Parents Against Childhood Epilepsy, Inc.

A Research and Education Fund

PACE RESEARCH PROJECTS 1998-2007

• Suppression of a Seizure Focus by Iinfusion of Botulinum Neurotoxin in Mouse Models of Temporal Lobe Epilepsy, at Istituto di Neuroscienze CNR, in Pisa, Italy, by Yuri Bozzi, PhD. Temporal lobe epilepsy (TLE) is a common form of human epilepsy that is frequently refractory to drug treatment. Novel therapeutic approaches are currently under investigation in animal models of TLE. In particular, new drugs specifically targeted to block nerve cell activity might be useful to treat the disease. In our project, we will test the efficacy of the bacterial enzyme Botulinum Toxin (BoNT), which is known to block nerve cell activity, as a new selective drug against TLE. We will evaluate whether delivery of BoNT can halt chronic seizures, and whether long-term suppression of epileptic activity leads to a permanent reduction of disease severity. We will examine the anticonvulsant effects of BoNTs in animal models resembling human TLE. The demonstration of antiepileptic effects of BoNTs in models of TLE is important due to the limited efficacy and serious side effects of current antiepileptic drugs. A strategy based on BoNTs might prove quite useful as an alternative to surgery in patients with intractable epilepsy.
  
  
• Rapid Post-translational Modification of Glutamate Receptors in Early Life Seizures: A Novel Target for Antiepileptogenesis. Frances E. Jensen, MD is Professor of Neurology at Harvard Medical School and Director of Epilepsy Research at Children’s Hospital. Recent research is beginning to shed light on how seizures alter networks and cells in the brain and lead to progression of epilepsy. Rapid changes appear to take place at the connections, or synapses, between brain cells. This process is especially robust in the infant and child’s brain. Dr. Jensen’s work is aimed at elucidating points along the pathway to the development of epilepsy that may be reversible, even after the initial seizures have occurred. Dr. Jensen’s work will examine how drugs that block glutamate receptors prevent the early changes at synapses and thereby prevent long term epilepsy. The goal of this project is to identify new therapies for the prevention of epileptogenesis, specifically in the infant and child brain.
  
  
• Identification of the Centrotemporal Sharp Wave Susceptibility Gene, at Columbia University Medical Center, by Deb K. Pal, MD, PhD. Rolandic epilepsy is the most common epilepsy of childhood. It is associated with an EEG signature known as centrotemporal sharp waves which Dr Pal's laboratory has isolated to chromosome 11. In this study, the exact gene variant that causes this abnormal EEG signature will be identified. This will be the first step to understanding the cause of Rolandic epilepsy and potential ways in which seizures may be stopped or prevented.
  
  
• Characterizing Novel Pathways in Seizure Pathophysiology, at the University of California at San Francisco by Louis Ptacek, M.D. Most currently available anti-seizure medications target ion channels in nerve cells that regulate electrical signaling. Although many of these medications work well for some patients, there remain many for whom they do not or in whom side effects are problematic. MASS1 is a gene that was cloned from a mouse with a genetic form of seizures that are precipitated by loud sounds. Interestingly, it is not an ion channel and the normal function of the MASS1 protein is not known. This project focuses on defining the function of this novel protein by studying other proteins with which it interacts. Knowledge of the function of the MASS1 protein and pathways in which it functions may lead to novel targets that can be used to screen for new anti-seizure medications.
  
  
• Examination of the Cognative-Behavior Intervention “Coping with Epilepsy: A Program for Youth”, at Medical University of South Carolina by Janelle Wagner, PhD. The goal of this pilot study is to design and explore the feasibility and effectiveness of a cognitive-behavioral intervention (CBT) specifically tailored to the needs of children with epilepsy and their parents. The study will consist of three phases: 1.) baseline assessment and randomization, 2.) participation in an 8 week group intervention versus waiting list, and 3.) post assessment. The aims of the child-focused intervention are threefold: 1.) to increase self-efficacy for seizure management, 2.) to increase the use of adaptive coping skills, and 3.) to reduce depressive symptoms and hopelessness. The aims of the parent-focused intervention are also threefold: 1.) to equip caregivers with skills to adequately reinforce epilepsy management behaviors and other healthy behaviors in their children and teens, 2.) to reduce caregiver stress, and 3.) to increase caregivers’ realistic sense of control over their child’s epilepsy. The proposed intervention, which utilizes components of empirically driven psychological interventions, targets challenges specific to epilepsy (e.g., self-efficacy, hopelessness, parenting stress), and includes both child and caregiver focused components, could provide an essential resource for health care providers and inform future large randomized, controlled clinical trials to examine the effectiveness of psychological intervention for youth with epilepsy.
  
