Jerome Engel Jr - US grants

An International Conference on the Surgical Therapy of Epilepsy is proposed to be held at the Miramar Hotel in Santa Monica February 20-22, 1986. This year will be the Centennial Anniversary of Horsley's Classic paper on surgical resection of an epileptic lesion which marked the beginning of the modern era of surgical therapy for epilepsy. Despite this one hundred year history, it is only relatively recently that surgery has become accepted as a serious alternative mode for treating epilepsy, and even today there are those who doubt its value. Furthermore, among advocates of surgical therapy, there are no agreed upon standard diagnostic approaches, or surgical procedures, and widely divergent views are held by practitioners in different centers throughout the world. There has never been a national, or international conference on this subject to attempt to discuss and resolve these issues. In the past decade in particular, it has become apparent that great numbers of patients with medically refractory seizures could benefit, or become seizure free, with modern surgical treatment. As many as 250,000 epileptic patients in the U.S. alone might be considered candidates for surgical therapy, while barely 200 of these procedures are performed in the U.S. annually. Consequently, centers that offer epilepsy surgery are faced with long waiting lists and are expanding, while new centers are rapidly developing in the U.S. and abroad. There is now a pressing need to evaluate and organize recent progress in the field of surgery for epilepsy, and to insure that efforts during this period of growth are directed to provide the most effective patient care and the greatest opportunities for research on the human brain. A formal conference is proposed to: 1) describe the current diagnostic approaches in surgical procedures that have become standard at the major epilepsy centers in the world, in order to define areas of agreement and controversy; 2) identify those aspsects of the presurgical evaluation, surgical treatment, and postsurgical follow-up where controversy can be resolved or improvements can be made by careful scientific scrutiny, in order to design collaborative clinical investigative approaches that can be undertaken at multiple centers; 3) demonstrate how epilepsy surgery programs provide opportunity for basic research on normal and abnormal human brain function, in order to encourage basic and clinical neuroscientist to work together to take maximum advantage of these unique facilities; and 4) publish a comprehensive and well referenced text that details the state of the art 100 years after Horsley's paper began the modern era of epilepsy surgery.

In persons with partial epilepsy seeking relief from seizures by surgical treatment arrays of stereotactically implanted intracerebral electrodes are placed in possible seizure foci and monitored by EEG pattern and extracellular action potentials for several weeks. The temporal-spatial relationship of the onset and development of the ictal EEG during simultaneous registration of the behavioral seizure has proven to be the most reliable evidence for the primary focus, obtained in approximately three-fourths of patients. Computer methods are being developed to quantify interictal abnormalities as a similar index. We hope to develop surface EEG correlates equivalent to detection of depth spiking, establishing areas of speech dominance and memory competence. At the cellular level studies are being conducted on the basic mechanisms of epileptogenesis of neurons in the limbic system, the effects of carbamazepine on these neurons, and ultrastructural and Golgi staining of neurons in excised specimens. Neurophysiological experiments correlate hippocampal neuronal responsiveness to tests of memory, spatial cognitive function, movement, behavioral sequencing, visual receptive fields and during sleep stages. Clinical neuropsychological studies examine the relationship of psychological manifestations of temporal lobe epilepsy to epileptiform discharges and clinical-pathological factors.

Since 1961, the Clinical Neurophysiology Program (CNP) at UCLA has made use of the unique opportunities provided by an epilepsy surgery facility to carry out direct research on the human brain. In the sixties and seventies, emphasis was placed on clinical research directed toward improving the diagnosis and surgical treatment of epilepsy, although basic research has always been an important part of the program. Over the past 20 years, resective surgery has become sufficiently accepted as a safe and effective mode of treatment for partial epilepsy to allow clinical activities of the CNP to be supported by hospital funds or supplemented by grants awarded to develop specific diagnostic techniques. We have requested support only for basic research projects that take advantage of knowledge gained from animal studies and the clinical setting to investigate fundamental mechanisms of normal and abnormal brain function. We are further focusing our research efforts only on basic mechanisms of human temporal lobe epilepsy associated with hippocampal sclerosis. Information from patients in our epilepsy surgery facility will be utilized by a multi disciplinary team of basic and clinical neuroscientists to define molecular biological, anatomical, and physiological substrates of epileptiform cerebral processes. In this renewal application, we propose to: 1.) examine alterations in molecular signals, cellular morphologies, synaptic organizations, and neurotransmitter localization in epileptogenic tissue; 2.) relate these findings to results of in vitro and in vivo electrophysiological and in vivo microdialysis studies of neuronal activity in the same brain regions; 3.) examine the possible role of glial influences in these abnormal neuronal properties; and 4.) use these data to characterize the fundamental mechanisms of epileptogenesis in the human hippocampus. The long-term objectives of the CNP are to: 1.) reveal cellular and synaptic mechanisms of epileptogenesis in order to suggest new medical, as well as surgical, approaches to antiepileptic therapy; and 2.) better understand the basis of pathological disruption of normal neuronal activity that results in abnormal behavior, in order to prevent or more effectively treat interictal behavioral disturbances associated with epilepsy and other neurological disorders.

