Geoffrey Ling

Explosive Blast Neurotrauma

Explosive blast traumatic brain injury (TBI) is one of the more serious wounds suffered by United States service members injured in the current conflicts in Iraq and Afghanistan. Some military medical treatments for blast TBI that have been introduced successfully in the war theater include decompressive craniectomy, cerebral angiography, transcranial Doppler, hypertonic resuscitation fluids, among others. Stateside neurosurgery, neuro-critical care, and rehabilitation for these patients have similarly progressed. With experience, military physicians have been able to clinically describe blast TBI across the entire severity spectrum. One important clinical finding is that a significant number of severe blast TBI victims develop pseudoaneurysms and vasospasm, which can lead to delayed decompensation. Another is that mild blast TBI shares clinical features with post-traumatic stress disorder (PTSD). Observations suggest that the mechanism by which explosive blast injures the central nervous system may be more complex than initially assumed. Rigorous study at the basic science and clinical levels, including detailed biomechanical analysis, is needed to improve understanding of this disease. A comprehensive epidemiological study is also warranted to determine the prevalence of this disease and the factors that contribute most to the risk of developing it. Sadly, this military-specific disease has significant potential to become a civilian one as well.

Lactated Ringer's solution resuscitation causes neutrophil activation after hemorrhagic shock

PURPOSE To determine the degree of neutrophil activation caused by hemorrhagic shock and resuscitation. METHODS Awake swine underwent 15-minute 40% blood volume hemorrhage, and a 1-hour shock period, followed by resuscitation with: group I, lactated Ringers solution (LR); group II, shed blood; and group III, 7.5% hypertonic saline (HTS). Group IV underwent sham hemorrhage and LR infusion. Neutrophil activation was measured in whole blood using flow cytometry to detect intracellular superoxide burst activity. RESULTS Neutrophil activation increased significantly immediately after hemorrhage, but it was greatest after resuscitation with LR (group I, 273 vs. 102%; p < 0.05). Animals that received shed blood (group II) and HTS (group III) had neutrophil activity return to baseline state after resuscitation. Group IV animals had an increase in neutrophil activation (259 vs. 129%; p < 0.05). CONCLUSION Neutrophil activation occurring after LR resuscitation and LR infusion without hemorrhage, but not after resuscitation with shed blood or HTS, suggests that the neutrophil activation may be caused by LR and not by reperfusion.

Wartime traumatic cerebral vasospasm: Recent review of combat casualties

OBJECTIVEBlast-related neurotrauma is associated with the severest casualties from Operation Iraqi Freedom (OIF). A consequence of this is cerebral vasospasm. This study evaluated all inpatient neurosurgical consults related to battle injury from OIF. METHODSEvaluation of all admissions from OIF from April 2003 to October 2005 was performed on patients with neurotrauma and a diagnostic cerebral angiogram. Differences between patients with and without vasospasm and predictors of vasospasm were analyzed. RESULTSFifty-seven out of 119 neurosurgical consults were evaluated. Of these, 47.4% had traumatic vasospasm; 86.7% of patients without vasospasm and 80.8% of patients with vasospasm sustained blast trauma. Average spasm duration was 14.3 days, with a range of up to 30 days. Vasospasm was associated with the presence of pseudoaneurysm (P = 0.05), hemorrhage (P = 0.03), the number of lobes injured (P = 0.012), and mortality (P = 0.029). Those with vasospasm fared worse than those without (P = 0.002). The number of lobes injured and the presence of pseudoaneurysm were significant predictors of vasospasm (P = 0.016 and 0.02, respectively). There was a significant quadratic trend towards neurological improvement for those receiving aggressive open surgical treatment (P = 0.002). In the vasospasm group, angioplasty with microballoon significantly lowered middle cerebral artery and basilar blood-flow velocities(P = 0.046 and 0.026, respectively). CONCLUSIONTraumatic vasospasm occurred in a substantial number of patients with severe neurotrauma, and clinical outcomes were worse for those with this condition. However, aggressive open surgical and endovascular treatment strategies may have improved outcome. This was the first study to analyze the effects of blast-related injury on the cerebral vasculature.

