Paul Vespa - US grants

DESCRIPTION (provided by applicant): The main aim of this proposal is to study the incidence of epileptiform discharges and seizures that occur during coma after traumatic brain injury, possible mechanisms of generating epileptiform activity and the neurochemical consequences of this activity. The investigator has made exciting preliminary observations that post-traumatic nonconvulsive seizure activity on continuous electroencephalography (EEG) occurs frequently, is associated with adverse neurochernical changes and increases mortality. Previous animal brain injury models have documented neurochernical and ionic perturbation with an energy crisis and compensatory hyperglycolysis. At the same time there is a selective loss of neuronal inhibition (GABA, y-amino-butyric acid, containing cells) and reduced extracellular magnesium that leads to a decrease in seizure threshold. As a consequence of early post traumatic seizures, cellular energy demand may be increased and lead to secondary injury of cells that survived the initial trauma. Preliminary studies demonstrate an increased incidence of EEG-defined seizures. and epileptiforin activity, however the relationship between early post-traumatic epileptiform activity, the disordered neurochernical state, increased glucose metabolism and secondary cellular injury remain unknown. Thus the central hypothesis of this grant is that early post-traumatic nonconvulsive epileptiform activity is common and leads to further hyperglycolytic neurochernical events (increased lactate, glutamate and decreased glucose) and additional neuronal membrane injury. The specific aims of this proposal will be: (1) delineate the incidence rate, type and duration of early EEG-defined post-traumatic epileptiform activity (TEEA); (2) define the mechanistic influence of impaired neuronal inhibition in generating TEEA; (3) determine if TEEA results in a hyperglycolytic response; and (4) determine if TEEA leads to additional brain tissue membrane injury, as determined by time-locked increases in extracellular glycerol. The application is intended to pen-nit the candidate to gain important didactic education in research and statistical methods and experience in conducting a human-based basic research paradigm complemented by future animal models. The hypothesis and unique approach come at a crucial time of failed clinical trials and address an important new therapeutic target.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Traumatic brain injury patients enrolled into the UCLA Brain Injury Research Center receive multiple brain MRI scans at time of admission, during ICU stay, and again during long-term followup after hospital discharge. Evidence to date demonstrates significant localized and regional white-matter and grey-matter atrophy in increments over time in these patients. We will seek to analyze volumetrics and cortical extractions using the LONI Pipeline V1 in the whole brain and in selected regions by hemisphere, including frontal, basal frontal, hippocampal, parietal and occipital regions, and we will also examine volumes and volume changes in hematoma and perihematomal areas on a case-by-case basis. Resulting volumes and cortical thicknesses will be analyzed by linear mixed modeling and by correlation studies with measures of metabolism and neurological and psychological status obtained in the same patient sample.