In February, 1986, an international conference on the surgical treatment of epilepsy was held in Palm Desert, California. By that time, a century of experience involved considerable technological development but relatively few quantitative clinical investigations, resulting in a great diversity of philosophies and practiced approaches; perhaps greater than in any other field of medicine. For the first time, representatives from over 50 epilepsy surgery centers, representing 17 countries, sat down to identify their agreements and disagreements, and to discuss controversies that required resolution. This conference, and the resultant text, essentially defined the field of epilepsy surgery as it existed in 1986. There has subsequently been an explosion of interest in surgical treatment of epilepsy and a tremendous expansion of epilepsy surgery centers worldwide, accompanied by an increase in both basic and clinical research on the subject, application of a number of new technological advances, and several ,ore international conferences. As the safety and efficacy of surgical intervention for medically refractory epilepsy has progressively improved, and the types of patients who might be considered surgical candidates has greatly increased, the number of surgeries performed has by no means kept up with the calculated need. This can be attributed in part to failure to educate referring physicians and third party payers concerning recent advances in the field, and in part to the persistence of both real and perceived controversies. In keeping with the recent NIH Consensus Conference on Surgery for Epilepsy (by at least tenfold), and that more multi-centered quantitative studies are necessary to resolve current differences in approaches and to document therapeutic efficacy, a second Palm Desert international conference is proposed. This conference will follow the same format as the first Palm Desert conference, but will be designed specifically to: 1. define the current state of the field and document progress made over the past 5-6 years; 2. document the increasing agreement that has occurred among workers in epilepsy surgery centers and determine whether this agreement is based on actual data; 3. identify areas of continued controversy, and determine whether these controversies could be resolved by cooperative efforts; 4. generate a plan to disseminate information concerning appropriate approaches for the surgical treatment for epilepsy, and a plan for resolving recognized controversies over the next five to ten years; 5. explore how basic and clinical neuroscientists can best work together to take maximum advantage of unique research opportunities; and 6. publish a second edition of Surgical Treatment of the Epilepsies.

DESCRIPTION (provided by applicant): Congressional language has recently specified high priority "benchmarks" for epilepsy research, the first of which is identification of a surrogate marker for epileptogenicity. Our current research, and the investigations proposed here, focus on the identification and characterization of one of the first putative surrogate markers for epileptogenicity, an interictal electrophysiological epileptiform event termed "fast ripples" (FR). We have used in vivo microelectrode recordings to describe interictal FR and other high frequency oscillations in the hippocampus and entorhinal cortex of patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS) and in the intrahippocampal kainic acid (KA) rat model of this disorder. We have described the field potential and unit correlates of interictal FR, demonstrated that these interictal events occur preferentially in areas capable of generating spontaneous seizures, particularly those associated with HS, localized FR generation to small neuronal clusters in hippocampus and entorhinal cortex, and begun to show that their pathophysiological substrates are the same as those responsible for the generation of spontaneous hippocampal seizures in MTLE with HS. We now propose to extend these studies to determine the anatomical and electrophysiological characteristics of FR during the transition to hypersynchronous seizures which do not propagate and low voltage fast seizures which do and to localize neuronal elements activated in induction of these events. These studies at the systems level complement investigations into fundamental mechanisms of FR at the cellular and molecular levels, being carried out with our program project grant (NS02808). In addition, we propose to carry out genomic screening in the KA rat using DNA microarray technology, to distinguish patterns of gene expression change specific to areas generating interictal FR that could underlie epileptogenicity from nonepileptogenic patterns of gene expression change that result from lesion and epileptic activity. We will also use in situ hybridization to identify the cells exhibiting these gene expression changes. The long-term goal of this research direction is not only to gain insights that will elucidate fundamental mechanisms of epileptogenicity, ictal onset and propagation, but also ultimately to identify one or more surrogate markers of epileptogenicity which can be used to screen potential antiepileptic and antiepileptogenic compounds, identify the boundaries of the epileptogenic region for resective surgery, adjust antiepileptic drug treatment in individual patients, and perhaps predict which patients will develop epilepsy after cerebral insults.

