Brain Injury Trials.

Background: Severe traumatic brain injury (TBI) is a condition often associated with grave consequences, and it remains a major public health problem globally. Clinical trials to improve management and treatment of this condition are a necessity; however, there are many issues that impact on the design and conduct of such trials, including the complex and sensitive issue of consent. Obtaining consent for severe TBI trials is inherently complicated and difficult because the family are being asked to make an informed decision when they are shocked, anxious, grieving, and frequently physically exhausted. We established a process during the DECRA trial to minimize the difficulties and to ensure that consent was obtained with sensitivity and in an informed manner.

Methods: The DECRA trial is a prospective randomized trial of 155 patients from Australia, New Zealand, and Saudi Arabia. Patients with severe traumatic brain injury and refractory intracranial hypertension were randomly assigned to receive either a decompressive craniectomy or to continue with standard medical management. Surrogate consent was obtained prior to randomization, and all participating hospitals had obtained approval from their human research and ethics committees.

Results: Guidelines for obtaining consent were included in the protocol manual of operations, and were discussed at investigator meetings. The guidelines highlighted the importance of early communication with the patient's medical team regarding possible recruitment into the trial, updating the family about the patient's condition prior to the consent discussion, following a basic script to ensure that all aspects of the trial were covered in the discussion, and allowing time for the discussion, including follow-up discussions, and listening carefully to the family's questions. DECRA commenced recruitment in 2003 and the last patient was enrolled in April 2010; 168 consent discussions were held with a 92% consent rate.

Conclusion: Consent rates in brain injury studies in the critical care setting can be optimized by following a protocolized consent process.

Zhang Bin Chen Xin Zhang Baoliang Zhang Jianning Tianjin Neurological Institute, General Hospital, Tianjin Medical University, Tianjin, China

P45 Effects of Methylprednisolone on the Paraventricular Nucleus in Rats After Traumatic Brain Injury.

Background: Post-traumatic neuroendocrine dysfunction is very common, but the incidence of hypothalamic, and particularly hypothalamo-pituitary-adrenocortical (HPA) axis insufficiency, is rarely reported. This paper investigates the effects of methylprednisolone (MP) on the paraventricular nucleus (PVN) in the hypothalamus in rats after traumatic brain injury.

Methods: Male Wistar rats were randomized into four groups: a naïve group, an injury control group, a low-dose MP group, and a high-dose MP group. After fluid percussion injury, the rats were sacrificed and the brains were collected at 7 and 14 days, and TUNEL assay, immunohistochemistry, and transmission electron microscopy (TEM) were used to detect the number of TUNEL-positive cells and CRH cells in the PVN of the hypothalamus.

Results: At 7 days, the number of TUNEL-positive cells was significantly higher in injured rats treated with high-dose MP, and there was also a significant reduction in CRH cells in injured rats treated with high-dose MP. Moreover, TEM revealed morphological changes characteristic of apoptosis in the PVN of the rats in the high-dose MP group.

Conclusion: These data suggest that MP therapy for TBI could increase neuronal apoptosis in the hypothalamus, and consequently exacerbate the hypothalamic insufficiency induced by TBI.

Zhang Baoliang Chen Xin Zhang Bin Zhou Ziwei Zhang Rongcai Zhang Jianning Tianjin Neurological Institute, General Hospital, Tianjin Medical University, Tianjin, China

P46 The Effect of Traumatic Brain Injury on Long-Term Depression in CA1 of the Hippocampus.

Traumatic brain injury (TBI) can result in remote symptomatic epilepsy. The induction of post-TBI symptomatic epilepsy has a close relationship with long-term depression (LTD) in the CA1 area of the hippocampus. Nonetheless, there are few data about how TBI affects LTD in the hippocampus. The present study was designed to determine whether TBI may injure the cellular circuits and regional excitability in the CA1 of the hippocampus. The electrophysiological action potential is thought to filter aberrant or excessive input from the dentate gyrus (DG) to the CA3 region, which amplifies the signal prior to entering CA1. Then the CA1 transmits the processed information to the cortex. Thus the CA1 area plays an important role in post-TBI symptomatic epilepsy. TBI resulted in significant inhibition of LTD in the CA1, such that the amplifying features of CA1 became unstable. TBI leads to the impairment of hippocampal synaptic strength due to changes in interneronal interactions. The injury-induced disruption of synaptic efficacy within the hippocampal circuitry may underlie the observed symptomatic epilepsy.

Zhou Ziwei Zhang Baoliang Shan Yang Liu Li Jiang Rongcai Dong Jingfei Zhang Jiangning Tianjin Neurological Institute, General Hospital, Tianjin Medical University, China

P47 Enhanced Cognitive Functional Recovery of Cold Water Swim–Pre-Condititoned Rats After Experimental Traumatic Brain Injury.

Background: Moderate stress is often required for adapting to changing circumstances. This research was designed to verify the hypothesis that cold water swim (CWS) pre-conditioning could promote cognitive functional recovery after experimental traumatic brain injury (TBI).

Methods: Adult male Wistar rats were pretreated via a single CWS, and then subjected to fluid percussion injury (FPI) 24 h after CWS. On day 7 after FPI, pre-conditioned rats and control rats that were subjected to the same procedure were tested and trained for spatial acquisition in the Morris water maze daily for 5 days. They were sacrificed to dissect brain tissue for immunohistochemical and apoptotic evaluations in the hippocampus. We also measured the numbers of circulating endothelial progenitor cells (EPCs), as defined by CD34 and CD133 double-positivity 3 h, 6 h, 24 h, 48 h, and 72 h after FPI by flow cytometry.

Results: We made the following observations. First, the training latency for the Morris water maze was significantly longer for rats with FPI than control rats. However, CWS preconditioning significantly reduced the latency of rats with FPI compared to those without preconditioning. Second, apoptotic cells as detected by TUNEL assay first appeared in the hippocampus 24 h after FPI, reaching peak levels at 48 h. Consistent with training latency, the numbers of TUNEL-positive cells were significantly lower in CWS pre-condititoned rats than those without preconditioning. Third, CWS pre-conditioned rats had a significantly higher number of CD34-positive cells in the hippocampus 3 days after FPI. Fourth, circulating EPCs in CWS pre-condititoned rats were significantly higher in the acute phase (3 h and 6 h after FPI), but returned at 24 h post-FPI to a level comparable to that of rats without preconditioning.

Conclusion: These findings indicate that CWS pre-conditioned rats have a better tolerance to TBI, and had some alleviation of cognitive functional defects. This protective effect could partially be due to increases in the numbers of circulating EPCs induced by moderate stress.

Gao Yong-Jun Li Ran Zhou Jie Wang Tao Zhao Ning-Hui Xu Wei The Second Affiliated Hospital of Kunming Medical College, Kunming, China

P48 The Effects of Selective Cerebral Ultra-Profound Hypothermia on Cytoskeletal Protein in Monkeys After Occlusion of Cerebral Blood Flow Under Different Time Limits.

Background: Here we examined the influence on the cytoskeleton of neurons and glial cells by studying the expression of cytoskeleton protein β-tubulin, MAP-2,vimentin, and GFAP, in experimental monkeys by occluding bilateral internal carotid arteries for 60 min under selective cerebral ultra-profound hypothermia, with occlusion for different durations (0, 10, 15, and 20 min).

Methods: Fifteen healthy adult rhesus monkeys were randomly divided into four groups: a 0-min group (resuscitation after 0 min of occlusion, n = 4), a10-min group (resuscitation after 10 min of occlusion, n = 4), a 15-min group (resuscitation after 15 min of occlusion, n = 4), and a 20-min group (resuscitation after 20 min of occlusion, n = 4). A catheter was inserted into the right internal carotid artery (ICA) to infuse 4° cooling Ringer's solution, and two catheters were distally and proximally inserted into the internal jugular vein (IJV) to extract the hypothermic diluted blood for ultrafiltration, and then the warm blood was perfused into the right inferior vena cava after rewarming. Then the left ICA and IJV were clamped, and 4° cooling Ringer's solution was perfused into the right ICA after ischemia at room temperature to cool the brain less 16°. After 60 min, perfusion was stopped. MRI scans were obtained during the preoperative and postoperative course. The monkey brains were immediately removed after euthanasia at 4 weeks. Immunohistochemistry was used to detect the levels of β-tubulin, MAP-2, vimentin, and GFAP protein expression.

Results: MRI scans were normal after surgery, and neurological function was normal. There were 2 long-term surviving animals, 1 severely disabled animal, and 1 died in the 15-min group. All monkeys in the 20-min group were not resuscitated after perfusion and died. The levels of β-tubulin and MAP-2 protein expression were significantly lower in the 15-min group and the 20-min group than in the other groups. However, this was not true for vimentin and GFAP.

Conclusions: It is safe for resuscitation after 0 min and 10 min of brain ischemia, with return to normal hemodynamic parameters, and brain and nervous function. It is possible to resuscitate after 15 min of brain ischemia, but this results in some degree of neurological deficits and death and disability. Resuscitation after 20 min of occlusion was not possible. Due to irreversible brain damage, tubulin and MAP-2 were disaggregated; glial cells were hyperplastic and hypertrophied, with increases seen in the expression of GFAP and vimentin protein. The best time of resuscitation after brain ischemia appears to be 0 min.

Gøran Moen Kent Skandsen Toril Arne Kvistad Kjell Folvik Mari Rydland Jana Vik Anne Norwegian University of Science and Technology/University Hospital of Trondheim, Trondheim, Norway

P49 Diffuse Axonal Injury in Different MRI Sequences in Patients with Moderate and Severe Traumatic Brain Injury.

Background: We wanted to study the sensitivity of different magnetic resonance imaging (MRI) sequences that are currently used in clinical practice in the detection of diffuse axonal injury (DAI) in the early phase after severe and moderate head injury.

Methods: From October 2004 to August 2008, 159 patients (aged 5–65 years) with GCS scores ranging from 3–13 were admitted to the University Hospital in Trondheim. Out of these, 106 patients were examined with an MRI at 1.5 T within 4 weeks post-injury (median 8 days), and 51 patients were examined within 7 days. The scan protocol included T2*-weighted gradient echo imaging (GRE), T2 fluid-attenuated inversion recovery (FLAIR) imaging, and diffusion weighted imaging (DWI) in the axial plane. The occurrence of DAI in each patient was described based on the localization of the lesions in the white matter; lesions were confined to the lobar white matter of the cerebral hemispheres, lesions were seen in the corpus callosum, and lesions were seen in the upper dorsolateral brainstem or cerebellar peduncles.

Results: DAI was detected in 76 patients (72%). In 72 of 73 patients (99%) with DAI lesions located in the lobar white matter, microbleeds were visible with the GRE sequence, whereas only 74% of the patients had lesions visible with the FLAIR sequence (p < 0.001). In 98% of 52 patients with lesions in the corpus callosum, and in 90% of 21 patients with DAI lesions in the brainstem, lesions were visible with the FLAIR sequence. In contrast, only 67% (p < 0.001) and 62% (p = 0.03) had microbleeds detected in these locations with the GRE sequence. In all patients with DAI lesions depicted with the DWI sequence, these lesions were also visible on either FLAIR or GRE, or both.

Conclusion: The GRE sequence was the most sensitive single MRI sequence in the detection of DAI lesions in the hemispheres, demonstrating that these lesions often are hemorrhagic. The FLAIR sequence detected lesions in the corpus callosum and in the brainstem in more patients than the GRE sequence, demonstrating that these lesions more frequently were non-hemorrhagic.

Suehiro Eiichi Fujisawa Hirosuke Koizumi Hiroyasu Yoneda Hiroshi Ishihara Hideyuki Suzuki Michiyasu Kenwakai Ohtemachi Hospital, Yamaguchi University School of Medicine, Yamaguchi, Japan

P50 Effects of Traumatic Brain Injury Treatment Guidelines on Management and Patient Outcome in Severe Traumatic Brain Injury.

The Japanese Society of Neurotraumatology announced guidelines for the management and standardization of the treatment for severe traumatic brain injury (TBI) in 2000. The present study was conducted to analyze the influence of the treatment guidelines on the management of TBI patients and their outcomes in our hospital. We report herein an analysis of 166 severe TBI (GCS score < 8) patients who were admitted to our hospital between January 1995 and October 2009. After establishment of the guidelines, we conformed to them. We divided these patients into two groups: group A (48 patients admitted before 2000), and group B (118 patients admitted after 2000). There was no significant difference between the two groups in the background. The rate of acute subdural hematoma decreased from 52.1% to 45.8%. The rate of brain contusion/intracranial hematoma decreased from 16.7% to 11.0%. The rate of diffuse injury increased from 29.2% to 39.8%. The rate of intracranial pressure (ICP) monitoring significantly increased, from 24.6% to 84.6%. Decompressive craniectomy was performed in 57.6% of those in group B, whereas external decompression was not performed in group A. Hypothermia therapy was administered to 39.6% of those in group A, and 51.7% of those in group B. There was no significant difference in the rate of favorable outcomes between the two groups (group A: 46.8%, group B: 45.7%). However, mortality was significantly decreased, from 35.4% in group A to 20.3% in group B. The development of new treatments that improve functional outcomes is expected.

Dave Jitendra Chen Zhiyong Liao Zhilin Cartagena Cassandra Yao Changping Lu X.-C. May Tortella Frank Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland

P51 Neuroprotective Efficacy of Nefiracetam in in vitro Models of Neurotoxicity.