  
• COX2 Signaling Pathways in Epileptogenesis, at Emory University School of Medicine by Ray Dingledine, PhD. Inflammation is a common feature of epilepsy and is often prominent in childhood-onset epilepsies. The role of inflammation in the development of epilepsy has received little attention. Interestingly, some of the same mechanisms that cause inflammation of the joints appear to be at work in the brain. In particular, the COX2 enzyme of Vioxx fame is highly active in the epileptic brain. We suspect this enzyme might contribute to the brain injury that accompanies severe seizures, as well as create the conditions favoring excessive neuronal firing that leads to seizures. Dr. Dingledine's work aims to identify the relevant prostaglandin receptors. The receptors that mediate COX2-induced neuropathies could then become new targets for drug discovery.
  
  
• Role of Brain Inflammation in Epileptogenesis, at Children's Memorial Hospital by Sookyong Koh, MD, PhD. There is currently no effective intervention for children with epilepsy after they have experienced seizures. It is unknown how the acute childhood seizures relate to later chronic epilepsy. Dr. Koh's laboratory studies the role of brain inflammation in seizure susceptibility and brain injury. Understanding the mechanisms of epileptogenesis is critical in opening new avenues for intervention. She will investigate anti-inflammatory drugs as a new preventive therapeutic strategy for children with epilepsy using animal models of early-life seizures.
  
  
• Ketone and Oxidative Modulation of Mitrochondrial Ion Channels, at St. Joseph's Hospital & Medical Center by Jong Rho, MD. The ketogenic diet is an proven treatment for pediatric epilepsy patients who fail to respond to medications. One of the essential features of the ketogenic diet is the production of ketone bodies by the liver. Ketone bodies are also produced during fasting or calorie restriction; they are used by the body as a source of energy when glucose levels are low. Interestingly, we have found that ketone bodies can protect brain cells from injury caused by molecules known as free radicals (which cause oxidative stress), and this protective effect may involve a specific protein channel in cells known as the mitochondrial ATP-sensitive potassium (mitoKATP) channel. Rho hypothesizes that ketone bodies can influence mitoKATP channels in brain cells, resulting in a protective effect against oxidative stress, and will demonstrate this using imaging and electrophysiological recording techniques.
  
  
• Development and Characterization of a De Novo Model of Infantile Spasms in the Immature Rat, at Albert Einstein College of Medicine by Morris Scantlebury, MD. Infantile spasms are a catastrophic epileptic disorder seen in very young children. They are associated with a dismal longterm prognosis with many children becoming mentally retarded with difficult to treat seizures despite being treated with the best available drugs. In order to improve the care of children with infantile spasms it is critical that we increase our understanding of the basic mechanisms underlying this disorder. In this regard progress has been slow because there is no validated animal model of infantile spasms that could be used to thoroughly test mechanisms that allow for the unique seizure types and to screen for new drugs. The purpose of this proposal is to create an animal model of infantile spasms that can be used to study this debilitating disorder. The establishment of a fully validated model will be pivotal to the development of innovative, effective and safe drugs to treat children with infantile spasms.
  
  
• The Development of an Intranasal Diazepam Delivery System for the Treatment of Seizure Emergencies, at the University of Minnesota by James Cloyd, PharmD. This program, if successful, will vastly improve the quality of life for children who suffer status seizures. Dr. Cloyd is developing a user-friendly nasal spray to be used during seizure emergencies. This could mean fewer trips to the emergency room and fewer status epilepticus. Nasal spray is a much easier intervention than rectal diazepam, which is the only current option for parents.
  
  
• Commonality Screening of Hippocampal Gene Expression During Epileptogeneisis and Development Using DNA Microarray Technologies at Beth Israel Deaconess Medical Center, Boston, Massachusetts by Robert Elliot, PhD. will be funded for a second year. This study explores the parallel between gene expression and epilepsy. They will study cell development in normal and epileptic cells and will attempt to identify the genes that are turned on or turned off when epilepsy develops. This will lead to the development of pharma therapy to target these molecules and prevent the development of epilepsy.
  
  
• Electrophysiological Characterization of Pediatric Neocortical Neurons at the University of Chicago, by Charles J. Marcuccilli, Ph.D., M.D. They will study the electrical properties of neurons obtained directly form children undergoing brain surgery. The study will characterize the firing patterns of these neurons, to compare them to adjacent regions and to measure the response to different antiepileptic drugs. This study could help doctors to understand why some medications initially work for the children and then become ineffective, why some drugs work on only some forms of epilepsy and why some drugs cause more general harm than good.
  