All basic research carried out within the Clinical Neurophysiology Program utilizes the same population of patients. The Core exists within a larger Epilepsy Surgery Program which provides state-of-the-art clinical care for this patient population and supports other complementary (largely clinical) research activities. The Core consists of an 8-bed Telemetry Unit which provides cable EEG telemetry with scalp and sphenoidal or intracerebral electrodes and video monitoring; complete surgical facilities for stereotactic placement of depth electrodes, as well as placement of strip or subdural grid electrodes where necessary, and subsequent surgical resection; personnel and equipment for ancillary diagnostic testing, including X-ray computed tomography, magnetic resonance imaging, positron emission tomography, digital subtraction and magnetic resonance angiography, specialized neuropsychological testing, intracarotid amobarbital procedures and quantitative EEG analysis; and support personnel which includes three neurosurgeons, three neurologists with special training in epilepsy and clinical neurophysiology, a psychiatrist, a neuropsychologist, neurology, neurohehavior, and clinical neuropsychology postdoctoral fellows, a clinical nurse specialist and other nurses, telemetry technologists, an electronics technician, an occupational therapist, a social worker, a patient care coordinator, the CNP program coordinator, and an administrator. All patients who are subjects for CNP research projects are treated according to a four-phase clinical protocol: Phase I - presurgical evaluation not requiring intracranial electrodes; Phase II - presurgical evaluation requiring intracranial electrodes; Phase Ill - surgical resection and pathological diagnosis; and Phase IV - postoperative follow-up with respect to epileptic seizures and psychosocial adaptation. Diagnostic and surgical procedures arc standardized for best patient care, which also facilitates the application of clinical data to basic research projects. All activities within the Core that are considered patient care are financially supported by the hospital and third party payers. The specific aims of the Core are: 1) to assure that all patients entered into the CNP protocols receive the best possible clinical care, and that research projects do not create additional risk, discomfort, or financial burden; 2) to ensure that all clinical data necessary for carrying out CNP research projects are made available to CNP investigators; 3) to increase safety and efficacy of presurgical evaluation and surgical treatment based on clinical data, CNP basic research, and advances made elsewhere; and 4) to coordinate other non-CNP research projects which involve CNP patients and may impact on CNP research.

It is estimated that between 100,000 and 200,000 people with epilepsy in the United States are potential candidates for surgical treatment; however, less than 3,000 receive surgery each year. Neuroimaging and EEG telemetry advances have greatly enhanced safety and efficacy of surgical intervention for epilepsy, and reasons for the continued apparent underutilization of this treatment modality are unclear. This must be attributable in part to the fact that surgical treatment is generally considered to be a "last resort" approach for patients with medically intractable seizures. Because there are so many antiepileptic drugs now available, it would take several lifetimes to carry out appropriate trials of each, as monotherapy and in combination, on any given patient Consequently, a randomized clinical trial (RCT) designed to determine when to offer surgical treatment for epilepsy would have a major positive influence on appropriate and timely referral. A RCT for epilepsy surgery has never been performed for any reason, primarily because epilepsy surgery teams have considered it unethical to deny surgery to those with medically refractory seizures who have been fully evaluated and found to be surgical candidates. Several recent developments make it now possible to design an ethically justifiable RCT: 1) A number of surgically remediable epileptic syndromes have been defined which have a poor response to antiepileptic drug treatment, but have a 70 to 90 percent chance of remission with surgical intervention; 2) Mesial temporal lobe epilepsy (MILE), the prototypic surgically remediable syndrome, is by far the most common form of epilepsy treated surgically in the U.S.; 3) Anecdotal data over many decades, and preliminary data from a few recent studies, suggest that early surgical intervention provides the best opportunity to completely eliminate habitual seizures and prevent or reverse disabling psychosocial consequences; 4) True equipoise exists, however, concerning the benefits of early surgical treatment over further medical treatment (within the first two years of refractoriness to first-line medications). This application requests funds to plan a multicenter RCT to test the hypothesis that: Patients who receive surgical intervention for MTLE within two years of failing first- line drugs will have better quality of life and will be more likely to become seizure free after two years, compared with those continuing on medical treatment. Twelve epilepsy surgery centers with ties to UCLA, the Clinical Trials Coordinating Center of the University of Rochester, and a multidisciplinary steering committee have already begun the planning process outlined.