Nefiracetam is a pyrrolidone derivative and a cyclic analogue of GABA. It was developed as a cognitive-enhancing agent. Similarly to other pyrrolidone derivatives, nefiracetam has also demonstrated antiepileptic effects in animal models of kainic-induced limbic seizures and amygdala-kindled seizures. In an earlier study we demonstrated antiepileptic effects of nefiracetam on non-convulsive seizures in a rat model of severe brain ischemia. In order to elucidate its potential mechanisms of action, the current study was designed to investigate the effects of nefiracetam in three different in vitro models of excitotoxicity. Excitotoxicity was induced by exposing cultured primary cerebral neurons to the excitotoxant glutamate, the sodium channel activator veratridine, or an inducer of apoptosis, staurosporine, all of which caused 65%, 50%, and 65% neuronal injury, respectively. Treatment of neuronal cultures with nefiracetam (1–500 nM) produced significant dose-dependent exitoprotection against veratridine toxicity, with a maximum of 70–80% inhibition of neuronal death observed with 50 nM nefiracetam. Nefiracetam was less potent against glutamate or staurosporine excitotoxicity, requiring higher concentrations of nefiracetam (250 nM) to produce only moderate, but significant (20–40%), neuroprotection. Our results suggest that nefiracetam-mediated excitoprotection, and most likely its antiepileptic property, may involve suppression of activated sodium channels to maintain the proper cellular ionic homeostasis. To our knowledge, this is the first study to demonstrate a mechanism of action of nefiracetam involving sodium channels.

Wei Huijie Liu Li Chen Fanglian Jiang Rongcai Lei Ping Wang Dong Yang Shuyuan Dong Jingfei Zhang Jianning Tianjin Medical University General Hospital; Tianjin Neurological Institute; Tianjin, China

P52 Clinical Relevance of Endothelial Progenitor Cells and Blood Glucose in Traumatic Brain Injury.

Background: Endothelial progenitor cells (EPCs) play a critical role in vascular repair and neovascularization in tissue damaged by traumatic and ischemic injuries. Hyperglycemia downregulates circulating EPCs, accelerates EPC senescence, and impairs EPC function. In this study, we investigated the relationship of EPCs and blood glucose level with clinical outcomes in traumatic brain injury (TBI) patients.

Methods: In all, 101 TBI patients and 37 normal subjects were enrolled in this clinical investigation. Circulating EPC numbers and blood glucose levels were measured at 1, 4, 7, 14, and 21 days after TBI by flow cytometry and an automatic biochemical analyzer. Clinical outcome was measured using the Glasgow Coma Scale (GCS), and was divided into improvement and deterioration groups.

Results: The number of EPCs significantly decreased 24 h after TBI, and increased at 7 days after TBI. The circulating EPC level was significantly decreased in deteriorated patients at 7, 14, and 21 days after TBI compared to the improved patients. Lower EPC levels at 7 days after TBI predicts worse clinical outcome after TBI. The blood glucose level was increased 24 h after TBI. The severity and clinical outcome of TBI patients were associated with blood glucose levels. The number of circulating EPCs negatively correlated with blood glucose levels (p < 0.05).

Conclusions: These results suggest that the level of circulating EPCs is associated with blood glucose levels and neurological outcomes post-TBI, and could serve as a prognostic biomarker for clinical outcome. Relieving EPC suppression, increasing EPC mobilization, and controlling blood glucose levels, could all offer alternative therapies for patients with TBI.

Ping Lei Xiao-Yan Kang Rong-Cai Jiang Fang-Lian Chen Shu-Yuan Yang Jian-Ning Zhang Tianjin Medical University General Hospital, Tianjin Neurological Institute, Tianjin, China

P53 The Effect of Exogenous MIRNA-21 and the Expression of Sprouty 2 in Traumatic Brain Tissue.

Background: Here we studied the effect of exogenous miRNA-21 intervention after TBI and the expression of sprouty 2, the target of miRNA-21.

Methods: Wistar rats were assigned randomly to a sham control comparison group, a TBI group, a sham intervention group, and a miRNA-21 intervention group. The rats were divided into seven subgroups according to the time point after brain injury, which were 2 h, 12 h, 24 h, 48 h, 72 h, 7 days, and 14 days. After rats were subjected to fluid percussion injury (FPI), and stereotactic injection techniques were used to inject combined liposomes and miRNA-21, neurological function was evaluated using the Modified Neurological Severity Score (mNSS). This score was used to ensure the relative uniformity of injury severity among rats receiving different treatments. The test was administered 24 h after FPI by observers who were blinded to the experimental conditions and treatments. The expression of miRNA-21 was detected by real-time PCR. Apoptosis of cortical cells was detected by TUNEL. The expression of sprouty 2 in the area was detected by immunohistochemical staining and Western blot.

Results: We observed TUNEL-positive cells in the cerebral cortex within the first 24 h after injury, and they peaked at 48 h post-injury, followed by a gradual decrease 1–2 weeks after injury. However, fewer TUNEL-positive cells were observed in the rats receiving treatment with liposomes complexed with miRNA-21 than in the rats without the miRNA-21 treatment at the same time points. More importantly, both TUNEL-positive cells and miRNA-21 expression in injured tissues was significantly changed in injured rats receiving miRNA-21 transfection. The protein level of sprouty 2 decreased rapidly thereafter, and reached a stationary phase at approximately 1 week after TBI, before declining to baseline. In comparison, sprouty 2-positive cells remained constantly lower in brain tissues from rats receiving miRNA-21 treatment during the same period.

Conclusion: We can infer that exogenous miRNA-21 caused the apoptotic cells to decrease in number. It has been suggested that the Sprouty 2 expression silenced by miRNA-21 leads to reductions in apoptotic neurons post-TBI, and that exogenous miRNA-21 can be protective after brain trauma.

Ping Lei Xiao-Yan Kang Rong-Cai Jiang Fang-Lian Chen Jian-Ning Zhang Shu-Yuan Yang Tianjin Medical University General Hospital, Tianjin Neurological Institute, Tianjin, China

P54 Dynamic Changes in MIRNA-21 Expression in Traumatic Brain Tissue and Exogenous MIRNA-21 Interventional Effects.

Background: Here we studied the dynamic expression of miRNA-21 in brain tissue post-traumatic brain injury, and moreover analyzed the effect of miRNA-21 intervention post-TBI.

Methods: Wistar rats were assigned randomly to a sham control comparison group, a TBI group, a sham intervention group, and an miRNA-21 intervention group. The rats were divided into seven subgroups according to the time point after brain injury, which were 2 h, 12 h, 24 h, 48 h, 72 h, 7 days, and 14 days. After rats were subjected to fluid percussion injury (FPI), and stereotactic injection techniques were used to inject combined liposomes and miRNA-21, neurological function was evaluated using the Modified Neurological Severity Score (mNSS). This score was used to ensure the relative uniformity of injury severity among rats receiving different treatments. The test was administered 24 h after FPI by observers who were blinded to the experimental conditions and treatments. The expression of miRNA-21 was detected by real-time PCR. Apoptosis of cortical cells was detected by TUNEL.

Results: We observed strong miRNA-21 expression in injured brain tissue at 48 h after TBI in the cerebral cortex, and the miRNA-21 expression level was significantly higher than those of the sham group and TBI group (p < 0.05). TUNEL-positive cells were detected in cerebral cortex within the first 24 h after injury, and peaked at 48 h, followed by a gradual decrease 1–2 weeks after injury. However, fewer TUNEL-positive cells were observed in rats treated with liposomes complexed with miRNA-21 than in rats without the miRNA-21 treatment at the same time points. More importantly, both TUNEL-positive cells and miRNA-21 expression in injured tissue significantly changed in injured rats receiving miRNA-21 transfection.

Conclusion: Our results indicate that miRNA-21 expression increases in response to acute TBI. We can infer that exogenous intervention enhancing the expression of miRNA-21 causes apoptotic cells to decrease in number, and can protect after brain trauma.

Wang Haining Yan Rong Zhang Lin Zhang Qi Li Jia Kang Xaokui Zhang Jianning Yang Shuyuan Yang Xinyu Tianjin Medical University General Hospital, Tianjin Neurological Institute, Tianjin, China

P55 Application of Gene Knockout in the study of Adult Neurogenesis: A Literature Review.

Abstract not Available

Wang Yushan Chavko Mikulas Weiss Tracy Adeeb Saleena Cho Taesup Defense R&D Canada Suffield; U.S. Naval Medical Research Center

P56 Blast-Exposure-Induced Glutamate Receptor Trafficking and Neurodegeneration in the Rat.

Traumatic brain injury (TBI) has been a leading cause of morbidity and mortality in war zones due to the increasing use of roadside improvised explosive devices (IEDs). However, the precise mechanisms of blast-induced TBI are currently unknown. Here we investigated blast-induced neuronal damage and changes in cell surface expression of glutamate receptors in the rat brain. Animals were exposed to a 120-kPa blast wave in a pneumatic pressure-driven shock tube and observed for different periods of time after blast. At the end of each observation period, the animals were euthanized and their brains harvested. Parietal cortices and hippocampi of both sides of the brain were processed to separate synaptic membranes. The expression of AMPA and NMDA receptor subunits were analyzed using Western blot analysis. Immunohistochemistry was used to investigate neuronal and glial degeneration in both sides of the hippocampi. The results showed that the NMDA receptor subunit, NR1, was significantly increased in the hippocampus 24 h after blast, while NR2A and NR2B subunits remain unchanged. In addition, the AMPA receptor subunits, GluR1 and GluR2, showed dramatic reductions in their cell surface expression 24 h after injury. The changes in GluR1 and GluR2 expression became less significant 1 week after blast, and showed increases 3 weeks after blast. Immunohistochemistry results showed that within 24 h of blast, axonal damage was apparent in the dentate gyrus and CA1 regions of both sides of the hippocampi, as assessed by staining of the neuronal marker neurofilament H (NFH). The blast-induced reduction in NFH staining persisted for at least 3 weeks. In contrast, glial fibrillary acidic protein (GFAP) staining showed that glial cells underwent similar decreases within 24 h after blast, but fluorescence intensity increased 1 week after blast, indicating gliosis. Together, the results from these experiments indicate that at 120 kPa, the blast wave produces consistent brain damage in the rat. The changes seen in the cell surface expression of glutamate receptors may contribute to neurodegeneration induced by blast.

Bonnelle Valerie Imperial College London, London, U.K.

P57 Default Mode Network Connectivity Predicts Sustained Attention Deficits Following Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) frequently produces impairments of attention. These can result in a failure to maintain consistent goal-directed behavior. A predominantly right lateralized fronto-parietal network is often engaged during attentionally-demanding tasks. However, lapses of attention have also been associated with a failure to maintain deactivation within the default mode network (DMN). Here we use complementary analysis of structural and functional connectivity to investigate the neural basis of sustained attention impairments after TBI.

Methods: We studied a group of TBI patients with varying levels of sustained attention impairment, defined on the basis of the consistency of their behavioral performance on a choice reaction task. A standard functional MRI analysis was used to explore the patterns of brain activation associated with sustained attention impairment in these patients. To further investigate the neural basis of these changes, we analyzed both functional and structural connectivity within a right fronto-parietal attentional network and the DMN. A dual regression analysis was used to obtain an individual voxel-based measure of network functional connectivity. Diffusion tensor imaging tractography was then used to investigate whether damage to the structural connections within the DMN and/or the right fronto-parietal network underlies sustained attention impairment. In TBI patients, sustained attention deficits are associated with a failure to maintain DMN deactivation over time, particularly within the precuneus and posterior cingulate cortex. Furthermore, despite all patients initially having similar behavioral performance, functional connectivity within the DMN during the first part of the task predicted who went on to show sustained attention deficits during the final portion. Focal brain injury does not explain our findings, as removing patients with lesions from the analysis did not affect this predictive relationship. Instead, the presence of white matter damage is likely to be critical. Using DTI, we showed that greater structural disconnection within the DMN is also associated with impairments of sustained attention.

Conclusion: These results demonstrate that abnormalities in DMN function are a sensitive marker of impairments of attention, and suggest that changes in structural and functional connectivity within the DMN, possibly as a result of diffuse axonal injury, are central to the development of attentional impairments after TBI. The variability in DMN function is not a non-specific effect of injury severity, and may partly explain the wide range of attentional impairments observed after injuries of apparently similar clinical severity.

Sun Hongtao Cheng Shi-xiang Tu Yue Zhang Sai Tianjin Wujing General Hospital, Tianjin, China

P58 Clinically Significant Changes in Brain Tissue Partial Pressure of Oxygen in the Course of Mild Hypothermia Treatment of Severe Traumatic Brain Injury.

Background: Here we investigate clinically significant changes in brain tissue partial pressure of oxygen (Ptio ₂) in the course of mild hypothermia treatment (MHT) of severe traumatic brain injury (sTBI).

Methods: There were 38 cases undergoing MHT for sTBI. Intracranial pressure (ICP), jugular venous oxygen saturation (Sjvo ₂), Ptio ₂, cerebra1 perfusion pressure (CPP), lactate-oxygen index (LOI), and arterial blood oxygen saturation (Sao ₂) were continuously monitored in the 38 patients. Clinical outcomes were assessed using the Glasgow Outcome Scale (GOS).

Results: Increasing Ptio ₂, Sjvo ₂, CPP, and ICP, and decreased lactates were found during the course of MHT. There was negative linear correlation between Ptio ₂ and ICP. There was a positive linear correlation between Ptio ₂ and Sjvo₂. The specificity to predict ischemia was 7.1.4% with Ptio ₂ values. This was higher than LOI, at 54.5%. The sensitivity to predict ischemia was 96.4% with LOI values, but specificity was 54.5%. Increasing Ptio ₂ and CPP were seen at the beginning of MHT, but there were no changes in Ptio ₂ and CPP after 36 h of MHT.

Conclusion: Continuous monitoring of Ptio ₂ can reflect the condition of regional cerebral oxygen metabolism and guide treatment and help predict outcome. Decreasing Ptio ₂ can be found after MHT.

Tu Yue Zhang Sai Li Yadong Tianjin Wujing General Hospital, Tianjin, China

P59 Proteomic Analysis of Cerebrospinal Fluid in Patients After Severe Traumatic Brain Injury.