  
• Immunologic Abnormalities in Developmental Aphasia at the University of California, San Diego, by Doris Trauner, M.D. has been continued for a second year.
  
  
• Commonality Screening of Hippocampal Gene Expression During Epileptogeneisis and Development Using DNA Microarray Technologies at Beth Israel Deaconess Medical Center, Boston, Massachusetts by Robert Elliot, PhD. Using cutting edge CHIP technology, this study seeks to examine and to understand the cellular changes, which occur in the hippocampus, associated with the onset of epilepsy. The hope is that this knowledge will allow doctors to devise strategies for the manipulation of those mechanisms and lead to therapeutic strategies for the treatment and cure of epilepsy.
  
  
• A Genetic Screen for Developmental Hippocampal Malformations in Mice at the University of California, San Francisco by Samuel Pleasure, M.D., PhD. Using carefully bred mutant mice this study will search for genes that regulate hippocampal development. The hippocampus is responsible for new memories and many types of learning. These functions are dependent on the intact organization of the hippocampal circuits. There is abundant evidence that mutations in a single gene can lead to major organizational defects in the developing hippocampus, thus leading to the onset of epilepsy and/or autism spectrum disorders. If successful, this study will lead to many novel animal models of abnormal brain development.
  
  
• Large Scale Analysis of Differential Gene Expression in Neocortical Epilepsy at the University of Pennsylvania Medical Center, Philadelphia, Pennsylvania by Peter Crino, M.D., PhD. This study will attempt to determine specific gene and protein families that are responsible for neocortical epilepsy. They will use a cutting edge technology to analyze single cells within identified genes. Cells that are discovered to account for mutations in genes can then be targeted directly for future drug therapies to treat and cure epilepsy.
  
  
• Caudal Subventricular Zone Neural Stem Cells and Epileptogenisis at the University of Michigan Medical Center, Ann Arbor, Michigan by Jack Parent, M.D. This study seeks to understand neural stem cell behavior. Understanding how seizures alter neural stem cell behavior offers potential insights into the onset of epilepsy. Knowledge and understanding of neural stem cell behavior is necessary for the potential therapeutic use of neural stem cells for brain repair.
  
  
• Neurogenesis and Gliogenesis in Pediatric Neocortical and Temporal Lobe Epilepsies at Columbia University, New York, New York by Guy McKhann II, M.D. This study will use single cell molecular biological techniques to examine neurons and astrocytes as they relate to pediatric epilepsy. Understanding the role of cellular proliferation as it relates to the development and maintenance of epilepsy may provide novel avenues for therapeutic interventions.
  
  
• Alternative Therapies Conference at NYU Medical Center. PACE, in conjunction with other charities, sponsored a conference for parents to learn about alternative treatments for their children with epilepsy. Doctors, nurses, acupuncturists, homeopaths, yogis and naturopaths were flown in from around the world to discuss different treatment options for children. The three day conference consisted of lectures and workshops. The entire conference was video taped and the tape was made available, free of charge, to parents nationwide.
  
  
• Prognosis of Children with Newly Diagnosed Epilepsy: Functional and Cognitive Aspects took place at Columbia-Presbyterian Medical Center. Dale C. Hesdorffer, Ph.D., and Douglas Nordli, M.D., head the research. The information obtained will aid health care professionals in determining the risk factors for developmental delay in children with seizures, with the hope that such children may receive more appropriate interventions earlier in the course of their seizure disorder.
  
  
• NIKON TE300 Imaging System for the Molecular Pathophysiology of Childhood Epilepsy. Peter B. Crino, M.D. Ph.D., used this grant at the University of Pennsylvania Medical Center to purchase the imaging system. This is a long-term study which hopes for the first time to provide a view of altered gene expression in the cerebral cortex which will shed light on the pathogenesis of these lesions. Ultimately, identification of a molecular fingerprint of individual neurons in epilepsy may provide mechanisms to directly target new therapies.
  
  
• The Charlie Foundation, whose main objective is to fund research into the ketogenic diet. This diet is one of the few non-drug therapies currently available to children suffering from seizure disorders. Unfortunately, very little is understood about how and why the diet is effective.
  
  
• The PACE Guestroom at the Osteopathic Center for Children in San Diego, California, is designed for out-of-town families seeking medical treatment. This room will be made available to families at a nominal cost during their stay at the center. Families come from around the world seeking medical treatment for their children. The doctors at this center embrace a holistic approach to health and healing.
  