DESCRIPTION (provided by applicant): This grant application for an early randomized surgical epilepsy trial (ERSET) was originally prepared with the help of planning grant R21 NS37897, awarded in recognition of the fact that mesial temporal lobe epilepsy (MTLE) is a surgically remediable syndrome, that surgical treatment for this disorder is underutilized, and that true equipoise exists concerning the relative benefits of surgery vs. continued treatment with new antiepileptic drugs, early in the course of the disorder. We now submit a revised proposal for a multicenter randomized controlled trial (RCT) to compare the efficacy of early surgical intervention for MTLE with continued optimal pharmacotherapy. The primary outcome measure will be freedom from disabling epileptic seizures (complex partial and secondarily generalized seizures, and simple partial seizures that are apparent to an observer). Patients aged 12 years and older with suspected MTLE will be candidates for recruitment if disabling seizures: 1) have not responded to two or more antiepileptic drugs, one of which must be either Dilantin, Tegretol, or Carbatrol, and 2) have not persisted, according to defined criteria, for more than two years. Fifteen epilepsy surgery centers spaced evenly across the country will actively recruit patients meeting these criteria. These patients will undergo a rigid presurgical evaluation protocol, standardized across centers, and 200 surgical candidates will then be randomized to either anteromesial temporal resection or two years of additional pharmacotherapy. Studies will test five hypotheses: 1) Surgical treatment will be more effective than medical treatment in reducingthe frequency and severity of epileptic seizures; 2) Surgical treatment will be more effective than medical treatment in improving quality of life; 3) Surgical treatment will be more effective than medical treatment in improving psychological and social function; 4) Morbidity and mortality associated with surgical treatment will be no greater than that associated with medical treatment; and 5) Progressive hippocampal atrophy and mesial temporal hypometabolism will occur only in patients who continue to have frequent complex partial and generalized tonic-clonic seizures.

model; temporal lobe /cortex disorder

The Core consists of three parts: a Clinical Core, an Animal Core, and a Histology Core. The Clinical Core[unreadable] provides state-of-the-art cable EEG telemetry with scalp and sphenoidal or intracerebral electrodes and video[unreadable] monitoring; complete surgical facilities for surgical resection and stereotactic placement of depth electrodes[unreadable] when necessary; ancillary diagnostic testing, including CT, MRI, PET, MEG, fMRI, MRS, digital subtraction[unreadable] magnetic resonance angiography, specialized neurocognitive testing, intracarotid amobarbital procedures,[unreadable] quantitative EEG analysis; and a team of neurosurgeons, neurologists, clinical neurophysiologists, a[unreadable] psychiatrist, a neuropsychologist, a neuroradiologist, clinical nurse-specialists, and telemetry technologists,[unreadable] all specialized in epilepsy, as well as personnel for technical and administrative support. Diagnostic and[unreadable] surgical procedures are standardized for best patient care, which also facilitates application of clinical data to[unreadable] basic research projects. The Animal Core is responsible for preparation of the pilocarpine rat and mouse[unreadable] models used by all investigators, with video-EEG facilities and personnel to monitor animals on a continuous[unreadable] basis, behaviorally to detect seizure occurrence, and electrophysiologically, in order to characterize the[unreadable] development of interictal and ictal epileptiform events when this is necessary. The Histology Core is[unreadable] responsible for carrying out routine cell counts, Timm's stain, immunocytochemistry, neurobiotin recovery[unreadable] and image analysis of human, rat, and mouse tissue used for experiments in the three subprojects. The[unreadable] specific aims of the Core are to: i) assure that all patients entered into the CNP protocols receive the best[unreadable] possible clinical care, and that research projects do not create additional risk, discomfort, or financial burden;[unreadable] ii) ensure that all clinical and animal data necessary for carrying out CNP research projects are made[unreadable] available to CNP investigators; iii) improve presurgical evaluation and surgical treatment of human temporal[unreadable] lobe epilepsy, and the cost-effective use of animal models to expand research on this disorder; and iv)[unreadable] coordinate both clinical and animal research being carried out collaboratively among the three Subprojects.