Current clinical assessment of patients with severe traumatic brain injury (sTBI) is largely dependent on routine neurological examinations and imaging findings. Here we examined the feasibility of proteomic approaches to identify biomarkers in cerebrospinal fluid (CSF) that may be correlated with the severity of brain injury after sTBI. A proteomic protocol based on two-dimensional gel electrophoresis (2-DE) combined with MALDI-TOF-MS, was used to compare the CSF protein profile of two pooled samples from patients with sTBI (n = 8), and patients with non-sTBI inflammatory central nervous system disorders (n = 4). Three images of each group were acquired, and automatic spot detection and quantification were carried out using PDQuest (version 7.0). An average of 487 ± 15 and 438 ± 19 spots were displayed in the sTBI group and control group, respectively. A total of 13 different protein spots distributed in pI values ranging from 4–7, and molecular mass from 19–80 kDa were identified. Among them, 10 spots were further identified by MALDI-TOF-MS analysis: nine proteins were significantly upregulated (glial fibrillary acidic protein, cathepsin D, glutathione synthetase, peroxiredoxin-6, MAPK/ERK-1, dihydropteridine reductase, coronin 1A, annexin II, and protein kinase C), and one protein was significantly downregulated (p21) in CSF from sTBI patients. These proteins were further confirmed by ELISA or Western blotting. In summary, our preliminary results with conventional 2-DE-based proteomic approaches identified new protein profiles in CSF after sTBI. Further functional and phenotype correlation investigations are required to validate their roles in clinical assessment and prognosis prediction.

Tu Yue Zhang Sai Cheng Shi-xiang Tianjin Wujing General Hospital, Tianjin, China

P60 Facilitation of Neural Differentiation From Bone-Marrow-Derived Mesenchymal Cells by Targeting Membrane Potential: A Pilot Study.

Background: Membrane potential plays an important role in regulating cell proliferation, differentiation, and migration, and this may represent a therapeutic target for regenerative medicine. In the present work, we tested the feasibility of neural differentiation from bone-marrow-derived mesenchymal cells (MSCs) by regulating the changes of membrane potential.

Methods: MSCs were separated from Wistar rat bone marrow using Friedenstein's whole bone marrow cultivation and reforming method. Then isolated MSCs were treated with 10 nM ouabain (depolarizing agent) and 10 nM pinacidil (hyperpolarizing agent). Transmembrane potential was recorded at 0, 12, 24, and 36 h after treatment by using a whole cell patch clamp technique. Immunohistochemical staining and Western blotting analysis for neuron specific enolase (NSE), neurofilament protein (NF), and glial fibrillary acidic protein (GFAP) were performed to evaluate neural differentiation.

Results: There was a trend toward continuously decreasing membrane potential of the hyperpolarization group, which dropped from −29.6 ± 4.1 mV at 0 h, to −50.4 ± 5.6 mV at 36 h after pinacidil treatment. On the contrary, membrane potential of the depolarization group had progressively increasing trend, as shown by a continuous elevation from −31.4 ± 4.7 mV at 0 h, to −7.4 ± 3.0 mV at 36 h after treatment with ouabain. In a control group (without treatment with agents affecting membrane potential), there was a small number of cells positive for NSF, NF, and GFAP, which presumably indicates the existence of potential neuron and gliocyte precursors in bone marrow. Hyperpolarization of membrane potential facilitated neural differentiation and impeded gliocyte differentiation, as demonstrated by increased proportions of NSE- and NF-positive cells, and a decreased proportion of GFAP-positive cells. Depolarization of membrane potential reversed the above changes, as shown by increased expression of GFAP, and decreased expression of NSF and NF.

Conclusion: Taken together, our pilot results indicate that hyperpolarization of membrane potential facilitates neural differentiation and inhibits gliocyte differentiation, whereas depolarization has the opposite effect. Further functional analyses are warranted to validate these findings.

Sai Zhang Tu Yue Sun Wen-Cai Tianjin Wujing General Hospital, Tianjin, China

P61 Decreased Soluble FAS Levels in Cerebrospinal Fluid of Patients with Severe Traumatic Brain Injury After Mild Hypothermia Treatment.

Background: Apoptosis-induced cell loss in the central nervous system (CNS) is one of the major contributors to compromised functional recovery after severe traumatic brain injury (sTBI). We hypothesized that mild hypothermia treatment after sTBI could inhibit the apoptotic response in the CNS, and result in decreased levels of apoptotic markers in cerebrospinal fluid (CSF).

Methods: Forty patients with sTBI (GCS score ≤ 8) were randomly assigned to receive normothermia (NT, n = 20) and mild hypothermia (HT, n = 20) treatment. Another 20 age- and sex-matched patients with no history of traumatic injury within 6 months were enrolled as a control group. Mild hypothermia was initiated within 24 h after brain injury, and rectal temperature (RT) was maintained at 33–35°C. When intracranial pressure returned to the normal range, the patients were allowed to rewarm to 36.5–37.5°C in 12–16 h, with an average increment of 1° per 6 h. The average duration of mild hyperthermia was 55.7 ± 18.5 h. The primary outcome was clinical score based on the Glasgow Outcome Scale (GOS) score at 6 months after treatment. CSF was obtained on days 1, 2, 3, and 4 after brain injury. We used soluble Fas as an apoptotic marker, and measured it by ELISA.

Results: At the time of discharge, the HT group had higher GCS scores than the NT group. Soluble Fas content in the CSF was significantly increased in sTBI patients, and peaked at 2–3 days after injury. Mild hypothermia treatment significantly decreased soluble Fas content in the CSF at all time points.

Conclusion: Thus our data indicate that mild hypothermia treatment combined with conventional strategies for treating sTBI, could improve functional recovery, partially via inhibition of apoptosis in the CNS.

Sai Zhang Tu Yue Yang Xi-Ping Tianjin Wujing General Hospital, Tianjin, China

P62 Increased Serum Level of Brain-Derived Neurotrophic Factor in Patients With Severe Traumatic Brain Injury After Mild Hypothermia Treatment.

Background: Brain-derived neurotrophic factor (BDNF) has been shown to influence the survival, growth, maintenance, and differentiation of central and peripheral neurons. We hypothesized that mild hypothermia in patients with severe traumatic brain injury (sTBI) may have an impact on BDNF expression, which is positively associated with a clinical benefit of mild hypothermia.

Methods: Fifty consecutive patients admitted to our hospital between April 2009 and December 2009 with sTBI (Glasgow Coma Scale score ≤ 8) were randomly assigned to two groups, treated with normothermia (NT, n = 24), or mild hypothermia (HT, n = 26). Mild hypothermia was induced within 24 h after brain injury, and rectal temperature (RT) was maintained at 32–35°C (33.5 ± 1.1°C). When intracranial pressure returned to the normal range, the patients were allowed to rewarm to 36.5–37.5°C in 12–16 h, with an average increment of 1°C per 6 h. The average duration of mild hyperthermia was 63.4 ± 21.7 h. Blood samples were obtained on days 1, 2, 3, and 4. Serum BDNF was determined by ELISA. Six months after treatment, all patients were evaluated according to the Glasgow Outcome Scale.

Results: No difference was observed in BDNF levels between the two groups at 1 day after treatment (HT: 1.21 ± 0.46 ng/mL versus NT: 1.17 ± 0.41 ng/mL; p > 0.05). However, BDNF in the HT group was significantly elevated from 2 days after treatment (HT: 2.47 ± 0.57 ng/mL versus NT: 1.88 ± 0.43 ng/mL; p < 0.01), and persisted until 4 days post-treatment (HT: 5.26 ± 0.61 ng/mL versus NT: 3.67 ± 0.71 ng/mL; p < 0.01), which was associated with favorable changes in intracranial pressure in the HT group.

Conclusion: In conclusion, our data demonstrate a significant upregulation of BDNF after hypothermia treatment, which may be one of the underlying mechanisms of mild hypothermia-induced neuroprotection.

Sai Zhang Tu Yue Jin Ming Tianjin Wujing General Hospital, Tianjin, China

P63 Beneficial Effects of Mild Hypothermia on Cardiac Protection in Patients with Severe Traumatic Brain Injury.

Background: Cardiac injury is a common clinical entity during severe traumatic brain injury (sTBI), and it has a negative impact on long-term survival after sTBI. Here we examined the hypothesis that mild hypothermia may reduce heart injury, thus decreasing serum markers of myocardial injury in patients with sTBI.

Methods: Sixty-three patients with sTBI (GCS score ≤ 8) were randomly assigned to receive normothermia (NT, n = 40), or mild hypothermia (HT, n = 23) treatment, respectively. Mild hypothermia was induced within 24 h after brain injury, and rectal temperature (RT) was maintained at 32–35°C. When intracranial pressure returned to the normal range, the patients were allowed to rewarm to 36.5–37.5°C in 12–16 h, with an average increment of 1°C per 6 h. Blood samples were obtained on days 1, 2, 3, 4, and 5 after brain injury. Cardiac enzyme tests included aspartate aminotransferase (AST), lactate dehydrogenase (LDH), α-hydroxybutyrate dehydrogenase (HBDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), and troponin I (TnI).

Results: Compared with the NT group, clinical outcomes of the HT group were significantly improved, which was accompanied by decreased levels of HBDH, CK, CK-MB, and TnI from 3 days after treatment. No differences in AST and LDH between the two groups were seen.

Conclusion: In summary, our data suggest that mild hypothermia has beneficial effects on myocardial protection during sTBI. Potential long-term benefits of mild hypothermia on cardiac function warrant further investigations.

Tu Yue Zhang Sai Wang Yan-ming Tianjin Wujing General Hospital, Tianjin, China

P64 Transplantation of Umbilical Cord Mesenchymal Stem Cells Modified with Brain-Derived Neurotrophic Factor Gene Into the Brain Injury Site Facilitates Neural Differentiation and Improves Neuromotor Function.

Background: Brain-derived neurotrophic factor (BDNF) has been reported to facilitate differentiation of stem cells into neurons. In the present study, we hypothesized that transplantation of stem cells after committed differentiation into neurons induced by BDNF could improve functional recovery of neuromotor function in a mouse model of experimental traumatic brain injury (TBI).

Methods: Human umbilical cord mesenchymal stem cells (UCMSCs) were transfected with adenovirus vector encoding BDNF gene. BDNF concentration was determined by ELISA. Experimental TBI was induced in athymic mice by a fluid percussion injury method, and UCMSCs treated with (n = 12), and without BDNF adenovirus (n = 12), were injected into the border region of the brain injury 24 h after injury. We dynamically evaluated neural functional scores according to Longa's method. Seven days later the animals were sacrificed, and brain tissue was prepared for immunohistochemical detection of cells expressing BDNF around neural injury sites. In addition, cells positive for neuron-specific enolase (NSE), and cells expressing glial fibrillary acidic protein (GFAP), around injury loci were quantified immunohistochemically. TUNEL was used to determine apoptosis.

Results: We found a persistently high level of expression of BDNF in culture medium 72 h after adenovirus transfection of UCMSCs. Compared with control animals transplanted with UCMSCs without BDNF gene transfection, transplantation of BDNF-UCMSCs was associated with higher neurological scores. Moreover, there was a significantly increased number of NSE-positive cells around injury sites, as well as a significantly decreased number of GFAP-expressing cells in the same region. Furthermore, in regions with high levels of BDNF expression, decreased numbers of apoptotic cells were observed.

Conclusion: In summary, our results provide evidence indicating that transplantation of UCMSCs overexpressing BDNF could enhance neural differentiation, reduce apoptosis, and improve neuromotor function, in a mouse model of experimental TBI, which may be of therapeutic potential.

Sai Zhang Tu Yue Fan Guang-Min Tianjin Wujing General Hospital, Tianjin, China

P65 Dynamic Changes of Serum Anti-Brain Antibody and C-Reactive Protein in Patients with Severe Traumatic Brain Injury After Mild Hypothermia Treatment.

Background: Increased serum levels of anti-brain antibody (ABAb) and C-reactive protein (CRP), markers for brain inflammatory response, are negatively correlated with prognosis in patients with severe traumatic brain injury (sTBI). Here we examined the hypothesis that mild hypothermia may have an impact on their expressions, which are associated with clinical benefits of hypothermia treatment in patients with sTBI.

Methods: Eighty patients with sTBI (GCS score ≤ 8) were randomly assigned to receive normothermia (NT, n = 40), or mild hypothermia (HT, n = 20) treatment. Another 20 age- and sex-matched patients with no history of traumatic injury within 6 months, and no potential disease conditions that might affect ABAb and CRP levels, were enrolled as a control group. Mild hypothermia was induced within 24 h after brain injury, and rectal temperature (RT) was maintained at 32–35°C. When intracranial pressure returned to the normal range, the patients were allowed to rewarm to 36.5–37.5°C in 12–16 h, with an average increment of 1°C per 6 h. The average duration of mild hyperthermia was 60.5 ± 20.5 h. The primary outcome was clinical score based on the Glasgow Outcome Scale (GOS) at 6 months after treatment. Blood samples were obtained on days 1, 3, 5, 7, and 14 after brain injury. ABAb and CRP were measured by ELISA and immunoturbidimetry, respectively.

Results: We found that the HT group had higher GCS scores than the NT group. In addition, mild hypothermia treatment significantly decreased sTBI-induced upregulation of ABAb and CRP serum levels at all time points (all p < 0.01). Moreover, in patients not receiving hypothermia treatment, serum levels of ABAb and CRP were negatively correlated with GCS scores.

Conclusion: These results show that mild hypothermia treatment could dramatically decrease serum levels of ABAb and CRP after sTBI, which may contribute to its clinical benefits.

Bin Dong Zhigang Lian Bo Zhang Tingzhun Zhu Meng-Kao Li Yinghui Xu The First Affiliated Hospital of Dalian Medical University, Dalian, China

P66 Influencing of Asics3 Expression Under Different Reperfusion Conditions After Brain Ischemia in Rats.

Background: The purpose of this study was to evaluate the role of ASICs in changes in reperfusion in Sprague-Dawley (SD) rats, and the relationship between acidosis and ASICs after global ischemic insults.