  
• Immunological Abnormalities in Epileptic Aphasia at the University of California, San Diego, headed by Doris A. Trauner, M.D., Professor of Neuroscience. The focus of this study is to identify potential immunologic markers or abnormalities in children with Epileptic Aphasia and to determine whether these markers, when present, identify the children who have the best response to steroid treatment. This study will also endeavor to determine whether the presence or absence of autistic features in children with Epileptic Aphasia is related to the occurrence of immunologic abnormalities. There has long been a suspicion that epilepsy and autism are in many instances related.
  
  
• The Immunological Basis of Pediatric Epilepsy at the University of California, San Francisco, headed by Jorge R. Oksenberg, Ph.D. This study will examine brain tissue from a group of patients that suffer from a progressive and intractable form of epilepsy. The significance of this project is its potential for identifying mechanisms underlying specific immune responses in the brain involved in the development of seizures. Novel and more specific ways of immuno-therapy are becoming readily available. An understanding of the underlying mechanisms in the development of seizures could allow for very specifically targeted and much more successful treatment of certain types of epilepsy.
  
  
• In Vivo Voltammetry with Microelectrodes for the Detection and Quantification of Neurotransmitters in Epileptogenic Cortex During Epilepsy Surgery, at the NYU/Mt. Sinai Comprehensive Epilepsy Center. Steven V. Pacia, M.D. and Patricia A. Broderick, Ph.D. will co-head the research. This technology is much less invasive than currently existing technology and will allow researchers to measure and study neurochemical changes in the live epileptic brain during surgery. It will be especially useful to study the biochemical basis of epilepsy as well as the mechanisms of action of commonly used antiepileptic medications which, to date, remain largely unknown.
  
  
• Hippocampal Malformations in Temporal Lobe Epilepsy at the University of Arizona by Robert S. Sloviter, Ph.D. The research will attempt to determine the nature of the underlying structural brain abnormality that causes febrile seizures, epilepsy, or both sequentially. Initial research by this institution has discovered a previously unreported structural abnormality that occurs in 30% of patients. If in fact these abnormalities can be identified and linked to seizure disorders, their presence will likely alter the course of clinical care and surgical treatment.
  
  
• Expression of Neurotrophic Factors Following Repetitive Seizures at Georgetown University Hospital by Ryder Gwinn, M.D. A host of genetic responses follow seizure activity. Recent research has shown that some of these changes triggered by seizures are adaptive; they may in fact "immunize" the brain against further insult. Further understanding of the potential adaptive role of limited seizures may help alter therapeutic strategies for seizure control and change rehabilitative efforts after trauma, stroke, or other forms of brain injury.
  
  
• The Role of Superoxide Radicals in Seizure-Induced Neuronal Death at the National Jewish Medical Research Center, Denver, Colorado, by Manisha N. Patel, Ph.D. This research seeks to understand the molecular and biochemical mechanisms by which prolonged seizure activity kills neurons. A better understanding of this process may lead to therapies aimed at preventing brain damage associated with chronic seizure disorders. It is possible that as a result of this research, strategies such as the use of antioxidants could be useful for improving brain damage associated with epileptic seizures.
  
  
• The Role of Superoxide Radicals in Seizure-Induced Neuronal Death at the National Jewish Medical Research Center, Denver, Colorado, by Manisha N.Patel, Ph.D. Has been continued for a second year.
  
  
• A Genetic Strategy to Prevent Seizures in the Malformed Brain at the University of California, San Francisco by Scott Baraban, Ph.D. This research seeks to focus on cellular mechanism of epileptogenesis associated with cortical malformations. Although it is widely recognized that malformations are present in the brains of children with medically intractable epilepsy, little is known about this potentially devastating form of childhood epilepsy can be treated. In the laboratory, over the past several years a novel animal model of cortical malformations that closely mimics features of the human epileptic condition has been developed. In this research grant, the animal model will be used to investigate unique, genetically based, strategies for the prevention of seizures in the malformed brain.
  
  
• Ketogenic Diet Modifications Efficacy in a Model of Chronic Epilepsy at the University of Wisconsin, Madison, headed by Carl E. Stafstrom, M.D., Ph.D., Associate Professor of Neurology and Pediatrics. This study will examine the effect of KD modifications on epileptogenesis, i.e., the process by which repeated seizures lead to refractory epilepsy. Using a well-established animal model of chronic epilepsy (induced by kainic acid), this study will examine the effect of several KD formulations on the occurrence of spontaneous seizures and the physiological measures of excitation and inhibition. This grant is funded jointly with The Charlie Foundation.