We propose a planning grant titled the Epilepsy Bioinformatics Study (EpiBloS) to develop a bioinformatics approach to identify reliable epilepsy biomarkers, a critical need for a Center without Walls (CwW) focused on antiepileptogenesis (AEG). Biomarkers of epileptogenesis are needed to limit the study population by identifying those patients at highest risk for epilepsy after a potential epileptogenic brain insult,, and to stage the epileptogenic process. Biomarkers of epileptogenicity are needed as surrogate markers in Phase II clinical trials, to document prevention or cure. From existing animal and patient data, we hypothesize that the three most promising classes of biomarkers will be derived from longitudinal studies of electroencephalographic (EEG), neuroimaging, and molecular changes occurring during the process of epileptogenesis, and existing after the development of epilepsy. Furthermore, we anticipate that no single reliable biomarker will emerge, but that predictive power will require a combination of biomarkers. To jumpstart the search for biomarkers we will utilize existing bioinformatics platforms to analyze available multimodality data longitudinally collected from patients and animals during development of epilepsy, and with epilepsy, to identify the most likely individual biomarkers, and/or combinations of biomarkers of epileptogensis and epileptogeniity, and to determine the best animal models for future studies. Anticipated problems will be addressed at semiannual focused workshops. At the end of this granting period we intend to submit three deliverables: 1) identification and validation of the most likely biomarkers using data derived from ongoing animal and human studies; 2) comprehensive position papers on strategy and problem solving derived from at least six workshops, and 3) an international, multimodality, interactive, open access, bioinformatics grid available for a large prospective clinical study of biomarkers of epileptogenesis and epileptogenicity. We also intend to use the results of this study to inform investigations into the basic mechanisms of epileptogenesis and the search for novel targets for AEG, essential to the CwW, and anticipate this bioinformatics approach to be the future of biomedical research.

DESCRIPTION (provided by applicant): We propose a planning grant titled the Epilepsy Bioinformatics Study (EpiBioS) to develop a bioinformatics approach to identify reliable epilepsy biomarkers, a critical need for a Center without Walls (CwW) focused on antiepileptogenesis (AEG). Biomarkers of epileptogenesis are needed to limit the study population by identifying those patients at highest risk for epilepsy after a potential epileptogenic brain insult, and to stage the epileptogenic process. Biomarkers of epileptogenicity are needed as surrogate markers in Phase II clinical trials, to document prevention or cure. From existing animal and patient data, we hypothesize that the three most promising classes of biomarkers will be derived from longitudinal studies of electroencephalographic (EEG), neuroimaging, and molecular changes occurring during the process of epileptogenesis, and existing after the development of epilepsy. Furthermore, we anticipate that no single reliable biomarker will emerge, but that predictive power will require a combination of biomarkers. To jumpstart the search for biomarkers we will utilize existing bioinformatics platforms to analyze available multimodality data longitudinally collected from patients and animals during development of epilepsy, and with epilepsy, to identify the most likely individual biomarkers, and/or combinations of biomarkers of epileptogenesis and epileptogenicity, and to determine the best animal models for future studies. Anticipated problems will be addressed at semiannual focused workshops. At the end of this granting period we intend to submit three deliverables: 1) identification and validation of the most likely biomarkers using data derived from ongoing animal and human studies; 2) comprehensive position papers on strategy and problem solving derived from at least six workshops, and 3) an international, multimodality, interactive, open access, bioinformatics grid available for a large prospective clinical study of biomarkers of epileptogenesis and epileptogenicity. We also intend to use the results of this study to inform investigations into the basic mechanisms of epileptogenesis and the search for novel targets for AEG, essential to the CwW, and anticipate this bioinformatics approach to be the future of biomedical research.