Neuropathology of explosive blast traumatic brain injury

During the conflicts of the Global War on Terror, which are Operation Enduring Freedom (OEF) in Afghanistan and Operation Iraqi Freedom (OIF), there have been over a quarter of a million diagnosed cases of traumatic brain injury (TBI). The vast majority are due to explosive blast. Although explosive blast TBI (bTBI) shares many clinical features with closed head TBI (cTBI) and penetrating TBI (pTBI), it has unique features, such as early cerebral edema and prolonged cerebral vasospasm. Evolving work suggests that diffuse axonal injury (DAI) seen following explosive blast exposure is different than DAI from focal impact injury. These unique features support the notion that bTBI is a separate and distinct form of TBI. This review summarizes the current state of knowledge pertaining to bTBI. Areas of discussion are: the physics of explosive blast generation, blast wave interaction with the bony calvarium and brain tissue, gross tissue pathophysiology, regional brain injury, and cellular and molecular mechanisms of explosive blast neurotrauma.

Quantitative analysis of injured, necrotic, and apoptotic cells in a new experimental model of intracerebral hemorrhage

ObjectiveTo develop a new survival model of intracerebral hemorrhage (ICH) in rabbits and study the patterns of cellular injury in different regions 24 hrs after introduction of hematoma. Quantitation and characterization of injured cells in regions adjacent and distant to the hematoma have not been performed. DesignProspective case-control study. SubjectsTen New Zealand rabbits. InterventionWe introduced ICH in six anesthetized New Zealand rabbits by autologous blood injection under arterial pressure in the deep white matter in the frontal lobe. Measurements and Main ResultsHematoxylin and eosin staining was performed in six animals with ICH after 24 hrs to quantify intact, injured, and necrotic cells in regions proximal and distant to the hematoma, and the results were compared with four control animals. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining was performed to quantify apoptotic cells in specified regions in five animals with ICH, and the results were compared with four control animals. All cell counts were performed by one investigator who used 100× oil emersion microscopy. The presence of localized hematoma was confirmed in all six animals with blood infusion. Compared with controls, animals with ICH had a significantly higher proportion of swollen cells in both the inner (55.9% ± 3.0% vs. 26.8% ± 1.7%;p < .05) and the outer (59.8% ± 4.6% vs. 27.7% ± 4.5%;p < .05) rim of the perihematoma region. A small proportion of shrunken dark cells were observed in both the inner (4.0% ± 1.5%) and the outer (3.6% ± 1.0%) rim of the perihematoma region. The remaining cells were considered morphologically intact. A large proportion of cells trapped within the matrix of the hematoma were either shrunken dark cells (48.8% ± 16.4%) or swollen (38.8% ± 15.1%). In the TUNEL-stained sections, a high burden of apoptotic cells was observed in the matrix of the hematoma (17.5 ± 6.3 cells per high power field) but not in the perihematoma regions (less than two cells per high power field). ConclusionsA reproducible model of ICH in rabbits is described. At 24 hrs, the perihematoma region contains relatively large proportions of morphologically intact or reversibly injured (swollen) cells, suggesting the possibility of an extended window for therapeutic intervention.

Common Data Elements for Traumatic Brain Injury: Recommendations From the Biospecimens and Biomarkers Working Group

Recent advances in genomics, proteomics, and biotechnology have provided unprecedented opportunities for translational research and personalized medicine. Human biospecimens and biofluids represent an important resource from which molecular data can be generated to detect and classify injury and to identify molecular mechanisms and therapeutic targets. To date, there has been considerable variability in biospecimen and biofluid collection, storage, and processing in traumatic brain injury (TBI) studies. To realize the full potential of this important resource, standardization and adoption of best practice guidelines are required to insure the quality and consistency of these specimens. The aim of the Biospecimens and Biomarkers Working Group was to provide recommendations for core data elements for TBI research and develop best practice guidelines to standardize the quality and accessibility of these specimens. Consensus recommendations were developed through interactions with focus groups and input from stakeholders participating in the interagency workshop on Standardization of Data Collection in TBI and Psychological Health held in Washington, DC, in March 2009. With the adoption of these standards and best practices, future investigators will be able to obtain data across multiple studies with reduced costs and effort and accelerate the progress of genomic, proteomic, and metabolomic research in TBI.

Time-dependent changes in serum biomarker levels after blast traumatic brain injury.