Methods: The SD rat ischemic models were randomly divided into three groups: group A, an adaptive ischemia-reperfusion group; group B, a one-time ischemia-reperfusion group; and group C, a severe cerebral ischemic injury group. Ischemia was induced by bilateral carotid artery occlusion for 10 min. After reperfusion and different reperfusion inflow, ASICs3 gene expression, pH insult and morphology and cerebral blood flow in the hippocampus CA1 region were all observed.

Results: After the severe brain damage, the reperfusion flow of group A was gradual, from 0.5 ± 0.1 mL/min to 3.2 ± 0.6 mL/min, whereas the reperfusion flow of group B was from 0.5 ± 0.1 mL/min to 6.2 ± 1.5 mL/min, with the perfusion flow significantly increasing. The pH values in group A saw the most significant improvement, increasing from 7.15 ± 0.05 to 7.38 ± 0.04 (p < 0.05), while the pH values in group B were from 7.15 ± 0.05 to 7.10 ± 0.04. Upon comparison of pH levels in group A with those in groups B and C, the differences were statistically significant (p < 0.05); CCA cerebral blood flow values in group B were higher than those in groups A and C, and the differences were statistically significant (p < 0.05). The gene expression of ASICs in group B was upregulated over that in group A, whereas there were more normal neuron cells in group A than in group B.

Conclusion: There was a strong relationship between ASIC expression and differences in reperfusion inflow, and low reperfusion inflow reduced cerebral ischemic insult.

Shuo Gu Nan Bao Bo Yang Zhi Xu Shanghai Children's Medical Center Affiliated with Shanghai Jiaotong University School of Medicine, Shanghai, China

P67 Clinical Application of Computer-Assisted Three-Dimensional Modeled Titanium Mesh in the Repair of Skull Defects in Children.

Background: Here we investigated the clinical utility of computer-assisted three-dimensional (3D) modeled titanium mesh in the repair of skull defects in young children.

Methods: Skull defects in 14 children were repaired using titanium mesh individually designed by computer-assisted 3D modeling. The mean age was 6.2 years (range, 2–13 years). The size of the defects ranged from 5 × 2 cm to 12 × 12 cm. Repair of the skull defects was performed at least 3 months after injury. Thin-section helical computed tomography (CT) scanning was performed before the operations. Computer-assisted 3D skull reconstruction was performed to generate a 3D model for a true-to-original repair of the skull of the patient. A 3D-modeled titanium mesh precisely matching the defect was designed and produced to repair the skull defect.

Results: All patients achieved excellent results. Primary healing occurred in all patients, and no local redness, swelling, infection, or subcutaneous fluid collection developed in any patient. The duration of follow-up ranged from 6 months to 6 years. The titanium mesh was stably fixed in all patients, and no patient experienced stabbing pain in the scalp, and no entrapment occurred. In all cases, no deformity in the skull was noted, the head and face were overall symmetrical, and the arc was acceptable. The rate of satisfactory outcomes was 100%.

Conclusion: Computer-assisted 3D-modeled titanium meshes can be applied for the treatment of skull defects in young children, and it has no significant effect on the growth of the skull. The mesh provides an accurate fit and shortened operative time. The procedure is simple, does not require intraoperative molding, and there is no postoperative tension. The fixation is stable and the appearance is excellent, and thus meets aesthetic and physiological requirements. The technique holds the prospect of becoming widely used for skull defect repair in children.

Lei Chen Chunli Wang Xuejian Cai Jiandong Zhang Jianchao Wang Likun Yang Jun Zhu Yuhai Wang

P68 Risk Factors for Posttraumatic Cerebral Infarction in Patients with Severe and Extremely Severe Head Injury.

Abstract not Available

Yuhai Wang Xuejian Cai Chunli Wang Sang Cai Lei Chen Jiandong Zhang Bin Liu Zhonghua Shi Jun Zhu Craniocerebal Trauma Treatment Center of CPLA, No. 101 Hospital, Wuxi, China

P69 CT Angiography in the Early Surveillance of Severe Traumatic Brain Injury and Prognostic Judgment.

Background: The prognosis of severe traumatic brain injury is directly correlated with the severity of primary brain injury, and is more closely associated with secondary brain injuries caused by cerebral blood flow disturbances. Although previous studies reported the use of transcervical Doppler ultrasonography to observe changes in cerebral blood flow following head injury, there are few direct imaging clues about changes in cerebral blood flow following severe traumatic brain injury, due to current limitations of patient conditions and imaging technologies. The aim of the present study was to explore the diagnostic value of CT angiography (CTA) in the early surveillance of severe traumatic brain injury, prognostic judgment, and detection of secondary vascular injuries.

Methods: Using 128-slice spiral CT, head CTA was performed in 58 patients with severe traumatic brain injuries before and after surgery to observe dynamic changes in cerebral blood flow.

Results: CTA showed that the brain vessels mainly underwent five changes following severe traumatic brain injury: vascular displacement (40 cases), spasm or occlusion of the cerebral arteries (16 cases), a reduced number of arterial perforators (35 cases), stenosis or occlusion of deep cerebral veins (8 cases), and stenosis or occlusion of superficial cerebral veins (39 cases). Of the 16 patients with spasm or occlusion of the major cerebral arteries, 4 patients had severe disabilities, 5 patients survived in a vegetative state, and the remaining 7 patients died. Five patients with occlusion of the deep cerebral veins such as the internal cerebral vein and the basilar vein all died. Stenosis or occlusion of the superficial cerebral veins was a reflection of intracranial pressure changes.

Conclusion: CTA can be used for early surveillance of severe traumatic brain injury and prognostic judgment, and CTA findings are significantly instructive in the early diagnosis and treatment of secondary vascular injuries following severe traumatic brain injury.

Yuhai Wang Sang Cai Xuejian Cai Jirong Dong Zhonghua Shi Bin Liu Likun Yang Chunli Wang Jiandong Zhang Craniocerebal Trauma Treatment Center of CPLA, No. 101 Hospital, Wuxi, China

P70 Management of Severe Traumatic Brain Injury by Controlled Decompression: Summary of 64 Clinical Cases.

Background: Occurrence of acute encephalocele during surgery for severe traumatic brain injury increases mortality and disability markedly. How to reduce the occurrence of acute encephalocele remains a clinical challenge in neurosurgery. Controlled decompression is a modality of craniotomy used to reduce intracranial pressure gradually by taking appropriate measures. The aim of controlled decompression is to minimize ischemia/reperfusion injury, control or palliate intraoperative brain swelling and acute encephalocele induced by the pressure tamponade effect, and protect the brain vessels and nerve functions. The main purpose of the present study was to explore the treatment effect of controlled decompression in the management of severe traumatic brain injury.

Methods: In this prospective study, 128 patients with severe traumatic brain injury were randomized to two groups: a controlled decompression group, and a routine craniotomy group as control.

Results: Compared with the control group, the good outcome rate of the study group was increased by 17.2%; intraoperative occurrence of acute encephalocele decreased by 17.2%, the occurrence of delayed hematoma decreased by 7.8%, and the occurrence of intraoperative acute encephalocele induced by delayed hematoma decreased by 12.5%, on the basis of GOS results (all p < 0.05).

Conclusion: Controlled decompression technique can reduce or delay the occurrence of intraoperative acute encephalocele induced by intracranial delayed hematoma, and improve the prognosis of patients with severe traumatic brain injury by gradual release of intracranial pressure.

Yuhai Wang Chunli Wang Caisang Xuejian Cai Jirong Dong Jiandong Zhang Jun Zhu Likun Yang Craniocerebal Injury Treatment Center of CPLA, No. 101 Hospital, Wuxi, China

P71 Surgical Management of Traumatic Interhemispheric Subdural Hematoma.

Background: Traumatic interhemispheric subdural hematoma (TISH) is a rare clinical event. As the early clinical presentation of TISH is non-characteristic, severe consequences may ensue if diagnosis is delayed or treatment is inappropriate. There is controversy over the management of TISH, and there are different reports about the outcome of TISH treatment. There are few studies reporting the outcome of surgical treatment of TISH in particular. The main purpose of the present study was to further improve the clinical outcome of TISH treatment.

Methods: Clinical data, surgical modalities, and outcomes of 21 patients with TISH who were treated with microsurgery were analyzed retrospectively.

Results: According to Glasgow Coma Scale (GCS) scores, good recovery was seen in 16 cases, moderate disability in two cases, severe disability in one case, vegetative survival in one case, and death in one case, during the post-operative follow-up period of 1–9 years. There were confirmed sources of hemorrhage in 21 cases. Hematoma in the whole cerebral longitudinal fissure was more frequently seen in patients with hemorrhage from rupture of the distal branch of the anterior cerebral artery, and veins in the cerebral longitudinal fissure, for which the prognosis of surgical outcome was usually good. Local hematoma, laceration, and edema in the cerebral longitudinal fissure were more frequently seen in patients with hemorrhage from brain tissue laceration of the longitudinal fissure, the prognosis of which was usually poor.

Conclusion: A good understanding of surgical indications, a good command of surgical skills, and timely surgical intervention are helpful in improving the prognosis of TISH patients.

Chuanyi Fu Chuixue Huang Pengcheng Wang Jiannong Zhao

P72 The Role of Antidiuretic Hormone and Growth Hormone.

Abstract not Available

Tu Chuan-jian Liu Jian-sheng Song Da-gang Zhen Gang Luo Hai-ming

P73 Preliminary Clinical Observations of Post-Traumatic Vasospasm.

Abstract not Available

Tu Chuan-Jian Liu Jian-Sheng Song Da-Gang Zhang Yue-Jiang Chen Hua-Wei Zhen Gang Luo Hai-Ming

P74 Prospective Study of Post-Traumatic Vasospasm Based on Transcranial Doppler.

Abstract not Available

Yuan-Fu Tan Yong-Qiang Huo First Affiliated Hospital of Guangxi Medical University, Nanning, China

P75 Clearance Therapeusis Treatment in Experimental Traumatic Brain Injury.

Background: Here we study the mechanism and effect of clearance therapeusis treatment in traumatic brain injury.

Methods: A rabbit traumatic brain injury model was made by utilizing a free-falling weight impactor device. The rabbits were randomly divided into three groups(n = 10 in each group): a sham operation group, an injury control group, a treatment group, and a clearance therapeusis group. The clearance therapeusis, including mannitol, furosemide, high-dose albumin, and a large quantity of normal saline given IV, were only carried out in the treatment group. Histological observation for each group was carried at 6 h post-injury. The water content of brain tissue was assessed using the wet-dry weight method, and the levels of Na⁺ and Ca⁺⁺ by ICP methods. The content of lactic acid was measured by an automatic biochemistry analyzer, and the content of glutamate by automatic amino acid analyzer at 6 h post-injury.

Results: The water content of brain tissue, lactic acid, glutamate, and Na⁺ and Ca⁺⁺ in the control group were markedly higher than those of sham-operated group (p < 0.01). Those of the clearance therapeusis group had dropped significantly at 6 h post-injury compared to the injury control group (p < 0.05).

Conclusion: The content of brain tissue water, lactic acid, glutamate, and Na⁺ and Ca⁺⁺ in the control group were increased markedly after traumatic brain injury. Clearance therapeusis caused decreases in the content of brain tissue water, lactic acid, glutamate, and Na⁺ and Ca⁺⁺ at 6 h post-injury, indicating that clearance therapeusis was effective after traumatic brain injury. The mechanism of action of clearance therapeusis treatment in traumatic brain injury may be that it promotes the elimination of toxic metabolites from injured brain tissue.

Yuan-Fu Tan Shao-Wen Xiao Chao-Yuan Zhang Liang Liang The First Affiliated Hospital of Guangxi Medical University, Nanning, China

P76 Efficacy Analysis of Hyperbaric Oxygen Therapy in Patients with Severe Traumatic Brain Injury.

Background: Here we explored the efficacy and common influencing factors of hyperbaric oxygen (HBO) therapy on patients with severe traumatic brain injury (sTBI).

Methods: Clinical data of 150 patients with sTBI were analyzed retrospectively. HBO therapy was performed in 82 cases, and routine therapy in 68 cases, over the same period. The efficacy of the two groups was compared. The influencing factors were investigated statistically, including sex, age, cause of injury, Glasgow Coma Scale score (GCS) at admission, type of craniocerebral surgery, incision of the trachea, and time of beginning of HBO treatment, were comparatively analyzed. Glasgow Outcome Score (GOS) at 6 months follow-up were analyzed statistically. Count data were compared with the chi-square test, and the potential influencing factors were evaluated with logistical regression.

Results: Significant differences were shown between the two groups; good recovery (GR; GOS score 4 or 5) of the HBO group was higher than that of the control group (p < 0.05), and the rates of vegetative state (VS) and death (D) were significantly lower than those in the control group (p < 0.01). GCS score at admission, circumstance of incision of the trachea, and time of beginning to treat with HBO post-injury, were the major influencing factors. Higher rates of GR and lower rates of VS and D were present in patients with GCS scores > 5 (p < 0.05), no tracheotomy (p < 0.01), and HBO treatment of less than 1 month (p < 0.05), respectively.

Conclusion: Treatment with HBO is beneficial to patients with sTBI. The higher the GCS score at admission, and the earlier HBO therapy begins, the better the outcome. Patients with sTBI should receive HBO treatment as early as possible without contraindications.

Yuan-Fu Tan Hui Li

P77 An Animal Model of Axonal Injury in Rabbits.

Abstract not Available

Zhenquan Song Minguang Zhao Di Fan Yang Liu General Hospital of Shenyang Military Region, Shenyang, China

P78 Fisher's Exact Test of Mild Traumatic Brain Injury.

Background: The authors retrospectively investigated the clinical symptoms, neuroimaging findings, and prognosis after mild traumatic brain injury (mTBI) in 224 cases.

