PEOPLE AGAINST CHILDHOOD EPILEPSY, INC.
A Research and Education Fund
PACE RESEARCH PROJECTS 1998-2010
- Role of Toll-like Receptor 4 in Seizure and Epileptogensis at Mario Negri Institte for Pharmacological Research, by Annamaria Vezzani, PhD. This study
addresses the role of endogenous “danger signals” (DS) released from brain cells
during tissue injury, in the etiopathogenesis of seizures. Specifically, we investigate the involvement of one DS,
High Mobility Group Box 1 (HMGB1), and the related toll-like receptor 4 (TLR4) signalling in precipitation and
recurrence of seizures using mouse models. TLR4 receptors are at the crossroad between infection and seizures since
they are activated both by pathogens and DS produced by damaged cells. Investigation of the role of TLR4 in seizures
may give further insights into the proposed link between CNS infection and the risk of developing epilepsy, which
is particularly relevant for children that are more likely to be exposed to peripheral and CNS infections.
- Computer-Based Cognitive Behavioral Therapy for Children with Epilepsy at the University
of Wisconsin School of Medicine and Public Health, by Jana E. Jones, PhD. Anxiety disorders are quite common in
children with epilepsy. This study will use a computer-based cognitive behavioral therapy program for children (age
8 to 13 years) with chronic epilepsy and anxiety. This computer-based cognitive behavioral therapy utilizes
interactive computer technology to assist in the delivery of the intervention. This study will measure the impact of
the intervention on symptoms of anxiety and the child’s functioning at school and at home.
- Pathogenesis and treatment of spasms in a new rodent model of infantile spasms at Elbert Einstein
College of Medicine, by Aristea S. Galanopoulou MD PhD, Solomon L. Moshé MD, and Morris Scantlebury MD PhD. Infantile spasms is one
of the catastrophic epilepsy syndromes of infancy that are difficult to treat. We will use the multiple-hit rodent model of
symptomatic infantile spasms, that recapitulates many of the key elements of the disease, to identify histopathological changes
linked with the expression to spasms. It is expected that this project will lead to better understanding of the pathogenesis of the
disease, improving our ability to treat this disease.
- Pharmacological Treatment of the Arx (GCG)10+7 Mutation Mouse Genetic Model of A Catastrophic Childhood
Epilepsy: X-linked Infantile Spasms Syndrome (ISSX) at Baylor College of Medicine by Maureen Price, Ph.D., James Frost, M.D.,
Richard Hrachovy, M.D., and Jeffrey Noebels, M.D., Ph.D. We have developed a strain of mice that have the same genetic mutation
that, in humans, is associated with infantile spasms, a severe seizure disorder of childhood. These mice exhibit characteristics of
the human disorder including increased spasm-like movements when young, persistent seizures and cognitive dysfunction. Our
preliminary examinations of these mice suggest that biochemical abnormalities of certain populations of brain cells may underlie
this disorder. Our study will determine whether the cellular and neurological defects can be corrected by current and novel
pharmacological therapies.
- Characterizing Novel pathways in Seizure Pathophysiology, at the University of
California at San Francisco, by Louis Ptacek, MD. 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.
The project focuses on defining the function of this novel protein by studying other proteins with which
it interacts. Knowledge of the function of MASS1 protein and pathways in which it functions may lead to
novel targets that can be used to screen for new anti-seizure medications.
- Suppression of a Seizure Focus by Infusion 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 epilepstic 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 in BoNTs might prove
quite useful as an alternative to surgery in patients with intractable epilepsy.
- 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.
- Rapid post-translational modification of glutamate receptors in early life seizures: A novel target for
antiepileptogenesis, by Frances E. Jensen, MD. Dr. Jensen 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.
- 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.
Last updated on July 22, 2010.