Neuronal and glial proteins detected in the peripheral circulating blood after injury can reflect the extent of the damage caused by blast traumatic brain injury (bTBI). The temporal pattern of their serum levels can further predict the severity and outcome of the injury. As part of characterizing a large-animal model of bTBI, we determined the changes in the serum levels of S100B, neuron-specific enolase (NSE), myelin basic protein (MBP), and neurofilament heavy chain (NF-H). Blood samples were obtained prior to injury and at 6, 24, 72 h, and 2 weeks post-injury from animals with different severities of bTBI; protein levels were determined using reverse phase protein microarray (RPPM) technology. Serum levels of S100B, MBP, and NF-H, but not NSE, showed a time-dependent increase following injury. The detected changes in S100B and MBP levels showed no correlation with the severity of the injury. However, serum NF-H levels increased in a unique, rapid manner, peaking at 6 h post-injury only in animals exposed to severe blast with poor clinical and pathological outcomes. We conclude that the sudden increase in serum NF-H levels following bTBI may be a useful indicator of injury severity. If additional studies verify our findings, the observed early peak of serum NF-H levels can be developed into a useful diagnostic tool for predicting the extent of damage following bTBI.

Time-dependent changes of protein biomarker levels in the cerebrospinal fluid after blast traumatic brain injury

Time‐dependent changes of protein biomarkers in the cerebrospinal fluid (CSF) can be used to identify the pathological processes in traumatic brain injury (TBI) as well as to follow the progression of the disease. We obtained CSF from a large animal model (swine) of blast‐induced traumatic brain injury prior to and at 6, 24, 72 h, and 2 wk after a single exposure to blast overpressure, and determined changes in the CSF levels of neurofilament‐heavy chain, neuron‐specific enolase, brain‐specific creatine kinase, glial fibrillary acidic protein, calcium‐binding protein β (S100β), Claudin‐5, vascular endothelial growth factor, and von Willebrand factor using reverse phase protein microarray. We detected biphasic temporal patterns in the CSF concentrations of all tested protein markers except S100β. The CSF levels of all markers were significantly increased 6 h after the injury compared to preinjury levels. Values were then decreased at 24 h, prior to a second increase in all markers but S100β at 72 h. At 2 wk postinjury, the CSF concentrations of all biomarkers were decreased once again; brain‐specific creatine kinase, Claudin‐5, von Willebrand factor, and S100β levels were no longer significantly higher than their preinjury values while neurofilament‐heavy chain, neuron‐specific enolase, vascular endothelial growth factor, and glial fibrillary acidic protein levels remained significantly elevated compared to baseline. Our findings implicate neuronal and glial cell damage, compromised vascular permeability, and inflammation in blast‐induced traumatic brain injury, as well as demonstrate the value of determining the temporal pattern of biomarker changes that may be of diagnostic value.

Characteristics of an Explosive Blast-Induced Brain Injury in an Experimental Model

Mild traumatic brain injury resulting from exposure to an explosive blast is associated with significant neurobehavioral outcomes in soldiers. Little is known about the neuropathologic consequences of such an insult to the human brain. This study is an attempt to understand the effects of an explosive blast in a large animal gyrencephalic brain blast injury model. Anesthetized Yorkshire swine were exposed to measured explosive blast levels in 3 operationally relevant scenarios: simulated free field (blast tube), high-mobility multipurpose wheeled vehicle surrogate, and building (4-walled structure). Histologic changes in exposed animals up to 2 weeks after blast were compared to a group of naive and sham controls. The overall pathologic changes in all 3 blast scenarios were limited, with very little neuronal injury, fiber tract demyelination, or intracranial hemorrhage observed. However, there were 2 distinct neuropathologic changes observed: increased astrocyte activation and proliferation and periventricular axonal injury detected with &bgr;-amyloid precursor protein immunohistochemistry. We postulate that the increased astrogliosis observed may have a longer-term potential for the exacerbation of brain injury and that the pattern of periventricular axonal injury may be related to a potential for cognitive and mood disorders.

MRSI of the medial temporal lobe at 7 T in explosive blast mild traumatic brain injury

Up to 19% of veterans returning from the wars in Iraq and Afghanistan have a history of mild traumatic brain injury with 70% associated with blast exposure. Tragically, 20–50% of this group reports persistent symptoms, including memory loss. Unfortunately, routine clinical imaging is typically normal, making diagnosis and clinical management difficult. The goal of this work was to develop methods to acquire hippocampal MRSI at 7 T and evaluate their sensitivity to detect injury in veterans with mild traumatic brain injury.