Methods: In all, 224 mTBI patients with Glasgow Coma Scale (GCS) scores of 13–15 were admitted to our neurosurgical outpatient clinic from August 2006 to August 2008. Any patients with a history of drinking, cognitive deficits, or age less than 16 years were excluded. The neurologic symptomatology referred to GCS scores, vomiting, and amnesia, while brain imaging studies included CT and/or MRI. Outcome evaluating protocols were: neurophysiological and/or neuropsychological syndrome; seizures; and changes in daily life before and after injury, as assessed using Awareness Questionnaire analysis. Using Fisher's exact test, on brain MRI but not on CT scans, 6 cases did not show intracerebral contusion both on repeated MRI and CT scans, and 33 cases had post-concussion syndrome. Among the 173 patients with GCS scores > 14, 32 cases had cerebral contusions (18%), of which 24 cases (75%) were diagnosed by MRI. Vomiting and amnesia were significantly related to brain contusion, whereas post-concussion syndrome was rare, and changes in daily life did not correlate with cerebral contusion. Moreover, 2 cases were found to have seizures by 20 months follow-up.

Conclusion: Cerebral contusion was a risk factor for post-concussion syndrome in mTBI patients with a GCS score of 13; MRI scans were needed for the diagnosis of cerebral contusion in mTBI patients with a GCS score > 14; both vomiting and amnesia were risk factors for the diagnosis of cerebral contusion in mTBI patients with a GCS score > 14; cerebral contusion had no effect on prognosis in mTBI patients with a GCS score > 14; and cerebral contusion was not a risk factor for seizures in mTBI patients.

Songsheng Shi Fujian Medical University, Fujian, China

P79 Post-Traumatic Hydrocephalus Amenable to Shunt Surgery Secondary to Decompressive Craniectomy (DC): Investigation and Management.

Background: The aim of this study was to determine the occurrence of PTH in the population with severe traumatic brain injuries who underwent DC, and the clinical factors related to the development of PTH after DC.

Methods: A total of 389 patients suffering from severe head trauma between January 2004 and March 2010 were included in the study. Clinical data were analyzed retrospectively. Of them, 129 patients underwent DC. Those who underwent DC were divided into two groups according to the presence of hydrocephalus: a hydrocephalus group (PTH) and a non-hydrocephalus group (NPTH). Related factors including preoperative Glasgow Coma Scale score (GCS), duration of coma, bilateral or unilateral decompression, duraplasty in DC, and cranioplasty after DC, were assessed by single-factor analysis to determine their relationship with the occurrence of PTH.

Results: Of 149 patients that underwent DC, 25 patients (18.1%) developed PTH, while 23 patients (9.6%) ????. In 240 patients without DC there was a statistically significant difference (p = 0.013). The occurrence of PTH was significantly higher in those with low preoperative GCS scores and bilateral decompression, while the chance of PTH was decreased in those with duraplasty in DC and cranioplasty after DC. Ventriculoperitoneal shunt surgery was performed in 23 of 25 patients with PTH after DC. The frontal horn was preferred for placement of the catheter. Sixteen of them were operated via a frontal approach, and 7 patients via an occipital approach. One patient eventually died because of severe pneumonia. Shunt-related infection occurred in one patient, which led to the removal of the catheter. After shunt surgery, both radiological and clinical improvements were observed in 19 patients. Radiological improvement was seen in 2 patients. For 19 patients with PTH synchronous with skull defects, cranioplasty was performed together with shunt surgery in 7 patients, and was staged secondary to shunt in 11 patients. No significant complications related to cranioplasty occurred.

Conclusion: We demonstrated in this study that the occurrence of PTH was higher in patients with large decompressive cranial defects. Low GCS scores and bilateral decompression may be risk factors for the development of PTH after DC. Duraplasty in DC and cranioplasty after DC can reduce PTH. Shunt surgery and cranioplasty should be deliberately arranged to restore anatomical and physiological integrity in order to facilitate neurological resuscitation.

Qiansuokai Denglei 94th Hospital of PLA, NanChang, China

P80 Effect of Hyperbaric Oxygen on the Expression of Aquaporin-4 in Brain Tissue of Rats Following Traumatic Brain Injury.

Background: This study explores the possible mechanisms of hyperbaric oxygen therapy (HBOT) therapy in traumatic brain injury (TBI) by investigating the effect on the expression of AQP-4 and brain edema.

Methods: Male Sprague-Dawley rats were traumatized using Feeney's brain injury model. The rats were randomly divided into three groups (n = 32 for each group): sham-operated, TBI with subsequent HBOT (2ATA), and untreated after TBI. The TBI + HBOT and the untreated groups were subdivided into 12-h, 1-day, 3-day, and 5-day subgroups (n = 8 in each). We measured the quantity of brain water, and measured the quantity of AQP-4 by immunohistochemical staining.

Results: The quantity of brain water in the TBI groups with subsequent HBOT was significantly lower than that in the untreated group, but was higher than that in the sham-operated group. The protein expression of AQP-4 was lower in normal brain tissue. From 12 h after operation, there was more protein expression of AQP-4 by foot process astrocyte cells in the contusion marginal region in the TBI group, peaking at 24 h after operation, and dropping by 3 days. The expression of AQP-4 in the HBOT group was significantly decreased compared to the TBI group (p < 0.05).

Conclusions: HBOT may reduce brain edema and protect brain tissue via a decline in AQP-4 expression.

Xiao Nian Liu Qiansuokai

P81 Effect of Hyperbaric Oxygen on the Expression of Survivin in Brain Tissue of Rats After Traumatic Brain Injury.

Abstract not Available

Qiansuokai Yangqifan

P82 Continuous Intracranial Pressure Monitoring in Bilateral Frontal Contusions and Laceration of the Brain: 15 Cases.

Abstract not Available

Niuhongquan Sheng Wang Jian Chen Jincao Chen Ting Lei Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China

P83 Clinical Analysis and Treatment of Geratic Severe Craniocerebral Injury.

Background: Here we investigate the risk factors and treatments for severe craniocerebral injury in aged patients.

Methods: In all, 215 aged severe craniocerebral injury patients surviving more than 24 h, admitted between July 2002 and June 2010 were included. The relationship between mortality and Glasgow Coma Scale score, brain herniation, contusion, and intracranial hematoma were studied retrospectively.

Results: The mortality rates in patients with brain herniation, contusions, and multiple hematomas were significantly higher than those without, and the main causes of death were brain herniation and malignant high intracranial pressure caused by diffuse brain swelling at early stages, and multiple organ failure at later stages.

Conclusion: The keys for treatment of geriatric patients with severe craniocerebral injuries are the establishment of a rapid emergency treatment system, with standard guidelines, diagnoses, and elimination of intracranial hematomas at the early stage, and effective decompression with bone flap removal, early brain protection, and nutritional support.

Lian-Sheng Long Ji-Yao Jiang Zhi-Chen Xin Wei-Ming Wang Zhao-Hui Zhao Xia-Liang Li Chao-Chao Jiang Qiang Su Hong-Mei Zhang The 98th Hospital of PLA, Huzhou, Zhejiang, China

P84 Clinical Value of Invasive ICP Monitoring in the Treatment of Post-Traumatic Acute Diffuse Brain Swelling.

Background: We sought to investigate the effect of invasive ICP monitoring in treating post-traumatic acute diffuse brain swelling.

Methods: A total of 27 patients with post-traumatic acute diffuse brain swelling (including 16 with GCS scores 6–8 and 11 with GCS scores 9–12) admitted between May 2009 and April 2010 were included. All cases in whom operative indications were uncertain were monitored for the first 6 h after trauma by using an invasive ICP monitoring device. The changes in ICP and GCS scores were recorded.

Results: In all 17 patients were treated with conservative treatment, and 10 patients were treated with decompressive craniectomy because of malignant intracranial hypertension. According to GOS data at 6–17 months post-injury, good recovery was seen in 18 cases (66.7%), moderate disability in6 cases (22.20%), and vegetative state in 3 cases (11.1%). None of the patients died, and none developed intracranial infection or intracranial hemorrhage caused by implanting an optical fiber transducer into the lateral ventricle or brain parenchyma. Conclusions: Continuous invasive ICP monitoring can aid in timely understanding of ICP changes to allow proper treatment of post-traumatic acute diffuse brain swelling, and it is safe.

Lian-Sheng Long Ji-Yao Jiang Zhi-Cheng Xin Wei-Ming Wang Zhao-Hui Zhao Jian-Zhong Zhang Chao-Chao Jiang Zhong-Hua Wu Hong-Mei Zhang The 98th Hospital of PLA, Huzhou, Zhejiang, China

P85 Risk Factor Analysis of Traumatic Arterial and Venous Cerebral Infarction in Patients with Moderate or Severe Craniocerebral Trauma.

Background: We sought to find risk factors for traumatic arterial and venous cerebral infarction.

Methods: In all, 154 cases of moderate or severe craniocerebral trauma that were treated with decompressive craniectomy were analyzed. Univariate analysis was carried out on 13 related factors, including gender, age, Glasgow Coma Scale score (GCS) on admission, pupil status, morphological changes of the ambient cisterns, brain midline, associated injuries, perioperative blood pressure, traumatic superficial cerebral venous injury, platelet count, plasma D-dimer value, dosage of dehydrating agent, and perioperative fluid balance. Multiple logistic regression analysis was carried out on significant indexes with SPSS v. 10.0 for Windows.

Results: Univariate analysis showed that seven factors, including pupil status, GCS on admission, age, associated injuries, perioperative blood pressure, morphological changes of the ambient cisterns, and brain midline were significantly correlated with traumatic arterial cerebral infarction (p < 0.05), and three factors including traumatic superficial cerebral venous injury, plasma D-dimer value, and associated injuries were significantly correlated with traumatic venous cerebral infarction (p < 0.05). Logistic multi-factoral regression analysis showed that mydriasis and hypotension may be independent risk factors for traumatic arterial cerebral infarction, and traumatic superficial cerebral venous injury may be an independent risk factor for traumatic venous cerebral infarction.

Conclusion: The pupil status, GCS score on admission, age, associated injuries, perioperative blood pressure, morphological changes of the ambient cisterns, and brain midline were risk factors for traumatic arterial cerebral infarction, and mydriasis and hypotension were independent risk factors. Traumatic superficial cerebral venous injury, plasma D-dimer values, and associated injuries were risk factors for traumatic venous cerebral infarction, and traumatic superficial cerebral venous injury was an independent risk factor.

Xianming Fu Yinbao Qi Ruobing Qian Minghui Zeng Chaoshi Niu Yehan Wang

P86 Executive Control Dysfunction in Patients with Prefrontal Cortex Injuries.

Abstract not Available

Yikai Yuan Zhi Chen Jiangkai Lin Gang Zhu Zhongming Qian Hua Feng Hui Meng Southwest Hospital, Third Military Medical University, Chongqing, China

P87 The Effect of Deferoxamine on Treating Rat Hydrocephalus After Intraventricular Hemorrhage and the Expression of WNT1 and WNT3A in Rat Brains.

Background: We sought to observe the expression of wnt1 and wnt3a in rat brains, and to study their correlation with chronic hydrocephalus after intraventricular hemorrhage (IVH).

Methods: A total of 150 Sprague-Dawley female rats were randomly divided into four groups: a normal control group, a false IVH control group, an IVH group, and a deferoxamine group. The rat hydrocephalus model was made by infusing autologous whole blood into the right lateral cerebral ventricle. The rats were sacrificed 1, 7, and 28 days later for measurement of the transverse diameter of the lateral ventricle on the coronal slice of rat brain 0.40 mm posterior to the bregma for the evaluation of hydrocephalus, as well as the expression of wnt mRNA and protein in the brain.

Results: The normal control group and the false IVH group had no hydrocephalus. There were significant differences of hydrocephalus rats between those in the IVH group (7/10) and those in the deferoxamine group (2/10) at 7 and 28 days. wnt3a mRNA expression in the IVH group gradually increased after 1 day, and peaked at 28 days, and in the deferoxamine group was increased slightly at 7 days. There were no significant differences between the IVH group and the normal control group at 28 days. The protein expression in the IVH group was higher than that in the normal group and in the false IVH control group (p < 0.01); the peak values reached 4–5 times above normal, while in the deferoxamine group wnt1 and wnt3a peaked at 7 days, and then decreased and returned to normal levels; the peak values were twice as high as those in the normal group. However, neither was significantly different from the normal group.

Conclusion: Deferoxamine did reduce hydrocephalus after IVH, and diminished expression of the wnt gene, which could influence arachnoid fibrosis.

Mei Li Fei Li Youan Shan Lijun Zhang Zhongming Qian Gang Zhu Jiangkai Lin Hua Feng Southwest Hospital, The Third Military Medical University, Chongqing, China

P88 Splenectomy Decreases Mortality and Improves Cognitive Function.

Background: Traumatic brain injury (TBI) frequently causes a considerable social burden because of its high incidence of death and long-term disability, especially in cases of severe TBI. Recent studies have revealed that the spleen might contribute to secondary brain injury after ischemia or intracerebral hemorrhage (ICH). The purpose of this study was to evaluate the significance of the spleen in traumatic brain edema after severe TBI.

Methods: We established a severe TBI model in the rats, and performed splenectomy to observe the mortality, brain water content, cognitive function (water maze), and cytokine levels, including IL-1β, TNF-α, IL-6, and IL-10, in the blood plasma (ELISA), and their mRNA expression levels in injured brain tissue (quantitative RT-PCR).

Results: Immediate splenectomy after TBI significantly decreased the death rate, from 35.42% to 14.89%, and eliminated water content of the injured brain, especially at days 2 and 3. The Morris water maze assessment showed an improved spatial reference memory in rats that underwent both TBI and splenectomy, compared to those in the TBI group 4 weeks later. Splenectomy reduced levels of IL-1β, TNF-α, and IL-6 in the blood serum after TBI, and their mRNA expression levels in the injured brain tissues were also decreased.