Metabolic Distress in the perihematomal tissue Intracerebral hemorrhage is crucially important neurologic emergency with high societal impact (Sacco 1994;Qureshi 2001;Broderick 2007). The pathophysiology of intracerebral hemorrhage ca,n be considered to consist of two phases. The first phase includes immediate necrosis of the brain cells in the hemorrhage core due to the acute bleed and early hemorrhagic expansion. It is now clear that hematoma enlargement contributes to deterioration in a subset of patients. Brott and colleagues (1997) reported hematoma expansion in 26% of patients within 1 hour of the initial CT and overall in 38% of patients within 20 hours. These findings are in accord with those of Kazui (1996) who reported an overall expansion rate of 20% in their series. Mayer et al (2005) demonstrated that hemorrhagic expansion occurs within 4 hours of onset. While the use factor Vila did not result in improved clinical outcome, hemorrhagic expansion was reduced (Mayer - oral presentation American Academy of Neurology meeting, 2007). It may be that prevention of hemorrhagic expansion is not enough, and that the metabolic distress surrounding the hemorrhage, due to edema or other mechanisms, must be relieved in order to improve outcome. The second phase is the slowly ensuing damage to perihematomal tissue due to mass effect, excitotoxic edema, and progressive neurotoxicity resulting from iron, thrombin, blood breakdown products, free radical formation, protease activation and inflammation (Gong 2000;Lee 1997;Wu 2002;Xi and Hoff 2006). These mechanisms lead to metabolic distress and subsequent damage in the perihematomal tissue which is progressive over time (Gebel 2002a, 2002b), perhaps through alteratiion of selected genetic pathways. We hypothesize that early removal of blood avoids the subsequent damage from progressive brain edema that occurs in the days following ICH. The slowly ensuing damage to the perihematomal tissue is complex and involves multiple mechanisms that are in one way or another linked to the presence of the mass of collected blood and progressive edema. It is recognized that perihematomal ischemia per se does not exist in experimental models (Qureshi 1999), however, sophisticated animal studies measuring blood flow, cerebral oxygen extraction, oxygen consumption, glucose utilization, and lactate production have demonstrated that metabolism is disturbed in the perihematomal tissue (Nath1987). Similar work in humans, using positron emission tomography (PET), demonstrated symmetrically reduced blood flow in both hemispheres in 12 patients imaged within 7-28 hours of onset. (Zazulia and Diringer 2001). In a recent study, Powers and colleagues also demonstrated that autoregulation of CBF was preserved in 14 patients with acute ICH during pharmacologic blood pressure reductions of mean arterial pressure of 15%. The same research group found disproportionately reduced focal perihematomal CBF, but no focal increase in oxygen extraction fraction, suggesting that the low perilesional CBF values reflected metabolic dysfunction (Powers 2001), as has been confirmed by mitochondrial respiration experiments on biopsied human mitochondria (Kim-Han 2006). Our group has demonstrated two independent findings that the perihematomal tissue is in a state of metabolic distress due to the hematoma. The first is the MRI finding of a rim of perihematomal decrease in ADC values in a subset of patients evaluated within 6 hours of symptom onset (Kidwell 2001). In our initial 5- year study period, we confirmed these findings demonstrating that 30% of patients have a rim of ADC reduction (see Preliminary Studies below). Of note, this rim of tissue bioenergetic compromise was not associated with focal perihematomal decreased blood flow and was not associated with the extent and severity of perihematomal edema. The second finding is that perihematomal microdialysis glutamate and lactate/pyruvate values are elevated for many days after ICH. Reduction of hematoma volume, through the use of stereotactic thrombolysis, resulted in normalization of glutamate values but not lactate/pyruvate values. This suggests that evacuation of hematoma can improve this metabolic distress (Miller 2006;Vespa 2006). We have validated microdialysis lactate/pyruvate ratio to be a robust marker of impaired oxidative metabolism (Vespa 2005). We have a considerable experience with human cerebral microdialysis and have demonstrated the safety and utility of this technique in determining sequential changes in brain metabolism after traumatic brain injury and intracerebral hemorrhage (Vespa 1998;Vespa 2003;Vespa 2006;Vespa 2007). We propose that endoscopic surgery will result in improvement in the metabolic state of the perihmatomal region, and we intend to measure this response using microdialysis and MRI in this study.

Animal studies have demonstrated a disturbance in oxidative and glucose metabolism after traumatic brain injury (TBI), with depression of metabolism being a significant feature. Our recent human studies have demonstrated two related findings: 1) There is a prolonged period of metabolic depression after brain injury and 2) extracellular glucose concentrations are frequently low during this metabolic depression. The duration and extent of low extracellular glucose concentration are independent predictors of neurologic outcome. At the same time, many experimental and clinical studies have demonstrated that systemic hyperglycemia adversely affects outcome after human TBI. Hence, the current standard of care requires the use of insulin to maintain nomoglycemia. However, little is known about the effects of glycemic control on brain metabolism nor the potential adverse effects of limiting glucose supply through strict glycemic control after TBI. We have demonstrated that insulin results in reduction in extracellular glucose and an increase in extracellular glutamate (Vespa, 2006) suggesting a possible adverse effect. Thus, there exists a controversy about on how best to manage systemic glucose concentrations in TBI. Given the potential therapeutic implications, there is a profound need to better understand the effects of glycemic control on brain metabolism after TBI. This project proposes to study the null hypothesis that limitation of glucose availability (serum glucose concentrations) reduces the rates of cerebral glucose and oxidative metabolism, by using a controlled insulin infusion to achieve normal serum glucose concentrations (80-110 mg/dl). In addition, we propose to test a secondary hypothesis that reduction of serum glucose to normal concentrations will result in microdialysis markers of metabolic distress in post-traumatic brain injured patients using a combined within-subjects and randomized cross over study design. This project is intricately inter-related with projects 1, 2 and 4 of this PPG.