Conclusion: Our study demonstrates that splenectomy is protective in rats with severe TBI by inhibiting proinflammatory cytokines, including IL-1β, TNF-α, and IL-6, both systemically and locally in the injured brain, thus leading to decreased mortality and improved cognitive function.

yujie Chen chunxia Luo bo Li zhi Liu mingyue Zhao zhi Chen Zhang John H. Hua Feng Southwest Hospital, Third Military Medical University, Chongqing, China

P89 A Pten Inhibitor, BPV(PIC), Ameliorates Early Brain Injury and Improves Neurological Outcomes After Experimental Subarachnoid Hemorrhage in Rats.

Background: The goal of this study was to investigate the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in early brain injury after subarachnoid hemorrhage (SAH).

Methods: A standard intravascular perforation model was used to produce experimental SAH in Sprague-Dawley rats. Dipotassium bisperoxo(pyridine-2-carboxyl)oxovanadate [BPV(pic); 0.2 mg/kg], a PTEN inhibitor, was evaluated for its effects on neurological scores, brain edema, blood–brain barrier (BBB) disruption, apoptosis of hippocampal neurons, and a-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate (AMPA) receptor subunit alterations after SAH. We found that BPV(pic) was effective in attenuating BBB disruption, lowering edema in all brain regions, reducing apoptosis of hippocampal neurons, and improving neurological outcomes. Also, the AMPA receptor subunit GluR2 on the cytomembrane was significantly reduced. Thus we believe that BPV(pic) could improve neurological outcome, and provides neuroprotection against acute events after SAH, such as BBB disruption, brain edema, and apoptosis. Glutamate AMPA receptor subunit alterations may play a critical role in these effects.

Haitao Zhu Chen Bian Bo Li Lijun Zhang Mingming Zou Yikai Yuan Hua Feng Gang Zhu Jiangkai Lin Southwest Hospital, Third Military Medical University, Chongqing, China

P90 Study of Minimally-Invasive Monitoring of Secondary Brain Injury Following High-Altitude Intracerebral Hemorrhage.

Background: We sought to observe the development of secondary brain injury following high-altitude intracerebral hemorrhage via several minimally-invasive monitoring methods, and to preliminarily investigate the pathophysiological mechanisms of secondary brain injury following high-altitude intracerebral hemorrhage.

Methods: Twenty-six minipigs were randomly divided into four groups: a high-altitude blood infusion group (HI), a high-altitude sham-operation group (HS), a plain blood infusion group (PI), and a plain sham-operation group (PS). A hypobaric chamber was used to simulate an altitude of 4000 m. A double-injection method was used to produce intracerebral hemorrhage (ICH). Autologous arterial blood (3 mL) was slowly infused into the right basal ganglia region. Hematoma formation was observed via CT scanning. Blood glucose, mean arterial pressure (MAP), arterial blood gases, intracranial pressure (ICP), tissue oxygenation (Pto ₂), regional cerebral blood flow (rCBF), cerebral microdialysis (CMD), and neurological function were monitored before ICH and after treatment (at 2 h, 24 h, 72 h, and 168 h). Brain water content and transmission electron microscopic examination of perihematoma tissue were performed at 168 h after ICH.

Results: Clear hematoma formation was observed by cranial CT scanning. Blood glucose and MAP were not significantly different between groups. Arterial oxygen saturation (Sao ₂) and arterial oxygen pressure (Pao ₂) in the high-altitude group were significantly lower than those in the plain group. At 72 h after ICH, ICP in the HI group was significantly higher than that in the PI group. Compared to the PI group, Pto ₂ was significantly lower at each time point after ICH in the HI group. rCBF was reduced in both the HI and PI groups after ICH, and the most significant difference occurred at 24 h. Glutamate concentrations in the PI and HI groups reached a peak at 6 h or 24 h after ICH, but there were no significant differences between the two groups at these two time points. The decrease of glutamate concentration in the PI group was significant after 24 h. Neurologic deficit scores in the HI group were significantly higher than those of the PI group. Higher brain water content and more severe pathological injuries were observed in the HI group compared to the PI group at 168 h after ICH.

Conclusions: Secondary brain injury following intracerebral hemorrhage at high altitude was worse than that at plain. This effect may be due to a delay in the cleaning of glutamate accumulations, which aggravates the dysfunction of cerebrovascular autoregulation by hypoxia at high altitude.

Lijun Zhang Rong Hu Mei Li Fei Li Hui Meng Zhongming Qian Hua Feng Southwest Hospital, Third Military Medical University, Chongqing, China

P91 Deferoxamine Attenuates Iron-Induced Long-Term Neurotoxicity After Traumatic Brain Injury in Rats.

Background: Traumatic brain injury (TBI) is associated with high morbidity and mortality, and progressive neurobehavioral deficits and brain atrophy continue for many years post-TBI. However, the underlying mechanisms remain largely unknown.

Methods: Thirty-nine male Sprague-Dawley rats were randomly divided into three groups: a sham group, an injury group, and a deferoxamine (DFX)-treated group. The rats were administered DFX (100 mg/kg IP) in the DFX-treated group, while the others received vehicle (saline). Before the rats were killed on day 28, Morris water maze testing was performed. Perl's reaction was used for iron staining, and nonheme iron of brain tissue was examined. Also, ferritin, transferrin, and TRPC6 were detected by Western blotting and immunochemistry. TRPC6-positive cells were identified with immunofluorescence double labeling.

Results: A notable increase in brain iron was observed following TBI on day 28. Brain ferritin L, ferritin H, transferrin, and transient receptor potential canonical channel 6 (TRPC6) levels were remarkably overexpressed post-TBI. Significantly, clear improvements in spatial learning, memory deficits, and brain atrophy were also detected. Interestingly, DFX administration markedly decreased the expression of ferritin L, ferritin H, and transferrin, and increased the number of TRPC6-positive cells, including neurons and astrocytes at the peri-injury zone compared with the injury group, and promoted spatial learning and memory in the injured rats.

Conclusions: Iron overload may play a critical role in long-term neurotoxicity in the brain post-TBI, and correlates with upregulation of ferritin, transferrin, and TRPC6 in brain, which suggests that iron may be a target for TBI therapy. DFX downregulates the levels of iron-handling proteins, and improves spatial learning and memory in injured rats, and may represent a potential therapeutic agent for TBI patients.

Yunfeng Yang Zhi Chen Shengli Hu Jiangtao Li Bo Li Zhongming Qian Jiangkai Lin Hua Feng Gang Zhu Southwest Hospital, Third Military Medical University, Chongqing, China

P92 Inhibition of IRAK-1/4 Ameliorates Acute Hypoxic/Ischemic Neuronal Injury in vivo and in vitro.

Background: Neuronal toll-like receptors (TLRs) have been proven to play a pivotal role in hypoxia/ischemia (H/I) brain injury, and the interleukin-1 receptor associated kinases (IRAKs) are considered to be the key signaling molecules downstream of TLRs. Here we investigated the existence of neuronal IRAKs, and tried to discover the effect of an IRAK-1/4 inhibitor on brain injury and neurological function after H/I injury in rats.

Methods: Controlled in vivo and in vitro laboratory studies were conducted. Seventy-four male Sprague-Dawley rats received H/I brain injury that was induced by permanent middle cerebral artery occlusion (MCAO), with or without IP treatment with an IRAK-1/4 inhibitor. In addition, rat neuroblastoma B35 cells were stimulated with cobalt chloride (CoCl₂), with or without IRAK-1/4 inhibitor treatment.

Results: The expression of IRAK-1 and - 4 were explored using RT-PCR, Western blot analysis, and immunofluorescence. Cerebral cortex and B35 cells expressed IRAK-1 and - 4, and responded to H/I stimulation. The IRAK-1/4 inhibitor decreased the mortality rate, functional deficits, and ischemic infarct area in a rat permanent focal ischemic model. In the in vitro studies, the IRAK-1/4 inhibitor attenuated CoCl₂-induced cytotoxicity and apoptosis in B35 cells. Also, the IRAK-1/4 inhibitor reduced the nuclear translocation of the p65 subunit of NF-κB and the subsequent release of inflammatory mediators, and decreased the levels of p-JNK and c-caspase 3 proteins in B35 cell cultures at 6 h after H/I.

Conclusions: Our results verify the existence of neuronal IRAKs, and suggest that an IRAK-1/4 inhibitor could confer potent neuroprotection against H/I brain injury via suppression of the neuron-mediated inflammatory response.

Mingming Zou Xingsen Xue Haitao Zhu Lan Li Yongzhi Xia Tianzhi Zhao Hua Feng JiangKai Lin Southwest Hospital, The Third Military Medical University, Chongqing, China

P93 Effect of Curcumin on the Expression of GFAP and Motor Function of Hindlimbs After Spinal Cord Injury in the Rat.

Background: Here we investigated the effects of curcumin on the morphology, the expression of GFAP, and the motor function of hindlimbs after spinal cord injury in the rat.

Methods: A total of 144 female Wistar rats were divided randomly into seven groups: a control group; a single-injured group; a curcumin pretreatment group; test groups treated with curcumin (high-dose 300 mg/kg; medium-dose 100 mg/kg, and low-dose 30 mg/kg groups); and a test group treated with methylprednisolone. The curcumin pretreatment group received curcumin before surgery. Fehlings' spinal cord injury rat model was constructed via compression by the placement of a modified aneurysm clip (50 g, 1 min) at the T9–T10 spinal segment. The neurofunction of the spinal cord was evaluated by the Basso-Beattie-Bresnahan (BBB) scale, and the Rivlin platform test, at 1 day, 3 days, and each week post-injury. The animals were sacrificed at 2 weeks and 8 weeks, respectively, after injury for morphological study. GFAP-mRNA expression in the spinal cord of each group was analyzed by RT-PCR. The expression of GFAP protein was analyzed by immunohistochemistry and Western blot.

Results: The recovery of hindlimb motor function of the curcumin group was clearly superior to that of the control group and the methylprednisolone group (p < 0.05).Conclusion: Curcumin can downregulate the expression of GFAP, attenuate the number and the size of reactive astrocytes, inhibit glial scar formation, and promote motor functional recovery of the hindlimb. The protective effect seen after acute SCI in rats is better than that of methylprednisolone.

Chunxia Luo Mei Li Liang Yi Jun Hu Bo Li Rong Hu Hua Feng Southwest Hospital, Third Military Medical University, Chongqing, China

P94 Inflammation Injury After Experimental Subarachnoid Hemorrhage in Rats and the Effect of Adenosine A3 Receptor Activation.

Background: The inflammatory response has been implicated in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). Recently, adenosine A3R has attracted attention for its ability to modulate inflammation. In this study, we investigate whether SAH can induce the activation of astrocytes and microglia; the changes of expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as IL-10; and evaluate the modulatory effects of adenosine A3 receptor activation on the SAH-induced inflammatory response early after brain injury in rats.

Methods: In a well-established endovascular perforation model of SAH, Nissl staining and TUNEL staining at 24 h were evaluated after surgery. The activation of microglia and astrocytes in the cortex and hippocampus were detected with immunofluorescence histochemistry at 24 h after SAH. The expression of mRNA and protein levels of inflammatory cytokines were examined by real-time RT-PCR and ELISA at 6, 12, and 24 h after SAH.

Results: Our results show that SAH can induce astrocyte and microglia activation, and induce upregulation of the mRNA and protein levels of inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-10, at 6, 12, and 24 h after SAH. Pretreatment with CL-IB-MECA, a specific adenosine A3 receptor agonist, reduced neuronal injury, suppressed astrocyte and microglia activation, and reduced the expression of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, but it had no effect on anti-inflammatory IL-10.

Conclusions: These data suggest that glial activation and proinflammatory cytokine release might play an important role early after SAH, and pretreatment with an adenosine A3 receptor agonist may also play a protective role.

Yi-Wu Dai Zhi-Jun Yang Yong-Chun Luo Hong-Tian Zhang Yan-Bin Fu Ru-Xiang Xu

P95 Injuries in the Mesencephalon or the Conjugative Area of the Mesendiencephalon Related to Vegetative State.

Abstract not Available

Yi-Wu Dai Zhi-Jun Yang Hong-Tian Zhang Yong-Chun Luo Ru-Xiang Xu

P96 Investigation of the Treatment of Brainstem Injury by the Autotransplantation of Bone Marrow Stromal Cell-Derived Stem Cells.

Abstract not Available

Xingang Li Donghai Wang Yunyan Wang Wandong Su Xueen Li Bin Huang Qilu Hospital, Shandong University, Shandong, China

P97 Early Diagnosis of Traumatic Carotid Cavernous Fistula.

Background: Here we discuss the factors affecting early diagnosis of traumatic carotid cavernous fistula (TCCF), and the contributions of imaging examinations to early diagnosis of TCCF.

Methods: We analyzed the clinical data of 23 TCCF patients treated in Qilu Hospital from July 2006 to July 2010. We identified the possible factors affecting the early diagnosis of TCCF, and the assessed the imaging examinations for these patients.

Results: The common clinical symptoms include pulsatile intracranial bruit, pulsating exophthalmos, and congested and edematous conjunctivae, which appeared 7 days post-trauma. These symptoms even appeared 2 months post-trauma in some patients. Among the 23 patients, 13 did not get a timely diagnosis and treatment when they presented with typical symptoms. All 13 patients had the intracranial bruit after injury. High density could be seen on CT in one or both cavernous sinuses in 10 of 13 patients. Digital subtraction angiography (DSA) is the gold standard for diagnosing TCCF.

Conclusions: The intracranial bruit should be sought and auscultated in order to diagnose the disease quickly. A clinical diagnosis can usually be established with the typical symptoms and one or more imaging examinations. DSA is decisive and absolutely necessary, and is the gold standard for diagnosing TCCE.

Chao Xiao-dong Liu Wen-bo Chen Tao Dong Wen-peng Luo Peng Fei Zhou Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China

P98 Osthole Attenuates Cerebral Ischemic Neuronal Injury via ENOS-Dependent and Nitric Oxide-Mediated Anti-Apoptotic Actions.

Background: Apoptosis contributes to cerebral ischemic injury, and both osthole and nitric oxide (NO) have been shown to exert anti-apoptotic effects in vitro and in vivo. However, the interrelationship between these two neuroprotective molecules remains completely unknown. The present study investigated the neuroprotective effect of osthole on acute ischemic stroke induced by middle cerebral artery occlusion (MCAO) in rats and the underlying mechanism.

Methods: Adult male Sprague-Dawley rats weighing 250–280 g were subjected to 2 h MCAO, and pretreated with vehicle (20% Tween-80), osthole alone, or osthole plus NG-nitro-L-arginine methyl ester (L-NAME, a nonselective NOS inhibitor), LY-294002 (a specific PI3K inhibitor), or GW9662 (a selective PPAR-γ antagonist), at 30 min before the transient occlusion. Neurological deficit scores (NDS) and infarct volumes of the brain were assessed at 24 h and 72 h after MCAO. Neuronal apoptosis, NO concentration, and activated caspase-3, iNOS, nNOS, eNOS, phosphorylated eNOS (p-eNOS), Akt, phosphorylated Akt (p-Akt), TNF-α, and arginase protein expression were also determined at 24 h after MCAO.

Results: Pre-administration of osthole to rats with MCAO-induced acute ischemic stroke resulted in a significant decrease both in NDS and infarction volume at 24 h and 72 h, and in the levels of neuronal apoptosis, activated caspase-3, and iNOS protein expression at 24 h after MCAO. However, NO concentration and eNOS protein expression were increased. The neuroprotective effect of osthole was completely blocked by the NOS inhibitor L-NAME. Furthermore, osthole-induced eNOS protein expression and phosphorylation were blocked by GW9662 and LY-294002, respectively. Also, the phosphorylation of eNOS had a greater effect on osthole neuroprotection than the expression of eNOS.

Conclusion: Our results provide direct evidence that osthole attenuates cerebral ischemic neuroinjury via eNOS-dependent and NO-mediated anti-apoptotic action, in which both eNOS protein upregulation and phosphorylation are involved, with the latter being the primary pathway.

Berger Elizabeth A. Barrett Ronald P. Rafols Jose A. Kreipke Christian W. Wayne State University School of Medicine, Detroit, Michigan

P100 Post-Trauma Vision Syndrome: Analysis and Treatment Using a Rat Model of Diffuse Traumatic Brain Injury.

Background: This study used a well-characterized model of diffuse TBI to: (1) investigate the inflammatory response along the afferent visual pathway; (2) correlate these findings with structural and functional alterations in the same pathway; and (3) determine the efficacy of vasoactive intestinal peptide (VIP) treatment in ameliorating the aforementioned changes post-injury.

Methods: TBI was induced in male Sprague-Dawley rats (350–400 g) using a weight drop (450 g, 2 m height) acceleration impact model modified after that of Marmarou. The superior colliculus, optic tract, optic nerve, and posterior eye were collected at 0, 24, and 48 h post-injury and processed for mRNA and protein analyses, histopathology, and diffusion tensor imaging (DTI).

Results: Eighty-four inflammatory cytokine/chemokine and receptor genes were examined by real-time RT-PCR, then selectively analyzed at the protein level, revealing differential expression of classic pro- and anti-inflammatory molecules (including IL-1 alpha, IL-1 beta, IL-6, IL-10, IFN-gamma, TNF-alpha, and TGF-beta), in all analyzed regional components of the visual pathway at 24 and 48 h post-injury compared to controls (sham). Histopathologic alterations at similar end-points further supported the presence of a strong inflammatory response. DTI revealed functional effects of TBI on the optic tract, as indicated by a significant decrease in fractional anisotropy measurements post-injury compared to pre-injury levels. Most strikingly, however, VIP treatment resulted in a significant decrease in both the expression of proinflammatory molecules and neuronal damage, while upregulating expression of anti-inflammatory molecules and preserving function of the visual system.

Conclusion: This study is first to show concurrent inflammation in functionally-related structures along the visual pathway. The correlative mRNA, protein, histopathologic, and functional imaging findings support the notion that inflammation may underlie PTVS. VIP treatment aims to target components of the inflammatory response in an effort to improve effects on the visual system by reducing inflammatory cell activation, decreasing neuronal damage, restoring axonal transport, regulating cell death, and promoting restoration of tissue homeostasis.

Cheng Shi-xiang Shen Ya-feng Zhang Sai Tianjin Wujing General Hospital, Tianjin, China

P101 The Effect of Moderate Hypothermia on Amyloid-β in Cerebrospinal Fluid After Severe Traumatic Brain Injury.

Background: Here we investigate the effects of moderate hypothermia on amyloid-β peptide in human CSF after sTBI and the relationship with outcome.

Methods: Sixty patients with head injury were randomly divided into hypothermic (HT) groups and normothermic (NT) groups. Inclusion criteria included a Glasgow Coma Scale (GCS) score of ≤ 8, and time from injury to admission < 6 h. We analyzed the concentration changes in cerebrospinal fluid by ELISA at different time points. We recorded the GCS score on admission, the level of ICP during treatment, and GOS outcome at 3 months post-injury.

Results: In the NT group, the amyloid-β peptide levels were time-related to sTBI; however, in the HT group, the amyloid-β peptide levels and the value of the ICP gradually decreased after 3 days of hypothermia; however, both of the NT groups were able to sustain higher levels, and in the HT groups the GOS ratings were significantly higher than those of the control groups.

Conclusion: Moderate hypothermia can inhibit the expression of amyloid-β, and improve the clinical prognosis.

Cheng Shi-xiang Jiang Hong-sheng Zhang Sai Tianjin Wujing General Hospital, Tianjin, China

P102 Protection by Limb Ischemia Postconditioning of Ischemic Neurons in the Rat Hippocampus via Activating the MAPK Pathway.

Background: The goal of this study was to elucidate the effects of limb ischemia post-conditioning following global cerebral ischemia, and to investigate the levels of ERK1/2 phosphorylation and protein expression in the hippocampal CA1 region of the rat.

Methods: Adult male Sprague-Dawley rats were subjected to global cerebral ischemia by four-vessel occlusion. Experimental animals were randomly divided into four groups: sham, ischemia/reperfusion (I/R), limb ischemia postconditioning (Lpost), and Lpost + PD98059. Cresyl violet staining was used to examine surviving neurons in the hippocampal CA1 region of the rats by light microscopy. ERK1/2 phosphorylation and its protein expression were detected by Western blot.

Results: Compared with the I/R groups, the Lpost groups had significant increases in the numbers of surviving neurons in the hippocampal CA1 region. The protection by limb ischemia postconditioning was suppressed by PD98059.

Conclusion: Limb ischemia postconditioning can protect neurons in the hippocampal CA1 region following global cerebral ischemia in rats, and the protection is effected by the activation of ERK1/2.

Zhao Miang-liang Cheng Shi-xiang Zhang Sai Tianjin Wujing General Hospital, Tianjin, China

P103 Increased Intrinsic Excitability and Synaptic Excitation in the Rat Hippocampus CA1 Following Cortical Contusion Head Injury.

Focal epilepsy often develops following traumatic brain injury, but the mechanisms underlying epileptogenesis are poorly understood. Because post-traumatic epilepsy appears in many cases as a temporal lobe epilepsy that originates in the hippocampus, we studied trauma-induced hyperexcitability at the cellular level in this brain area. Whole cell voltage-clamp recordings were used to examine evoked synaptic events from CA1 pyramidal cells in slices prepared from fluid percussion injury (FPI) rat at various time points after brain injury. Localized strokes in the somatosensory cortex induce long-term reductions in intrinsic excitability and evoked synaptic excitation of CA1 pyramidal cells by the end of the first week after injury. We found that CA1 pyramidal cells in injured rats showed (1) decreased membrane input resistance and time constant, (2) increased paired-pulse facilitation ratio (PPR), and (3) stronger evoked excitatory synaptic responses. Further, we detect and demonstrate significantly reduced expression of KCC2 protein and mRNA expression in the injury group, which could cause a depolarizing shift in GABA(A) reversal potential, and result in reduced inhibitory efficiency. These findings suggest that there is a trauma-induced increase in excitability and decreased inhibition at the cellular level in the rat hippocampus CA1 following cortical contusion head injury. These alterations may facilitate the progress toward the development of epilepsy.

Li Zhi-qiang shen Dongqing Quan Zhe FengXian District Center Hospital, Shanghai, China

P104 Clinical Manifestations and CT Examinations in Patients with Severe Traumatic Brain Injury with Intracranial Hematomas: an Assessment of the Prognostic Indicators.

Background: Here we evaluate prognostic indicators in severe traumatic brain injury and intracranial hematomas with herniation, and explore which is the most important indicator.

Methods: We retrospectively analyzed data from 84 cases of severe traumatic brain injury. Age, GCS, pupil reflex, midline shift, compression of the cistern, decompression time, and complex injuries were considered as possible prognostic indicators. SPSS v13.0 was employed to analyze the data. Logistic regression (forward conditional) analysis was done to confirm which were the most important prognostic indicators for severe traumatic brain injury, and to evaluate the practical value in predicting prognosis.

Results: Eighteen patients died and 24 survived; 56 (6%) patients had a poor prognosis (GOS ≤ 3), and 28 (33%) had a good prognosis (GOS > 3). Those who had a shorter decompression time (≤3 h) had a better prognosis than those who had a longer decompression time (>3 h), with mortality rates of 11% and 67%, respectively. Less cisternal compression predicted better outcome. GCS, pupil reflex, midline shift, and complex injuries did not enter the logistic regression equation. According to compression time, 90.5% of the patients' prognoses were accurately predicted, and according to compression time and cisternal compression 95.2% were accurately predicted.

Conclusion: The mortality rate of severe traumatic brain injury with herniation is high, and surgical intervention can be effective. Decompression time and cisternal compression were the most important factors affecting prognosis in severe traumatic brain injury, and they could be used to correctly predict prognosis in most cases.

Hu-fuguang Zhang-haofeng Wang-liqun Fan-zhenzeng The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

P105 Genetic Character of CNS Injury and Autoimmunity Neuroprotection.

Background: Previous studies have shown that the T-cell-mediated autoimmune response promotes recovery from central nervous system (CNS) injury. However, our data indicated a different result. The aim of this article is to study the appearance in different strains of rats, and to explore the genetic character of autoimmune neuroprotection after CNS injury.

Methods: The experimental work was divided into two steps. First, experimental autoimmune encephalomyelitis (EAE) models were produced in adult Sprague-Dawley (SD) rats (n = 10), and Wistar rats (n = 10), immunized with myelin basic protein (MBP) to observe rat morbidity and to determine the progress of EAE. Second, adult SD rats (n = 10) and Wistar rats (n = 10) were subjected to spinal cord contusion at T7, using the New York University impactor, and were injected systemically with MBP at the time of contusion. Functional recovery was assessed by praxiology scoring, the open-field behavioral test of Basso, Beattie, and Bresnahan, and morphometric analysis, including immunohistochemical staining and transmission electron microscopy.

Results: Compared with SD rats, the onset of EAE was earlier, its symptoms were worse, and the course of disease was longer in Wistar rats. Recovery outcomes were also worse in Wistar rats after spinal cord injury, and functional scores were significantly different (Wistar rats, 3.1 ± 0.5, n = 8; SD rats, 7.3 ± 0.8, n = 9; p < 0.05). Histological analysis showed that the behavioral outcomes were correlated with tissue preservation.

Conclusion: This study showed that the Wistar rat is an EAE-susceptible strain, which has insufficient autoimmunity neuroprotective mechanisms in vivo. Genetic factors are critical in determining the recovery outcomes in different strains of rats after CNS injury.

Xiaofei Xu Hua Zhan Tianyi Zang Qiusheng Zhang Xianjian Huang Meng Zhang Harbin Medical University, Harbin, China

P106 The Smart Service System of Health-Cure for Traumatic Brain Injury.

With the rapid development of the national economy and increasing vehicle traffic, traumatic brain injury has increasingly become a serious public health crisis in China. It is second only to systemic trauma, and is the main cause of death for young people. There are many problems with the public health care system in China, such as a lack of communication among medical institutions and standardized treatments, and discrepancies in the treatment levels of different hospitals, particularly in their ability to deliver first aid and to transfer from one hospital to another. Patients often spend a lot of time and money on medical treatment, or even worse may not even receive treatment. The Smart Service System of Health-Cure (S3HC) was developed for different types of hospitals and related centers, including medical vendors and medical equipment manufacturers and insurance companies. It features the following aspects: (a) internet links, (b) internet cloud computing environment, (c) medical knowledge and content management, (d) medical service and application systems (smart service center), and (e) medical service and functional departments. The core of S3HC is the Medical Information Integration Platform (MIIP). The MIIP is able to effectively improve medical services by integrating business processes, and sharing and exchanging medical information and resources. It offers communication in real time, online reservations, and remote consultation. Improved efficiency of first aid, referral, diagnosis, treatment, and rehabilitation are also supported. In addition, S3HC promotes medical service evolution and optimization by establishing evaluation criteria for medical services and optimization systems. It will have a significant effect not only on the treatment and rehabilitation of traumatic brain injury patients, but also on the health care industry in general.

Xiaohua Hu Hui Li Yan Dong Hangzhou Hospital of Zhejiang, Hangzhou, Zhejiang, China

P107 Effects of Ventriculoperitoneal Shunts for Hydrocephalus Patients on Activities of Daily Living.

Background: Here we observe the effects of ventriculoperitoneal (V-P) shunts on activities of daily living of patients with hydrocephalus.

Methods: In all, 51 patients with hydrocephalus who received V-P shunts were observed, of which 42 were in comas and 9 were conscious. Among the patients in comas, Glasgow Coma Scale (GCS) scores and Barthel index ratings were evaluated before and 6 months after V-P shunt placement. Among conscious patients only the Barthel index was evaluated before and 6 months after V-P shunt placement.