The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx), a CWOW proposal in response to RFA-NS-16-012, is designed to facilitate the development of antiepileptogenic therapies by removing barriers and promoting large-scale collaborative research efforts by multidisciplinary teams of basic and clinical neuroscientists with access to extensive patient populations, well-defined and rigidly standardized animal models, and cutting-edge analytic methodology. We focus our proposal on antiepileptogenesis in post- traumatic epilepsy (PTE) following traumatic brain injury (TBI), as this condition offers the best opportunity to determine the time of onset of the epileptogenic process in patients. The EpiBioS4Rx Scientific Premise is: Epileptogenesis after TBI can be prevented with specific treatments; the identification of relevant biomarkers and performance of rigorous preclinical trials will permit the future design and performance of economically feasible full-scale clinical trials of antiepileptogenic therapies. Based on the work from a P20 planning grant, our program will consist of the following: (1) identify biomarkers of epileptogenesis in our animal model and in patients, (2) Develop and utilize a standardized platform for preclinical trials of potential antiepileptogenic (AEG) drugs, (3) Identify 1 or more lead antiepileptogenic drugs for a future interventional clinical trial, (4) Establish a network of advanced TBI centers capable of carrying out future clinical trials featuring our lead antiepileptogenic drugs used in the context of a personalized, medicine-based approach utilizing our panel of biomarkers, and (5) Develop and incorporate a public engagement program involving the mutual education and collaboration of consumers, consumer organizations and professionals to design and execute future large-scale interventional clinical trials of antiepileptogenic therapies.

ABSTRACT / PROJECT SUMMARY ? PROJECT 3 ? BIOMARKERS OF HUMAN EPILEPTOGENESIS AFTER TRAUMATIC BRAIN INJURY The mechanisms underlying human acquired epileptogenesis remain poorly understood and a novel multimodal approach to study the process from inception to manifest clinical epilepsy is needed. We have selected Post-Traumatic Epilepsy (PTE) as a model to pursue this understanding because the timing of the potential epileptogenic insult is known and the period of epileptogenesis can be determined. The EpiBioS4Rx Scientific Premise is Epileptogenesis after TBI can be prevented with specific treatments; the identification of relevant biomarkers and performance or rigorous preclinical trials will permit the future design and performance of economically feasible full-scale clinical trials of antiepileptogenic therapies. In Project 3, we plan to perform a multicenter, multidisciplinary observational study of early epileptogenesis after moderate-severe TBI in 300 subjects with the specific injury phenotype of temporal and/or frontal lobe hemorrhagic contusional injury that matches the experimental injury models in animal Projects 1 and 2. We plan four specific aims that feature determining measuring the presence of early electroencephalographic, MRI and blood biomarkers of epileptogenesis. In aim 4, we plan to create the ideal clinical trial network and trial design informed by our animal Project 2 as well as shared data from large biomarkers trials in both adults (TRACK, CENTER) and children (ADAPT) with TBI. In the Public Engagement Core, we have recruited an outstanding multidisciplinary team of consumers, consumer advocates and key opinion leaders in TBI, PTE, and Epilepsy Clinical Trials to work in this project. We plan a highly integrated and adaptive study design across all 3 Projects and 3 Cores of EpiBioS4Rx to enable a rigorous experimental design for robust and unbiased results. Integration is demonstrated by injury type, methodology, mechanistic investigation, shared analysis and methods, shared public engagement core, and shared DSMB The ultimate goal is to develop a personalized medicine approach for a future definitive clinical trial for an antiepileptogenic drug for PTE.

Project Summary Delayed cerebral ischemia (DCI) is the most devastating complication after aneurysmal subarachnoid hemorrhage (aSAH) and has an incidence rate of 30%. Current practice relies on intermittent assessment of neurological status and daily cerebral blood flow velocity (CBFV) by Transcranial Doppler ultrasound (TCD) to guide medical management to prevent DCI. Only after medical management fails, is endovascular treatment (EVT) including intraarterial vasodilator infusion and/or intracranial angioplasty initiated. This reactive practice does not account for early predictors of DCI and may miss the optimal EVT window at an early stage of DCI development before symptoms or severe deviations from normal hemodynamics. The goal of this project is to develop algorithms to predict DCI and related targets at an early stage in their development. An accurate prediction of DCI will enable a more proactive strategy to prevent and treat the underlying cause of DCI. The following three aims will be pursued towards the goal of the project: 1) Develop aSAH-specific intracranial pressure (ICP) pulse-based cerebral arterial state index; 2) Develop and validate predictive models of targets related to delayed cerebral ischemia after aSAH; 3) Conduct a prospective institution- specific adaption and validation of the developed models. Our DCI predictive algorithms only need data available in current clinical practice hence they can be readily adopted. If validated, these algorithms will enable clinicians to monitor risk of DCI continuously and to proactively deliver appropriate treatment. The proposed prospective study of algorithm implementation and adaptation will well prepare future clinical trials to test the efficacy of algorithm-informed interventions.