Results: The average GCS score of patients in comas before V-P shunt placement was 7.00 ± 1.96, and it was 9.50 ± 3.30 6 months later. The score was significantly improved (p < 0.05). The average Barthel indices of patients in comas before and 6 months after V-P shunt placement were 0.00 ± 0.00 and 15.24 ± 21.92, respectively. This score was also significantly improved (p < 0.05). The Barthel index of conscious patients was 55.56 ± 34.77 before V-P shunt placement, and 63.89 ± 34.98 6 months after placement. It was not significantly improved (p > 0.05).

Conclusion: V-P shunts improve GCS and activities of daily living in comatose patients with hydrocephalus, while they have little effect on activities of daily living of conscious patients.

Weiping Li Guodong Huang Jianzhong Wan Qiusheng Zhang Xianjian Huang Meng Zhang First Affiliated Hospital of Shenzhen University, Shenzhen, China

P108 Applications of Multi-Parameter Monitoring During the Treatment of Traumatic Brain Injury.

Here we introduce a single-center, prospective study of the meaning and effect of the monitoring of multiple parameters in the clinical treatment of severe traumatic brain injury (sTBI). These parameters include: intracranial pressure (ICP), cerebral perfusion pressure (CPP), mean arterial blood pressure (MABP), brain tissue oxygen (PbtO₂), cerebral blood flow (including systolic flow velocity [Vp], diastolic blood flow velocity [Vd], mean flow velocity [Vm], pulsatility index [PI], and resistance index [RI]), electroencephalogram (EEG), and brainstem auditory evoked potential (BAEP) monitoring. We monitored ICP, CCP, PABP, PbtO₂, cerebral hemodynamics, EEG, and BAEP, individually or collectively, in 309 TBI patients, and studied the relationships between the monitoring parameters and the extent of brain injury, outcome, and prognosis. We found that PbtO₂ was negatively correlated with ICP only when 25 mm Hg ≤ ICP ≤ 55 mm Hg (r = –0.693; p < 0.001); otherwise there was no correlation with ICP. CPP was positively correlated with PbtO₂ when 0 < CPP < 80 mm Hg, and there was no correlation with PbtO₂ when CPP was > 80 mm Hg. PI, RI, and ICP were positively correlated (PI: r = 0.881, p < 0.0001; RI: r = 0.789, p < 0.0001); multiple stepwise regression analysis showed that PI and ICP, CCP, PI, and MABP were most closely related (p < 0.0001). The grade of acute traumatic brain injury was positively correlated with early EEG changes (chi² = 58.86, p < 0.01). The level of EEG abnormalities in patients early after injury was negatively correlated with better prognosis (chi² = 58.86, p < 0.01). Compared with patients without epileptic seizure waves on EEG, the incidence of early seizures was significantly increased in patients with seizure waves presenting early after injury (chi² = 39.47, p < 0.01). Compared with patients without administration of antiepileptic drugs, there was a significantly increased rate of early epilepsy wave disappearance in patients with administration of antiepileptic drugs (p = 0.024, p < 0.05). Compared with patients with no low-voltage EEG changes, the mortality was significantly higher in patients with low-voltage EEG changes (chi² = 13.72, p  < 0.01). The grade of acute brain injury was positively correlated with BAEP changes (chi² regression = 21.518, p < 0.005; chi² bias = 3.291, p < 0.75). There was a linear correlation between different BAEP grades at 1 week post-injury and prognosis (chi² regression = 25.523, p < 0.005; chi² bias = 3.675, p < 0.75). The prognoses of patients presenting with BAEP changes were significantly different (chi² = 8.922, p < 0.005), compared with others, and mortality was significantly higher in patients presenting with disappearance of BAEP waveforms within 3 days after injury (chi² = 22.05, p < 0.005).

Conclusion: This study shows that dynamic multi-parameter monitoring can more comprehensively and more timely reflect the status and variation in patient hemodynamics, brain tissue oxygen metabolism, and brain physiological electrical potential, and it has significant potential for more accurate guidance of clinical treatment, and for evaluating the prognosis of patients with severe traumatic brain injury.

Xiaofei Xu Hua Zhan Tianyi Zang Qiusheng Zhang Xianjian Huang Meng Zhang

P109 A Smart Service System of Health-Cure for Traumatic Brain Injury.

Abstract not Available

Li Xiangdong Hui Guozhen Wu Zhiyuan Guo Lihe Department of Neurosurgery, the First Hospital Affiliated with Suzhou University, Suzhou, China; Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

P110 Experimental Study of the Treatment of Spinal Cord Injury in Rhesus Monkeys with Transplantation of Human Amniotic Epithelial Cells.

Background: Amniotic epithelial cells (AECs) are low in immunogenicity and lack the expression of human leukocyte antigens (HLAs). AECs can synthesize and secrete various neurotrophic factors. Our study investigated the effects of the transplantation of human AECs (hAECs) in spinal cord hemisection injury in rhesus monkeys.

Methods: A hemisection injury of the spinal cord was made in anesthetized rhesus monkeys, and hAECs or hAECs transfected with brain-derived neurotrophic factor (BDNF) were transplanted into the injured sites. At 70 days following injury, Fluoro Gold was administered into the spinal cord at 4 cm under the hemisection site. At 80 days following injury, behavioral observations and histological examinations were performed.

Results: The recovery of the locomotor function of the hindlimbs in the treatment group was better than that in the control group. Nerve fibers with acetylcholinesterase (AChE)-positive or tyrosine hydroxylase (TH)-positive glial cells with glial fibrillary acidic protein (GFAP)-positive and Fluoro Gold staining were observed in the graft in the treatment group.

Conclusion: The locomotor function of rhesus monkeys after spinal cord hemisection injury was notably improved by the transplantation of hAECs.

Du Yanli Li Yu Lan Qing Second Affiliated Hospital of Suzhou University, Jiangsu, China; Second Affiliated Hospital of Inner Mongolia University for the Nationalities, Inner Mongolia, China

P111 Magnetic Resonance Diffusion Tensor Imaging Combined with the 1H-Magnetic Resonance Spectroscopy Can Predict Injury Degree Severity and Provide the Prognosis of Severe Brain Injury.

Background: Here we investigate the degree of injury severity and provide the prognosis of severe traumatic brain injury (TBI) by using magnetic resonance diffusion tensor imaging (DTI) and 1H-magnetic resonance spectroscopy (1H-MRS).

Methods: Examinations using DTI and 1H-MRS were carried out in 72 patients with severe TBI. We correlated our imaging data with Glasgow Coma Scale (GCS) scores or Glasgow Outcome Scores (GOS). The role of 1H-MRS in predicting the duration of coma after severe TBI was also investigated.

Results: DTI showed that most severe TBI patients had marked changes in nerve fiber bundles and nerve integrity destruction. 1H-MRS indicated that for severe TBI patients the ratios of N-acetylaspartate (NAA)/choline (Cho) and NAA/creatinine (Cr) were decreased, while that of Cho/Cr was increased compared with those of the control group. 1H-MRS indicated poor prognosis when severe destruction of neural axons and increased lactic acid (Lac) levels were present. In severe TBI patients, a lack of neural axon integrity and changes in NAA/Cr, NAA/Cho, and Cho/Cr ratios were correlated with changes in GCS scores and GOS outcomes. The NAA values obtained with 1H-MRS were positively correlated with coma duration in severe TBI patients.

Conclusion: A combination of DTI with 1H-MRS may play a role in the assessment of injury location and the degree of severity in TBI patients. This combination can be regarded as a tool to estimate coma duration and to predict prognosis in severe TBI patients.

xi-an Fu guo-yi Gao jun Pu jun-feng Feng kui-ming Zhang ji-yao Jiang wei Xu Suzhou Hospital of Nanjing Medical University, Nanjing, China; Renji Hospital of Shanghai Jiaotong University School Of Medicine, Shanghai, China; The Second Affiliated Hospital of Kunming Medical University, China

P112 The Expression of PPAR-Γ in the Cortex of Rats with Lateral Fluid Percussion Injury.

Background: Here we study the early expression of PPAR-γ mRNA in the cortex of rats receiving lateral fluid percussion injury by randomization.

Methods: Twelve Male Sprague-Dawley rats were randomly divided into two groups: a control group (n = 6), and a fluid percussion injury group (n = 6). We performed lateral fluid percussion injury, then detected the changes in PPAR-γ mRNA in the hippocampus at 3 h post-injury using real-time PCR.

Results: Compared with the control group, the expression of PPAR-γ mRNA in the lateral fluid percussion injury group was clearly degraded (p < 0.05).

Conclusions: Suppressing the expression of PPAR-γ and promoting the release of inflammatory factors may be among the mechanisms of brain injury.

Baxter Dave Leech Robert Midwinter Mark Kinnunen Kirsi M. Ham Tim Bonnelle Valerie Patel Maneesh C. Greenwood Richard Sharp David J. The Royal Centre for Defence Medicine, Birmingham, U.K.; The Computational, Cognitive and Clinical Neuroimaging Laboratory, The Division of Experimental Medicine, Imperial College London, Hammersmith Hospital Campus, London, U.K.; Goldsmiths, University of London, London, U.K.; The MRC Clinical Sciences Centre, Imperial College London, London, U.K.; Imaging Department, Charing Cross Hospital, Imperial College Healthcare NHS, U.K.; The Institute of Neurology, University College London, London, U.K.

P113 White Matter Damage Secondary to Military Blast and Civilian Traumatic Brain Injury: A Comparative Study.

Background: Blast injury has become a significant cause of morbidity and mortality in the military population. Injuries result from a complex mix of primary blast injury resulting directly from the explosive shockwave, and other damage resulting from penetrating and blunt trauma. Relatively little is known about the effects of the primary blast on the brain, although patients exposed to blast often develop persistent cognitive and neuropsychiatric impairments. Diffuse axonal injury is an important cause of cognitive problems after TBI in the civilian population. Diffusion tensor imaging (DTI) can be used to study this. We have previously applied a voxel based technique—tract based spatial statistics (TBSS)—to this problem. Here we use TBSS to investigate the pattern of axonal damage in servicemen injured by blast and in a civilian TBI population. Multivariate approaches are employed to investigate whether primary blast injury is associated with a unique pattern of white matter damage.

Methods: Seven soldiers recently exposed to blast in the Afghanistan conflict have been studied, with additional recruitment underway. All had moderate-to-severe TBI clinically and persistent cognitive deficits. Forty civilian TBI patients not exposed to blast injury and 40 healthy controls were also studied. Scanning was performed on a Philips 3T Achieva scanner. High-resolution T1 and gradient-echo (T2*) imaging were used to assess focal brain injury and microbleeds. Sixty-four-direction DTI data were collected. Voxelwise analysis of the fractional anisotropy (FA) and mean diffusivity (MD) was carried out using TBSS in FSL. The high dimensionality of the TBSS data was reduced using independent components analysis to identify several distinct patterns of axonal injury. Machine learning techniques were then used to classify individuals into different groups, allowing for comparisons of the differences between axonal injury of blast and civilian TBI.

Results: Both civilian and blast TBI groups can be distinguished from healthy controls using DTI. Analysis of the specific pattern of axonal damage associated with blast injury revealed considerable heterogeneity in blast injury for white matter structure, with a subset of patients clearly identifiable as injured, and others indistinguishable from controls. In addition, the analysis shows that DTI is a more sensitive measure of white matter damage following TBI than the assessment of microbleeds, revealing a more extensive distribution of white matter damage.

Conclusion: Voxel-based analysis of white matter following blast and civilian TBI is able to demonstrate white matter abnormalities.

Mori Tatsuro Maeda Takeshi Tado Masahiro Igarashi Takahiro Moro Nobuhiro Fukushima Masamichi Kojima Jun Hirayama Teruyasu Katayama Yoichi Department of Neurological Surgery and Division of Applied System Neuroscience, Nihon University School of Medicine, Tokyo, Japan

P114 Pitfalls in the Management of the Elderly Patient After Traumatic Brain Injury: Pathophysiology and Management of Hyponatremia.

Background: Following traumatic brain injury (TBI), elderly patients commonly have several pre-existing conditions. This should be taken into account, not only when considering neurointensive treatments, but also for systemic management of those patients. Prolonged immobility and long-term hospitalization result in disuse syndrome and cause additional complications. Hyponatremia is the most common electrolyte disorder encountered in the clinical course of CNS diseases, particularly in elderly patients. Mild hyponatremia induces activity loss and changes in personality, and severe hyponatremia causes seizures, confusion, and even uncontrolled intracranial pressure such as brain edema formation. The incidence of hyponatremia among patients with TBI is around 5–10%. Another report indicated that most patients with TBI will have sodium levels < 140 mmol/L. In the present study, we investigated the incidence of hyponatremia in patients with intracranial lesions following TBI, and clarify the pathophysiology of hyponatremia.

Methods: Retrospective analysis of 185 patients was performed. The incidence, background, clinical data, and outcome were evaluated. In some of those patients, we measured serum sodium levels and total blood volume, and calculated sodium and water balances.

Results: Of the 185 patients, 50 cases (27.3%) presented with hyponatremia during the disease course, and elderly patients with cerebral contusions had a markedly high rate of incidence. The length of hospital stay was significantly longer in the group with cerebral contusions (p < 0.05). In these cases, excessive sodium and diuresis caused sodium losses and water balances concomitant with decreasing total blood volume. We tested the effects of hydrocortisone, which has a mineralocorticoid effect of enhancing sodium reabsorption in the kidney. Hydrocortisone ameliorated the negative shift of sodium balance. A large degree of sodium excretion and decreased circulating volume strongly suggest that cerebral salt-wasting syndrome (CSWS) is closely involved in the occurrence of hyponatremia.

Conclusion: A high rate of hyponatremia following TBI was observed, particularly in elderly patients with cerebral contusions. Hospitalization periods were significantly longer in these patients. Further studies are required to establish the underlying mechanism of CSWS due to TBI. Hydrocortisone may have therapeutic potential for the treatment of CSWS-induced hyponatremia.